Enantioselective 1,3-Dipolar [6+4] Cycloaddition of Pyrylium Ions and Fulvenes towards Cyclooctanoids

Article abstract of DOI:10.1002/chem.202001369

Organocatalytic enantioselective 1,3-dipolar [6+4] cycloadditions of pyrylium ion intermediates with fulvenes promoted by a chiral primary amine catalyst have been developed to proceed in moderate to good yields and high enantioselectivities. The resultant chiral bicyclo[6.3.0]undecane scaffold containing a transannular bridging ether is densely functionalised providing a rigid scaffold for further manipulations. Computational studies give important insights into the role of the primary amine catalyst. Analysis of the reaction shows that the catalytic reaction proceeds in a step-wise manner and rationalises the stereochemical outcome of the reaction. Several stereoselective complexity-generating transformations, facilitated by the diverse functional groups and transannular bridge, are presented, highlighting the versatility of the core towards a number of the cyclooctanoid natural products.

Full text of DOI:10.1002/chem.202001369

A Journal of
Accepted Article
Title: Enantioselective 1,3-Dipolar [6+4] Cycloaddition of Pyrylium Ions
and Fulvenes towards Cyclooctanoids
Authors: Karl Anker Jørgensen, David McLeod, Alessio Cherubini-Celli,
Nisanhi Sivasothirajah, Christina H. McCulley, and Mette
Louise Christensen
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Chem. Eur. J. 10.1002/chem.202001369
Link to VoR: http://dx.doi.org/10.1002/chem.202001369
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10.1002/chem.202001369
Chemistry - A European Journal
RESEARCH ARTICLE
Enantioselective 1,3-Dipolar [6+4] Cycloaddition of Pyrylium Ions
and Fulvenes towards Cyclooctanoids
David McLeod,[a] Alessio Cherubini-Celli,[a] Nisanhi Sivasothirajah,[a] Christina H. McCulley,[a] Mette
Louise Christensen,[a] and Karl Anker Jørgensen*,[a]
Dedicated to Professor Rolf Huisgen on the occasion of his 100 years birthday
Abstract: Organocatalytic enantioselective 1,3-dipolar [6+4]
cycloadditions of pyrylium ion intermediates with fulvenes promoted
by a chiral primary amine catalyst have been developed to proceed in
moderate to good yields and high enantioselectivities. The resultant
chiral bicyclo[6.3.0]undecane scaffold containing a transannular
bridging ether is densely functionalised providing a rigid scaffold for
further manipulations. Computational studies give important insights
into the role of the primary amine catalyst. Analysis of the reaction
shows that the catalytic reaction proceeds in a step-wise manner and
rationalises the stereochemical outcome of the reaction. Several
stereoselective complexity-generating transformations, facilitated by
the diverse functional groups and transannular bridge, are presented,
highlighting the versatility of the core towards a number of the
cyclooctanoid natural products.
Cycloadditions constitute one of the most powerful and versatile
methods for the synthesis of carbocyclic ring systems.[1] Whereas
the enantioselective construction of five- or six-membered rings
has been made trivial by progress in the catalysis of
cycloadditions—most notably the Diels-Alder reaction[2] and 1,3-
dipolar cycloadditions[3]—eight-membered rings represent a more
Figure 1. Selected cyclooctane containing natural products.
challenging task due to ring-strain and entropic reasons.[4,5] While
The 1,3-dipolar [6+4] cycloaddition of a pyrylium ylide precursor
with a fulvene (e.g. 1 and 2, Scheme 1) provides a concise
approach to the 5-8 fused cyclooctane framework 3, while also
embedding several attractive reactive functional groups.[11,12] The
products can thus be subjected to stereoselective elaboration to
afford a diverse array of chiral structures in just one or two steps
the cyclooctanoid terpenes represent an important class of
structurally diverse natural products exhibiting a wide range of
biological activity (Figure 1)—the most recognisable member
being Taxol—total synthesis of cyclooctane scaffolds encounters
difficulty as a result of the dearth of general synthetic methods.
Higher-order cycloadditions have proven to be an attractive
concept for strategic disconnections to the rapid and efficient
synthesis of cyclooctane scaffolds.[6] These approaches have
typically relied on transition metal-complexed cycloheptatrienes
reacting with 2π-components,[6,7] Ni0- or photochemically-
promoted [4+4] cycloadditions,[6,8] three component transition
metal-catalysed cycloadditions,[8] and the (4+3) cycloaddition of
cyclic oxyallyl cations with 4π-components (dienes). Despite the
manifest utility of these higher-order cycloadditions in the
construction of cyclooctane ring systems, asymmetric examples
have to date been mainly limited to diastereoselective
variants[9]—in general, few catalytic enantioselective methods for
the preparation of cyclooctanes exist.[10]
(vide infra). Historically, chiral activation of pyrylium ions has
proven difficult; however, Jacobsen et al. have recently described
an organocatalytic dual catalyst system for (5+2)
cycloadditions.[13] Herein, we disclose the development of
enantioselective 1,3-dipolar [6+4] cycloadditions to construct the
bicyclo[6.3.0]undecane scaffold and elaboration of the chiral
cycloadducts obtained, in combination with computational studies
in accordance with Huisgen’s definition: “the concept of
cycloaddition gives a formal description of an overall reaction but
not a mechanistic interpretation.”[3]
[a]
Dr. D. McLeod, A. Cherubini-Celli, N. Sivasothirajah, Dr. C. H.
McCulley, M. L. Christensen, Prof. Dr. K. A. Jørgensen
Department of Chemistry, Aarhus University
Langelandsgade 140, 8000 Aarhus C (Denmark)
E-mail: kaj@chem.au.dk
Scheme 1. Enantioselective 1,3-dipolar [6+4] cycloadditions of pyrylium ions
and fulvenes.
The data supporting the findings of this study are available in the
article and its Supporting Information.
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10.1002/chem.202001369
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Racemic benzyloxypyranone 1a was initially chosen to explore
the feasibility of the reaction. When the catalyst system developed
for the (5+2) cycloaddition was examined,[13] the desired reaction
proceeds in the presence of a variety of bifunctional primary
aminothiourea catalysts, affording the 1,3-dipolar [6+4]
cycloadduct 5 with moderate enantioselectivity, but in poor yield
(Table 1, entry 1).
in chlorinated solvents. While catalyst 6 furnished cycloadduct 5
with reasonable enantioselectivity, a significant drop in its ability
to effectively transfer chirality was observed on switching from
6,6-diphenylfulvene 2a to 6,6-dimethylfulvene 2c as substrate
(88% ee vs. 40% ee). Investigation of numerous primary amine
catalysts (see Tables in Supporting Information) identified 7 as a
catalyst giving more robust enantioselectivity than 6. An
expansive screening of solvents and acid additives led to the
identification of chlorobenzene and 3,4,5-trifluorobenzoic acid
(the conjugate acid of the leaving group) as optimal (entries 7-13).
Whereas none of the acid additives tested had any effect on the
enantioselectivity of the reaction, they did display a noticeable
influence on both the reaction rate and the final yield of
cycloadduct 5. Finally, independent optimisation of all reaction
additives led to conditions suitable for exploring the reaction
scope (entry 13). For the assignment of the absolute configuration
of 5 see Supporting Information.
Table 1. Summary of reaction optimisation for the 1,3-dipolar [6+4]
cycloaddition of pyranones 1a-c with 6,6-diphenylfulvene 2a.
When these conditions were applied to the reaction of pyranones
1 and a variety of fulvenes 2, a range of 5-8 fused cyclooctane
products were prepared in reasonable yields and good
enantioselectivities (Figure 2).
Entry[a]
Cat.
Solvent
Additive
Conv.[b]
[%]
Yield[b]
[%]
ee[c]
[%]
1
Figure 2. Scope of the organocatalytic 1,3-dipolar [6+4] cycloaddition of
pyranones 1 with fulvenes 2.
1a
1b
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
6
6
6
6
6
6
-
1
2
PhMe
PhMe
AcOH
AcOH
BzOH
BzOH
BzOH
-
<20%
32
nd
nd
nd
nd
5
60
60
85
88
63
88
nd
94
94
94
92
92
93
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
16
4
29
5[d]
6
7
24
13
0
7
BzOH
BzOH
BzOH
19
7
7
7
7
7
7
8
67
8
9
1,2-
DCE
20
11
17
33
42
60
10[e]
11[e,f]
12[e,f]
13[e,f,g]
1,2-
DCE
3,4,5-
F3BzOH
34
1,2-
DCE
3,4,5-
F3BzOH
73
PhCl
3,4,5-
F3BzOH
82
[a] Reactions were performed with pyranones 1 (0.2 mmol) and fulvenes 2 (0.6
mmol) at 0.25 M. [b] Determined by 1H NMR analysis using methyl 4-methyl-3-
nitrobenzoate as internal standard. [c] Determined by UPCC using commercial
columns with chiral stationary phases. [d] Reactions were run at 35 °C.
PhCl
3,4,5-
F3BzOH
100
[a] Reactions were performed with pyranones 1a-c (0.1 mmol) and 6,6-
diphenylfulvene 2a (0.11 mmol) at 0.25 M for 24 h. [b] Determined by 1H NMR
analysis using tetraethylsilane as internal standard. [c] Determined by UPCC
using commercial columns with chiral stationary phases. [d] Catalyst 8 was
omitted. [e] Two equivalence of 2a was used. [f] Catalyst 7 (30 mol%) was used.
[g] Catalyst 8 (10 mol%) was used. 3,4,5-F3Bz = 3,4,5-trifluorobenzoyl, UPCC
= ultra performance convergence chromatography.
Simple 6,6-di-substituted fulvenes perform well in the reaction
with 85-91% ee for cycloadducts 5, 9-11 (Figure 2). Cyclic
aliphatic substitution of fulvenes, affording the spirocyclic
products 12-14 proceed also with good enantioselectivity, but
lower yield. Although the yields are in the lower range, spirocyclic
compounds of this nature, as well as the cycloadducts 5, 9-11,
are not easily obtained by other methods. While yields appear low
for some entries, similar trends have been observed for other
catalytic enantioselective cycloadditions involving pyrylium
ions.[13] A mono-substituted fulvene also underwent a highly
Exploration of various substituents on the benzoate leaving group
in 1 led to enhancement of reactivity with no change in the
enantioselectivity observed in toluene as the solvent (Table 1,
entries 1,2). An unexpected, but significant solvent effect resulted
in significant improvement of both reactivity and enantioselectivity
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10.1002/chem.202001369
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enantioselective reaction with formation of cycloadduct 15 in 91%
ee and good diastereoselectivity. The low yields obtained are
partially attributable to decomposition of the starting pyranone,
which is unstable under the reaction conditions and was never
recovered, and to a parasitic 2:1 cycloadduct. Excess fulvene was
able to be recovered. Unfortunately, despite many attempts,
multiple pyranones having alkyl substituents at R2 required mild
heating to proceed at reasonable reaction rates and gave
complex reaction mixtures (dimerisation, 2:1 cycloadducts, etc.).
The preparation of pyranones with R1-substituents proved
challenging by existing methods and were not explored. In
screening mono-substituted fulvenes, other than the one leading
to cycloadduct 15, the diastereoselectivity was difficult to control
(vide infra). Importantly, unlike the base-promoted racemic
reactions,[12a] the catalysed reactions exhibit exceptional
regioselectivity in the cycloaddition.
Figure 3. 1,3-Dipolar [6+4] cycloaddition transition state structures of pyrylium
ion 4 reacting with 6,6-diphenylfulvene 2a. Predicted activation barriers are
shown below each structure in kcal/mol from B3LYP-D3/6-311+G(2d,p)
calculations. Selected distances are shown in Å.
When the 1,3-dipolar [6+4] cycloaddition of pyrylium ion 4 and
6,6-diphenylfulvene 2a is performed with catalyst 7 the reaction
pathways for both cycloadduct 5 and 5R proceed through a
stepwise mechanism (Figure 4 and 5). The activation barrier for
the major product cycloadduct 5 was calculated to be 13.9
kcal/mol, 9.3 kcal/mol lower in energy than that of the minor
product (see Supporting Information for reaction coordinate for
5R). This appears to be a consequence of the proximity of the
catalyst’s bulk relative to the fulvene.
In an attempt to elucidate the basis for the high regio- and
enantioselectivity
observed
for
the
organocatalytic
enantioselective 1,3-dipolar [6+4] cycloaddition of pyrylium
precursors 1 with fulvenes 2 in the presence of catalyst 7
computational investigations were initiated. Our efforts began with
pyrylium cation 4 (Scheme 1) reacting with 6,6-diphenylfulvene
2a, in the absence of an organocatalyst, in order to understand
the fundamental reaction mechanism for the 1,3-dipolar [6+4]
cycloaddition. This is followed by analysis of the role of catalyst 7
in the enantioselective reaction of 4 with different fulvenes to
describe the regio-, diastereo-, and enantioselectivity.
Computations were performed using Gaussian09,[14] at the
B3LYP/6-31+G(d),[15,16,17] and B3LYP-D3/6-311+G(2d,p)[18] levels
of theory in CH2Cl2 using SMD continuum solvent model.[19] All
minima and transition state structures (TSSs) were confirmed by
frequency analysis, and intrinsic reaction coordinate (IRC)
calculations were performed on the transition state structures to
confirm the corresponding minima.[20] All energies shown are free
energies at room temperature unless otherwise labelled. Three-
dimensional molecular images were generated with CylView.[21]
For the 1,3-dipolar [6+4] cycloaddition of pyrylium ion 4 and 6,6-
diphenylfulvene 2a in the absence of the organocatalysts, two
regioisomeric transition states, TSS 5R (R refer to the minor
regioisomer) and TSS 5, were calculated and these were
specifically examined along with their corresponding minima
(Figure 3). Interestingly, the pathway that proceeds through TSS
5R is a highly asynchronous concerted mechanism and produces
the minor cycloadduct, synthetically observed in the non-
catalysed reaction. In contrast, formation of the major cycloadduct
proceeds through a stepwise pathway with the initial, rate-
determining step being TSS 5. This stepwise pathway was found
to have an activation barrier 11.8 kcal/mol lower than the
concerted pathway. In addition, cycloadduct 5 has a lower relative
free energy than cycloadduct 5R (see Figures in Supporting
Information).
Figure 4. The transition state structures for the 1,3-dipolar [6+4] cycloaddition
structures of 4 and 6,6-diphenylfulvene 2a catalysed by 7. Predicted activation
barriers are shown below each structure in kcal/mol from B3LYP-D3/6-
311+G(2d,p) calculations. Selected distances are shown in Å.
It also appears from the reaction pathway in Figure 5 that the ring-
closing step has the highest transition state energy, compared to
the first carbon-carbon bond forming step—but is lower in
activation barrier. In the first step that proceeds through TSS 5,
the catalyst is positioned in an almost 180o dihedral angle from
the two phenyl groups of the fulvene, unlike TSS 5R (Figure 4 and
SI). This positioning of the catalyst also rationalises the
cycloadduct 5 being 4 kcal/mol lower in energy than the
cycloadduct 5R. The lack of diastereoselectivity observed in the
case of mono-substituted fulvenes, can be rationalised by the
absence of any functionality on the catalysed pyrylium ion 4 that
is able to sterically shield the incoming fulvene in such a way as
to determine a specific reaction path, when the exo-cyclic olefin is
mono-substituted at the exo-position.
When the activation barrier for the major product, cycloadduct 5,
is compared with that of its enantiomer, 5-enant, TSS 5 was
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10.1002/chem.202001369
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calculated to be 1.2 kcal/mol lower in energy than TSS 5-enant.
Determination of the reaction pathway for 5-enant showed that
the barrier for ring closure is almost equivalent to that of the
barrier of reverting to reactants (2.9 and 3.0 kcal/mol). These
observations would seem to rationalise the lack of significant
formation of the enantiomeric cycloadduct.
be 10.6 kcal/mol lower in energy than TSS 9R (observed minor
cycloadduct, see Supporting Information). However, it seems that
the change from phenyl to methyl does not change the activation
barriers significantly, with TSS 9 being 1.2 kcal/mol lower than
TSS 5 and TSS 9R being 1.2 kcal/mol higher than TSS 5R. This
observation seems to confirm that the proximity of the
substituents on the fulvene to the catalyst has a greater effect on
the activation energy than the identity of the substituents.
Calculations were next performed to determine the effect of
substituents R1 and R2 on the pyrylium cation 4 (see Figure 2 for
the position of R1- and R2 substituents) reacting with 6,6-
diphenylfulvene 2a catalysed by 7 on the reaction mechanism and
activation barrier. TSS 5 was optimised with R1 and R2 as H,
methyl, ethyl, isopropyl and phenyl groups to compare with the
results in Table S6 in Supporting Information. Not unexpectedly,
when R1, R2 ≠ H the activation barrier is higher than when only
one position is substituted; however, these activation energies do
not necessarily increase with size of substituent. A consistent
trend observed is that barriers for substituents at R1 are reliably
lower than R2, by as much as 4.7 kcal/mol for the isopropyl
substituent. It seems likely that this decrease is due to the
positioning of the R2 substituent ortho to the carbonyl, placing it
close to catalyst 7. This hypothesis would rationalise the higher
activation energies calculated for the substituents at R2 compared
with R1. It also explains the jump in activation energy difference
when the substituent changes from ethyl to isopropyl (0.6 to 4.7
kcal/mol) as the bulk of isopropyl does not allow for any
conformational adjustment of the substituent to avoid interaction
with the catalyst.
Figure 6. 1,3-Dipolar [6+4] cycloaddition transition state structures of pyrylium
ion 4 with 6,6-dimethylfulvene 2b catalysed by 7. Predicted activation barriers
are shown below each structure in kcal/mol from B3LYP-D3/6-311G+(2d,p)
calculations. Selected distances are shown in Å.
Importantly, the prepared cycloadducts 5-15 are densely
functionalised for structural elaboration. The cycloadduct 5 was
synthesised in 57% yield and 92% ee on a 1 mmol scale from 1c
using the conditions described in Figure 2 as a molecular platform
to demonstrate the synthetic potential of the developed
organocatalytic enantioselective 1,3-dipolar [6+4] cycloaddition.
Typically, reactions on cyclooctanes are complicated by their
propensity to undergo transannular reactions and, perhaps more
importantly, compared to smaller carbocycles, cyclooctane
reaction stereoselectivity can be difficult to predict and control,
due to the conformational flexibility of eight-membered rings.[22]
However, in the current case, subsequent transformations are
completely controlled by the rigid conformation enforced by the
bridging ether. Indeed, the products of the Corey-Chaykovsky
(16),[23] conjugate addition (17) and Diels-Alder (22)[24] reactions
were generated with high diastereoselectivity. Reduction of the
α,β-unsaturated ketone with NiCl2•6H2O/NaBH4 proceeds to give
alcohol 24 as a single diastereomer, originating from the hydride
approaching from the exo-face; concomitant reduction of the
fulvene disubstituted alkene is also observed as a minor, but
separable product (<5%).[25] Luche reduction of 5 also proceeds
with complete diastereoselectivity to give allylic alcohol 23. The
cycloadduct 5 can also be subjected to hydrogenation to generate
the saturated ketone 18, which can then be elaborated to the
tosylhydrazone 20 or hydrazone 21 upon condensation.
Unsurprisingly, direct addition of a Grignard reagent to the ketone
of 18 also occurs diastereoselectively to the least-hindered face
to give the tertiary alcohol 19. Hydrogenation of 10, followed by
NaBH4 reduction gives the saturated alcohol 27 which was then
subjected to reductive cleavage[26] of the transannular ether to
cleanly liberate the embedded cyclooctane carbocycle 28. Thus,
the ether bridge enforces conformational rigidity allowing
efficacious transfer of stereoselectivity in subsequent
transformations, and importantly, this bridge can then be removed
Figure 5. Reaction coordinate diagram for the reaction of pyrylium ion 4 and
6,6-diphenylfulvene 2a catalysed by 7 generating cycloadduct 5. Relative free
energies in kcal/mol from B3LYP-D3/6-311+G(2d,p) calculations are shown.
To determine the effect of the substituents on the fulvene on the
reaction mechanism, the reaction of pyrylium ion 4 and 6,6-
dimethylfulvene 2b (R3,4 = Me) with catalyst 7 was examined
(Figure 6). As observed for fulvene 2a (R3,4 = Ph), the reaction of
2b is also stepwise for both regioisomers. In this case, TSS 9,
which corresponds to the major cycloadduct, was determined to
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10.1002/chem.202001369
Chemistry - A European Journal
RESEARCH ARTICLE
by reductive cleavage to furnish the open bicyclo[6.3.0]undecane
core.
25867) from The Villum Foundation. A.C.C. thanks Università
degli Studi di Padova for financial support.
Keywords: 1,3-dipolar [6+4] cycloaddition • organocatalysis •
cyclooctane scaffolds • mechanism • calculations
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Scheme 2. Structural elaboration of cycloadducts. Reaction conditions: a) 2a (3
equiv.), 7 (30 mol%), 8 (10 mol%), 3,4,5-F3BzOH (20 mol%), PhCl, rt. b)
Me3SO+I-, NaH, DMSO, rt. c) Me2CuLi, Et2O, -20 °C. d) 10% Pd/C, H2 (1 atm),
EtOAc, rt. e) Cyclopentadiene, ZnCl2, PhH, rt. f) NaBH4, CeCl3•7H2O, MeOH,
0 °C. g) NiCl2•6H2O, NaBH4, THF, 0 °C. h) MeMgBr, Et2O, 0 °C. i) TsNHNH2,
THF, H2O, rt. j) 4-Bromo-2-nitrophenylhydrazine hydrochloride, EtOH, rt. k) 4-
Bromobenzoyl chloride, DMAP, pyr, CH2Cl2, rt. l) NaBH4, MeOH, 0 °C. m) Li0,
EtNH2, rt. Ts = toluene-4-sulphonyl, DMAP = 4-dimethylaminopyridine, pyr =
pyridine.
In summary, the first enantioselective 1,3-dipolar [6+4]
cycloaddition of pyrylium ion intermediates with fulvenes has
been developed applying primary-amine organocatalysis. The
methodology provides rapid and stereoselective access to
cyclooctane rings, for which few enantioselective catalytic routes
exist. The scope of the reaction allows for various substitution
patterns forming chiral bicyclo[6.3.0]undecane scaffolds that are
densely functionalised and embedded with a transannular ether
bridge which enforces conformational rigidity. Computational
studies of both the uncatalysed and catalysed reactions show that
the reaction proceeds in a step-wise manner and accounts for the
regio- and stereochemical outcome in nice agreement with the
experimental results. A large diversity of transformations have
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been
performed,
demonstrating
an
exceptional
diastereoselectivity, expanding chemical space and allowing
efficient procedures for obtaining complex molecular scaffolds.
Acknowledgements
This work was made possible by generous support from Villum
Foundation, Carlsberg Foundation “Semper Ardens” and Aarhus
University. K.A.J. was funded by a Villum Investigator grant (no.
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10.1002/chem.202001369
Chemistry - A European Journal
RESEARCH ARTICLE
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10.1002/chem.202001369
Chemistry - A European Journal
RESEARCH ARTICLE
Entry for the Table of Contents
RESEARCH ARTICLE
1,3
+ 6+4 =
D. McLeod, A. Cherubini-Celli, N. Sivasothirajah, C. H. McCulley,
M. L. Christensen, and K. A. Jørgensen*
Cyclooctanes.
Organocatalysis
brings
the
Page No. – Page No.
pyrylium ion and
fulvenes
Enantioselective 1,3-Dipolar [6+4] Cycloaddition of Pyrylium
Ions and Fulvenes towards Cyclooctanoids
together in an
enantioselective
manner
affording
densely
functionalised
cyclooctanoid
scaffolds.
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