Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative Dearomatization and N-Hydroxycarbamate Dehydrogenation: Molecular Diversity Inspired by Tetrodotoxin

Article abstract of DOI:10.1021/jacs.7b07745

Benzenoids in principle represent attractive and abundant starting materials for the preparation of substituted cyclohexanes; however, the synthetic tools available for overcoming the considerable aromatic energies inherent to these building blocks limit the available product types. In this paper, we demonstrate access to heretofore unknown heterotricyclic structures by leveraging oxidative dearomatization of 2-hydroxymethyl phenols with concurrent N-hydroxycarbamate dehydrogenation using a common oxidant. The pairwise-generated, mutually reactive species then participate in a second stage acylnitroso Diels-Alder cycloaddition. The reaction chemistry of the derived [2.2.2]-oxazabicycles, bearing four orthogonal functional groups and three stereogenic centers, is shown to yield considerable diversity in downstream products. The methodology allows for the expeditious synthesis of a functionalized intermediate bearing structural and stereochemical features in common with the complex alkaloid tetrodotoxin.

Full text of DOI:10.1021/jacs.7b07745

Communication
pubs.acs.org/JACS
Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative
Dearomatization and N‑Hydroxycarbamate Dehydrogenation:
Molecular Diversity Inspired by Tetrodotoxin
Steffen N. Good, Robert J. Sharpe, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
*
S Supporting Information
Scheme 1. Synthetic Strategy for Tetrodotoxin and Proposed
Pairwise Oxidation/Cycloaddition Cascade
ABSTRACT: Benzenoids in principle represent attractive
and abundant starting materials for the preparation of
substituted cyclohexanes; however, the synthetic tools
available for overcoming the considerable aromatic
energies inherent to these building blocks limit the
available product types. In this paper, we demonstrate
access to heretofore unknown heterotricyclic structures by
leveraging oxidative dearomatization of 2-hydroxymethyl
phenols with concurrent N-hydroxycarbamate dehydro-
genation using a common oxidant. The pairwise-generated,
mutually reactive species then participate in a second stage
acylnitroso Diels−Alder cycloaddition. The reaction
chemistry of the derived [2.2.2]-oxazabicycles, bearing
four orthogonal functional groups and three stereogenic
centers, is shown to yield considerable diversity in
downstream products. The methodology allows for the
expeditious synthesis of a functionalized intermediate
bearing structural and stereochemical features in common
with the complex alkaloid tetrodotoxin.
he latent functionality embedded within the benzene
T
nucleus offers opportunities to chemists seeking to deploy
the parent aromatic core structure as a point of departure for
synthesizing chiral, functionalized cyclohexanes. The key
challenge thwarting the realization of this potential is the design
not only of transformations that overcome the formidable
1
−7
aromatic stabilization energy associated with benzenoids but
also a suitable second stage reaction that takes advantage of the
functionality, often of tenuous stability, revealed in the first stage.
The work described here uses the cyclohexane substructure of
the complex natural product tetrodotoxin (TTX, 1, Scheme 1a)
as an inspiration to develop a new oxidative dearomatization
cascade sequence for the de novo creation of heterotricyclic
compounds presenting four orthogonal functional groups. We
demonstrate that considerable product diversity is available from
this new platform.
Tetrodotoxin (1), a potent neurotoxin first isolated from
puffer fish, has garnered significant attention since its structure
was first elucidated in 1964 due to its unique biological properties
total syntheses, each enabled by the development of creative
11−19
tactics to access the densely functionalized core.
“Tetrod-
8
amine” (2, Scheme 1a) is a common conceptual target in
and densely functionalized structure (Scheme 1a). (−)-TTX
1
1−18
tetrodotoxin syntheses.
The C6−C7−C8−C8a stereo-
inhibits voltage gated sodium ion channels and is consequently a
9
tetrad comprises a challenging functional group constellation.
leading molecular probe for further study in this area.
Additionally, (−)-TTX has been under study as a treatment for
1
0
chemotherapy-induced neuropathic pain. Since the first
synthesis of (±)-TTX by Kishi in 1972, there have been five
Received: July 24, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b07745
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
The C7/C8 syn diol is suggestive of a cis alkene difunctionaliza-
Table 1. Optimization of the Sequential and One-Pot Adler
Oxidation/Acylnitroso Cycloaddition Protocol
tion; direct dihydroxylation of a suitably substituted benzene has
20
been suggested as a potential entry point for tetrodotoxin and
OsO -catalyzed alkene functionalization was realized en route to
4
18
1.
Perhaps more nettlesome is the C6/C8a syn-1,4-amino-
cyclohexanol where both heteroatoms reside at fully substituted
stereogenic centers (Scheme 1a).
In considering retrosynthetic approaches, the presence of a
C7/C8 alkene and antithetic reconnection of the C6/C8a amino
alcohol (red arrows) would create a retron for an acylnitroso
21
Diels−Alder cycloaddition. We envisioned oxidative remodel-
ing of an achiral benzenoid could be triggered by Adler oxidation
22
of the corresponding salicyl alcohol 4. Trapping the resulting
spiroepoxydienone 6 with a concurrently generated dienophile 5
might trigger a second stage hetero-Diels−Alder cycloaddition
(Scheme 1b). An enabling feature of the envisioned strategy is
that acyl nitroso 5 and epoxydienone 6 could in principle be
23
prepared by oxidation of N-hydroxycarbamate 3 and salicyl
24
alcohol 4, respectively, with a common oxidant. Development
of this methodology would allow for the rapid preparation of
rigid, bicyclic products with four orthogonal functional groups
from simple, aromatic feedstock while potentially allowing for an
expeditious, flexible synthesis of the tetrodamine substructure
25
and ultimately (±)-TTX and its structural congeners.
We began by investigating the proposed acylnitroso Diels−
Alder cycloaddition. The known dimerization of spiroepox-
26
ydienones was a concern; therefore, spiroepoxydienone 7, a
compound we observed to be resistant to dimerization, was
chosen as a model substrate. Moreover, dienone 7 bears an
analogous substitution pattern to an idealized substrate for
elaboration to TTX. Treating spiroepoxydienone 7 with N-
hydroxycarbamate 8 under Cu(II)-catalyzed aerobic oxidation
a
b
CuCl (10 mol %), L = 2-ethyloxazoline (20 mol %). 1.5 equiv 8.
2
c
d
1
.5 equiv 8, 1.5 equiv nBu NIO . 2.0 additional equiv of nBu NIO
4
4
4
4
e
and 8 (2 h addition) were added. 2.0 equiv 8, 2.0 equiv nBu NIO .
4
4
f
g
0
.75% EtOH as stabilizer. 2.0 equiv 10, 2.0 equiv nBu NIO .
4 4
i
h
Isolated yields. Initial full conversion to 15 was observed followed by
2
8
j
k
conditions afforded a 1.5:1 mixture of the desired Diels−Alder
cycloadduct 9 (5.4:1 dr) and salicyl alcohol 12 (Table 1a, entry
reduction back to 13. 10 mol %. Isolated yields in parentheses.
1
). Formation of alcohol 12 only occurred in the presence of 8,
diminished yields at elevated temperatures indicated possible
thermal instability of the cycloadducts. Specifically, retro Diels−
Alder cycloaddition followed by incomplete recombination and
decomposition of the acylnitroso species was hypothesized. This
hypothesis was later confirmed via a crossover experiment (vide
infra).
suggesting the in situ reduction of 7 could not be prevented under
these reaction conditions. Stoichiometric quantities of tetra-n-
butylammonium periodate (nBu NIO ) in CH Cl afforded
cycloadduct 9 (2.3:1 dr) in low conversion without any
observable formation of 12 (entry 2). Repeating the reaction
in CDCl at 45 °C showed trace conversion to 9, but full
consumption of 8 after 1 h. On the basis of these observations, we
speculated decomposition of the transient acylnitroso species,
which has a lifetime on the order of 1 ms at infinite dilution, was
likely the source of the poor reactivity.
Accordingly, we proposed the reactivity could be enhanced by
maintaining an excess of spiroepoxydienone 7 relative to the
acylnitroso species; therefore, an additional 2 equiv of nBu NIO4
4
4
2
2
3
To explore the viability of a one-pot Adler oxidation/
acylnitroso cycloaddition sequence, we added a solution of 10
over 2 h to a mixture of salicyl alcohol 13 and NaIO in
4
23
methanol/water (Table 1b, entry 1). Full conversion of phenol
13 to spiroepoxydienone 15 was observed after 15 min, but
complete reduction of 15 back to 13 was observed after 1 h.
Screening nBu NIO as the oxidant and removing methanol as a
4
4
4
solvent returned identical results (entries 2−4). Excluding water
from the reaction afforded cycloadduct 14 (>20:1 dr), albeit in
low conversion (entry 5). These results indicated that excess
water was promoting the Adler oxidation while simultaneously
promoting the reduction of intermediate spiroepoxydienone in
the presence of the acylnitroso species in water-miscible solvents.
These results collectively suggested that biphasic reactions under
phase-transfer catalysis conditions might be efficacious (entry 6,
7). Indeed, using CH Cl as the cosolvent afforded 14 in
was added followed by the dropwise addition of 8 (2 equiv) over
2
3
1
h, affording cycloadduct 9 (3.2:1 dr) in 57% conversion (entry
). When the reaction was conducted in CHCl (entry 5), phenol
3
2 was observed in similar quantities relative to the Cu(II)-
catalyzed aerobic oxidation conditions (entry 1). The variance in
reactivities observed between CHCl3 and its deuterated
counterpart are likely the result of reduction of 7 promoted by
ethanol, typically present in CHCl as a stabilizer. Indeed, a
3
2
2
similar effect was observed when methanol was used as the
solvent (entry 1). In light of these observations, we avoided these
and similar reaction media in subsequent experiments. Further
optimization showed increased conversion of 7 using Cbz analog
excellent yield with complete consumption of 13 (entry 7).
We next probed the scope of the corresponding one-pot
procedure (Table 2). Electron-rich and electron-poor salicyl
29−31
alcohols
were tolerated, affording the derived cycloadducts
1
0, but cycloadduct 11 was isolated in only 12% yield (entries 5,
in good yield. For most substrates, the cycloadduct is initially
formed with >20:1 dr; however, cycloadducts 11 and 19 were
isolated as a mixture of equilibrating diastereomers (determined
6). Repeating the reaction at cooler temperatures resulted in
increased conversions and isolated yields of 11 (entries 7, 8). The
B
DOI: 10.1021/jacs.7b07745
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Scope of the One-Pot Oxidative Dearomatization/
Acylnitroso Cycloaddition Cascade
Scheme 2. Chemoselective Reactions of Heterocycloadducts*
a
b
c
Equilibrated dr. Thermal isomerization occurs ≥40 °C. Isomeriza-
tion is observed after standing at rt (see SI).
by chemical derivatization and selective 1D NOESY NMR
analysis; see the Supporting Information (SI) for details).
An X-ray diffraction study of bicyclic dihydrooxazine 9
revealed a regiochemical preference for the illustrated isomer,
*
a
b
Conditions: NaBH (0.33 equiv), THF, 0 °C; Br (2.0 equiv),
4
2
c
27
Me
2
S (2.5 equiv), CH
2
Cl
2
, 0 °C to rt; OsO
4
(1 mol %), NMO (6.0
which matched that needed for extrapolation to TTX, and
acylnitroso approach from the methylene face of the epoxide of 7.
The observed facial selectivity was surprising as CC dienophile
approach from the oxygen face of spiroepoxydienones is well
d
equiv), THF/acetone/H O (5:5:1), 0 °C to rt; i. Pd/C (10 wt %),
AcOH (5.0 equiv), MeOH, rt, ii. HCl in 1,4-dioxane (4 N, 25.0 equiv),
rt; mCPBA (1.5 equiv), NaHCO (2.0 equiv) CH Cl , rt; HONH ·
HCl (1.5 equiv), NaOAc (2.0 equiv), THF, rt; NaBH (2.0 equiv),
anhydrous MeOH, 0 °C; p-O NC H COCl (2.2 equiv), TEA (3
equiv), DMAP (10 mol %), anhydrous THF, rt; NaH (60 wt %, 1.1
equiv), Me SO·I (1.1 equiv), anhydrous THF, 0 °C.
2
e
f
3
2
2
2
g
4
2
6
h
documented. By contrast, an X-ray diffraction study of
dihydrooxazine 14 revealed acylnitroso approach from the
oxygen face of the epoxide (see SI). We hypothesize acylnitroso
approach from the oxygen face of the epoxide is kinetically
favored whereas the “methylene endo” product is the more
thermodynamically stable diastereomer. This hypothesis is
additionally supported by the diminished pre-equilibration
diastereoselectivities observed for cycloadducts 11 and 19 (see
SI), the slow isomerization of cycloadduct 22 at rt, and the
thermally promoted isomerization of cycloadduct 16 (40−65 °C
for 50 h). A crossover experiment between 19 and Boc−NO
confirmed a retro-Diels−Alder/recombination sequence, pro-
viding a likely pathway for isomerization of the dihydroxazine
cycloadducts (see the SI for details of the crossover experiment
and thermal isomerization).
2
6
4
i
3
interference from the distal benzylic alcohol, the desired
cycloadduct 34 was prepared with excellent facial selectivity
through the action of both the sequential and one-pot Adler
oxidation/ANDA procedures on salicyl alcohol 33 (Scheme 3).
Scheme 3. Application of the Oxidation/Cycloaddition
Cascade Procedure towards the TTX Core Structure*
The reactivity of cycloadduct 16 was explored in a number of
orthogonal transformations that independently probed each
functional group (Scheme 2). Reduction of the ketone afforded
alcohol 24 in good yield while ring-opening of the epoxide was
achieved by treating ketone 16 with bromodimethylsulfonium
3
2
bromide, yielding bromohydrin 25. Gram-scale dihydroxyla-
tion of 16 gave diol 26 with high diastereoselection and matched
the stereochemistry needed for elaboration toward tetrodamine
3
3
2
. Subsequent one-pot oxazinane reduction and epoxide ring-
34
opening afforded cyclohexanone 27 in good yield. Oxidative
rearrangement of 16 provided fused lactone 28 in 50% yield.
Reductive fragmentation of epoxyoxime 29 afforded primary
35
36
alcohol 30 and thence the crystalline bis(p-nitrobenzoate) 31.
3
7
Corey−Chaykovsky epoxidation afforded bis-epoxide 32
*
Conditions: ai. NaIO , MeOH/H O (2:1), ii. BnO CNHOH (2
4
2
2
(
relative stereochemistry assigned by NOESY analysis, see SI).
Potential extrapolation of this new oxidative dearomatization/
cycloaddition cascade reaction to the synthesis of (±)-TTX
would require deployment of a more functionalized phenolic
starting material. To that end, we prepared salicyl alcohol 33 in
five steps from commercial 2,3,6-trimethyl phenol. Without
equiv, 2 h addition), BnEt NCl (20 mol %), NaIO (2.1 equiv),
CH Cl /H O (1.3:1), 0 °C; NaIO (5.1 equiv), BnEt NCl (20 mol
%
addition), 0 °C; OsO (1 mol %), NMO (5.0 equiv), THF/acetone/
H O (5:5:1), rt; H , Pd/C (10 wt %), AcOH (5 equiv), MeOH/THF
(3:2).
3
4
b
2
2
2
4
3
), CH Cl /H O (1.3:1), rt then BnO CNHOH (4 equiv, 3 h
2 2 2 2
c
4
d
2
2
C
DOI: 10.1021/jacs.7b07745
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
The relative stereochemistry of 34 was confirmed via X-ray
crystallographic analysis (see SI). Subsequent dihydroxylation
proceeded on a 3 g scale with excellent diastereoselectivity to
afford diol 35, which underwent reductive N−O cleavage on
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́
(
33
gram scale to yield lactol 36. The favorable display of
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(
̀
tetrodamine (2) provides flexibility in exploring reactions that
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products bearing four orthogonal functional groups from simple,
aromatic feedstocks. The synthetic utility of these new
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ASSOCIATED CONTENT
Supporting Information
■
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b07745.
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Crystallographic data for 9 (CIF)
Crystallographic data for 14 (CIF)
Crystallographic data for 31 (CIF)
Crystallographic data for 34 (CIF)
Crystallographic data for 35 (CIF)
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AUTHOR INFORMATION
Corresponding Author
jsj@unc.edu
■
*
́
Sodium Periodate. e-EROS Encyclopedia of Reagents for Organic Synthesis;
John Wiley & Sons, Ltd: [Online], 2006. http://onlinelibrary.wiley.
com/doi/10.1002/047084289X.rs095.pub2/full.
ORCID
Jeffrey S. Johnson: 0000-0001-8882-9881
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Notes
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The authors declare no competing financial interest.
(27) CCDC 1549797 (9), CCDC 1548692 (14), CCDC 1478943
(
31), CCDC 1548690 (34) and CCDC 1548691 (35) contain the
ACKNOWLEDGMENTS
■
supplementary crystallographic data for this paper. This data can be
obtained free of charge from the Cambridge Crystallographic Date
Centre via www.ccdc.cam.ac.uk/data_request/cif.
The project described was supported by Award R35 GM118055
from the National Institute of General Medical Sciences. R.J.S.
acknowledges an NSF Graduate Research Fellowship. X-ray
crystallography was performed by Dr. Peter White and Blane
Zavesky (UNC). We thank Dr. Roger Sommer (North Carolina
State University) for helpful discussions regarding the X-ray
structures.
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DOI: 10.1021/jacs.7b07745
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX