Concise Construction of the ACDE Ring System of Calyciphylline A Type Alkaloids by a [5+2] Cycloaddition

Article abstract of DOI:10.1002/chem.201901690

A concise route for construction of the ACDE ring skeleton in calyciphylline A type alkaloids was developed using an intramolecular [5+2] cycloaddition reaction of an oxidopyrylium species bearing a tetrasubstituted olefin. Key to the success of this reaction was the combination of acid and base, which accelerated the construction of this skeleton containing a spiro ring and vicinal quaternary carbon centers. The resultant tricyclic ADE ring compound was converted to an ACDE ring model through C?H oxidation and an aza-Wittig reaction.

Full text of DOI:10.1002/chem.201901690

A Journal of
Accepted Article
Title: Concise construction of the ACDE ring system of calyciphylline A-
type alkaloids via [5+2] cycloaddition
Authors: Hugh Nakamura, Manami Kawakami, Chihiro Tsukano, and
Yoshiji Takemoto
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To be cited as: Chem. Eur. J. 10.1002/chem.201901690
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COMMUNICATION
Concise construction of the ACDE ring system of calyciphylline
A-type alkaloids via [5+2] cycloaddition
Hugh Nakamura, Manami Kawakami, Chihiro Tsukano,* and Yoshiji Takemoto*
Abstract: A concise route for construction of the ACDE ring
skeleton in calyciphylline A-type alkaloids was developed using
an intramolecular [5+2] cycloaddition reaction of an oxidopyrylium
species bearing a tetrasubstituted olefin. Key to the success of
this reaction was the combination of acid and base, which
accelerated the construction of this skeleton containing a spiro
ring and vicinal quaternary carbon centers. The resultant tricyclic
ADE ring compound was converted to an ACDE ring model
through C–H oxidation and an aza-Wittig reaction.
calyciphylline A-type alkaloids have been reported, the
construction of this complex ring system in short step remains
challenging.
The Daphniphyllum alkaloids are complex polycyclic
alkaloids isolated from plants of the genus Daphniphyllum. [1]
This class of alkaloids has received much attention owing to
its complex three-dimensional structure and interesting
biological activities. In particular, calyciphylline A-type
alkaloids are Daphniphyllum alkaloids that contain a unique
hexacyclic skeleton bearing two contiguous quaternary
carbon centers and a spiro[4.5]decane skeleton (Figure 1).[2]
Among them, and in addition to calyciphylline A, simple
congeners including daphniyunnines and daphnipaxianines,[3]
dimeric congener logeracemin A,[4a] and hybrid congeners
hybridaphniphyllines[4b] have been elucidated. These natural
products show various biological activities, including
cytotoxicity and anti-HIV activity.[3,4]
Figure 1. Representative calyciphylline A-type alkaloid.
Owing to their interesting structures, many research groups
have engaged in synthetic studies toward calyciphylline A-
type alkaloids.[5] At the end of 2017, asymmetric total
Key to the synthesis of calyciphylline A-type alkaloids is
construction of the ADE ring skeleton containing a spiro ring
(E ring) and vicinal quaternary carbon centers. In previous
synthetic studies, stepwise sequences were used to obtain
this structure. We envisaged constructing the ADE ring
skeleton in one step using a [5+2] cycloaddition reaction,
which has successfully been employed in the synthesis of
other complex natural products.[9] However, it was not clear
whether an intramolecular [5+2] cycloaddition reaction could
be applied to oxidopyrylium species bearing a tetrasubstituted
olefin, with no examples reported. To investigate this
possibility, ACDE ring core 1 was selected as a model
compound. The C ring would be constructed through an aza-
Wittig reaction of compound 2, followed by oxidation of the A
ring to install an oxygen functionality. Compound 2 would be
synthesized from compound 4 by introducing a C1 unit onto
the seven-membered D ring followed by C–H oxidation of
compound 3. Formation of a tetrahydrofuranyl unit would
provide the foothold to construct F ring. Compound 4 would
be constructed from the [5+2] cycloaddition of oxidopyrylium
species 5, which would be generated from acetoxylpyranone
6. Two quaternary carbon centers are constructed in this
intramolecular [5+2] cycloaddition. Herein, we report the
synthesis of the ACDE ring model compound, in which an
intramolecular [5+2] cycloaddition was used to construct the
congested skeleton.
syntheses
accomplished by Li,[6] Zhai,[7] and Dixon and Paton.[8] Li and
coworkers constructed tetracyclic intermediate of
of
calyciphylline
A-type
alkaloids
had
a
daphniyunnine C (longeracinphyllin A) through a Ag-catalyzed
alkyne cyclization and Luche radical cyclization, followed by a
[3+2] cyclization to construct the sterically congested E ring
[6a]
bearing a quaternary carbon center.
Based on this total
synthesis, the authors also synthesized daphnipaxianine A,
[6b,c]
himalenine D, and hybridaphniphylline B.
Zhai and
coworkers also reported the total synthesis of (−)-
daphnilongeranin using an intermolecular [3+2]
B
cycloaddition to construct the E ring bearing a quaternary
carbon center and a late-stage aldol cyclization.[7] Dixon and
Paton et al. achieved the total synthesis of (−)-himalensine A
using an organocatalyzed enantioselective prototropic shift
and intramolecular Diels–Alder reaction to construct the ACD
ring skeleton.[8] Although several elegant total syntheses of
Dr. H. Nakamura, M. Kawakami, Dr. C. Tsukano, Prof. Dr. Yoshiji Takemoto
Graduate School of Pharmaceutical Sciences
Kyoto University
Yoshida, Sakyo-ku, Kyoto, 606-8501 (Japan)
E-mail: tsukano@pharm.kyoto-u.ac.jp
E-mail: takemoto@pharm.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of the
document.
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10.1002/chem.201901690
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Scheme 2. Synthesis of cyclization precursor 6.
With cyclization precursor 6 in hand, we examined the
[5+2] cycloaddition of oxidopyrylium species 5 (Table 1).
Initially, we attempted the cyclization of 6 at 150 C using no
additive. As expected, the reaction afforded no desired
product, presumably due to the low reactivity of the
tetrasubstituted olefin (entry 1). When trifluoroacetic acid
(TFA) was added, the starting material was consumed within
1 h, but the reaction gave desired product 4 in a low yield
along with byproduct 13 (entry 2). In contrast, the reaction
with iPr2NH gave 4 in 66% yield, but required a long reaction
time (entry 3). Interestingly, combining iPr2NH and TFA
accelerated the reaction to completion within 24 h while
maintaining the good yield (entry 4). This tendency was also
observed in the reaction using 2,2,6,6-tetramethylpiperidine
(TMP) and acetic acid (entries 5 and 6). Therefore, we next
investigated combinations of a base (2.0 equiv.) and acid (1.0
equiv.). When piperidine was employed as base, the reaction
gave only byproduct 14 containing furan in 40% yield, while
congested secondary amines, such as TMP, were effective
(entries 5 and 7). When 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) was used as base,[12] the starting material was
decomposed, presumably due to the strong basicity (entry 8).
4-Dimethylaminopyridine (DMAP) was effective, although the
reaction time had to be prolonged to 7 h (entry 9). Several
tertiary amines, including triethylamine, quinuclidine, and 1,4-
diazabicyclo[2.2.2]octane (DABCO) were also examined
(entries 10–12). Although the cyclization with triethylamine
gave the desired product in 35% yield along with a significant
amount of byproduct 13, quinuclidine and DABCO were
effective. Considering the yield and reaction time, DABCO
was employed as base for further investigations. Combining
DABCO with acetic acid instead of TFA resulted in a lower
yield (entry 13). Further investigations regarding temperature
resulted in an improved yield of 70% at 180 C (entries 14
and 15). These results indicated that the bulkiness and
basicity of the amine were important for this [5+2]
Scheme 1. Retrosynthetic analysis of ACDE model compound 1.
Cyclization precursor 6 was synthesized from commercially
available 2-methylcyclohexane-1,3-dione 7 (Scheme 2). The
formation of a vinylogous methyl ester was followed by the
nucleophilic addition of Grignard reagent 8[10] and acidic
workup to give ,-unsaturated ketone 9. After removing the
tetrahydropyranyl (THP) group, the resultant primary alcohol
was oxidized to aldehyde 10, which was then coupled with 2-
furanylmagnesium bromide to give alcohol 11. An
Achmatowicz rearrangement[11] of compound 11 by treating
with N-bromosuccinimide (NBS) was followed by the
acetylation of hemiacetal 12 to give cyclization precursor 6 in
68% yield from aldehyde 10.
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cycloaddition. Notably, this established sequence including a
[5+2] cycloaddition readily furnished the ADE ring core
bearing the spiro structure and vicinal quaternary carbon
centers from commercially available material through eight
steps and three purifications using silica gel chromatography.
Having established
compound 4, it was then converted to tricyclic compound 16
a
concise route to cyclized
through hydrogenation and reductive ring-opening using
13
SmI2 (Scheme 3). After silylation of the resulting secondary
alcohol 16, the Takai reaction was used to introduce an exo-
methylene moiety,14 affording compound 18, whereas the
Wittig reaction using Ph3P=CH2 did not proceed. The
hydroboration of 18 with 9-borabicyclo[3.3.1]nonane (9-BBN)
proceeded stereoselectively to give alcohol 3. After an
extensive investigation into functionalization of the E ring, C–
H oxidation using I2 and PhI(OAc)2 under light irradiation15
afforded tetracyclic compound 19. Functionalizing this
Table 1. Investigation into [5+2] cycloaddition of tetrasubstituted olefin.
complex molecule in
a
high yield with excellent
regioselectivity was beneficial to this strategy. The TBS group
of the secondary alcohol on the seven-membered ring could
be selectively removed, because the other siloxy group,
which is oriented in the axial position, is sterically hindered by
an angular methyl group. Dess–Martin oxidation16 of the
resultant alcohol gave ketone 20 in 75% overall yield from
exo-methylene compound 18. Our attention then turned to the
stereoselective introduction of another one-carbon unit on the
D ring. After treating ketone 20 with MeLi, the resulting
tertiary alcohol was dehydrated under using SOCl2 and
pyridine to give exo-methylene compound 22 in excellent
yield. This site-selectivity was attributed to the less hindered
proton of the methyl group in 21 being selectively
deprotonated instead of a methylene proton. Exo-methylene
compound 22 was derivatized to azide 23 through
hydroboration, mesylation, and SN2 azide displacement. After
removing the TBS group using aqueous HF, the resulting
secondary alcohol was directly oxidized to enone 2 using 2-
iodoxybenzoic acid (IBX).17
entry reagents[a]
temp (°C)
150
time
24 h
1 h
yield[b] byproduct[b]
0%[c]
1
2
3
4
5
6
7
none
TFA
150
11%
64%
66%
61%
56%
0%
13 (26%)
iPr2NH
150
69 h
24 h
24 h
5 h
iPr2NH, TFA[d]
TMP
150
150
TMP, AcOH[d]
, TFA
150
150
23 h
14 (40%)
With enone 2 in hand, the introduction of an oxygen
functionality on the A ring was investigated extensively.
However, we realized that oxidation of the -position in enone
2 via a silyl enol ether was difficult. For example, treating 2
with a base (lithium diisopropylamide, KOtBu, or Et3N) and
TMSCl (or TMSOTf) gave no reaction. Therefore, we focused
on an intramolecular aza-Wittig reaction of enone 2 and
oxidation (Scheme 3). Reduction of the azide group using
PPh3 in THF at 100 °C smoothly produced an amine.
Intramolecular nucleophilic attack of the amine was used to
form unstable enaminone 24, which was then trapped using
CbzCl as dienamide 25 in 72% yield. Various oxidation
8
DBU, TFA
DMAP, TFA
Et3N, TFA
, TFA
150
150
150
150
1 h
0% [e]
68%
35%
49%
-
9
7 h
-
10
11
1.5 h
1 h
13 (35%)
-
12
13
14
15
DABCO, TFA
150
2 h
61%
42%
37%
70%
-
-
-
-
DABCO, AcOH 150
2 h
DABCO, TFA
DABCO, TFA
100
180
5.5 h
0.5 h
conditions,
including
H2O2/HCO2H,18
MoO5·pyridine
complex,19 and PhNO,20 were tested, but compound 25 did
not react at all under these conditions. Furthermore, using 3-
chloroperoxybenzoic acid (mCPBA)21 or NBS22 resulted in the
decomposition of starting material 25. Interestingly, a facile
[4+2] cycloaddition of 25 with O2 in the presence of a catalytic
amount of tetraphenylporphyrin under light irradiation23
proceeded to give a peroxide that was too unstable to isolate.
While treating the peroxide with Me2S gave a mixture of
desired product 26 and ring-opening product 27, using PPh3
suppressed formation of the ring-opening product 27. As
separating the desired product from Ph3P=O was difficult, it
[a] 2 equiv. of base and/or 1 equiv. of acid were employed. [b] Isolated
yield. [c] No reaction. [d] equiv. of acid was employed. [e]
Decomposition. TFA trifluoroacetic acid, TMP 2,2,6,6-
tetramethylpiperidine, DABCO
= 1,4-diazabicyclo[2.2.2]octane.
2
=
=
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Scheme 3. Construction of ACDE ring model compound 1.
was directly subjected to hydrogenation conditions using Pd/C
to afford pentacyclic model 1 as a single diastereomer. The
newly generated stereochemistry was determined using a
NOESY experiment.
Aid for JSPS fellows (H.N.) and the JSPS KAKENHI (Grant No.
JP17H05051, C.T.), and JSPS KAKENHI (Grant No.
JP18H04407, C.T.) in the Middle Molecular Strategy.
In summary, we have established a concise route for the
synthesis of a tricyclic compound containing a spiro structure
and vicinal quaternary carbon centers using an intramolecular
[5+2] cycloaddition. In this reaction, a combination of acid and
base accelerates the [5+2] cycloaddition of compound 6
containing a tetrasubstituted olefin. To our knowledge, this is
Keywords: Daphniphyllum alkaloids • [5+2] cycloaddition •
synthetic strategy • calyciphylline A • daphniyunnine
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COMMUNICATION
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COMMUNICATION
Entry for the Table of Contents
Communication
A concise route to the ACDE ring
skeleton of calyciphylline A-type
alkaloids was developed using the
intramolecular [5+2] cycloaddition of
an oxidopyrylium species bearing a
tetrasubstituted olefin. This ring
system containing a spiro ring and
vicinal quaternary carbon centers was
successfully constructed using a
combination of acid and base to
accelerate the reaction. The tricyclic
ADE ring system was converted to the
ACDE ring model through C–H
H. Nakamura, M Kawakami, C.
Tsukano*, Y. Takemoto*
Page No. – Page No.
Concise construction of the ACDE
ring system of calyciphylline A-type
alkaloids via [5+2] cycloaddition
oxidation and an aza-Wittig reaction.
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