Application of chiral triazole-substituted iodoarenes in the enantioselective construction of spirooxazolines

Article abstract of DOI:10.1039/d1cc03246a

A catalytic highly enantioselective synthesis of spirooxazolines is presented. Starting from readily available 2-naphthol-substituted benzamides and using catalytic amounts of a chiral triazole-substituted iodoarene catalyst, a variety of spirooxazolines

Full text of DOI:10.1039/d1cc03246a

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DOI: 10.1039/D1CC03246A
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Application of Chiral Triazole-Substituted Iodoarenes in the
Enantioselective Construction of Spirooxazolines
Ayham H. Abazid and Boris J. Nachtsheim*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
reported based on radical cyclizations,12 rearrangements,13
ABSTRACT:
A catalytic highly enantioselective synthesis of
oxidative or reductive coupling reactions14 and cycloadditions.15
spirooxazolines is presented. Starting from readily available 2-
naphthol-substituted benzamides and using catalytic amounts of a
chiral triazole-substituted iodoarene catalyst,
spirooxazolines can be isolated through an enantioselective
oxidative dearomatization in up to 92% yield and 97% ee. The
further synthetic utility of the optically enriched spirooxazolines
was examined providing a corresponding 2-naphthalenole and an
oxepin.
Br
Br
OH
Br
OH
O
O
N
H
O
a variety of
N
O
O
N
H
Br
N
O
O
HO
Br
HO
Br
R
1a: anti: Agelorin A
1b: syn: Agelorin B
O
N
O
O
N
O
Br
O
H
N
N
H
Spirocycles are well represented in many natural products and
commercial drugs.1–5 These unique molecular scaffolds have the
advantage of providing stiff three-dimensional arrangements
based on the tetrahedral nature of the spirocarbon. This allows
O
Br
N
O
O
O
(R = OMe or H)
2: Calafianin
O
3
Figure 1. Examples of natural products containing spirooxazoline.
enzyme pocket binding in a highly specific manner in terms of
6
H-bonding, hydrophobic, and -stacking interactions.7,8 While
흅
Metal-catalyzed reactions such as the metathesis reaction, the
Heck- and the Pauson–Khand reaction16 as well as the Nazarov-
cyclization17 have been applied for the de novo synthesis of
spirocyclic scaffolds. A variety of spirocyclic natural-products
have been synthesized by metal-catalyzed approaches, such as
(−)-vitrenal,18 (+)-majusculone,19 and α-acoradiene.20 Another
important approach for the synthesis of spirocycles is the
intramolecular oxidative dearomatization of phenol and
naphthol derivatives which can be efficiently accomplished
spirocycles can be found in abundance in natural products, they
are only rarely found in pure synthetic pharmacophores due to
their difficult enantioselective synthesis.
A
particular
underrepresented class of synthetic spirocycles are
spiro(is)oxazolines, although they can be found in a variety of
natural products such as Agelorin A and B (1a and 1b), isolated
from marine sponges of the genus Agelas,9 or Calafianin 2 from
the sponge Aplysina gerardogreeni.10 The oxazoline derivatives
3 were extracted from the plant Gemmingia chinensis (Figure
1).11
21–29
through the application of hypervalent iodine reagents.
The first report for such a reaction was in 1998, when Ciufolini
et al. reported the oxidative cyclization of tyrosine to form
spirolactams, mediated by (diacetoxyiodo)benzene (DIB) in
moderate yields.30 Many variants followed.31,32
Enantioselective spirocyclizations, with the Kita-spirocyclization
being the most prominent example, have been developed with
great success as well.33–37 In this regard, spirooxazolines have
been widely neglected as target structures for oxidative
cyclizations.38,39 Recently, Moran and co-workers determined a
new method for synthesizing spirooxazolines through the
oxidative cyclization of phenols containing pendent amides
The benefits of spirooxazolines as a unique class of spirocyclic
compounds and their potential as highly variable scaffolds in
medicinal chemistry and material science are encouraging
chemists to develop new strategies for their synthesis.
Synthetic strategies of spirocycles in general have been
University of Bremen, Institute of Organic and Analytical Chemistry, Leobener
Straße 7, 28359 Bremen, Germany.
E-mail: nachtsheim@uni-bremen.de
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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[a] Reaction conditions: 4a (0.15 mmol, 1.00 eq.), cat (0.015 mmol, 10
mediated by iodine(III). In this seminal report, they also applied
this reaction to 2-naphthol using chiral urea-derived
iodoarenes, unfortunately with only modest results. In
particular the stereoinduction was moderate with 14% ee in the
best case.40,41
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mol%), m-CPBA (0.23 mmol, 1.50 eq.), solvent (0.05 M). [b] Ratio of 3:1.
DOI: 10.1039/D1CC03246A
[c] Reaction performed at 0 °C for 16 h for full conversion of 4a.
Under these optimized conditions, the applicable substrate
scope was examined (Scheme 2). Initially, we introduced
diverse substituents on the 2-naphthol ring. Halogen-
substituents are well tolerated for example giving the 6-bromo
derivative 5b in 92% yield and 93% ee. 7-Methoxy- and
hydroxyderivatives as electron rich examples can also be
submitted to the spirocyclization giving 5c and 5d with good
results. Even though the latter was isolated in high
enantioselectivity (93% ee), yield significantly dropped to 54%,
possibly due to undesired oxidations of the phenol.
3-Carboxyalkylesters and ketones gave spirooxazolines 5e and
5f in up to 86% yield and 88% ee. A tetrahydro 2-napthalenone
can be transformed into target compound 5g in 84% and 95%
ee. Next, we varied the substitution pattern of the aryl amide.
Introduction of halogen substituents yielded target compounds
5h–m with good yields of 64–87%, and enantioselectivities of
up to 97% for the 4-chloro derivative 5i. The presence of
strongly electron-withdrawing trifluoromethyl or nitro groups
was tolerated as well in the cyclization, resulting in formation of
5n and 5o in good yields and excellent enantioselectivities of up
to 94% ee. Methoxy- and ethoxy-substituted arenes 4p and 4q
gave spirooxazolines 5p and 5q in high yields of 91% and 86%,
respectively, with an excellent enantioselectivity for 5p of 95%
ee and a moderate enantioselectivity of 73% ee for 5q. A highly
electron rich trimethoxy-substituted derivative yielded the
corresponding spirooxazoline 5r in high yield, but with a
Our group recently developed chiral triazole-substituted
iodoarenes and successfully applied these chiral C1-symmetric
iodoarene catalysts in a plethora of oxidative enantioselective
transformations such as α-oxytosylations, (spiro)lactonizations,
rearrangements and benzylic hydroxylations.36,37,42 Intrigued by
their high reactivity, we wondered whether these omnipotent
catalysts can be applied in the yet underexplored generation of
spirooxazolines through an oxidative spirocyclization of suitable
substrates. We started our investigations using N-((2-
hydroxynaphthalen-1-yl)methyl)benzamide 4a as the model
compound (Table 1). Oxidative spirocyclization of 4a by a
dearomatizing oxidative C-O-bond connection between the
amides carbonyl oxygen and C1 of the 2-napththol unit as
shown in Int1 should give spirocyclic 2-naphthalenone 5a.
We initially investigated four successful catalysts (6a–6d) from
our recent work (entries 1-4).43 It was found that catalyst 6d
showed the highest reactivity and selectivity for the desired
product 5a (entry 4). While ethyl acetate and pure hexafluoro-
2-propanol (HFIP) as well as MeOH/MeCN mixtures did not
improve yields and selectivities (entries 5-7), a further
optimization of the reaction conditions revealed a mixture of
acetonitrile and HFIP to be a highly effective solvent system
(entry 8). Performing the reaction at 0 °C finally improved the
stereoselectivity of product 5a slightly to 96% ee (entry 9). The
absolute configuration of 5a was proven by comparison
between a calculated CD-spectrum and the observed spectrum
(see ESI , Figure S-1).
diminished enantioselectivity of 70% ee.
A 2’-pyridine-
substituted amide was also tolerated in this cyclization, forming
the corresponding spirooxazoline 5s with 82% yield and 81% ee.
R2
Table 1. Optimization of the reaction conditions.
R2
O
Ph
H
N
N
NH
OH
O
O
6d
(10 mol%), m-CPBA ( 1.5 eq.)
Ar*
O
O
I
R1
R1
X
(MeCN:HFIP, 3:1) (0.05 M), 0 °C , 16 h
I
OTIPS
O
Ph
NH
OH
Int1
Ph
O
4
5
R
N
Bn
N
Ar*I 6
(10 mol%)
m-CPBA (1.5 eq.)
O
N
N
O
Ph
Ph
Ph
Ph
N
6a,
6c,
6b,
6d,
R = Me;
R = Bz;
R = Et
R = iPr
N
N
N
solvent, (0.05 M), rt , 12 h
O
O
O
O
O
R1O
5c
O
O
O
5a
4a
Br
R1
CO
, R1 = Me, 71%, 84% ee
R1 = H, 54%, 93% ee
, R1 = OMe, 86%, 88% ee
, R1 = Et, 61%, 84% ee
5b
5g
5e
5f
Entry[a]
Catalyst
6a
6b
6c
6d
6d
6d
6d
6d
Solvent
Yield [%] ee [%]
92%, 93% ee
84%, 95% ee
5d
,
1
2
3
4
5
6
7[b]
8[b]
9[b, c]
MeCN
MeCN
MeCN
MeCN
EtOAc
HFIP
MeCN:MeOH 68
MeCN:HFIP
MeCN:HFIP
60
68
63
76
71
72
67
74
78
85
64
76
72
90
96
R2
X
N
N
N
N
O
O
O
O
O
O
, X = 4-Br, 64%, 91% ee
, X = 4-Cl, 75%, 97% ee
, X = 4-F, 70%, 76% ee
, R2 = 4-CF3, 68%, 94% ee
, R2 = 4-NO2, 64%, 91% ee
, R2 = 4-OMe, 91%, 95% ee
5s
5h
5n
5o
5p
82%, 81% ee
5i
5j
, X = 2-Br, 87%, 91% ee
X = 3-Br, 82%, 88% ee
R
2 = 2-OEt, 86%, 73% ee
R
2 = 3,4,5-(OMe)3, 91%, 70% ee
5k
5q,
5r,
80
81
5l
,
6d
5m
, X = 3,5-Br2, 78%, 88% ee
2 | J. Name., 2012, 00, 1-3
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Scheme 2. Substrate scope.
In conclusion, we herein present the first highly
View Article Online
DOI: 10.1039/D1CC03246A
enantioselective oxidative spirocyclization of amide-substituted
To prove the synthetic robustness of our method, a large-scale
synthesis was performed, giving spirooxazoline 5a in constant
yield and enantioselectivity on a 4 mmol scale. (Scheme 3-a).
2-naphthols using chiral hypervalent iodine catalysis. This
method provides a variety of enantioenriched spirooxazolines
in remarkable yields and enantioselectivities.53 The reaction is
compatible with a wide variety of substrates, including electron-
rich and electron-poor naphthalene benzamides as well as N-
heterocycles. The further synthetic utility of these compounds
allows the preparation of two interesting derivatives by a
diastereoselective 1,2-reduction of the 2-naphthalenone and
ring-enlargement through a Baeyer-Villiger oxidation. Finally,
the principle photo-switchable properties of the so observed
chiral spirooxazoline is demonstrated.
a)
O
Ph
NH
OH
Ph
N
O
6d
c)
(10 mol%.), m-CPBA (1.5 eq.)
O
MeCN (0.05 M), 0°C, 24 h
4a
5a
(4.0 mmol)
77% yield, 96% ee
b)
Ph
N
O
Ph
N
Ph
N
m-CPBA
phosphate buffer
(pH = 7)
O
O
O
OH
O
CeCl3, NaBH4
O
DCM, rt, 3 h
MeOH/THF
-78 °C, 20 min
8
5a
7
Author Contributions
86% yield, 95% ee
( >19:1 dr)
63% yield, 96% ee
d)
340 nm
The manuscript was written by Ayham H. Abazid and Boris J.
Nachtsheim. Ayham H. Abazid performed the experiments. All
authors have given approval to the final version of the manuscript.
N
Ph
O
O
9
Conflicts of interest
quant.
The authors declare no competing financial interests.
Scheme 3. Synthetic applicability.
The further synthetic utility of the optically enriched
spirooxazolines was also investigated. A diastereoselective
Luche reduction of 5a yielded the C2-spirocyclic
tetrahydronaphthalenole 7, with almost the same
enantiopurity (Scheme 3-b).44 The given relative configuration
was determined by an NOE experiment. By addition of m-CPBA
5a was oxidized through a Baeyer-Villiger oxidation to the
oxepin 8, again with excellent retention of the stereocenter
(Scheme 3-c). Interestingly, this reaction was not observed so
far as a significant undesired oxidative decomposition pathway
during our investigations.
Acknowledgements
Ayham H. Abazid acknowledges the Scholars at Risk
organization for personal funding.
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