Asymmetric Total Syntheses of Di- and Sesquiterpenoids by Catalytic C?C Activation of Cyclopentanones

Article abstract of DOI:10.1002/anie.201915821

To show the synthetic utility of the catalytic C?C activation of less strained substrates, described here are the collective and concise syntheses of the natural products (?)-microthecaline A, (?)-leubehanol, (+)-pseudopteroxazole, (+)-seco-pseudopteroxazole, pseudopterosin A–F and G—J aglycones, and (+)-heritonin. The key step in these syntheses involve a Rh-catalyzed C?C/C?H activation cascade of 3-arylcyclopentanones, which provides a rapid and enantioselective route to access the polysubstituted tetrahydronaphthalene cores presented in these natural products. Other important features include 1) the direct C?H amination of the tetralone substrate in the synthesis of (?)-microthecaline A, 2) the use of phosphoric acid to enhance efficiency and regioselectivity for problematic cyclopentanone substrates in the C?C activation reactions, and 3) the direct conversion of serrulatane into amphilectane diterpenes by an allylic cyclodehydrogenation coupling.

Full text of DOI:10.1002/anie.201915821

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Asymmetric Total Syntheses of Di- and Sesqui-Terpenoids via
Catalytic C–C Activation of Cyclopentanones
Authors: Guangbin Dong, Si-Hua Hou, Adriana Y. Prichina, and
Mengxi Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915821
Angew. Chem. 10.1002/ange.201915821
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10.1002/anie.201915821
Angewandte Chemie International Edition
RESEARCH ARTICLE
Asymmetric Total Syntheses of Di- and Sesqui-Terpenoids via
Catalytic C–C Activation of Cyclopentanones
Si-Hua Hou,a Adriana Y. Prichina,a Mengxi Zhanga and Guangbin Donga*
[a]
Dr. S.-H. Hou, A. Y. Prichina, M. Zhang, Prof. Dr. G. Dong
Department of Chemistry
University of Chicago
Chicago, Illinois, 60637, United States
E-mail: gbdong@uchicago.edu
Supporting information for this article is given via a link at the end of the document.
to streamline construction of the tetrahydronaphthalene cores in
these natural products.
Abstract: To show the synthetic utility of the catalytic C–C
activation of less strained substrates, here we describe
collective and concise syntheses of natural products (−)-
microthecaline A, (−)-leubehanol, (+)-pseudopteroxazole, (+)-
seco-pseudopteroxazole, pseudopterosin A-F and G-J
aglycones, and (+)-heritonin. The key step in these syntheses
involve a Rh-catalyzed C–C/C–H activation cascade of 3-
arylcyclopentanones,
which
provides
a
rapid
and
enantioselective route to access the polysubstituted
tetrahydronaphthalene cores presented in these natural
products. Other important features include (i) the direct C−H
amination of the tetralone substrate in the synthesis of (–)-
microthecaline A, (ii) the use of phosphoric acids to enhance
efficiency and regioselectivity for problematic cyclopentanone
substrates in the C–C activation reactions, and (iii) the direct
conversion of serrulatane to amphilectane diterpenes via an
allylic cyclodehydrogenation coupling.
Introduction
Reactions involving cleavage of carbon–carbon (C–C) σ bonds,
such as Baeyer−Villiger oxidation, Grob fragmentation and
various rearrangement reactions (Schmidt, Cope, Wolff, Pinacol-
type, Wagner–Meerwein, etc.), have found broad utilities in
synthesis of complex and biologically active compounds.[1]
Besides classical approaches, the transition metal-catalyzed C–
C bond activation enables conversion of a relatively inert C–C
bond to a more reactive C–metal bond under redox and near
pH-neutral conditions,[2] therefore offering unique opportunities
for unusual bond disconnections to access complex scaffolds
from simpler substrates. To date, activation of highly strained
three or four-membered rings has been employed as key steps
in several total syntheses;[3,4] however, utility of methods that
activate less strained 5-, 6-membered rings or linear substrates
in constructing complex target molecules remain elusive,[5] as
these methods often either are non-constructive (e.g.
decarbonylation or fragmentation of the substrate) or need
permanent directing groups (DGs).[6] Recently, through merging
catalytic C–C and C–H activation, an initial approach was
Scheme 1. Collective Asymmetric Syntheses of Serrulatane/Amphilectane
Diterpene and Cadinane Sesquiterpene Nature Products via Catalytic
Activation of C–C bonds in 3-Arylcyclopentanones.
α-Tetralones have been found in numerous bioactive
compounds, and frequently serve as versatile building blocks in
syntheses of complex natural products and pharmaceutical
intermediates.[8,9] While a number of methods for preparing α-
tetralones are available,[10] it remains challenging to introduce a
stereocenter at the C4 position with controlled absolute
stereochemistry.[11] Given that 3-arylcyclopentanones can be
easily prepared in high enantioselectivity via asymmetric 1,4-
addition,[12] the catalytic C–C/C–H cascade reaction therefore
provides a rapid approach to access various C4-substiutted α-
tetralones in a high enantiopurity (Scheme 1). To demonstrate
the efficiency of this strategy, serrulatane diterpenes, such as
realized
to
transform
3-arylcyclopentanones
and
(−)-microthecaline
A,
(−)-leubehanol
and
(+)-seco-
cyclohexanones into functionalized α-tetralones and α-
indanones (Scheme 1).[7] In this full article, we describe our
detailed efforts towards collective asymmetric syntheses of
seven natural products in the serrulatane/amphilectane
diterpene and cadinane sesquiterpene families, where catalytic
C–C activation of cyclopentanones is employed as the key step
pseudopteroxazole, amphilectane diterpenes, such as (+)-
pseudopteroxazole, pseudopterosin A-F and G-J aglycones, and
cadinane sesquiterpene (+)-heritonin have been chosen as the
synthetic targets (Scheme 1).
1
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10.1002/anie.201915821
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RESEARCH ARTICLE
[Rh(COD)Cl]2 as the catalyst, the desired racemic
cyclopentanone (11) was isolated in 98% yield. Moderate
enantioselectivity was obtained with the Rh(C2H4)2(acac)/(S)-
BINAP catalyst system;[15] switching to the [Rh(C2H4)2Cl]2/(S,S)-
Ph-bod combination, 3-arylcyclopentanone 11 was isolated in a
high yield with excellent optical purity (95% ee).[16] The key C–C
activation reaction was investigated next. To our delight, under
the previously reported conditions,[7a] the desired α-tetralone 10
was isolated in a 76% yield uneventfully with retention of high
enantiopurity (92% ee), which is the major product through
cleavage of the proximal C1–C2 bond; the undesired 1-indanone
product (10-1) was generated in a 14% yield via cleavage of the
distal C1–C5 bond and can be separated from the main product.
Attempts to combine these two Rh-catalyzed steps were
unfruitful, as different ligands were required for each step.
Results and Discussion
Microthecaline A. (–)-Microthecaline A (1) is a unique nitrogen-
containing serrulatane-type natural product (Figure 1), isolated
recently by the Davis group in 2018 from the roots of a
Australian desert plant Eremophila microtheca.[13] It contains a
penta-substituted quinoline scaffold and exhibits antimalarial
activity against Plasmodium falciparum (IC50
= 7.7 μM).
Compared to a typical serrulatane diterpene, distinct features of
microthecaline A include a nitrogen substituent at the C5
position and a higher oxidation at the C18 terminal carbon. To
date, there is only one racemic synthesis of microthecaline A
reported in 15 steps with a 5% overall yield.[14]
Figure 1. Structure of (–)-Microthecaline A (1).
One key question to synthesize (–)-microthecaline A is how to
efficiently introduce the C1 stereocenter and the C5 nitrogen
moiety. We envisioned that the penta-substituted quinoline core
in 1 could be constructed using the Friedländer Condensation
between aldehyde
8 and amine-substituted α-tetralone 9
(Scheme 2). Aniline 9 could be possibly prepared via C–H
amination of intermediate 10 in a straightforward manner. α-
Tetralone 10 is expected to be synthesized through the catalytic
C–C activation of 3-arylcyclopentanone 11 that can be
conveniently accessed from 2-cyclopentenone and commercially
available 1-bromo-2-methoxy-4-methylbenzene.
Scheme 3. Synthesis of α-Tetralone 10.
With α-tetralone 10 in hand, the next question was how to
install an amino group at the C5 position (Scheme 4).
Gratifyingly, bromination of the arene was found to occur
selectively at the C5 instead of the C7 position; subsequent
Buchwald−Hartwig amination followed by Boc-deprotection
afforded the desired aniline 9 in a 63% yield over three steps.
Given the high site-selectivity observed in the electrophilic
bromination step, an intriguing question is whether direct
electrophilic amination could be realized for α-tetralone 10. To
the best of our knowledge, the direct C−H (NH2)-amination of
arenes that contain a ketone substituent (like substrate 10) has
not been reported yet.[17] The challenge is three-fold: 1) as a
strong electron-withdrawing group, the ketone moiety would
deactivate the arene for electrophilic substitution; 2) the amine
reagent or product could condense with the ketone to give imine
side-products; and 3) amination at the enolizable ketone α
position could be a side reaction pathway. Towards the end, a
number of arene amination conditions have been evaluated
(Table 1). Under the Ritter’s condition with MsONH2 as the
electrophile and FeSO4 as the catalyst,[17e] aniline 9 was not
observed and substrate 10 was fully decomposed likely due to
the elevated reaction temperature (entry 1, Table 1). Switching
solvent to MeCN/H2O (2:1) and running the reaction at room
Scheme 2. Retrosynthetic Analysis of (–)-Microthecaline A (1).
Our synthesis started with the asymmetric conjugation to
prepare cyclopentanone 11 (Scheme 3). Lithiation of 1-bromo-2-
methoxy-4-methylbenzene followed by in situ treatment with
B(OMe)3 generated the corresponding arylborate salt, which can
directly participate in the Rh-catalyzed 1,4-addition of 2-
cyclopentenone in the same reaction vessel.[15] Using
2
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10.1002/anie.201915821
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RESEARCH ARTICLE
temperature (Morandi’s condition),[17c] the desired aniline product
(9) was isolated in 52% yield along with oxime 9-1 in 6% yield
(entry 2, Table 1). Further tuning the reaction conditions, e.g. the
reagent and catalyst loading and solvent, improved the yield to
68% without amination at other positions (entries 3-5, Table 1).
Meanwhile, the Kurti/Falck’s rhodium-catalyzed amination was
also found to be efficient (entries 6-9, Table 1).[17b] Finally, after
some modification of the reaction conditions, aniline 9 was
isolated in 79% yield along with a separable minor isomer 9-2 in
14% yield (entry 9, Table 1).
Scheme 5. Completion of the Total Synthesis of (–)-Microthecaline A (1).
Serrulatane and Amphilectane Diterpenes. Serrulatane and
amphilectane diterpenes exhibit a broad spectrum of promising
biological activities including anti-malarial, anti-inflammatory,
analgesic, anti-tuberculosis and antibacterial, etc. (Figure 2).[20]
Consequently, intensive efforts have been continuously devoted
in the last three decades to the asymmetric syntheses of these
3-step synthetic route
BocNH
Xantphos, Cs2CO3
68%
b)
2, [Pd(allyl)Cl]2
Me OMe
Me OMe
Me OMe
1
a) NBS, MeCN
95%
7
c) TFA, DCM, 0 o
C
Me
Me
Me
5
98%
NH2
O
O
Br
H
O
9
10
one step, 79% yield, see Table 1
direct C H amination
Scheme 4. Synthesis of Aniline 9.
Table 1. Optimization of the Direct C−H Arene Amination.
Me OMe
Me OMe
Me OMe
Me OMe
reaction
NH2
condition
+
+
Me
Me
Me
Me
NH2
O
N
O
O
MsO
9-2
9
9-1
10
yield[b]
reaction condition[a]
entry
9
9-1
9-2
10
n.d.[c]
n.d.
n.d.
n.d.
1
MsONH2·HOTf (2 equiv.),FeSO4·7H2O (1 mol%),
HFIP, 60 oC, 24h
2
MsONH2·HOTf (2 equiv.), FeSO4·7H2O (5 mol%),
MeCN/H2O (2:1, 0.1M), rt, 24h
52%
38%
6%
n.d.
n.d.
n.d.
n.d.
20%
< 2%
n.d
3
MsONH2·HOTf (4 equiv.), FeSO4·7H2O (5 mol%),
MeCN/H2O (2:1, 0.1M), rt, 24 h
< 2%
n.d.
4
MsONH2·HOTf (3.5 equiv.), FeSO4·7H2O (10 mol%),
TFE/H2O (2:1, 0.1M), rt, 12h
61%
.
5[d]
6
MsONH2·HOTf (4.5 equiv.), FeSO4·7H2O (5 mol%)
, MeCN/H2O (2:1, 0.1M), rt, 48 h
68%
< 5%
n.d.
n.d.
MesONHBoc (1.5 equiv.), Rh2(esp)2 (2 mol%),
TFA (2 equiv.), HFIP (0.1 M), rt, 40h
6%
6%
13%
13%
14%
48%
n.d.
n.d.
n.d.
7
TsONHBoc (1.5 equiv.), Rh2(esp)2 (2 mol%),
TFA (2 equiv.), HFIP (0.1 M), rt, 40h
64%
73%
79%
n.d.
8
TsONHBoc (1.5 equiv.), Rh2(esp)2 (2 mol%),
TFA (2 equiv.), TFE (0.1 M), rt, 40h
n.d.
9
TsONHBoc (1.3 equiv.), Rh2(esp)2 (2 mol%),
TFA (1.5 equiv.), TFE (0.1 M), rt, 24h
n.d.
[a] The reaction was run on a 0.1 mmol scale. [b] Isolated yield. [c] Not
detected. [d] MsONH2·HOTf was added portion-wise to the reaction mixture in
3 times.
The stage was now set for the Friedländer condensation[18]
between aniline 9 and known aldehyde 8 (prepared in three
steps from inexpensive dihydropyran)[19] to form the quinoline
ring (Scheme 5). A number of conditions have been examined:
while sulfuric acid, acetic acid and tosylic acid failed to promote
this reaction, use of diphenylphosphoric acid in toluene afforded
the desired quinoline 12 in 94% yield. Finally, removal of the
methyl group by NaSEt gave (–)-microthecaline A (1) in 91%
yield, which displays identical spectral and physical properties to
those of natural sample.[13] Overall, the asymmetric total
synthesis of (–)-microthecaline A (1) was completed in only 5
steps in the longest linear sequence (LLS) with a 43% overall
yield.
Figure 2. Examples of Serrulatane and Amphilectane Diterpenoids.
natural products.[20a,b] Despite the seemingly uncomplex
structures, significant challenges have been found for 1)
controlling the relative and absolute stereochemistry for
constructing these non-polar stereogenic centers and 2)
synthesizing penta- and hexa-substituted benzene rings in most
of these natural products. After seminar works by Broka[24a] and
3
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10.1002/anie.201915821
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RESEARCH ARTICLE
Corey[24b]
, a number of elegant and innovative synthetic
approaches have been devised.[21-24] However, there is still room
to develop a unified and concise route (with less than 10 steps)
to access diverse serrulatane and amphilectane diterpenes.
A proposed general retrosynthetic strategy is described in
Scheme 6. Compared to serrulatanes, amphilectane diterpenes
contain an additional six-membered ring through bond forming at
the C5 and C13 positions. Thus, a straightforward approach to
access amphilectanes would be to directly oxidize the
corresponding serrulatane at the allylic C13 position to forge
C−C bond formation with the aromatic ring. Serrulatane
diterpenes are expected to be assembled through coupling a
tetrahydronaphthalene fragment (e.g. 13) and an alkyl fragment
(e.g. 14). While a number of asymmetric sp3-sp3 cross coupling
methods have been established,[25] we feel that Aggarwal’s
lithiation-borylation approach could be most suitable in this
scenario to construct the C4-C11 bond with excellent control of
the diastereoselectivity.[25b,26] The carbamate fragment 13 could
be prepared from α-tetralone 15, which would again be
synthesized via the asymmetric conjugate addition and
C−C/C−H cascade approach.[7a]
Scheme 7. Total Synthesis of (−)-Leubethanol (2).
The syntheses of structurally related terpenoids 3-6 were
pursued next. Compared with (–)-leubethanol (2), these
terpenoids exhibit opposite stereochemistry at the C1 and C4
positions, as well as an additional substituent at the C7 position
(Figure 2).
The synthesis started with preparing boronic acid 20 on a
decagram scale via ortho lithiation of commercially available 2,3-
dimethoxytoluene followed by quenching with trimethylborate
(Scheme 8).[29] The Rh-catalyzed asymmetric 1,4-addition
proceeded efficiently to deliver cyclopentanone 21 in 98% yield
with 98% ee using (R,R)-Ph-bod as the chiral ligand.[30] Under
the standard conditions for the C−C activation of 3-
arylcyclopentanones,[7a] however, only moderate conversions for
the desired α-tetralone product (22) were observed (entry 1,
Table 1). This is likely due to the presence of the OMe group
para to the aryl C−H bond to be activated (vide infra, Table 3),
as the resulting electron-rich aryl group could destabilize the
aryl−Rh intermediate (or transition state) during the C−H
activation step.[7a] A solution was ultimately found: by changing
Scheme 6. A General Streamlined Strategy for Preparing Serrulatane and
Amphilectane Diterpenoids.
To examine the proposed strategy, (–)-leubethanol (2) was
chosen as the first target, which is a serrulatane diterpene
isolated from the roots of Leucophyllum frutescens by Waksman
in 2011[22a] with a promising level of anti-tuberculosis activity
(MIC 6.25-12.50 μg/mL). In a forward manner, α-tetralone 10
(prepared in the prior section) was first converted to the
secondary alcohol (17) in an excellent yield and 7:1 dr under the
Noyori asymmetric reduction[27] conditions (Scheme 7). Note that
enantio-enrichment (92% ee 99% ee) was observed in this
situation, as the minor enantiomer of 10 became the minor
Scheme 8. Synthesis of Key Intermediate 24.
diastereomer
of
17.[28]
Carbamoylation
with
N,N-
the acid co-catalyst from TsOH to (PhO)2PO2H (10 mol%), both
the conversion and selectivity were notably enhanced. It is
possible that (PhO)2PO2H promoted the C−H arene metalation
step to some extent,[31] though the exact reason remains to be
disclosed. Eventually, α-tetralone 22 was isolated in 77% yield
and 94% ee (entry 3, Table 2). Increasing the loading of 2-
aminopyridine (C1) decreased the tetralone/indanone selectivity
(entry 4, Table 2). In addition, changing aminopyridine from
simple C1 to a more electron-rich C2 only gave a moderate yield
with 83% ee, though the tetralone/indanone selectivity was
improved. Subsequent Noyori asymmetric reduction of the
diisopropylcarbamoyl chloride (CbCl) delivered carbamate 18,
which can then be used to couple with the chiral organoborane
fragment (S-14, prepared in three steps from 5-bromo-2-methyl-
2-pentene) using Aggarwal’s lithiation-borylation reaction.[9d] The
treatment of TBAF gave primarily retention of the
stereochemistry at the C4 position;[26b] the major desired
diastereomer (19) can be isolated in its pure form. Upon removal
of the methyl group in a good yield, synthesis of (–)-leubethanol
(2) was furnished in 6 LLS steps and a 29% overall yield.
4
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10.1002/anie.201915821
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RESEARCH ARTICLE
ketone moiety and carbamate formation, followed by Aggarwal’s
lithiation-borylation reaction (vide supra, Scheme 8), afforded
the key serrulatane intermediate 24 with the desired
stereochemistry at the C1, C4 and C11 positions (different from
leubethanol).
Diastereomeric compounds 26 and 27 can be readily separated
by reverse phase HPLC.
With compounds 26 and 27 in hand, removal of the methyl
protecting groups afforded (+)-pseudopterosin G-J aglycone (5)
and (–)-pseudopterosin A-F aglycone (6), respectively (Scheme
9); the deprotection of compounds 24 and 26 followed by a one-
pot oxidative oxazole formation furnished the total syntheses of
(+)-seco-pseudopteroxazole (3) and (+)-pseudopteroxazole (4)
in 8 and 9 LLS steps, respectively. [23e,38]
Table 2. Optimization of the C−C Activation of Cyclopentenone 21.[a]
Me OMe
OMe
(PhSe)2, H2O2
Me
then t-BuO2H
H
MeSO3H, DCM;
80%, dr 2:1
Me
74%
or, BF3·Et2O,DCM;
60%, dr 1:1.4
OH
Me
25
CDCl , rt;
or,
85%; dr 1.7:1
3
Me
Me OMe
Me OMe
Me OMe
OMe
Me
OMe
Me
OMe
Me
1
4
o-chloranil, MeCN, rt
+
5
H
5
H
H
5
11
40%, dr 1.4:1
13
Me
Me
Me
13
13
Me
Me
Me
Me
Me
Me
26
27
24
amphilectane-type
serrulatane-type
a) NaSEt,
b) Ag2O,
NH2CH2CO2H;
56%
a) NaSEt,
b) Ag2O,
NH2CH2CO2H;
54%
NaSEt;
94%
NaSEt;
89%
[a] The reaction was run on
a 0.2 mmol scale. [b] NMR yields using
Me OH
Me OH
OH
Me
O
Me
O
dibromomethane as the internal standard. [c] Determined by chiral HPLC. [d]
Ratio between 22 and 22-1. [e] Numbers in parentheses are isolated yields. [f]
The loading of C1 was 25 mol%.
N
N
OH
Me
Me
Me
Me
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
To access amphilectane diterpenes, the remaining challenge
was to form the C5−C13 bond (Scheme 9). Conversion of olefin
24 to allylic alcohol 25 was realized though oxyselenation and
oxidative elimination.[32,33] The expected cyclization was found to
be effectively promoted by MeSO3H or BF3·Et2O to deliver
amphilectane-type compounds 26 and 27, and it appears that
these two acids showed somewhat opposite diastereoselectivity.
It is interesting to observe that tricyclic compounds 26 and 27
were formed simultaneously in a high yield from a CDCl3
solution in NMR tube after 4 days, likely due to a trace amount
of acid in the NMR solvent.[28] While this two-step protocol is
efficient, it would be more attractive to realize a direct cross-
dehydrogenative-coupling (CDC)[34] at the C5/C13 positions,
which, to our knowledge, has not been reported in the syntheses
of these types of natural products. If an allyl cation or an allyl
radical could be generated at the C13 position, such a species
would in principle be trapped by the arene to form the C5−C13
bond. However, the challenge of this CDC strategy is also
obvious: substrate 24 contains a number of weak C−H bonds;
therefore, besides the three allylic positions, oxidation at the
tertiary and benzylic C1 and C4 positions could be a significant
concern. In addition, the arene moiety in substrate 24 is highly
electron-rich, thus selective allylic oxidation instead of arene
oxidation would also be difficult. After examining numerous
allylic oxidation conditions,[35] including the use of transition-
(+)-pseudopterosin
G-J aglycone (5)
(
)-pseudopterosin
A-F aglycone (6)
(+)-seco-pseudo
pteroxazole (3)
(+)-pseudopteroxazole
(4)
Scheme 9. Conversion of Serrulatane to Amphilectane-type Diterpenes and
Total Syntheses of 3-6.
(+)-Heritonin. The application of the catalytic C−C activation of
cyclopentanones could also be demonstrated in the
enantioselective synthesis of (+)-heritonin (7), which was
isolated from the mangrove plant Heritiera littoralis in 1989 by
Miles and belongs to the family of cadinane sesquiterpenes.[39]
this nnatural product exhibits potent piscicidal activity and has
been used by local fishermen to kill invasive fishes. To date, a
number of synthetic routes have been reported to access
heritonin;[40] however, only two of them are asymmetric, which
require 9-15 steps.[11a,40h] We proposed that the α-tetralone
intermediate (28) (Scheme 10) in Chavan’s synthesis[11a] could
be accessed by the C−C/C−H cascade approach in
a
convenient manner, which would lead to
a streamlined
preparation of 7.
Following the same procedure of preparing compound 11,
compound 29 was obtained in 95% yield and 99% ee with the
[Rh(C2H4)2Cl]2/(R, R)-Ph-bod catalyst system (Scheme 10). As
expected, the presence of the meta OMe group (vide supra,
Table 2) in cyclopentenone 29 posted substantial difficulty for
the key C−C activation reaction. Using the original C−C
activation conditions,[7a] the desired α-tetralone 28 was only
obtained in 19% yield with 77% ee (entry 1, Table 3). After
examining various acid co-catalysts, the desired tetralone 28
was ultimately isolated in 68% yield (83% ee) by switching TsOH
metal
catalysts,
e.g.
Pd(OAc)2/BQ,
Pd(TFA)2,
and
[RhCp*Cl2]2,[36] finally the treatment with o-chloranil in MeCN at
room temperature was found to be most effective.[37] DDQ also
afforded the desired products albeit in a lower yield (30%).[28]
5
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10.1002/anie.201915821
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RESEARCH ARTICLE
to the binol-derived phosphoric acid (rac-acid 1)[41] with 20 mol%
aminopyridine C1 (entry 2, Table 3). After recrystallization, 91%
ee was obtained, which can be used in the next step. Use of
(PhO)2PO2H, the best acid for substrate 21, gave a high
conversion but somewhat a lower yield and selectivity (entry 3,
Table 3). Increasing the loading of 2-aminopyridine C1 reduced
the tetralone/indanone selectivity (entry 4, Table 4). Interestingly,
use of the more electron-rich aminopyridine (C2) instead gave
the desired product 28 in a high yield and excellent selectivity,
albeit with a low optical purity (entry 5, Table 4). Further
enhancing the reaction temperature only led to a diminished
yield (entry 6, Table 4).
Ratio between 28 and 28-1. [e] Numbers in parentheses are isolated yields. [f]
The loading of C1 was 25 mol%. [g] The reaction temperature was 150 oC
Conclusion
In summary, the use of catalytic C–C activation of
cyclopentanones as a key step has been illustrated in the
enantioselective total syntheses of a range of di- and sesqui-
terpenoids 1-7 in 4-9 steps. This strategy can accelerate
asymmetric
construction
of
the
polysubstituted
tetrahydronaphthalene cores, therefore significantly simplifying
the overall syntheses. In addition, some other features, such as
(i) the direct C−H amination of the tetralone substrate in the
synthesis of (–)-microthecaline A, (ii) the use of phosphoric acids
to enhance efficiency and selectivity for problematic substrates
in the C–C activation reactions and (iii) the direct conversion of
serrulatane to amphilectane diterpenes via an allylic
cyclodehydrogenation, should have implications beyond this
work.
Acknowledgements
NIGMS (2R01GM109054) and University of Chicago are
acknowledged for research support. S.-H. H. acknowledges the
International Postdoctoral Exchange Fellowship Program 2017
from the Office of China Postdoctoral Council. M.Z. thanks Xi’an
Jiaotong University for a summer fellowship. Dr. Ying Xia is
thanked for helpful discussions. Prof X. Hu (NWU, China) is
thanked for providing a NMR sperta of 4 and 16. Umicore AG &
Co. KG is acknowledged for a generous donation of Rh salts.
Scheme 10. Total Synthesis of (+)-Heritonin (7).
At this stage, formal synthesis of heritonin was accomplished;
however, a different end-game from Chavan’s synthesis[11a] was
pursued via merging merits of other routes. Stereoselective α-
hydroxylation of tetralone 28 gave compound 30 with a 7:1
dr.[40h] After further recrystallization, 96% ee and >20:1 dr could
be obtained. Finally, the tandem acylation/Wittig olefination[40f]
afforded (+)-heritonin (7) in a good yield.
Keywords: C–C activation • Total synthesis • Terpenoid •
Asymmetric synthesis • C–H activation
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8
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Entry for the Table of Contents
To show the synthetic utility of the Rh-catalyzed C–C/C–H activation cascade of 3-arylcyclopentanones, here we describe collective
concise asymmetric syntheses of terpenoids (−)-microthecaline A, (−)-leubehanol, (+)-pseudopteroxazole, (+)-seco-
pseudopteroxazole, pseudopterosin A-F and G-J aglycones, and (+)-heritonin (see scheme) in 4-9 steps.
9
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