Synthesis of Polycyclic Spirocarbocycles via Acid-Promoted Ring-Contraction/Dearomative Ring-Closure Cascade of Oxapropellanes

Article abstract of DOI:10.1021/acs.orglett.9b02835

We report herein the development of an acid-promoted rearrangement of oxa[4.3.2]propellanes to afford polyaromatic-fused spiro[4.5]carbocycles. DFT calculations suggest that the reaction pathway involves generation of a cyclobutyl cation, ring contraction

Full text of DOI:10.1021/acs.orglett.9b02835

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Polycyclic Spirocarbocycles via Acid-Promoted Ring-
Contraction/Dearomative Ring-Closure Cascade of Oxapropellanes
Naoki Ogawa, Yousuke Yamaoka, Hiroshi Takikawa, and Kiyosei Takasu*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
S
* Supporting Information
ABSTRACT: We report herein the development of an acid-promoted rearrangement of oxa[4.3.2]propellanes to afford
polyaromatic-fused spiro[4.5]carbocycles. DFT calculations suggest that the reaction pathway involves generation of a
cyclobutyl cation, ring contraction to the cyclopropylcarbinyl cation, and dearomative ring closure by an internal 2-naphthol
moiety. The resulting spirocarbocycles are synthetically valuable, as they could be transformed into two different polycyclic
aromatic hydrocarbons via skeletal rearrangement. Syntheses of optically pure spirocarbocycles via a central-to-axial-to-central
chirality transfer are also described.
mong the many attractive spirocarbocycles, the
benzospiro[4.5]decane skeleton (I) attracts considerable
A
attention in a wide variety of research areas. A number of
compounds possessing this skeleton in combination with
polycyclic ring systems appear as biologically active com-
pounds1 and synthetic dyes2 (Figure 1). They are also
important as organic functional materials such as light-emitting
diodes,3 hole-transporting materials for solar cells,4 and
functional polymers.5
The advantage of this class of compounds, especially in
materials science, is their rigid and stable and three-
dimensional structures derived from the spirocyclic rings that
enable the engineering of solid-state structures and properties.6
In addition, their fused π-conjugation system is important for
the luminescence and semiconducting properties of organic
functional materials. Thus, developing new methods to prepare
polycyclic spirocycles with benzospiro[4.5]decane skeletons is
an important research objective in synthetic organic chemistry.
One rational approach to synthesizing this skeleton is the
dearomative spirocyclization of naphthol compounds (Scheme
1). It is well-known that heterocyclic spiro-compounds can be
synthesized by intramolecular nucleophilic attack from an
internal heteroatom to a naphthol moiety in the presence of a
hypervalent iodine reagent (Scheme 1a).7 However, utilization
of this dearomatization strategy to give a carbocyclic spiro
system like the benzospiro[4.5]decane skeleton is relatively
limited. It has been shown that the elegant use of transition-
metal catalysts8 enables the spirocyclization of β-naphthols to
produce the benzospiro[4.5]decane skeleton. These methods
Figure 1. Representative examples of polycyclic spirocarbocycles
possessing benzospiro[4.5]decane skeleton (I).
utilized organometallic species as the electrophile and a
naphthol ring as the nucleophile (Scheme 1b).9 Herein, we
report a new strategy for the construction of the
benzospiro[4.5]decane skeleton where the naphthol ring is
dearomatized by cyclopropylcarbinyl cation (Scheme 1c).
Received: August 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02835
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Letter
metastable intermediate by a ring-contraction rearrangement.
If the cyclopropane ring of 3 reacts with the C1 carbon of the
internal naphthol moiety, the desired benzo-fused spiro[4.5]-
decane 4 will be produced. It is well-known that Friedel−
Crafts (type) alkylations of alkyl cations with aromatics usually
suffer from undesired hydride or alkyl group migrations due to
the instability of the carbocations, leading to undesired
products, mixtures of isomers, or both.12 We envisaged that
the utilization of cyclopropylcarbinyl cation intermediate 3
would overcome these side reactions thanks to the stabilization
of the carbocation by the cyclopropane ring13 while having
sufficient reactivity toward the naphthol ring owing to its high
ring strain.
Scheme 1. Two Modes of the Dearomative Spirocyclization
of Naphthols and the Strategy of This Work
We first investigated the reaction of oxa[4.3.2]propellane 1a
by treatment with various acids (Table 1). The treatment of
We previously reported that a cyclobutyl cation (B)
generated from the corresponding cyclobutanol (A) under-
went a ring-contraction rearrangement to form a cyclopropane
intermediate (C), which reacted with external nucleophiles
such as solvents and counteranions to form functionalized
phenanthrenes (D) (Scheme 2a).10 We also reported the
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Previous Work and Current Strategy toward
Polycyclic Spirocarbocycles
% yield
entry
acid
TfOH
TfOH
TfOH
MsOH
BF3OEt2
B(C6F5)3
Ph3C+BF4
temp (°C)
time (h)
4a
75
38
83
0
0
5a
22
46
7
trace
0
15
1
2
3
4
5
6
7
rt
50
−20
rt
rt
rt
2.0
0.33
0.33
3.0
2.0
5.5
31
trace
−
80
15
19
a
Reactions were performed with 1a (0.050 mmol) and acid (2.0
equiv) in DCE (1.0 mL). Yields were determined by 1H NMR of the
crude reaction mixtures using Ph3CH as an internal standard. TfOH =
trifluoromethanesulfonic acid; MsOH = methanesulfonic acid; DCE =
1,2-dichloroethane.
compound 1a with TfOH at room temperature afforded the
desired spirocarbocycle 4a in 75% yield, although the
undesired oxacycle 5a was also formed in 22% yield (entry
1). The structures of these two compounds were unambigu-
ously determined by X-ray crystallographic studies (Figure 2).
Compound 4a was formed by nucleophilic attack from the C1
carbon of the naphthol ring to the cyclopropane ring at the
more substituted carbon atom, which is in accordance with
reported regioselectivity.14 Compound 5a apparently formed
synthesis of oxapropellanes 1 via a KHMDS-promoted domino
[2 + 2] cycloaddition−SNAr reaction of readily available biaryl
compounds (Scheme 2b).11 Based on these findings, we
envisioned that oxapropellane 1 would be a viable precursor
for the construction of a benzospiro[4.5]decane skeleton via
dearomative spirocyclization (Scheme 2c): compound 1 would
undergo C−O bond cleavage upon an acid treatment to form
cyclobutyl cation 2 possessing a β-naphthol moiety, which
would transform into cyclopropylcarbinyl cation 3 as a
Figure 2. Crystal structures of compounds 4a and 5a. Thermal
ellipsoids are shown at 50% probability.
B
DOI: 10.1021/acs.orglett.9b02835
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Letter
via nucleophilic attack to the cyclopropane ring of intermediate
3 from the oxygen atom of the naphthol moiety instead of the
carbon atom. The selectivity of products sifted toward oxacycle
5a preference at a higher reaction temperature (entry 2). On
the other hand, lowering the reaction temperature to −20 °C
effectively improved the selectivity to give the desired
compound 4a in 83% yield (entry 3). MsOH, a weaker
Brønsted acid, did not promote the spirocyclization of
compound 1a, and desired compound 4a was not detected
(entry 4). Lewis acids such as BF3·OEt2, B(C6F5)3, and
affording compounds 4i and 4j in 84% and 79% yields,
respectively.
DFT calculations were conducted to evaluate the working
mechanistic hypothesis proposed in Scheme 2c (Figure 3).
−
Ph3C+BF4 were not effective (entries 5−7).
With the optimized reaction conditions in hand, the scope of
the reaction was examined with attention to the reactivity
dependence upon the substituent(s) and aromatic ring systems
(Table 2). Both electron-donating and -withdrawing groups on
a
Table 2. Scope of the Reaction
Figure 3. Computed energy profile for the rearrangements of
oxapropellane 1f. Free energies (kcal/mol) calculated at
mPW1PW91/6-311+G(2d,p)-CPCM(DCE)//B3LYP/6-31G(d,p)-
CPCM(DCE) are displayed.
The calculations suggested that in the presence of a Brønsted
acid oxapropellane 1 undergoes rapid ring opening (ΔG⧧ =
0.80 kcal/mol) followed by essentially barrierless ring
contraction to form cyclopropylcarbinyl cation 3. The single
bonds of the cyclopropane ring adjacent to the carbocation,
C1−C2 and C1−C3, are significantly longer (1.60 and 1.61 Å,
respectively) than that of unsubstituted cyclopropane (1.51
Å),15 which confirms that stabilization of the carbocation by
the cyclopropane ring is effective in this case. The driving force
of the rapid ring-opening/ring-contraction sequence is the
release of the high ring strain of the propellane structure and
the formation of a carbocation stabilized by the adjunct
cyclopropane ring. The rate-determining step of the reaction is
the key dearomative spirocyclization, whose activation free
energy barrier was calculated to be 20.7 kcal/mol. The
competitive nucleophilic attack from the oxygen atom to the
cyclopropane ring of 3, which affords oxacycle 5f, was
calculated to be disadvantageous by 3.6 kcal/mol.
We recognized that these rearrangements of oxapropellanes
have great potential for the synthesis of optically active
spirocycles via chirality transfer from starting materials 1
(Scheme 3). To examine this hypothesis, optically active
(+)-1a (99% ee) was prepared by preparative chiral HPLC and
subjected to the optimized reaction conditions. We were
pleased to find that (+)-4a was obtained without any loss of
optical purity. The chirality transfer from oxapropellane (+)-1f
(99% ee) to compound (+)-4f was also successful. These
results indicated that the epimerization/racemization by bond
rotation along the chiral axis in intermediates 2 and 316,17 did
not occur during the entire reaction cascade, realizing the
sequential central-to-axial-to-central chirality transfer.18−20 The
absolute configurations of these compounds, shown in Scheme
3, were determined by X-ray crystallography (for (+)-1a,
a
Reaction conditions: oxapropellanes 1 (0.10−0.20 mmol) and TfOH
(2.0 equiv) in DCE (0.05 M) at −20 °C for 20 min. Isolated yields
are shown. Reaction was carried out for 80 min. Reaction was
carried out at room temperature for 10 min.
b
c
the benzene ring (Ar1) of substrates 1 were well tolerated, and
the desired spirocycles 4b and 4c were obtained in high yields.
An electron-donating group on the naphthalene ring (Ar3) was
also tolerated, and compound 4d was obtained in 92% yield.
Incorporating a heteroaromatic ring system resulted in
compound 4e in 62% yield. In this case, oxacycle 5e was
also obtained in 31% isolated yield. The geminal dimethyl
group on the oxapropellane was not essential; compounds 4f−
h lacking the gem-dimethyl group on the cyclopentane ring
moiety could also be obtained in good to excellent yields by
using a slightly higher reaction temperature. To our delight,
reaction with a further extended π-system was also successful,
C
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Letter
yield over two steps along with 9% of compound 7. Oxidation
of compound 8 afforded a helical PAH, benzo-fused [5]-
helicene 10, whose unique structure and properties have
attracted considerable attention in a variety of research
areas.22,23 These results highlight the synthetic utility of
spirocycles 4 obtained by this method. Although the origin of
the bond selectivity during the skeletal rearrangement is not
yet fully clear, the elimination of the leaving group and
migration of the C−C bond seemed to proceed in a stepwise
rather than concerted manner under both reaction conditions,
as the relative configuration of the OH group did not
significantly affect the bond selectivity.24
Scheme 3. Chirality Transfer in the Rearrangement of
Oxapropellanes 1a and 1f
In summary, an acid-promoted cascade ring-contraction/
dearomative ring-closure reaction was developed to synthesize
polycyclic spirocarbocycles. A variety of substituted and π-
extended targets were obtained in high yields. Optically active
spirocycles were also successfully synthesized via sequential
central-to-axial-to-central chirality transfer. Bond-selective
rearrangement of the reaction products highlighted the
synthetic utility of the spirocycles obtained by this method.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02835.
(+)-4a, and (+)-4f) or CD spectra (for (+)-1f, see the
Supporting Information for details).
Finally, the synthetic application of the spirocarbocycles
prepared by this method was investigated. It was found that
spirocarbocycles are attractive as synthetic intermediates for
two different types of polycyclic aromatic hydrocarbons
(PAHs) via bond-selective skeletal rearrangements (Scheme
4). 1,2-Reduction of the enone moiety of 4f by Luche’s
Supplementary figures, experimental procedures, char-
1
acterization data, H and 13C NMR spectra (PDF)
Accession Codes
CCDC 1944319−1944325 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 4. Synthetic Transformations of Spirocarbocycle 4
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kay-t@pharm.kyoto-u.ac.jp.
ORCID
Naoki Ogawa: 0000-0002-1120-7467
Yousuke Yamaoka: 0000-0003-3641-8823
Hiroshi Takikawa: 0000-0002-4414-2129
Kiyosei Takasu: 0000-0002-1798-7919
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
method proceeded smoothly to give alcohol 6 in good yield.
After several reaction conditions for the skeletal rearrangement
of alcohol 6 were screened, it was found that treatment with
MsOH in hexafluoroisopropanol (HFIP) facilitated elimina-
tion of the OH group followed by bond-selective migration of
the adjacent Csp3−Csp2 bond (bond A) and rearomatization of
the naphthalene ring to give compound 7 in 76% isolated yield
along with 16% of minor product 8. Oxidation of compound 7
gave benzo-fused picene 9, which would be attractive as an
organic field-effect transistor.21 Alternatively, mesylation of
alcohol 6 followed by treatment with silica gel in EtOAc
resulted in the elimination of the OMs group and migration of
the Csp3−Csp3 bond (bond B) to afford compound 8 in 61%
■
We thank JSPS KAKENHI (Grant Nos. JP19H03350 and
JP19K22185), MEXT KAKENHI (Grant No. JP18H04406 in
Middle Molecular Strategy), AMED Platform for Supporting
Dr ug Discovery an d Life Scie nce Research
(JP19am0101092j0003), and the Sasakawa Scientific Research
Grant from The Japan Science Society. N.O. appreciates JSPS
for a research fellowship for young scientists (JP19J14061).
REFERENCES
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