Asymmetric Synthesis of a 5,7-Fused Ring System Enabled by an Intramolecular Buchner Reaction with Chiral Rhodium Catalyst

Article abstract of DOI:10.1021/acs.orglett.9b04048

A Rh-catalyzed asymmetric intramolecular Buchner ring expansion of α-alkyl-α-diazoesters has been developed. The present protocol generates a 5,7-fused ring system in an enantioselective manner while minimizing β-hydrogen migration, which has been a competing reaction when using α-alkyl-α-diazoesters. The ester functionality at the bridgehead position would be a useful synthetic handle for further derivatization to complex molecules including natural products.

Full text of DOI:10.1021/acs.orglett.9b04048

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis of a 5,7-Fused Ring System Enabled by an
Intramolecular Buchner Reaction with Chiral Rhodium Catalyst
Takayuki Hoshi,† Eisuke Ota,† Yasuhide Inokuma,‡ and Junichiro Yamaguchi*,†
†Department of Applied Chemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan
‡Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Kita 13 Nishi 8 Kita-ku, Sapporo, Hokkaido
060-8628, Japan
S
* Supporting Information
ABSTRACT: A Rh-catalyzed asymmetric intramolecular Buchner ring
expansion of α-alkyl-α-diazoesters has been developed. The present
protocol generates a 5,7-fused ring system in an enantioselective
manner while minimizing β-hydrogen migration, which has been a
competing reaction when using α-alkyl-α-diazoesters. The ester
functionality at the bridgehead position would be a useful synthetic
handle for further derivatization to complex molecules including natural
products.
fused polycyclic architecture is one of the most
even in an enantioselective manner,6 undesired 6,6-fused ring
Acharacteristic motifs in bioactive molecules. Particularly, is often observed via rearomatization in a broad range of
substrates due to the electrophilic nature of the carbonyl group
at the β-position.7 Meanwhile, Buchner reaction of α-alkyl-α-
diazoesters predominantly results in β-hydrogen migration to
give α,β-unsaturated esters.5,8
Despite extensive research on the intramolecular Buchner
reaction, only one example demonstrated 5,7-fused ring
formation with high chemoselectivity over β-hydride migra-
tion.9,10 Moreover, its enantioselective variant has not been
reported to our knowledge.11 Thus, we sought to extend the
capability of the intramolecular Buchner reaction to enable
facile access to chiral 5,7-fused ring systems with an all-carbon
quaternary center at the bridgehead position, which could be
help facilitate the asymmetric synthesis of complex terpenoidal
natural products.
To overcome the main issue of β-hydride migration, we set
out to screen various rhodium catalysts with α-diazo
benzenepentanoic acid methyl ester (1A) as a substrate
(Table 1).12 The reaction was performed using 1A with 1 mol
% rhodium catalyst in 1,2-dichloroethane (1,2-DCE) at 0 °C.
With Rh2(OAc)4, 5-phenyl-2-pentenoic acid methyl ester (3A)
was predominantly obtained, which is consistent with previous
studies (Table 1, entry 1).5,8 Use of Rh2(TFA)4 and
Rh2(TPA)4 did not suppress the formation of 3A although
a 5,7-fused ring system is broadly recognized in terpenoidal
frameworks with multiple stereocenters.1 For example,
anticancer agents ingenol2a and pseudolaric acids2b,c as well
as rudmollin2d and other natural products2e,f have an all-carbon
quaternary center at the bridgehead position (Figure 1A).
Construction of this quaternary carbon at the bridgehead
position frequently requires multiple synthetic sequences and
cumbersome transformations, making facile access to this
skeleton challenging. As a powerful approach for the
preparation of such 5,7-fused ring systems, intramolecular
Buchner ring expansion of α-diazocarbonyl has been
utilized.1c,3,4 An attractive feature of this reaction is the ability
to form 5,7-fused rings with a quaternary carbon at the
bridgehead position in a single step from readily prepared
substituted benzenes (Figure 1B). However, the nature of the
substituents on the diazo carbon significantly affects the
reaction outcome, restricting the structural diversity of α-diazo
carbonyls that can be used.
In the intramolecular Buchner reaction, a carbene species
prepared from the diazo compounds attacks to the benzene
ring to form a cyclopropane as an intermediate, and then
subsequent divinylcyclopropane rearrangement provides the
5,7-fused ring. Rhodium and copper have been the most
commonly employed catalysts for the generation of the
carbene.3 The vast majority of α-diazo carbonyl substrates
have hydrogen or methyl group on the diazo carbon because a
competing β-hydride migration frequently occurs when the α-
diazocarbonyl has β-hydrogen atom.5 The propensity of β-
hydride migration is related to β-C−H bond strength, where
the C−H bond in a methyl group is the least likely to migrate.
On the other hand, β-keto-α-diazoester furnishes a 5,7-fused
ring with an angular quaternary ester group as a versatile
synthetic handle. Although this ring formation can proceed
Rh2(OPiv)4 furnished 55% of 2A with decreased amount of 3A
13a
(Table 1, entries 2−4).9 Rh2(esp)2
further improved the
yield along with a suppressed amount of 3A (Table 1, entry 5).
Thus, by a judicious choice of Rh catalyst, suppression of β-
hydride migration was achieved. Next, we turned our attention
to enantioselective Buchner ring expansion. When chiral Rh
13b
catalyst Rh2(S-PTPA)4 was used, 2A was produced in 58%
Received: November 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04048
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield in an enantioselective manner while maintaining the low
13c
yield of 3A (Table 1, entry 6). Rh2(S-PTTL)4 and Rh2(S-
13d
TCPTTL)4
were more effective and the latter exhibited
excellent enantioselectivity (Table 1, entries 7 and 8). Finally,
13e
we found that Rh2(S-TCPTAD)4
is the most effective
catalyst affording 2A in 72% yield with 91% ee (Table 1, entry
9).
With the optimal conditions (Table 1, entry 9) in hand, we
investigated the substrate scope using substituted benzenes
(Table 2). Buchner reaction of fluorobenzene 1B, chlor-
Table 2. Substrate Scope of Buchner Reaction with
Substituted Benzenes*
a
ab
,
entry
R
2, 5, 8 (%)
3, 6, 9 (%)
1
2
3
4
5
6
7
4-F
4-Cl
4-Br
4-Me
4-OMe
38
22
17
60
41
48
58
66
30
54
55
<5
c
2-OMe (4)
3-OMe (7)
24
c
87
Figure 1. (A) Natural products with a 5,7-fused ring system and a
bridgehead quaternary carbon. (B) Rhodium-catalyzed intramolecular
Buchner reaction of α-diazo carbonyl compounds.
*
Conditions: 1, 4, or 7 (0.20 mmol), Rh2(S-TCPTAD)4 (1 mol %),
a
1,2-DCE (4.0 mL), 0 °C, 15 min. 1H NMR yield was determined by
b
c
using CH2Br2 as an internal standard. E/Z mixture. single
regioisomer.
Table 1. Screening of Rhodium Catalysts*
obenzene 1C, and bromobenzene 1D all furnished 2 along
with significant amounts of olefin 3 (Table 2, entries 1−3).
Since electron-donating substituents would enhance nucleo-
philicity of the benzene ring and accelerate the Buchner
reaction,3 electron-donating groups were also examined.
Although methyl group (1E) furnished bicyclic skeleton 5 in
60% yield with less formation of 3, use of more electron-
donating methoxy (1F) substituents did not improve the yield
of 2 (Table 2, entry 5). These results indicated that a steric
effect rather than an electronic effect of the substituents on the
benzene ring influences the product distribution in this
Buchner ring expansion. To compare the effect of the
substituent position on the benzene ring, we further examined
the reaction using substrates possessing a methoxy group on
different positions (Table 2, entries 6 and 7). Whereas the 2-
methoxy substituent 4 gave 24% yield of the desired product 5,
3-methoxy 7 furnished the corresponding product 8 in
excellent yield along with a suppressed amount of the
migration product 9.
Given that 3-substituted benzenes are suitable substrates for
minimizing the formation of olefins, we next examined the
applicability of this reaction for enantioselective ring formation
(Scheme 1). A 3-methyl substituent on the parent benzene
(7B) successfully resulted in enantioenriched 5,7-fused ring
8B. Fluoro (7C), chloro (7D), and bromo (7E) groups were
accommodated to form the corresponding products 8C−8E
with high levels of enantioselectivity. Methoxy (7A), phenoxy
(7F), as well as trifluoromethoxy (7G), which is particularly
attractive for the pharmaceutical industry, were tolerated.
Additionally, a variety of aromatic rings including phenyl (7H),
*
Conditions: 1A (0.20 mmol), rhodium catalyst (1 mol %), 1,2-DCE
a
(4.0 mL), 0 °C, 15 min. 1H NMR yield was determined by using
CH2Br2 as an internal standard. The number in parentheses is the
isolated yield.
b
B
DOI: 10.1021/acs.orglett.9b04048
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
interaction in this intermediate was assumed between the
aromatic ring in the substrate and the phthalimide ligand as
well. The methylene chain linking the benzene and ester would
adopt the least strained conformation to form a transition state
involving the double bond on the benzene ring. In this
assembly, steric repulsion between the substituent at the 4-
position and the phthalimide ligand would interfere with
cyclopropanation to decrease the yield of cyclized product 2,
providing poor chemoselectivity because of the competing β-
hydrogen migration. On the other hand, the substituent at the
3-position is more distant from the ligand and reduces steric
hindrance, leading to the preferential formation of desired
product 2.15 To determine the absolute configuration of the
product 2, X-ray crystallographic analysis was performed. The
crystal structure of 8E possessing a bromide on the 7-
membered ring revealed that the cyclized product has an (R)-
configuration, which is expected as a result of the Buchner ring
expansion via the proposed transition state.
Scheme 1. Substrate Scope of Buchner Reactions with 3-
Substituted Benzenes
a
In conclusion, we present a new catalytic method for the
asymmetric synthesis of a 5,7-fused ring system that possesses
a chiral center at the bridgehead carbon. The choice of Rh2(S-
TCPTAD)4 minimized the competing olefination to enable
access to a wide range of bicyclic products starting from an α-
diazoester possessing a β-hydrogen. The development of more
efficient catalysts and the expansion of the substrate scope, as
well as application to natural product synthesis, are currently
under investigation in our laboratory.
a
Conditions: 7 (0.20 mmol), Rh2(S-TCPTAD)4 (1 mol %), 1,2-DCE
(4.0 mL), 0 °C, 15 min. Yields signify isolated and purified materials.
Enantiomeric excess was determined by HPLC analysis.
ASSOCIATED CONTENT
■
4-methoxyphenyl (7I), and even bulky 3,5-dimethylphenyl
(7J) and thienyl (7K) were found to be suitable substrates.
Remarkably, in all cases the reaction provided 5,7-fused rings
as a single regioisomer.
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04048.
At this moment, we can only speculate on structure of the
rhodium carbenoid intermediate that rationalizes the chemo-
and regioselectivity observed above. Davies and co-workers
reported a rhodium-catalyzed asymmetric intermolecular C−H
insertion in which the stable structure of Rh2(S-
TCPTAD)4[(p-Br-C6H4)C(COOMe)] carbene intermediate
was proposed by a combination of X-ray structural analysis and
computational studies.14 According to this study, π−π
interaction between the aromatic ring in the substrate and
phthalimide in the rhodium catalyst, as well as CO−π
interaction exists in the intermediate carbene. If a similar
rhodium carbenoid is generated in our ring expansion, a
plausible intermediate to provide the cyclopropane could be as
depicted in Figure 2. Similar to Davies’ proposal, the π−π
Detailed experimental procedures, spectral data for all
1
compounds, and H, and 13C NMR spectra (PDF)
Accession Codes
CCDC 1962381−1962382 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: junyamaguchi@waseda.jp.
ORCID
Yasuhide Inokuma: 0000-0001-6558-3356
Junichiro Yamaguchi: 0000-0002-3896-5882
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant No.
JP19H02726, JP18H04272 (to J.Y.). We thank Mr. Yumehiro
Manabe (Hokkaido University) for his support of single-crystal
X-ray analysis. The Materials Characterization Central
Laboratory at Waseda University is acknowledged for HRMS
measurement.
Figure 2. (A) Plausible transition state of the rhodium carbenoid
derived from α-diazoester and Rh2(S-TCPTAD)4. (B) X-ray
crystallographic analysis. ORTEP drawing of 8E with 50% thermal
ellipsoid.
C
DOI: 10.1021/acs.orglett.9b04048
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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