The Total Synthesis of Chalcitrin

Article abstract of DOI:10.1021/jacs.8b12612

The first total synthesis of the yellow pigment chalcitrin, a structurally distinct pulvinic acid dimer obtained from Chalciporous piperatus, has been achieved in 17 linear steps from commercially available materials. Key elements of the design include the use of a Au(I)-catalyzed Conia ene reaction and an N-heterocyclic carbene-mediated acyloin addition to rapidly fashion its unique polycyclic core, with the two high oxidation state side chains introduced in a single step via a late-stage double Stille coupling. Of note, many alternate designs based on differential final couplings failed, likely because of the hindered nature of the core. In addition, significant challenges in final natural product characterization in terms of matching NMR spectra were experienced; our studies reveal that the originally characterized material was its carboxylate salt form not its free acid.

Full text of DOI:10.1021/jacs.8b12612

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Communication
The Total Synthesis of Chalcitrin
Ming Yang, Fangjie Yin, Haruka Fujino, and Scott A. Snyder
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Feb 2019
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The Total Synthesis of Chalcitrin
Ming Yang, Fangjie Yin, Haruka Fujino, and Scott A. Snyder*
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637
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challenges in its protonated and acidified forms in a variety of
ABSTRACT: The first total synthesis of the yellow pigment
chalcitrin, a structurally distinct pulvinic acid dimer obtained
from Chalciporous piperatus, has been achieved in 17 linear
steps from commercially available materials. Key elements of
the design include the use of a Au(I)-catalyzed Conia ene reac-
tion and an N-heterocyclic carbene-mediated acyloin addition
to rapidly fashion its unique polycyclic core, with the two high
oxidation state sidechains introduced in a single step via a
late-stage double Stille coupling. Of note, many alternate de-
signs based on differential final couplings failed, likely be-
cause of the hindered nature of the core. In addition, signifi-
cant challenges in final natural product characterization in
terms of matching NMR spectra were experienced; our studies
reveal that the originally characterized material was its car-
boxylate salt form, not its free acid.
solvents, we have determined that chalcitrin was also initially
obtained as an alkali metal salt, suggesting that it might also pos-
sess distinct metal complexation ability in Nature. Such studies
should be readily fueled by these efforts given that ~70 mg of 5
have already been prepared to date in the absence of specific ef-
forts at large-scale synthesis.
Key elements of our overall approach are shown at the bottom
of Scheme 1. First, we disconnected the two pulvinic acid
sidechains, projecting their incorporation in a final C–C bond
formation through some type of Pd-based coupling using tricyclic
core 7 and lactone derivative 6. Whether both couplings could be
achieved in tandem or would have to be effected in a stepwise
manner was unclear; we left projected flexibility at the positions
labeled here as X and Y to address that concern. If successful, a
final deprotection of six benzyl ethers would then deliver the tar-
get. That particular protecting group was selected based on our
past experiences with other polyphenols where rapid and global
cleavage proved necessary to enable product isolation where fur-
ther oxidation and/or decomposition was possible.7,8 Such con-
cerns arose from the comment above on chalcitrin presence being
dependent on sample condition.
Although Nature generates a vast array of dimeric natural
products, there appears to be only a modest number of collections
where a single building block has the ability to unite with itself to
generate several structurally distinct dimers.1 One of those rare
starting materials is xerocomic acid (1, Scheme 1), a highly-
oxidized polyphenolic material which is the putative monomeric
precursor for norbadione A (2), badione A (3), sclerocitrin (4),
and chalcitrin (5); that supposition is based on the fact that all of
these more complex materials have been co-isolated with xero-
comic acid (1) from various species of fungi and that dimer con-
centration relative to 1 tends to increase as the natural sources
age.2,3 The processes proposed for their biogenesis are equally
interesting. For example, with 4 and 5, yellow colored pigments
of Scleroderma citrinum and Calciporus piperatus, respectively,
their dearomatized4 polycyclic cores are surmised to arise from an
array of pericyclic ring formations and openings, among other
steps.3 Biologically, their function may be to complex metal ions
given that 2 and 3 occur as potassium salts in the producing fungi2
and norbadione A (2) can complex cesium ions better than func-
tionalized monomers; intriguingly, 2 was first isolated from mush-
room species in areas of high radioactive 137Cs concentration due
to the Chernobyl reactor incident.5
Scheme 1. Selected Structures of Pulvinic Acid Dimers Presumed to Arise from
Xerocomic Acid (1) and a Retrosynthetic Analysis of Chalcitrin (5).
O
O
OH
OH
H
O
OH
O
O
H
O
O
H
O
O
HO
O
OH
CO2H
OH
CO2H
4: sclerocitrin
HO2C
OH
HO
HO
1: xerocomic acid
O
O
O
OH
O
n
O
O
HO
H
O
O
O
O
HO
OH
O
HO
HO2C
O
HO
HO2C
CO2H
Our interest in the collection was piqued principally by chal-
citrin (5), arguably the rarest dimer of the group given that the
others have been obtained in relative large quantities from several
sources.6 By contrast, 5 has only been obtained from Calciporus
piperatus, with 300 g of fresh fruit bodies affording just 2 mg of
chalcitrin (5) along with 40 mg of sclerocitrin (4); the presence of
5 was also denoted as being strongly dependent on the age and
condition of the samples.3 Our initial synthetic efforts sought
biomimetic constructions along the lines of the original Steglich
proposals; however, in line with our experiences with other di-
meric collections such as those of the resveratrol,7 rosmarinic
acid,8 and coccinellid classes,9 we were unable to reduce such
strategies to practice. Herein, we document that an alternate,
stepwise approach can lead to 5 in 17 linear steps from commer-
cial materials. It features a number of regio- and chemoselective
transformations along with a very specific sequence for final
sidechain incorporation. Critically, as a result of characterization
O
OH
HO
HO2C
2: n = 0, norbadione A
3: n = 1, badione A
OH
5: chalcitrin
OH
[Pd-catalyzed
couplings]
SiMe2Ph
O
O
H
[NHC-promoted
acyloin addition]
H
BnO
OH
O
O
O
Y
+
H
O
OBn
BnO2C
I
I
X
7
6
8
O
[Conia ene
Cyclization]
I
O
OR
SiMe2Ph
H
H
PhMe2Si
O
TMS
H
SiMe2Ph
H
OR
OR
9
I
10
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sAuOTf on hundred milligram scale in a 10:1 mixture of tolu-
From here, the presence of an α-hydroxy ketone within the
tricyclic core of 7 suggested its potential formation via an acyloin
addition10 from 8. Then, after excision of its alkyl aldehyde
sidechain to arrive at 9, careful consideration of this new architec-
ture, particularly in the second drawn form, suggested that a Co-
nia ene reaction could potentially fashion its bicy-
cle[3.2.1]alkenone from a 1,2-trans-difunctionalized cyclopenta-
none precursor (10). This critical step was inspired by Barriault’s
total synthesis of hyperforin,11 among several other Conia ene
cyclizations12 such as our own towards the scaparvins.13 In this
design, assuming that the silicon group within 10 would arise via
nucleophilic addition onto a precursor α,β-unsaturated ketone, it
would then effect all of the stereocontrol in the synthesis, though
it ultimately would become a ketone in the final polycyclic core.
1
2
3
4
5
6
7
8
ene/t-BuOH. However, on gram scale, only CyJohnPhosAuOTf
gave comparable yields. This outcome was fortunate from a cost
perspective given that CyJohnPhosAuCl, the precursor to the
triflate version, is cheaper than JohnPhosAu(NCMe)SbF6.17
Pressing forward, exposure of 9 (with R = H and OMOM) to a
strong Lewis acid in the form of SnCl4 enabled addition of an allyl
group to occur onto the intermediate allyl cation with complete
regio- and diastereocontrol; this SN1 substitution process was
likely controlled as a result of addition onto the cancave face of 9
with the steric demand of the ketone being less than that of the
neighboring C–H group on the bicycle.18 Subsequent hydrobora-
tion of the resultant terminal alkene with (Sia)2BH and oxidation
with NaBO3•H2O afforded diol 16 in 83% yield in which the ke-
tone was also reduced. Exposure to Dess–Martin periodinane
then proved capable of oxidizing its two alcohols into 8, with a
small amount of lactone 17 (22%) formed as well; the latter could
be recycled into 16 via reduction using LiAlH4.19 Finally, treat-
ment of 8 with 20 mol % of N-heterocyclic carbene salt 1820 in the
presence of Et3N smoothly effected the desired acyloin addition to
afford tricycle 19 in 83% yield.10f
9
10
11
12
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15
16
17
18
19
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21
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23
24
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Our efforts commenced with forming the full carbon frame-
work of the bridged tricyclic core. Starting from commercially
available 2-cyclopentanone (11, Scheme 2), a 1,4-addition/aldol
14
reaction with PhMe2Si(Me)Cu(CN)Li2
and trimethylsilyl
propynal (12) afforded ketone 13 following MOM-protection of
the newly formed secondary alcohol. Although this operation
produced a 1.45:1 ratio of diastereomers about that new alcohol,
this mixture was of no consequence since that center would be
ablated later. More significant was that the desired material was
formed as a single diastereomer in terms of the chiral centers on
the cyclopentane ring. We note that although we have not explic-
itly performed an asymmetric preparation of this material, the
exact same silyl addition followed by trapping with benzaldehyde
has been reported by Hoveyda to lead to closely related products
in 80% ee.15 Next, in anticipation of probing the projected Conia
ene cyclization, ketone 13 was transformed into 14 in 76% overall
yield through iodination of the TMS-protected alkyne using Ag-
NO3 and N-iodosuccinimide16 followed by silyl enol ether for-
mation (KHMDS, TIPSCl). Pleasingly, after extensive screening,
we found that the desired Conia ene reaction generating 9 (as a
separable mixture of both protected and deprotected alcohols due
to the acidic conditions) could indeed be effected using either
Our goal now was to incorporate the two sidechains through
some variant of Pd-based C–C bond-forming chemistry.21 In
practice, however, this task proved to be highly challenging. Ini-
tially, we envisioned an approach in which one of the sidechains
would be introduced by a Stille coupling between the stannane
variant of the readily synthesized 2322 (4 steps from tetronic acid,
Scheme 3) and the vinyl iodide motif of 19; the other sidechain
would be added via a Heck reaction between 23 and an enone
generated on the right-hand ring of 19. In practice, however, we
were never able to directly form a stannane from iodolactone 23.
As a result, alternate coupling partners were developed by con-
verting 19 into stannane 22 through a two-step Tamao–Fleming
oxidation23 of the alkyl silane, concomitant alcohol oxidation and
enone formation using IBX under acidic conditions,24 and conver-
sion of the alkenyl iodide into a stannane. Critically, while the
yield in the step converting 20 to 21 was modest at 52%, in the
absence of catalytic p-TsOH demonstrably lower yields were
obtained with most of the starting material decomposing instead.
Pleasingly, the initial coupling between 22 and 23 proceeded
smoothly to afford 24 in the presence of Pd(PPh3)4 and CuTC in
45% yield.25 Unfortunately, all attempts to advance beyond 24
using a variety of Heck-type additions with 23 failed to deliver
25. We reason that steric hindrance coupled with the rigidity of
the core is the main culprit for this failure given their likely im-
pact on the migratory insertion step.
catalytic
JohnPhosAu(NCMe)SbF6
or
CyJohnPho
Scheme 2. Gram-Scale Synthesis of the Core Tricycle of Chalcitrin (5).a
a) PhMe2SiLi,
MeLi,
CuCN; 12
O
TIPSO
OMOM
OMOM
H
O
H
c) AgNO3,
NIS
b) MOMBr,
i-Pr2NEt
d) KHMDS,
TIPSCl
TMS
I
SiMe2Ph
SiMe2Ph
(76% over
two steps)
11
(77% over
two steps)
13
14
e) CyJohnPhosAuOTf
SiMe2Ph
SiMe2Ph
SiMe2Ph
f) allylTMS,
SnCl4
H
H
g) (Sia)2BH;
NaBO3
H
H
O
O
Scheme 3. Selected Challenges in Sidechain Introduction.a
OH
(44% over
two steps)
H
(83%)
H
H
OH
SiMe2Ph
OR
a) BF3•2AcOH
b) H2O2, KF,
NaHCO3
O
H
H
H
I
I
I
H
OH
H
15
OH
c) IBX,
p-TsOH
OH
O
OH
O
O
9: R = H or MOM
16
H
H
O
(52%)
(84% over
two steps)
h) Dess-
Martin
(22% 17 )
(56% 8)
N
I
N
C6F5
I
I
i) LiAlH4
H
19
20
21
N
(80%)
d) Me6Sn2,
Pd(PPh3)4
18
BF4
12
TMS
(77%)
O
O
O
H
SiMe2Ph
SiMe2Ph
H
OH
SiMe2Ph
OH
O
O
OH
H
H
O
H
O
OH
O
j)18, Et3N
H
H
O
O
+
23, [Pd],
conditions
X
O
O
(83%)
O
e) Pdo,
H
Me3Sn
H
H
O
O
22
BnO
OBn
BnO2
O
O
CuTC
(45%)
I
I
I
O
H
8
H
17
H
19
BnO
OBn
CO2Bn
O
C
CO2Bn
I
aReagents and conditions: (a) MeLi (1.05 equiv), CuCN (1.1 equiv), THF, -50 °C, 20
min; PhMe2SiLi (1.1 equiv), -78 °C, 30 min; 11 (1.0 equiv), -78 °C, 30 min, then 12 (1.0
equiv), -78 °C, 30 min, 91%, 1.45:1 dr; (b) i-Pr2NEt (4.3 equiv), MOMBr (3.6 equiv),
CH2Cl2, 23 °C, 48 h, 85%, 1.6:1 dr; (c) AgNO3 (0.4 equiv), NIS (1.1 equiv), DMF, 23
°C, 6 h, 86%, 1.67:1 dr; (d) TIPSCl (1.3 equiv), KHMDS (1.0 M in THF, 1.3 equiv), THF,
-78 °C, 15 min, 88%, 1.6:1 dr; (e) CyJohnPhosAuCl (0.1 equiv), AgOTf (0.095 equiv),
toluene/t-BuOH = 10:1, 40 °C, 17 h; (f) allyltrimethylsilane (1.21 equiv), SnCl4 (1.2
equiv), 0 °C, 1 h, 44% over two steps; (g) 2-methyl-2-butene (4.5 equiv), BH3•SMe2
(2.1 equiv), hexanes, 0 °C, 2 h; 15 (1.0 equiv), 23 °C, 3 h, then NaBO3•H2O (6.6
equiv), THF/H2O = 1:1, 23 °C, 8 h; 83%; (h) Dess-Martin periodinane (2.5 equiv),
CH2Cl2, 23 °C, 2 h, 22% for 17, 56% for 8; (i) LiAlH4 (2.4 equiv), CH2Cl2, 23 °C, 5 h,
80%; (j) 18 (0.2 equiv), Et3N (0.2 equiv), THF, 65 °C, 1 h, 83%.
BnO
OBn
BnO2C
23 [4 steps]
BnO
24
25
OBn
a Reagents and conditions: (a) BF3•2AcOH (4.8 equiv), CH2Cl2, 23 °C, 2 h; (b) KF (10 equiv), NaHCO3
(10 equiv), H2O2, THF/MeOH = 1:1, 23 °C, 12 h, 84% over two steps; (c) IBX (3.0 equiv), p-TsOH•H2O
(0.2 equiv), DMSO, 80 °C, 1 h, 52%; (d) Me6Sn2 (1.5 equiv), Pd(PPh3)4 (0.1 equiv), THF, 60 °C, 1 h,
77% w/grease; (e) 23 (1.2 equiv), Pd(PPh3)4 (0.1 equiv), CuTC (1.5 equiv), NMP, 60 °C, 30 min, 45%.
However, given the successful nature of the initial Stille cou-
pling leading to 24, we wondered next whether a tandem, double
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Stille coupling using 23 could rise to the occasion. As a result,
obtained following several runs of different parts of the sequence.
Unfortunately, our 1H and 13C spectra in acetone-d6 and DMSO-d6
did not match the values reported for the natural isolate.32 Given
that failure to obtain matching spectra can result from many is-
sues,12e,33 something we ourselves have recently experienced with
other targets,9b,34 we attempted a number standard alterations such
as titrating in acid (TFA) as well as playing with counterions.
Nothing afforded identical spectral values35 until we obtained the
sodium dicarboxylate salt by titrating synthetic chalcitrin (5) in
DMSO-d6 with NaDMSO-d6;33a as such, we surmise that natural
chalcitrin exists in its carboxylate form with alkali metal counteri-
ons present. Worth noting is that in its neat and protonated form,
chalcitrin (5) is not stable under ambient conditions.
1
2
3
4
5
6
7
8
access to compound 33 (Scheme 4) became the synthetic objec-
tive, hoping that the vinylogous bromide, as part of an electron-
deficient and hindered system, would be capable of also being
converted into the requisite stannane and then productively partic-
ipating in a Stille reaction at the same time as the previously suc-
cessful left-hand alkenyl stannane. As shown in Scheme 4, access
to that key compound was ultimately achieved over several steps
via several regio- and chemospecific functionalizations.26 First,
tricycle 19 was converted into methyl enol ether 28 over 3 steps,
using CSA to recycle the minor amounts of 26 formed from the
initial Tamao–Fleming/ketal formation sequence. From here,
subsequent allylic oxidation proved incredibly challenging, with
only Yeung’s conditions [t-BuOOH, PhI(OAc)2, Cs2CO3]27 af-
fording sufficient material throughput (35% yield).28 Next, hy-
drolysis with LiOH afforded a mixture of 30 and 31 (in a 1:5 ra-
tio) in which the minor enol tautomer favored the indicated and
desired orientation, likely due to hydrogen bonding with the
neighboring bridgehead tertiary alcohol. Subsequent treatment
with (COBr)2 and DMF afforded an ~1:1 mixture of 32 and 33,29
structures which were both confirmed by X-ray diffraction. The
former could be converted into the latter in near quantitative yield
(96%) through treatment with (n-Bu3Sn)2O in hot (80 °C) tolu-
ene,30 thus affording a 45% yield of 33 over three steps from 30.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Introduction of the Side-Chains via a Double Stille Coupling and Completion
of a 17-Step Total Synthesis of Chalcitrin (5).a
a) Pd(Ph3P)4,
Me6Sn2,
LiCl
O
O
O
OH
OH
BnO
O
O
O
SnBu3
H
(50%)
H
I
Me3Sn
OBn
BnO2C
Br
SnMe3
35 [6 steps]
33 [X-ray]
34
b) 35, Pd(PPh3)4,
CuTC
[Pd], 23
X
O
O
OH
OH
O
O
O
H
H
O
O
c) BBr3
O
O
HO
OH
BnO
OBn
(52% over
two steps)
O
O
Scheme 4. Synthesis of the Double Vinyl Halide Intermediate (33).a
O
HO2C
BnO2C
c) CSA, 4Å MS
CO2H
CO2Bn
(62%; 78% b.r.s.m.)
HO
BnO
OH
a) BF3•2AcOH
b) CSA,
CH(OMe)3,
MeOH;
OH
SiMe2Ph
H
H
H
OH
OH
25
5: chalcitrin
OH
OH
OBn
OMe
OMe
OMe
O
a Reagents and conditions: (a) Me6Sn2 (2.5 equiv), LiCl (10.0 equiv), Pd(Ph3P)4 (0.2 equiv),
THF, 60 °C, 30 min, 50% w/grease; (b) 35 (4.3 equiv), Pd(PPh3)4 (0.2 equiv), CuTC (4.0
equiv), NMP, 60 °C, 1.5 h; (c) BBr3 (20 equiv), CH2Cl2, -78 to -20 °C, 3 h, 52% over two steps.
+
H
H
H
H2O2, KF,
NaHCO3
I
I
I
19
26
27 [X-ray]
(26: 14%)
(27: 71%)
In conclusion, we have completed the first total synthesis of
chalcitrin (5) through a route which utilized several effective C–C
bond constructions to fashion the core along with a number of
regio- and chemoselective transforms to place appropriate func-
tional handles at the two sites needed for sidechain incorporation.
Such flexibility proved essential as only one specific variant of
the possible Stille coupling partners probed proved successful in
achieving the desired transformation, executed here in a highly
hindered setting to afford a tandem bond-forming process. Given
recent interest in such couplings, many for natural product total
synthesis, we anticipate that its success here will provide further
inspiration for similar events in other contexts. Finally, the se-
quence is scalable, having delivered ~35 times the material re-
sources obtained from an initial isolation effort using 300 g of
fungi to obtain this intriguing polyphenol.36
d) Dess-Martin
periodinane
(85%)
e) t-BuOOH,
O
O
H
O
PhI(OAc)2,
Cs2CO3
OH
OH
OH
OMe
O
OMe
f) LiOH
H
H
(35%)
I
I
I
OH
O
28
29
30
h) (n-Bu3Sn)2O
(30:31 = 1:5)
(96%)
O
O
O
H
O
H
H
O
OH
OH
O
O
O
g) (COBr)2
+
H
(32: 25%, 8:1 r.r.)
(33: 21%, 8:1 r.r.)
I
I
I
Br
32 [X-ray]
Br
O
31
33 [X-ray]
a Reagents and conditions: (a) BF3•2AcOH (3.7 equiv), CH2Cl2, 23 °C, 2 h; (b) trimethyl
orthoformate (7.5 equiv), CSA (0.11 equiv), MeOH, 65 °C, 3 h, then added THF, KF (7.4
equiv), NaHCO3 (7.4 equiv), H2O2, 23 °C, 12 h, 14% for 26, 71% for 27 over two steps; (c)
4Å MS, CSA (0.2 equiv), THF, 23 °C, 12 h, 62% (78% brsm); (d) Dess-Martin periodinane
(1.5 equiv), NaHCO3 (10 equiv), CH2Cl2, 30 min, 85%; (e) 4Å MS, Cs2CO3 (9.0 equiv),
PhI(OAc)2 (9.0 equiv), t-BuOOH (15 equiv), n-butyl butyrate/CH2Cl2 = 5:2, -15 °C, 36 h,
35%; (f) LiOH•H2O (5.0 equiv), MeOH/H2O = 2:1, 80 °C, 3 h; (g) (COBr)2 (1.5 equiv),
CH2Cl2/DMF = 4:1, 0 to 23 °C, 10 h, 25% for 32, 21% for 33 over two steps; (h) (n-
Bu3Sn)2O (2.0 equiv), toluene, 80 °C, 1 h, 96%; 45% yield of 33 over three steps.
ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures, copies of all spectral data,
cif files, and full characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
From here, 33 was converted into bis-stannane 34 (Scheme 5)
under standard conditions. Unfortunately, attempted coupling
with 23 did not succeed in delivering 25; only decomposition
products were observed. As a result, in a final effort, we devel-
oped an alternate route to synthesize the stannylated version of 23
(i.e. 35, 6 steps from tetronic acid, see SI for details), and pleas-
ingly, its union with 33 at both reactive sites could be achieved
smoothly using catalytic Pd(PPh3)4 in the presence of CuTC.25,31
Subsequent exposure to excess BBr3 (20 equiv) in CH2Cl2 from –
78 to –20 °C then effected a smooth deprotection of all six benzyl
groups to deliver material in 52% yield over these final two steps
which we presumed to be chalcitrin (5). As one measure of the
overall efficiency of the route, ~70 mg of the final compound was
AUTHOR INFORMATION
Corresponding author: sasnyder@uchicago.edu.
Notes: the authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Prof. Wolfgang Steglich (Leibniz Institut für Pflan-
zenbiochemie) for helpful discussions and kindly providing us
with a physical copy of the original 13C NMR spectra and isola-
tion method for chalcitrin (5). We also thank Prof. Steglich,
Dr. Norbert Arnold, and Dr. Serge Fobofou for supplying a
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ses of Rufescenolide, Yunnaneic Acids C and D, and Studies toward
Yunnaneic Acids A and B. J. Org. Chem. 2014, 79, 88.
specimen of Chalciporus piperatus. We also thank Dr. Alexan-
der Filatov for obtaining X-ray crystal structures of 27, 32 and
33 and Dr. Antoni Jurkiewicz and Dr. C. Jin Qin for assistance
with NMR and mass spectrometry, respectively. Financial
support came from the University of Chicago and a JSPS Re-
search Fellowship for Young Scientists (DC2, to H.F.). As
alumni of Lanzhou University, M.Y. and F.Y. wish to dedicate
this work to their alma mater on the occasion of its 110th an-
niversary.
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(9) (a) Sherwood, T. C.; Trotta, A. H.; Snyder, S. A. A Strategy for
Complex Dimer Formation When Biomimicry Fails: Total Synthesis
of Ten Coccinellid Alkaloids. J. Am. Chem. Soc. 2014, 136, 9743. (b)
Gao, A. X.; Hamada, T.; Snyder, S. A. The Enantioselective Total
Synthesis of Exochomine. Angew. Chem. Int. Ed. 2016, 55, 10301.
(10) (a) Hachisu, Y.; Bode, J. W.; Suzuki, K. Catalytic Intramolec-
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sis of Functionalized Preanthraquinones. J. Am. Chem. Soc. 2003,
125, 8432. (b) Hachisu, Y.; Bode, J. W.; Suzuki, K. Thiazolium
Ylide-Catalyzed Intramolecular Aldehyde−Ketone Benzoin-Forming
Reactions: Substrate Scope. Adv. Synth. Catal. 2004, 346, 1097. (c)
Enders, D.; Niemeier, O.; Balensiefer, T. Asymmetric Intramolecular
Crossed-Benzoin Reactions by N-Heterocyclic Carbene Catalysis.
Angew. Chem. Int. Ed. 2006, 45, 1463. (d) Takikawa, H.; Hachisu, Y.;
Bode, J. W.; Suzuki, K. Catalytic Enantioselective Crossed Alde-
hyde–Ketone Benzoin Cyclization. Angew. Chem. Int. Ed. 2006, 45,
3492. (e) Takikawa, H.; Suzuki, K. Modified Chiral Triazolium Salts
for Enantioselective Benzoin Cyclization of Enolizable Keto-
Aldehydes:ꢀ Synthesis of (+)-Sappanone B. Org. Lett. 2007, 9, 2713.
(f) Ema, T.; Oue, Y.; Akihara, K.; Miyazaki, Y.; Sakai, T. Stereose-
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by N-Heterocyclic Carbenes. Org. Lett. 2009, 11, 4866. (g) Perreault,
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(17) Recent pricing: 250 mg of CyJohnPhosAuCl is $25 from Al-
drich, while 250 mg of JohnPhosAu(NCMe)SbF6 is $97 from Strem.
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indicated peaks from a sample in DMSO-d6, the SI section table indi-
cated acetone-d6 instead, with the latter being the same solvent used to
characterize sclerocitrin. Complicating our analysis further was the
absence of any physical spectra from the original paper for 5; pleas-
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formation of 17 while providing only trace amounts of 8.
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A Versatile Protocol for Stille–Migita Cross Coupling Reactions.
Chem. Commun. 2008, 2873. (d) Lim, H. N.; Parker, K. A. Total
Synthesis of the Potent Androgen Receptor Antagonist (−)-Arabilin:
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Synthesis of Rubriflordilactone A. J. Am. Chem. Soc. 2014, 136,
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(26) Several other routes to 33 from 19 were attempted. Those ef-
forts included attempts to prepare different coupling partners, such as
the vinyl triflate variant of 33, but those efforts were all unsuccessful.
They also included studies with the enone derived from 19, but supe-
rior solutions were not identified.
(27) Zhao, Y.; Yeung, Y.-Y. An Unprecedented Method for the
Generation of tert-Butylperoxy Radical Using DIB/TBHP Protocol:
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Doyle, M. P. Dirhodium(II) Caprolactamate:ꢀ An Exceptional Catalyst
for Allylic Oxidation. J. Am. Chem. Soc. 2004, 126, 13622) gave a
low yield, with additional decomposition products making material
purification challenging. The use of PhI(OTFA)2 and t-BuOOH
(Sparling, B. A.; Moebius, D. C.; Shair, M. D. Enantioselective Total
Synthesis of Hyperforin. J. Am. Chem. Soc. 2013, 135, 644) was a
faster reaction, but not higher yielding. Additional options, such as
Pd(OH)2/C and t-BuOOH (Yu, J.-Q.; Wu, H.-C.; Corey, E. J.
Pd(OH)2/C-Mediated Selective Oxidation of Silyl Enol Ethers by tert-
Butylhydroperoxide, a Useful Method for the Conversion of Ketones
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were not attempted due to the vinyl iodide.
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α,β-Unsaturated Ketones. Tetrahedron Lett. 1989, 30, 3753.
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pare boronic acid/ester variants from iodide 23 were not successful.
Also, given that Suzuki couplings require strong base, we were con-
(34) Gan, P.; Pitzen, J.; Qu, P.; Snyder, S. A. Total Synthesis of the
Cage Indole Alkaloid Arboridinine Enabled by aza-Prins and Metal-
Mediated Cyclizations. J. Am. Soc. Chem. 2018, 140, 919.
(35) We believe that one 13C signal for a hard to see carbonyl car-
bon C-3) was misassigned from the original sample as 202.3 ppm,
whereas we see a very clear signal instead at 216.3 ppm for the diso-
dium salt; all other peaks are in near-perfect agreement. See SI for
more details.
(36) Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouységu, L.
Plant Polyphenols: Chemical Properties, Biological Activities, and
Synthesis. Angew. Chem. Int. Ed. 2011, 50, 586.
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O
H
O
OH
BnO
O
O
O
SnBu3
O
O
OH
O
OR
[Conia ene
Cyclization]
O
H
OBn
BnO2C
O
HO
OH
O
H
TMS
[double Stille coupling]
[Acyloin
addition]
I
HO2C
CO2H
SiMe2Ph
Br
17 steps
~70 mg prepared
HO
9
chalcitrin
OH
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