One-pot enantioselective synthesis of 1,4-naphthoquinone-derived polycycles through oxidative dearomatization and aminocatalysis

Article abstract of DOI:10.1002/ejoc.201403597

A synthetic process merging oxidative dearomatization and asymmetric aminocatalysis in a single vessel is reported. The PhI(OAc)₂-mediated oxidation of 1,4-dihydroxynaphthalene is followed by a trienamine-mediated Diels-Alder cycloaddition/aldol reaction or a trienamine-mediated Diels-Alder cycloaddition/oxidation sequence depending on the dienal substitution pattern. The polycyclic compounds are obtained in good yields with enantiomeric excesses up to 99%. Additionally, these polycyclic architectures can be synthesized with similar enantioselectivities through an unprecedented one-pot marriage of bodipy-photocatalyzed oxidative dearomatization of 1-naphthol and asymmetric aminocatalysis. A catalytic cycle is suggested to explain the reaction outcome. The asymmetric synthesis of diversely substituted 1,4-naphthoquinone-derived polycycles is described by merging dearomatization and aminocatalysis in a single vessel. The dearomatization step is promoted by PhI(OAc)₂ or oxygen in the presence of a bodipy photosensitizer and two products are selectively isolated depending on the dienal substitution.

Full text of DOI:10.1002/ejoc.201403597

Job/Unit: O43597
/KAP1
Date: 11-02-15 15:28:21
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201403597
One-Pot Enantioselective Synthesis of 1,4-Naphthoquinone-Derived Polycycles
through Oxidative Dearomatization and Aminocatalysis
[a]
[a]
[a]
[a]
Loïc Pantaine, Vincent Coeffard,* Xavier Moreau, and Christine Greck*
Keywords: Asymmetric synthesis / Organocatalysis / Dearomatization / Cycloaddition / Photooxidation / Polycycles
A synthetic process merging oxidative dearomatization and
asymmetric aminocatalysis in a single vessel is reported. The
PhI(OAc) -mediated oxidation of 1,4-dihydroxynaphthalene
2
is followed by a trienamine-mediated Diels–Alder cycload-
dition/aldol reaction or a trienamine-mediated Diels–Alder
cycloaddition/oxidation sequence depending on the dienal
substitution pattern. The polycyclic compounds are obtained
in good yields with enantiomeric excesses up to 99%. Ad-
ditionally, these polycyclic architectures can be synthesized
with similar enantioselectivities through an unprecedented
one-pot marriage of bodipy-photocatalyzed oxidative dearo-
matization of 1-naphthol and asymmetric aminocatalysis. A
catalytic cycle is suggested to explain the reaction outcome.
[
5]
Introduction
carbocycles with excellent selectivities. Among other ex-
[
6]
[7]
amples, the groups of You and Jørgensen have reported
asymmetric transformations dealing with one-pot oxidative
dearomatization and asymmetric organocatalytic function-
3
The straightforward access to enantioenriched sp -rich
polycyclic architectures is a focal point for extensive re-
search efforts in both academic and industrial settings.
These structures are exceptionally interesting because an
increase in saturation, as measured by the fraction of sp3
carbon atoms, and a high number of asymmetric centers
in the molecular structures, tend to correlate with clinical
[8]
alizations. Most of these dearomatization processes have
been combined with an organocatalytic intramolecular
functionalization; this dramatically limits access to a vast
array of diverse and complex cyclic optically active struc-
tures. To overcome this challenge, our group has recently
reported the implementation of a new one-pot strategy that
directly converts hydroquinone derivatives into enantioen-
riched tricyclic architectures by merging PhI(OAc) -medi-
ated dearomatization and aminocatalysis. The synthetic
sequence proceeds through a trienamine-mediated asym-
metric Diels–Alder cycloaddition with benzoquinone deriv-
atives generated in situ, followed by an intramolecular
Michael addition to form the tricyclic architectures
[
1]
success. In terms of making natural products, synthetic
strategies based on the formation of nonaromatic chiral
polycycles from simple building blocks has been harnessed
by several research groups.[ In particular, the marriage of
oxidative dearomatization and asymmetric catalysis in a
single vessel has emerged as an attractive strategy to in-
crease molecular complexity from simple and readily-intro-
duced functionalities.[ Within this context, the successful
2
2]
[9]
3]
3
synthesis of densely functionalized sp -rich cyclic molecules
(
Scheme 1). To prevent intramolecular C–C bond formation
has mainly involved the combination of oxidative dearoma-
tization and asymmetric metal-catalyzed functionalization.
Comparatively, the tactics, which involve loss of aromaticity
followed by in-situ asymmetric organocatalyzed desymme-
through Michael addition, we reasoned that 1,4-dihydro-
naphthalene 2a might be a suitable partner in the oxidative
dearomatization/trienamine-mediated Diels–Alder cyclo-
[10]
addition.
[
4]
trization processes, have received less attention thus far.
In this article, we report a selective process that directly
converts 1,4-dihydroxynaphthalene 2a by reaction with
dienal 1 into enantioenriched 1,4-naphthoquinone-derived
polycycles 3 or 4 depending on the dienal 1 substitution
As a striking example within this field, Gaunt and co-
workers described in 2008 the one-pot oxidative dearomati-
zation of phenols followed by a desymmetrizing amine-
catalyzed asymmetric Michael addition to form bicyclic
pattern. The reaction proceeds through a PhI(OAc) -medi-
2
ated oxidation of 1,4-dihydroxynaphthalene 2a to produce
corresponding 1,4-naphthoquinone which further reacts
a] Institut Lavoisier Versailles, UMR CNRS 8180, Université de with dienals by aminocatalysis to produce products 3 or 4.
[
Versailles-St-Quentin-en-Yvelines,
In addition, we describe herein an unprecedented strategy
4
5 Avenue des Etats-Unis, 78035 Versailles cedex, France
E-mail: vincent.coeffard@uvsq.fr
merging organic-dye photocatalytic oxidative dearomatiza-
tion and asymmetric aminocatalysis in a single vessel in or-
der to prepare optically active compounds 3 from dienal 1
and 1-naphthol 2b.
christine.greck@uvsq.fr
http://www.ilv.uvsq.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403597.
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1

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L. Pantaine, V. Coeffard, X. Moreau, C. Greck
FULL PAPER
Scheme 1. Dearomatization and dienal chemistry.
Results and Discussion
tion of 1a with 2a, in the presence of the aminocatalyst 5c,
furnished optically active polycyclic compound 3a in 38%
yield as a mixture of diastereomers (Table 1, Entry 4). En-
antiomeric excesses of 96% were obtained for both dia-
stereomers of 3a. Replacement of the TMS group with a
bulkier TBS moiety led to interesting results by producing
We started our investigations by reacting 1a, as a model
substrate, with commercially available 1,4-dihydroxy-
naphthalene 2a in the presence of PhI(OAc) and various
aminocatalysts. The results are depicted in Table 1.
2
4
a in 36% yield as a 2:1 mixture of diastereomers with 98%
Table 1. Optimization of reaction conditions.[a]
ee (Table 1, Entry 5). Among the solvent systems tested in
the model reaction, toluene gave the best results by enabling
production of 3a in 63% yield as a 2:1 mixture of dia-
stereomers in 98% ee for each diastereomer (Table 1, En-
tries 6–8). Lowering the catalyst loading from the initial
10 mol-% to 3 mol-% of 5d led to a substantial decrease in
yield (Table 1, Entry 9).
Having identified optimal reaction conditions (Table 1,
Entry 8), we set out to explore the substrate scope of
this chemistry with respect to other dienal substrates
(Scheme 2).
Entry
Catalyst Solvent
Yield [%][b]
dr[c]
ee [%][d]
The reaction of 1,4-dihydroxynaphthalene 2a with
dienals 1a–c bearing hydrogen as the R substituent gave
1
2
3
4
5
6
7
8
l-Proline CHCl
3
3
3
3
3
n.r.
n.r.
n.r.
38
36
n.r.
31
n.d.
n.d.
n.d.
2:1
2:1
n.d.
1:1
n.d.
n.d.
n.d.
96
98
n.d.
94
3
5a
5b
5c
5d
5d
5d
5d
5d
CHCl
CHCl
CHCl
CHCl
DMF
MeCN
toluene
toluene
rise selectively to products 3a–c by a trienamine-mediated
Diels–Alder/aldol reaction sequence. For instance, com-
pounds 3a and 3b were obtained in 63% and 36% yield
respectively as a non-separable mixture of diastereomers
with excellent enantioselectivities (ee = 98%). The indole-
derived dienal provided 3c in 42% yield as a 2:1 mixture
63
30
2:1
2:1
98
n.d.
[
e]
9
[
a] Reaction conditions: the reactions were performed on 0.5 mmol of diastereomers with 96% ee for each diastereomer. The
scale using 1 equiv. of 1a, 1.5 equiv. of 2a, 1.3 equiv. of PhI(OAc)
2
dearomatization/asymmetric functionalization process
starting from dienals 1d–f led to a different reaction out-
come by producing tricyclic products 4d–f whereas com-
and 10 mol-% of the catalyst for 16 h at 55 °C in 2 mL of solvent
unless otherwise noted; n.r.: no reaction, n.d.: not determined.
[b] Isolated yields of the non-separable diastereomers. The structure
[
9]
of 3a has been determined in light of our previous work (see ref. ) pounds of scaffold 3 were not detected in the crude reaction
and by comparison with literature data, see experimentals. [c] Dia-
stereomeric ratios were determined by 1H NMR analysis of the
crude product mixture. [d] Enantiomeric excesses were measured
by chiral HPLC on pure analytical fractions of each diastereomer.
3
mixture. Therefore, the presence of substituents R other
than hydrogen in dienals 1d–f appears to prevent the aldol
reaction and only aldehydic products 4d–f are formed after
subsequent oxidation of the initial [4 + 2] cycloadducts.
Substrates 1d–f behaved similarly and enabled fair yields
[e] 3 mol-% of 5d was used.
The use of l-Proline or catalysts 5a and 5b shut down (42–65%) and excellent enantioselectivities (99% ee) for
the reaction and the formation of the polycyclic compound preparation of products 4d–f. In addition, the preparation
3a could not be detected (Table 1, Entries 1–3). The reac- of 4d was amenable to gram-scale production. Starting
2
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Synthesis of 1,4-Naphthoquinone-Derived Polycycles
Scheme 2. Substrate scope.
from 5 mmol of 1d, tricyclic compound 4d (1.31 g) was iso-
lated in 76% yield and with 98% ee. It is worth noting that
the described one-pot sequence merging PhI(OAc) -medi-
2
ated dearomatization and Diels–Alder reaction with 5d as
the catalyst produced cycloadducts 4 with higher enantio-
selectivities than previously reported by Jørgensen and co-
workers for their reaction of dienals with 1,4-naphthoquin-
one promoted by aminocatalysts bearing H-bond-directing
[
10]
groups. In the course of further studies, dienals 1 lacking
1
2
substituents R and/or R were investigated. Nevertheless,
1
2
3
(
2E,4E)-hexadienal (R = R = R = H), (2E,4E)-heptane-
1
2
3
dienal (R = R = H, R = Me) and (E)-5-methyl-2,4-hexa-
1
3
2
dienal (R = R = H, R = Me) turned out to be inert under
the reaction conditions. This lack of reactivity for such sub-
strates has been previously observed by our group during
studies of the trienamine-mediated reaction of dienals 1
with benzoquinone derivatives.[ A postulated catalytic
cycle explaining the selective formation of polycyclic com-
pounds 3 or 4 is outlined in Scheme 3.
9]
Scheme 3. Hypothesized catalytic cycle explaining generation of 3
and 4.
The catalytic cycle starts with condensation of aminocat-
alyst 5d and dienal 1 to produce trienamine intermediate A
which further reacts with the in-situ formed benzoquinone
using an endo approach. Hydrolysis of enamine B then af-
3
fords enantioenriched aldehydic compound C. If R = H,
further cyclization affords products 3 through an aldol reac-
tion which is favoured due to a lower steric hindrance; com-
pounds bearing the 4 scaffold are obtained by oxidation.
The 1,4-naphthoquinone tricyclic derivatives 3 might be
amenable to oxidation and as a result, a one-pot sequence
involving trienamine-mediated Diels–Alder cycloaddition/
aldol reaction followed by in-situ oxidation has also been
developed (Scheme 4).
Scheme 4. One-pot Diels Alder cycloaddition/aldol reaction/oxid-
ation sequence.
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L. Pantaine, V. Coeffard, X. Moreau, C. Greck
FULL PAPER
Scheme 5. Merging of photocatalysis and aminocatalysis.
PhI(OAc) is the central reagent for the one-pot transfor- naphthol enabled in-situ formation of 1,4-naphthoquinone
2
mation and compound 6 is synthesized in 29% yield from which underwent a [4 + 2] cycloaddition with a range of
dienal 1a and 2a. During the course of further studies, we dienals. Depending on precise dienal substitution, the
envisaged that 1-naphthol 2b could be a suitable starting Diels–Alder reaction was followed by either an oxidative
material for a new synthetic route merging photocatalytic process leading to 1,4-naphthoquinone-derived aldehydic
oxidative dearomatization and asymmetric organocatalyzed products or an intramolecular aldol reaction to form the
functionalization process. In recent years, the combination corresponding alcohols as a mixture of diastereomers. Re-
of photoredox catalysis and asymmetric organocatalysis has gardless of the sequence, high enantiomeric excesses for the
spawned the development of new reactions by providing ac- polycyclic compounds are obtained and a catalytic cycle is
[
11]
cess to unprecedented retrosynthetic disconnections.
readily envisioned that rationalizes the observed stereoselec-
However, despite enormous achievements within this field, tivities.
to the best of our knowledge the marriage of a photocata-
lytic oxidative dearomatization and asymmetric organocat-
alyzed functionalization in a single vessel has never been
Experimental Section
reported. For the dearomatization step, metal-free iodo-
BODIPY 7 was chosen as a photosensitizer due to its ease
General Methods: 1H NMR (200 or 300 MHz) and 13C (50 or
of synthesis, strong visible light absorption and ability of 75 MHz) spectra were recorded with Bruker Avance 200 or
[
12]
oxidize phenol derivatives under aerobic conditions.
An 300 MHz spectrometers using tetramethylsilane as an internal stan-
intensive screening of reaction conditions involving the na- dard. Chemical shifts (δ) are given in parts per million and coupling
constants are given as absolute values expressed in Hertz. Electro-
ture of solvents, photosensitizers, additives, reaction time
spray ionization (ESI) mass spectra were collected using a Q-TOF
and oxygen sources has been carried out (see the Support-
instrument supplied by WATERS. Samples (solubilized in ACN at
ing Information) and the best results are depicted herein
1
mg/mL and then diluted by 1000) were introduced into the MS
(Scheme 5).
via an UPLC system whilst a Leucine Enkephalin solution was co-
injected via a micro pump. Infrared spectra were recorded with a
Nicolet iS10 Infrared FT ATR spectrometer. Optical rotation val-
ues were measured at room temperature with a Perkin–Elmer 241
Under an oxygen rich atmosphere, the mixing of 1-
naphthol 2b in toluene for 6 h in the presence of 2 mol-%
of iodo-BODIPY 7 gave rise to corresponding 1,4-naphtho-
quinone. The addition of dienal 1a and the catalytic system polarimeter. Thin-layer chromatography (TLC) was carried out on
(
aminocatalyst 5d/PhCO H) afforded polycycle 3a in 39% aluminium sheets precoated with silica gel 60 F254 (Merck). Col-
2
yield (dr: 2:1, ee = 98%) through a one-pot sequential umn chromatography separations were performed using Merck
multicatalytic photooxygenation/Diels–Alder/aldol reac-
tion. Under similar conditions, indole-derived polycycle 3c
was obtained in 27% yield as a 2:1 mixture of diastereomers
with 95% ee by using CHCl as the solvent. Unfortunately,
all attempts to extend the methodology to other naphthols
failed.
Kieselgel 60 (0.040–0.060 mm). HPLC analyses were performed
with a JASCO machine equipped with a UV/Vis detector at 30 °C
employing chiral OD-H, AD or OJ-H columns. HPLC grade hept-
ane and isopropyl alcohol were used as the eluting solvents (90:10,
heptane/isopropyl alcohol; 1 mL/min). HPLC traces were com-
3
pared to racemic samples prepared by mixture of two enantiomeric
[
13]
final products obtained using (S) and (R) catalysts. Toluene was
dried immediately before use by distillation from standard drying
agents while non-distilled chloroform was used for the one-pot re-
actions. For the bodipy-photocatalyzed oxidative dearomatization
Conclusions
step, the reaction mixture was irradiated with 35-W Xe lamp
In conclusion, we have developed an enantioselective
process merging oxidative dearomatization and asymmetric
aminocatalysis. Hypervalent iodine-mediated oxidation of photosensitizer 7[ were prepared according to literature pro-
–1
(
2
0.72 molL NaNO solution was used as filter so that light with
[14]
wavelength Ͻ 385 nm was blocked). Dienals 1
and the bodipy
12]
1,4-dihydroxynaphthalene or photooxygenation of 1- cedures.
4
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Synthesis of 1,4-Naphthoquinone-Derived Polycycles
PhI(OAc)
Procedure A: To a solution of 1,4-dihydroxynaphthalene (2a)
120 mg, 0.75 mmol, 1.5 equiv.) in toluene (1 mL) was added (300 MHz, CDCl
PhI(OAc) (210 mg, 0.65 mmol, 1.3 equiv.), under heavy stirring. 7.81–7.77 (m, 2 H, ArH, A), 7.75–7.70 (m, 2 H, ArH, B), 5.34 (br.
The dienal 1 (0.5 mmol, 1 equiv.) and catalyst 5d (18 mg,
.05 mmol, 0.1 equiv.) were then dissolved in toluene (0.5 mL each)
2
-Mediated Dearomatization/Aminocatalysis. General
B); dr: A/B, 3:2, ee = 98% (determined after oxidation of the
1
alcohol function), TLC (PE/EtOAc, 8:2): R
f
= 0.37. H NMR
(
3
, 20 °C): δ = 8.18–8.03 (m, 4 H, ArH, A + B),
2
s, 1 H, C=CH, A), 5.13 (br. s, 1 H, C=CH, B), 4.44–4.38 (m, 2 H,
CH, A + B), 3.32 (br. s, 1 H, CH, A), 3.16 (d, J = 6.1 Hz, 1 H,
0
and added to the previous solution, in that order. The reaction was
left to stir at 55 °C for 16 h. The reaction mixture was washed with
water. The aqueous phase was extracted with DCM and the or-
CH, B), 3.12 (s, 1 H, CH, B), 3.05 (m, 1 H, CH
6.2 Hz, 1 H, CH, A), 2.75–2.35 (m, 5 H, CH , A + B), 1.87 (ddd,
J = 13.4, 6.1, 4.4 Hz, 1 H, CH , B), 1.80 (d, J = 1.8 Hz, 3 H, CH
A), 1.78 (d, J = 1.7 Hz, 3 H, CH , B), 1.68 (dt, J = 14.1, 2.9 Hz, 1
H, CH , A), 1.66 (br. s, 2 H, OH, A + B) ppm. C NMR (75 MHz,
CDCl , 20 °C): δ = 199.1 (A), 199.0 (A), 197.0 (B), 196.4 (B), 142.1
2
, A), 2.96 (d, J =
2
2
3
,
ganic phases were combined, dried on anhydrous MgSO
4
, filtered
3
1
3
and concentrated under vacuum. The diastereomeric ratio was de-
2
1
termined by H NMR at this stage. The crude product was passed
3
through column chromatography (PE/EtOAc, 9:1) and then on a (A or B), 141.6 (A or B), 136.7 (A or B), 136.6 (A or B), 134.6 (A),
preparative TLC (PE/EtOAc, 8:2) to afford corresponding tricyclic 134.5 (A), 134.4 (A), 134.0 (B), 133.9 (B), 133.8 (B), 127.4 (A or
compounds 3 or 4.
B), 126.7 (A or B), 126.4 (2 C, A + B), 117.6 (A), 116.2 (B), 82.3
(
(
B), 77.3 (A), 77.2 (B), 58.8 (A), 58.7 (A), 58.3 (A), 56.6 (B), 44.7
B), 41.4 (A), 40.3 (A), 36.1 (A), 29.3 (B), 22.0 (2 C, A + B) ppm.
Photooxidative Dearomatization/Aminocatalysis. General Procedure
B: Bodipy 7 (2.5 mg, 0.04 mmol, 0.02 equiv.) was dissolved in tolu-
ene (2.5 mL) and added to 1-naphthol 2b (36 mg, 0.25 mmol,
IR: ν˜ = 3482, 3371, 2958, 2931, 2850, 1674, 1592, 1442, 1318, 1268,
–1
+
1
037 cm . HRMS (ESI) Calcd for C17
found 269.1176. Enantiomeric excess was determined on product
b, which underwent alcohol oxidation, by HPLC analysis em-
ploying a chiral OD-H column (heptane/2-propanol, 90:10, 1.0 mL/
min), t = 10.51 min for the major enantiomer and t = 12.00 min
for the minor enantiomer.
17 3
H O [M + H] : 269.1178,
1
.5 equiv.). After O
the reaction was left to stir for 6 h under white light irradiation
under O atmosphere. The solution was left to cool and excess O
was removed by bubbling argon into the solution. dienal 1a or 1c
0.15 mmol, 1 equiv.), benzoic acid (3.7 mg, 0.03 mmol, 0.2 equiv.)
2
was left bubbling into the solution for 5 min,
3
2
2
r
r
(
and catalyst 5d (11 mg, 0.030 mmol, 0.2 equiv.) were added to the
solution, in that order. The reaction was left to stir at 55 °C for
Polycyclic Compound 3c: tert-Butyl 2-methyl-3-(3-oxoprop-1-enyl)-
H-indole-1-carboxylate (1c) (147 mg) reacted following the gene-
1
16 h. The crude was concentrated and directly passed through a
ral procedure A (for the procedure B, 49 mg of 1c was used) and
was isolated as a yellow oil (108.0 mg, 48% yield, mixture of dia-
stereomers A + B); dr: A/B, 2:1; ee = 96%; TLC (PE/EtOAc, 8:2):
R
column chromatography (PE/EtOAc, 8:2) to afford corresponding
tricyclic compound 3a or 3c.
Polycyclic Compound 3a: (2E,4Z)-4-Phenylhexa-2,4-dienal (1a)
1
f
= 0.23. H NMR (300 MHz, CDCl
3
, 20 °C): δ = 8.22–8.09 (m,
(86.1 mg) reacted following the general procedure A (for the pro-
6
H, ArH, A + B), 7.85–7.81 (m, 2 H, ArH, B), 7.80–7.72 (m, 2
cedure B, 25.8 mg of 1a was used), and was isolated as an orange
oil (102.5 mg, 63% yield, mixture of diastereomers A + B); dr: A/
H, ArH, A), 7.56–7.51 (m, 2 H, ArH, A + B), 7.33–7.25 (m, 4 H,
ArH, A + B), 4.54 (dd, J = 9.8, 2.4 Hz, 1 H, CH, B), 4.49 (dd, J
1
B, 2:1; ee: 98%; TLC (PE/EtOAc, 8:2): R
300 MHz, CDCl
7
7
f
= 0.24; 0.27. H NMR
=
(
3
6.8, 1.5 Hz, 1 H, CH, A), 4.24 (d, J = 5.5 Hz, 1 H, CH, A), 4.09
d, J = 19.0 Hz, 1 H, CH , B), 4.06 (d, J = 4.9 Hz, 1 H, CH, B),
.76 (d, J = 18.6 Hz, 1 H, CH , A), 3.51 (d, J = 18.6 Hz, 1 H, CH
, B), 3.28
, B), 2.54 (m, 1 H, CH , A),
, A + B), 1.92 (br. s, 2 H, OH, A + B), 1.72
(
3
, 20 °C): δ = 8.11–8.03 (m, 4 H, ArH, A + B),
.80–7.73 (m, 2 H, ArH, B), 7.73–7.66 (m, 2 H, ArH, A), 7.45–
.25 (m, 10 H, ArH, A + B), 5.98 (app t, J = 3.5 Hz, 1 H, C=CH,
2
2
2
,
A), 3.45 (s, 1 H, CH, B), 3.42 (d, J = 19.0 Hz, 1 H, CH
s, 1 H, CH, A), 2.62 (m, 1 H, CH
.11–2.02 (m, 2 H, CH
s, 9 H, tBu, B), 1.71 (s, 9 H, tBu, A) ppm. C NMR (75 MHz,
CDCl , 20 °C): δ = 198.4 (A), 198.3 (B), 196.3 (A), 195.8 (B), 150.3
B), 150.2 (A), 136.6 (2 C, A + B), 136.3 (A), 136.2 (B), 136.1 (2
C, A + B), 134.9 (B), 134.6 (B), 134.3 (B), 134.2 (A), 134.1 (A),
33.9 (B), 132.2 (B), 130.8 (2 C, A + B), 127.6 (2 C, A + B), 127.0
B), 126.9 (A), 126.8 (2 C, A + B), 126.7 (A), 126.6 (B), 124.1 (A),
2
B), 5.82 (app t, J = 3.5 Hz, 1 H, C=CH, A), 4.49 (m, 2 H, CH, A
B), 3.93 (d, J = 6.3 Hz, 1 H, CH, A), 3.71 (d, J = 6.5 Hz, 1 H,
CH, B), 3.40 (s, 1 H, CH, B), 3.30 (dd, J = 19.1, 4.2 Hz, 1 H, CH
B), 3.22 (s, 1 H, CH, A), 2.90 (dd, J = 19.1, 3.2 Hz, 1 H, CH , A),
.80 (dd, J = 19.1, 4.0 Hz, 1 H, CH , A), 2.71–2.54 (m, 3 H, CH
A] & CH [B]), 2.20 (s, 2 H, OH, A + B), 2.05 (ddd, J = 13.5, 6.5,
.2 Hz, 1 H, CH , A), 1.83 (dt, J = 13.7, 2.8 Hz, 1 H, CH , B) ppm.
C NMR (75 MHz, CDCl , 20 °C): δ = 199.0 (2 C, A + B), 196.6
A), 196.1 (B), 144.7 (B), 144.4 (A), 139.5 (2 C, A + B), 136.8 (A
or B), 136.5 (A or B), 134.7 (B), 134.6 (B), 134.5 (B), 134.1 (A),
33.8 (2 C, A), 133.7 (A), 128.6 (A or B), 128.5 (A or B), 127.5 (A
(
2
(
2
2
+
2
2
,
13
2
3
2
2
2
(
[
2
4
2
2
1
(
1
3
3
(
1
1
(
(
23.9 (B), 123.1 (B), 123.0 (A), 122.9 (A), 122.8 (B), 117.6 (A),
17.5 (B), 115.6 (2 C, A + B), 84.0 (A), 83.9 (B), 82.3 (A), 77.3
A), 76.8 (B), 59.6 (2 C, A + B), 57.3 (A), 46.8 (A), 42.4 (B), 37.2
1
or B), 127.4 (A or B), 127.3 (A or B), 126.9 (A or B), 126.5 (A or
B), 126.4 (2 C, A or B), 125.2 (4 C, A + B), 120.9 (B), 119.3 (A),
A), 32.8 (A), 29.9 (B), 28.3 (2 C, A + B) ppm. IR: ν˜ = 3473, 2974,
–1
2
932, 1726, 1680, 1592, 1454, 1359, 1270, 1249, 1153, 1134 cm .
8
4
3
2.7 (A), 77.3 (B), 59.2 (B), 59.1 (B), 58.8 (B), 57.0 (A), 46.0 (A),
+
HRMS (ESI) Calcd for C27
66.1635. Enantiomeric excesses have been determined on a 3:2
mixture of diastereomers A and B by HPLC analysis employing a
chiral AD column (heptane/2-propanol, 90:10, 1.0 mL/min), trA
0.82 min for the minor enantiomer and trA = 18.19 min for the
major enantiomer. trB = 12.52 min for the minor enantiomer and
rB = 15.50 min for the major enantiomer.
5
H25NO Na [M + H] : 466.1630, found
2.2 (B), 38.4 (A), 38.1 (B), 36.5 (A), 29.7 (B) ppm. IR: ν˜ = 3435,
4
–1
057, 2931, 1670, 1591, 1063 cm . HRMS (ESI) Calcd for
+
22 19 3
C H O [M + H] : 331.1334, found 331.1333. Enantiomeric ex-
=
cesses have been determined on analytical fractions of dia-
stereomers A and B by HPLC analyses employing a chiral OJ-H
column (heptane/2-propanol, 90:10, 1.0 mL/min), trA = 29.59 min
for the minor enantiomer and trA = 47.02 min for the major
1
t
Tricyclic Compound 4d: (2E,4Z)-4-phenylhepta-2,4-dienal (1d)
93 mg) reacted following the general procedure A and was isolated
as a yellow oil (112 mg, 65% yield); ee = 99%; TLC (PE/EtOAc,
enantiomer. trB = 28.40 min for the minor enantiomer and trB
5.84 min for the major enantiomer.
=
(
4
1
Polycyclic Compound 3b: (2E,4E)-4-Methylhexa-2,4-dienal (1b) 9:1): R
55 mg) reacted following the general procedure A and was isolated
as a colorless oil (48 mg, 36% yield, mixture of diastereomers A +
f 3
= 0.32. H NMR (300 MHz, CDCl , 20 °C): δ = 9.54 (app
(
t, J = 3.1 Hz, 1 H, CHO), 8.07–8.00 (m, 2 H, ArH), 7.70–7.63 (m,
2 H, ArH), 7.40–7.23 (m, 5 H, PhH), 6.06 (d, J = 5.0 Hz, 1 H,
Eur. J. Org. Chem. 0000, 0–0
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5

Job/Unit: O43597
/KAP1
Date: 11-02-15 15:28:21
Pages: 8
L. Pantaine, V. Coeffard, X. Moreau, C. Greck
FULL PAPER
C=CH), 4.62 (dt, J = 6.1, 3.3 Hz, 1 H, CH), 3.82–3.72 (m, 1 H, The mixture was washed with saturated Na
CH), 2.57 (ddd, J = 15.2, 5.5, 2.7 Hz, 1 H, CH ), 2.46 (ddd, J = phase was extracted with DCM and the organic phases were com-
), 1.32 (d, J = 7.0 Hz, 3 H, CH ) ppm. bined, washed with saturated NaHCO (aq) and then brine, dried
, 20 °C): δ = 200.3, 184.4, 183.8, 147.7, on anhydrous MgSO , filtered and concentrated under vacuum.
2 2 3
S O (aq). The aqueous
2
1
5.2, 6.4, 3.3 Hz, 1 H, CH
C NMR (75 MHz, CDCl
2
3
3
1
3
3
4
1
1
2
43.5, 138.9, 137.1, 133.9, 133.8, 132.2, 132.0, 128.9 (2 C), 128.6,
The crude product was passed through column chromatography
(PE/EtOAc, 9:1) and then on a preparative TLC (PE/EtOAc, 8:2)
28.1, 126.6 (2 C), 126.5 (2 C), 49.2, 32.7, 32.1, 22.0 ppm. IR: ν˜ =
–1
933, 2890, 2830, 2736, 1721, 1654, 1621, 1590, 1289 cm . HRMS
to afford corresponding product 6 57 mg, 29% yield, ee: 98%. TLC
+
1
(ESI) Calcd for C23
H
19
O
3
[M + H] : 343.1334, found 343.1327.
= –26.5 (c = 0.34, CHCl ). Enantiomeric excess has been de-
termined by HPLC analysis employing a chiral OJ-H column
heptane/2-propanol, 90:10, 1.0 mL/min), t = 16.45 min for the
minor enantiomer and t = 25.47 min for the major enantiomer.
NMR analyses were in complete agreement with the reported
(PE/EtOAc, 9:1): R
f
= 0.20. H NMR (300 MHz, CDCl
3
, 20 °C):
2
0
[α]
D
3
δ = 8.18 (dt, J = 13.9, 4.1 Hz, 2 H, ArH), 7.80 (t, J = 4.4 Hz, 2 H,
ArH), 7.46–7.32 (m, 5 H, PhH), 6.02 (t, J = 3.2 Hz, 1 H, C=CH),
4.20 (d, J = 5.3 Hz, 1 H, CH), 3.66 (s, 1 H, CH), 3.10 (dd, J =
(
r
r
19.2, 4.0 Hz, 1 H, CH
2.71–2.55 (m, 2 H, CH
δ = 209.9, 195.0, 191.3, 143.5, 138.8, 135.6, 135.1 (2 C), 134.5, 128.7
2 C), 127.9, 127.5, 127.3, 125.3, 120.4, 77.3, 63.7, 56.8, 47.1, 36.7,
2
), 2.95 (dd, J = 19.2, 2.7 Hz, 1 H, CH
2
),
1
3
2
) ppm. C NMR (75 MHz, CDCl , 20 °C):
3
[
10]
ones.
(
Tricyclic Compound 4e: (2E,4Z)-7-methyl-4-phenylocta-2,4-dienal
3
1
5.0 ppm. IR: ν˜ = 3059, 3030, 2971, 2900, 1750, 1683, 1589,
(1e) (110 mg) reacted following the general procedure A and was
–1
+
17 3
270 cm . HRMS (ESI) Calcd for C22H O [M + H] : 329.1178,
isolated as a yellow oil (98 mg, 55% yield); ee = 99%; TLC (PE/
EtOAc, 9:1): R
20
found 329.1176. [α]
D 3
= +14 (c = 1, CHCl ).
1
f
= 0.33. H NMR (300 MHz, CDCl
3
, 20 °C): δ =
9
7
1
4
.68 (t, J = 2.6 Hz, 1 H, CHO), 8.15–8.08 (m, 2 H, ArH), 7.78–
.72 (m, 2 H, ArH), 7.50–7.32 (m, 5 H, PhH), 6.12 (d, J = 4.8 Hz,
H, C=CH), 4.78 (dt, J = 5.7, 4.1 Hz, 1 H, CH), 3.86 (q, J =
Acknowledgments
.4 Hz, 1 H, CH), 2.56 (dd, J = 5.7, 2.6 Hz, 2 H, CH
2
), 2.34–2.23
), 0.89 (d, J = 6.9 Hz,
, 20 °C): δ = 199.7,
The authors thank the Fondation de Coopération Scientifique
Campus Paris Saclay for a Ph.D. grant to L. P. This work was sup-
ported by the French National Research Agency (ANR) under the
Program Investing in the Future (grant number ANR-10-IDEX-
(m, 1 H, CH), 1.21 (d, J = 6.9 Hz, 3 H, CH
3
3
1
1
3
1
+
H, CH
3
) ppm. 13C NMR (75 MHz, CDCl
3
84.5, 184.1, 146.3, 144.8, 139.7, 139.4, 133.9, 133.8, 132.2, 132.0,
28.8 (2 C), 128.2, 126.8 (2 C), 126.5 (2 C), 123.9, 50.2, 42.0, 32.9,
2.1, 21.8, 18.9 ppm. IR: ν˜ = 3059, 2955, 2928, 2868, 2730, 1721,
0003-02). The authors acknowledge financial support from Centre
National de la Recherche Scientifique (CNRS) and Université de
Versailles-St-Quentin-en-Yvelines.
–
1
655, 1618, 1592, 1284 cm . HRMS (ESI) Calcd for C25
H
23
O
3
[M
+
20
H] : 371.1647, found 371.1654. [α] = –44 (c = 1, CHCl ). Enan-
D 3
tiomeric excess has been determined by HPLC analysis employing
a chiral OJ-H column (heptane/2-propanol, 90:10, 1.0 mL/min), t
11.34 min for the minor enantiomer and t = 15.65 min for the
major enantiomer.
[
1] D. C. Kombo, K. Tallapragada, R. Jain, J. Chewning, A. A.
Mazurov, J. D. Speake, T. A. Hauser, S. Toler, J. Chem. Inf.
Model. 2013, 53, 327–342.
r
=
r
[
[
2] S. P. Roche, J. A. Porco Jr., Angew. Chem. Int. Ed. 2011, 50,
4068–4093; Angew. Chem. 2011, 123, 4154.
Tricyclic Compound 4f: (2E,4E)-4-methylhepta-2,4-dienal (1f)
65 mg) reacted following the general procedure A and was isolated
as an orange oil (60 mg, 42% yield); ee = 99%; TLC (PE/EtOAc,
3] a) Q. Ding, X. Zhou, R. Fan, Org. Biomol. Chem. 2014, 12,
807–4815; b) C.-X. Zhuo, W. Zhang, S.-L. You, Angew. Chem.
Int. Ed. 2012, 51, 12662–12686; Angew. Chem. 2012, 124,
2834.
4] G. Maertens, M.-A. Ménard, S. Canesi, Synthesis 2014, 46,
573–1582.
.3 Hz, 1 H, CH), 3.64–3.55 (m, 1 H, CH), 2.68 (ddd, J = 15.7, [5] N. T. Vo, R. D. M. Pace, F. O’Hara, M. J. Gaunt, J. Am. Chem.
.8, 2.7 Hz, 1 H, CH ), 2.59 (ddd, J = 15.7, 5.8, 2.7 Hz, 1 H, CH ), Soc. 2008, 130, 404–405.
) ppm. 1 C NMR [6] Q. Gu, S.-L. You, Org. Lett. 2011, 13, 5192–5195.
.84 (s, 3 H, CH ), 1.25 (d, J = 7.2 Hz, 3 H, CH
, 20 °C): δ = 200.9, 184.4, 183.9, 148.1, 143.9,
33.8, 133.7, 132.5, 132.2, 132.0, 126.7, 126.4 (2 C), 48.9, 34.0, 30.7,
2.1, 21.1 ppm. IR: ν˜ = 2967, 2930, 2873, 2730, 1720, 1656, 1621,
(
4
1
9
=
:1): R
2.7 Hz, 1 H, CHO), 8.11–8.03 (m, 2 H, ArH), 7.74–7.68 (m, 2
H, ArH), 5.65 (br. d, J = 4.8 Hz, 1 H, C=CH), 3.95 (dt, J = 5.8,
f 3
= 0.30. H NMR (300 MHz, CDCl , 20 °C): δ = 9.84 (t, J
1
[
1
3
5
1
2
2
3
3
3
[
[
7] K. L. Jensen, P. T. Franke, L. T. Nielsen, K. Daasbjerg, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2010, 49, 129–133; Angew.
Chem. 2010, 122, 133.
(
75 MHz, CDCl
3
1
2
1
8] For selected examples of oxidative dearomatization followed by
asymmetric organocatalyzed functionalization, see: a) Q. Liu,
T. Rovis, J. Am. Chem. Soc. 2006, 128, 2552–2553; b) Q. Gu,
Z.-Q. Rong, C. Zheng, S.-L. You, J. Am. Chem. Soc. 2010, 132,
4056–4057; c) R. Tello-Aburto, K. A. Kalstabakken, K. A.
Volp, A. M. Harned, Org. Biomol. Chem. 2011, 9, 7849–7859;
d) Q. Gu, S.-L. You, Chem. Sci. 2011, 2, 1519–1522; e) R.
Leon, A. Jawalekar, T. Redert, M. J. Gaunt, Chem. Sci. 2011,
–1
592, 1326, 1288 cm . HRMS (ESI) Calcd for C18
H
17
O
3
[M +
). Enan-
tiomeric excess has been determined by HPLC analysis employing
a chiral OJ-H column (heptane/2-propanol, 90:10, 1.0 mL/min), t
10.24 min for the major enantiomer and t = 12.41 min for the
minor enantiomer. NMR analyses were in complete agreement with
+
20
D 3
H] : 281.1178, found 281.1175. [α] = +13 (c = 1, CHCl
r
=
r
[
10]
the reported ones.
2
, 1487–1490; f) M.-Q. Jia, S.-L. You, Chem. Commun. 2012,
Polycyclic Compound 6: To a solution of 1,4-dihydroxynaphthalene
48, 6363–6365; g) D. M. Rubush, M. A. Morges, B. J. Rose,
D. H. Thamm, T. J. Rovis, J. Am. Chem. Soc. 2012, 134, 13554–
(
120 mg, 0.75 mmol, 1.5 equiv.) in toluene (1 mL) was added
PhI(OAc) (210 mg, 0.65 mmol, 1.3 equiv.), under heavy stirring.
The dienal 1a (86.1 mg, 0.5 mmol, 1 equiv.) and catalyst 5d (18 mg,
.05 mmol, 0.1 equiv.) were then dissolved in toluene (0.5 mL each)
13557; h) M.-Q. Jia, C. Liu, S.-L. You, J. Org. Chem. 2012, 77,
10996–11001; i) M. T. Corbett, J. S. Johnson, Chem. Sci. 2013,
4, 2828–2832; j) W. Wu, X. Li, H. Huang, X. Yuan, J. Lu, K.
2
0
Zhu, J. Ye, Angew. Chem. Int. Ed. 2013, 52, 1743–1747; Angew.
Chem. 2013, 125, 1787; k) C. Martín-Santos, C. Jarava-Barrera,
S. delPozo, A. Parra, S. Díaz-Tendero, R. Mas-Ballesté, S. Cab-
rera, J. Alemán, Angew. Chem. Int. Ed. 2014, 53, 8184–8189.
For a review, see: X. Yang, J. Wang, P. Li, Org. Biomol. Chem.
2014, 12, 2499–2513.
and added to the previous solution, in that order. The reaction was
left to stir at 55 °C for 16 h. The reaction was cooled down to room
temperature. Additional PhI(OAc) (245 mg, 0.76 mmol, 1.5 equiv.)
2
and TEMPO (16 mg, 0.1 mmol, 0.2 equiv.) were added to the solu-
tion. The reaction was left to stir at room temperature for 24 h.
6
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Job/Unit: O43597
/KAP1
Date: 11-02-15 15:28:21
Pages: 8
Synthesis of 1,4-Naphthoquinone-Derived Polycycles
[
[
9] F. Portalier, F. Bourdreux, J. Marrot, X. Moreau, V. Coeffard,
C. Greck, Org. Lett. 2013, 15, 5642–5645.
[12] L. Huang, J. Zhao, S. Guo, C. Zhang, J. Ma, J. Org. Chem.
2013, 78, 5627–5637, and references cited therein.
[13] Under bodipy 7-photocatalyzed oxygenation, 5-(benzyloxy)-
naphthalen-1-ol, anthracene-1,8,9-triol and tert-butyl 4-
hydroxy-1H-indole-1-carboxylate did not react and only the
starting materials were recovered.
10] During the course of our studies, the formation of 4 has been
described by Jørgensen through an H-bond-directed trien-
amine-mediated Diels–Alder cycloaddition between dienal 1
and 1,4-naphthoquinone derivatives; 3 was not isolated, see: Ł.
Albrecht, C. V. Gómez, C. Borch Jacobsen, K. A. Jørgensen,
Org. Lett. 2013, 15, 3010–3013.
[14] Y. Liu, M. Nappi, E. Arceo, S. Vera, P. Melchiorre, J. Am.
Chem. Soc. 2011, 133, 15212–15218.
[11] M. N. Hopkinson, B. Sahoo, J.-L. Li, F. Glorius, Chem. Eur.
Received: December 9, 2014
J. 2014, 20, 3874–3886.
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43597
/KAP1
Date: 11-02-15 15:28:21
Pages: 8
L. Pantaine, V. Coeffard, X. Moreau, C. Greck
FULL PAPER
Organocatalysis
L. Pantaine, V. Coeffard,* X. Moreau,
C. Greck* ......................................... 1–8
One-Pot Enantioselective Synthesis of 1,4-
Naphthoquinone-Derived
Polycycles
through Oxidative Dearomatization and
Aminocatalysis
The asymmetric synthesis of diversely sub-
stituted 1,4-naphthoquinone-derived poly-
cycles is described by merging dearomatiz-
ation and aminocatalysis in a single vessel.
The dearomatization step is promoted by
PhI(OAc)
2
or oxygen in the presence of a
bodipy photosensitizer and two products
are selectively isolated depending on the
dienal substitution.
Keywords: Asymmetric synthesis / Organo-
catalysis
/ Dearomatization / Cycload-
dition / Photooxidation / Polycycles
8
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