Rapid Construction of Tetralin, Chromane, and Indane Motifs via Cyclative C-H/C-H Coupling: Four-Step Total Synthesis of (±)-Russujaponol F

Article abstract of DOI:10.1021/jacs.0c12484

The development of practical C-H/C-H coupling reactions remains a challenging yet appealing synthetic venture because it circumvents the need to prefunctionalize both coupling partners for the generation of C-C bonds. Herein we report a cyclative C(sp3)-H/C(sp2)-H coupling reaction of free aliphatic acids enabled by a cyclopentane-based mono-N-protected β-amino acid ligand. This reaction uses inexpensive sodium percarbonate (Na2CO3·1.5H2O2) as the sole oxidant and generates water as the only byproduct. A range of biologically important scaffolds, including tetralins, chromanes, and indanes, can be easily prepared by this protocol. Finally, the synthetic application of this methodology is demonstrated by the concise total synthesis of (±)-russujaponol F in a four-step sequence starting from readily available phenylacetic acid and pivalic acid through sequential functionalizations of four C-H bonds.

Full text of DOI:10.1021/jacs.0c12484

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Rapid Construction of Tetralin, Chromane, and Indane Motifs via
Cyclative C−H/C−H Coupling: Four-Step Total Synthesis of
( )-Russujaponol F
Zhe Zhuang, Alastair N. Herron, Shuang Liu, and Jin-Quan Yu*
Cite This: J. Am. Chem. Soc. 2021, 143, 687−692
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ABSTRACT: The development of practical C−H/C−H coupling reactions remains a challenging yet appealing synthetic venture
because it circumvents the need to prefunctionalize both coupling partners for the generation of C−C bonds. Herein we report a
cyclative C(sp3)−H/C(sp2)−H coupling reaction of free aliphatic acids enabled by a cyclopentane-based mono-N-protected β-
amino acid ligand. This reaction uses inexpensive sodium percarbonate (Na2CO3·1.5H2O2) as the sole oxidant and generates water
as the only byproduct. A range of biologically important scaffolds, including tetralins, chromanes, and indanes, can be easily prepared
by this protocol. Finally, the synthetic application of this methodology is demonstrated by the concise total synthesis of
( )-russujaponol F in a four-step sequence starting from readily available phenylacetic acid and pivalic acid through sequential
functionalizations of four C−H bonds.
focused on the coupling of two relatively reactive C(sp2)−H
bonds for biaryl synthesis,3 whereas only a few reactions have
been reported for the construction of more challenging
C(sp3)−C(sp2) bonds. Because these existing reaction
protocols require exogenous directing groups (DGs) to
promote cyclometalation, additional steps to install and
remove the DG are necessary.5,6 Additionally, reported
methods pose practical limitations, such as the stoichiometric
use of precious silver salts4b,c,5,6b,c and harsh condi-
tions,4b,c,5a,b,6 with temperatures as high as 160 °C being
reported. Moreover, current methods for C(sp3)−H/C(sp2)−
H coupling initiated by C(sp3)−H activation are largely
limited to more reactive heterocyclic C(sp2)−H bonds.5a,b,6
Despite the great value that C−H/C−H coupling reactions
might have for organic synthesis, the development of C(sp3)−
H/C(sp2)−H coupling reactions that use both a practical
oxidant and native substrates remains a significant challenge.
Recent advances in C−H functionalization have provided
chemists with creative and strategic retrosynthetic disconnec-
tions that are otherwise difficult to achieve using traditional
methods.7 However, for C−H functionalization strategies to
truly improve the overall efficiency of synthesis, three criteria
should be met: (1) the ability to use a wide range of simple
starting materials to enable the synthesis of diverse natural
product families; (2) the use of native functionalities as DGs;
(3) precise control of the site selectivity of the C−H
functionalization reaction. Given the ubiquitous nature of
arbon−carbon (C−C) bond formation constitutes one of
Cthe most important classes of reactions in organic
synthesis. Because of its potential to shorten synthesis, the
past two decades have witnessed rapid developments in using
C−H activation strategies for the construction of C−C bonds.1
While most coupling methods require prefunctionalized
coupling partners (e.g., organoborons and organohalides),
C−H/C−H coupling reactions offer a complementary strategy
to construct C−C bonds directly from two simple C−H bonds
(Scheme 1A).2 Compared with traditional coupling methods,
this green and atom-economical approach is highly attractive
because water is potentially the sole stoichiometric byproduct
of this process (Scheme 1A). To date, extensive studies have
Scheme 1. C−H Activation/C−C Bond-Forming Reactions
Received: November 30, 2020
Published: January 4, 2021
https://dx.doi.org/10.1021/jacs.0c12484
J. Am. Chem. Soc. 2021, 143, 687−692
© 2021 American Chemical Society
687

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Table 1. Ligand Investigation for the Cyclative C(sp3)−H/
C−H bonds in organic molecules, synthetic sequences that
incorporate multiple C−H functionalizations are particularly
attractive for the efficient synthesis of natural products.
However, approaches that meet these aforementioned criteria
are challenging to execute and thus are uncommon in the
literature.7a,8
a b
,
C(sp2)−H Coupling Reaction
To address these challenges, we herein report a cyclative
C(sp3)−H/C(sp2)−H coupling reaction using a native free
carboxylic acid as the DG (Scheme 1B). The use of a
cyclopentane-based mono-N-protected β-amino acid ligand
and a practical and inexpensive oxidant, sodium percarbonate
(Na2CO3·1.5H2O2), proved crucial to the success of this
reaction. Tetralins, chromanes, and indanes, which are
common frameworks in natural products, can be readily
prepared by this protocol (Figure 1). The synthetic application
a
Conditions: 1a (0.1 mmol), Pd(OAc)2 (10 mol %), ligand (L) (10
mol %), LiOAc (1.0 equiv), Na2CO3·1.5H2O2 (2.0 equiv), HFIP (1.0
b
mL), 60 °C, 12 h. The yields were determined by 1H NMR analysis
of the crude products using CH2Br2 as the internal standard. Isolated
c
Figure 1. Biologically significant natural products containing tetralin,
chromane, or indane frameworks.
yield.
L3 (57% vs 19−45%), as was also observed in other C(sp3)−H
functionalization reactions of free acids via Pd(II)/Pd(IV)
catalytic cycles.10d,i,j Through systematic modifications of the
backbone of the β-amino acid ligand (L5−L10), we found that
cis-cyclopentane-based ligand ( )-L9 gave the optimal
reactivity (78% isolated yield). The superior reactivity of
( )-L9 might be attributed to the more rigid conformation
enforced by the cyclopentane linkage. Control experiments
showed that the yields were low in the absence of the ligand or
in the presence of the γ-amino acid ligand L11 (23% or 20%,
respectively), indicating the importance of six-membered
chelation by the ligand for reactivity.
With the optimal ligand and reaction conditions in hand, we
evaluated the scope of the cyclative C(sp3)−H/C(sp2)−H
coupling reaction (Table 2). A wide range of tertiary aliphatic
acids bearing a single α-methyl group (1a−e and 1h) or an α-
gem-dimethyl group (1f and 1g) were all compatible, affording
the tetralin products in moderate to good yields (45−78%).
The reaction could also be conducted on a 2.0 mmol scale,
delivering 2a in 69% yield. The attempted desymmetrization of
the α-gem-dimethyl group of 1f using enantioenriched L9
resulted in racemic product. Less reactive free carboxylic acids
containing α-hydrogens (1i−l) also reacted in synthetically
useful yields (35−63%). Among these, a variety of function-
alities on the aryl rings such as methyl (2b), methoxy (2j and
2k), fluoro (2c, 2g, and 2l), and chloro (2d) as well as
naphthyl (2e) were tolerated, with the halogen moiety (2d)
serving as a useful synthetic handle for subsequent
derivatization. This protocol could also be successfully
extended to the synthesis of biologically important chromane
products. β-Phenoxy carboxylic acids containing an α-gem-
dimethyl group (1m−r) or α-hydrogens (1s, from Roche
ester) were all reactive substrates. While a range of electron-
donating (methoxy, tert-butyl, cyclohexyl, and benzyl) groups
on the aryl ring (2s and 2n−p) were well-tolerated to afford
the desired products in good yields (70−85%), aliphatic acids
containing electron-withdrawing (bromo and trifluoromethyl)
of this methodology is further demonstrated by a concise total
synthesis of ( )-russujaponol F (the shortest and highest-
yielding synthesis reported to date) via multiple C−H
functionalizations in four steps from readily available phenyl-
acetic acid and pivalic acid (Scheme 1C), demonstrating the
potential of C−H activation disconnections to enhance the
ideality of synthesis.9
Aliphatic carboxylic acids are ubiquitous and synthetically
versatile motifs and are often inexpensive reagents in organic
chemistry; as such, they are privileged substrates for C−H
activation reactions.10 Following our recent disclosure of the β-
C(sp3)−H lactonization10i and acyloxylation10j of free
carboxylic acids using tert-butyl hydrogen peroxide (TBHP)
as the sole oxidant, we initiated our investigation of cyclative
C(sp3)−H/C(sp2)−H coupling reactions by selecting TBHP
as the bystanding oxidant and aliphatic acid 1a as a model
substrate. Under the optimal conditions of the aforementioned
β-acyloxylation reaction,10j we were delighted to observe a 50%
1H NMR yield of the desired product 2a without the formation
of competing reductive elimination products, such as the β-
lactone or β-hydroxy acid (see Table S1). Further investigation
of the bystanding oxidants and bases revealed that the
combination of Na2CO3·1.5H2O2 and LiOAc could further
improve the yield to 57% (see Tables S1 and S2). The yields
using LiOAc are generally better than those using NaOAc as
the metal additive under the optimized conditions (see Table
S4). The use of sodium percarbonate, one of the cheapest and
most easily handled oxidants,11 potentially renders this
protocol practical and scalable. In light of recent advances in
ligand-accelerated Pd(II)-catalyzed C−H activation,12 we next
searched for ligands that could substantially improve the
reactivity of the catalyst. Guided by mono-N-protected amino
acid (MPAA) ligand-enabled C(sp3)−H activation reactions of
free carboxylic acids,10c,d,g,i,j we tested a series of commercially
available MPAA ligands L1−L4 (Table 1): β-amino acid ligand
L4 showed superior reactivity over α-amino acid ligands L1−
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Table 2. Substrate Scope of the Cyclative C(sp3)−H/
bearing a tert-butyl group (1n) afforded a mixture of
regioisomers (2n/2n′ = 3/1). Considering the previously
observed high para selectivity of Pd(IV)-mediated C−H
coupling reactions of anisoles,3g,5c,22 it is likely that the
alkyl−Pd(II) intermediate is oxidized to Pd(IV) prior to C−H
activation. Under the present conditions, carboxylic acid 1t
containing either NBoc or NTs groups failed to deliver
tetrahydroisoquinoline (THIQ) product 2t. This cyclative C−
H/C−H coupling reaction was also amenable to the syntheses
of indane scaffolds (2u−w). Notably, an [F+] oxidant3g,13 (1-
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate) showed
superior reactivity for tertiary aliphatic acids containing an α-
gem-dimethyl group (2v and 2w) (see Table S5).
a b
,
C(sp2)−H Coupling Reaction
Illudalane sesquiterpenes constitute a large family of natural
products that typically feature an indane core (for which
various oxidation states are possible) bearing a challenging all-
carbon quaternary center (Scheme 2A).14 Because of their
a
Scheme 2. Total Synthesis of ( )-Russujaponol F
a
Conditions: (a) SOCl2, EtOH, reflux, overnight; I2 (0.5 equiv),
Selectfluor (0.5 equiv), CH3CN, 60 °C, 3 h. (b) Pd(OAc)2 (10 mol
%), L12 (10 mol %), pivalic acid (3.0 equiv), CsOAc (1.0 equiv),
Ag2CO3 (2.0 equiv), HFIP, 80 °C, 12 h. (c) Pd(CH3CN)4(BF4)2 (10
mol %), Ag2CO3 (1.0 equiv), 1-fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate (2.0 equiv), HFIP, 90 °C, 12 h. (d) LAH (3.0
equiv), THF, 0 °C to rt, overnight.
a
Conditions A: 1 (0.1 mmol), Pd(OAc)2 (10 mol %), ( )-L9 (10
mol %), LiOAc (1.0 equiv), Na2CO3·1.5H2O2 (2.0 equiv), HFIP (1.0
b
c
mL), 60 °C, 12 h. Isolated yields are shown. Conditions B: 1 (0.1
mmol), Pd(CH3CN)4(BF4)2 (10 mol %), Ag2CO3 (1.0 equiv), 1-
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (2.0 equiv), HFIP
d
(1.0 mL), 90 °C, 12 h. The reaction was run on a 2.0 mmol scale.
promising biological activities, tremendous efforts have been
devoted to the total syntheses of these targets.15,16 Given the
power of this methodology for the construction of indane
scaffolds, we embarked on the total synthesis of ( )-russuja-
ponol F via multiple C−H functionalizations (Scheme 2B).
Baudoin’s group reported the first total synthesis of
russujaponol F in racemic and enantioselective forms based
on a C(sp3)−H arylation strategy in 13 steps (26% yield) and
15 steps (12% yield), respectively.15 Beginning with phenyl-
acetic acid 3, which is commercially available or can be
synthesized through o-C−H methylation,17 we were able to
prepare aryl iodide 4 by esterification and subsequent
groups (2q and 2r) showed comparatively low reactivity (31%
and 17%), likely due to the sluggish nature of C(sp2)−H
activations of electron-deficient arenes. Although intermolec-
ular kinetic isotope effect (KIE) experiments of electron-rich
1m and 1m-d5 (kH/kD = 1.1) suggest that C(sp2)−H activation
is not the rate-determining step (see the KIE experiments
section in the Supporting Information), the possibility of
C(sp2)−H activation with electron-deficient substrates as the
rate-determining step cannot be ruled out. It is noteworthy
that high regioselectivity was observed for the aliphatic acids
containing m-methoxy groups (1j and 1s), while the substrate
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Communication
monoiodination18 of 3 using I2 and Selectfluor in 79% yield.
Investigation of the C−H arylation of pivalic acid indicated
that with ligand L1210f,19 the monoarylated product 5 could be
obtained in 62% yield, along with a 12% yield of the cyclative
C−H/C−H coupling product 6 (see Table S6). The formation
of 6 under these conditions might be attributed to a second
arylation of 5 with additional aryl iodide serving as the
bystanding oxidant.20 The cyclative C−H/C−H coupling was
then performed under the standard conditions using an [F+]
oxidant to give the desired product 6 in 41% yield. Finally,
global reduction of 6 using LAH cleanly delivered
( )-russujaponol F in 96% yield, completing the total
synthesis in four steps and 28% overall yield; this is the
shortest and highest yielding total synthesis of russujaponol F
to date.
In summary, we have realized a Pd(II)-catalyzed cyclative
C(sp3)−H/C(sp2)−H coupling reaction enabled by a cyclo-
pentane-based mono-N-protected β-amino acid ligand. The
use of inexpensive sodium percarbonate as the sole oxidant and
native free carboxylic acids as directing groups renders this
reaction highly practical and potentially amenable to large-scale
manufacturing. A range of biologically significant scaffolds,
including tetralins, chromanes, and indanes, could be readily
prepared by this protocol. The synthetic application of this
methodology was demonstrated by a concise total synthesis of
( )-russujaponol F via multiple C−H functionalizations in
four steps from readily available phenylacetic acid and pivalic
acid.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12484.
■
On the basis of literature precedents3−5 and our recent work
on the C−H activation of free acids,10i,j we propose that this
cyclative C(sp3)−H/C(sp2)−H coupling reaction proceeds via
a Pd(II)/Pd(IV) catalytic cycle as outlined in Scheme 3. First,
sı
Full experimental details and characterization of new
compounds (PDF)
Scheme 3. Proposed Mechanism of the Cyclative C(sp3)−
H/C(sp2)−H Coupling Reaction
AUTHOR INFORMATION
Corresponding Author
■
Jin-Quan Yu − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0003-3560-5774; Email: yu200@
scripps.edu
Authors
Zhe Zhuang − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United
States; orcid.org/0000-0001-6679-0496
Alastair N. Herron − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United
States; orcid.org/0000-0001-7141-3986
Shuang Liu − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12484
Notes
The authors declare no competing financial interest.
coordination of Pd(OAc)2 to an MPAA ligand generates the
active LPd(II) species. After coordination of acid substrate 1 to
Pd, both the Na+ or Li+ countercation and the MPAA ligand
accelerate the cyclopalladation of the β-C(sp3)−H bond to
form int-I. Next, oxidative addition of the hydrogen peroxide
occurs to produce int-II, a process established in previous
studies on the oxidation of Pd(II) to Pd(IV) by benzoyl
peroxide,21a tert-butyl peroxyacetate,21b or hydrogen perox-
ide.21c,d In the previously reported β-lactonization10i and
acetoxylation10j reactions, selective reductive elimination yields
the β-lactone and β-acetoxylated carboxylic acid, respectively.
In this case, a reactive phenyl group on the side chain of the
substrate undergoes a second C(sp2)−H activation of int-II to
deliver int-III via a seven- or six-membered palladacycle,
enabled by the facile dissociation of the weakly coordinating
free acid.22 However, it is also possible that the Pd(II) species
int-I performs the second C−H activation prior to the
oxidative addition of hydrogen peroxide that generates int-III.
Finally, reductive elimination of int-III generates the cyclative
C−H/C−H coupling product 2 and regenerates the LPd(II)
species.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the NIH (NIGMS,
R01GM084019), the NSF under the CCI Center for Selective
C−H Functionalization (CHE-1700982), and The Scripps
Research Institute for financial support. Z.Z. thanks Dr. Nelson
Y. S. Lam for proofreading.
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2
́
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