Total Synthesis of Kadcoccinic Acid A Trimethyl Ester

Article abstract of DOI:10.1021/jacs.1c05521

The first total synthesis of the trimethyl ester of kadcoccinic acid A is described. The central structural element of our synthesis is a cyclopentenone motif that allows the assembly of the natural product skeleton. A gold(I)-catalyzed cyclization of an enynyl acetate led to efficient construction of the cyclopentenone scaffold. In this step, optimization studies revealed that the stereochemistry of the enynyl acetate dictates regioisomeric cyclopentenone formation. The synthesis further highlights an efficient copper-mediated conjugate addition, merged with a gold(I)-catalyzed Conia-ene reaction to connect the two fragments, thereby forging the D-ring of the natural product. The synthetic strategy reported herein can provide a general platform to access the skeleton of other members of this family of natural products.

Full text of DOI:10.1021/jacs.1c05521

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Total Synthesis of Kadcoccinic Acid A Trimethyl Ester
Barry M. Trost,* Guoting Zhang,† Hadi Gholami,† and Daniel Zell
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ABSTRACT: The first total synthesis of the trimethyl ester of kadcoccinic acid A is
described. The central structural element of our synthesis is a cyclopentenone motif
that allows the assembly of the natural product skeleton. A gold(I)-catalyzed
cyclization of an enynyl acetate led to efficient construction of the cyclopentenone
scaffold. In this step, optimization studies revealed that the stereochemistry of the
enynyl acetate dictates regioisomeric cyclopentenone formation. The synthesis
further highlights an efficient copper-mediated conjugate addition, merged with a
gold(I)-catalyzed Conia-ene reaction to connect the two fragments, thereby forging
the D-ring of the natural product. The synthetic strategy reported herein can
provide a general platform to access the skeleton of other members of this family of
natural products.
Scheme 1. Kadcoccinic Acid A (1), Its Trimethyl Ester (2),
and a Retrosynthetic Analysis
INTRODUCTION
■
The Kadsura species belong to the family of Schisandraceae, a
rich source of complex polycyclic structures and triterpenoids.1
These plants are commonly used as traditional Chinese herbal
medicines for the treatment of a wide array of diseases such as
gastroenteric disorders, duodenal ulcers, and gynecological
problems to name a few.2 Some of the compounds isolated
from these plants were tested for their activities as
antihepatitis, antitumor, anti-HIV activities, and so forth.2
Kadcoccinic acids are a newly discovered subset of triterpenoid
natural products isolated form Kadsura coccinea, also named as
“Heilaohu”, a climbing plant distributed in the southwestern
provinces of China.3 Due to the complex composition of these
traditional medicines, little is known about the mechanism and
pharmacological action of these compounds. Establishing a
synthetic method to access the core structure of this family of
natural products and their viable analogs would be impactful
for future structural determination, as well as phytochemical
and pharmacological research on Kadsura coccinea.
Structurally, kadcoccinic acids possess a rearranged lano-
stane structure, which is a very common natural product
framework featuring a 6/6/5/6-fused tetracyclic ring system
(named as rings A−D). Kadcoccinic acid A (1) in particular is
one of the first isolated compounds of this family that features
a 2,3-seco-6/6/5/6-fused tetracyclic triterpenoid skeleton. This
triacid consists of a tricyclic core with a unique skipped diene
motif and seven stereogenic centers. So far, the synthesis of
kadcoccinic acids or any of their closely related analogues has
not been achieved. Herein, we report a total synthesis of
kadcoccinic acid A trimethyl ester (2), which could enable
rapid access to this intriguing family of natural products.
In a retrosynthetic perspective, we envisioned a C2−C3
vicinal diol as a surrogate to install the dicarboxylic acid of the
natural product at a late stage of synthesis (Scheme 1). This
Received: May 28, 2021
Published: July 29, 2021
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© 2021 American Chemical Society
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strategy would allow to selectively cleave the latter C−C bond
and it would also add extra polarity to an otherwise very non-
polar hydrocarbon skeleton throughout the synthetic route.
One of the key features of kadcoccinic acid A that motivated us
to pursue a synthetic endeavor was the skipped 1,4-diene.
Stemming from our long-standing interest in the utilization of
transition metal catalyzed alkene-alkyne coupling and cyclo-
isomerization reactions, we envisioned to access the skipped
diene of kadcoccinic acid A via an intramolecular Ru-catalyzed
alkene-alkyne coupling reaction of the enyne compound 4a.4
Alternatively, the D ring can also be obtained through a
gold(I)-catalyzed intramolecular Conia-ene reaction of a silyl
enol ether moiety into the pendant terminal alkyne.5
Intermediate 4b could be obtained from a copper-mediated
conjugate addition of an alkyl lithium reagent from alkyl iodide
5 into enone 6. The cyclopentenone core in 6 could be
accessed via a key gold(I)-catalyzed enynyl acetate [3,3]-
rearrangement followed by a Nazarov cyclization.6 Enynyl
acetate 7 could be accessed from ketone 8, and the side chain 5
could be synthesized from geraniol.
With enynyl acetate 7-rac in hand, we set out to carry out
the key cyclization reaction by following the reported
procedure by the Zhang group.6,9 Treatment of 7-rac with
AuCl(PPh3)/AgSbF6 in wet CH2Cl2 led to complete
conversion of the starting material and formation of the
desired cyclopentenone 6 and its enol acetate 14 as well as the
undesired cyclopentenone 15 (entry 1, Table 1). In contrast to
the reported procedure by the Zhang group, the enol acetate
14 was not fully hydrolyzed to 6 under the gold-catalyzed
conditions, presumably due to steric hindrance.6 Nonetheless,
treatment of reaction mixture with bis(trifluoromethane-
sulfonyl)amine (Tf2NH) led to hydrolysis of the enol acetate
and the desired product 6 was isolated in moderate yield of
38%. Less electrophilic NHC-based gold complex
(IPrAuNTf2) led to a slightly improved ratio of 14 to 15
since hydrolysis of 15 was not observed under the reaction
condition and 6 was isolated after treatment of the mixture
with Tf2NH in 36% yield (entry 2). Screening of other solvents
did not lead to further improvement of the reaction results.
Using acetone as solvent resulted in completion of the reaction
and 14 and 15 were isolated in nearly equal yields (entry 3).
Other solvents such as toluene and THF only gave partial
conversion of the starting material even after extended reaction
times (entries 4 and 5). With acetone as solvent, in situ
generation of the activated gold complexes did not improve the
ratio of the desired product (entries 6 and 7). Interestingly,
[JohnPhosAu(CH3CN)]SbF6 as catalyst, with its sterically
demanding ligand, resulted in partial conversion of the starting
material 7-rac in ∼2 h and more importantly, predominantly
RESULTS AND DISCUSSION
■
Our synthesis commenced with the known ketone 8 that was
prepared from 2-methyl-1,3-cyclohexadione (9) in four steps
and 69% overall yield (Scheme 2).7 With the well-defined
Scheme 2. Synthetic Route to Access Enynyl Acetate 7
1
the desired enol acetate 14 was observed based on H NMR
analysis (entry 7). These results indicate the impact of the
stereochemistry of the enynyl acetate center in 7-rac (1:1 dr at
the propargylic acetate carbon), on the observed product
distribution.
To further deconvolute this stereochemical effect, we
prepared 7-R and 7-S by coupling the vinyl triflate 13 with
enantiopure (R)-2-butyn-3-ol and (S)-2-butyn-3-ol to access 7-
R and 7-S in 75% and 82% yields, respectively (Scheme 2). In
agreement with our hypothesis, these two diastereomers led to
complementary products upon treatment with catalytic
IPrAuNTf2 in acetone. Enynyl acetate 7-R predominantly led
to the undesired regioisomeric cyclopentenone 15 (entry 9),
while 7-S under the same reaction conditions, gave rise mainly
to enol acetate 14 and cyclopentenone 6 was isolated in 57%
yield after hydrolysis (entry 10). Carrying out the reaction of
7-S in CH2Cl2 as solvent gave a slightly improved ratio of the
desired product 14 and 66% isolated yield of cyclopentenone 6
after hydrolysis (entry 11). Furthermore, performing the
reaction of 7-S at 4 °C in CH2Cl2, instead of room
temperature, led to exclusive formation of 14 and 91% isolated
yield of this compound (Table 1, entry 12, see the Supporting
Information (SI) for the stacked NMR spectra of 7-rac, 7-S,
and 7-R under gold catalysis). Transfer of chirality from
optically pure enynyl acetate to the ensuing cyclization product
has been demonstrated and harnessed in total synthesis of
natural products.10 However, the current diastereodivergent
phenomenon has not been disclosed before. Thus these
findings could lead to applications in the stereoselective
synthesis of regioisomeric cyclopentenones controlled by the
stereochemistry of the enynyl acetate and add to the toolbox of
total synthesis empowered by gold catalysis.11
geometry of the trans-decalin core in 8 to drive the following
diastereoselective reactions, we set out to install a handle for
late stage cleavage of C2−C3 bond in 8. A highly efficient
aerobic oxidation of the α-carbon to the carbonyl in 8 was
carried out by using potassium tert-butoxide in tert-butanol
under an atmosphere of oxygen.8 The resulting α-diketone 10
(exists as keto−enol) was directly subjected to sodium
borohydride reduction to deliver the syn-diol 11 after
deprotection of the acetal group under the acidic workup
conditions. The resulting diol was protected as a cyclic
carbonate and the ketone group in 12 was elaborated to vinyl
triflate 13 in 52% overall yield and as a single isolable
diastereomer from ketone 8. Sonogashira coupling of vinyl
triflate 13 with the racemic 2-butyne-3-ol followed by
acetylation of the resultant propargylic alcohol delivered the
enynyl acetate 7-rac in 83% yield as a 1:1 diastereomeric
mixture due to the newly added stereocenter.
With these results in hand, the enone 6 was obtained in 66%
isolated yield from the enynyl acetate 7-S with 3 mol %
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a
Table 1. Gold(I)-Catalyzed Nazarov Cyclization of 7
a
b
b
c
entry
7
[Au] (5 mol %)
solvent
conv. (%)
14:15
yield (%) 14/15/6
d
e
1
7-rac
7-rac
7-rac
7-rac
7-rac
7-rac
7-rac
7-rac
7-R
AuCl(PPh3)3/AgSbF6
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
AuCl(PPh3)3/AgSbF6
IPrAuCl/AgSbF6
[JohnPhosAu(CH3CN)]SbF6
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
CH2Cl2
CH2Cl2
acetone
PhCH3
THF
acetone
acetone
acetone
acetone
acetone
CH2Cl2
CH2Cl2
>95
90
>95
20
1:1.5
1.4:1
1:1
1:1
1.5:1
1:1
1:1
6:1
1:5
5:1
6:1
−/−/38
−/−/36
46/43/−
−/−/−
−/−/−
41/46/−
44/52/−
−/−/−
−/−/−
−/−/57
−/−/66
91/−/69
d
2
3
f
4
f
5
40
6
7
8
9
10
11
12
>95
>95
60
>95
>95
>95
>95
7-S
7-S
7-S
h
IPrAuNTf2
>20:1
a
Reactions were performed with 7 (0.1 mmol, 0.4 M conc.) at room temperature for 3−5 h; Cyclopentenone 6 is obtained by treatment of the
b
c
reaction mixture with Tf2NH solution (10 mol % in CH2Cl2). Conversions of 7 and the ratios of 14:15 are estimated from 1H-NMRs. Yields of
isolated products. Wet dichloromethane was used. A portion of 14 was hydrolyzed to 6 under the reaction conditions; ratio of 14+6 is nearly
equal to 15. Reaction time was 18 h. Conversion after 2 h. Reaction was performed at 4 °C for 12 h.
d
e
f
g
h
IPrAuNTf2 in CH2C2 as solvent followed by a mild acidic
hydrolysis using a CH2Cl2 solution of Tf2NH (Scheme 3a).
The relative stereochemistry of enone 6 was established using
NOESY spectroscopy. Some of the important NOESY
correlations in 6 are shown in Scheme 3a (see the SI for
additional details).
hydrogen shown in red) would not create the same degree of
strain in the B-ring, thus rendering the latter 1,5-hydride shift
less likely to proceed. Indeed, energy minimized structures of
14 and 21 revealed that the B-ring adopts a more favorable
chairlike conformation in 14 as opposed to a twisted boat
conformation in 21 (14 is more stable than 21 by 2.5 kcal/
mol, Scheme 3c). It should be noted that enol acetate 22 is less
sterically hindered than 14, thus it can be hydrolyzed to
cyclopentenone 15 under the reaction conditions, while the
hydrolysis of 14 required addition of Tf2NH to generate
cyclopentenone 6.
Analogous to the mechanism reported by the Zhang group,6
and the work of Fensterbank and Malacria,12,10b we have
proposed a simplified mechanism for the gold(I)-catalyzed
[3,3]-rearrangement/Nazarov-type cyclization of enynyl ac-
etate 7 with emphasis on the observed diastereodivergent
phenomenon (Scheme 3b). The enynyl acetate moiety in 7
would undergo a [3,3]-rearrangement in the presence of the
gold(I) catalyst leading to the allenoic acetates 16-S and 16-R.
While 7-rac would lead to pseudo-enantiomeric allenoic
acetates (16-S and 16-R) in an equal ratio, 7-S and 7-R
would exclusively generate 16-S and 16-R, respectively. These
intermediates would then coordinate to the gold(I) catalyst
through the central carbon of allene, leading to the so-called
“bent-allene”12,10b complexes 17a and 17b. On the basis of the
reported studies, presence of bent-allene intermediates is
fundamental to retain and transfer the chirality of the allenoic
acetates to the ensuing intermediates. Intermediates 17a and
18a (also illustrated by their resonance forms 17b and 18b)
are precursors for the cyclization reactions. Electrocyclic ring
closure of 17b and 18b would give rise to 19 and 21,
respectively. Analogous to the precedent reports,10b,e,f,9 transfer
of chirality from bent-allenes 17a and 18a leads to the cyclized
intermediates 19a and 20a with the illustrated stereo-
chemistries. Au-carbenoids 19a and 20a would then undergo
a facile 1,2-hydride shift, followed by the collapse of
carbocations 19b and 20b to deliver the enol acetates 14
and 21, respectively. Presumably, cyclopentadiene 21 under-
goes a facile 1,5-hydride shift to alleviate the imposed strain on
the B-ring due to the stereochemistry of the angular methylene
group (with its hydrogen shown in blue). Conversely, the
stereochemistry of the angular methylene group in 14 (with its
Preparation of the second fragment began with the
preparation of known diol 24,13 which was obtained via a
Sharpless asymmetric epoxidation of geraniol,14 followed by a
regio- and diastereoselective epoxide opening induced by
sodium cyanoborohydride and BF3-etherate conditions
(Scheme 4).13 The hydride addition to the epoxide proceeded
from the anti-face of the epoxide, delivering the diol 24 in 79%
yield from geraniol with >10:1 d.r. Treatment of diol 24 with
sodium hydride/tosylimidazole gave access to the terminal
epoxide 25 in 87% yield.15 The epoxide was further elaborated
to allylic alcohol 27 in 82% yield using in situ generated sulfur
ylide of 26.16 The alcohol group was converted to allylic
phosphate 28 using diethyl chlorophosphate in pyridine as
solvent in 91% yield.17 With this chiral secondary allylic
phosphate 28 in hand, the stage was set to implement a copper
catalyzed allylic alkynylation under the conditions reported by
Sawamura and co-workers.17b They developed an allylic
alkynylation of chiral secondary allylic phosphate in the
presence of chiral NHC ligands (L1) that proceeded with
the retention of stereochemistry on the allylic center. Upon
treatment of 28 with TBS-protected acetylene in the presence
of catalytic copper chloride and (S,S)-L1 as the ligand, we were
pleased to obtain 29 in 92% yield, with >20:1 branched/linear
ratio and >12:1 d.r. It should be noted that, in line with the
Sawamura’s report,17b the chirality of the NHC ligand,
employing (S,S)-L1 or (R,R)-L1, had no impact on the
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Scheme 3. (a) Access to enone 6. (b) A proposed
mechanism of the gold(I)-catalyzed [3,3]-rearrangement/
Nazarov cyclization, and possible origin of the
Scheme 4. Preparation of the Side Chain 5
diastereodivergent event. (c) Geometries of 14 and 21 at
B3LYP/6-31G* (most hydrogens are omitted for clarity)
5 to the cyclopentenone in 6 as a viable method to connect the
two pieces (Scheme 5).19 Sterically hindered cyclopentenones,
similar to compound 6, have been shown to be challenging in
copper-mediated conjugate additions. The same challenge was
Scheme 5. Fusion of the Two Fragments and Attempts to
Construct the Ring D
diastereoselectivity or the yield of the allylic alkylated product
29, and the reaction was fully substrate controlled. Nonethe-
less, performing the reaction in the absence of NHC ligands
resulted only in the formation of the linear allylic alkynylated
product. Lastly, the terminal double bond in 29 was converted
to alkyl iodide 5 via a hydroboration/iodination reaction with a
moderate yield.18
With the two fragments in hand, we envisioned a copper-
mediated conjugate addition of the alkyl lithium reagent from
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Scheme 6. Construction of Ring D via a Gold-Catalyzed Conia-ene Strategy, and Installation of the Skipped Diene
obvious in our synthesis as various conditions with different
copper sources were unsuccessful in delivering the desired
coupling product. Ultimately, lithium-halogen exchange20
followed by the treatment with (2-thienyl)Cu(CN)Li21
transformed the alkyl iodide 5 into a reactive organocuprate
that resulted in efficient conjugate addition with the assistance
of TMSCl leading to the corresponding TMS-enol ether.22
The labile TMS group was then removed under acidic workup
conditions to yield the cyclopentenone 30 in 96% yield. The
ketone group in 30 was converted to vinyl triflate 32 using
Comins’ reagent (31) in 69% yield. Pd-catalyzed hydride
reduction of the vinyl triflate gave access to cyclopentene 33 in
80% yield.23 Desilylation of the terminal alkyne in 33 resulted
in the tetracyclic structure 4a, which was the precursor to carry
out the envisioned Ru-catalyzed alkene-alkyne coupling.
Treatment of 4a with ruthenium catalyst resulted in clean
conversion of the starting material. However, the product of
this reaction was compound 34 and the desired product 35
was not formed. The undesired alkene-alkyne coupled product
34 is presumably formed via the ruthenium metallacycle 36.
The ruthenium-catalyzed alkene-alkyne coupling reactions are
generally selective toward less substituted double bonds, thus
providing a unique selectivity tool to construct C−C bonds.
Unfortunately, in this particular case, the trisubstituted double
bond was shown to be the much more reactive alkene, leading
to coupling with the terminal alkyne as opposed to the
disubstituted endocyclic double bond. Perhaps, the steric
hindrance surrounding the endocyclic double bond renders the
latter selectivity. We further converted the trisubstituted
double bond in 4a to an epoxide to eliminate the competing
pathway. However, that strategy was not successful in forming
the desired C−C bond using the ruthenium catalyst, and we
observed complete decomposition of the starting material
without any detectable product. It should be noted that
engagement of the endocyclic double bond in an alkene−
alkyne coupling requires formation of a ruthenacycle
embedded in a fused multicyclic framework that appeared
unlikely to be achieved.24 Alternatively, palladium-catalyzed
cycloisomerization reactions that obviate intermediacy of the
latter metallacycle were pursed. Nonetheless, under various Pd-
catalyzed cycloisomerization conditions using 4a, formation of
35 was not observed. Additionally, multiple attempts to
convert the terminal alkyne in 4a to vinyl halides (bromide or
iodide) for carrying out an intramolecular Heck-cyclization
with the endocyclic double bond were not successful.25 In
most cases, we were not able to obtain the latter vinyl halides.
On the basis of these results, we turned our attention to an
alternative approach to construct the desired C−C bond. A
Conia-ene reaction was envisioned as a suitable manifold to
form the D-ring of the natural product with the exocyclic
double bond (Scheme 6).5b Through a similar operation as
shown in Scheme 5, the copper-mediated conjugate addition of
5 to enone 6 proceeded smoothly and the coupled products
were obtained in 96% yield with a 10:1 ratio of TMS-enol
ether 37 to the ketone 30 without treatment by HCl. One of
the early attempts to construct the D-ring was to carry out a
Conia-ene reaction on the TMS-enol ether 37. However,
under various gold(I)-catalyzed conditions only hydrolysis of
the TMS-enol ether to ketone 30 was observed.5a,26,26d In an
alternative route, deprotected terminal alkyne 38 was accessed
through desilylations of 37 and 30 with high yields. The ketone
group in 38 was then converted to the corresponding TBS-
enol ether 4b using TBSOTf and 2,6-lutidine. With a short
optimization, exposure of 4b to catalytic [JohnPhosAu-
(CH3CN)]SbF6 (5 mol %) in CH2Cl2 led to the desired
product 39 in 93% yield and excellent diastereoselectivity.26c,d
Of note, the standard gold(I)-catalyzed Conia-ene conditions
developed by the Toste group5a,26a and utilized by others,26b
mainly resulted in the hydrolysis of the TBS-enol ether, leading
to ketone 38.
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With the key C−C bond installed, elaboration of the ketone
group to a double bond with the correct regiochemistry was
the next key transformation (Scheme 6). Enolization of the
ketone group in 39 to form a vinyl triflate, for a palladium
hydride reduction, was not successful. Thus, we set out to
reduce the ketone group to an alcohol for a dehydration
reaction in order to access the desired double bond. Luche
conditions to reduce the ketone group in 39 proved to be
ineffective and only partial hydrolysis of the carbonate
protecting group, without any reduction of the ketone group,
was observed. Next, a samarium iodide (SmI2) reduction of the
ketone into secondary alcohol was pursued. Under excess SmI2
(50 equiv) in THF, ketone 39 was reduced to the secondary
alcohol 40 in ∼80% conversion. Complete conversion of the
ketone could not be reached by further addition of SmI2. The
diastereoselectivity of the reduction was estimated to be ∼2.5:1
based on 1H-NMR analysis. Reductions of ketones by SmI2 are
demonstrated to be influenced by various additives.27 A survey
of different additives revealed that tetramethylethylenediamine
(TMEDA) could significantly improve the conversion as well
as the diastereoselectivity of the reaction.28 Thus, the
reduction of 39 in the presence of TMEDA (10 equiv),
SmI2 (10 equiv), and water (20 equiv) was completed within
30 min, delivering the desired alcohol 40 in 88% isolated yield
and with >10:1 d.r.. The stereochemistry of the carbinol
carbon in 40 was established using NOE analysis (see the SI
for additional details). Dehydration of alcohol 40 was achieved
in 52% yield using Burgess reagent in refluxing toluene. The
yield of this reaction was further improved to 65% by
perfoming the reaction under microwave irradiation in the
presence of 4 Å molecular sieves.29 Judicious choice of the
Burgess reagent for a syn-elimination resulted in the correct
regioselectivity of the newly formed double bond, and the
regioisomeric conjugated diene was not observed. The latter
further signifies the stereochemistry of the secondary alcohol
and highlights the impact of the diastereoselective reduction of
the ketone 39. It should be noted that the minor diastereomer
of alcohol 40 did not undergo dehydration under various
conditions.
Scheme 7. Ring Opening of Ring A through Oxidative
Cleavage of C2−C3 Diol
Scheme 8. Ring Opening of Ring A through Oxidative
Cleavage of C2−C3 α-Diketone
The trisubstituted double bond in 35 was converted to the
Z-olefinic methyl ester 3 via a selective cleavage of this double
bond followed by a Still-Gennari olefination in 66% overall
yield (Scheme 7).30 Deprotection of the carbonate protecting
group under methanolic potassium hydroxide, followed by the
treatment of the resulting diol with periodic acid gave access to
dialdehyde 41. Any attempts to further oxidize the dialdehyde
intermediate under various oxidative conditions, such as
Pinnick oxidation31 and Tollens’ oxidation,32 failed to deliver
the desired dicarboxylic acid 42, and mainly led to
decomposition of the dialdehyde 41.
generated α-hydroxyl ketone 43 by Dess-Martin periodinane
led to 1,2-diketone 44. Oxidative cleavage of 44 by lead tetra-
acetate in methanol gave rise to the corresponding trimethyl
ester of kadcoccinic acid A (2) in 54% yield over two steps.
Our successful synthesis of the trimethyl ester of kadcoccinic
acid A provides an efficient and highly selective synthetic route
to the 6/6/5/6-fused tetracyclic ring systems that is a common
structural motif in this natural product family.
We then turned our attention to oxidative cleavage of the
C2−C3 bond through an α-diketone33 intermediate, generated
from the oxidation of the diol intermediate (Scheme 8). After
deprotection of the carbonate group in 3, treatment of the
resulting diol intermediate under various conditions was
pursued. Typical oxidants such as DMP, PDC, and PPC, led
to decomposition of the starting marterial. Fortunately,
dipyridine chromium oxide in pyridine gave access to α-
hydroxyl ketone 43 in 43% yield with high chemoselectivity for
C3 oxidation.34 Furthermore, a combination of Bobbitt’s salt,
4-(acetylamino)-2,2,6,6-tetramethyl-1-oxo-piperidinium tetra-
fluoroborate, and p-toluenesulfonic acid improved the yield
of this transformation to 83%.35 Further oxidation of the
CONCLUSIONS
■
In summary, we report the first total synthesis of kadcoccinic
acid A trimethyl ester. A cyclopentenone core was targeted as a
strategic centerpiece of the synthesis which enabled assembly
of the natural product skeleton. We utilized a gold-catalyzed
Nazarov cyclization as an effecient methodology to access the
cyclopentenone core. This reaction revealed a diastereodiver-
gent process by which the stereochemistry of the enynyl
acetate determined the regiochemistry of the cyclopentenone.
Additionally, the synthesis evoked an efficient gold(I)-
catalyzed Conia-ene reaction to construct the D ring of
natural product with its characteristic exocyclic double bond. A
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Challenging Metal-Catalyzed Rearrangements and Mechanistic In-
sights. Angew. Chem., Int. Ed. 2008, 47, 4268. (c) Trost, B. M.;
Ferreira, E. M.; Gutierrez, A. C. Ruthenium- and Palladium-Catalyzed
Enyne Cycloisomerizations: Differentially Stereoselective Syntheses of
Bicyclic Structures. J. Am. Chem. Soc. 2008, 130, 16176.
highly efficient samarium iodide reduction of a sterically
hindered cyclopentenone followed by a chemoselective
dehydration gave rise to chemoselective formation of the
skipped diene of the natural product. This modular and
convergent synthesis presents a facile and unique strategy
toward this family of triterpenoid natural products.
(5) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. Gold(I)-
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05521.
■
Philipps, A. R.; Enders, D. Catalytic Conia-ene and related reactions.
Chem. Soc. Rev. 2015, 44, 6059.
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Experimental procedures, analytical data (1H-NMR, 13C-
NMR, HRMS, and [α ]D) for all new compounds,
additional details, NOESY analysis, and computational
data (PDF)
AUTHOR INFORMATION
Corresponding Author
Barry M. Trost − Department of Chemistry, Stanford
University, Stanford, California 94305-5580, United States;
orcid.org/0000-0001-7369-9121; Email: bmtrost@
stanford.edu
■
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Cyclopentenones by Gold(I)-Catalyzed Rautenstrauch Rearrange-
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Authors
V.; Cariou, K.; Hours, A.; Fukuyama, T.; Dhimane, A.-L.;
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pentenylidene Gold Species: Four Pathways to Polycyclic Com-
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Guoting Zhang − Department of Chemistry, Stanford
University, Stanford, California 94305-5580, United States;
orcid.org/0000-0002-8516-317X
Hadi Gholami − Department of Chemistry, Stanford
University, Stanford, California 94305-5580, United States;
orcid.org/0000-0001-6520-0845
Daniel Zell − Department of Chemistry, Stanford University,
Stanford, California 94305-5580, United States;
orcid.org/0000-0002-2241-6301
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M. Gold(i)-catalyzed stereoselective cyclization of 1,3-enyne
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05521
(11) (a) Zhang, Y.; Luo, T.; Yang, Z. Strategic innovation in the
total synthesis of complex natural products using gold catalysis. Nat.
Prod. Rep. 2014, 31, 489. (b) Dorel, R.; Echavarren, A. M. Gold(I)-
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Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̀
(12) Gandon, V.; Lemiere, G.; Hours, A.; Fensterbank, L.; Malacria,
We thank the DFG Research Fellowship (D.Z.) and the
Tamaki Foundation and Chugai Pharmaceutical for financial
support. We also thank Dr. Tayeb Kakeshpour (National
Institute of Health) for computational support of this work and
Dr. Stephen Lynch (Stanford University) for NMR experi-
ments.
M. The Role of Bent Acyclic Allene Gold Complexes in Axis-to-
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