Copper-catalyzed enantioselective synthesis of bridged bicyclic ketals from 1,1-disubstituted-4-methylene-1,6-hexanediols and related alkenols

Article abstract of DOI:10.1039/d0cc06404a

Bridged bicyclic ketals display a range of bioactivities. Their catalytic enantioselective synthesis from acyclic 1,1-disubstituted alkene diols is disclosed. This reaction combines asymmetric catalysis with a distal radical migration. Alkynes and arenes

Full text of DOI:10.1039/d0cc06404a

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DOI: 10.1039/D0CC06404A
COMMUNICATION
Copper-Catalyzed Enantioselective Synthesis of Bridged Bicyclic
Ketals from 1,1-Disubstituted-4-methylene-1,6-hexanediols and
Related Alkenols
Received 00th January 20xx,
Accepted 00th January 20xx
Ameya S. Burde,a Shuklendu D. Karyakarte,a,b Eric D. Sylvester,a and Sherry R. Chemler* a
DOI: 10.1039/x0xx00000x
Bridged bicyclic ketals display a range of bioactivities. Their bicyclic ketals.6-7 Considerable effort has also been put toward
catalytic enantioselective synthesis from achiral, acyclic 1,1- their de novo chemical synthesis.1 A ketal stereocenter is
disubstituted alkene diols is disclosed. This reaction combines frequently created via cyclization of two pendant alcohols onto
asymmetric catalysis with a distal radical migration. Alkynes and a ketone, where the lowest energy diastereomer is typically
arenes undergo the group transfer. Product distribution depends favored.1 The acid-catalyzed addition of an alcohol to an enol
on substrate and conditions and informs mechanistic analysis.
ether is a related approach.8 Transition metal-catalyzed
[including (Pt),9 (Ag)10 and (Au)11] additions of alcohols,
carbonyls or carbenes [catalyzed by (Rh)12] to alkynes have also
been applied.1
Bridged bicyclic ketals (e.g. those in Figure 1) are rigid organic
structures composed of saturated cyclic ethers that can place
substituents in precise relative locations in three dimensions.1
Bridged bicyclic ketal natural products include the zaragozic
acids, a class of squalene synthesis inhibitors,2 and the
saliniketals, which have demonstrated inhibition of ornithine
decarboxylase induction.3 A bridged bicyclic ketal that inhibits
In recent years, excellent progress has also been made toward
the catalytic enantioselective synthesis of spirocyclic ketals.13-16
The catalytic enantioselective synthesis of bridged bicyclic
ketals is less common, and all such methods reported to date
involve catalytic enantioselective conjugate addition of various
nucleophiles to enones, followed by diastereoselective addition
of pendant alcohols to the resident carbonyl (Scheme 1a). Along
these lines, Shi and co-workers have reported a [Pd]-catalyzed
method.17 Liu and co-workers have reported a Bronsted acid
catalyzed method.18 Related organocatalytic methods have
been reported independently by Pan,19 Jorgensen,20 and
Franzen.21 A copper-catalyzed cyclization of a ketone onto an
alkene in the presence of DMSO for the synthesis of (±)-
sodium-dependent glucose cotransporter
2
has been
developed to treat type 2 diabetes (e.g. Steglatro).4 An alkyne-
substituted bridged bicyclic ketal has demonstrated cytotoxicity
toward leukemia cells.5
Microbial production is a common route to complex bridged
OEt
O
OH
Ph
O
AcO
OH
HO
OH
OH
Ph
HO2C
HO2C
O
O
benzobicyclo[3.2.1]octanes has also been disclosed.22
O
CO2H
O
OH
Cl
a) Enantioselective 1,4-addition to enones and ketalization
R2
zaragozic acid C
squalene sythase inhibitor
OH
Steglatro (ertugliflozin)
Type 2 diabetes drug
R3
O
chiral cat.
+
R3
refs. 17-21
O
R2
O
R1
H2N
O
OH
O
F3C
R1
O
O
N
H
N
O
O
b) Distal radical group migration
O
O
OH OH
R2
R2
O
OH
•R3
n
Ar
saliniketal A
inhibits ornithine decarboxylase induction
R1
cytotoxic to chronic
lymphocytic leukaemia cells
R3
n = 0, 1
ref. 23
R1
Ar
n
c) This work: enantioselective oxycupration followed by radical group migration
Figure 1. Bioactive bridged bicyclic ketals
OH
R
R
n
[Cu(II)], L*, [O]
R
R
O
R
O
a. Chemistry Department, Natural Science Complex, State University of New York at
Buffalo, Buffalo, New York, 14260, USA.
OH
n
[Cu(II)]
O
R
b. Currently employed at Southern Research Institute, Birmingham, Alabama,
35255, USA.
n
OH
- [Cu(I)]
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1. Bridged bicyclic ketals and distal group migration
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Journal Name
Table 1. Effect of Reaction Conditionsa
Cu(OTf)2 (20 mol %), L2 (25 mol %)
We report herein a strategy for the enantioselective synthesis
of chiral bridged bicyclic spiroketals that involves a radical group
transfer step (Scheme 1c). Radical migration reactions enable
the scission and transfer of unsaturated carbon moieties within
a molecule. A number of recent reports have highlighted the
power of the distal radical migration strategy in organic
synthesis (e.g. Scheme 1b).23-26 Herein we report the first distal
radical migration reaction to occur in the context of asymmetric
catalysis.
View Article Online
DOI: 10.1039/D0CC06404A
OH
O
Ph
Ph
Ph
Ph
MnO2 (2.6 equiv), K2CO3, 4 Å MS
O
O
Ph
O
+
Ph
OH
PhCF3, 120 °C, 60 h
1a
3a
2a
L1, R = H
O
O
L2, R = t-Bu
L3, R = i-Pr
N
N
R
R
entry change from standard conditions 2a + 3a 2a:3ab
ee (%)
2ac
92
In recent years, our group has established that enantioenriched
tetrahydrofurans can be synthesized from copper-catalyzed
carboetherifications of 4-pentenols.27-30 Enantioselective cis-
oxycupration across the alkene,26 followed by in situ homolysis
of the resulting C-Cu(II) bond is proposed to result in carbon
radical formation (Scheme 1c and Scheme 4, vide infra).
Subsequent C-C bond formation can occur via addition of the
carbon radical to styrenes28-29 or pendant arenes,27, 30 which, in
prior reports, underwent subsequent oxidation under the
conditions to form higher substituted alkenes or arenes (net C-
H functionalization). We have also shown that copper(II)-
promoted oxyamination and dioxygenation can occur in the
(%)
1
2
3
4
5
6
None
L1, 48 h
L3
64
61
68
55
46
72
>10:1
5:1
--
4:1
57
24 h
>10:1
>20:1
5:1
92
nd
92 (3a:
86)
nd
15 mol % [Cu], 48 h
25 mol % [Cu], 72 h
7
8
30 mol % [Cu], 48 h
60 mol % [Cu], 48 h
62
70
3:1
1.7:1
2:1
nd
nd
9d
10
50 mol % [Cu], L1, 48 h
Ag2CO3 (1.5 equiv) instead of
MnO2
ca. 90
76
5:1
nd
absence of p
-bond radical group acceptors,31 where the carbon-
11
12
25 mol % [Cu], 10 % KMnO4
combined with the MnO2
25 mol % [Cu], PhCH3 instead of
PhCF3, 48 h
68
51
1.4:1
4:1
nd
78
heteroatom bond formation is thought to occur via a Cu(III)
intermediate and a Kharash-Sosnovsky type mechanism.32-33
Although we anticipated 1,1-diphenyl-4-methylene-1,6-
hexanediol (1a) would undergo the oxycupration step, it was
unclear if the resulting radical intermediate would favor 1,4-
phenyl transfer, followed by cyclization to form bridged bicyclic
ketal 2a, or a Cu(III)-facilitated dioxygenation to form bis(ether)
3a (Table 1). In the event, we found that the reaction conditions
and the substrate structure both impact the course of the
reaction and subsequently, product formation (vide infra).
Various reaction conditions for the oxidative transformation of
1a are presented in Table 1. Bridged bicyclic ketal 2a is formed
in 64% yield, >10:1 selectivity of 2a over 3a, in 92% ee, using 20
mol% Cu(OTf)2 and 25 mol% of (S,S)-t-BuBox (L2) as catalyst,
MnO2 (2.6 equiv) as oxidant, with K2CO3 and 4 Å mol. sieves as
additives, in PhCF3 at 120 °C for 60 h (Table 1, entry 1). The first
indication of the major product’s identity as a ketal was its
distinctive 13C NMR signal at 106 ppm.
A ligand effect on product ratio was observed: when the
reaction was run using the achiral bis(oxazoline) ligand (L1), a
5:1 ratio of racemic ketal 2a and bis(ether) 3a was obtained in a
combined 61% yield (entry 2). When (S,S)-i-Pr-Box (L3) was
applied, a 4:1 mixture of 2a and 3a was observed where 2a was
formed in 57% ee (entry 3). Catalyst loading had a more
significant impact on the ratio of products. Increased catalyst
loading decreased the ratio of 2a:3a, tending to form more 3a
as the loading increased (entries 6-8). At 60 mol % [Cu] loading,
the ratio of products was close to 1:1. At 25 mol% [Cu] loading,
using (S,S)-t-Bu-Box (L2), the ratio of 2a to 3a was 5:1; bis(ether)
3a was isolated and its enantiomeric excess was measured at
86% (entry 6). Changing the oxidant to Ag2CO3 did not strongly
impact the reaction while addition of KMnO4 (10 mol%)
increased the amount of bis(ether) 3a produced (entries 10 and
11). While the reaction worked in both toluene and DCE
13
14d
DCE instead of PhCF3, 48 h
Cu(NTf2)2 instead of Cu(OTf)2,
48 h
38
53
>10:1
1.5:1
50
nd
aReactions run on 0.1 mmol of 1a in 1 mL of PhCF3 with a [Cu]:L ratio of 1:1.25 in a
sealed tube (heated in 120 °C oil bath). Isolated yield following chromatography on
silica gel, unless otherwise noted. bRatio obtained from analysis of the crude 1H
NMR. cEnantiomeric excess measured by chiral HPLC. dEstimated crude 1H NMR
yield. Nd = not determined.
(1,2-dichloroethane, entries 12 and 13), neither reaction was
superior to the reaction in a,a,a-trifluorotoluene. Cu(NTf2)2
was tried as an alternative source but was found to give lower
2a:3a selectivity for substrate 1a (entry 14). The ratio of 2a and
3a is kinetically controlled; both products were re-subjected to
the reaction conditions and were not observed to interconvert.
1,1-Diaryl-4-methylene-1,6-hexanediols bearing various aryl
substituents were next examined in the enantioselective
[3.2.1]-bridged bicyclic ketal synthesis (Table 2). While the
parent 1,1-diphenyl substrate gave ketal 2a in 64% yield and
92% ee, 4- and 3-toluyl analogs gave ketals 2b and 2c in
moderate yields (40-42%) but good enantioselectivities (87%
and 92%, respectively, Table 2, entries 2 and 3). The remainder
of the mass was attributed to oxepanes 4, formed via a
competing SN1 process enabled by presumably more stabilized
benzylic carbocations. Under the standard conditions, oxepane
4e was the predominant product (61% yield) with bis(4-
methoxyphenyl) hexanediol 1e as substrate (Table 2, entry 6).
By changing the catalyst to Cu(NTf)2, we were able to obtain
ketal 2e in a modest 40% isolated yield and in 70% ee (Table 2,
entry 7). Substrates with electron-withdrawing substituents
fared better in the ketal synthesis reaction. 4-
Trifluoromethylphenyl, 4-chlorophenyl, 3-chlorophenyl and 4-
sulfonamidophenyl substituted hexane diols underwent the
2 | J. Name., 2012, 00, 1-3
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OH
cyclization in 52-73% yield and with 88-97% ee (entries 4, 8, 9
and 10). Reaction of the 4-trifluoromethylphenyl substituted
hexane diol was performed on 1 mmol scale (entry 5).
Surprisingly, a 4-phenylbenzene substrate gave ketal 2i in 59%
yield but with only 20% ee under standard conditions (entry 11).
The enantioselectivity was improved to 56% ee by changing to
the less sterically demanding (S,S)-i-Pr-Box ligand (L3) (entry
12). Ketal 2i was crystalline and its X-ray structure enabled its
View Article Online
Cu(OTf)2 (25 mol%), L1 (31 mol%)
MnO2 (2.6 equiv), K2CO3 (1 equiv)
Ar
Ar
DOI: 10.1039/D0CC06404A
Ar
+
O
O
O
O
Ar
Ar
4 Å MS, PhCF3, 120 °C, 24 h
OH
Ar
2
3
1m, Ar = Ph
Ar = Ph, 52%, 3m only
Ar = 4-PhC6H4, 58%, 2n only
1n, Ar = 4-PhC6H4
Scheme 3. Reactions of allylic alcohols
rigorous structural assignment (see Supporting Information for Conversely, bis(biaryl) allylic alcohol 1n provided the [2.2.1]-
details). Reaction of 4-methylene-1,1-diphenylheptane-1,7- bicyclic ketal exclusively. Ketal 2n was not stable under
diol, whose more substituted alcohol chain is more enantiomeric excess measurement conditions (chiral HPLC or
conformationally pre-disposed toward cyclization, led to the GC) and oxetane 3m is achiral, so the reaction with the achiral
[4.2.1]-bridged bicyclic ketal 2j, (entry 13).
bis(oxazoline) L1 is shown for these examples.
A mechanistic analysis is illustrated in Scheme 4. Complexation
of the [Cu(II)] catalyst to the tertiary alcohol leads to
intermediate I, which can enter the oxycupration TS-A,
generating tetrahydrofuran II enantioselectively. In this
transition state, the alkene terminal carbon approaches the
copper anti to the t-Bu group on the nearest oxazoline ring.28
Organocopper intermediate II undergoes C-[Cu(II)] homolysis to
give the carbon radical III. Carbon radical III can undergo ipso
aryl addition, to give IV, which undergoes subsequent C-C bond
cleavage/group transfer to give the alkoxy-stabilized carbon
radical V. Oxidation of V then gives oxonium ion VI and
subsequent ketalization provides bicyclic ketal 2 (Scheme 4A). A
potential path for diminished enantioselectivity is ring opening
of carbon radical III to give alkoxy radical VII, which could cyclize
to give a racemic tetrahydrofuranyl carbon radical (±)-III
(Scheme 4B).27 Alternatively, homolysis of the RO-[Cu(II)] bond
of intermediate I could also give alkoxy radical VII. Substrates
with resonance-donating aryl substituents (e.g. 1d, R = Ph and
1e, R = OMe, Scheme 4) give products 2d and 2e in lower
enantioselectivity (Table 2) compared to substrates with neutral
or electron-withdrawing substituents (e.g. 1a, R = H, 1d, R = CF3,
Scheme 4 and Table 2). Electron-donating arene substituents
could lower the oxidation potential of the nearby alcohol.34
A route to bis(ether) 3a involves carbon radical III combining
with [Cu(II)] to give [Cu(III)] intermediate VIII. Coordination to
the pendant alcohol then gives IX, and reductive elimination
provides 3a.32-33 The rate of conversion of VIII to IX should
increase with decreasing carbon tether length (forming 5- vs. 6-
membered chelate) which could explain why allylic alcohol 1m
forms the bis(ether) 3m (Scheme 3) while the homoallylic
alcohol 1a forms ketal 2a (Tables 1 and 2).
Table 2. Arene substituent scope and variable tether lengtha
Cu(OTf)2 (20 mol%)
(S,S)-t-Bu-box (25 mol%)
MnO2 (2.6 equiv), K2CO3
OH
Ar
Ar
n
Ar
Ar
+
Ar
O
O
O
n
Ar
OH
4 Å MS, PhCF3
120 °C, 24-72 h
2
4
1
Entry
1
Ar
Ph
n
1
1
1
1
1
1
1
1
1
1
1
1
2
Product
2a
2b
2c
2d
2d
4e
2e
2f
2g
2h
2i
2i
2j
yield (%)b
64
ee (%)c
92
2d
4-MeC6H4
3-MeC6H4
4-CF3C6H4
4-CF3C6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
3-ClC6H4
4-TsMeNC6H4
4-PhC6H4
4-PhC6H4
Ph
40
42
71
51
61
40
53
58
73
59
64
68
87
92
3d
4e
>95
>95
--
5f
6
7d,g
8
70
88
94
90
20
56
93
9g
10
11
12h
13
aTable 1, entry 1 conditions were applied with 0.1 mmol of substrate 1. bIsolated
yield of major product following chromatography on silica gel. cEnantiomeric
excess measured by chiral HPLC. d30-40% of an SN1 product 4 was also formed. e25
mol% Cu(OTf)2 and 31 mol% (S,S)-t-Bu-Box was used. f1 mmol of 1d was used. 34%
of starting 1d was recovered. gCu(NTf2)2 was used. h(S,S)-i-Pr-Box was used,
reaction temperature was 105 °C (at 120 °C, 58% of 2i was obtained in 50% ee).
1,1-Diynyl-4-methylene-1,6-hexane diols readily underwent the
cyclization and group transfer process to provide bridged
bicyclic ketals 2k and 2l in moderate yield and very good
enantioselectivity (Scheme 2). The absolute configuration of 2l
was assigned by X-ray crystallography.
That the bis(biaryl) allylic alcohol 1n forms ketal 2n, while the
diphenyl allylic alcohol 1m forms oxetane 3m may be due to a
faster rate of ipso addition to the phenyl-substituted arene,
generating a more stabilized aryl radical intermediate.25
1,1-Diaryl-4-methylene-1,5-pentane diols 1m and 1n were
investigated for their ability to form [2.2.1]-bridged bicyclic
ketals (Scheme 3). Surprisingly, the 1,1-diphenyl substrate 1n
exclusively formed spirooxetane 3m.
Substrates 5 that lack the second alcohol form bridged bicyclic
[3.2.1] heterocycles 6. Terminal alkene 5a provides adduct 6a in
67% yield (Eq. 1).27 The 1,1-disubstituted alkene 5b, differing
from 5a only in alkene substitution, provided adduct 6b and
14% of ketone 7 (Eq. 2). Ketone 7 is likely formed via group
transfer and subsequent hydrolysis of the resulting
intermediate. The higher substitution of 5b results in greater
bond angle compression of its carbon radical intermediate,
placing the radial closer to the arene ipso carbon, leading to 7.
Cu(OTf)2 (20 mol%)
(S,S)-t-Bu-box (25 mol%)
MnO2 (2.6 equiv), K2CO3 (1 equiv)
Ar
Ar
OH
Ar
O
O
Ar
OH
4 Å MS, PhCF3, 120 °C, 24-48 h
1k, Ar = Ph
2k, Ar = Ph, 71% (87% ee)
2l, Ar = 4-ClC6H4, 62% (92% ee)
1l, Ar = 4-ClC6H4
Scheme 2. Alkyne-substituted examples
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J. Name., 2013, 00, 1-3 | 3
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Journal Name
1
2
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View Article Online
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A
DOI: 10.1039/D0CC06404A
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O
O
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O
O
N
N
Ar
O
N
N
Cu
N
Cu
t-Bu
t-Bu
O
Cu
t-Bu
-HOTf
TfO OTf
t-Bu
O
Ar
Ar
Ar
HO
N
+
OH
Ar
Ar
OTf
O
3
OTf
t-Bu
HO
OH
1
TS-A
I
4
5
R
R
R
O
t-Bu
OH
N
Cu
O
N
-[Cu(I)]
ipso
O
6
O
O
HO
t-Bu
OH
OTf
R
R
R
R
II
III
IV
7
8
9
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O
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OH
V
VI
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B
C
OH
Ar
Ar
-[Cu(I)]
(±)-III
(±)-2
I
O
VII
Ar
Ar
-H+
Ar
Ar
[Cu(II)]
Ar
Ar
Ar
-[Cu(I)]
[Cu(III)]
[Cu(III)
O
O
O
O
O
Ar
O
IX
III
OH
OH
VIII
3
Scheme 4. Proposed mechanism to 2 and 3
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Soc. 2012, 134, 12149.
In conclusion, a new route to enantioenriched bridged bicyclic
ketals from achiral, acyclic alkenols has been developed. The
polar / radical cross-over mechanistic abilities of copper (II)
catalysis enable both polar enantioselective alkene addition and
radical-based group transfer reactivity. Some reactivity trends
associated with radical stability have been identified; these
observations can be used to guide new reaction design.
We thank the National Institutes of Health (GM078383) for
support of this work and Prof. Jason Benedict for assisting E.D.S.
with the X-ray structures of 2i and 2l.
Cu(OTf)2 (20 mol %)
bis(oxazoline) L1 (25 mol %)
Ph
Ph
(1)
MnO2 (2.6 equiv), K2CO3 (1 equiv)
PhCF3, 120 °C, 12 h
OH
O
Ph
5a
6a, 67%
+ 18% starting material
O
Ph
Ph
as above
24 h
+
Ph
Ph
(2)
OH
O
OH
Ph
5b
6b, 52%
7, 14%
+ ca. 10% 5b
28 M. T. Bovino, T. W. Liwosz, N. E. Kendel, Y. Miller, N.
Tyminska, E. Zurek, S. R. Chemler, Angew. Chem. Int. Ed.
2014, 53, 6383.
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30 S. D. Karyakarte, C. Um, I. A. Berhane, S. R. Chemler, Angew.
Chem. Int. Ed. 2018, 57, 12921.
Conflicts of interest
There are no conflicts to declare.
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32 J. A. Mayoral, S. Rodriguez-Rodriguez, L. Salvatella, Chem.
Eur. J. 2008, 14, 9274.
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Notes and references
Crystal structures of 2i and 2l have been deposited in the
Cambridge Database, CCDC 2020673 and 1978089.
4 | J. Name., 2012, 00, 1-3
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Table of Contents sentence:
Bicyclic ketals via copper-catalyzed enantioselective bis(cyclization) involving radical group
transfer is disclosed.