(Poly)cationic λ3-Iodane-Mediated Oxidative Ring Expansion of Secondary Alcohols

Article abstract of DOI:10.1002/ejoc.201800118

Herein, a simplified approach to the synthesis of medium-ring ethers through the electrophilic activation of secondary alcohols with (poly)cationic λ³-iodanes (N-HVIs) is reported. Excellent levels of selectivity are achieved for C–O bond migration over established α-elimination pathways, enabled by the unique reactivity of a novel 2-OMe-pyridine-ligated N-HVI. The resulting hexafluoroisopropanol (HFIP) acetals are readily derivatized with a range of nucleophiles, providing a versatile functional handle for subsequent manipulations. The utility of this methodology for late-stage natural product derivatization was also demonstrated, providing a new tool for diversity-oriented synthesis and complexity-to-diversity (CTD) efforts. Preliminary mechanistic investigations reveal a strong effect of alcohol conformation on the reactive pathway, thus providing a predictive power in the application of this approach to complex molecule synthesis.

Full text of DOI:10.1002/ejoc.201800118

A Journal of
Accepted Article
Title: (Poly)cationic λ3-Iodane Mediated Oxidative Ring Expansion of
Secondary Alcohols
Authors: Jennifer C. Walters, Anthony F. Tierno, Aimee H. Dubin, and
Sarah E. Wengryniuk
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800118
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800118
Supported by

10.1002/ejoc.201800118
European Journal of Organic Chemistry
COMMUNICATION
l3
(Poly)cationic –Iodane Mediated Oxidative Ring Expansion of
Secondary Alcohols
Jennifer C. Walters,‡ Dr. Anthony F. Tierno,‡ Aimee H. Dubin, and Prof. Dr. Sarah E. Wengryniuk*[a]
Abstract: Herein, we report a simplified approach to the synthesis of
medium-ring ethers through the electrophilic activation of secondary
alcohols with (poly)cationic l3-iodanes (N-HVI). Excellent levels of
selectivity are achieved for C–O bond migration over established a-
elimination pathways, enabled by the unique reactivity of a novel 2-
OMe-pyridine-ligated N-HVI. The resulting HFIP-acetals are readily
derivatized with a range of nucleophiles, providing a versatile
functional handle for subsequent manipulations. The utility of this
methodology for late-stage natural product derivatization was also
demonstrated, providing a new tool for diversity-oriented synthesis
and complexity-to-diversity (CTD) efforts. Preliminary mechanistic
investigations reveal a strong effect of alcohol conformation on
reactive pathway, thus providing a predictive power in the application
of this approach to complex molecule synthesis.
To address these challenges, we recognized that the
ability to leverage the venerable hydroxyl group as a handle to
directly access medium-ring ethers would be highly enabling
(Figure 1). Alcohols are among the most readily synthesized and
commonly encountered intermediates in synthetic sequences.
Additionally, they are ubiquitous in bioactive natural product
scaffolds (4-5, Figure 1) and, thus, would provide a novel
approach for accessing medium-ring analogues in “complexity-
to-diversity” (CTD) type derivatizations.[5] In devising such a
method, we drew inspiration from the Criegee rearrangement of
alkyl peroxides[6] and hypothesized that treatment of an alcohol
with a l3-hypervalent iodine reagent (HVI)[7] would provide a
similar electrophilic oxygen intermediate (7), enabling a carbon-
to-oxygen ring expansion (driven by loss of aryl iodide) to give
functionalized medium-ring ethers (8) in a single step (Scheme
1).
Medium-ring cyclic ethers (7-11 atoms) are commonly
encountered structural motifs in bioactive natural products (1-3,
Figure 1); however, their synthesis remains a preeminent
challenge in organic chemistry due to the high strain energy
associated with these systems (i.e. entropic penalties,
transannular and angle strain).[1] Current approaches include
ring-closing metathesis, cycloadditions, pericyclic reactions,
epoxide openings, cross-couplings, and ring fragmentations,[2]
however, these methods are not general and often require multi-
step sequences and highly engineered starting materials,
decreasing the efficiency and practicality of total syntheses.
Additionally, while medium-ring ethers are commonly
encountered in Nature, they are relatively scarce in de novo
medicinal chemistry libraries, where synthetic design is reliant
on robust methods that allow for rapid structural diversification.[3]
Recent reports highlighting the lack of structural diversity in
pharmaceutical screening platforms emphasize the importance
of accessing complex architectures which possess drastically
altered three-dimensional topography and increased structural
flexibility.[4] The development of new methodologies to directly
access medium-ring ethers from simple, readily-accessible
precursors would enable more efficient total syntheses of
complex molecules as well as enable these scaffolds to be
viewed as viable platforms for small molecule library synthesis.
A.
H
Me
Me
OH
Me
OH
O
H
O
O
Me
Me
Br
Me
O
H
1
Me
Br
Cl
Me
Me
Me
O
Me
O
Me
O
HO
3
OH
2
simplified synthetic strategies
OH
enabling synthetic
disconnection
R
X
O
R
n
n
“N-HVI"
R
N
N
I
R
2 OTf–
novel reaction development
late-stage natural product derivatization
B.
OR
O
OAc
O
Me
RO
Me
OH
O
OH
HO
Me
Me
Me
H
H
H
[a]
J. C. Walters, Dr. A. F. Tierno, A. H. Dubin, Prof. Dr. S. E.
Wengryniuk
HO
BzO
AcO
O
5
4
Department of Chemistry
Temple University
1901 N. 13th St. Philadelphia, PA 19122
E-mail: sarahw@temple.edu; wengryniuklab.weebly.com
These authors contributed equally to the results disclosed in this
manuscript.
Figure 1. A. Medium ring ether scaffolds in bioactive natural products. B.
Hydroxyl groups provide a ubiquitous functional handle in bioactive natural
products.
‡
Supporting information for this article is given via a link at the end of
the document.
A preliminary report from our laboratory[8] described the
application of this electrophilic alcohol ring expansion approach
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10.1002/ejoc.201800118
European Journal of Organic Chemistry
COMMUNICATION
to tertiary, benzylic alcohols to give diverse benzofused ether
scaffolds. These efforts revealed that (poly)cationic l3-iodanes
(N-HVIs), possessing two heterocyclic nitrogen ligands datively
bonded to the central iodine, were uniquely effective as
electrophilic activators in this transformation (Scheme 1, inset).
Readily synthesized from commercially available phenyliodine
diacetate (PIDA), N-HVIs are a potentially powerful class of l3-
iodanes whose utility as synthetic reagents has gone relatively
unexplored since their discovery over 20 years ago.[9]
Herein, we describe the application of N-HVIs to the
electrophilic ring expansion of secondary, aliphatic alcohols (6)
to give diverse cyclic ether scaffolds (Scheme 1). The inherent
challenge to utilizing secondary alcohols is achieving selective
rearrangement (path a) over direct oxidation via a-elimination
(path b), reactivity well-established with traditional hypervalent
iodine reagents.[7,10] In this regard, it was found that both the
electronics of the N-HVI as well as the use of
hexafluoroisopropanol (HFIP) as a hydrogen-bonding solvent
were critical to achieving high levels of selectivity. The
secondary alcohol ring expansion was also explored in CTD
applications, producing several complex, medium-ring scaffolds
via late-stage natural product derivatization. The resulting HFIP-
acetals are readily functionalized with a range of nucleophiles,
providing a highly general approach to diverse medium-ring
ether scaffolds from simple starting materials.
(entry 3), showing
a
clear divergence between the two
stereoisomers, and thus, cis-14 was selected for continued
optimization. We then examined the effect of the electronics of
the N-heterocycle on the N-HVI and found that a more electron-
rich heterocyclic ligand (12, entry 4) showed extremely low
reactivity, whereas the electron-deficient 13 gave an improved
ratio to 47:53 and significantly shortened reaction time (entry 5).
Interestingly, the use of 2-OMe-Py-HVI 11 gave a ratio favoring
acetal 15 for the first time (59:41) after prolonged reaction times
(entry 6), and subsequently increasing the temperature to 60 °C
led to increased reaction efficiency without affecting product
ratios (entry 7). Increasing the concentration from to 0.3 M gave
a slight improvement in ratio (entry 8); however, any further
increases in either temperature or concentration led to
significant amounts of byproduct formation and decomposition.
After an extensive screening effort, it was found that pre-mixing
the substrate with a 1:1 ratio of DCE:HFIP was crucial, followed
by addition of 11 in a solution of HFIP, which gave a 91:9 ratio of
15:16 after just 1 h (entry 9).[11]
Table 1. Optimization of electrophilic ring expansion.
F3C
CF3
OH
OH
O
N-HVI
additive
Me
O
O
Me
or
Me
Me
[solvent]
temperature
+
16
cis-14
trans-14
15
Ar
R1= –CH(CF3)2
OR1
X
I
H
path a
OH
product ratio
(15:16)[b]
entry
conditions[a]
time (h)
O
R
O
R
N-HVI
path a
R
path b
C–O
migration
– ArI
HFIP
10, cis-14 or trans-14, DCM (0.2 M),
–25 °C to rt
1
>72
0:100
n
n
n
6
7
8
O
2
3
4
5
6
7
8
9
10, cis-14, DCE (0.2 M), 40 °C
10, trans-14, DCE (0.2 M), 40 °C
12, cis-14, DCE (0.2 M), 40 °C
13, cis-14, DCE (0.2 M), 40 °C
11, cis-14, DCE (0.2 M), 40 °C
11, cis-14, DCE (0.2 M), 60 °C
11, cis-14, DCE (0.3 M), 60 °C
58
10
>72
3
20:80
0:100
n.r.
X
2-OMe-Py-HVI (11) enables
high selectivity for 8 over 9
R
path b
α-elimination
n
9
47:53
59:41[c]
59:41[c]
67:37[c]
91:9[c]
"N-HVI"
R
AcO
I
OAc
N
I
N
TMSOTf
54
4
R
N-heterocycle
2 OTf–
CH2Cl2
PIDA
free flowing white solids
3.5
1
R = H, (10) R = 2-OMe (11) R = 4-NMe2 (12) R = 4-CF3 (13)
11, cis-14, DCE:HFIP (1:1)[d] (0.3 M),
60 °C
Scheme 1. Synthesis of medium-ring ethers from secondary alcohols via
electrophilic activation with (poly)cationic l3-iodanes (N-HVIs).
[a] Reaction conditions: DCM = dichloromethane, DCE = 1,2-dichloroethane,
N-HVI (2.0 equiv), HFIP (20.0 equiv), 3 Å MS. [b] Ratio based on integration of
crude 1H-NMR. [c] Combined mixture of diastereomers of HFIP-acetal. [d] (v:v).
With selective conditions in hand, a range of C2–substituted
cis-alcohols were examined, with R-groups selected to be
representative of varied migratory aptitude and sterics (Scheme
2). Substrates possessing 2–Me, 2,2-dimethyl, 2–Ph, and 2–iPr
(15, 17-19), all underwent rearrangement to the desired HFIP-
acetals with excellent selectivity and yield. The low isolated
yields of 15 and 17 are due to volatility of the acetal products
with both TLC and crude 1H-NMR showing clean conversion to
desired products (see SI for details). t-Butyl derivative 20
proceeded with high selectivity for rearrangement but low
We began our studies with both cis- and trans-2-Me-
cyclohexanol (14) as model substrates in order to probe any
potential effects of ring stereochemistry on selectivity for
rearrangement over oxidation (Table 1). Subjecting both cis-14
and trans-14 to our previously optimized conditions[8] gave
exclusively oxidation after prolonged reaction times (entry 1);
however, increasing the temperature to 40 °C gave full
conversion after ~2 days, with cis-14 giving an encouraging
20:80 ratio of desired HFIP-acetal (15) to ketone (16) (entry 2).
In contrast, trans-14 gave exclusively 16, with none of acetal 15
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10.1002/ejoc.201800118
European Journal of Organic Chemistry
COMMUNICATION
isolated yield, due to significant amounts of open chain aldehyde
products. Benzylic alcohol derivatives with either electron neutral
(21, 22) or electron-rich (23) aromatic rings also proceeded in
good to excellent yield to the corresponding benzoxepanes,
notably including an aryl boronic ester. The ring expansion was
also applicable to the synthesis of substituted tetrahydrofurans
from the corresponding cis- or trans-cyclobutanols, giving 24-26
in excellent yield. The rearrangement of cyclopentanols to the
corresponding pyrans could also be achieved, however this was
restricted to the use of aryl-substituted alcohols (27-28) and
rearrangement of 2-indanol to give 29 proceeded in low yield
along with significant formation of unidentified byproducts.
hypothesized the lack of reactivity of the C-ring alcohol was due
to steric hinderance from two axial methyl groups. We therefore
protected the D-ring alcohol as the carbonate (32) and this
resulted in clean rearrangement of the C-ring to oxepane 33,
albeit in low yield, despite use of a more reactive N-HVI 13 and
prolonged reaction times. In contrast, acetyl deoxycholic acid
(34), with
a sterically unencumbered a-OH on its C-ring,
underwent clean rearrangement to give analogue 35 in 54%,
with no loss of yield on 1-gram scale, even in the presence of a
free carboxylic acid. Deoxycholic acid (36) with an unprotected
A-ring alcohol gives a 76% yield of the double oxidation product
(37) when 4 equiv. of 11 are used. Finally, the ring expansion of
(+)-neomenthol (38) proceeded in excellent yield to give chiral
oxepane 39 with no erosion of chirality on the migrating bond. In
contrast, rearrangement of (+)-menthol, with a trans-alcohol,
gave only a 31% yield, giving a 1:2 ratio of acetal to (+)-
menthone (not shown); this result further supported our
preliminary finding that the relative alcohol stereochemistry had
a dramatic effect on selectivity (see Table 1). These examples
show the promise of our alcohol ring expansion approach for
producing medium-ring analogues of bioactive molecules that
would be highly impractical to access via de novo synthetic
strategies.
OH
11 (2.0 equiv)
X
R
R
O
CF3
CF3
HFIP (20 equiv)
X =
O
ClCH2CH2Cl:HFIP (1:1)
[(v:v) 0.3 M]
3 Å MS, 60 ºC
Me
Me
X
Me
X
O
O
OH
R
15
17
15%[a] (91:9)[b]
20%[a] (>95:5)[b]
O
R = –H
(30)
R = –COEt
R1
OR
OH Me
Me
Me
Me
(32)
Me
X
X
X
O
O
O
Me
Me
(blue)
(red)
R1= –CH2OAc
O
hydrocortisone acetate
O
18
19
20
81% (>95:5)[b]
23%[c] (95:5)[b]
99% (>95:5)[b]
O
X
OAc
Me
HO
Me
O
Me
X
X
X
OCOEt
O
O
O
O
Bpin
H
H
Me
OAc
H
H
H
MeO
O
21
22
23
81% (>95:5)[b][d]
31
33
O
99% (>95:5)[b][d]
65%c (91:9)[b][d]
82% (>95:5)[a]
10% (>95:5, 95% brsm)[a]
O
Me
Me
OH
X
R = –OAc
(34)
R = –H
(36)
OH
X
Me
Me
O
O
R
24
OH
deoxycholic acid
R
(cis/trans)
OH
91% (>95:5)[b]
27
98% (91:9)[b]
Me
O
OR
X
O
X
O
X
X
O
X
5
Me
Me
Me
O
O
X
Br
25
98% (>95:5)[b] 83% (>95:5)[b]
26
28
60% (91:9)[b]
29
Me
H
Me
H
18% (>95:5)[b]
H
H
35
54% (>95:5)[a]
[1 gram] scale = 60% (>95:5)[a]
37
O
AcO
76% (>95:5)[a]
Scheme 2. Scope of electrophilic ring expansion of secondary alcohols. [a]
Low yield due to volatility of acetal products. [b] Ratio of HFIP-acetal to ketone
by 1H-NMR. [c] Formation of open chain aldehyde products. [d] Reaction run
using N-HVI 10 (1.5 equiv), DCM, –25 °C.
H
H
Me
OH Me
Me
O
X
*no epimerization
observed[b]
Me
We then explored the ring expansion of several natural
product scaffolds, to probe the utility of our approach as a tool
for late-stage CTD manipulations (Scheme 3). Hydrocortisone
acetate (30), which possesses both a C-ring and D-ring alcohol,
underwent selective rearrangement of the D-ring to give
dihydropyran 31, without affecting the A-ring enone. We
38
(+)-neomenthol
39
Me
71% (>95:5)[a]
Me
Scheme 3. Application to complex scaffold derivatization. X= HFIP [a] Ratio of
HFIP-acetal to ketone by 1H-NMR. [b] 1H-NMR of 39 shows only two
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10.1002/ejoc.201800118
European Journal of Organic Chemistry
COMMUNICATION
diastereomers, resulting from HFIP-acetal. Lack of epimerization further
established after reduction of 39. See SI for details.
the highly activated nature of 51 is known to result in competitive
double addition products.[12] Simple exchange to the methyl
acetal (52) could be accomplished using HCl in a 14:1 mixture of
MeOH:HFIP. Conveniently, 52 can also be accessed in a one-
pot fashion simply by quenching the crude rearrangement
reaction with MeOH after removal of the molecular sieves (Ssee
SI for details). Conditions to access 48-50 were also found to be
readily applicable to deoxycholanoic acid acetal 35, thus
providing conditions for derivatization of both simple and
complex HFIP-acetal scaffolds (see SI for details).
At this stage, we wished to better understand the
observation that cis-14 displayed high selectivity for
rearrangement whereas trans-14 gave exclusively oxidation (see
Table 1). We hypothesized that this could be a result of
differences in the conformational equilibria of the cyclohexanols
(Scheme 4). In the cis-alcohols, the alcohol would exist
preferentially in the axial position, and FMO analysis reveals this
would strongly favor desired path a via reactive conformer 40,
due to significant 1,3-diaxial interactions disfavoring conformer
41 (Scheme 4A). In contrast, the same analysis on the trans-
alcohols (Scheme 4B) predicts low levels of selectivity. To test
this hypothesis, conformationally locked cis- and trans-decalinol
(44, 45) were subjected to rearrangement (Scheme 4C) and as
predicted, 44 (OHax) favored acetal 46 in a 95:5 ratio, whereas
45 (OHeq) gave almost exclusively ketone 47. Thus,
extrapolating from these findings, one could conclude that any
substrate or complex natural product that is either
conformationally locked or would have a preferentially axial
alcohol would react with high selectivity to give medium-ring
ether products.
Me
Me
O
CF3
CF3
R
O
O
Me
Me
[Nucleophile]
Acid Source,
CH2Cl2:HFIP
Me
Me
39
Me
48-52
Me
Me
N
H
C
O
O
O
Me
Me
Me
Me
Me
Me
Me
49
50
48
[Et3SiH] (70%)[a]
[TMSCN] (92%)[b]
[allyl TMS] (94%)[a]
NTs
Me
A. cis-alcohols: Axial alcohol favored
OMe
O
O
Me
Me
1,3-diaxial interactions
X
Ar
I
X
I
Ar
H
O
H
σ* O
(via cis-14)
H
H
Me
52 Me
[MeOH] (60%)[d]
51
H
[N-tosyl indole] (40%)[a][c]
H
R
R
Scheme 5. Functionalization of HFIP-acetals. Lewis Acid: [a] TMSOTf [b]
BF3ŸOEt2. [c] Et2O used in place of DCM [d] Conditions: HCl, 14:1 MeOH:HFIP.
path a (40)
path b (41)
OH(Ax): strongly favor path a
B. trans-alcohols: Equatorial alcohol favored
In conclusion, we report a method for the direct conversion
of readily available secondary, aliphatic alcohols to medium-ring
ethers. The reaction proceeds via electrophilic oxygen activation
by a novel (poly)cationic l3-iodane, with exquisite selectivity for
C–O bond migration over prototypical a-elimination pathways,
further demonstrating the unique reactivity of this reagent class.
The reaction is applicable to the synthesis of 5-7 membered
ethers with diverse substitution at the C2-position, including
migration of chiral centers with no observed epimerization, and
the resulting HFIP-acetals can be readily derivatized. The
ubiquity of secondary alcohols in bioactive molecules makes this
method a valuable tool for CTD and diversity-oriented synthesis
efforts, and its utility was demonstrated through the synthesis of
several novel medium-ring natural product analogues. Future
studies including more detailed mechanistic investigations as
well as targeted CTD efforts on several natural product classes
are underway and will be reported in due course.
X
H
H
H
H
I
H
H
Ar
(via trans-14)
O
O
R
R
I
Ar
X
path a (42)
OH(Eq): little selectivity path a vs. path b
C. trans-decalinol model system
path b (43)
OH
O
X
2-OMe-Py-HVI (11)
HFIP (20 equiv)
O
+
44-OH(Ax)
DCE:HFIP (1:1)
3 Å MS, 60 ºC
or
46
47
5
HO
44-OH(Ax) 95
45-OH(Eq) 10
45-OH(Eq)
90
Scheme 4. Role of alcohol conformation on reaction pathway.
Significantly, the HFIP-acetals can be readily functionalized
under mild conditions, providing versatile handle for
Acknowledgements
a
subsequent derivatizations (Scheme 5). Under optimized
conditions, treatment of 39 with Lewis acid in CH2Cl2:HFIP
allows for facile reduction with Et3SiH (48) or C–C bond
formation with TMSCN (49) or allyl silane (50). The addition of
N-tosyl indole gave 51 in 40% yield, a notable result considering
The authors are grateful to the National Institutes of Health
(R01GM-123098-01) for the financial support of this work and
would also like to acknowledge the Donors of the American
Chemical Society Petroleum Research Fund for partial support
of this research (DNI-56603). J. C. W. was supported in part by
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800118
European Journal of Organic Chemistry
COMMUNICATION
a Temple University Future Faculty Fellowship. We thank Dr.
Charles DeBrosse (Temple University) for NMR spectroscopic
assistance and Dr. Charles W. Ross III, Director: Automated
Synthesis and Characterization at University of Pennsylvania
Chemistry for providing chromatographic and mass spectral
method development, analyses, and data interpretation.
Keywords: medium-ring; cyclic ethers; hypervalent iodine; ring
expansion
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10.1002/ejoc.201800118
European Journal of Organic Chemistry
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Jennifer C. Walters,‡ Dr. Anthony F.
Tierno,‡ Aimee H. Dubin, and Prof. Dr.
Sarah E. Wengryniuk*
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(Poly)cationic l3–Iodane Mediated
Oxidative Ring Expansion of
Secondary Alcohols
The unique reactivity of poly(cationic) l3-iodanes (N-HVIs) enables a simplified
approach to cyclic ethers through the oxidative ring expansion of secondary
alcohols. The method can be applied to the synthesis of 5-, 6-, and 7-membered
rings as well as the late-stage derivatization of natural product scaffolds. The
obtained HFIP-acetals are readily functionalized, providing a versatile approach to
the synthesis of valuable cyclic ether scaffolds.
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