Organocatalytic Formation of Chiral Trisubstituted Allenes and Chiral Furan Derivatives

Article abstract of DOI:10.1002/anie.201806238

A novel reaction that provides chiral allenes by amino catalytic activation of either aldehydes or α,β-unsaturated aldehydes for reaction with alkynyl-substituted enones is presented. The reaction forms a variety of trisubstituted allenes in high yields a

Full text of DOI:10.1002/anie.201806238

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Accepted Article
Title: Organocatalytic Formation of Chiral Trisubstituted Allenes and
Chiral Furan Derivatives
Authors: Karl Anker Jørgensen, Pernille Hartveit Poulsen, Yang Li,
Vibeke Henriette Lauridsen, Danny Kaare Bech Jørgensen,
Teresa Ann Palazzo, and Marta Meazza
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806238
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10.1002/anie.201806238
Angewandte Chemie International Edition
COMMUNICATION
Organocatalytic Formation of Chiral Trisubstituted Allenes and
Chiral Furan Derivatives
Pernille H. Poulsen, Yang Li, Vibeke H. Lauridsen, Danny K. B. Jørgensen, Teresa A. Palazzo, Marta
Meazza, and Karl Anker Jørgensen*
Abstract: A novel reaction concept providing chiral allenes by amino
catalytic activation of aldehydes or -unsaturated aldehydes react-
ing with alkynyl-substituted enones is presented. The reaction forms
a variety of trisubstituted allenes in high yields and excellent stereose-
lectivities. The utility of the reaction concept is demonstrated by the
synthesis of chiral furan derivatives in high yields and stereoselectivi-
ties.
numerous natural products and pharmaceuticals.[15] Besides
forming a challenging axially chiral trisubstituted allenic moiety,
two additional point chiral centers are also formed.
The present strategy is based on the reaction of aldehydes or
-unsaturated aldehydes, via enamine and dienamine interme-
diates, respectively, with alkynyl-substituted enones (Scheme 1).
Furthermore, the chiral allene products, obtained from the
enamine-mediated reactions, are converted into functionalized,
chiral furan derivatives.
Allenes have attracted interest since their discovery by van’t Hoff
in 1875.[1] Their unique chemical structure is found in many bio-
active natural products and pharmaceuticals,[2] and is of im-
portance in organic synthesis and materials science as highly ver-
satile intermediates.[3] A commonly highlighted characteristics is
their potential to exhibit axial chirality, when appropriately substi-
tuted, as a result of the orthogonal relationship between the cu-
mulated -systems.
The development of asymmetric catalytic methods for the syn-
thesis of chiral allenes has been an area of increased focus.[4]
Traditional approaches rely on chirality transfer from enantioen-
riched propargylic alcohols or amines,[5] kinetic resolution of pre-
formed racemic allenes[6] and the use of chiral ylide reagents in
olefination of ketenes.[7] Contemporary endeavors have focused
on the development of asymmetric catalytic strategies, particu-
larly via metal-catalyzed reactions. Various metals, e.g. Pd, Cu,
Rh, and Ni have been utilized in these asymmetric methodolo-
gies.[8] In comparison, organocatalytic approaches are underex-
plored, and a limited number of methodologies have been de-
vised.[9] Marouka et al. presented a phase-transfer catalyzed al-
leno-Mannich reaction,[10] List et al. reported an enantioselective
disulfonimide-catalyzed alkynylogous Mukaiyama aldol reac-
tion,[11] and Sun et al. have disclosed an ion-pair catalyzed reac-
tion of propargylic alcohols.[12] However, several of these methods
are often limited to the formation of disubstituted allenes with
higher substitution patterns largely being limited to allenoates.[13]
Thus, the direct construction of chiral trisubstituted allenes from
achiral or racemic starting materials via catalytic asymmetric strat-
egies remains challenging. In the light of the limitations of the ex-
isting synthetic methodologies of chiral trisubstituted allenes and
their attractive synthetic utility as intermediates in e.g. cycloisom-
erization reactions[3b,3f,14] in the construction of multi-substituted
furans, we present a novel strategy for their synthesis. The syn-
thetic utility of the chiral allenes is demonstrated by transforming
them into chiral furan derivatives, which are important scaffolds in
Scheme 1. Reaction concept for the formation of chiral trisubstituted allenes by
the organocatalytic reaction of aldehydes or -unsaturated aldehydes with al-
kynyl-substituted enones.
We envisioned that it might be possible to generate chiral
trisubstituted allenes by applying secondary amine organocataly-
sis. In Scheme 2, this strategy is based on the formation of an
enamine intermediate, formed by reaction of an aldehyde with the
diphenylprolinol trimethylsilyl ether catalyst.[16] The nucleophilic
chiral enamine intermediate attacks the -alkynyl-substituted
enone, thereby generating an enol intermediate, leaving the al-
kyne moiety untouched. In this step, a Brønsted acid is envisioned
to be important for (i) stabilizing the enol intermediate, and (ii)
providing the proton to be delivered in a stereoselective manner
from the enol to the alkynyl moiety forming the trisubstituted allene.
The stereoselective formation of the allene might also be influ-
enced by the two stereocenters generated in the first step of the
reaction.
Scheme 2. Envisioned reaction design for the generation of chiral trisubstituted
allenes by the application of an organocatalytic strategy.
[*]
Dr. P. H. Poulsen, Dr. Y. Li, Dr. V. H. Lauridsen, D. K. B. Jørgensen,
Dr. T. A. Palazzo, Dr. M. Meazza, Prof. Dr. K. A. Jørgensen
Department of Chemistry, Aarhus University
8000 DK-Aarhus C (Denmark)
Optimization studies of the organocatalytic formation of the
chiral trisubstituted allenes were initiated by reacting hydrocin-
namaldehyde 1a with the -alkynyl-,-enone 2a applying 20
mol% of the diphenylprolinol trimethylsilyl ether catalyst 3a in the
presence 20 mol% of benzoic acid in toluene at room temperature
(Table 1, entry 1). We were pleased to observe that 80% conver-
sion to the allene product 4a was achieved. Although 2a remained
E-mail: kaj@chem.au.dk
Supporting Information for this article is given via a link at the end of
the document.
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10.1002/anie.201806238
Angewandte Chemie International Edition
COMMUNICATION
present in the reaction mixture, the two equivalents of 1a were
fully consumed. The unproductive consumption of 1a was at-
tributed to homo-aldol condensation of the aldehyde also cata-
lyzed by 3a. It is notable that <5% of allene 4a was obtained in
absence of benzoic acid. In order to improve conversion of 2a to
4a several reaction parameters were varied. Alternative Brønsted
acid additives with varied pKa values were tested, unfortunately,
without any improvement of the conversion of 2a (Table 1, entries
2,3). Catalyst 3b was unable to promote the reaction and no for-
mation of product 4a was observed (Table 1, entry 4). We also
attempted to facilitate the conversion of 2a by applying larger ex-
cess of 1a and it was found that 3 equiv. of the aldehyde were
optimal (Table 1, entries 5,6). In contrast, reversing the stoichiom-
etry of 1a and 2a (1:2 or 1:3) did not improve the outcome of the
reaction (Table 1, entries 7,8). By adding the aldehyde in two por-
tions (2 equiv. from the beginning, followed by 1 equiv. 5 h later)
the conversion was improved from 87% to 93% (Table 1, entry 5
vs. entry 9). A screening using hexanal as the aldehyde showed
that the use of more polar solvents, such as CHCl3 and CH2Cl2,
resulted in lower diastereomeric ratios. Remarkably, no conver-
sion was observed when performing the reaction in THF.[17] It was
found in the screening that 3 equiv. of aromatic aldehyde 1a was
optimal, while for aliphatic aldehydes 2 equiv. was applied (vide
infra).
Aminocatalysis combined with Brønsted acid activation al-
lowed us to develop a protocol for the direct synthesis of trisubsti-
tuted chiral allenes. The generality of the reaction was explored
by reacting a series of aldehydes 1a-g with -alkynyl-,-enone
2a and the results are outlined in Table 2. Performing the reaction
with hydrocinnamaldehydes bearing electron-neutral, electron-
donating, and electron-withdrawing groups on the aromatic ring
afforded the allenes 4a-c in high yields and excellent stereocon-
trol (Table 2, entries 1-3). Homologated aldehyde 1d also reacted
smoothly to provide allene 4d in high yield and excellent enantio-
meric excess, although a small amount of a second diastereoiso-
mer was observed (Table 2, entry 4). Reactions of both linear and
cyclic aliphatic aldehydes proceeded with the same excellent en-
antioselectivity (96-99% ee) and afforded the allene adducts 4e-
g in 87-95% yield (Table 2, entries 5-7).
Table 2. Asymmetric catalytic synthesis of chiral trisubstituted allenes from
aldehydes. Scope of aldehydes 1.[a]
entry
R1
yield
(%)
dr[b,c]
ee
Table 1. Asymmetric catalytic synthesis of chiral trisubstituted allenes.
Screening results.[a]
(%)[d]
1[e]
2[e]
3[e]
4[e]
5
PhCH2 (1a)
4a-95
4b-83
4c-77
4d-82
4e-87
4f-95
4g-95
>20:1 (>20:1)
>20:1 (>20:1)
>20:1 (>20:1)
14:1 (12:1)
>99
>99
>99
99
p-MeO-C6H4-CH2 (1b)
p-MeO2C-C6H4-CH2 (1c)
PhCH2CH2 (1d)
Me (1e)
15:1 (10:1)
96
6
n-Bu (1f)
>20:1 (16:1)
>20:1 (12:1)
99
7
cyclohexyl-CH2 (1g)
98
[a] Reactions performed with 1 (0.2 mmol) and 2a (0.1 mmol) in toluene (0.4
mL). [b] Diastereomeric ratio determined by 1H NMR of the crude reaction
mixture. [c] Ratio in parentheses refers to the diastereomeric ratio deter-
mined by 1H NMR of the isolated product. [d] Enantiomeric excess deter-
mined by UPC2 (see Supporting Information). [e] Reactions performed with
0.3 mmol of 1 added in two portions (0.2 mmol from the beginning followed
by 0.1 mmol 5 h later). BA: Benzoic acid.
conv.
entry
1a:2a
3
acid
(%)[b]
80
1
2
3
4
5
6
7
8
9c
2:1
2:1
2:1
2:1
3:1
4:1
1:2
1:3
3:1
3a
3a
3a
3b
3a
3a
3a
3a
3a
BA
CH3CO2H
o-NBA
BA
78
72
nr
BA
87
88
83
83
93
With the positive results obtained for the variation of alde-
hydes 1, attention was turned to the reactivity of different -al-
kynyl-,-enones 2. We set out to vary all three substituents of
the -alkynyl-,-enone and commenced by reacting 2b-d carry-
ing aromatic and aliphatic groups, at the alkene moiety with hex-
anal 1f (Table 3, entries 1-3). Satisfyingly, all three -alkynyl-,-
enones were tolerated under the optimized reaction conditions
and the corresponding chiral allenes 4h-j were obtained in high
yields and excellent enantioselectivities. Excellent results were
obtained with -alkynyl-,-enones 2e-h having electronically
varied alkynyl aromatic rings providing allenes 4k-n in 85-99%
yield (Table 3, entries 4-7). In the case of strong electron-with-
drawing substituents, such as trifluoromethyl and nitro groups, the
reaction times were reduced to 4 and 2 h, respectively. When an
BA
BA
BA
BA
[a] Reactions performed on a 0.05 mmol scale. [b] Determined by 1H NMR
of the crude reaction mixture at full consumption of 1a. [c] Aldehyde 1a was
added in two portions (2 equiv. from the beginning followed by 1 equiv. 5 h
later). BA: Benzoic acid; o-NBA: ortho-Nitrobenzoic acid.
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10.1002/anie.201806238
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COMMUNICATION
aliphatic substituent is introduced, the allene 4o is formed as a
single stereoisomer, however, with decreased yield (40%, Table
3, entry 8). Replacement of the methyl at the ketone with a phenyl
substituent also afforded allene 4p with similar results (entry 9).
despite the increased distance between the catalyst and the re-
active center of the dienamines. Allene 6a was isolated as a single
stereoisomer in 41% yield after in-situ Wittig reaction. Similar re-
sults were obtained for -unsaturated aldehydes fused with both
electron-rich, electron-poor, and multi-substituted aromatic sys-
tems providing allenes 6b-d with excellent stereoselectivities and
moderate yields. We were pleased to observe that a dihydrochro-
mone derived -unsaturated aldehyde and a fused heterocyclic
furan reacted smoothly providing chiral allenes 6e,f. The -un-
saturated aldehydes obtained by the organocatalytic reactions
were difficult to purify, therefore a Wittig transformation was per-
formed affording 6a-f to ease purification.
Table 3. Asymmetric catalytic synthesis of chiral trisubstituted allenes from
aldehydes. Scope of -alkynyl--enones 2.[a]
Scheme 3. Asymmetric catalytic synthesis of chiral trisubstituted allenes from
-unsaturated aldehydes. Scope of -unsaturated aldehydes 5.[a]
entry
1
R2, R3, R4
yield (%)
dr[b,c]
ee (%)[d]
p-Me-C6H4, Ph, Me
(2b)
4h-88
>20:1 (>20:1)
>99
2
p-Cl-C6H4, Ph, Me
(2c)
4i-94
16:1 (11:1)
>99
3
Me, Ph, Me (2d)
4j-85
14:1 (7:1)
84
98
4[e]
Ph, p-Me-C6H4, Me
(2e)
4k-99
>20:1 (16:1)
5
Ph, p-Br-C6H4, Me
(2f)
4l-85
>20:1 (>20:1)
>20:1 (8:1)
16:1 (4:1)
99
6[f]
Ph, p-CF3-C6H4, Me
(2g)
4m-92
4n-91
>99
>99
7[g]
Ph, p-NO2-C6H4, Me
(2h)
8[e,h]
9[e,h]
Ph, n-Bu, Me (2i)
Ph, Ph, Ph (2j)
4o-40
4p-80
>20:1 (12:1)
16:1 (12:1)
>99
96
[a] Reactions performed with 1f (0.2 mmol) and 2 (0.1 mmol) in toluene (0.4
mL). [b] Diastereomeric ratio was determined by 1H NMR of the crude reac-
tion mixture. [c] Ratio in parentheses refers to the diastereomeric ratio de-
termined by 1H NMR of the isolated product. [d] Enantiomeric excess deter-
mined by UPC2 (see Supporting Information). [e] Reactions performed with
0.3 mmol of 1f added in two portions (0.2 mmol from the beginning followed
by 0.1 mmol 5 h later). [f] Reaction time 4 h. [g] Reaction time 2 h. [h] Reac-
tion time 30 h. BA: Benzoic acid.
[a] Reactions performed with 5 (0.2 mmol) and 2a (0.1 mmol) in toluene (0.4
mL) at rt. The diastereomeric ratio determined by 1H NMR of the isolated prod-
ucts. Enantiomeric excess determined by UPC2 (see Supporting Information).
BA: Benzoic acid.
Encouraged by the successful synthesis of chiral trisubsti-
tuted allenes bearing a range of substituents in a highly stereose-
lective fashion, we decided to explore the possibility of applying
the methodology to -unsaturated aldehydes. -Unsaturated
aldehydes 5 can condense with organocatalyst 3a and generate
reactive dienamine intermediates[18] which react as nucleophiles
with the -alkynyl-,-enone 2a. A challenge of applying diena-
mines is that they contain an additional nucleophilic center. Thus,
the reaction could potentially take place at both the - and -car-
bon atoms yielding two regioisomeric products.
We initiated our investigations by reacting the cyclic -un-
saturated aldehyde 5a with -alkynyl-,-enone 2a (Scheme 3).
We were pleased to find that only a single regioisomeric product
6a was formed, which corresponds to nucleophilic attack of the -
carbon of the -unsaturated aldehyde at the alkene moiety of
2a. The excellent stereocontrol found in the reactions of alde-
hydes was maintained for this class of -unsaturated aldehydes,
Additionally, we have demonstrated that the chiral trisubsti-
tuted allenes, obtained via enamine intermediates, can be used
for the synthesis of chiral furan derivatives. Scheme 4 shows the
results for the one-pot transformation of the allenes 4 into chiral
furan derivatives 7 catalyzed by a combination of AgOTf (10
mol%) and Ph3PAuCl (10 mol%). The functionalized furans were
obtained in high yields and excellent stereoselectivities.
The absolute configuration of allenes 4 obtained by the ste-
reoselective reaction of the aldehydes 1 has been assigned by X-
ray analysis of furan derivative 7b combined with CD (both exper-
imentally and computationally).[17] For proposed assignment of mi-
nor diastereoisomer (in select cases), see Supporting Information.
Scheme 4. Au/Ag-Catalyzed transformation of chiral trisubstituted allene inter-
mediates into chiral furan derivatives 7.[a]
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Keywords: asymmetric catalysis • chiral allenes • chiral furans •
organocatalysis
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at rt for 24 h. The crude reaction mixture was flushed with argon, and Ph3PAuCl
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[4]
[5]
In an attempt to obtain crystals suitable for X-ray analysis of
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Scheme 5. Allene 6b’ was isolated[19] and reacted with 1,3-pro-
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In conclusion, a novel reaction concept affording chiral trisub-
stituted allenes via aminocatalytic activation of aldehydes or ,-
unsaturated aldehydes has been demonstrated. The methodol-
ogy allows for formation of axially chiral trisubstituted allenes in
high yields and excellent stereoselectivities. The utility of this pro-
cedure has been demonstrated via one-pot synthesis of densely
functionalized chiral furan derivatives maintaining the high stere-
oselectivities. In addition, the formation of a complex tetracyclic
compound has been demonstrated.
Acknowledgements
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This work was made possible by generous support from the Carls-
berg Foundations Semper Aude, FNU, Aarhus University and
DNRS. YL thanks the Chinese Scholarship Foundation for a PhD
fellowship. Thanks are expressed to Professor Daniel Otzen for
assistance with the CD spectra.
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[19] Aldehyde 6’ was difficult to purify via FC and was isolated with other side
products. This mixture was used directly in the transformation. The re-
ported yield is the overall yield for two steps.
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Text for Table of Contents
Pernille H. Poulsen, Yang Li, Vibeke H.
Lauridsen, Danny K. B. Jørgensen, Te-
resa A. Palazzo, Marta Meazza, Karl
Anker Jørgensen*
Page No. – Page No.
Organocatalytic formation of chiral
trisubstituted allenes and chiral furan
derivatives
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