Chiral Diaryliodonium Phosphate Enables Light Driven Diastereoselective α-C(sp3)-H Acetalization

Article abstract of DOI:10.1021/jacs.8b05962

C(sp³)-H bond functionalization has emerged as a robust tool enabling rapid construction of molecular complexity from simple building blocks, and the development of asymmetric versions of this reaction creates a powerful methodology to access enantiopure sp³-rich materials. Herein, we report the stereoselective functionalization of C(sp³)-H bonds of cyclic ethers employing a photochemically active diaryliodonium salt in combination with an anionic phase-transfer catalyst. The synthetic strategy outlined herein allows for regio- and stereochemical control in the α-C-H acetalization of furans and pyrans using alcohol nucleophiles, thus providing the ability to control the configuration at the stereogenic exocyclic acetal carbon.

Full text of DOI:10.1021/jacs.8b05962

Article
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Chiral Diaryliodonium Phosphate Enables Light Driven
3
Diastereoselective α‑C(sp )−H Acetalization
†
,§
†,§
†
‡
,†
Baihua Ye, Jie Zhao, Ke Zhao, Jeffrey M. McKenna, and F. Dean Toste*
†
Department of Chemistry, University of California, Berkeley, California 94720, United States
‡
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States
*
S Supporting Information
3
ABSTRACT: C(sp )−H bond functionalization has emerged
as a robust tool enabling rapid construction of molecular
complexity from simple building blocks, and the development
of asymmetric versions of this reaction creates a powerful
3
methodology to access enantiopure sp -rich materials. Herein,
3
we report the stereoselective functionalization of C(sp )−H
bonds of cyclic ethers employing a photochemically active
diaryliodonium salt in combination with an anionic phase-
transfer catalyst. The synthetic strategy outlined herein allows
for regio- and stereochemical control in the α-C−H
acetalization of furans and pyrans using alcohol nucleophiles,
thus providing the ability to control the configuration at the
stereogenic exocyclic acetal carbon.
INTRODUCTION
can engage in polymerization. While trapping of the cationic
species by external nucleophiles can lead to undesired
termination of the polymerization, it can be employed to
functionalize heterocyclic C(sp )−H bonds. Encouraged by
diverse applications of the 2,5-disubstituted tetrahydrofuryl
■
3
The stereoselective functionalization of C(sp )−H bonds has
the potential to become a powerful synthetic tool to access
biologically important, stereochemically complex hetero-
3
1
−3
cycles.
This promise has resulted in the development of a
1
0
11
acetals in drug discovery, liquid crystal display devices, and
number of transition-metal catalyzed reactions that employ
1
2
3
DNA-sequencing, we targeted asymmetric α-C(sp )−H
acetalization of readily accessible chiral tetrahydrofurans
through oxidative coupling with alcohols (Scheme 1). We
envisioned that the outlined strategy would provide a new
avenue in the stereochemical control of exocyclic acetals (trans
directing groups to guide the metal center into close proximity
3
4
with a targeted C(sp )−H bond. Importantly, the availability
of a diverse array of ligands for the modulation of reactivity, as
well as the control of stereochemistry, has rendered this
5
approach an attractive one. However, in cases where either
the directing group installation or access to the metal-
13
versus cis).
promoted C−H activation are not feasible, the alternative
The successful implementation of these reagents in a stereo-
3
3
radical-mediated undirected C(sp )−H bond functionalization
and regioselective C(sp )−H bond functionalization requires a
strategy has been developed through the merging of hydrogen
atom transfer technology (HAT) with conventional transition-
means to control two key steps: the HAT transfer event to
mediate the regioselectivity and the nucleophilic trapping to
effect the stereoselectivity. While the diaryliodonium salt might
impact the regioselectivity of the HAT, its likely absence in the
nucleophilic addition precludes the use of chiral iodonium
reagents as stoichiometric stereocontrol element. In contrast,
we hypothesized that the counterion might serve as a means to
control both of the desired steps: coordination of the Lewis
basic native oxygen of a cyclic ether to the iodine(III) center or
the iodonium cation radical prior to C−H bond activation
could enable regiocontrol through proximity of the chiral
anion. Critically, we also desired that the chiral anion
participate in the stereodetermining step by association with
6
metal catalysis. In the latter scenario, an appropriate radical
abstractor matching the polarity of the targeted C−H bond is
7
required. Since the development of related asymmetric
transformations implies a considerable challenge, very few
enantioselective methods that employ this technology have
8
been reported so far.
Inspired by onium salt-catalyzed polymerization reactions,
we envisioned an alternative strategy for the stereoselective
functionalization C(sp )−H bonds. In the case of diary-
liodonium salts, the homolytic fragmentation into an iodonium
3
cation radical and an aryl radical upon irradiation (254−3509
nm) is proposed to initiate the polymerization (Scheme 1a).
These resulting radical species participate in hydrogen atom
transfer (Scheme 1b) and further oxidation of the resulting
ether radical to generate a cationic species (Scheme 1c) that
Received: June 6, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b05962
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Scheme 1. Control of Regio- and Diastereoselectivities in α-C(sp )−H Acetalization
Article
3
a cationic electrophilic species, thereby also controlling the
stereochemistry of the transformation (Scheme 1, bottom).
enhanced regioselectivity in favor of abstraction of the
unsubstituted C−H bond is unexpected on the basis of
16
ionization energies (THF 9.38 eV vs 2-methylTHF 9.22 eV).
RESULTS AND DISCUSSION
Nevertheless, these results clearly demonstrate that the
■
phosphate anion has an influence in both regio- and
Reaction Optimization. Key to the above strategy was
previous experiments concluding that quantum yields of
photoinitiated polymerization were dependent on solubility
and ion pairing of the diaryliodonium salt. This observation
provides a basis for the hypothesis that the desired trans-
formation might be controlled through chiral anion induced
solubilization of the diaryliodonium salt. Therefore, at the
outset of investigation, various reaction parameters were
established using the direct coupling of 2a with alcohol 1a
with diaryliodonium chlorides in the presence of achiral
catalyst C1 as anionic phase-transfer catalyst (see Supple-
mentary Table S1). Among these reaction parameters,
irradiation was found to be essential for the α-C(sp )−H
bond activation: a common household compact fluorescent
light (CFL, 23 W) promoted the formation of 3aa without the
need for UV light. While the reaction in the absence of base
gave low conversions and modest diastereoselectivity, a strong
base (KOtBu) produced significant amounts of aryl ether (B)
through the competing arylation of alcohol 1a. On the other
hand, the use of a weak base (NaHCO or K CO ) in methyl-
17
stereoselectivity determining steps.
Next, we addressed the question whether the selectivity of
this process might be further altered by the nature of
iodine(III) reagent and therefore examined a range of
stereoelectronically different diaryliodonium chloride re-
14
1
8
agents. Substitution at the para-position of the diary-
liodonium reagent was evaluated in order to ascertain the
impact of electronic changes on regio- and diastereoselectivity
of the reaction. Modifications at the para-position of
symmetric analogues had little influence on the efficiency;
however, relative to the unsubstituted I1, a modest improve-
ment in regioselectivity was observed with the 4-fluoro analog
I2 (Table 1, entries 3−6, and Supplementary Table S2) while
maintaining good diastereoselectivity. Given the increase in
regioselectivity afforded by the fluorine-substituted diary-
liodonium salt, and previous reports of increased efficiency
of hydrogen atom abstraction by fluorine-substituted phenyl
15
3
19
radicals, we chose to further examine fluorine substituted
3
2
3
diaryliodonium reagents.
t-butyl ether (MTBE) allowed for good conversions,
regioselectivity, and diastereoselectivity without the competing
arylation of the alcohol.
Previous reports using electronically unsymmetrical diary-
20
liodonium salts in photopolymerization prompted us to
examine I5 in the tetrahydrofuranyl functionalization reaction
Having determined the reaction conditions for the racemic
transformation, a variety of chiral phosphoric acids and
diaryliodonium chlorides were evaluated in order to establish
the viability of a stereoselective protocol. A screen of solvents
revealed that MTBE was optimal leading to improvements in
both regio- and diastereoselectivities (entry 3). The combina-
tion of achiral phosphoric acid C1 and diaryliodonium salt I1
resulted in unselective formation of diastereomers 3aa and
acid-labile acetal 4 without notable diastereoselectivity. In
contrast, (R)-TRIP C2 favored activation of the more
(
entry 7). This fluorine containing reagent again provided an
increase in regioselectivity relative to the symmetrical I3
entries 5 vs 7). On the basis of the hypothesis that the C−H
(
abstraction and stereodetermining are decoupled, we sought to
maintain the favorable regioselectivity afforded by p-
fluorophenyl substitution, while modifying the p-methoxy-
phenyl moiety to gain improvements in diastereoselectivity and
yield. In the event, we observed that unsymmetrical diary-
liodonium reagent I7 bearing a potential coordinating group
maintained the diastereoselectivity and provided 3aa in 82%
yield with improved regioselectivity (entry 9).
accessible C−H bond giving 3aa in higher yield with a useful
a
diastereoisomeric ratio of 81:19 (Table 1, entries 1 vs 2). The
B
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Article
a
Table 1. Optimization Studies
conjugate acid. One possible explanation is that the C−H
abstraction is mediated by the aryliodonium radical cation,
which would be associated with the chiral counteranion, rather
than the phenyl radical; although anion effects on the latter
22
cannot be discounted. Second, the observations from Table 1
clearly show the influence of the diaryliodonium species in the
stereodetermining step (see also Supplementary Tables S2 and
S4). The initial hypothesis that the reaction proceeds through
an oxonium intermediate generated from oxidation of the
tetrahydrofuranyl radical would not account for the impact of
the iodonium structure on diastereoselectivity. Therefore, it
seems unlikely that the transformation is proceeding via a
simple chiral phosphate-paired oxocarbenium intermediate.
Substrate Scope. Having established general conditions
for the desired reaction, we probed the generality of this
transformation using the two variants of the optimal reaction
conditions. As depicted in Scheme 2A, achiral primary and
secondary alcohols 1b−1h bearing a range of substituents,
such as alkyl, aryl, silyl, alkynyl, boronic ester, and heterocycle,
were well tolerated as the nucleophilic partner. For these
reactions, control of diastereoselectivity was achieved through
the chirality of C5. Possible double stereodifferentiation using
chiral alcohols 1i and 1j resulted in a negligible impact upon
the stereoselectivity of the reaction. Similarly, amino alcohol
1k underwent direct acetalization forming 3ka with excellent
chemo- and diastereoselectivity. Secondary alcohols 1p and 1s
were found to be less reactive toward C−H acetalization due
to the considerable steric hindrance. The decrease in reactivity
of the secondary alcohols allowed for competitive trapping by
residual water and the formation of undesired acetals C and C′
+
entries
CPA
C1
[I ]
3aa/4
trans/cis
yield (3aa, %)
b
1
I1
I1
I1
I2
I3
I4
I5
I6
I7
I7
I7
I7
I7
I1
58:42
65:35
80:20
84:16
73:27
71:29
78:22
73:27
86:14
64:36
84:16
85:15
75:25
86:14
47:53
19:81
13:87
15:85
16:84
14:86
14:86
22:78
15:85
37:63
15:85
34
50
67
61
61
54
68
56
82
28
63
b
2
(R)-C2
(R)-C2
(R)-C2
(R)-C2
(R)-C2
(R)-C2
(R)-C2
(R)-C2
(R)-C3
(R)-C4
(R)-C5
(S)-C5
(S)-C5
3
4
5
6
7
8
9
(
see also Supplementary Table S9).
In addition to the scope of alcohols, the scope of both
10
11
12
13
14
achiral 2b,2c and optically pure cyclic ethers 2d−2j was further
examined (Scheme 2B). Successively increasing the steric
requirements at the α-oxy position of cyclic ether ring showed
a trend toward an enhanced selectivity of bond scission
accompanied by an improvement in diastereoselectivity. The
selective access to either trans- or cis-2,3-dideoxyfuranose
derivatives 3ae−3ah highlights the breadth of this reaction
where a notable example is the diastereoselective and
regioselective functionalization of 2h, which possesses multiple
α-oxy C−H bonds. In addition, reaction with tetrahydropyr-
anyl substrate 2i was also tested. In this case, we observed
similar trend in regioselectivity between both α-C−H bonds
but with moderate stereochemical control.
c
d
14.5:85.5
78.5:21.5
82.5:17.5
81
57
68
e
d
a
Reaction conditions: 1a (0.05 mmol), 2a (1.25 mmol), CPA (5.0
μmol), [I ] (2.50 equiv), NaHCO (0.25 mmol), 3 Å MS, MTBE
0.20 mL, ∼0.20 M), 23 W CFL, 24 h. Ratio of diastereomers (trans-/
cis-3aa) and ratio of regioisomers (3aa/4) were determined by H
NMR. Yield of 3aa was determined by H NMR using internal
standard 3,5-dinitrobenzene. PhH instead of MTBE. cis-3aa: 95%
ee. Isolated yield. trans-3aa: 96% ee.
+
3
(
1
1
b
c
d
e
With these results in hand, optimization of chiral phosphoric
acid catalyst (entries 10−12, see also Supplementary Table S3)
was undertaken, ultimately revealing catalyst (R)-C5 and
iodine(III) I7 as the optimal combination for the formation of
cis-acetals 3aa (entry 12). On the other hand, inversion of the
absolute stereochemistry of the phosphoric acid to (S)-C5
favored the generation of trans-3aa with similar diastereose-
lectivity, thereby demonstrating that the catalyst dominated the
stereochemical outcome of the reaction (entries 13−14).
Several notable conclusions can be gleaned from observa-
tions arising from the optimization studies above. First, while it
was anticipated that the iodonium reagent would impact the
regioselectivity of the reaction, the observation that the chiral
phosphate anion also impacts the regioselectivity implies that it
is associated with the C−H abstraction event. While
counteranion effects of photoinduced polymerization have
A large excess of cyclic ether was required to achieve useful
yields of the desired acetals; however, a roughly equal amount
of 2a relative to the alcohol was consumed during the reaction,
and the unreacted 2a was simply recovered by distillation
under vacuum. We also explored the impact of lowering the
equivalents of cyclic ether on reaction outcome. With alcohols
possessing reactive C−H bonds (e.g., para-methoxybenzyl
alcohol), excess of the cyclic ether is required to overcome
competing oxidation of the alcohols to the corresponding
carbonyl compound A (see Supplementary Table S7). When
alcohols less prone to C−H abstraction were employed as
nucleophiles, lower equivalents of tetrahydrofuran resulted in
competing arylation of the alcohol to form aryl ethers B, even
in the absence of a strong base (see Supplementary Table
23
S8). Finally, we note that introduction of molecular sieves to
the reaction medium was critical to maximizing the yield of
3aa. In the absence of molecular sieves, residual water was
identified as the competing nucleophile leading to a mixture of
2
1
been previously observed, these have generally been
attributed to the generation and strength of the corresponding
C
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3
a
Scheme 2. Scope of Alcohols and Substituted Cyclic Ethers in Diastereoselective α-C(sp )−H Acetalization
a
Reaction conditions: (A) 1X (0.10 mmol), 2Y (2.50 mmol), (R)-C5 (10.0 μmol), I (0.25 mmol), NaHCO (0.50 mmol), 3 Å MS, MTBE (0.20
3
mL, ∼0.20 M), 23 W CFL, 24 h; (B) 1X (0.10 mmol), 2Y (2.50 mmol), (S)-C5 (10.0 μmol), I1 (0.25 mmol), NaHCO (0.50 mmol), 3 Å MS,
3
1
MTBE (0.20 mL, ∼0.20 M), 23 W CFL, 24 h. Ratio of diastereomers (cis-/trans-3XY) and ratio of regioisomers were determined by H NMR.
Isolated yields of 3XY are shown.
D
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Scheme 3. Investigation of Mechanism
mono- and bis-acetals as side products C and C′ (see
Supplementary Table S9)
Mechanistic Studies. Functionalization reactions of THF
were explored in order to gain a better understanding of the
mechanistic pathway and origin of the observed selectivities
influence on the stereochemical outcome of the transformation
(Scheme 3B, eq 4, see also Supplementary eqs S4 and S5).
The results above are consistent with a C−H functionaliza-
tion event likely occurring by a light induced H-atom
abstraction that is separate from the C−O bonding forming
event; therefore, we sought to gain insight into the mechanism
of the stereodetermining C−O bond forming reaction. A
control experiment using complex (R)-7 in the absence of
benzyl alcohol led to the identification of 2,3-dihydrofuran as a
potential intermediate in the transformation (Supplementary
eq S11). Consistent with this hypothesis, under identical
reaction conditions, utilizing benzyl alcohol and 2,3-dihydro-
furan as the ether substrate, we observed the formation of
desired acetal without decomposition of (R)-7 (Scheme 3D, eq
(Scheme 3). Since irradiation was essential for any of the C−H
bond cleavage events, we determined the UV−Vis spectra of
various diaryliodonium salts. Consistent with previous reports,
these salts displayed relatively weak absorptions in the near
UVA region (Figure S2−S5). The employed CFL showed
emission range of 360−440 nm; however, previous reports
have suggested appreciable quantum yield of photolysis can
occur at wavelengths >300 nm at the tail end of the absorption
21b
band of the diaryliodonium salts.
Indeed, experiments
6, see also Supplementary eq S15). Moreover, almost identical
conducted with filtered light from a 100 W xenon lamp showed
that wavelengths in the low 400 nm range effectively promoted
the transformation (Scheme 3A).
stereochemical outcome was observed starting with either 2,3-
dihydrofuran or THF (Scheme 3D, eq 5). Finally, the
stereoselectivity outcome of these transformations was
significantly different from that obtained using conventional
Having established a light-driven process as critical for the
transformation, we next explored the C−H functionalization
event. The measured competition deuterium kinetic isotope
effect (KIE = 4.88, Scheme 3B, eq 2) is comparable to that
previously measured for processes involving phenyl radical
25
Brønsted acid catalysis, in which the product was formed in
lower enantiomeric excess (Supplementary eq S17).
These observations suggest two possibly competing path-
ways for C−O bond formation: direct trapping of the initially
formed ion-paired oxonium intermediate 4 to give the product
24
abstraction from THF. On the other hand, use of THF-d as
8
a substrate did not influence the stereochemistry of the
transformation, which indicates that the C−H abstraction is
decoupled from the stereodetermining step (Scheme 3B, eq 3).
Consistent with this conclusion, although both arenes of
iodine(III) species can act as the HAT abstractors, the
selectivity of their homolytic cleavage gave no notable
3
or conversion of 4 to the dihydrofuran, which undergoes acid
mediated conversion to 3. The difference in stereoselectivity
observed between phosphoric acid-catalyzed reaction in the
presence and absence of the diaryliodonium salt and the
impact of diaryliodonium salt structure on selectivity from the
tetrahydrofuranyl starting materials suggest that the diary-
E
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Article
liodonium reagent is intimately involved in the C−O forming
step. Notably, interaction between the alcohol and chiral
phosphate-paired diaryliodonium complex (R)-7 was detected
Materials and methods, synthetic and characterization
procedures, supplementary figures, and spectral data
(PDF)
1
by H NMR spectroscopy (Scheme 3D). All together, these
results support the putative mode of hydroalkoxylation of an
enol ether catalyzed by the chiral phosphate-paired Lewis-
acidic diaryliodonium species (Scheme 4). This hypothesis is
AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
■
*
Scheme 4. Putative Mechanism
ORCID
F. Dean Toste: 0000-0001-8018-2198
Author Contributions
§
B.Y. and J.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank NIGMS (R35 GM118190) for support of this work.
B.Y. is grateful to the Swiss National Science Foundation
■
(
(
SNSF) for a postdoctoral mobility fellowship
P2ELP2_158881). We thank Jingjing Yang and Nichlolas
Settineri (UC Berkeley) for X-ray crystallography assistance.
We thank Dr. Vaneet Saini (Novartis) for help with the
preparation of chiral cyclic ethers. We thank Dr. Ming Gong
for help with Xenon light equipment and Dr. Miao Zhang for
help with HRMS and IR studies. Metrical parameters for the
structures of compound (R)-6 are available free of charge from
Cambridge Crystallographic Data Centre under reference
number CCDC 1580352 with all other data available in the
supplement.
consistent with the observation that, while the stereoselectivity
is not impacted by the selectivity of iodonium aryl cleavage, the
identity of the intact diaryliodonium reagent influences the
stereocontrol and is therefore involved in the stereodetermin-
ing step.
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26
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27
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28
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3
(
2
(
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b05962.
■
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(
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G
DOI: 10.1021/jacs.8b05962
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX