Synthesis of Spirocyclic Ethers by Enantioselective Copper-Catalyzed Carboetherification of Alkenols

Article abstract of DOI:10.1002/anie.201808554

Spirocyclic ethers can be found in bioactive compounds. This copper-catalyzed enantioselective alkene carboetherification provides 5,5-, 5,6- and 6,6-spirocyclic products containing fully substituted chiral carbon centers with up to 99 % enantiomeric exce

Full text of DOI:10.1002/anie.201808554

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Accepted Article
Title: Synthesis of Spirocyclic Ethers Via Enantioselective Copper-
Catalyzed Carboetherification of Alkenols
Authors: Sherry R. Chemler, Shuklendu Karyakarte, Chanchamnan
Um, and Ilyas Berhane
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10.1002/anie.201808554
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of Spirocyclic Ethers Via Enantioselective Copper-
Catalyzed Carboetherification of Alkenols**
Shuklendu D. Karyakarte, Chanchamnan Um, Ilyas A. Berhane and Sherry R. Chemler*
Abstract: Spirocyclic ethers can be found in bioactive compounds.
This copper-catalyzed enantioselective alkene carboetherification
provides 5,5-, 5,6- and 6,6-spirocyclic products containing fully
substituted chiral carbons with up to 99% enantiomeric excess. This
reaction features formation of two rings from acyclic substrates, 1,1-
disubstituted alkenols functionalized with arenes, alkenes or alkynes
absolute stereochemistry at the quaternary carbon is even more
rare.[10] The spirocyclic ether synthesis strategy disclosed herein
enables the enantioselective doubly intramolecular 1,2-
difunctionalization of unactivated 1,1-disubstituted alkenes using
a copper-catalyzed alkene carboetherification (Scheme 1b). This
strategy forms both rings of the spirocyclic ether in one step and
forms the fully substituted tertiary ether carbon with control of
absolute stereochemistry, thus expanding the repertoire of
strategies available to the synthetic and medicinal chemist.
and clearly constitutes
spirocyclic ethers.
a powerful way to synthesize chiral
Spirocyclic ethers are frequently found in bioactive small
molecules including those exhibiting anti-viral,[1] antibiotic[2], anti-
fungal,[3] anti-cancer[4] and analgesic activity (Figure 1).[5]
Spirocycles are attractive scaffolds for medicinal chemistry as
they allow precise placement of functional groups in three-
dimensional space.[6]
1a, Previous work
includes:
•Wacker-type cyclizations
•intramolecular Heck
•ring-closing metathesis
•C-H functionalization
•ring-expanding rearrangements
Z
n
n
Z
X
X
n
Y
n
Y
n
n
1b, This work: enantioselective alkene carboetherification / spirocyclization
O
R2
R2
H
R2
O
R1
O
O
O
O
or
HO
R1
H
H
R1
O
endo
addition
and [O]
enantioselective
oxycupration
N
O
[Cu(II)•L]
H
exo
N
addition
and [O]
or [R]
HO
R2
R2
C-[Cu(II)] homolysis
O
O
(+)-Ophiobolin A
anti-cancer antibiotic
enadoline
analgesic activity
R1
R1
[CuII]
O
O
O
OMe
O
Scheme 1. Spirocycle synthesis strategy.
OH
H
O
O
N
N
O
S
O2
O
Cl
Ph
Griseofulvin
anti-fungal medication
We have previously reported the synthesis of bicyclic fused-ring
and bridged-ring ethers as well as monocyclic tetrahydrofurans
using copper(II)-catalyzed alkene carboetherification.[11] The
present methodology examines the much less studied reactions
HIV protease inhibitor
Figure 1. Bioactive spirocyclic ethers.
of
carboetherifications produce enantiomerically enriched fully-
substituted chiral carbons and new rings connected in
spirocycle (Scheme 1). The enantioselective alkene
1,1-disubstituted
alkenes,
whose
enantioselective
The attractive biological features of spirocyclic ethers have
inspired the development of a number of strategies for their
efficient synthesis,[6a, 7] including methods reliant on asymmetric
catalysis as an efficient way to introduce chirality.[8] A common
strategy for spirocycle synthesis involves cyclization of the ends
of two substituents on a fully-substituted carbon that is already
a
carboetherification strategy has been explored by our group[11b]
and others[12] for the synthesis of chiral oxygen heterocycles. We
hypothesized that the 1,1-disubstituted alkenols would undergo
enantioselective cis-oxycupration with the chiral [Cu(II)] catalyst
and that the resulting C-[Cu(II)] bond would homolyze to
produce a carbon radical intermediate (Scheme 1b). Addition of
the intermediate to its pendant unsaturated carbon would then
produce the desired spirocycle via either endo or exo cyclization
and subsequent oxidation or reduction of the resulting carbon
radical (Scheme 1b). Herein is disclosed the results of this
study.
embedded in a ring (Scheme 1a).[7g,8a,8b,8d,8e]
Aside from
spiroketals, which can be made by intramolecular addition of two
alcohols to a ketone,[8d] rarely are both rings of the spirocyclic
ether formed in the same step,[7b, 9] and de novo formation of
both rings of the spirocyclic ether with concomitant control of
[*]
S. D. Karyakarte, C. Um, Prof. S. R. Chemler
Department of Chemistry
State University of New York at Buffalo
618 Natural Science Complex, Buffalo, NY 14260 (USA)
E-mail: schemler@buffalo.edu
The majority of the 1,1-disubstituted alkenols investigated were
synthesized via a Mannich / Claisen / nucleophilic addition route
(see Supporting Information).[13] The copper(II)-catalyzed
oxidative cyclization of 1,1-disubstituted alkenol 1a was first
investigated (Table 1). In the event, we found that 1,1-
disubstituted alkenol 1a could readily undergo the desired
alkene difunctionalization/oxidative cyclization to form racemic
spirocyclic ether 2a using catalytic Cu(OTf)2 in the presence of
[**]
This work was supported by the National Institutes of Health
GM078383.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201808554
Angewandte Chemie International Edition
COMMUNICATION
an unsubstituted, achiral bis(oxazoline) ligand, K2CO3, and
MnO2 as the stoichiometric oxidant, in PhCF3 at 120 °C (Table 1,
entry 1).[11b] The observed product 2a is the result of formal endo
addition of the presumed carbon radical (Scheme 1) onto the
pendant phenyl (as opposed to ipso addition). This
carboetherification reaction was optimized for efficiency, isolated
yield and enantioselectivity by varying ligand structure, catalyst
and ligand loading, solvent and reaction time (Table 1). The use
of the (S,S)-t-Bu-Box ligand in PhCF3 proved critical to obtaining
spirocycle 2a with respectable enantioselectivity (Table 1,
entries 3, 5 and 7). Toluene was not used due to the potential
for H-atom abstraction side reactivity.[14] While a catalyst loading
of 20 mol% Cu(OTf)2 proved efficient (Table 1, entry 5, optimal
conditions), reducing the loading to 15 mol % diminished the
isolated yield (Table 1, entry 7). Conducting the reaction for 48
h rather than 24 h maximized isolated yield (compare entries 3
and 5, Table 1).
and CF3 were compatible, and a 2-fluoropyridyl substrate also
underwent productive spirocyclization to give 2g. Minor
regioisomers were observed with para-substituted substrates
(vide infra, Scheme 4). Spirophthalanes 2i and 2j could also be
formed using this alkene carboetherification (Scheme 1).
Unfortunately, neither spirophthalane was formed in high
enantioselectivity, but the tertiary ether substrate reacted more
selectively. In the case of the primary benzylic alcohol substrate
leading to 2i, Ag2CO3 was used as terminal oxidant as it proved
milder than MnO2, where oxidation of the benzylic alcohol to its
corresponding benzaldehyde was competitive.
Cu(OTf)2 (20 mol%)
(S,S)-t-Bu-Box (25 mol%)
K2CO3 (1 equiv)
R
R
OH
X
O
R
R
MnO2 (2.6 equiv), PhCF3
120 °C, 48 h, 4 Å mol. sieves
1
2
O
O
Table 1. Optimization of the enantioselective carboetherification.
O
Ph
Ph
2a, 74% yield, 73% ee
2b, 84%, 97% ee
2c, 77% yield, 90% ee
20 mol % Cu(OTf)2, 20 mol % Ligand
OH
K2CO3 (1 equiv), MnO2 (2.6 equiv)
O
O
O
O
PhCF3,120 °C, 48 h, 4 Å mol. sieves
"optimal conditions"
CF3
O
Br
1a
2a
2d, 83% yield
regioselectivity = 7:1
>99% ee
2e, 76% yield
regioselectivity = 7:1
>99% ee
2f, 83% yield
regioselectivity = 8:1
98% ee
O
O
O
R = H, Box
R = i-Pr: (S,S)-i-Pr-Box
R = t-Bu: (S,S)-t-Bu-Box
(S)-t-Bu-Pyrox
N
N
N
N
R
R
O
O
O
O
Entry[a]
Ligand
Box
Yield (%)[b]
N
Variation from optimal
conditions
ee
(%)[c]
F
2h, 83% yield
87% ee
2i, 90% yield
24% ee
2j, 77% yield
63% ee
2g, 86% yield
regioselectivity = 7:1:1
97% ee
30 mol% [Cu], 35 mol%
ligand, 24 h
1
2
3
4
5
6
7
46
60
60
57
74
79
46
—
(S,S)-i-Pr-
Box
24 h
24 h
<5
67
47
73
<5
76
Scheme 3. Scope of the enantioselective carboetherification. Conditions from
Table 1, entry 5 were used. In the reaction leading to 2i, Ag2CO3 was used as
oxidant instead of MnO2.
(S,S)-t-Bu-
Box
(S,S)-t-Bu-
Box
1,2-dichloroethane,
105 °C
The reaction of 1d was run on 1.8 mmol scale. The minor isomer
2d’, isolated as a mixture with 2d, appears to be the result of
exo (ipso) addition to the arene followed by rearrangement and
rearomatization (Scheme 4).[15]
(S,S)-t-Bu-
Box
None
None
(S)-t-Bu-
Pyrox
Cu(OTf)2 (20 mol%)
(S,S)-t-Bu-Box (25 mol%)
K2CO3 (1 equiv)
O
O
OH
O
+
O
(S,S)-t-Bu-
Box
15 mol % [Cu], 18 mol %
ligand
MnO2 (2.6 equiv), PhCF3
120 °C, 48 h, 4 Å mol. sieves
O
68% yield,
regioselectivity = 14:1
major >99% ee
2d
2d'
1d
[a] Optimal conditions: Reaction was run on 0.13 mmol scale 1a with 20 mol%
Cu(OTf)2 and 25 mol% Ligand, 260 mol % MnO2 (85%, <5 µ), 100 mol %
K2CO3, 4 Å mol. sieves (flame-dried, 20 mg/mL) in PhCF3 at 120 °C for 48 h
unless otherwise noted. [b] Isolated yield after flash chromatography on SiO2.
[c] Enantioselectivity measured by chiral GC analysis (CP-Chirasil-Dex CB
column).
O
O
A
Scheme 4. Scale-up (1.8 mmol 1d) and regioisomer rationale.
In addition to aryl ring radical acceptors, the alkenols 3 and the
alkynol 5 were examined (Scheme 5). In both cases, 5-exo
cyclization was favored over 6-endo cyclization. Alkenol 3a
formed oxaspiro[4.4]nonane 4a both in the presence and
absence of H-atom donor 1,4-cyclohexadiene, indicating that
oxidation of the intermediate benzylic radical to the alkene is
faster than H-atom transfer. In the case of alkynol 5, a vinyl
The reactivity and selectivity of a range of 1,1-disubstituted
alkenols
were
examined
in
this
enantioselective
carboetherification reaction (Scheme 3).
In general, tertiary
alcohol substrates such as 1b react with higher
enantioselectivity than primary alcohol substrates such as 1a.
Increasing backbone substitution, however, did provide
increased enantioselectivity for the primary alcohol substrate
leading to 2h. Functional groups on the arene, such as Br, OMe
radical is the projected intermediate (not shown).
While
formation of a vinyl copper(II) and subsequent protonation to
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Scheme 6. Conditions from Table 1, entry 5 were used unless otherwise noted.
give 4a is possible, it was noted that a more complex reaction
mixture was obtained when 1,4-cyclohexadiene was omitted,
indicating H-atom transfer to the vinyl radical could be a major
pathway to the formation of 4a. Similarly, cyclization of alkenols
3b and 3c led to oxaspiro[4.4]nonanes 4b and 4c, respectively.
In the case of 3c, the isolated yield was higher when the less
hindered (S,S)-i-Pr-box ligand was used (62% versus 35% when
(S,S)-t-Bu-box was used). Substrate 3d (R1 = R2 = H, not
shown) did not give the desired spirocycle in this reaction.
The reaction to give 2o was run using (S,S)-i-Pr-Box instead of (S,S)-t-Bu-Box.
The absolute configuration of 2k was assigned (S) by X-ray
crystallography (Figure 2). The S-enantiomer is consistent with
major transition state A.[11b] All other 5,6-spirocyclic products
were assigned analogous absolute stereochemistry although
group priorities dictate if they are designated R or S. An X-ray
structure of 7 was obtained to assign its configuration as R (see
Supporting Information).
Cu(OTf)2 (20 mol%)
(S,S)-t-Bu-Box (25 mol%)
OH
Ph
K2CO3 (1 equiv)
4a, 68% yield
dr = 1:1
93% ee/89% ee
O
MnO2 (2.6 equiv), PhCF3
1,4-cyclohexadiene (0 or 3 equiv)
120 °C, 48 h, 4 Å mol. sieves
3a
OTf
[O]
N
Ts
N
Cu
O
O
O
N
Ph
NTs
O
4a, 67% yield
dr = 1.3:1
>99% ee/98% ee
OH
as above but
2k
(S,S)-i-Pr-Box (25 mol%)
1,4-cyclohexadiene (1.5 equiv)
Transition State A
Ph
5
Figure 2. Proposed transition state consistent with the crystal structure of 2k.
R1
O
OH
R1
R2
R2
O
Ar
as in 3a above but
or
Ar
Ar
using (S,S)-i-Pr-box for 3c
Further functionalization of spirocycle 2c was performed by
benzylic C-H oxidation with Co(acac)2 in the presence of tert-
butylhydroperoxide (TBHP) (Eq. 1). Oxidation of 2c, 2h and 2j
(see Supporting Information for 2h and 2j) were required to
measure enantiomeric excess as we were unable to separate
the enantiomers using a number of chiral HPLC columns.
4b, 76% yield,
dr = 2:1
99% ee/96% ee
4c, 62% yield,
dr = 1:1
85% ee/86% ee
3b, R1 = Et, R2 = H, Ar = 4-MeOC6H4
3c, R1 = H, R2 = Me, Ar = 4-MeOC6H4
Scheme 5. Substrates with pendant alkenes and alkyne.
When an ether, amine or thioether (the X group on 1) links the
alkenol to the arene, an additional heterocycle is formed upon
cyclization (Scheme 6). In these reactions, the nature of the
heteroatom, X, was observed to have an impact on the
enantioselectivity. Specifically, for products 2k-2p it appears
electron-deficient allylic X groups like NTs, NC(O)Ph and NCbz
give higher levels of enantioinduction than more electron-rich
allylic X groups like NPh, O and S. It is possible the more
electron-rich groups can coordinate, to some extent, with the
[Cu] center in the transition state leading to a change in relative
transition state (major versus minor enantiomer) energy. Such
spirocyclic bis-heterocycles have enjoyed significant interest in
pharmaceutical applications.[16]
O
Co(acac)2 (10 mol%)
TBHP (6 equiv)
O
Ph
Ph
O
Ph
Ph
rt, 24 h
27%
(1)
O
2c
8, 90% ee
In summary, a new catalytic enantioselective route to spirocyclic
ethers from acyclic alkenols has been developed. Key features
involve good functional group compatibility, the installation of a
fully substituted chiral carbon, direct C-H functionalization of
arenes with good levels of regioselectivity and the synthesis of
both spirocyclic tetrahydrofurans and spirophthalanes. While
aryl-substituted alkenols favor formation of the net endo addition
product, to give 5,6- and 6,6-spirocycles, alkenyl and alkynyl-
substituted alkenols favor formation of the exo addition product
and provide the 5,5-spirocycles. Given the significant interest in
bioactive spirocyclic ether compounds, it is possible this method
will find use in drug discovery endeavors.
The synthesis of a spirocyclic morpholine, where the additional
heteroatom resides in the cyclic ether ring, is also possible as
demonstrated in the conversion of 6 to 7 (Scheme 6). This
example also illustrates the possibility of 6-membered ring
formation in the initial cyclization step to form a 6,6-spirocycle.
Cu(OTf)2 (20 mol%)
(S,S)-t-Bu-Box (25 mol%)
K2CO3 (1 equiv)
X
R
R
OH
X
Y
Y
O
R
R
MnO2 (2.6 equiv), PhCF3
120 °C, 48 h, 4 Å mol. sieves
Acknowledgements
1
2
R
N
O
S
We thank Dr. Jason Benedict, Mr. Jordan M. Cox, Mr. Eric
Sylvester and Mr. Gage Bateman for obtaining the X-ray
structures of 2k, CCDC 1572209, and 7, CCDC 1858280.
O
O
O
O
2o, 60% yield
regioselectivity = 10:1
78% ee
2k, R = Ts, 81% yield, 96% ee
2l, R = C(O)Ph, 64% yield, 90% ee
2m, R = Cbz, 76% yield, 95% ee
2p, 92% yield, 76% ee
Keywords: copper • catalysis • spirocycle • enantioselective •
2n, R = Ph, 60% yield, 78% ee (at 130 °C)
alkenol
OH
as in 1,
above
O
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SO2Ph
7
6
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Entry for the Table of Contents
COMMUNICATION
Shuklendu D. Karyakarte,
Chanchamnan Um, Sherry R. Chemler*
Page No. – Page No.
Synthesis of Spirocyclic Ethers Via
Enantioselective Copper-Catalyzed
Carboetherification of Alkenols
A copper-catalyzed enantioselective alkene carboetherification that provides 5,5-,
5,6-, and 6,6-spirocyclic products containing fully substituted chiral carbons with up
to 99% enantiomeric excess is disclosed. This reaction features formation of two
rings from acyclic 1,1-disubstituted alkenols functionalized with arenes, alkenes or
alkynes and is a powerful approach to the synthesis of chiral spirocyclic ethers.
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