Aminocatalytic Synthesis of Uracil Derivatives Bearing a Bicyclo[22.2]octane Scaffold via a Doubly Cycloadditive Reaction Cascade

Article abstract of DOI:10.1055/s-0040-1707313

Aminocatalytic synthesis of highly enantiomerically enriched uracil derivatives bearing a bicyclo[2.2.2]octane scaffold is described. The developed strategy utilizes 1,3,6-trimethyl-5-formyluracil and α,β-unsaturated aldehydes as starting materials and has been realized employing various aminocatalytic activation strategies operating in a synergistic manner. The reaction cascade can be described as doubly cycloadditive as it consists of two consecutive Diels-Alder cycloadditions allowing for a facile construction of the bicyclo[2.2.2]octane scaffold. Notably, both steps proceed with dearomatization of the partially aromatic uracil moiety. Excellent stereoselectivity of the reaction cascade is ensured by the use of 2-(diphenylmethyl)pyrrolidine as aminocatalyst.

Full text of DOI:10.1055/s-0040-1707313

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–I
feature
A
en
M. Saktura et al.
Feature
Synthesis
Aminocatalytic Synthesis of Uracil Derivatives Bearing a
Bicyclo[2.2.2]octane Scaffold via a Doubly Cycloadditive
Reaction Cascade
Maciej Saktura
Ph
O
O
OHC
O
Sebastian Frankowski
O
N
R
H
Ph
Bartłomiej Joachim
Łukasz Albrecht*
N
N
CHO
+
O
N
aminocatalytic
doubly cycloadditive
reaction cascade
0
0
0
0
-
0
0
0
2-4
6
6
9
-7
6
7
0
O
N
R
R
Institute of Organic Chemistry, Lodz University of Technology,
Żeromskiego 116, 90-924 Łódź, Poland
lukasz.albrecht@p.lodz.pl
10 examples
45–86% yield
>25:1 dr
R = Ph, 4-BrC6H4, 4-ClC6H4, 4-O2NC6H4,
4-MeC6H4, 3-MeC6H4, 2-MeC6H4, 4-MeOC6H4,
2-MeOC6H4, 2-furyl
from 97:3 to >99:1 er
Dedicated to Professor Grzegorz Mlostoń on the occasion of his
70th birthday
Corresponding Author
Łukasz Albrecht
Received: 06.08.2020
Accepted after revision: 02.09.2020
Published online: 22.10.2020
Flourouracil is an antitumor agent, sorivudine possesses
antiviral properties, and elagolix is a GnRH antagonist (Fig-
ure 1, bottom panel).
DOI: 10.1055/s-0040-1707313; Art ID: ss-2020-z0419-fa
The design and development of novel and stereocon-
trolled synthetic strategies leading to organic compounds of
biological relevance constitute fundamental tasks in the
contemporary organic chemistry. Recently, their realization
is strictly combined with the rapid evolution of catalytic
methods involving chiral reaction promotors.4 Within this
field of research, asymmetric organocatalysis has provided
Abstract Aminocatalytic synthesis of highly enantiomerically en-
riched uracil derivatives bearing a bicyclo[2.2.2]octane scaffold is de-
scribed. The developed strategy utilizes 1,3,6-trimethyl-5-formyluracil
and ,-unsaturated aldehydes as starting materials and has been real-
ized employing various aminocatalytic activation strategies operating in
a synergistic manner. The reaction cascade can be described as doubly
cycloadditive as it consists of two consecutive Diels–Alder cycloaddi-
tions allowing for a facile construction of the bicyclo[2.2.2]octane scaf-
fold. Notably, both steps proceed with dearomatization of the partially
aromatic uracil moiety. Excellent stereoselectivity of the reaction cas-
cade is ensured by the use of 2-(diphenylmethyl)pyrrolidine as amino-
catalyst.
O
HN
R
O
N
H
Key words asymmetric synthesis, organocatalysis, aminocatalysis,
uracil, bicyclic compounds, Diels–Alder cycloaddition
bicyclo[2.2.2]octane
uracil
High structural rigidity
Present in RNA
Bridged bicyclic compounds, their chemistry and biolo-
gy constitute important research areas given the wide oc-
currence of such structural motifs in natural products and
compounds relevant in the life sciences.1,2 Their structural
rigidity defines alignment of substituents making them
suitable for biological applications. In particular, bicyclo-
[2.2.2]octane and related scaffolds (Figure 1, top panel, left)
constitute important representatives of this class of
compounds with interesting properties. For instance, (–)-
atiserene is a diterpenoid isolated from the tropical tree
Erythroxylon monogynum and mitindomide exhibits anti-
tumor activity (Figure 1, bottom panel).
Well-defined alignment of substituents
Structural motif responsible for biological
activity of many bioactive molecules
O
O
HN
NH
O
O
(–)-atiserene
O
mitindomide
O
Br
Ph
O
HN
N
OMe
F
NH
F
HN
O
N
O
N
HO
F
O
N
H
O
Uracil is a pyrimidine derivative (Figure 1, top panel,
right), very common in nature due to the presence as nu-
cleobase in ribonucleic acid (RNA).3 Furthermore, it can be
found in many bioactive molecules with selected represen-
tatives depicted below in the bottom panel of Figure 1. 5-
CO2H
CF3
elagolix
OH
sorivudine
HO
5-fluorouracil
Figure 1 The importance of bicyclo[2.2.2]octane, uracil, and their de-
rivatives
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Saktura et al.
Feature
Synthesis
novel solutions within the last 20 years.5–10 Owing to the
implementation of innovative reactivity concepts (with
well-defined approaches to control stereochemical reaction
outcomes), asymmetric organocatalysis has significantly
expanded the arsenal of modern synthetic methods.6,7
Among such concepts, vinylogy – allowing for a transfer of
either nucleophilic or electrophilic properties of a given
position through the neighboring conjugated -system –
occupies a prominent position.6,8–10 Following this princi-
ple, unique reactivities have been identified and described.
Many of these rely on the usage of polyenamines and relat-
ed polyenolates as nucleophiles, dienes, or dienophiles (Fig-
ure 2, top panel).6,8–10 The diversity of such reactants result-
ing in building chemical and stereochemical complexity is
astonishing. Within this research area, dearomative forma-
tion of such reaction intermediates using (hetero)aromatic
Biographical Sketches
Maciej Saktura studied chem-
istry at Lodz University of Tech-
nology, where he obtained his
M.Sc. under the guidance of
Prof. Tadeusz Gajda in 2016.
Upon graduation he decided to
change his scientific interests to
organocatalysis and started his
Ph.D. studies under the guid-
ance of Prof. Łukasz Albrecht at
the same university. His current
research focuses on the applica-
tion of asymmetric organocatal-
ysis in cycloaddition reactions,
and functionalizations of poly-
ene systems.
Sebastian Frankowski was
born in 1992 in Łódź (Poland).
He studied chemistry at Lodz
University of Technology, where
he obtained his M. Sc. degree in
2016. In the same year he
joined Łukasz Albrecht’s group
and started his Ph.D. studies at
the same university. His current
research focuses mainly on new
cycloadditions for asymmetric
synthesis.
Bartlomiej Joachim studied
at Lodz University of Technolo-
gy, where he obtained his B.Sc.
under the guidance of Professor
Łukasz Albrecht in 2019. After
graduation, he started his M.Sc.
studies in the same group.
Łukasz Albrecht was born in
Łódź, Poland. He obtained his
M.Sc. degree (2004), Ph.D.
(2009), and habilitation (2015)
from the Lodz University of
Technology, Poland. He was ap-
pointed a full professor in 2019.
In 2009–2012 he stayed as a
postdoctoral researcher with
Professor Karl Anker Jørgensen
at the Center for Catalysis, Aar-
hus University, Denmark work-
ing on new applications of
asymmetric
organocatalysis.
Since 2013 he is a group leader
at the Institute of Organic
Chemistry, Lodz University of
Technology, Poland.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

C
M. Saktura et al.
Feature
Synthesis
compounds as their precursors constitutes a powerful strat-
egy for the functionalization of the specific positions in
their side-chains (Figure 2, bottom panel).10
the presence of diphenylprolinol trimethylsilyl ether 4a in
dichloromethane (Table 1, entry 1). However, the reaction
yield was not satisfactory. Therefore, the additive screening
was initiated (entries 2–6). While in the presence of acidic
additive no reaction was observed (entry 2), the use of basic
co-catalyst allowed to improve the yield (entries 3–6) with
the use of sodium acetate providing the best result (entry
6). Importantly, at this stage attempts to isolate 3a in a pure
form were undertaken and proved unsuccessful. Therefore,
the derivatization of 3a via a Wittig olefination with ylide 8
was performed. Diolefin 9a thus obtained proved stable un-
der flash chromatography conditions and such protocol was
utilized throughout the study. Furthermore, we were
pleased to observe that 9a was obtained as single diastereo-
isomer and with excellent enantioselectivity. In order to
further improve the result in terms of yield, the catalyst
screening was performed (entries 6–10). Surprisingly,
among catalysts 4 tested, simple 2-diphenylmethylpyrroli-
dine (4e) allowed to significantly improve the yield and di-
astereoselectivity of the cascade, while maintaining the ex-
cellent enantioselectivity of the process (entry 10). Subse-
quently, the solvent screening was performed (entries 10–
15). It was found that the reaction proceeded most effi-
ciently in chlorinated solvents (entries 10–12) with di-
chloromethane affording 9a in 74% isolated yield (entry 10).
Further studies focused on the concentration (compare en-
tries 10, 16, 17) and temperature effects (compare entries
Recently, we have developed a new strategy for the syn-
thesis of bicyclo[2.2.2]lactones (Scheme 1, top panel).11 It
was based on dienamine-mediated [4+2] cycloaddition be-
tween ,-unsaturated aldehydes and corresponding coum-
alates. In continuation of our efforts towards the develop-
ment of vinylogous organocatalytic synthetic strategies
leading to bicyclic compounds, we turned our attention to
1,3,6-trimethyl-5-formyluracil (1) (Scheme 1, bottom pan-
el).12 Its use seemed particularly attractive as it should lead
to the formation of uracil hybrids 3 bearing a bicyclo-
[2.2.2]octane ring system via a doubly cycloadditive reac-
tion cascade consisting of two consecutive Diels–Alder cyc-
loadditions (for a detailed reaction mechanism, see Scheme
2, vide infra). It was anticipated that dearomatized dien-
amine intermediate 5 (derived from 1 and 4) should be able
to participate as an electron-rich diene in the initial Diels–
Alder cycloaddition. ,-Unsaturated aldehydes 2 were se-
lected as model dienophiles as their ability to undergo
Diels–Alder cycloaddition under iminium ion activation is
well recognized.13 The second Diels–Alder cycloaddition of
the cascade was expected to involve the formation of
trienamine intermediate 6 acting as a diene reacting with
dienophile 7 to construct bicyclo[2.2.2]octane scaffold. No-
tably, at the outset of our studies both cycloadditions were
expected to proceed with temporary dearomatization of
uracil moiety.
Our previous studies:
Herein, we present our studies on the development of
doubly cycloadditive reaction cascade allowing for a con-
struction of uracil hybrids 3 bearing a bicyclo[2.2.2]octane
scaffold. The developed protocol benefits from operational
simplicity and utilizes readily available starting materials.
Optimization studies were initiated using 1,3,6-
trimethyl-5-formyluracil (1) and cinnamaldehyde (2a) as
model reactants (Table 1). To our delight, the devised, dou-
bly cycloadditive cascade proved to be possible to realize in
Ph
O
O
EWG
O
Ph
OTBS
N
R1
O
H
EWG
+
R2
aminocatalytic
dienamine-mediated
all-carbon
inverse-electron-demand
Diels–Alder cycloaddition
R2
O
O
R1
This work:
R1
N
O
N
O
H
OHC
O
O
R
4
N
CHO
R
R(H)
+
O
N
O
N
R2
aminocatalytic
doubly cycloadditive
reaction cascade
R2
O
N
R1
R
R1
R
polyenolates
polyenamines
1
2
3
Useful reactive intermediates for stereocontrolled organic synthesis
Diverse reactivity and applications
Key dienes of the cascade:
Dienophile:
R1
R1
R1
O
N
O
N
N
R
N
X
Dearomative catalytic strategies
N
N
Precursors of dearomatized
Y
O
N
O
R
polyenamine and polyenolate
R
X
Y
intermediates
7
5
6
R
Figure 2 Polyenamines and polyenolates as useful synthons in organic
Scheme 1 Organocatalytic synthesis of bicyclo[2.2.2]lactones and
synthesis
synthetic objectives of present studies
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

D
M. Saktura et al.
Feature
Synthesis
10 and 18) did not improve results, thus indicating entry 10
as the best conditions for the developed cascade.
ing substituent in the para-position (entry 4). Furthermore,
the position of the substituent had no significant influence
on the stereochemical reaction outcome (compare entries
5–7 and 8, 9). However, in the case of ortho-substituted de-
rivatives a decrease in the yield was observed (entries 7, 9).
Heteroaromatic substituents proved also possible to be
present in 2 as demonstrated in the synthesis of 9j (entry
10). Delightfully, excellent diastereo- and enantioselectivi-
ties of the doubly cycloadditive cascade were obtained in all
of the cases. However, no reactivity was observed when ali-
phatic ,-unsaturated aldehydes 2 were employed.
With the optimized reaction conditions for the doubly
cycloadditive reaction cascade in hand, the scope of the
methodology was studied (Table 2). Therefore, various ,-
unsaturated aldehydes 2 were allowed to react with 1,3,6-
trimethyl-5-formyluracil (1). In all of the cases, for the ease
of isolation and enantiomeric excess determination, crude
cycloadducts 3 were subjected to the Wittig olefination
with ylide 8 to give 9. The reaction proceeded smoothly for
a wide variety of enals 2 with different electronic proper-
ties and positions of substituents on the aromatic ring.
Enals 2b–i containing either electron-withdrawing (Table 2,
entries 2–4) or -donating substituents (entries 5–9) were
well tolerated. Slightly lower yield was obtained in the case
of reaction involving 2d bearing strong electron-withdraw-
The absolute configuration of stereogenic centers in 3h
was established by the chemical correlation (Scheme 2, to
the left).12 The stereochemistry of remaining products was
assigned by analogy assuming that all 3 were obtained in
Table 1 Optimization Studies on the Asymmetric Organocatalytic Doubly Cycloadditive Cascade Reactions Involving 1,3,6-Trimethyl-5-formyluracil (1)a
Ph3P
CO2Me
4 (20 mol%)
additive
(x equiv.)
MeO2C
O
O
OHC
O
O
Ph
Ph
O
N
8 (3 equiv.)
CO2Me
Ph
N
N
CHO
solvent (y M)
25 °C, 20 h
O
CH2Cl2
N
O
N
O
N
10 °C, 20 h
Ph
Ph
1
2a
3a
9a
Ar
Ar
Ph
Ph
Ph
Ph
Ph
Ph
OTMS
4a
Ph
ODPMS
4c
Ph
N
N
H
N
N
N
H
H
H
H
OTMS
OMe
4d
4b
4e
Ar = 3,5-(CF3)2C6H3
Entry
Catalyst
Additive (x equiv.)
Solvent (concentration
[M])
Temp (°C)
NMR yield (%)b
drc
erd
1
2
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4e
4e
4e
4e
4e
4e
4e
4e
–
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CHCl3 (0.25)
ClCH2CH2Cl (0.25)
THF (0.25)
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
40
42
>25:1
n.d.
3:1
n.d.
PhCO2H (0.4)
NMM (0.4)
NaHCO3 (0.4)
NaOAc (0.4)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
<5
n.d.
3
41
n.d.
4
44
>25:1
7:1
n.d.
5
53
n.d.
6
49 (45)
<5
11.5:1
n.d.
>99:1
n.d.
7
8
48 (42)
68 (60)
82 (74)
63
8.5:1
>25:1
>25:1
>25:1
>25:1
2:1
2:98
>1:99
99:1
n.d.
9
10
11
12
13
14
15
16
17
18
82 (72)
40
>99:1
n.d.
MeCN (0.25)
MeOH (0.25)
CH2Cl2 (0.125)
CH2Cl2 (0.5)
<5
n.d.
n.d.
12
n.d.
n.d.
74 (68)
82 (72)
65 (46)
>25:1
>25:1
>25:1
>99:1
>99:1
>99:1
CH2Cl2 (0.25)
a All reactions were performed in a 0.1 mmol scale using 1 (1.0 equiv.) and 2a (2.2 equiv.).
b Determined by 1H NMR analysis of the crude reaction mixture for the reaction performed in the presence of 1,3,5-tris(trifluoromethyl)benzene (1.0 equiv.). In
parenthesis isolated yield is given.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

E
M. Saktura et al.
Feature
Synthesis
Table 2 Asymmetric Organocatalytic Doubly Cycloadditive Cascade
Involving 1,3,6-Trimethyl-5-formyluracil (1)a
the reaction proceeding according to the same mechanistic
scenario and that the subsequent Wittig olefination does
not influence the stereochemical reaction outcome. Given
the assigned configuration, a plausible reaction mechanism
is proposed (Scheme 2, to the right). The developed doubly
cycloadditive reaction cascade is initiated by two activation
processes. The first one involves activation of 1,3,6-trimeth-
yl-5-formyluracil (1) via its condensation with aminocata-
lyst 4e and subsequent dearomative deprotonation under
basic conditions. The second one leads to the formation of
iminium ion 7 in the reversible reaction of 2 with 4e. With
the two reactants 5 and 7 formed, the initial endo-selective
[4+2] cycloaddition occurs with the approach of both chiral
reactants controlled by the bulky diphenylmethyl substitu-
ent present in the 2 position of the pyrrolidine ring in both
5 and 7. The reaction proceeds with the rearomatization of
the pyrimidine ring yielding iminium ion 11 that undergoes
eliminative cleavage of catalyst 4e. Subsequently, the dearo-
mative deprotonation of 12 occurs to afford trienamine in-
termediate 6. Notably, two distal double bonds in trienam-
ine 6 are in s-cis conformation making them perfectly suit-
able for the second Diels–Alder reaction. This step is again
doubly stereocontrolled as both reactants (diene 6 and di-
enophile 7) are chiral. This important feature is responsible
for the proper alignment of iminium ion 7 with respect to 6
in order to avoid disfavored steric interaction between
bulky moieties in pyrrolidine rings present in both 7 and 6,
thus resulting in the second endo-selective cycloaddition.
Hydrolysis of diiminium ion 13 thus obtained regenerates
the catalyst 4e and terminates the catalytic cycle.
Ph
1)
N
H
Ph
4e (20 mol%)
NaOAc (1 equiv.)
CH2Cl2 (0.25 M)
25 °C, 20 h
MeO2C
O
O
O
O
N
CO2Me
R
N
Ph3P
CO2Me
2)
O
N
O
N
R
8 (3 equiv.)
R
9
CH2Cl2
10 °C, 20 h
1
2
Entry
R
Yield (%)b
drc
erd
1
2
Ph (9a)
74
58
52
45
86
83
58
62
52
73
>25:1
99:1
97:3
4-BrC6H4 (9b)
4-ClC6H4 (9c)
4-O2NC6H4 (9d)
4-MeC6H4 (9e)
3-MeC6H4 (9f)
2-MeC6H4 (9g)
4-MeOC6H4 (9h)
2-MeOC6H4 (9i)
2-furyl (9j)
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
3
>99:1
>99:1
>99:1
>99:1
>99:1
99:1
4e
5
6
7
8
9
99:1
10
99:1
a All reactions were performed in a 0.1 mmol scale using 1 (1.0 equiv.) and
2 (2.2 equiv.) in 0.4 mL of CH2Cl2.
b Isolated yields of 9 are given.
c Determined by 1H NMR analysis of the crude reaction mixture.
d Determined by chiral UPC2 analysis of 9.
e Reaction performed using 2d (4.0 equiv.) at 40 °C for 48 h.
Ph
Ph
Ph
Ph
O
N
H
N
H
N
4e
O
N
dearomative
deprotonation
iminium ion
formation
10
B
Ph
Ph
O
O
5
R1
R
O
N
N
R
R1
O
O
N
N
N
Ph
N
O
N
Ph
O
R1
N
N
N
N
OHC
O
N
eliminative
catalyst
cleavage
R1 = CHPh2
N
R
O
O
N
CHO
1
H
O
N
R
7
11
B
R
12
O
R = 4-MeOC6H4 (3h)
iminium ion
formation
dearomative
deprotonation
>25:1 dr, 99:1 er
[α ]Drt 52.5 (c = 1.0, CHCl3)
[lit.11 [α ]Drt 56.0 (c = 1.0, CHCl3)]
Ph
Ph
R
N
H
2
7
Ph
4e
Ph
N
Ph
N
OHC
O
N
Ph
O
N
R
N
Ph
O
CHO
N
R
Ph
Ph
R
N
O
N
hydrolysis
Ph
O
N
O
N
R
R
R
3
13
6
Scheme 2 Asymmetric, organocatalytic doubly cycloadditive cascade involving 1,3,6-trimethyl-5-formyluracil (1) – mechanistic considerations
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

F
M. Saktura et al.
Feature
Synthesis
In conclusion, an organocatalytic, asymmetric route to
uracil hybrids bearing bicyclo[2.2.2]octane scaffold was de-
veloped. The strategy was based on two consecutive Diels–
Alder reactions enabling the construction of the bicyclo-
[2.2.2]octane ring system. Notably, dienes for both of these
reactions were formed via dearomative deprotonations of
the corresponding uracil derivatives. The stereochemical
reaction outcome was governed by simple 2-diphenylmeth-
ylpyrrolidine (4e) acting as the aminocatalyst.
°C and the ylide 8 (100 mg, 0.3 mmol, 3 equiv.) was added and stirring
was maintained at 10 °C for 20 h. Pure products 9 were isolated as
single diastereoisomers by flash chromatography on silica gel (eluent:
hexanes/EtOAc from 4:1 to 3:1).
Dimethyl (2E,2′E)-3,3′-[(5R,7S,8S,9S,10S)-1,3-Dimethyl-2,4-dioxo-
7,9-diphenyl-1,2,3,4,5,6,7,8-octahydro-5,8-ethanoquinazoline-
6,10-diyl]diacrylate (9a)
Following the general procedure, 9a was isolated by FC on silica gel in)
25
as an off-white semi-solid (>25:1 dr); yield: 40.1 mg (74%); []D
–15.2 (c 1.0, CHCl3).
The er was determined by UPC2 using a Chiralpak IB column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 3.28 min (major),
tR = 4.05 min (minor) (>99:1 er).
1H NMR (700 MHz, CDCl3):  = 7.47–7.43 (m, 2 H), 7.38–7.35 (m, 1 H),
7.34–7.31 (m, 2 H), 7.22–7.19 (m, 3 H), 7.18 (dd, J = 15.8, 5.9 Hz, 1 H),
6.81–6.77 (m, 2 H), 6.71 (dd, J = 15.7, 6.8 Hz, 1 H), 5.92 (dd, J = 8.3, 1.6
Hz, 1 H), 5.90 (dd, J = 8.3, 1.6 Hz, 1 H), 3.76 (s, 3 H), 3.71–3.70 (m, 1 H),
3.68 (s, 3 H), 3.47 (s, 3 H), 3.24–3.21 (m, 1 H), 3.20 (t, J = 1.8 Hz, 1 H),
3.18 (d, J = 7.7 Hz, 1 H), 3.08 (s, 3 H), 2.78 (d, J = 7.2 Hz, 1 H), 2.76–2.73
(m, 1 H).
NMR spectra were acquired on a Bruker Ultra Shield 700 instrument,
running at 700 MHz for 1H and 176 MHz for 13C, respectively. Chemi-
cal shifts () are reported in ppm relative to residual solvent signals
1
(CDCl3: 7.26 ppm for H NMR, 77.16 ppm for 13C NMR). Mass spectra
were recorded on a Bruker Maxis Impact spectrometer using electro-
spray (ES+) ionization (referenced to the mass of the charged species).
Optical rotations were measured on a PerkinElmer 241 polarimeter
and []D values are given in deg·cm·g–1·dm–1; concentration c is listed
in g·(100 mL)–1. Analytical TLC was performed using pre-coated alu-
minum-backed plates (Merck Kieselgel 60 F254) and visualized by ul-
traviolet irradiation. The enantiomeric ratios (er) of the products
were determined by chiral stationary phase UPC2 (Daicel Chiralpak IA,
IB, IG column). Unless otherwise noted, analytical grade solvents and
commercially available reagents were used without further purifica-
tion. For flash chromatography (FC) silica gel (Silica Gel 60; 35–70 m,
Sigma Aldrich) was used. ,-Unsaturated aldehydes 2 were prepared
according to literature procedure.14a
13C NMR (176 MHz, CDCl3):  = 166.7, 166.6, 160.4, 154.3, 152.2,
149.5, 147.2, 142.3, 138.2, 129.5 (2 C), 129.4 (2 C), 128.3 (2 C), 128.0,
127.7, 127.0 (2 C), 123.1, 121.3, 110.0, 51.9, 51.7, 50.9, 49.2, 47.7, 42.0,
37.8, 37.4, 31.2, 28.7.
HRMS: m/z calcd for [C32H32N2O6 + H+]: 541.2333; found: 541.2346.
Dimethyl (2E,2′E)-3,3′-[(5R,7S,8S,9S,10S)-7,9-Bis(4-bromophenyl)-
1,3-dimethyl-2,4-dioxo-1,2,3,4,5,6,7,8-octahydro-5,8-ethano-
quinazoline-6,10-diyl]diacrylate (9b)
1,3,6-Trimethyl-5-formyluracil (1)
Following the general procedure, 9b was isolated by FC on silica gel as
a white semi-solid (>25:1 dr); yield: 40.2 mg (58%); []D –27.9 (c
1.0, CHCl3).
1,3,6-Trimethyl-5-formyluracil (1) was prepared according to litera-
ture procedure.14b To a flame-dried 25 mL flask equipped with a stir-
ring bar were added 1,3,6-trimethyluracil14b (924 mg, 6 mmol) and
DMF (3 mL). The resulting suspension was stirred for 5 min in an ice-
cold bath. Subsequently, POCl3 (3 mL) was added dropwise and the re-
action mixture was stirred in an ice-cold bath for 20 min. Next, the
mixture was placed in an oil bath (at 120 °C) and stirring was main-
tained for 3 h. Then the dark-brown suspension was brought to r.t.
and subsequently H2O (15 mL) was added. The resulting mixture was
extracted with CHCl3 (4 × 20 mL) and the combined organic layers
were washed with H2O (2 × 10 mL) and dried (anhyd MgSO4). After
evaporation under reduced pressure, the crude brown residue was
purified using column chromatography on silica gel (eluent: hex-
anes/EtOAc 80:20 to 70:30) to obtain pure 1; yield: 305 mg (28%);
white, amorphous solid.
25
The er was determined by UPC2 using a Chiralpak IA column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 3.50 min (major),
tR = 3.80 min (minor) (97:3 er).
1H NMR (700 MHz, CDCl3):  = 7.60–7.57 (m, 2 H), 7.38–7.35 (m, 2 H),
7.20–7.17 (m, 2 H), 7.11 (dd, J = 15.8, 6.0 Hz, 1 H), 6.70–6.68 (m, 2 H),
6.66 (dd, J = 15.8, 6.8 Hz, 1 H), 5.90–5.86 (m, 2 H), 3.76 (s, 3 H), 3.70–
3.69 (m, 1 H), 3.68 (s, 3 H), 3.46 (s, 3 H), 3.14–3.11 (m, 2 H), 3.10 (s, 3
H), 3.06 (dd, J = 7.7, 1.5 Hz, 1 H), 2.73 (d, J = 7.4 Hz, 1 H), 2.67 (dd, J =
7.8, 5.7 Hz, 1 H).
13C NMR (176 MHz, CDCl3):  = 166.6, 166.4, 160.2, 153.5, 152.1,
148.8, 146.5, 141.0, 137.1, 132.7 (2 C), 132.6 (2 C), 129.9 (2 C), 128.7
(2 C), 123.4, 122.1, 121.8, 121.7, 110.1, 52.0, 51.8, 50.3, 49.2, 47.3,
41.7, 37.9, 37.3, 31.3, 28.7.
1H NMR (700 MHz, CDCl3):  = 10.27 (s, 1 H), 3.52 (s, 3 H), 3.40 (s, 3
H), 2.78 (s, 3 H).
13C NMR (176 MHz, CDCl3):  = 190.1, 162.73, 160.6, 151.3, 108.1,
31.9, 28.1, 16.1.
HRMS: m/z calcd for [C32H30Br2N2O6
+
H+]: 697.0543; found:
697.0538.
Dimethyl (2E,2′E)-3,3′-[(5R,7S,8S,9S,10S)-7,9-Bis(4-chlorophenyl)-
1,3-dimethyl-2,4-dioxo-1,2,3,4,5,6,7,8-octahydro-5,8-ethano-
quinazoline-6,10-diyl]diacrylate (9c)
Asymmetric Organocatalytic Doubly Cycloadditive Cascade Reac-
tion; General Procedure
In an ordinary 4 mL glass vial, equipped with a Teflon-coated magnet-
ic stirring bar and a screw cap, the corresponding aldehyde 2 (0.22
mmol, 2.2 equiv.), 1,3,6-trimethyl-5-formyluracil (1; 18.2 mg, 0.10
mmol, 1 equiv.), and NaOAc (8.2 mg, 0.10 mmol, 1 equiv.) were dis-
solved in CH2Cl2 (0.4 mL) and the catalyst 4e (4.7 mg, 0.02 mmol, 0.2
equiv) was added and the mixture was stirred for 20 h at 25 °C. After
this time, the mixture was diluted with CH2Cl2 (0.4 mL), cooled to 10
Following the general procedure, 9c was isolated by FC on silica gel as
a white semi-solid (>25:1 dr); yield: 32.0 mg (52%); []D25 –4.1 (c 1.0,
CHCl3).
The er was determined by UPC2 using a Chiralpak IA column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 3.21 min (major),
tR = 3.48 min (minor) (>99:1 er).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

G
M. Saktura et al.
Feature
Synthesis
1H NMR (700 MHz, CDCl3):  = 7.45–7.42 (m, 2 H), 7.26–7.24 (m, 2 H),
7.22–7.19 (m, 2 H), 7.14–7.10 (m, 1 H), 6.76–6.73 (m, 2 H), 6.66 (dd,
J = 15.7, 6.8 Hz, 1 H), 5.90–5.87 (m, 2 H), 3.76 (s, 3 H), 3.71–3.69 (m, 1
H), 3.68 (s, 3 H), 3.46 (s, 3 H), 3.15–3.13 (m, 1 H), 3.12 (t, J = 1.7 Hz, 1
H), 3.10 (s, 3 H), 3.09–3.07 (m, 1 H), 2.77–2.74 (m, 1 H), 2.69–2.66 (m,
1 H).
Dimethyl (2E,2′E)-3,3'-[(5R,7S,8S,9S,10S)-1,3-Dimethyl-2,4-dioxo-
7,9-di(m-tolyl)-1,2,3,4,5,6,7,8-octahydro-5,8-ethanoquinazoline-
6,10-diyl]diacrylate (9f)
Following the general procedure, 9f was isolated by FC on silica gel as
25
a white semi-solid (>25:1 dr); yield: 47.0 mg (83%); []D –17.1 (c
1.0, CHCl3).
13C NMR (176 MHz, CDCl3):  = 166.6, 166.4, 160.2, 153.6, 152.1,
148.8, 146.5, 140.5, 136.6, 134.1, 133.8, 129.8 (2 C), 129.6 (2 C), 129.6
(2 C), 128.4 (2 C), 123.4, 121.6, 110.1, 52.0, 51.8, 50.3, 49.3, 47.4, 41.6,
37.9, 37.8, 31.3, 28.7.
The er was determined by UPC2 using a Chiralpak IB column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 3.08 min (major),
tR = 3.59 min (minor) (>99:1 er).
1H NMR (700 MHz, CDCl3):  = 7.35–7.32 (m, 1 H), 7.20–7.16 (m, 2 H),
7.15–7.12 (m, 1 H), 7.11–7.07 (m, 2 H), 7.00 (br d, J = 7.5 Hz, 1 H), 6.70
(dd, J = 15.7, 6.7 Hz, 1 H), 6.60 (s, 1 H), 6.56 (d, J = 7.5 Hz, 1 H), 5.93
(dd, J = 15.8, 1.8 Hz, 1 H), 5.89 (dd, J = 15.7, 1.4 Hz, 1 H), 3.76 (s, 3 H),
3.70–3.69 (m, 1 H), 3.67 (s, 3 H), 3.47 (s, 3 H), 3.21–3.15 (m, 3 H), 3.09
(s, 3 H), 2.75–2.72 (m, 2 H), 2.40 (s, 3 H), 2.23 (s, 3 H).
13C NMR (176 MHz, CDCl3):  = 166.8, 166.6, 160.4, 154.5, 152.2,
149.7, 147.4, 142.3, 139.1, 139.0, 138.2, 129.4, 129.3, 129.2, 128.7,
128.4, 128.1, 125.2, 123.6, 123.0, 121.2, 110.0, 51.9, 51.7, 50.8, 49.1,
47.7, 41.9, 37.9, 37.4, 31.2, 28.7, 21.8, 21.51.
HRMS: m/z calcd for [C32H30Cl2N2O6
+
H+]: 609.1554; found:
609.1562.
Dimethyl (2E,2′E)-3,3′-[(5R,7S,8S,9S,10S)-1,3-Dimethyl-7,9-bis(4-
nitrophenyl)-2,4-dioxo-1,2,3,4,5,6,7,8-octahydro-5,8-ethano-
quinazoline-6,10-diyl]diacrylate (9d)
Following the modified general procedure (4 equiv. of 4-nitrocin-
namaldehyde, reaction time 48 h, 40 °C), 9d was isolated by FC on
25
silica gel as a yellow semi-solid (>25:1 dr); yield: 28.2 mg (45%); []D
–23.0 (c 1.0, CHCl3).
HRMS: m/z calcd for [C34H36N2O6 + H+]: 569.2646; found: 569.2648.
The er was determined by UPC2 using a Chiralpak IA column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 4.22 min (major),
tR = 4.57 min (minor) (>99:1 er).
1H NMR (700 MHz, CDCl3):  = 8.38–8.31 (m, 2 H), 8.14–8.10 (m, 2 H),
7.52 (d, J = 8.5 Hz, 2 H), 7.12 (dd, J = 15.8, 6.0 Hz, 1 H), 7.03–6.97 (m, 2
H), 6.67 (dd, J = 15.7, 6.9 Hz, 1 H), 5.94–5.88 (m, 2 H), 3.79–3.78 (m, 1
H), 3.77 (s, 3 H), 3.69 (s, 3 H), 3.48 (s, 3 H), 3.25–3.22 (m, 2 H), 3.17
(dd, J = 7.4, 1.7 Hz, 1 H), 3.14 (s, 3 H), 2.95–2.92 (m, 1 H), 2.78–2.74
(m, 1 H).
13C NMR (176 MHz, CDCl3):  = 166.3, 166.1, 160.0, 152.5, 151.9,
148.9, 147.8, 147.8, 147.7, 145.5, 145.3, 129.2 (2 C), 128.0 (2 C), 124.8
(2 C), 124.8 (2 C), 124.0, 122.3, 110.3, 52.1, 51.9, 50.7, 49.3, 46.4, 42.4,
38.0, 37.3, 31.4, 28.8.
Dimethyl (2E,2′E)-3,3′-[(5R,7S,8S,9S,10S)-1,3-Dimethyl-2,4-dioxo-
7,9-di(o-tolyl)-1,2,3,4,5,6,7,8-octahydro-5,8-ethanoquinazoline-
6,10-diyl]diacrylate (9g)
Following the general procedure, 9g was isolated by FC on silica gel as
25
a white semi-solid (>25:1 dr). 58% (32.8 mg); []D –40.8 (c 1.0,
CHCl3).
The er was determined by UPC2 using a Chiralpak IG column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 3.66 min (major),
tR = 3.97 min (minor) (>99:1 er).
1H NMR (700 MHz, CDCl3):  = 7.50–7.47 (m, 1 H), 7.38–7.34 (m, 1 H),
7.29–7.24 (m, 3 H), 7.07–7.03 (m, 2 H), 7.03–7.00 (m, 1 H), 6.67 (dd,
J = 15.7, 6.6 Hz, 1 H), 6.65–6.63 (m, 1 H), 5.92 (dd, J = 15.8, 1.8 Hz, 1 H),
5.87 (dd, J = 15.7, 1.3 Hz, 1 H), 3.79–3.78 (m, 1 H), 3.78 (s, 3 H), 3.66 (s,
3 H), 3.53 (dd, J = 7.9, 1.4 Hz, 1 H), 3.48 (s, 3 H), 3.35 (br t, J = 7.2 Hz, 1
H), 2.94–2.92 (m, 1 H), 2.92 (s, 3 H), 2.88–2.84 (m, 1 H), 2.71 (t, J = 1.6
Hz, 1 H), 2.29 (s, 3 H), 1.65 (s, 3 H).
HRMS: m/z calcd for [C32H30N4O10 + H+]: 631.2035; found: 631.2043.
Dimethyl (2E,2′E)-3,3′-[(5R,7S,8S,9S,10S)-1,3-Dimethyl-2,4-dioxo-
7,9-di(p-tolyl)-1,2,3,4,5,6,7,8-octahydro-5,8-ethanoquinazoline-
6,10-diyl]diacrylate (9e)
13C NMR (176 MHz, CDCl3):  = 166.8, 166.6, 160.4, 154.5, 152.2,
149.5, 147.5, 140.0, 136.9, 135.8, 135.5, 132.0, 131.2, 128.0, 127.3,
127.0, 126.8, 126.8, 124.8, 123.0, 121.0, 110.0, 51.9, 51.7, 48.7, 47.7,
45.8, 37.4, 36.9, 36.4, 30.9, 28.7, 20.0, 19.2.
Following the general procedure, 9e was isolated by FC on silica gel as
a white semi-solid (>25:1 dr); yield: 49.1 mg (86%); []D –22.0 (c
1.0, CHCl3).
25
The er was determined by UPC2 using a Chiralpak IA column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 3.08 min (major),
tR = 3.29 min (minor) (>99:1 er).
1H NMR (700 MHz, CDCl3):  = 7.25–7.22 (m, 2 H), 7.21–7.19 (m, 2 H),
7.16 (dd, J = 15.8, 5.9 Hz, 1 H), 7.00 (br d, J = 7.8 Hz, 2 H), 6.71–6.67 (m,
3 H), 5.90 (dd, J = 10.2, 1.6 Hz, 1 H), 5.88 (dd, J = 10.1, 1.6 Hz, 1 H), 3.75
(s, 3 H), 3.68–3.67 (m, 1 H), 3.67 (s, 3 H), 3.46 (s, 3 H), 3.19–3.13 (m, 3
H), 3.08 (s, 3 H), 2.74–2.68 (m, 2 H), 2.39 (s, 3 H), 2.26 (s, 3 H).
HRMS: m/z calcd for [C34H36N2O6 + H+]: 569.2646; found: 569.2651.
Dimethyl (2E,2′E)-3,3′-[(5R,7S,8S,9S,10S)-7,9-Bis(4-methoxyphe-
nyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,6,7,8-octahydro-5,8-ethano-
quinazoline-6,10-diyl]diacrylate (9h)
Following the general procedure, 9h was isolated by FC on silica gel as
25
a white semi-solid (>25:1 dr); yield: 37.2 mg (62%); []D –24.2 (c
1.0, CHCl3).
13C NMR (176 MHz, CDCl3):  = 166.8, 166.7, 160.4, 154.5, 152.3,
149.7, 147.4, 139.3, 137.7, 137.4, 135.2, 130.1 (2 C), 129.9 (2 C), 128.2
(2 C), 126.9 (2 C), 123.0, 121.2, 110.0, 51.8, 51.7, 50.5, 49.3, 47.9, 41.6,
37.9, 37.4, 31.2, 28.6, 21.1, 21.0.
The er was determined by UPC2 using a Chiralpak IA column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 3.26 min (major),
tR = 3.45 min (minor) (99:1 er).
1H NMR (700 MHz, CDCl3):  = 7.24–7.22 (m, 2 H), 7.16 (dd, J = 15.8,
5.9 Hz, 1 H), 6.99–6.94 (m, 2 H), 6.75–6.71 (m, 4 H), 6.69 (dd, J = 16.0,
7.1 Hz, 1 H), 5.92–5.86 (m, 2 H), 3.85 (s, 3 H), 3.76 (s, 3 H), 3.74 (s, 3
H), 3.68–3.67 (m, 1 H), 3.67 (s, 3 H), 3.46 (s, 3 H), 3.15–3.10 (m, 3 H),
3.09 (s, 3 H), 2.72–2.70 (m, 1 H), 2.70–2.67 (m, 1 H).
HRMS: m/z calcd for [C34H36N2O6 + H+]: 569.2646; found: 569.2654.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

H
M. Saktura et al.
Feature
Synthesis
13C NMR (176 MHz, CDCl3):  = 166.8, 166.7, 160.4, 159.2, 159.0,
154.5, 152.3, 149.6, 147.4, 134.3, 130.1, 129.4 (2 C), 128.1 (2 C), 123.0,
121.2, 114.8 (2 C), 114.7 (2 C), 109.9, 55.5, 55.4, 51.9, 51.7, 50.2, 49.4,
48.2, 41.1, 38.1, 37.3, 31.3, 28.7.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707313. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
HRMS: m/z calcd for [C34H36N2O8 + H+]: 601.2544; found: 601.2546.
References
Dimethyl (2E,2′E)-3,3′-[(5R,7S,8S,9S,10S)-7,9-bis(2-methoxyphe-
nyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,6,7,8-octahydro-5,8-ethano-
quinazoline-6,10-diyl]diacrylate (9i)
(1) (a) Büchi, G.; Erickson, R. E.; Wakabayashi, N. J. Am. Chem. Soc.
1961, 83, 927. (b) Wolff, G.; Ourisson, G. Tetrahedron 1969, 25,
4903. (c) Terhune, S. J.; Hogg, J. W.; Lawrence, B. M. Tetrahedron
Lett. 1973, 4705. (d) Dunn, A. W.; Johnstone, R. A. W.; Sklarz, B.
J. Chem. Soc., Chem. Commun. 1976, 270a. (e) Dunn, A. W.;
Johnstone, R. A. W.; Sklarz, B.; Lessinger, L.; King, T. J. J. Chem.
Soc., Chem. Commun. 1978, 533. (f) Kobayashi, J.; Ueno, S.;
Morita, H. J. Org. Chem. 2002, 67, 6546. (g) Morita, H.; Ishioka,
N.; Takatsu, H.; Iizuka, T.; Kobayashi, J. J. Nat. Prod. 2006, 69,
418. (h) Hao, X.; Shen, Y.; Li, L.; He, H. Curr. Med. Chem. 2003, 10,
2253. (i) Li, S-H.; Wang, J.; Niu, X.-M.; Shen, J.-H.; Zhang, H.-J.;
Sun, H.-D.; Li, M.-L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org.
Lett. 2004, 6, 4327. (j) Rakotonandrasana, O. L.; Raharinjato, F.
H.; Rajaonarivelo, M.; Dumontet, V.; Martin, M.-T.; Bignon, J.;
Rasoanaivo, P. J. Nat. Prod. 2010, 73, 1730. (k) Moustafa, G. A. I.;
Nojima, S.; Yamano, Y.; Aono, A.; Arai, M.; Mitarai, S.; Tanakaa,
T.; Yoshimitsu, T. Med. Chem. Commun. 2013, 4, 720.
(2) (a) Deutsch, H. M.; Gelbaum, L. T.; McLaughlin, M.; Fleischmann,
T. J.; Earnhart, L. L.; Haugwitz, R. D.; Zalkow, L. H. J. Med. Chem.
1986, 29, 2164. (b) Hasinoff, B. B.; Creighton, A. M.; Kozlowska,
H.; Thampatty, P.; Allan, W. P.; Yalowich, J. C. Mol. Pharmacol.
1997, 52, 839. (c) Cao, S.-G.; Sng, V. H. L.; Wu, X.-H.; Sim, K.-Y.;
Tan, B. H. K.; Pereira, J. T.; Goh, S. H. Tetrahedron 1998, 54,
10915. (d) Zhou, H.-B.; Collins, M. L.; Gunther, J. R.; Comninos, J.
S.; Katzenellenbogen, J. A. Bioorg. Med. Chem. Lett. 2007, 17,
4118. (e) Martens, E.; Demain, A. L. J. Antibiot. 2011, 64, 705.
(f) do Vale, A. E.; David, J. M.; dos Santos, E. O.; David, J. P.; de
Silva, L. C. R. C.; Bahia, M. V.; Brandão, H. N. Phytochemistry
2012, 76, 158. (g) Zhu, G.; Wadavrao, S. B.; Liu, B. Chem. Rec.
2017, 17, 584. (h) Drummond G. J., Grant P. S., Brimble M. A.;
Nat. Prod. Rep; 2020, in press; DOI: 10.1039/d0np00039f
Following the general procedure, 9i was isolated by FC on silica gel as
a white semi-solid (>25:1 dr); yield: 31.3 mg (52%); []D –62.0 (c
1.0, CHCl3).
25
The er was determined by UPC2 using a Chiralpak IG column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 4.20 min (major),
tR = 4.86 min (minor) (99:1 er).
1H NMR (700 MHz, CDCl3):  = 7.44–7.41 (m, 1 H), 7.36–7.33 (m, 1 H),
7.19 (dd, J = 15.8, 5.6 Hz, 1 H), 7.14–7.08 (m, 2 H), 6.97–6.94 (m, 1 H),
6.77 (td, J = 7.5, 1.0 Hz, 1 H), 6.71–6.69 (m, 1 H), 6.69–6.65 (m, 2 H),
5.94 (dd, J = 15.8, 1.8 Hz, 1 H), 5.87 (dd, J = 15.7, 1.4 Hz, 1 H), 3.81 (s, 3
H), 3.76 (s, 3 H), 3.71–3.69 (m, 1 H), 3.65 (s, 3 H), 3.58 (d, J = 8.5 Hz, 1
H), 3.45 (s, 3 H), 3.37 (s, 3 H), 3.26 (t, J = 7.3 Hz, 1 H), 3.14 (t, J = 1.6 Hz,
1 H), 3.12–3.09 (m, 1 H), 3.07 (s, 3 H), 2.77–2.74 (m, 1 H).
13C NMR (176 MHz, CDCl3):  = 167.0, 166.9, 160.6, 157.9, 156.8,
155.9, 152.4, 150.0, 148.2, 130.2, 128.6, 128.3, 127.4, 126.5, 125.8,
122.6, 121.0, 120.9, 120.7, 110.9, 110.8, 109.3, 55.5, 55.1, 51.8, 51.6,
47.3, 44.9, 44.5, 37.4, 35.4, 34.2, 30.8, 28.5.
HRMS: m/z calcd for [C34H36N2O8 + H+]: 601.2544; found: 601.2550.
Dimethyl (2E,2′E)-3,3′-[(5R,7S,8S,9S,10R)-7,9-Di(furan-2-yl)-1,3-di-
methyl-2,4-dioxo-1,2,3,4,5,6,7,8-octahydro-5,8-ethanoquinazo-
line-6,10-diyl]diacrylate (9j)
Following the general procedure, 9j was isolated by FC on silica gel as
25
a white semi-solid (>25:1 dr); yield: 38.0 mg (73%); []D –13.9 (c
1.0, CHCl3).
The er was determined by UPC2 using a Chiralpak IA column gradient
from 100% CO2 up to 40%; i-PrOH, 2.5 mL/min; tR = 2.81 min (major),
tR = 2.92 min (minor) (99:1 er).
1H NMR (700 MHz, CDCl3):  = 7.46 (d, J = 1.5 Hz, 1 H), 7.26–7.23 (m, 1
H) 7.10 (dd, J = 15.7, 6.6 Hz, 1 H), 6.68 (dd, J = 15.7, 6.8 Hz, 1 H), 6.41
(dd, J = 3.2, 1.9 Hz, 1 H), 6.29 (d, J = 3.3 Hz, 1 H), 6.23 (dd, J = 3.2, 1.9
Hz, 1 H), 5.95 (dd, J = 5.3, 1.5 Hz, 1 H), 5.93 (dd, J = 5.3, 1.5 Hz, 1 H),
5.89 (d, J = 3.3 Hz, 1 H), 3.76 (s, 3 H), 3.70 (t, J = 2.2 Hz, 1 H), 3.69 (s, 3
H), 3.60–3.58 (m, 1 H), 3.41 (s, 3 H), 3.30–3.27 (m, 1 H), 3.26 (s, 3 H),
3.05–3.01 (m, 1 H), 2.82–2.79 (m, 1 H), 2.59–2.56 (m, 1 H).
(3) (a) Evdokimov, N. M.; Van Slambrouck, S.; Heffeter, P.; Tu, L.; Le
Calve, B.; Lamoral-Theys, D.; Hooten, C. J.; Uglinskii, P. Y.; Rogelj,
S.; Kiss, R.; Steelant, W. F. A.; Berger, W.; Yang, J. J.; Bologa, C. G.;
Kornienko, A.; Magedov, I. V. J. Med. Chem. 2011, 54, 2012.
(b) Brulikova, L.; Hlavac, J. Beilstein J. Org. Chem. 2011, 7, 678.
(c) Pałasz, A.; Cież, D. Eur. J. Med. Chem. 2015, 97, 582.
(d) Turkoglu, E. A.; Senturk, M.; Supuran, C. T.; Ekinci, D.
J. Enzyme Inhib. Med. Chem. 2017, 32, 74. (e) Cavdar, H.; Senturk,
M.; Guney, M.; Durdagi, S.; Kayik, G.; Supuran, C. T.; Ekinci, D.
J. Enzyme Inhib. Med. Chem. 2019, 34, 429. (f) Sanduja, M.;
Gupta, J.; Virmani, T. J. Appl. Pharm. Sci. 2020, 10, 129.
13C NMR (176 MHz, CDCl3):  = 166.7, 166.6, 160.4, 154.8, 153.3,
152.4, 152.2, 148.6, 146.8, 143.1, 142.3, 123.4, 121.6, 110.8, 110.7,
109.7, 108.2, 106.3, 51.9, 51.7, 46.9, 43.8, 41.8, 38.0, 36.7, 36.3, 31.2,
28.6.
(4) (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive
Asymmetric Catalysis; Springer: Berlin, 1999. (b) Mikami, K.;
Lautens, M. New Frontiers in Asymmetric Catalysis; Wiley-Inter-
science: New Jersey, 2007.
HRMS: m/z for [C28H28N2O8 + H+]: 521.1918; found: 521.1932.
(5) For selected reviews on organocatalysis, see: (a) Jiang, L.; Chen,
Y.-C. Catal. Sci. Technol. 2011, 1, 354. (b) Alemán, J.; Parra, A.;
Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890.
(c) Quigley, C.; Rodríguez-Docampo, Z.; Connon, S. J. Chem.
Commun. 2012, 48, 1443. (d) Tsakos, M.; Kokotos, C. G. Tetrahe-
dron 2013, 69, 10199. (e) Dzięgielewski, M.; Pięta, J.; Kamińska,
E.; Albrecht, Ł. Eur. J. Org. Chem. 2015, 677. (f) Krawczyk, H.;
Dzięgielewski, M.; Deredas, D.; Albrecht, A.; Albrecht, Ł. Chem.
Eur. J. 2015, 21, 10268. (g) Flanigan, D. M.; Romanov-Michailidis,
Funding Information
This project was realized within the Opus programme (grant number:
2016/23/B/ST5/01927) from the National Science Centre, Poland.
N
aro
d
o
weCe
n
tru
m
Nau
k
i
2(
0
1
6
/2
3
/B/S
T
5
/0
1
9
2
7)
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

I
M. Saktura et al.
Feature
Synthesis
F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307.
(h) Koutoulogenis, G.; Kaplaneris, N.; Kokotos, C. G. Beilstein J.
Org. Chem. 2016, 12, 462. (i) Teng, B.; Lim, W. C.; Tan, C.-H.
Synlett 2017, 28, 1272. (j) Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.;
Kwon, O. Chem. Rev. 2018, 118, 10049. (k) Frankowski, S.;
Romaniszyn, M.; Skrzyńska, A.; Albrecht, Ł. Chem. Eur. J. 2020,
26, 2120.
(9) (a) Pawar T. J., Mitkari S. B., Peña-Cabrera E., Gómez C. V., Cruz
D. C.; Eur. J. Org. Chem.; 2020, in press; DOI:
10.1002/ejoc.202000570 (b) Marcos, V.; Alemán, J. Chem. Soc.
Rev. 2016, 45, 6812. (c) Hepburn, H. B.; Dell’Amico, L.;
Melchiorre, P. Chem. Rec. 2016, 16, 1787. (d) Vicario, J. L. Synlett
2016, 27, 1006. (e) Jiang, H.; Albrecht, Ł.; Jørgensen, K. A. Chem.
Sci. 2013, 4, 2287. (f) Jurberg, I. D.; Chatterjee, I.; Tannert, R.;
Melchiorre, P. Chem. Commun. 2013, 49, 4869.
(6) For selected reviews on vinylogy, see: (a) Curti, C.; Battistini, L.;
Sartori, A.; Zanardi, F. Chem. Rev. 2020, 120, 2448.
(b) Choudhury, A. R.; Mukherjee, S. Chem. Soc. Rev. 2020, 49,
6755. (c) Chauhan, P.; Kaya, U.; Enders, D. Adv. Synth. Catal.
2017, 359, 888. For selected examples, see: (d) Dell’Amico, L.;
Albrecht, Ł.; Naicker, T.; Poulsen, P. H.; Jørgensen, K. A. J. Am.
Chem. Soc. 2013, 135, 8063. (e) Tian, X.; Melchiorre, P. Angew.
Chem. Int. Ed. 2013, 52, 5360. (f) Zhu, B.; Zhang, W.; Lee, R.; Han,
Z.; Yang, W.; Tan, D.; Huang, K. W.; Jiang, Z. Angew. Chem. Int. Ed.
2013, 52, 6666. (g) Dell’Amico, L.; Rassu, G.; Zambrano, V.;
Sartori, A.; Curti, C.; Battistini, L.; Pelosi, G.; Casiraghi, G.;
Zanardi, F. J. Am. Chem. Soc. 2014, 136, 11107. (h) Li, X.; Lu, M.;
Dong, Y.; Wu, W.; Qian, Q.; Ye, J.; Dixon, D. J. Nat. Commun.
2014, 5, 4479. (i) Zhang, Y.; Wei, B.; Lin, H.; Cui, W.; Zeng, X.;
Fan, X. Adv. Synth. Catal. 2015, 357, 1299. (j) Gu, X.; Guo, T.; Dai,
Y.; Franchino, A.; Fei, J.; Zou, C.; Dixon, D. J.; Ye, J. Angew. Chem.
Int. Ed. 2015, 54, 10249. (k) Nielsen, A. J.; Jenkins, H. A.;
McNulty, J. Chem. Eur. J. 2016, 22, 9111. (l) Albrecht, A.;
Bojanowski, J. Adv. Synth. Catal. 2017, 359, 2907. (m) Zhou, Z.;
Wang, Z.-X.; Zhou, Y.-C.; Xiao, W.; Ouyang, Q.; Du, W.; Chen, Y.-
C. Nat. Chem. 2017, 9, 590. (n) Frias, M.; Más-Balleste, R.; Arias,
S.; Alvarado, C.; Alemán, J. J. Am. Chem. Soc. 2017, 139, 672.
(o) Skrzyńska, A.; Romaniszyn, M.; Pomikło, D.; Albrecht, Ł.
J. Org. Chem. 2018, 83, 5019. (p) Frankowski, S.; Skrzyńska, A.;
Sieroń, L.; Albrecht, Ł. Adv. Synth. Catal. 2020, 362, 2658.
(7) For reviews, see: (a) Dell’Amico L., Vega-Penaloza A., Mateos J.,
Companyo X., Escudero-Casao M.; Angew. Chem. Int. Ed.; 2020;
59: in press; DOI: 10.1002/anie.202006416. (b) Sinibaldi, A.;
Nori, V.; Baschieri, A.; Fini, F.; Arcadi, A.; Carlone, A. Catalysts
2019, 9, 928. (c) Buzzetti, L.; Crisenza, G. E. M.; Melchiorre, P.
Angew. Chem. Int. Ed. 2019, 58, 3730. (d) Silvi, M.; Melchiorre, P.
Nature 2018, 554, 41. (e) Du, Z.; Shao, Z. Chem. Soc. Rev. 2013,
42, 1337.
(10) (a) Xiao, B.-X.; Gao, X.-Y.; Du, W.; Chen, Y.-C. Chem. Eur. J. 2019,
25, 1607. (b) Przydacz, A.; Skrzyńska, A.; Albrecht, Ł. Angew.
Chem. Int. Ed. 2019, 58, 63. For our contributions, see:
(c) Skrzyńska, A.; Przydacz, A.; Albrecht, Ł. Org. Lett. 2015, 17,
5682. (d) Dyguda, M.; Przydacz, A.; Krzemińska, A.; Albrecht, Ł.
Org. Biomol. Chem. 2019, 17, 6025. (e) Gao, X. Y.; Yan, R. J.; Xiao,
B. X.; Du, W.; Albrecht, Ł.; Chen, Y. C. Org. Lett. 2019, 21, 9628.
(f) Przydacz, A.; Dyguda, M.; Topolska, A.; Skrzyńska, A.; Xu, C.-
J.; Chen, Y.-C.; Albrecht, Ł. Org. Biomol. Chem. 2020, 18, 5816.
(g) Xu, C.-J.; Du, W.; Albrecht, Ł.; Chen, Y.-C. Synthesis 2020, 52,
2650.
(11) Saktura, M.; Grzelak, P.; Dybowska, J.; Albrecht, Ł. Org. Lett.
2020, 22, 1813.
(12) During the preparation of this manuscript, the following paper
appeared in the literature: Curti C., Rassu G., Lombardo M.,
Zambrano V., Pinna L., Battistini L., Sartori A., Pelosi G., Zanardi
F.; Angew. Chem. Int. Ed.; 2020, in press; DOI:
10.1002/anie.202007509
(13) For selected examples, see: (a) Ahrendt, K. A.; Borths, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243.
(b) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 11616. (c) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.;
Liao, J.-H. Org. Lett. 2006, 8, 2217. (d) Hong, B.-C.; Wu, M.-F.;
Tseng, H.-C.; Huang, G.-F.; Su, C.-F.; Liao, J.-H. J. Org. Chem. 2007,
72, 8459. (e) Bench, B. J.; Liu, C.; Evett, C. R.; Watanabe, C. M. H.
J. Org. Chem. 2006, 71, 9458. (f) Hong, B.-C.; Tseng, H.-C.; Chen,
S.-H. Tetrahedron 2007, 63, 2840. (g) de Figueiredo, R. M.;
Fröhlich, R.; Christmann, M. Angew. Chem. Int. Ed. 2008, 47,
1450. (h) Brindani, N.; Rassu, G.; Dell’Amico, L.; Zambrano, V.;
Pinna, L.; Curti, C.; Sartori, A.; Battistini, L.; Casiraghi, G.; Pelosi,
G.; Greco, D.; Zanardi, F. Angew. Chem. Int. Ed. 2015, 54, 7386.
(i) Rassu, G.; Curti, C.; Zambrano, V.; Pinna, L.; Brindani, N.;
Pelosi, G.; Zanardi, F. Chem. Eur. J. 2016, 22, 12637.
(8) (a) Li, H.; Yin, L. Tetrahedron Lett. 2018, 59, 4121. (b) Frías, M.;
Cieślik, W.; Fraile, A.; Rosado-Abón, A.; Garrido-Castro, A. F.;
Yuste, F.; Alemán, J. Chem. Eur. J. 2018, 24, 10906. (c) Chauhan,
P.; Kaya, U.; Enders, D. Adv. Synth. Catal. 2017, 359, 888.
(d) Schneider, C.; Abels, F. Org. Biomol. Chem. 2014, 12, 3531.
(14) (a) Daubresse, N.; Francesch, C.; Rolando, C. Tetrahedron 1998,
54, 10761. (b) Egg, H.; Volgger, I. Synthesis 1982, 1071.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I