Catalytic, Asymmetric Dearomative Synthesis of Complex Cyclohexanes via a Highly Regio- And Stereoselective Arene Cyclopropanation Using α-Cyanodiazoacetates

Article abstract of DOI:10.1021/jacs.9b13080

Arene cyclopropanation offers a direct route to higher-order, non-aromatic carbocycles; however, the inherent issue of dictating site selectivity has cumbered the development of novel intermolecular reactions that directly engage the arene pool. This paper describes a highly regio- and stereoselective, Rh₂[(S)-PTTL]₄-catalyzed arene cyclopropanation using α-cyanodiazoacetates to afford stable norcaradienes bearing three stereogenic centers, one of which is an all-carbon quaternary center. The enantioenriched norcaradienes served as tunable templates for further transformation into stereochemically dense, fused and bicyclic carbocycles containing transmutable functionality.

Full text of DOI:10.1021/jacs.9b13080

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Catalytic, Asymmetric Dearomative Synthesis of Complex
Cyclohexanes via a Highly Regio- and Stereoselective Arene
Cyclopropanation Using α‑Cyanodiazoacetates
Kendrick L. Smith, Cody L. Padgett, William D. Mackay, and Jeffrey S. Johnson*
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ABSTRACT: Arene cyclopropanation offers a direct route to higher-order, non-aromatic carbocycles; however, the inherent issue
of dictating site selectivity has cumbered the development of novel intermolecular reactions that directly engage the arene pool. This
paper describes a highly regio- and stereoselective, Rh2[(S)-PTTL]4-catalyzed arene cyclopropanation using α-cyanodiazoacetates to
afford stable norcaradienes bearing three stereogenic centers, one of which is an all-carbon quaternary center. The enantioenriched
norcaradienes served as tunable templates for further transformation into stereochemically dense, fused and bicyclic carbocycles
containing transmutable functionality.
enzenoid compounds are important feedstock chemicals
Bin organic synthesis. Their abundance from petrochemical
refining and emergent availability from renewable resources
have provided an impetus for the development of new
methodologies that use the aromatic pool.1 Dearomatization
reactions, transformations that mobilize the aromatic π-system
for the generation of new bonds at the expense of aromatic
stabilization, have allowed for the upcycling of simple
benzenoid feedstocks into higher-order carbocyclic products.
The ample supply of benzenoid chemicals has fueled the
development of dearomative strategies, resulting in a fertile
research field spanning a diverse range of chemical
approaches.2 In particular, the direct dearomative mono-
functionalization of benzenoids holds high synthetic value
(Scheme 1a) by engaging a single π-bond of the aromatic
system, thereby revealing a latent 1,3-cyclohexadiene motif that
can be further decorated to complex molecules. Asymmetric
dearomatization reactions of this type would enable the rapid
conversion of the aromatic pool to an array of complex, chiral
cyclohexane building blocks.
Transition metal-catalyzed arene cyclopropanations are
powerful reactions for the synthesis of non-aromatic structures,
with their feasibility established in foundational work from
Noels and Hubert in 1981,3 and built upon by numerous other
laboratories in substantial ways in the intervening time.4
Scheme 1b illustrates inherent challenges in such reactions:
regiocontrol for the three non-equivalent sites, stereo-
selectivity, and tautomeric composition. For the former,
tethering strategies have proven to be effective by restricting
access to distal sites,4 and the illustrated case from Mander
(Scheme 1c) is an excellent representative example from a
substantial corpus of work.5,6 Much of the work on absolute
stereocontrol has focused on intramolecular cases; however,
Beeler and Fleming recently showed that flow chemistry
improves the site selectivity in intermolecular enantioselective
Buchner reactions with electron-rich arenes, allowing for the
preparation of enantioenriched cycloheptatrienes (CHTs,
Scheme 1c).7 Within this landscape, we wondered if a direct,
intermolecular arene cyclopropanation that afforded enantio-
enriched, regioisomerically pure norcaradienes (NCDs) might
serve as a useful contribution to this evergreen field.8 Herein,
we report an asymmetric, intermolecular arene cyclopropana-
tion to prepare enantiomerically enriched 7-carboxyalkyl-7-
cyanonorcaradienes bearing three stereogenic centers, one of
which is an all-carbon quaternary center, from simple benzene
congeners.
The electronic identities of the C-7 substituents influence
the NCD−CHT equilibrium, with strong π-acceptors favoring
the norcaradiene valence tautomer (Scheme 2a).9,10 Access to
the desired NCD tautomer necessarily mandates a C-7
disconnection to a geminally disubstituted carbene/carbenoid
bearing the requisite stabilizing groups, which can arise from
acceptor/acceptor diazo compounds. α-Cyano-acceptor diazo
compounds exhibit high reactivity and selectivity in catalytic
cyclopropanation reactions of π-systems by virtue of the
enhanced carbenoid electrophilicity conferred by the inherent
cylindrical symmetry of the nitrile.11 We considered the
intermolecular, photolytic carbene cyclopropanation of ben-
zene with 4-diazo-1,2,3-triazoles reported by Shechter
(Scheme 2b) as reasonable precedent for the proposed
catalytic transformation.12 Furthermore, β-cyanoesters are
versatile handles for translation into other functional
groups.4b,13 These considerations directed our attention to
the development of an intermolecular cyclopropanation
Received: December 10, 2019
https://dx.doi.org/10.1021/jacs.9b13080
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© XXXX American Chemical Society
A

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Scheme 1. Using Norcaradienes to Streamline the Synthesis
of Chiral Cyclohexane Building Blocks
Table 1. Optimization of the Asymmetric Cyclopropanation
a
b
c
d
entry
catalyst
Rh2(esp)2
E
yield (%)
rr
er
1
2
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Bn
57
55
58
56
63
55
27
66
57
10:1
6:1
13:1
8:1
11:1
11:1
7:1
14.5:1
11:1
−
Rh2[(S)-DOSP]4
Rh2[(S)-PTAD]4
Rh2[(S)-BTPCP]4
Rh2[(S)-PTTL]4
Rh2[(S)-PTTL]4
Rh2[(S)-PTTL]4
Rh2[(S)-PTTL]4
Rh2[(S)-TFPTTL]4
69:31
74:26
66:34
83:17
83:17
76:24
94:6
e
3
e
4
e
5
f
6
f
7
f
t
8
CO2 Bu
f
t
9
CO2 Bu
84:16
a
Reactions performed using 0.10 mmol of cyanodiazoacetate, 1 mol%
b
catalyst, 20 equiv of arene, and CH2Cl2 as solvent. Determined by
1H NMR spectroscopic analysis of the crude mixture using mesitylene
c
as an internal standard. Determined by integral ratio of the olefinic
d
1H NMR resonances. Determined by HPLC using a chiral stationary
e
f
phase. Reaction performed at 0 °C. Reaction performed using 0.25
mol% catalyst, 10 equiv of arene, and 1,2-dichloroethane as solvent.
(carboxylate) dimers were surveyed in an effort to develop
the asymmetric cyclopropanation. Davies’s Rh2[(S)-DOSP]4
gave modest enantioselectivity accompanied with a decrease in
regioselectivity in the cyclopropanation. (Table 1, entry 2).
Rh2[(S)-PTAD]4 and Rh2[(S)-BTPCP]4 displayed high
reactivity and enantioinduction in an asymmetric Buchner
ring expansion reported by Beeler.7 Increases in both
regioselectivity and enantioselectivity to 13:1 and 74:26,
respectively, were observed when Rh2[(S)-PTAD]4 was
employed at 0 °C (Table 1, entry 3). The tert-leucine-derived
dimer Rh2[(S)-PTTL]4 disclosed by Hashimoto15 displayed
enhanced performance, leading to increases in reaction yield as
well as both regio- and enantioselectivity (Table 1, entries 5
and 6). Increasing the steric demand of the ester by switching
to the tert-butyl ester had a positive effect, affording 3c in 66%
yield with 14.5:1 rr and 94:6 er (Table 1, entry 8).
Scheme 2. Substituent Effects on NCD−CHT Equilibrium:
Stable 7-Carboxyalkyl-7-cyanonorcaradienes
Using the optimal conditions obtained, the reactivities of
various arenes were surveyed in the reaction (Table 2). An
interesting trend emerged with haloarenes, where considerable
amounts of a bis(cyclopropanated) side product were present
using the standard conditions. The electronegative substituent
deactivates the arene nucleus to dearomative cyclopropanation,
thereby allowing the competitive cyclopropanation of the more
reactive norcaradiene. Increasing the haloarene charge to 60
equiv allowed for the obtention of acceptable yields of
halogenated norcaradienes 3e−3g with high enantiopurities
and regiopurities. Cyclopropanation of methyl benzoate under
the standard conditions gave results consistent with our
hypothesis regarding the reactivity of haloarenes. Accordingly,
employing methyl benzoate (60 equiv) in the reaction allowed
for preparation of acrylate 3h, albeit in low yield and
employing α-cyanodiazoacetates, which are readily prepared
following known diazo transfer protocols.14
The reaction catalyzed by the achiral Rh2(esp)2 dimer
afforded norcaradiene 3a in 57% yield as a 10:1 mixture of
regioisomers (Table 1, entry 1). Encouraged by the high
regioselectivity observed, various chiral rhodium(II) bis-
B
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formations. A convex facial approach to the bicyclo[4.1.0]-
heptane should reinforce highly diastereoselective trans-
formations; however, careful determination of downstream
transformations that would not sensitize the norcaradiene to
rearomatization was paramount. Previously reported norcar-
adiene functionalizations largely rely on substituted NCDs that
restrict rearomatization or in situ-generated NCDs from the
CHT valence tautomer.4b,6 Chemoselective epoxidation has
been used extensively to prepare vinyl epoxides from 1,3-
dienes.16 Furthermore, vinyl oxiranes readily serve as electro-
philes in epoxide opening reactions by carbon and heteroatom
nucleophiles.17 Treating 3c with m-CPBA/KF effected clean
mono-epoxidation, affording norcaradiene oxide 5 in 72% yield
as a single diastereomer (Scheme 3a).18,19
Table 2. Survey of Substituted Arenes in the Asymmetric
Cyclopropanation
BF3·OEt2-promoted opening of epoxide 5 with allyltributyl-
stannane supplied the diastereomeric SN2′ products 6/6′ in a
combined 63% yield.20 Alternatively, azidolysis of 5 using
TMSN3 mediated by Ti(OEt)4 generated allylic azides 7/7′ as
Scheme 3. Selected Transformations of Norcaradienes 3b/
3g
a
b
Reaction performed on 5 mmol scale. Refer to the Supporting
Information.
diminished regioselectivity. Sulfonamides and protected
alcohols were tolerated in the reaction as evident by products
3j, 3k, and 3l. Notably, the lower yield with 3k compared to
the chain-extended 3l highlights the sensitivity of the reaction
to steric factors on the arene. Cyclopropanation of anisole
furnished the formal C−H insertion product 3m, likely arising
from facile rearomatization of the transiently generated
norcaradiene. Enantiotopic group selection was feasible
under the conditions allowing for the desymmetrization of
TBS-protected benzhydrol, furnishing 3n with good diastereo-
selectivity and high enantioselectivity.
Norcaradienes from cyclopropanation of the xylene series
displayed unique stability profiles. Cyclopropanation of o-
xylene proceeded with high regioselectivity for C3−C4 to
generate 3p which was easily isolated post-reaction. The m-
xylene-derived norcaradiene was isolated as its 4-phenyl-1,2,4-
triazole-3,5-dione (PTAD) cycloadduct 4q given the instability
of norcaradiene to conventional chromatography. The p-xylene
norcaradiene exhibited disparate reactivity; cyclopropanation
occurred with slight kinetic regioselectivity at C1−C2;
however, the product isomerizes to meso-3r during purification.
The catalyst did not show site selectivity in the reaction with o-
chlorotoluene, furnishing an equimolar mixture of enantio-
enriched norcaradienes 3s and 3s′. Cyclopropanation of 1,3,5-
mesitylene was unsuccessful, likely due to the distributed
increase in steric hindrance around the ring.
a
Reagents and conditions: (a) m-CPBA (1.2 equiv), KF (1.2 equiv),
CH2Cl2; (b) BF3·Et2O (1.5 equiv), allylBu3Sn (3 equiv), CH2Cl2; (c)
TMSN3 (5 equiv), Ti(OEt)4 (1 equiv), PhMe; (d) maleic anhydride
(10 equiv), brine, 110 °C; (e) N-phenyl maleimide (5 equiv), brine,
110 °C; (f) PTAD (3 equiv), Et2O; (g) OsO4 (10 mol%), NMO (5
equiv), THF:tBuOH:H2O; (h) OsO4 (10 mol%), NMO (1.5 equiv),
With enantioenriched norcaradienes available, we explored
the synthetic viability of the products in further trans-
b
THF:tBuOH:H2O. Isolated mixture of regioisomeric cycloadducts.
C
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an equilibrating mixture by virtue of a [3,3]-Winstein
rearrangement.21,22 None of the analogous cyclopropane
opening products were observed, illustrating the high chemo-
selectivity toward epoxide activation.
Scheme 4. Benzene Dearomatization and Norcaradiene
Desymmetrization
NCDs readily engage activated dienophiles in [4+2]-
cycloadditions.23 Indeed, [4+2]-cycloadditions of NCD 3c in
brine under microwave heating offered access to cycloadducts
8 and 9 (Scheme 3b). The poor yield of the maleic anhydride
cycloadduct 8 can be understood in light of significant
rearomatization and maleic anhydride hydrolysis that tran-
spired during the reaction. The combination of elevated
temperature and acidic medium would amplify an undesired
acid-promoted rearomatization. Bicyclic urazole 4c was
obtained in excellent yield after exposure to PTAD in ethereal
solvent. X-ray diffraction studies on a single crystal assigned
the absolute configuration of 4c, indirectly assigning the
[1S,6R,7S] enantiomer of 3c.
Cyclohexene dihydroxylation has been employed routinely
toward the preparation of highly oxygenated cyclohexane
scaffolds such as those seen in the isocarbostyryl alkaloid
family (Scheme 3c).24 Upjohn conditions effected clean global
dihydroxylation of NCD 3c, furnishing tetraol 10 in good yield
and diastereoselectivity. Achieving mono-dihydroxylation of 3c
posed a challenge due to over-oxidation; however, we
conjectured that the electronically differentiated bromo-NCD
3g would present an avenue for mono-dihydroxylation by
relying on the comparatively slow oxidation of vinyl
halides.2c,25 Under similar conditions, NCD 3g was readily
oxidized to diol 11 in 69% yield as a single diastereomer with
no indication of bis(dihydroxylation).
We next targeted the direct dearomatization of benzene
(Scheme 4). Applying the standard catalytic conditions to
benzene gave the Schecter meso-norcaradiene 3u in 58% yield.
Desymmetrization reactions are useful for the preparation of
enantioenriched, stereochemically complex products from meso
starting materials.26 Jacobsen demonstrated the enantio-
selective epoxidation of unactivated dienes using sterically
and electronically tuned (salen)Mn complexes.27 Desymmet-
rization of 3u under similar conditions afforded norcaradiene
oxide 12 in 66% yield in 84:16 er as a single diastereomer.
Subsequent dihydroxylation furnished diol 13 in excellent
yield. Nitrile oxide cycloaddition of alkene 12 enabled the
preparation of tricyclic isoxazoline 14 in 71% yield and high
regioselectivity, representing a tunable three-step sequence that
upcycles benzene24a to value-added fused tetracyclic com-
pounds bearing seven stereocenters. Alkylative opening of 12
with methyl Gilman reagent proceeded smoothly, affording
preferentially allylic alcohol 15 resulting from SN2′ addition in
52% yield.28 Employing a recent protocol reported by
Rychnovsky, preparation of crystalline osmate ester 15·
OsO4(TMEDA) allowed for unambiguous assignment of its
absolute configuration, therefore identifying the [1R,2R,4S,-
7S,8R] enantiomer of epoxide 12.29 Microwave-assisted [4+2]-
cycloaddition of 3u with a hydrazide-derived maleimide
delivered the cycloadduct 16 as a single diastereomer in 89%
yield. Structurally, tetracycle 16 maps onto the class of ST-246
orthopox antivirals.30,31
a
Reagents and conditions: (a) standard conditions using 40 equiv of
benzene; (b) A (5 mol%), NaOCl (4 equiv), 4-phenylpyridine N-
oxide (19 mol%), EtOAc; (c) OsO4 (10 mol%), NMO (3 equiv),
THF:tBuOH:H2O; (d) B (3 equiv), Et3N (3.5 equiv), CH2Cl2; (e)
Me2CuLi (3 equiv), ZnCl2 (3 equiv), THF; (f) OsO4 (1 equiv),
TMEDA (1 equiv), CH2Cl2; (g) C (3 equiv), brine, 110 °C. Ratio
after purification.
b
Scheme 5. Isotopic Labeling and Racemization Studies
Intrigued by the high regioselectivities observed in the
reaction, an isotopic labeling study was performed (Scheme 5).
Rhodium carbenoid cyclopropanations have been reported to
proceed through asynchronous, concerted carbene transfers,
displaying small secondary isotope effects.32 An intramolecular
competition study of mono-deuterated toluene 2v gave a
1.06:1.00 product mixture of 3v, with the ratio determined by
2H NMR spectroscopy. During the course of our investigation,
we observed enantioerosion of older samples of 3b. A slow
D
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[1,5]-migration by a polar C−C bond scission/closure
sequence could account for the racemization.4f,33,34 Given
the instability of norcaradienes 3q and 3r to chromatography,
we considered that exposure of 3b to a sufficiently ionizing
Brønsted or Lewis acidic reagent should promote racemization.
Indeed, exposure of enantioenriched 3b to (CF3)2CHOH35
led to complete racemization in 120 min, with partial
rearomatization.
In summary, a highly regioselective, intermolecular arene
cyclopropanation was developed that provided access to a
diverse set of enantioenriched 7-carboxyalkyl-7-cyanonorcar-
adienes. The products were subjected to a range of
transformations that allowed for the modular syntheses of
unique bicyclo[4.1.0]heptanes that would be difficult to access
via alternative methods. Further investigations into the origins
of the regioselectivity and the use of these norcaradienes in
target-based synthesis are currently underway.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b13080.
■
sı
X-ray crystallographic data for compound 4c (CCDC
1857545) (CIF)
X-ray crystallographic data for compound 15·
OsO4(TMEDA) (CCDC 1990391) (CIF)
Experimental procedures, characterization, and spectral
data (PDF)
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AUTHOR INFORMATION
Corresponding Author
Jeffrey S. Johnson − Department of Chemistry, University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599-3290, United States; orcid.org/0000-0001-8882-
9881; Email: jsj@unc.edu
■
Authors
Kendrick L. Smith − Department of Chemistry, University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599-3290, United States
Cody L. Padgett − Department of Chemistry, University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599-3290, United States
William D. Mackay − Department of Chemistry, University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599-3290, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.9b13080
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Access to Tetrahydropyranone-Fused Cycloheptatrienes from Prop-
The project described was supported by an award from the
National Science Foundation (CHE-1665008). X-ray crystal-
lography was performed by Dr. B. P. Zavesky (compound 4c,
CCDC 1857545) and Dr. C.-H. Chen (compound 15·
OsO4(TMEDA), CCDC 1990391). Analyses were conducted
on instrumentation acquired under National Science Founda-
tion Grants CHE-1726291 (mass spectrometry) and CHE-
1828183 (NMR).
E
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