Synthesis of Vicinal Quaternary All-Carbon Centers via Acid-catalyzed Cycloisomerization of Neopentylic Epoxides

Article abstract of DOI:10.1021/acs.orglett.0c02296

We report our studies on the development of a catalytic cycloisomerization of 2,2-disubstituted neopentylic epoxides to produce highly substituted tetralins and chromanes. Termination of the sequence occurs via Friedel-Crafts-type alkylation of the remote (hetero)arene linker. The transformation is efficiently promoted by sulfuric acid and proceeds best in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as the solvent. Variation of the substitution pattern provided detailed insights into the migration tendencies and revealed a competing disproportionation pathway of dihydronaphthalenes.

Full text of DOI:10.1021/acs.orglett.0c02296

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Letter
Synthesis of Vicinal Quaternary All-Carbon Centers via Acid-
catalyzed Cycloisomerization of Neopentylic Epoxides
Matthias Schmid,‡ Kevin R. Sokol,‡ Lukas A. Wein, Sofia Torres Venegas, Christina Meisenbichler,
Klaus Wurst, Maren Podewitz, and Thomas Magauer*
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ABSTRACT: We report our studies on the development of a
catalytic cycloisomerization of 2,2-disubstituted neopentylic epox-
ides to produce highly substituted tetralins and chromanes.
Termination of the sequence occurs via Friedel−Crafts-type
alkylation of the remote (hetero)arene linker. The transformation
is efficiently promoted by sulfuric acid and proceeds best in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as the solvent. Variation of the
substitution pattern provided detailed insights into the migration tendencies and revealed a competing disproportionation pathway
of dihydronaphthalenes.
icinal quaternary carbon centers are present in many
was achieved by exploiting ring strain, carbon−carbon bond
strengths, and carbocation stabilities. This allowed for the
synthesis of a library of polyfunctionalized tetralin and
chromane systems.
V
bioactive natural products (e.g., salimabromide (1),1
lingzhiol (2),2 calycanthine (3),3 communesin F (4),4 and
koumine (5)5) and pharmaceuticals such as buprenorphine
(6)6 (Scheme 1A). The presence of these structural units was
reported to increase the structural rigidity allowing for tighter
binding to their molecular targets in many cases and greater
selectivity than with more flexible congeners.7 In nature, all-
carbon quaternary centers are, for instance, accessible via
reactions that proceed via carbocation intermediates.8,9 For
their construction in the chemical laboratory, a well-assorted
toolbox has been established in the past.9,10 However,
synthetic challenges remain, as multistep procedures that are
accompanied by low-yielding transformations are often
required.
For the initial optimization of the reaction conditions, we
employed readily available electron-rich arene 11a (Scheme
2A). We were pleased to find that the cycloisomerization
proceeded most efficiently in 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP)15 at 0 °C with sulfuric acid (10 mol %) as catalyst,
affording tetralin 12a in 83% yield within 15 min. Alternative
solvents and Brønsted or Lewis acids were found to be inferior
and led to significantly reduced yields (entries 2−7).16 Higher
temperatures (23 °C, entry 9; 58 °C, entry 8) were less
effective for this transformation, leading to complex mixtures of
uncyclized byproducts.
In the context of the synthesis of salimabromide (1), we
were investigating methods to efficiently construct the fully
substituted tetrahydronaphthalene core.11 We found that ring
formation and installation of the two crucial vicinal quaternary
carbon centers were possible in a single step by means of a
powerful cycloisomerization reaction of a 2,2-disubstituted
neopentylic epoxide. This chemistry was inspired by the
seminal reports by Bogert12 and Cook13 in 1933 (Scheme 1B).
In this work, a tandem hydride migration/Friedel−Crafts-type
cyclization of tertiary alcohol 7 enabled the synthesis of
octahydrophenanthrene system 8. In 2010, Khalaf extended
the rearrangement−cyclization cascade by resorting to acyclic
tertiary alcohols such as 9 to enable installation of two vicinal
gem-dimethyl groups.14
Unfortunately, both of these reports were strictly limited to a
few unfunctionalized hydrocarbon frameworks. Herein we
disclose the synthesis of vicinal all-carbon quaternary centers
by the consecutive 1,2-rearrangement/cyclization of 2,2-
disubstituted neopentylic epoxides under mild conditions
(Scheme 1C). Selective migration of various alkyl residues
With the optimized conditions in hand, we investigated the
scope of the cycloisomerization in more detail (Scheme 2B).
As a first parameter, we studied different aromatic residues as
the nucleophilic component for the Friedel−Crafts termination
step. Activating methyl and tert-butyl substituents provided
yields of up to 83% (12c and 12d). Methoxy-substituted
tetralins were obtained in virtually identical yields as for
unsubstituted tetralin 12b, with only a little influence of the
substitution pattern (69% for 12e and 70% for 12f). It is
noteworthy that 12e was previously synthesized by the same
cascade under nonoptimized conditions in only 43% yield.11
Remarkably, a fully methylated pyrogallol-derived epoxide
Received: July 11, 2020
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A

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Scheme 1. Occurrence of Vicinal All-Carbon Quaternary Centers in Bioactive Molecules and Concept of this Work
formed the corresponding tetralin 12h in only 57% yield, while
benzodioxole derivative 12g was isolated in 82%. We believe
that this results from the trajectory of the approaching arene,
which leads to severe steric interaction between the outer
methoxy groups and the tertiary carbocation unit. As expected,
substrates with deactivating substituents delivered the
corresponding tetralins in only low yields or completely shut
down the reaction (see Scheme 2D, limitations). Fluorinated
tetralins 12i and 12j were formed in 35 and 41% yield,
respectively. Pinacol boronate 12k, which is a valuable building
block for further derivatizations via Suzuki−Miyaura cross-
coupling reactions, was formed in 29% yield. Electron-rich,
nonbasic heterocycles also proved to be compatible with the
reaction conditions. For a thiophene substrate, efficient
alkylation took place to afford the annealed 6/5-system 12l
in 77% yield. Furans 12m and 12n were formed in lower yields
under the reaction conditions, probably because of competing
hydrolysis or polymerization.17 We were pleased to see that the
methodology is not limited only to aromatic nucleophiles:
oxane 12o was formed in 43% yield from the corresponding
primary alcohol. Interestingly, even for this relatively small
nucleophile no oxolane formation was observed. This under-
pinned our assumption that the formation of a less-strained six-
membered ring must be one of the major driving forces for the
cascade (vide infra). This hypothesis was also experimentally
supported by product 12p, which was formed from a distal
epoxide via a formally inverse methyl migration along the alkyl
chain. The non-rearranged 7/6 system was not observed under
these conditions.
Having investigated the conversion of a panel of variously
substituted (hetero)arenes to afford tetralins, we proceeded to
vary the carbon chain connecting the epoxide and (hetero)-
arene (Scheme 2C). By replacement of the ethylene linker with
an oxymethylene unit, we envisioned being able to access
heterocyclic chromane systems. We were pleased to see that a
series of these readily available phenyl ethers delivered highly
substituted chromanes 13a−l in medium to good yields. For all
of the substrates investigated, a competing hydride shift to
form a stabilized phenoxycarbocation ion was not observed.
Electron-rich phenyl and naphthyl ethers underwent the
cascade reaction in up to 76% yield. Similarly substituted
chromanes were generated in only slightly reduced yields
compared to the corresponding tetralin analogues. An
exception was methoxy derivative 13d, which was formed in
only 33% yield together with a 7% yield of its ortho regioisomer
13e. Interestingly, we observed an unexpected effect of the
substitution pattern of methoxyphenols, affording the highest
yield (58%) for the ortho-substituted derivative 13f. The p-
fluoro- and p-chlorophenyl ethers delivered the corresponding
chromanes 13i and 13j in 73% and 68% yield, respectively. For
substrates carrying a (boronic) ester (CO2Et or Bpin), only
small amounts of the corresponding chromanes were isolated
(23% yield for 13k and 39% yield for 13l). In these cases, the
phenyl ether proved to be less stable, leading to the isolation of
free phenols in substantial amounts. Electron-poor (hetero)-
arenes turned out to be incompatible not only for the
formation of tetralins but also for chromane systems (Scheme
2D). The 2,3-substituted pyridine 12q was not observed even
in the presence of excess acid and prolonged reaction times. A
trifluoromethyl group (12r), amide (12s), or nitrile (13m)
prevented the final cyclization and gave mostly complex
mixtures of uncyclized elimination products. To our surprise,
protected aniline derivative 13n was not accessible either, and
only a complex mixture was obtained.
To better understand the reaction sequence, we studied the
migration tendencies of different alkyl residues (Scheme 3).
For this purpose, we replaced the tert-butyl group attached to
the epoxide with different aliphatic rings (ring size = 4, 5, 6).
Highly strained methylcyclobutyl epoxide 14a exclusively
underwent ring expansion/alkyl migration, affording cis-
benzohydrindane 16a in 76% yield. The same behavior was
observed for the formation of tetralin 16d (82%) and
chromane 16e (87%). The less-strained cyclopentyl derivative
14b afforded both cis-benzodecalin 16b and spirane 15b as an
inseparable mixture (9:1 ratio), still preferring the ring-
expanded product 16b in 54% yield. Cyclohexyl derivative
14c exclusively formed spirane 15c (71%) with no detectable
amount of the 7/6/6-expansion product 16c.
In an effort to investigate the requirements for successful 1,2
migration, we further modified the tert-butyl group and
replaced one of the three methyl groups with an allyl, prenyl,
benzyl, or vinyl group. Epoxide 17a afforded allyl-migrated
tetralin 18a in 38% yield as the major product. Preferential
migration of the weaker allylic bond was also observed for the
prenyl substrate 17b. For this particular case, we observed
protonation of the remote double bond of 18b and subsequent
spiroxane formation with the neopentylic alcohol (39% yield of
19). Similar migration was observed for the benzyl group,
B
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Scheme 2. Optimization and Scope of the Cycloisomerization
a
1H NMR yields with 2,3,5,6-tetrachloronitrobenzene as the internal standard are shown, with isolated yields in parentheses. n.o. = not observed.
affording 18c in 36% yield. The competing methyl migration
was also observed for this substrate, leading to the formation of
20 as a mixture of diastereomers (1.6:1 d.r.) in 19% yield.
Careful analysis of the product mixture revealed the unusual 6/
6/6/6-product 21 (hexahydrobenzo[c]phenanthrene) as the
major product (41%). Despite the stronger sp2−sp3 bond (t-
Bu−vinyl = 97.8 kcal mol−1 vs t-Bu−methyl = 87.5 kcal
mol−1),18 the migration of a vinyl group was also observed to
afford tetralin 18d in 22% yield together with a complex
product mixture. The eight-membered-ring product 22,
originating from at least two alkyl migration steps, was isolated
as the only byproduct in 7% yield.19
R2 = R3 = H). As expected, no cycloisomerization was
observed for this epoxide, but disproportionated naphthalene
27a (47%) and tetralin 28a (49%) were obtained in nearly
quantitative combined yield. The same results were observed
for substrates carrying an ethyl (23b) or benzyl (23c) group.
When an isopropyl group was present, naphthalene 27d (29%)
and tetralin 28d (34%) still prevailed. However, a 1,2-hydride
shift was also observed to afford cycloisomerized tetralin 24d
in 28% yield. Diphenylmethyl derivative 23e afforded the
corresponding products in similar yields. Surprisingly, in this
case only phenyl migration with low diastereoselective control
(23e, 36% yield, 1.9:1 d.r.) was observed. Epoxide 11a, which
was used for the optimization, delivered disproportionated
naphthalene 27f (8%) and tetralin 28f (9%) under the reaction
conditions. For the methoxymethyl group in substrate 23g, we
To investigate the requirements for successful migratory
cycloisomerization, we varied the degree of substitution of the
terminal alkyl carbon starting with a methyl group (23a, R1 =
C
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Scheme 3. Investigation of the Migration Tendencies of Substituents
exclusively observed direct alkylation leading to a mixture of
In conclusion, we have reported a powerful cycloisomeriza-
tion reaction of 2,2-disubstituted neopentylic epoxides. The
reaction does not require transition metal catalysts and
proceeds under mild conditions in HFIP as the solvent.
Variation of the terminating nucleophile enabled rapid access
to functionalized chromanes and tetralins featuring vicinal all-
carbon quaternary centers. The use of cycloalkyl moieties
allowed for the formation of tricyclic ring systems in one step.
Analysis of the byproducts revealed fast disproportionation of
dihydronaphthalenes to form naphthalenes and tetralins.
dihydronaphthalene 26g and its disproportionation products,
the corresponding naphthalene 27g and tetralin 28g.19 Fast
disproportionation was observed not only for dihydronaph-
thalenes but also for cycloisomerized neopentylic thiol 30. The
use of thiirane 29 directly gave a mixture of desulfurized
tetralin 31 (41%) and the corresponding disulfide 32 (22%).20
While the disproportionation of thiols to disulfides and
hydrogen is a common reaction,21 the formation of a
hydrocarbon and a disulfide is unprecedented to the best of
our knowledge.
Finally, we also screened a panel of chiral Lewis and
Brønsted acid catalysts employing substrates 11a and 17d.
Unfortunately, we did not observe any asymmetric induction
(see the Supporting Information for screening).22 It is
noteworthy that for all of the substrates investigated, no five-
or seven-membered-ring systems were observed.23
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02296.
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REFERENCES
Experimental procedures, optimization screens, com-
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computational studies, and spectral data (PDF)
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Accession Codes
CCDC 2010932 contains the supplementary crystallographic
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AUTHOR INFORMATION
Corresponding Author
■
Thomas Magauer − Institute of Organic Chemistry and Center
for Molecular Biosciences, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria; orcid.org/0000-0003-
1290-9556; Email: thomas.magauer@uibk.ac.at
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Overman, L. E. Catalytic Enantioselective Synthesis of Quaternary
Authors
Matthias Schmid − Institute of Organic Chemistry and Center
for Molecular Biosciences, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria
Kevin R. Sokol − Institute of Organic Chemistry and Center for
Molecular Biosciences, Leopold-Franzens-University Innsbruck,
6020 Innsbruck, Austria
Lukas A. Wein − Institute of Organic Chemistry and Center for
Molecular Biosciences, Leopold-Franzens-University Innsbruck,
6020 Innsbruck, Austria
Sofia Torres Venegas − Institute of Organic Chemistry and
Center for Molecular Biosciences, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria
Christina Meisenbichler − Institute of Organic Chemistry and
Center for Molecular Biosciences, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria
Klaus Wurst − Institute of Organic Chemistry and Center for
Molecular Biosciences, Leopold-Franzens-University Innsbruck,
6020 Innsbruck, Austria
Maren Podewitz − Institute of Organic Chemistry and Center
for Molecular Biosciences, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria; orcid.org/0000-0001-
7256-1219
Carbon Stereocenters. Nature 2014, 516, 181. (d) Buschleb, M.;
̈
Dorich, S.; Hanessian, S.; Tao, D.; Schenthal, K. B.; Overman, L. E.
Synthetic Strategies toward Natural Products Containing Contiguous
Stereogenic Quaternary Carbon Atoms. Angew. Chem., Int. Ed. 2016,
55, 4156.
(11) (a) Schmid, M.; Grossmann, A. S.; Mayer, P.; Muller, T.;
̈
Magauer, T. Ring-expansion Approaches for the Total Synthesis of
Salimabromide. Tetrahedron 2019, 75, 3195. (b) Schmid, M.;
Grossmann, A. S.; Wurst, K.; Magauer, T. Total Synthesis of
Salimabromide: A Tetracyclic Polyketide from a Marine Myxobacte-
rium. J. Am. Chem. Soc. 2018, 140, 8444.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02296
(12) Bogert, M. T. A New Process for the Synthesis of Phenanthrene
and of Phenanthrene Derivatives; Science 1933, 77, 289.
(13) Cook, J. W.; Hewett, C. L. The Synthesis of Compounds
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Crafts Chemistry. Part 301. Facile Synthesis of Isomeric Tri-and
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of Suitably Methylated 1-(1- and 2-naphthyl)-3-pentanols. Indian J.
Chem. 2010, 49B, 203.
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(16) For a full optimization table, see the Supporting Information.
(17) In the case of 12n, the corresponding hydrolyzed diketone was
isolated in 11% yield.
Author Contributions
‡M.S. and K.R.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.M. acknowledges the European Research Council under the
European Union’s Horizon 2020 Research and Innovation
Programme (Grant Agreement 714049) and the Center for
Molecular Biosciences (CMBI). M.S. gratefully acknowledges
financial support from the German Academic Scholarship
Foundation and the German National Academy of Sciences
Leopoldina. L.A.W. and S.T.V. gratefully acknowledge financial
support by the Tyrolean Science Fund (TWF) (F.16642/5-
2019 to L.A.W. and UNI-0404/2354 to S.T.V). M.P. thanks
the Austrian Science Fund (FWF) (M-2005).
(18) Blanksby, S. J.; Ellison, G. B. Bond Dissociation Energies of
Organic Molecules. Acc. Chem. Res. 2003, 36, 255.
(19) For a proposed reaction mechanism, see the Supporting
Information.
E
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(20) The combined yield increased to 92% when trimethylsilyl
trifluoromethanesulfonate was used instead of sulfuric acid.
(21) Choi, J.; Yoon, N. M. Synthesis of Disulfides by Copper-
Catalyzed Disproportionation of Thiols. J. Org. Chem. 1995, 60, 3266.
(22) The use of an enantiomerically enriched epoxide (82% ee)
provided tetralin 12e with 70% ee (see ref 11).
(23) This result was also supported by computational studies at the
ωB97X-D/6-311G(d,p)/ SMD(F3CCH2OH) level employing 11e
(see the Supporting Information for details).
F
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