A Concise, Enantiospecific Total Synthesis of Chilocorine C Fueled by a Reductive Cyclization/Mannich Reaction Cascade

Article abstract of DOI:10.1021/jacs.0c04914

Among defensive alkaloids isolated from ladybugs, the heterodimeric member chilocorine C possesses an alluring monomeric unit that combines quinolizidine and indolizidine substructures. Indeed, the overall stereochemical disposition of its ring fusions is distinct from those of related natural products. Herein we show that a carefully orchestrated sequence with several chemoselective transformations, including a designed cascade that accomplishes nine distinct chemical reactions in one-pot, can smoothly forge that domain and ultimately enable a 15-step, 11-pot enantiospecific synthesis of the natural product. Mechanistic studies, density functional theory calculations, and the delineation of several other unsuccessful approaches highlight its unique elements.

Full text of DOI:10.1021/jacs.0c04914

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Communication
A Concise, Enantiospecific Total Synthesis of Chilocorine C
Fueled by a Reductive Cyclization/Mannich Reaction Cascade
Vladislav G Lisnyak, and Scott A. Snyder
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04914 • Publication Date (Web): 17 Jun 2020
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Journal of the American Chemical Society
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A Concise, Enantiospecific Total Synthesis of Chilocorine C Fueled
by a Reductive Cyclization/Mannich Reaction Cascade
Vladislav G. Lisnyak and Scott A. Snyder*
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637
1
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5
5
5
5
5
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0
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0
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0
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8
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0
Supporting Information Placeholder
that transformation that would be observed experimentally, given
ABSTRACT: Among defensive alkaloids isolated from ladybugs,
its stereochemical uniqueness discussed above, and the potential
for addition from either face as indicated in the inset box. Assum-
ing success, we hoped in turn that iminium ion 10 could arise in a
single pot through a reductive cyclization cascade commencing
from 11, itself prepared expeditiously from commercially availa-
the heterodimeric member chilocorine C possesses an alluring
monomeric unit that combines quinolizidine and indolizidine
substructures. Indeed, the overall stereochemical disposition of
its ring fusions is distinct from related natural products. Herein,
we show that a carefully orchestrated sequence with several
chemoselective transformations, including a designed cascade that
accomplishes 9 distinct chemical reactions in one pot, can
smoothly forge that domain and ultimately enable a 15-step, 11-
pot enantiospecific synthesis of the natural product. Mechanistic
studies, DFT calculations, and the delineation of several other
unsuccessful approaches highlight its unique elements.
8
ble 12 using the unique chemistry of nitrones.
Scheme 1. Structures of selected coccinellid alkaloid dimers (1-4) all bearing consistent
ring fusions, the structure of chilocorine C (5) that possesses a unique ring fusion relative
to other tricyclic alkaloids containing one five-membered ring (such as 6 and 7), and a
retrosynthetic approach to access that unique stereochemical arrangement.
H
H
N
H
H
Me
H
H
H
Over the past several decades, a number of alkaloids have
Me
N
N
Me
H
N
been isolated and characterized from ladybugs of the Coccinelli-
H
1
H
N
dae genus. These structures include tricyclic alkaloids as well as
H
H
trans-fused
cis-fused
more complex hexa- and heptacyclic members that have been
termed as either homo- (as in 1, Scheme 1) or heterodimeric (2–4)
based on the structural homology between their two respective
Me
1: psylloborine A
1: psylloborine A
O
2
Me
Me
O
Me
Me
N
H
major domains. All of these drawn compounds (1–4) have a con-
N
H
O
N
N
N
N
served 6/6/6-tricycle with consistent cis- and trans-ring fusions as
indicated within the inset boxed structure. Breaking this trend is
chilocorine C (5), a compound obtained in minute quantities (0.6
mg from 460 beetles) and structurally characterized by Meinwald
*
H
H
H
H
H
2: exochomine
Me
3: chilocorine A
4: chilocorine B
2
d
in 1998. Indeed, it possesses a saturated monomeric unit with a
/6/5 fusion that formally combines one quinolizidine and two
H
H
6
Me
Me
H
O
N
N
indolizidine subunits. While the overall patterning of its cis- and
trans-ring fusions matches those of its 6/6/6 tricyclic counterparts,
including the co-isolated and previously characterized natural
N
OH
*
H
N
H
H
N*
OH
2
b
2c
Me
products chilocorines A (3) and B (4), it possesses an overall
stereochemical disposition that is, to the best of our knowledge,
distinct among known natural products. For example, while there
O
trans-fused
cis-fused
5: chilocorine C
5: chilocorine C
Me
N
OH
3
Me
Me
H
Me
Me
N
are a few alkaloids with 6/6/5 systems, some of which are shown
Ph
3
b,4
3ac
H
H
in Scheme 1 (6 and 7 ), their 5-membered rings possess one
cis- and one trans-fusion with their 6-membered neighbors; in 5,
H
N
H
H
H
N
H
OH
H
5
Me
H
however, both of these fusions are cis. Herein, we show that forg-
Me
Ac Me
ing this overall domain of chilocorine C is quite challenging and
could only be achieved through a designed cascade conducted
under carefully orchestrated conditions, terminating in a reversi-
ble Mannich reaction with a distinct nucleophile class. This oper-
ation, coupled with further unique and chemoselective steps, af-
6: alkaloid (–)-205B
5 syntheses)4
6: alkaloid (–)-205B
7: crepidine
(
Me
S
Me
Me
H
O
N
N
MeO2C
N
N
S
O
*
H
+
H
6
H
H
8
H
forded a 15-step, 11-pot enantiospecific synthesis of the title
9
OBz
OH
: chilocorine C
alkaloid from commercially available materials, reflecting the
5
7
shortest pot effort for any related “dimeric” target.
(proposed structure)
H
N
Nu
Me
H
Our overall approach to chilocorine C (5) is shown retrosyn-
thetically in Scheme 1. Assuming that its one unassigned chiral
center, denoted with a star in the original depiction, matched that
of exochomine (2), a molecule we previously synthesized in 16-
OBz
H
1
0
Me
Me
Me
N
Me
OBz
H
H
H
H
H
7b
N
O
N
steps, the two major domains could be connected through a simi-
O
N
H
CO2H
OBz
OBz
lar terminating aldol/cyclization sequence. As such, with 8 in
hand, we needed access to 9, a compound whose electrophilic
aldehyde could hopefully be installed from iminium 10 through a
Strecker reaction. Unclear was the ease and stereoselectivity of
EtO
O
Me
CF CO
3
2
O
1
2
11
10
9
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Synthetic efforts commenced by using the carboxylic acid
domain of 12 to effect a regiospecific formation of chiral nitrone
3 as shown in Scheme 2. This decarboxylative oxidation was
zene, and heating at reflux for 3 h under azeotropic conditions
achieved both enamine formation and aldol condensation to forge
20. A terminating conjugate reduction in the same pot then gen-
erated 10 in 70% yield, completing a 7-step, 6-pot synthesis from
12. Pleasingly, this final 7-operation cascade could be conduct-
ed with no decrease in yield on 3 g scale.
9
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
ultimately achieved following extensive screening (see Support-
ing Information for more details) by adapting a literature proto-
1
8
1
0
col utilizing H O and Na WO in 74% yield on decagram scale.
2
2
2
4
Next, an anti-diastereoselective nitrone variant of the
Mukaiyama–Mannich reaction, using silylenol ether 14, afford-
ed the desired adduct and established two new chiral centers with
7:1:1 dr [(8S,2R):(8R,2R):(8R,2S)]. Subsequent treatment with
11
With iminium salt 10 in hand, we proceeded to install the at-
oms needed to forge the key aza-quaternary center and complete
the unique tricyclic domain of chilocorine C. As denoted in
Scheme 3, a Strecker reaction using KCN proceeded to afford a
mixture of nitriles 28 and 33 with 8:1 dr, initially of unknown
configuration. We became concerned, however, that the incorrect
diastereomer had been formed preferentially when subsequent
LiAlH achieved both reduction of the ester and TBS ether cleav-
4
1
2
age to afford 15 in 72% overall yield. Next, in order to introduce
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a second sidechain using nitrone chemistry, 15 was oxidized with
8a,13
IBX
to provide an 8:1 mixture of 16 and its ketonitrone isomer
in near quantitative yield; no other condition screened was as
regioselective. The remaining carbon chain was then introduced
efforts to reduce this newly installed functionality with an array of
®
aluminum-based hydrides [including LiAlH
(EtO)
,
Red-Al ,
4
1
4
via an exo-selective (3+2)-cycloaddition with ethyl vinyl ether
that, when followed by in situ treatment with BzCl, afforded isox-
azolidine 11 with high 2,6-trans-diastereoselectivity (dr >10:1).
Pleasingly, an X-ray crystal structure of its ketal-deprotected vari-
ant (17) confirmed its relative configuration.
2
AlH, and DIBAL-H] led to decyanation with the corre-
sponding saturated amine being a major product. In addition, we
found that unlike the parent exochomine-related analog, both 10
and 28 readily participated in the addition of organometallic rea-
19
gents (preceeded by decyanation with 28), producing a single
diastereomer in each case. Eventually, material suitable for X-ray
crystallographic diffraction was obtained from the HCl salt of 29
(acquired by the addition of allylzinc to 10) confirming that the
kinetic product for these additions was the trans-fused diastere-
Scheme 2. Expeditious preparation of key iminium intermediate 10 fueled by a cascade sequence.a
Me
Me
Me
a) H
Na
2 2
O ,
b) 14, ZnI
c) LiAlH
(72% overall)
2
OH
O
2
WO
4
H
20
2
omer 27, thus reflecting the skeleton of alkaloid (–)-205B and
N
H
CO
2
H
(74%)
N
4
N
8
[10 g scale]
O
crepidine (6 and 7, cf. Scheme 1).
OH
1
2
13
15
O
Me
OEt
Scheme 3. Studies in adding nucleophiles into key iminium intermediate 10 in service of delivering
Me
O
d) IBX
structures of type 32. Free energy values (ΔG 298K) were calculated within ideal gas/1-D hindered
0
O
H
OTBS
14 (1 step)
Me
rotor/harmonic oscillator model using DFT with PW6B95-D3/def2-TZVPPD//IEFPCM/B97-D/6-31+G(d,p)
method (see SI for details).
Me
Me
Me
(ketal and
acetal
cleavage;
H
nOe
H
OBz
O
OH
O
e)
fast
addition
Nu
H
H
H
H
H
H
OEt
H
H
Nu
N
Nu
N
N
N
O
N
N
..
N-O bond
cleavage;
then BzCl
(68% overall)
Me
Me
O
TFA
OBz
OBz
H
H
O
Me
CF
3
CO
2
iminium EtO
O
Me
O
Me
CF CO2
OBz
OBz
3
24
25
1
9
formation)
11
16
10
(
28: Nu = CN)
slow addition
and N-inversion
ΔΔG0298K
(
enamine
f) Mo(CO)
TFA, H O,
CH CN
,
6
(
70% overall)
[3 g scale]
dr
formation; aldol
condensation)
Nu
kcal/mol
32-27/25)a
N-inversion
2
(32:27/25)
Me
Nucleophiles
allylZnBr
NCCH2ZnBr allylMgBr
3
(
Me
..
H
CN
Me
N
Me
N
OBz
H
Me
H
. .
H
CN
1:8
8:1
7:1
5:1
2.1
-1.5
-1.5
1.1
H
(conjugate
reduction)
N
O
N
N
Nu
21
O
O
O
O
Nu
H
H
H
H
O
H
22
23
OBz H
RO
O
O
O
2
2
Me
OBz
CN
26
OBz
OBz
31
Me Me
1
1
7: R = Et [X-ray]
8: R = H
O
H
CF
3
CO
2
CF
10
(3.0 equiv), K
O, 5 °C to 23 °C, 1.5 h, 74%; (b) 14 (1.2 equiv), ZnI
, -78 °C to 23 °C, 9 h; (c) LiAlH (4.0 equiv), THF, 66 °C, 3 h, 72% for 2 steps; (d) IBX
1.1 equiv), MgSO (3.0 equiv), CH Cl , -20 °C to 23 °C, 1.5 h; (e) ethyl vinyl ether (10.0 equiv),
toluene, 55 °C, 17 h; then concentrate; then BzCl (1.0 equiv), 4-DMAP (0.1 equiv), Et N (3.0
equiv), CH Cl , 0 °C to 23 °C, 2 h, 68%; (f) Mo(CO) (1.5 equiv), TFA (2.0 equiv), CH CN/H
4:1), 0 °C to 90 °C, 8 h; TFA (5.0 equiv), 90 °C, 0.5 h; benzene, Dean-Stark, 90 °C, 3 h, 70%.
IBX = 2-iodoxybenzoic acid; 4-DMAP = 4-dimethylaminopyridine; TFA = trifluoroacetic acid.
3
CO
2
TFA
23
21
2
0
ring flip
ring flip
Me
Me
N
a
Reagents and conditions: a) H
Et NCl (0.1 equiv), CH Cl /H
CH Cl
2
O
2
3
PO
4
(1.2 equiv), Na
2
WO
4
•2H
2
O (0.1 equiv),
(0.2 equiv),
. .
Me
..
H
4
2
2
2
2
H
H
H
N
2
2
4
N
N
Nu
Nu
(
4
2
2
H
OBz H
H
3
OBz
OBz
H
2
2
6
3
2
O
Nu
32
OBz
Nu
27
trans-fused
nOe
27
(
32
(33: Nu = CN)
34: Nu = CH CN)
cis-fused
(29: Nu = allyl)
(30: Nu = CH CN)
X-ray for 29•HCl]
(
2
2
[
We next sought to convert 11 into iminium 10, a task requir-
ing an initial N–O cleavage to introduce a β-aminoaldehyde moie-
ty. However, given the sensitive nature and general instability of
Given this information, we attempted to shift the equilibrium
of the Strecker reaction through numerous variations in reaction
conditions as well as additional substrate modifications (not
shown); these efforts were unsuccessful. As a result, we won-
dered if Mannich-type additions, processes which are reversible,
could offer a solution. Gratifyingly, we discovered that 1,3-
dicarbonyl compounds such as 21 and 22, can, in fact, favor for-
mation of the desired diastereomer. For example, when 10 react-
1
5
such functionality, we expected that this event likely had to be
coupled with an aldol condensation in a one-pot operation to pre-
vent decomposition, thus requiring acidic conditions to enable the
requisite events to proceed in a cascade fashion. Following exten-
16
sive screening and optimization (see SI), we found that
17
Mo(CO)6 alone proved capable of rising to the occasion, afford-
ing the means to achieve the full sequence. Thus, following dis-
21
ed with 21 (in the form of its potassium salt) in MeOH, it readily
solution of 11 in a 4:1 mixture of MeCN/H O and sequential
2
formed the corresponding zwitterionic product with an initial dr
of 1:1 that reached an equilibrium dr of 8:1 favoring the desired
treatment with Mo(CO) (1.5 equiv) and TFA (2.5 equiv) at 0 °C,
6
the contents were heated to reflux for 8 h to effect conversion to
22
cis-fused isomer 32 upon standing. Unfortunately, the synthetic
1
9 via 4 distinct chemical events: ketal cleavage, acetal hydroly-
sis, N–O bond cleavage, and iminium formation. In this process,
7, 18, and 19 were observed by NMR analysis, and 17 and 18
were also isolable. Further addition of TFA, dilution with ben-
utility of these addition products was found to be rather limited, as
they were not readily able to be converted into the desired alde-
hyde. As such, other derivatives of malonic acid were considered,
1
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and eventually it was found that a decarboxylative Mannich reac-
the final elements of the route: MeLi addition, dehydration, and
2
3
1
2
3
4
5
6
7
8
9
tion with the mono-salts of malonates could promote the desired
outcome. For example, potassium cyanoacetate 23 was able to
provide a 1:1 ratio of 34 to 30 when the reaction was performed in
thioacetal deprotection. Pleasingly, initial screens showed that the
conditions used for the first two operations could also accomplish
removal of the Bz protecting group at the same time. However,
2
3c
32
refluxing 1,4-dioxane, while switching to a protic solvent such
the final thioacetal deprotection with PhI(OAc)2 proceeded with
as i-PrOH boosted the dr to 5:1 favoring the desired 34. In ac-
cordance with literature precedent, the addition precedes decar-
boxylation based on MS analysis of the crude reaction mixture.
a disappointingly low yield (20% here; 31% for exochomine).
Eventually, we found a DMSO/HCl protocol could promote a
23d
33
very clean and chemoselective thioacetal removal in high yield
(86%). In order to reduce the isolation of highly sensitive inter-
mediates, the MeLi addition/dehydration reaction was ultimately
combined with the DMSO-promoted thioacetal removal protocol,
which, after purification, provided chilocorine C•HCl (5•HCl) in a
42% isolated yield. The spectral data for 5•HCl matched that of
In order to quantify these results and to potentially explain the
observed reactivity, we computed free energy differences between
each pair of isomers using DFT (for the full details, see SI). As
can be seen from the inset table in Scheme 3, the trends for the
preference in the major diastereomer for the addition of the cya-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2d
1
13
the natural sample, noting that both its H and C chemical
0
34
nide anion and 21–22 correlate well with the estimated ΔG
shifts displayed a dependence on concentration, with only rela-
2
98K
values. Furthermore, the most stable conformation for the major
aminonitrile isomer 28 was found to have an antiperiplanar ar-
rangement between the lone pair and CN group (drawn here as
conformation 25 and confirmed by nOe experiments). This find-
ing helps to explain the reactivity of 28 towards aluminum-based
hydrides, since decyanation is a common pathway for strained
tively concentrated solutions matching the reported chemical
3
5,36
shifts (see SI).
An X-ray structure of 5•HCl was also obtained.
24
antiperiplanar aminonitriles. However, the difference in free
energies computed for the two possible addition products of 23 to
10 (prior to decarboxylation), favor the trans isomer
0
[ΔΔG 298K(cis-trans) = 1.1 kcal/mol], suggesting kinetic control.
The investigation of the potential energy surface for the two pos-
sible pathways with DFT revealed several key features that may
provide an explanation for the observed selectivity. First, the bar-
‡
riers for the Mannich reaction differ significantly (ΔH = 4.7
0
K
kcal/mol), with the pathway leading to trans-fused isomer 26
20
having the lower barrier. Most important was the finding that the
rate-limiting transition state is decarboxylation, rather than the
Mannich reaction. Thus, the kinetics of the reaction are most like-
2
5
ly controlled by the Curtin–Hammett principle. With the energy
of the decarboxylation transition state for the cis-pathway being
‡
lower than that of the trans-pathway (ΔH 0 = 1.4 kcal/mol), the
K
cis-fused isomer 34 is predicted to be the major product, in ac-
26
cordance with experimental results.
Having established access to the desired diastereomer, we
found that we could successfully integrate the addi-
tion/decarboxylation step (i.e. 10 to 34) into the full cascade with-
out any compromise in stereoselectivity. Therefore, 34 could be
obtained from 11 in a single-pot, 2-step operation that combined 9
2
7
distinct reactions in 47% yield (Scheme 4).
Seeking now to
couple the two halves of chilocorine C, we sought to convert the
nitrile of 34 into the aldehyde of 9. To this end, hydration of 34
2
8
with 35 quantitatively afforded the corresponding carboxamide;
however, the following Hofmann rearrangement turned out to be
quite capricious. For example, under neutral conditions with any
III
29
I
source, the major and/or exclusive isolated product was
30
aminimide 37, hence, an acid additive was needed to suppress
the nucleophilicity of the tertiary nitrogen. Additionally, we
found that conducting the reaction under anhydrous conditions
produced substantial amounts of urea 38. After extensive opti-
mization, the use of Koser’s reagent in aqueous MeCN with p-
2
9c
2
9bc
TsOH•H O as an additive provided reproducible and scalable
2
results, producing 36 in 65% yield on gram scale. Finally, while
3
1
several efforts were made to oxidize the primary amine, we
3
1b
found that a modified protocol with dehydroascorbic acid (39)
could afford 9 in good yield (60%).
In conclusion, we have completed the first total synthesis of
chilocorine C via a highly convergent strategy. Our approach
featured a series of chemo- and stereoselective reactions using the
power of nitrones to attach key carbon sidechains and stereocen-
ters in advance of the critical 9 chemical event reaction cascade
that enabled construction of the unique 6/6/5-saturated tricycle of
With a route to 9 now secured, we proceeded to couple the
7
b
two fragments (8 and 9) following our reported sequence; these
processes worked well, with minor modifications effected in some
cases to achieve improved yields. Most critical among those was
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the target. The final reaction of that cascade included the for-
D, a novel heptacyclic alkaloid from a coccinellid beetle (Chilocorus
renipustulatus). Tetrahedron Lett. 2002, 43, 7465–7467.
1
2
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8
9
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mation of the key aza-quaternary stereocenter via a Mannich reac-
tion/decarboxylation sequence with 23, with computational analy-
sis affording mechanistic insights on the reactivity of iminium 10.
Finally, a series of carefully orchestrated reactions converted 34
into 9, and was followed by a further optimized sequence to com-
plete the synthesis of chilocorine C in just 15-steps (11-pots) from
commercially available starting materials, while also assigning a
previously unknown chiral center. That brevity and general
scalability, with more than half of the steps performed on gram-
scale, should provide efficient access to other indolizidine, quino-
lizidine, and pyrrole alkaloids as well as reaction parameters suit-
able for other problems of significance.
(
3) (a) Elander, M.; Leander, K.; Rosenblom, J.; Ruusa, E. Studies
on Orchidaceae Alkaloids. XXXII. Crepidine, Crepidamine and Den-
drocrepine, Three Alkaloids from Dendrobium crepidatum Lindl.
Acta Chem. Scand. 1973, 27, 1907–1913. (b) Tokuyama, T.;
Nishimori, N.; Shimada, A.; Edwards, M. W.; Daly, J. W. New clas-
ses of amidine, indolizidine and quinolizidine alkaloids from a poi-
son-frog, dendrobates pumilio (dendrobatidae). Tetrahedron 1987, 43,
6
43–652. (c) Hu, Y.; Zhang, C.; Zhao, X.; Wang, Y.; Feng, D.;
Zhang, M.; Xie, H. (±)-Homocrepidine A, Pair of Anti-
a
inflammatory Enantiomeric Octahydroindolizine Alkaloid Dimers
from Dendrobium crepidatum. J. Nat. Prod. 2016, 79, 252–256. (d)
Xu, X.; Li, Z.; Yang, R.; Zhou, H.; Bai, Y.; Yu, M.; Ding, G.; Li, B.
Crepidatumines C and D, Two New Indolizidine Alkaloids from
Dendrobium crepidatum Lindl. ex Paxt. Molecules 2019, 24, 3071.
0
1
2
3
4
5
6
7
8
9
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3
4
5
6
7
8
9
0
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6
7
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9
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ASSOCIATED CONTENT
Supporting Information
(
4) For total syntheses of alkaloid (−)-205B (6), see: (a) Toyooka,
N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Total Synthesis of the
Antipode of Alkaloid 205B. Angew. Chem. Int. Ed. 2003, 42,
3808−3810. (b) Smith, A. B.; Kim, D.-S. Total Synthesis of the Neo-
tropical Poison-Frog Alkaloid (−)-205B. Org. Lett. 2005, 7,
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.
3
247−3250. (c) Tsukanov, S. V.; Comins, D. L. Concise Total Syn-
AUTHOR INFORMATION
thesis of the Frog Alkaloid (–)-205B. Angew. Chem. Int. Ed. 2011, 50,
8626–8628. (d) Yang, D.; Micalizio, G. C. Synthesis of Alkaloid (−)-
Corresponding author: sasnyder@uchicago.edu.
Notes: the authors declare no competing financial interest.
2
05B via Stereoselective Reductive Cross-Coupling and Intramolecu-
lar [3+2] Cycloaddition. J. Am. Chem. Soc. 2012, 134, 15237−15240.
e) Rao, N. N.; Cha, J. K. Concise Synthesis of Alkaloid (−)-205B. J.
(
ACKNOWLEDGMENT
Am. Chem. Soc. 2015, 137, 2243−2246.
(5) Simple cis-indolizidines are very rare, see, for example: (a)
Lüning, B.; Lundin, C. Studies on Orchidaceae Alkaloids. VI. Synthe-
sis and Relative Configuration of 5,7-Dimethyloctahydroindolizines.
Acta Chem. Scand. 1967, 21, 2136−2142. (b) Tokuyama, T.; Shi-
mada, A.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. The Isolation
and Structure of the Novel cis-Fused Indolizidine 249H from Frog
Skin: cis- vs. trans-Fused Indolizidines Distinguished by NMR. Het-
erocycles 1998, 49, 427−436. (c) Daly, J. W.; Spande, T. F.; Garraffo,
H. M. Alkaloids from Amphibian Skin: A Tabulation of Over Eight-
Hundred Compounds. J. Nat. Prod. 2005, 68, 1556−1575. (d) Mi-
chael, J. P. Indolizidine and quinolizidine alkaloids. Nat. Prod. Rep.
2008, 25, 139–165.
(6) The identification of pot operations refers to the letters used in
the schemes, wherein starting material does not leave the reaction
flask. The identification of the end of a step refers either to an explic-
it work-up procedure (such as an extraction or direct filtration) or the
removal of solvent while starting material remains in the flask. ꢀ
We wish to acknowledge Dr. Jianbin Wu for some initial explora-
tions into the synthesis of intermediates of type 16 and 11. We
thank Dr. Alexander Filatov and Mr. Andrew McNeece for ob-
taining X-ray crystal structures of 5•HCl, 17, 29•HCl, and
3
6•2HCl; the X-ray of 5•HCl was taken at the Argonne National
Laboratory, and NSF’s ChemMatCARS Sector 15 is supported by
the Divisions of Chemistry (CHE) and Materials Research
(
DMR), National Science Foundation, under grant number
NSF/CHE-1834750. Use of the Advanced Photon Source, an
Office of Science User Facility operated for the U.S. Department
of Energy (DOE) Office of Science by Argonne National Labora-
tory, was supported by the U.S. DOE under Contract No. DE-
AC02-06CH11357. We also thank Dr. Josh Kurutz, Dr. Antoni
Jurkiewicz, and Dr. C. Jin Qin for assistance with NMR and mass
spectrometry, respectively. Support for the calculations per-
formed was completed in part with resources provided by the
University of Chicago’s Research Computing Center. Financial
support for this work came from the University of Chicago and
the National Institutes of Health (NIH R01-124295A).
(
7) (a) Sherwood, T. C.; Trotta, A. H. A Strategy for Complex Di-
mer Formation When Biomimicry Fails: Total Synthesis of Ten Coc-
cinellid Alkaloids. J. Am. Chem. Soc. 2014, 136, 9743–9753. (b) Gao,
A. X.; Hamada, T.; Snyder, S. A. The Enantioselective Total Synthe-
sis of Exochomine. Angew. Chem. Int. Ed. 2016, 55, 10301–10306.
(8) (a) Lisnyak, V. G.; Lynch-Colameta, T.; Snyder, S. A. Man-
nich-type Reactions of Cyclic Nitrones: Effective Methods for the
Enantioselective synthesis of Piperidine-containing Alkaloids. Angew.
Chem. Int. Ed. 2018, 57, 15162–15166. (b) S.-I. Murahashi, Y. Imada.
Synthesis and Transformations of Nitrones for Organic Synthesis.
Chem. Rev. 2019, 119, 4684–4716.
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18) Critical to the final operation was extended reaction time, not-
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6
0 was subjected to the cascade cyclization conditions with Mo(CO) ,
6
2
no conjugate reduction has occured, likely suggesting that low-valent
II
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1
1
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2
2
2
2
2
2
2
2
2
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3
3
3
3
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4
4
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(
30) To the best of our knowledge, an “interrupted” Hofmann rear-
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(
31) (a) Buckley, T.F.; Rapoport, H. Mild and Simple Biomimetic
Conversion of Amines to Carbonyl Compounds. J. Org. Chem. 1982,
104, 4446−4450. (b) Srogl, J.; Voltrova, S. Copper/Ascorbic Acid
Dyad as a Catalytic System for Selective Aerobic Oxidation of
Amines. Org. Lett. 2009, 11, 843−845.
(
32) Shi, X.-X.; Wu, Q.-Q. Deblocking of Dithianes with Diace-
toxyiodobenzene. Synth. Commun. 2000, 30, 4081−4086.
(33) Prato, M.; Quintily, U.; Scorrano, G.; Sturaro, A. Cleavage of
the 1,3-Dithiane Protective Group. Synthesis 1982, 8, 679−680.
(
34) Mitra, A.; Seaton, P. J.; Assarpour, R. A.; Williamson, T. Un-
precedented Concentration Dependent Chemical Shift Variation in
1
H-NMR Studies: A Caveat in the Investigations of Molecular
Recognition and Structure Elucidation. Tetrahedron 1998, 54,
15489−l5498.
(
35) One possible explanation for that phenomenon is an intermo-
lecular π–π stacking present in concentrated samples (Ref. 34). As
evidence for that assertion, an obtained X-ray crystal structure of
5
•HCl identified π–π stacking and a unique hydrogen bonding net-
work in the crystal lattice between two monomeric units. The same
phenomenon might be responsible for mismatch between the NMR of
the natural exochomine and its synthetic sample, despite their identi-
ties both being confirmed by X-ray analysis (see Ref. 7b).
(
36) As noted by a referee, we have not explicitly prepared the en-
antiomer of 8 for coupling with 9 to afford a diastereomer of 5•HCl to
ensure that it does not, also, have similar spectra. We believe such
additional structural proof is unnecessary given the level of NMR
match between synthetic and natural material and that the consistency
observed for the pyrrole subunit within other dimeric members of the
family that is supported either by X-ray crystallographic analysis
[
exochomine (2) and chilocorine B (4)] or nOe studies (chilocorine
D). Moreover, since chilocorine B (4) has been co-isolated with
chilocorine C (5), as reported by Meinwald (Ref. 2d), it would seem
to be a fair assumption that 5 would have the same configuration.
Additionally, if such a preparation were undertaken and the spectra
were similar, optical rotation data could not distinguish the diastere-
omers since no value has been reported for natural 5•HCl that we can
identify.
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7
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9
1
1
1
1
1
1
1
1
1
1
2
2
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2
2
2
2
2
2
2
3
3
3
3
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3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
Me
Me
O
Mo(CO)6,
TFA
Me
H
OBz
O
N
H
N
N
H
H
N
O
NC
CO2K
CN (7 steps)
OBz
H
H
reductive cyclization
cascade
Mannich reaction
(one-pot, 2 step,
-transformation cascade)
OH
EtO
O
Me
chilocorine C
(11 pots,
15 steps total)
(6 steps)
9
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