Organocatalytic stereoselective [8+2] and [6+4] cycloadditions

Article abstract of DOI:10.1038/nchem.2682

Cycloadditions that involve more than six I € electrons are termed higher-order cycloadditions and are an excellent tool for solving complex synthetic challenges, as they provide direct access to polycyclic scaffolds that contain medium-sized rings. They have interesting synthetic potential for the discovery of new bioactive molecules and in natural product synthesis. It is peculiar that stereocontrolled [8+2] and [6+4] cycloadditions have been largely neglected for the past 50 years. Here we demonstrate a cross-dienamine activation of 2-cyclopentenone and the unprecedented endocyclic linear-dienamine activation of 2-cyclohexenones and 2-cycloheptenones. These dienamine intermediates undergo aminocatalytic stereoselective [8+2], [6+4] and formal [4+2] cycloadditions with various heptafulvenes. The periselectivities of the cycloadditions are controlled based on the ring size of the 2-cycloalkenones and the substitution patterns of the heptafulvenes. The chiral products obtained undergo various chemical and photochemical single-step transformations that give access to other classes of all-carbon polycyclic scaffolds.

Full text of DOI:10.1038/nchem.2682

ARTICLES
PUBLISHED ONLINE: 19 DECEMBER 2016 | DOI: 10.1038/NCHEM.2682
Organocatalytic stereoselective [8+2] and [6+4]
cycloadditions
Rasmus Mose, Gert Preegel, Jesper Larsen, Sofie Jakobsen, Eva Høgh Iversen
and Karl Anker Jørgensen
*
Cycloadditions that involve more than six π electrons are termed higher-order cycloadditions and are an excellent tool for
solving complex synthetic challenges, as they provide direct access to polycyclic scaffolds that contain medium-sized rings.
They have interesting synthetic potential for the discovery of new bioactive molecules and in natural product synthesis. It
is peculiar that stereocontrolled [8+2] and [6+4] cycloadditions have been largely neglected for the past 50 years. Here
we demonstrate a cross-dienamine activation of 2-cyclopentenone and the unprecedented endocyclic linear-dienamine
activation of 2-cyclohexenones and 2-cycloheptenones. These dienamine intermediates undergo aminocatalytic
stereoselective [8+2], [6+4] and formal [4+2] cycloadditions with various heptafulvenes. The periselectivities of the
cycloadditions are controlled based on the ring size of the 2-cycloalkenones and the substitution patterns of the
heptafulvenes. The chiral products obtained undergo various chemical and photochemical single-step transformations that
give access to other classes of all-carbon polycyclic scaffolds.
he seminal paper by Woodward and Hoffmann in 1965 stating found in small quantities23–25. The thermodynamic distributions
a simple set of rules for pericyclic reactions was the onset of a of the dienamine mixtures are not reflected in the aminocatalytic
T
new era in chemistry1. In addition to the [8+2] cycloaddition reactions and 3-alkyl-2-cycloalkenones react through either cross-
reported in 1960, they proposed that [6+4] cycloadditions would dienamine26–29 or exocyclic linear-dienamine intermediates29–31
,
also be symmetry allowed2–4. Furthermore, based on the orbital whereas 2-cycloalkenones are known to react through cross-diena-
symmetry rules, the [6+4] cycloaddition was predicted to proceed mine intermediates27–29,32. In contrast, the catalytic γ functionaliza-
with exo-selectivity, whereas the [8+2] and [4+2] cycloadditions tion via an endocyclic linear dienamine is uncommon and has only
should both be endo-selective. A proof of concept was provided been observed for 3-phenyl-2-cyclopentenone33.
the following year when the first [6+4] cycloaddition was demon-
We envisioned that stereoselective [8+2], [6+4] and [4+2]
strated by the reaction of tropone with cyclopentadiene5.
cycloadditions could be accessed via aminocatalysis34. The periselec-
Higher-order cycloadditions (cycloadditions that involve more tivities of these reactions are considered to be determined by the possi-
than six π electrons) often suffer from a lack of periselectivity as bility that 2-cycloalkenones can generate different catalytic dienamine
several competitive reaction pathways are possible. For example, intermediates by reaction with an aminocatalyst. As outlined in
tropone has been reported to react as a 2π component in [2+4] Fig. 1b, it is postulated that a cross-dienamine intermediate35 will
(ref. 6) cycloadditions, a 4π component in [4+2] (refs 7–9) and lead to a [6+4] cycloaddition, whereas a linear dienamine can
[4+6] (ref. 10) cycloadditions, a 6π component in [6+3] (refs 11–13), undergo either an [8+2] or formal [4+2] cycloaddition.
[6+4] (refs 5,14–18) and [6+6] (ref. 19) cycloadditions, and as an
We initiated our studies by investigating the reaction of 2-cyclopen-
8π component in [8+2] (ref. 20) cycloadditions. Although no tenone 2a with tropone 3A catalysed by cinchona alkaloid primary
general guidelines to control the reaction pathway of higher-order amines 1 (ref. 36) (screening and optimization results are given in
cycloadditions are known, it is highly desirable to be able to Supplementary Table 1). With catalyst 1c the [6+4] cycloadduct
perform periselective reactions for synthetic applications.
4aA was readily formed in 51% yield and excellent stereoselectivities
Numerous examples of the thermally allowed [8+2] and [6+4] (95% e.e., >20:1 d.r.) and represents the first catalytic stereoselective
cycloadditions have been reported over the past 50 years, but intermolecular [6+4] cycloaddition (Table 1, entry 1). Surprisingly,
there is a remarkable lack of their enantioselective equivalents. A no reaction was observed when heptafulvenes 3B and 3C were
singular example of a catalytic intramolecular [6+4] cycloaddition applied under Conditions A (Table 1, footnotes); however, the [6+4]
exists (80% yield, 40% e.e.)14,21, and a metal-catalysed enantioselective cycloadduct 4aB was formed in 50% yield, >20:1 d.r. and 42% e.e.
aza-[8+2] cycloaddition was reported only recently22. In addition, after the tuning of several reaction parameters (Table 1, entry 2).
enantioselective versions of the [4+2] cycloadditions with
When cycloadditions between 2-cyclohexenone 2b with tropone
3A and dicyanoheptafulvene 3B were attempted, the formal inverse-
heptafulvenes have also received limited attention9.
The aminocatalytic activation of 2-cycloalkenones provides a electron-demand [4+2] cycloadducts 6bA and 6bB were isolated
mixture of dienamine species that consists of a cross dienamine, instead of the expected [6+4] cycloadducts (Table 1, entries 4 and 5).
an endocyclic linear dienamine and an exocyclic linear dienamine This observation is notable, as 2-cyclohexenones are known to
(only for 3-alkyl-2-cycloalkenones) (Fig. 1a). The thermodynamic react via cross-dienamine intermediates27–29,32, but the catalytic γ
distribution of the dienamine mixtures lies in favour of the endo- functionalization via an endocyclic linear dienamine had not been
or exocyclic linear dienamines for 3-alkyl-2-cycloalkenones and observed previously33. We hypothesized that the [4+2] cycloadducts
towards the endocyclic linear dienamine for 2-cycloalkenones, were formed by an initial [8+2] cycloaddition followed by a
whereas the cross dienamine is generally not observed or only rearrangement into the [4+2] cycloadducts (Fig. 2c)37. Thus, when
Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark. e-mail: kaj@chem.au.dk
*
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1
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2682
ARTICLES
a
Cat
Cat
R1
Cat
O
NH
NH
NH
R1 = alkyl
CatNH2
R2
R1
R1
Cross dienamine
Endocyclic
Exocyclic
linear dienamine
linear dienamine
H
b
O
X
[8+2] cycloaddition
O
X
H
n–1
H
H
N
O
[6+4] cycloaddition
Cat
+
H
N
H
n
n–1
O
n > 1
X
Cat
X = O, C(CN)2, C(CN)CO2Et
Formal
n = 1
n–1
[4+2] cycloaddition
H
X
Figure 1 | Aminocatalytic dienamine activation of 2-cycloalkenones and their applications in higher-order cycloadditions. a, Aminocatalytic activations of
enones provide mixtures of dienamine species. Reactivity is usually observed through the cross-dienamine or exocyclic linear-dienamine species. b, Work
presented herein; mixtures of 2-cycloalkenones and heptafulvenes can undergo various cycloadditions. 2-cyclopentenone reacts through a cross-dienamine
intermediate in a [6+4] cycloaddition, whereas reactions with 2-cyclohexenone and 2-cycloheptenone provide an [8+2] or formal [4+2] cycloadduct through
an endocyclic linear-dienamine intermediate. CatNH2, chiral primary amine catalyst.
Table 1 | Organocatalytic enantioselective reaction of 2-cycloalkenones 2a–2c with heptafulvenes 3A–3C.
X
O
R1
2a: n = 1
2b: n = 2
2c: n = 3
3A: X = O
3B: X = C(CN)2
3C: X = C(CN)CO2Et
+
NH2
n
N
2
3
N
1a: R1 = H 1b: R1 = OMe
R2
H
H
H
O
n
X
N
NH2
O
O
n–1
H
n–1
H
N
X
X
1c: R2 = H 1d: R2 = OMe
4
5
6
Entry
n
X
O
[6+4] cycloadduct
[8+2] cycloadduct
[4+2] cycloadduct
1*
1
1
1
4aA; 51% yield, 95% e.e., >20:1 d.r.
4aB; 50% yield, 42% e.e., >20:1 d.r.
NR
–
–
2†
3*,†
–
–
C(CN)2
C(CN)CO2Et
NR
NR
4*
5†
6†
2
2
2
–
–
–
–
–
6bA; 72% yield, 71% e.e., >20:1 d.r.
O
C(CN)2
6bB; 56% yield, 87% e.e., >20:1 d.r.
C(CN)CO2Et
5bC; 58% yield, 98% e.e., 85:15 d.r.
–
7*,†
9†,‡
3
3
3
NR
NR
NR
–
–
O
8†
4cB; 5% yield, 52% e.e., >20:1 d.r.
5cB; 48% yield, >99% e.e., 9:1 d.r.
5cC; 61% yield, 99% e.e., >20:1 d.r.
C(CN)2
C(CN)CO2Et
–
*Conditions A: 1c (0.02 mmol), 2 (0.2 mmol), 3A (0.1 mmol) and (–)-CSA (0.04 mmol) in 1,4-dioxane (0.1 ml) at 60 °C. †Conditions B: 1b (0.02 mmol), 2 (0.2 mmol), 3B or 3C (0.1 mmol) and EtCO2H
(0.02–0.06 mmol) in toluene (0.1 ml) at 60 °C (Supplementary Information gives the details). ‡Performed at 80 °C. NR, no reaction; dashes indicate that no product was observed.
the less electron-poor cyanoesterheptafulvene 3C was applied, 3A + 2b no reaction was observed). In addition, no reactions were
the [8+2] cycloadduct 5bC was isolated in good yield (58%) and observed when Conditions A were applied to the reactions of
excellent stereoselectivities (98% e.e., 85:15 d.r.) (Table 1, entry 6). dicyanoheptafulvene 3B and cyanoesterheptafulvene 3C with the
2-Cycloheptenone 2c did not react with tropone 3A, whereas it 2-cycloalkenones 2. In general, all the reactions reported in
underwent an [8+2] cycloaddition with both heptafulvenes 3B Table 1 do not reach full conversion of the starting materials and
and 3C in 48–61% yield and excellent stereoselectivities (9:1 to the products are only isolated in moderate-to-good yields.
>20:1 d.r., 99 to >99% e.e.) (Table 1, entries 7–9). The only reaction Prolonged reaction times only led to degradation of the starting
not being completely periselective was the reaction between 2-cyclo- materials without improvements in the yield of the reactions. No
1
heptenone 2c and dicyanoheptafulvene 3B, which gave the [6+4] or few by-products were observed by H NMR spectroscopy on
cycloadduct 4cB as a by-product (Table 1, entry 8).
Whereas tropone 3A readily reacted with 2a and 2b under the starting materials is ascribed to polymerization reactions.
Conditions A, only moderate results were obtained under At this point, the reaction pathways for the formation of the
Conditions B (3A + 2a: 48% yield, >20:1 d.r., 65% e.e. and for products were not clear. The products might be formed by three
the crude reaction mixtures and the apparent disappearance of
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2682
ARTICLES
a
O
H
O
O
O
Conditions A
+
+
O
2 days
H
O
4bA
O
4bA
6bA
3A
Racemic
26% yield
>20:1 d.r.
72% e.e.
42% yield
>20:1 d.r.
73% e.e.
20% yield
b
O
O
NC
H
NC
CN
H
H
Conditions B
10 min
CN
CN
CN
CN
+
+
H
H
H
H
CN
O
H
5bB
Racemic
ent-6bB
65% yield
>20:1 d.r.
7% e.e.
5bB
3B
11% yield
19% yield
>20:1 d.r.
18% e.e.
c
O
Cat
NH
n
H
X
O
X
O
n–1
H
H
CatNH2
H2O
H
X
n–1
+
H
H
X
H
H
N
n
N
4
Cat
Cat
[6+4] cycloadduct
5
[8+2] cycloadduct
n–1
Cross dienamine
Linear dienamine
n = 1
n > 1
H
O
H
+
Cat
H
N
+
N
–
CatNH2
H2O
X
Cat
n–1
H
X
n–1
H
6
H
n–1
H
–
H
X
Formal
[4+2] cycloadduct
Figure 2 | Elucidating the reaction pathway. a, Equilibration of 4bA to the thermodynamically most stable cycloadduct 6bA. b, Equilibration of 5bB to the
thermodynamically most stable cycloadduct 6bB. c, The reaction pathways in accordance with the equilibration experiments. Cross-dienamine activation of a
2-cycloalkenone leads to a [6+4] cycloaddition with the heptafulvene, whereas-linear dienamine activation leads to an [8+2] cycloaddition. The formal [4+2]
cycloadducts were formed by an initial [8+2] cycloaddition followed by a rearrangement to give the formal [4+2] cycloadducts. Conditions A and B are
given in the footnotes to Table 1.
distinct cycloadditions, or by interconversion of the cycloadducts; faster (ten minutes) compared with the reaction of 2-cyclohexenone
for example, interconversion of [6+4] and [8+2] cycloadducts via 2b with dicyanoheptafulvene 3B (18 hours) and yielded the enantio-
a [3,3]-sigmatropic rearrangement/oxy-Cope rearrangement38,39
,
mer of 6bB with a very low 7% e.e. In addition, the interconversion
or interconversion of [8+2] and [4+2] cycloadducts via zwitterionic of racemic 5bB to ent-6bB was completely retarded in the absence
intermediates37,40. In an attempt to elucidate the reaction pathways, of the aminocatalyst. These results show that the aminocatalyst is
racemic samples of the [8+2] cycloadduct 5bB and [6+4] cyclo- involved in the interconversion of the [8+2] cycloadduct 5bB into
adduct 4bA were prepared (we were unable to obtain 4bB and the [4+2] cycloadduct 6bB and that the interconversion does not
5bA) because their respective [4+2] cycloadducts 6bA and 6bB proceed via 2-cyclohexenone 2b and dicyanoheptafulvene 3B. The
have lower potential energies (vide infra). Under Conditions A, results are summarized in Fig. 2c.
used for the formation of the [4+2] cycloadduct 6bA, the racemate
In accordance with the results in Table 1 and the proposed reaction
of the [6+4] cycloadduct 4bA was converted into the [4+2] cyclo- pathway in Fig. 2c, both 2-cyclohexenone 2b and 2-cycloheptenone
adduct 6bA with similar stereoselectivities as for the reaction 2c underwent an initial [8+2] cycloaddition with the heptafulvenes
between 2-cyclohexenone 2b and tropone 3A (Fig. 2a). 3A–3C through a linear-dienamine intermediate (Table 1, entries
Furthermore, unreacted [6+4] cycloadduct 4bA was recovered in a 4–9). All the reactions with cyanoesterheptafulvene 3C were found
high optical purity (the e.e. of the recovered 4bA was dependent to give the [8+2] cycloadducts, whereas both tropone 3A and dicyano-
on the reaction time), which indicates a resolution of the racemic heptafulvene 3B produced [4+2] cycloadducts with 2-cyclohexenone
starting material. These results show that the organocatalyst is 2b through an unobserved [8+2] cycloadduct intermediate.
involved in a retro [6+4] cycloaddition of 4bA followed by the for-
To investigate the influence of the electronic properties of the
mation of the cycloadduct 6bA. To investigate the [8+2] to [4+2] 2-cyclohexenone on the periselectivity of the reaction, a series of
interconversion, a racemic sample of [8+2] cycloadduct 5bB, substituted 2-cyclohexenones 7 was prepared and reacted with
which was not observed in the organocatalytic reaction (Table 1, tropone 3A, dicyanoheptafulvene 3B and cyanoesterheptafulvene
entry 5), was subjected to Conditions B used for the formation of 3C (Fig. 3). It was observed that 3A did not react with 7 under
the [4+2] cycloadduct 6bB (Fig. 2b). The reaction was significantly either Conditions A or B, whereas a formal [4+2] cycloaddition
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2682
ARTICLES
O
a
1b (20 mol%)
O
X
a: n = 1
b: n = 2
c: n = 3
A: X = O
H
3B
B: X = C(CN)2
C: X = C(CN)CO2Me
(–)-CSA (20 mol%)
Toluene, 80 °C, 18 h
H
n
Formal [4+2]
cycloaddition
2
3
R
CN
NC
–60
–80
8
8a R = CO2Me 29% yield, >20:1 d.r., 61% e.e.
O
53% yield, 10:1 d.r., 69% e.e.
69% yield, >20:1 d.r., 80% e.e.
8b R = H
8c R = OMe
Ar
O
7
1b (20 mol%)
H
CO2Et
CN
3C
–100
–120
EtCO2H (20 mol%)
Toluene, 80 °C, 18 h
H
H
[8+2]
cycloaddition
R
A B C
A B C
A B C
9
9a R = CO2Me 20% yield, >20:1 d.r., 99% e.e.
[6+4]
[8+2]
Formal [4+2]
55% yield, 4:1 d.r., 99% e.e.
52% yield, 14:1 d.r., >99% e.e.
49% yield, >20:1 d.r., >99% e.e.
9b R = H
9c R = OMe
9d R = Br
b
H
N
N
Ar
R
H
N
Ar
+
N
H
Figure 3 | Control of formal [4+2] and [8+2] periselectivity of the
cycloadditions of 2-cyclohexenones 7 by reactions with heptafulvenes.
Using the common starting material 7, one can obtain either the [4+2] or
[8+2] product. By varying the nature of the acid used, synthetically useful
yields of products with a variety of substituents can be obtained with
excellent diastereo- and enantioselectivity.
+
O
H
N
I
II
[6+4] cycloaddition
Good fit
[6+4] cycloaddition
Poor fit
proceeded with dicyanoheptafulvene 3B to yield the cycloadduct 8b
under Conditions B (27% yield, 10:1 d.r., 49% e.e.). Improvements
in yield and enantioselectivity were found when (–)-CSA (CSA,
camphorsulfonic acid) was used as the acid additive to form 8b
(53% yield, 10:1 d.r., 69% e.e.). In the reactions to generate the
[4+2] cycloadducts 8, yields and stereoselectivities were found to
be dependent on the electronic properties of the substituents in 7.
Improvements in yield and enantioselectivity were observed when
the 2-cyclohexenone 7 is more electron rich (Fig. 3, top reaction).
When the 2-cyclohexenones 7 were reacted with cyanoesterhepta-
fulvene 3C under Conditions B an [8+2] cycloaddition was realized
in all cases (Fig. 3, bottom reaction). For this reaction path the
different substituents did not have any significant influence on the
enantioselectivities (99 to >99% e.e.), but resulted in variations of
the diastereoselectivities (4:1 to >20:1). These results demonstrate
that the periselectivity of the cycloaddition reactions of 2-cyclohex-
enones depends solely on the nature of the heptafulvene 3 and not
on the electronic properties of the 2-cyclohexenone.
+
N
H
H
+
N
N
H
H
O
R
Ar
HN
Ar
NH
III
IV
[8+2] cycloaddition
Good fit
[8+2] cycloaddition
Poor fit
Figure 4 | Rationalization of peri- and stereoselectivities. a, Relative
potential energies of [6+4] cycloadducts 4, [8+2] cycloadducts 5 and [4+2]
cycloadducts 6 to their respective starting materials. The observed products
are marked within dotted boxes. Density functional theory calculations were
performed using the ωb97X-D functional and the pc-2 basis set. b, Proposed
transition-state structures for the aminocatalytic [6+4] and [8+2]
cycloadditions.
The moderate-to-good enantioselectivities for the formation of potential energy relative to the [8+2] cycloaddition products, but
the [4+2] cycloadducts 8 (Fig. 3, top reaction) can be rationalized are in the same range as the formal [4+2] cycloaddition products.
based on the reaction pathway in Fig. 2c. The catalyst performs Thus, the calculations predict the formation of a mixture of [6+4]
the [8+2] to [4+2] rearrangement most rapidly for the minor enan- and [4+2] cycloadducts under thermodynamic conditions.
tiomer of the [8+2] cycloadduct, which rearranges to 8 (extrapolated Interestingly, only the [6+4] cycloadducts were observed, which
from Fig. 2b). As the [8+2] cycloaddition is assumed to be revers- suggests a kinetic preference for this reaction. In two cases, the for-
ible, the decreased nucleophilicities of the linear dienamines from mation of the [4+2] cycloadducts was observed. These [4+2]
7 compared with the linear dienamines from 2b (80 °C for reactions cycloadducts were formed under the thermodynamic conditions
of 7 versus 60 °C for reactions of 2b) lead to a deterioration of the shown in Fig. 2 and also supported by the calculations (>20 kJ mol–1
enantioselectivity of the reaction when 7 becomes less electron preference for the [4+2] cycloadducts over the [6+4] and [8+2]
rich because of a slower [8+2] to [4+2] rearrangement.
cycloadducts). Finally, the observed [8+2] cycloadducts 5bC, 5cB
To obtain a better understanding of the periselectivity of these and 5cC were calculated to have lower relative potential energies
higher-order cycloadditions, the potential energies of all classes of than their respective [6+4] cycloadducts (>20 kJ mol–1). These [8+2]
products 4, 5 and 6 were calculated relative to their respective start- cycloadducts are thermodynamically less stable or similar in energy
ing compounds. Figure 4a displays the relative potential energies of to the [4+2] cycloadducts. As the [4+2] cycloadducts were not observed
the possible products obtained from the reactions of 2-cycloalke- in these reactions, the activation barrier for the [8+2] to [4+2]
nones 2a–2c with heptafulvenes 3A–3C and the observed products cycloadduct rearrangement is predicted to be too high to proceed
are marked within dotted boxes (see Supplementary Table 2 for under the reaction conditions.
specific values). For 2-cyclopentenone 2a the [6+4] cycloadditions
To sum up, the periselectivity of the cycloadditions can be
are more exothermic (∼20 kJ mol–1) compared with the [6+4] explained as follows: for cases in which the activation barrier for
cycloadditions with 2-cyclohexenone 2b and 2-cycloheptenone 2c. the [8+2] to [4+2] cycloadduct rearrangement is too high to
The two [6+4] cycloaddition products obtained are lower in proceed under the reaction conditions, the [6+4] or [8+2]
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2682
ARTICLES
O
a
Ph
N
O
O
O
O
6π disrotatory
H
N
CO2Et
N
10
Ar
electrocyclization
H
H
Br
CO2Et
CN
CN
CO2Et
CN
H
H
Br
H
H
H
H
CDCl3, r.t., 3 h
O
N
H
N
H
NPh
9d
11
O
>20:1 d.r.
>99% e.e.
48% yield
>20:1 d.r.
99% e.e.
b
H
H
H
O
H
hν (254 nm)
hν (254 nm)
H
O
H
H
H
O
MeCN
2 d
MeOH, 3 h
H
O
O
H
O
H
H
H
H
CO2Me
•
O
12
6bA
13
85% yield
>20:1 d.r.
75% e.e.
>20:1 d.r.
74% e.e.
50% yield
>20:1 d.r.
74% e.e.
Figure 5 | Selected transformations. a, Cycloheptatrienes exist in equilibrium with their norcaradiene tautomer, which can be trapped selectively in a
Diels–Alder reaction. b, The formal [4+2] cycloadduct 6bA can undergo either a photochemical [3,3]-sigmatropic rearrangement or a photochemical 1,3-acyl
shift. The reaction pathway can be controlled by the selection of a nucleophilic/non-nucleophilic solvent.
cycloadduct with the lowest relative potential energy is formed,
To demonstrate the synthetic potential of these cycloadducts,
whereas when the [8+2] to [4+2] cycloadduct rearrangement selected transformations were performed to show the ease with
readily proceeds, the thermodynamically most stable [6+4], [8+2] which they can be turned into other molecular scaffolds.
or [4+2] cycloadduct is formed.
Cycloheptatrienes can co-exist in equilibrium with small amounts
The mechanistic aspects of the reactions catalysed by cinchona of their norcaradiene tautomer through a thermally allowed 6π
alkaloid primary amines 1 have been investigated recently by Houk disrotatory electrocyclization. The norcaradiene tautomer of 9d
and co-workers41,42. Based on these mechanistic investigations, we could be trapped through a Diels–Alder reaction with triazolinedione
are able to propose transition-state models for the [6+4] and [8+2] 10 to form the hexacyclic compound 11 (Fig. 5a). The [4+2] cyclo-
cycloadditions that rationalize the results presented in Table 1 (Fig. 4b). adduct 6bA was found to undergo a photochemical [3,3]-sigmatropic
The [6+4] cycloaddition is initiated by the condensation of shift to form a ketene intermediate that could be trapped with metha-
2-cyclopentenone 2a with the aminocatalyst 1. This intermediate, nol to form 12 (Fig. 5b). Alternatively, in the absence of a nucleophile,
in its protonated form, is set up for hydrogen bonding to tropone product 13 was formed through the less efficient 1,3-acyl shift.
3A as it places the 6π component of tropone for the exo-selective
The absolute configurations of 11, tribrominated 4aA and mono-
interactions with the 4π component of the cross-dienamine inter- brominated 6bB were unambiguously determined by single-crystal
mediate (Fig. 4b, I). Spatial considerations of the transition state X-ray diffraction and the configurations of all the remaining pro-
account for the stereochemical outcome of the reaction, which is ducts were assigned by analogy (Supplementary Information).
in accordance with the absolute configuration obtained by X-ray
In conclusion, we have developed novel and unprecedented orga-
analysis of the [6+4] cycloadduct. Whereas tropone 3A can easily nocatalytic asymmetric higher-order cycloaddition reactions exem-
be placed in close proximity to the cross dienamine in an exo-tran- plified by intermolecular [8+2], [6+4] and formal [4+2]
sition state when being activated and directed through hydrogen cycloadditions. The reactions proceed with excellent stereoselectiv-
bonding to the catalyst, dicyanoheptafulvene 3B does not fit this ities for 2-cycloalkenones that reacted with heptafulvenes in the
model well, as hydrogen bonding to the cyano group places the hep- presence of cinchona alkaloid primary amines as catalysts. The
tafulvene moiety too far away from the cross dienamine (Fig. 4b, II). periselectivity can be controlled by the ring size of the 2-cycloalke-
These different approaches are reflected in the high (95% e.e.) and nones and the substitution pattern of the heptafulvenes. This set of
low (42% e.e., 52% e.e.) enantioselectivities of the reactions reactions provides an easy set-up for the generation of a variety of
(Table 1, entries 1, 2 and 8).
polycyclic scaffolds from commercial or readily available starting
The [8+2] and [4+2] cycloadducts are formed through reactions materials. In addition, it was demonstrated that the products from
of a linear dienamine intermediate (Fig. 2c). As the catalyst directs the cycloaddition reactions can undergo simple one-step transform-
the approach of the heptafulvene 3B or 3C through hydrogen ations to give access to other all-carbon polycyclic compounds.
bonding to the cyano group, the 8π component of the heptafulvene
and the 2π component of linear dienamine are placed in an endo-
Data availability
transition state (Fig. 4b, III). This provides a rationale for the absol- X-ray crystallographic data for compounds 4aA, 11, 15 and 16 are
ute configuration of the cycloadducts obtained. For reactions that freely available from the Cambridge Crystallographic Data Centre
take place via a linear dienamine, the nucleophilic double bond of (CCDC 1434123, 1469731, 1457777 and 1470038, respectively).
the dienamine is placed further away from the catalyst compared
Received 25 May 2016; accepted 20 October 2016;
published online 19 December 2016
with that of the cross dienamine. Hydrogen bonding between the
catalyst and the cyano group of 3B and 3C places the heptafulvene
in an optimal spatial orientation towards an endo-selective [8+2]
cycloaddition (Fig. 4b, III), whereas tropone is moved too close to
the catalyst and away from the nucleophilic double bond on hydrogen
bonding to the catalyst (Fig. 4b, IV). These considerations are
reflected in the stereoselectivities of the reactions (Table 1, entries 4–9).
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Acknowledgements
This work was made possible by grants from Aarhus University and Carlsberg
Foundation’s ‘Semper Ardens’ programme. This research was supported by European
Social Fund’s Doctoral Studies and Internationalisation Programme DoRa, which is carried
out by Foundation Archimedes. Our thanks are expressed to L. Næsborg, V. H. Lauritsen
and M. E. Jensen for X-ray analysis.
Author contributions
R.M. and G.P. optimized the reactions. R.M., G.P., J.L. and E.H.I. performed the
experiments. S.J. performed the calculations. R.M. and K.A.J. wrote the manuscript.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to K.A.J.
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reactions catalysed by supramolecular self-assemblies formed from chiral amines Competing financial interests
and poly(alkene glycol)s. Chem. Eur. J. 18, 1055–1059 (2012).
The authors declare no competing financial interests.
6
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