γ-Substituted Allenic Amides in the Phosphine-Catalyzed Enantioselective Higher Order Cycloaddition with Azaheptafulvenes

Article abstract of DOI:10.1021/acs.orglett.0c01523

Racemic γ-substituted allenes undergo enantioselective higher order [8 + 2]-cycloaddition with azaheptafulvenes using a chiral amino acid derived amidophosphine as catalyst, providing the corresponding azaazulenoid cycloadducts with excellent levels of regio-, diastereo-, and enantioselectivities. In this reaction, the activated allylic phosphonium ylide intermediate participates as the C2-component of the reaction, in contrast to the conventional reactivity of this type of zwitterionic intermediates as C3-components in cycloaddition reactions.

Full text of DOI:10.1021/acs.orglett.0c01523

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Letter
γ‑Substituted Allenic Amides in the Phosphine-Catalyzed
Enantioselective Higher Order Cycloaddition with Azaheptafulvenes
́
Ruben Manzano,* Aketza Romaniega, Liher Prieto, Estíbaliz Díaz, Efraim Reyes, Uxue Uria,
Luisa Carrillo, and Jose L. Vicario*
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ABSTRACT: Racemic γ-substituted allenes undergo enantioselective higher
order [8 + 2]-cycloaddition with azaheptafulvenes using a chiral amino acid
derived amidophosphine as catalyst, providing the corresponding azaazulenoid
cycloadducts with excellent levels of regio-, diastereo-, and enantioselectivities. In
this reaction, the activated allylic phosphonium ylide intermediate participates as
the C2-component of the reaction, in contrast to the conventional reactivity of
this type of zwitterionic intermediates as C3-components in cycloaddition
reactions.
Scheme 1. γ-Substituted Allenes in Phosphine-Catalyzed
Enantioselective Cycloadditions
he ability of electrophilic allenes to form 1,3-dipoles upon
activation with a Lewis base catalyst has become a
T
landmark for the development of a wide variety of annulation
reactions. Since the pioneering reports by the groups of Lu and
Kwon,1 many examples of enantioselective cycloaddition
reactions involving electron-deficient allenes have been
disclosed,2 in parallel with the development of chiral tertiary
phosphines as nucleophilic organocatalysts.3 However, most of
the examples reported in the literature are typically limited to
(achiral) allenes that do not contain any substituent at the γ-
position.4 There are some particular examples in which γ-
substituted allenes have been employed as C3-scaffolds in
asymmetric (3 + 2) cycloadditions (Scheme 1, eq 1).5
However, their use as C2-components has been scarce and it
is restricted to their reactivity at the γ,δ-positions, which
requires either an enolizable γ-substituted allenoate6 or a
particularly functionalized substrate that incorporates a leaving
group at the δ-position (Scheme 1, eqs 2 and 3 respectively).7
In view of the state of the art, we envisaged the potential use
of racemic γ-substituted allenes as 2π-components in catalytic
and enantioselective higher order [8 + 2]-cycloaddition with
azaheptafulvenes under phosphine catalysis (see Scheme 1, eq
4). This type of cycloadditions, which involve more than 6π-
electrons, are currently experiencing a renaissance.8 In
particular, and despite pioneering nonasymmetric precedents
on [8 + 2]-cycloadditions,9 enantioselective variants of higher
order cycloadditions have only been successfully accomplished
in the past few years.8 On the other hand, there are two
precedents regarding enantioselective [4 + 3]10 and [4 + 4]11
higher-order cycloadditions using allenes as the 1,3-dipole
source, but both cases involve the participation of the allene
reagent as a C4-component and therefore as the source of the
4π-partner of the reaction.
butadienoate (2a) in the presence of amidophosphine 3a,
which has demonstrated its proficiency for the activation of
allenoates in other examples of enantioselective reactions.3d
Two cycloadducts (4a and 5a) derived from the 2π- and 4π-
Received: May 4, 2020
As a proof of concept (see Table 1, entry 1), we reacted N-
sulfonyl derivative 1a with commercially available ethyl 2,3-
https://dx.doi.org/10.1021/acs.orglett.0c01523
© XXXX American Chemical Society
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A

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a
11). Interestingly, optimal results were achieved with
threonine-based catalysts (entries 12 and 13), and in particular,
using the silyl-protected analogue 3g, which afforded cyclo-
adduct 4g almost quantitatively with 99% ee (entry 13). The
stereostructure of cycloadducts 4 and 5 was confirmed by X-
ray diffraction analysis of compounds 4g and 5a.
Table 1. Preliminary Results and Catalyst Screening
With optimal reaction conditions in hand, we decided to
study the scope of the reaction with respect to structural
modifications on both components (Scheme 2). In a first
a
Scheme 2. Scope of the Reaction
Yield
ee
(%)
b
c
d
Entry
R1
EWG
Cat.
4/5
(%)
e
f
1
2
3
4
5
6
7
8
Ns (1a) CO2Et (2a)
Ns (1a) CO2t-Bu (2b)
Ns (1a) CO2Ph (2c)
Ns (1a) C(O)SPh (2d)
Ns (1a) C(O)Ph (2e)
Ns (1a) C(O)NPh2 (2f) 3a
Ts (1b) C(O)NPh2 (2f) 3a
Ts (1b) C(O)NPh2 (2f) 3b
Ts (1b) C(O)NPh2 (2f) 3c
Ts (1b) C(O)NPh2 (2f) 3d
Ts (1b) C(O)NPh2 (2f) 3e
Ts (1b) C(O)NPh2 (2f) 3f
Ts (1b) C(O)NPh2 (2f) 3g
3a
3a
3a
3a
3a
0.3:1
0.2:1
2.4:1
29
47
37
28
e
e
g
54
18
16
22
96
95
87
92
74
80
96
99
h
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
22 (4d)
72 (4e)
88 (4f)
96 (4g)
98 (4g)
99 (4g)
70 (4g)
92 (4g)
99 (4g)
98 (4g)
9
10
11
12
13
a
Reactions carried out with 0.05 mmol of 1 and 2 and 10 mol % of 3
b
1
in toluene (0.05 M) at 25 °C. Determined by H NMR analysis of
c
crude reaction mixture. Yields of isolated pure products 4.
d
Enantiomeric excess of 4 determined by HPLC on a chiral stationary
e
f
phase. Combined yield for both isomers 4 and 5. The structure and
the absolute configuration of 5a (90% ee) were determined by X-ray
diffraction analysis. 5b: 87% ee. 5c: 10% ee.
g
h
reactivity of the allenoate were isolated, but the target
cyclohepta[b]pyrrole product 4a was the minor one and the
enantioselectivity was poor. When tert-butyl allenoate (2b) was
employed, the enantiocontrol was improved, but the [8 + 2]-
cycloadduct was still the minor product (entry 2). This
tendency was reversed when phenyl ester 2c was used, isolating
4c as the major product, but with very poor enantiocontrol
(entry 3). Interestingly, phenyl thioester 2d and phenyl ketone
2e behaved exclusively as 2π components (entries 4 and 5),
and cycloadducts 4d and 4e were obtained as single isomers,
still with poor enantiocontrol, but in a good yield in the latter
case. Strikingly, allenic amide 2f turned out to be an excellent
2π component in this reaction, since the corresponding [8 +
2]-cycloadduct 4f was formed as a single regioisomer, with
high yield and with excellent enantiocontrol (entry 6).
In order to further improve the reaction, azaheptafulvene 1b
was evaluated, providing similar levels of selectivity, although
we could observe that this substrate was significantly more
reactive than 1a, leading to the formation of cycloadduct 4g in
96% yield and with 95% ee, in a significantly shorter time
(entry 7). A series of experiments were then carried out in
order to fine-tune the chiral scaffold of the catalyst (entries 7−
13). Slightly inferior results were produced by tert-leucine and
valine analogues (3b−c), and a significant drop in performance
and enantiocontrol was observed with phenylglycine derivative
3d (entry 10), while phenylalanine-derived catalyst 3e
provided a good yield and moderate enantiocontrol (entry
a
Reactions carried out with 0.1 mmol of 1 and 2 and 10 mol % of 3g
in toluene (0.05 M) at 25 °C. Yields refer to pure isolated products,
and ee was determined by HPLC on a chiral stationary phase.
b
c
Reaction carried out at 50 °C. Reaction carried out on 1.0 mmol
d
scale of 1b and 2f. n.d.: not determined.
analysis, we could observe that the performance of the reaction
was not affected at all by the nature of the sulfonamide group
attached to the azaheptafulvene, isolating the corresponding
cycloadducts in all cases in excellent yields and with very high
enantioselectivity after 2−5 h (compounds 4f−i).
We next focused on the performance of allenic amides
incorporating aryl groups of different electronic nature at the γ-
position (Substrates 2g−o). A slight increase of the reaction
temperature was required to overcome the reduced reactivity
observed with this type of allenic amides, and reaction times
could be shortened from 72 to 96 h at 25 °C to 18−36 h at 50
°C, while maintaining the excellent levels of enantiocontrol. In
all cases, the corresponding [8 + 2]-cycloadducts 4j−r were
isolated as a single regio- and diastereoisomer with exquisite
enantiocontrol (99% ee or superior). The electronic nature of
the aromatic ring did not affect the reaction performance
significantly. Thus, the presence of one electron-withdrawing
substituent on the different positions of the aryl group of the
allenic amide was virtually irrelevant and the corresponding
cycloadducts 4k−l and 4o−p were isolated essentially as a
B
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single enantiomer in high yields (71−86%). Alkoxy sub-
stituents were also well tolerated, and the enantioselectivity
was excellent in all cases (adducts 4m, 4n, and 4q). Similarly,
the naphthyl derivative 4r was isolated in good yield and with
excellent enantiocontrol. The robustness of the reaction was
evaluated with cycloadduct 4j at a higher 1.0 mmol scale with
satisfactory results (see example in Scheme 2). Additionally,
several racemic γ-alkyl substituted allenic amides 2p−r were
evaluated using the optimal reaction conditions, observing that
both γ-methyl and γ-ethyl-susbtituted substrates 2p and 2q
reacted efficiently, providing adducts 4s and 4t. Remarkably,
no side product involving reactivity through the enolizable
position of the γ-alkyl substituent was observed. An exception
to the generally good reaction performance arose from the use
of the bulkier γ-isopropyl substituted allenic amide (2r), which
did not afford the corresponding cycloadduct after 96 h at 50
or 80 °C.12 The absolute and relative configurations of
disubstituted azaazulenes 4k and 4s were also determined by
X-ray diffraction analysis, and the absolute stereostructure of
all other cycloadducts 4 obtained was assigned assuming an
identical stereochemical outcome for all reactions.
The selectivity of the reaction can be rationalized on the
basis of the following stereochemical model. Based on previous
calculations carried out for amino acid derived phosphines and
benzyl allenoate,13 a similar nucleophilic attack is assumed to
occur between catalyst 3g and allenic amides 2. In these
reported computational studies, the allenic component serves
as a three-carbon component in (3 + 2)-cycloaddition
reactions with imines13a and enones,13b in contrast to our
allenic amides, which behave as two-carbon synthons (2π
components). Despite these differences, our reaction must
involve the same type of allyl phosphonium ylide intermediate
that suggests a very plausible similar three-dimensional
arrangement during the cycloaddition process. Taking into
account this difference and in analogy with these reports, we
propose a tentative stereochemical model for the reaction in
which an H-bond is established between the amide group of
the catalyst and the sulfonyl group of the azaheptafulvene
(Figure 1).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01523.
■
sı
Complete experimental procedures, characterization
data for the prepared compounds and crystallographic
characterization data for compounds 4g, 4k, 4s, and 5a
(PDF)
Accession Codes
CCDC 1982287−1982290 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Jose L. Vicario − University of the Basque Country (UPV/
EHU), 48080 Bilbao, Spain; orcid.org/0000-0001-6557-
1777; Email: joseluis.vicario@ehu.es
́
Ruben Manzano − University of the Basque Country (UPV/
EHU), 48080 Bilbao, Spain; orcid.org/0000-0001-7290-
3979; Email: ruben.manzano@uah.es
Authors
Aketza Romaniega − University of the Basque Country (UPV/
EHU), 48080 Bilbao, Spain
Liher Prieto − University of the Basque Country (UPV/EHU),
48080 Bilbao, Spain
Estíbaliz Díaz − University of the Basque Country (UPV/EHU),
48080 Bilbao, Spain
Efraim Reyes − University of the Basque Country (UPV/EHU),
48080 Bilbao, Spain
Uxue Uria − University of the Basque Country (UPV/EHU),
48080 Bilbao, Spain
Luisa Carrillo − University of the Basque Country (UPV/
EHU), 48080 Bilbao, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01523
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Spanish MCIU (FEDER-
CTQ2017-83633-P), the Basque Government (IT908-16 and
postdoctoral contract to R.M.), and the UPV/EHU (predoc-
toral fellowship to E.D.).
Figure 1. Stereochemical model.
In conclusion, we have demonstrated that racemic γ-
substituted allenic amides are excellent 2π components for
the enantioselective [8 + 2]-cycloaddition with azaheptaful-
venes catalyzed by amino acid derived amidophosphines. This
reaction represents a direct strategy for the easy preparation of
azaazulenoids scaffolds which have demonstrated to present
important pharmacological and physical properties. Under
optimal conditions a variety of mono- and disubstituted
cycloadducts have been obtained in high yields with exquisite
levels of peri-, regio-, diastereo-, and enantioselectivity.
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dienoate) in the reaction with 1a under these optimized conditions,
but only decomposition products were obtained. The reaction under
nBu3P catalysis provided minor amounts of [8 + 4] cycloaddition
product of type 5 detected on the reaction mixture by NMR.
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E
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