Expeditious synthesis of the fused hexacycle of puberuline C: Via a radical-based cyclization/translocation/cyclization process

Article abstract of DOI:10.1039/c6sc00671j

The fused 6/7/5/6/6/6-hexacyclic ring system of puberuline C was assembled in 18 steps from 2-(ethoxycarbonyl)cyclohexanone. After the azabicyclo[3.3.1]nonane derivative was sequentially coupled with propargyl magnesium bromide, 2-iodo cyclopentenone and allyl bromide, the pentacycle was constructed in a single step via a radical-based cyclization/translocation/cyclization process. The C11-bridgehead radical generated via C-Br homolysis participated in a 7-endo cyclization, and the 1,5-hydrogen translocation of the resultant radical was followed by transannular 6-exo cyclization to simultaneously realize the construction of the two rings and the introduction of the five contiguous stereocenters. The last 6-exo cyclization was induced by the Mukaiyama aldol reaction, and the C16-ketone was stereoselectively reduced by the action of SmI₂/t-BuOH, leading for the first time to the synthesis of the entire hexacycle of puberuline C.

Full text of DOI:10.1039/c6sc00671j

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EDGE ARTICLE
Expeditious synthesis of the fused hexacycle of puberuline C via
radical-based cyclization/translocation/cyclization process
Received 00th January 20xx,
Accepted 00th January 20xx
Koichi Hagiwara, Toshiki Tabuchi, Daisuke Urabe and Masayuki Inoue*
The fused 6/7/5/6/6/6-hexacyclic ring system of puberuline
C
was assembled in 18 steps from 2-
DOI: 10.1039/x0xx00000x
(ethoxycarbonyl)cyclohexanone. After the azabicyclo[3.3.1]nonane derivative was sequentially coupled with propargyl
magnesium bromide, 2-iodo cyclopentenone and allyl bromide, the pentacycle was constructed in a single step via a
radical-based cyclization/translocation/cyclization process. The C11-bridgehead radical generated via C-Br homolysis
participated in 7-endo cyclization, and the 1,5-hydrogen translocation of the resultant radical was followed by
transannular 6-exo cyclization to simultaneously realize the construction of the two rings and the introduction of the five
contiguous stereocenters. The last 6-exo cyclization was induced by the Mukaiyama aldol reaction, and the C16-ketone
was stereoselectively reduced by the action of SmI2/t-BuOH, leading for the first time to the synthesis of the entire
hexacycle of puberuline C.
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Plants of the genera Aconitum and Delphinium have been used the efficient synthesis of the unique hexacyclic ring system of
for centuries in traditional oriental medicines for their anti- puberuline
C
by
utilizing
a
radical-based
and the
inflammatory, analgesic, and anti-rheumatic activities.1 Efforts cyclization/translocation/cyclization
process
to identify the pharmacologically important compounds in Mukaiyama aldol reaction as the two key transformations.
these plant families have resulted in the determination of over
OH
H
H
600 structurally complex C19-diterpenoid alkaloids, of which
aconitine is representative (Scheme 1).2 In 2009, puberuline C
MeO
MeO
MeO
MeO
16
14
16
13
13
F
F
F
12
H
H
H17
H
10
9
H
17OMe
17OMe
1
2
BzO
HO
MeO
H10
14
C
1
15
9
D
was isolated from
a
traditional Chinese medical plant,
D
11
5
11
5
A
E
Aconitum barbatum var. puberulum,3 and was found to belong
to the C19-diterpenoid alkaloid family. Its architecturally
complex hexacyclic system is composed of fused 6/7/5/6/6/6-
membered (A/B/C/D/E/F) rings containing the one nitrogen
group and six oxygen-based polar functionalities. These
structural features significantly increase the challenge of
chemically synthesizing puberuline C.4
8
B
B
8
B
8
N
Et
OH
N
Et
N
Et
3
7
AcO
7
7
6
H
H 4
18
6 HO 4
CO2Et
HO
19
MeO
O
OMe
18
OMe
aconitine
puberuline C
1
C
13
I
17
O
10Br
Br
O
A
15
O
A
9
11
5
Puberuline C differs structurally from the majority of C19-
diterpenoid alkaloids in its C17-bond connection. Specifically,
the C8-17 bond of puberuline C constitutes the six-membered
F-ring, while the C7-17 bond of aconitine forms the five-
membered counterpart. To date, considerable synthetic effort
E
N
5
Et
N
Et
8
15
16'
6
Br
16
HO 4
CO2Et
7
B
16
CO2Et
8
16'
MgBr
3
2
6
C
5 , 6
Scheme 1. Structures of aconitine and puberuline C, and synthetic plan of the model
target compound 1.
has been focused on the aconitine-type alkaloids,
culminating in the historic total syntheses of talatisamine,
chasmanine and 13-desoxydelphonine by the Wiesner’s
group,7 neofinaconitine by the Gin’s group,8 and weisaconitine
D and liljestrandinine by the Sarpong’s group.9 In sharp
contrast, the molecular framework of puberuline C has not
been chemically assembled.10 In this manuscript, we describe
To devise a novel strategy for the total synthesis of
puberuline C, we designed a simplified puberuline C (
model target compound (Scheme 1). Although the oxidation
states at C1, 5, 6, 7 and 18 positions of are different from
those of puberuline C, retains its entire hexacyclic framework
and nine stereocenters (C4, 8, 9, 10, 11, 13, 14, 16, 17). In our
retrosynthesis, the three ring structures of were
disconnected at the C10-11, C13-16 and C8-17 bonds to set
as a pivotal intermediate. Compound was planned to be
1) as a
1
1
1
2
2
used as the precursor of the bridgehead radical at C11. We
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presumed that the bridgehead radical would enable molecule through chelation.
stereoselective construction of the sterically hindered C10-11 reactions from
bond because of its potent reactivity, stereochemically intermediate . The five-membered C-ring
predestined nature, and high orthogonality to diverse polar the terminal alkyne of by Sonogashira coupling
functional groups.11 In the synthetic direction, the C11- [PdCl2(PPh3)2 and CuI], providing tricyclic compound
. Upon
bridgehead radical generated through C-Br homolysis of triene treatment of
with PdCl2(PPh3)2 and n-Bu3SnH,15 the C8
would chemoselectively react with the C9-10 double bond of position of the internal triple bond was regioselectively
the C-ring enone, leading to formation of the seven-membered functionalized with the n-Bu3Sn group to form , presumably
B-ring. After radical cyclization, the remaining C16-16’ and C7- because the C8 position was less sterically shielded by the
8 double bonds were to be utilized to connect the C13/16 and bulky azabicyclic AE-ring. Additionally, stereoselective
C8/17 atoms to transannulate the six-membered D- and F- hydrostannylation defined the syn-relationship of the AE- and
rings of respectively, thereby establishing the C-rings, which later served as an important structural factor to
stereochemistry of the four positions. As the radical precursor facilitate 7-endo cyclization. The thus introduced C8-stannyl
has only three stereocenters (C4, 5, 11), the route to would moiety of was changed to the allyl group by –allyl Stille
be greatly simplified. Highly unsaturated
would be prepared coupling. Namely, Pd2(dba)3∙CHCl3 and Ph3As16 17 effected the
through a series of carbon chain extensions by step-wise coupling between and allyl bromide to furnish triene
attaching the three achiral units (five-membered C-ring Therefore, only six steps were required for conversion of
and ) to the chiral 6/6-fused AE-ring monocycle to tricycle , which possesses all the requisite
Next, three Pd-catalyzed
6
completed the synthesis of the key
was attached to
2
A
14
6
7
7
2
8
1,
2
2
8
π
,
2
8
B
2.
A, B
C
3.
4
2
carbons for the synthesis of the skeleton of
the key radical cyclization, the substrates
1
. To prepare for
and 11a were
9
derivatized from
allyl group. Dihydroxylation of the least sterically shielded
olefin of triene afforded triol as a 1:1 C16-diastereomixture.
2 via chemoselective manipulations of the C8-
2
9
Alternatively, dibenzyl acetal 11a was formed by oxidative
glycol-cleavage with H5IO6, followed by In(OTf)3-catalyzed
acetalization with benzyl alcohol.18
Table 1. Radical-based cyclization/translocation/cyclization process[a]
entry
1
substrate
R2
product
yield
29%
2
12
Scheme 2. Synthesis of the three substrates of the radical reaction. Reagents and
conditions: a) Br2, Et2O, 0 °C to RT; b) aq. HCHO, aq. EtNH2, MeOH, 0 °C to RT; c) C, cat.
ZnBr2, CH2Cl2, -78 °C, 49% (dr at C5 = 3.2:1); recrystallization 29% for 6 (3 steps); d) A,
16
HO
2
3
9[b]
13[c]
14a
55%
54%
OH
PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), i-Pr2NEt, CH3CN,
0 °C, 65%; e) n-Bu3SnH,
PdCl2(PPh3)2 (5 mol%), THF; f) B, [Pd2(dba)3]·CHCl3 (4 mol%), Ph3As (16 mol%), THF, 60
°C, 59% (2 steps); g) OsO4 (10 mol%), NMO, THF, H2O, 81% (dr = 1:1); h) H5IO6, THF, 0
°C, 72%; i) BnOH, In(OTf)3, CH2Cl2, 0 °C, 79%. Bn = benzyl, dba = dibenzylideneacetone,
NMO = N-methylmorpholine N-oxide, THF = tetrahydrofuran.
11a
[a] Conditions: substrate (1.0 equiv), n-Bu3SnH (5 equiv), V-40 (0.4
equiv), toluene (0.02 M), reflux. n-Bu3SnH and V-40 (0.2 equiv) in
toluene were added by syringe pump over 3 h. Reactions were
performed on a 0.10 mmol scale. [b] 9 was used as a 1:1 C16-
diastereo mixture. [c] Products 13 were obtained as the hemiacetal
forms (13α:13β = 1:1.5). V-40 = 1,1’-azobis(cyclohexanecarbonitrile).
The synthesis of
material 312 (Scheme 2). 2-(Ethoxycarbonyl)cyclohexanone (
was first brominated to , which was treated with ethylamine
and formaldehyde to induce the double Mannich reaction,
giving rise to equipped with the C11-bromo group. Propargyl
magnesium bromide which was prepared from 3-
bromopropyne, magnesium turnings, and catalytic ZnBr2,13
then attacked the C5-ketone of to afford the three carbon
extended as the major product (dr = 3.2:1). In this reaction,
the tertiary amine of would assist stereoselective delivery of
1 was started by preparing the known
4
)
5
3
C
,
Remarkably, the single radical reaction of
2 promoted
cyclization not only of the requisite seven-membered B-ring,
but also of the six-membered F-ring (entry 1, Table 1).
3
6
Treatment of tricycle
2 with n-Bu3SnH and V-40 in refluxing
3
toluene provided pentacycle 12, with formation of the two C-C
the organomagnesium reagent from the
β-face of the
bonds (C10-11, C8-17) and five stereocenters (C8, 9, 10, 11,
2 | Chem. Sci. 2012, 00, 1-3
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17). The low yield (29%) of 12 from
2 was attributed to terminated by the hydrogenation of Int-4a from the convex
involvement of the C16-olefin in the undesired radical face of the BC-ring to generate the C9-stereocenter of 14a
.
pathways. Consequently, compounds 9 and 11a with no C16 The multiple radical reactions proposed above were
radical acceptor were next submitted to the same reaction evaluated by DFT calculation of the energy diagram at the
conditions (entries 2 and 3): the yields of the corresponding UM06-2X/6-31G(d) level of theory (Scheme 3B).23 To facilitate
pentacyclic products 13 and 14a from 9 and 11a, respectively, the calculations, we used the structurally abbreviated radical
almost doubled (55% for 13 and 54% for 14a).19,20 After the intermediates, in which R2 and R3 were changed from
reaction of entry 2, 13 was obtained as C16-epimeric CH(OBn)2 and Et to H and Me, respectively (see 11a and 11b).
hemiacetals (13
secondary hydroxy group to the C14-ketone. The structure of smaller than that from the same Int-1b to the C10-epimeric
crystalline C16- -alcohol 13 was unambiguously determined Int-2Bb
G‡ = +8.2 kcal/mol for TS-1A, +9.4 kcal/mol for TS-
α:13β = 1:1.5) due to addition of the C16- The calculated activation energy from Int-1b to Int-2Ab is
β
β
(Δ
by X-ray crystallographic analysis (Figure 1), revealing its 1B), supporting the observed C10-stereoselectivity of the 7-
unusually complicated shape. On the other hand, the newly endo cyclization. The higher energy of TS-1B than TS-1A would
formed ring systems of 12 and 14a were established by the originate from the close C14O-C15H contact in TS-1B (2.42 Å,
judicious NMR analyses and the chemical derivatizations.21
Scheme 3C) within the sum of the van der Waals radii (2.72 Å)
in comparison with that in TS-1A (2.68 Å). After formation of
the stable delocalized radical Int-2Ab through the endothermic
Figure 1. X-ray structure of C16-β-alcohol 13β
HO
O
H
14
reaction (-23.2 kcal/mol), 1,5-hydrogen abstraction (Int-2Ab
→
H
O
H
14
Int-3b) requires a relatively large activation energy (+19.5
kcal/mol) and gives a less stable intermediate (+5.8 kcal/mol).
However, TS-3 is lower in energy than TS-2 by -6.6 kcal/mol.
Thus, the forward reaction from Int-3b to Int-4b is favored
H
16
N
Et
HO
N
Et
16
HO
HO
OH
HO
CO2Et
CO2Et
13 '
13
over the reverse reaction to Int-2Ab
.
Furthermore, 6-exo
cyclization gives the thermodynamically more preferred radical
Int-4b than Int-3b (-15.1 kcal/mol). The gain in energy of the
overall process from the start radical Int-1b to the end radical
Int-4b is -32.5 kcal/mol, corroborating the high efficiency of
the present cyclization/translocation/cyclization process.
Having constructed the five fused ring system with the
seven stereocenters, the remaining tasks for synthesis of the
target 1 were the construction of the six-membered D-ring and
the introduction of the C13,14,16-stereogenic centers (Scheme
4). We anticipated that intramolecular aldol reaction between
the C14-ketone and the C16-aldehyde of 15a would
stereoselectively form the C13-16 bond. The aldol substrate
13
X-ray structure of
(CCDC1452192)
The present cascade pathway involved three essential
radical reactions: 7-endo cyclization at C10 and C11, 1,5-radical
translocation from C7 to C17, and 6-exo cyclization at C17 and
C8. This intricate reaction course is illustrated in Scheme 3A
using the transformation from 11a to 14a as an example. The
bridgehead radical Int-1a is first generated from 11a by the
action of the stannyl radical. To maximize the SOMO/LUMO
interaction, the electron rich C11-radical of Int-1a selectively
reacts with the electron deficient sp2-carbon atom at C10,
thereby connecting the C10-11 bond of Int-2Aa through 7-
endo cyclization. The C10-stereochemistry is controlled at this
stage, while the configuration of the fixed C11-bridgehead
position is retained. The vinylogous ketone moiety of Int-2Aa
bestows an electron deficient character to the C7-radical,
15a was readily prepared from hemiacetal 13
β through
oxidative cleavage by H5IO6. However, treatment of 15a under
acidic or basic conditions (e.g., aq. HCl/dioxane or
DBU/benzene) resulted in either decomposition or recovery of
15a
.
These negative results were rationalized by DFT
calculation of 15b and 16b, in which Et (R3) was replaced with
Me. Although the reacting C13 and C16 atoms of 15b are in
close proximity, C13-16 bond formation significantly increases
the potential energy of 16b (+17.6 kcal/mol). The bond angle
(θ = 101.3˚) between C14-13 and C13-16 of 16b deviates
significantly from the ideal value, indicating its unusually
strained character. Accordingly, the retro-aldol reaction from
16a to 15a would readily occur, even when 16a was produced.
The above data and considerations led us to employ an
irreversible Mukaiyama aldol reaction for cyclization of the
which preferentially reacts with the electron rich N-α C-H bond
,
25
strained D-ring (Scheme 5).24 To realize the transformation,
alternative aldol substrate 17 was designed to have the silyl
enol ether as the nucleophile and the dibenzyl acetal as the
at the proximal C17 position via facile 1,5-hydrogen
abstraction.22 Next, transannular 6-exo cyclization of the
translocated nucleophilic C17-radical with the electrophilic C8-
9 double bond produces Int-4a
. This intramolecular radical
activatable electrophile.
structure of 17 was regioselectively built by applying TBSOTf
and Et3N to C14-ketone 14a A number of Lewis acids (e.g.,
The requisite TBS enol ether
addition occurs within the fused rings to introduce the correct
C8,17-stereogenic centers. Finally, the radical process is
.
SnCl2, Sn(OTf)2, ZnBr2, BF3∙OEt2, AlCl3 and TiCl4) activated the
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acetal moiety, yet failed to give the requisite product because oxidation/reduction sequence. After removal of the benzyl
the C14-oxygen atom instead of the C13 atom reacted with the group from 21, the resultant hydroxy group of 22 was
C16-cation. Eventually, it was found that SnCl4 attained the chemoselectively oxidized to the ketone of 23 in the presence
requisite C13-16 bond formation. Treatment of 17 with SnCl4 of tertiary amine by using the reagent combination
in CH2Cl2 at -78 to 0 °C permitted effective construction of AZADO/CuCl/2,2’-bipyridine/DMAP under air. 26 However,
hexacycle 19 with installing the C13,16-stereocenters. NaBH4 reduction of 23 only afforded its precursor 22: hydride
Therefore, capping the C16-hydroxy group with the benzyl selectively attacked from the convex face to generate the
group indeed inhibited the retro-aldol type reaction from the undesired
adduct 19 under the reaction conditions. As illustrated by 18 electron reducing agent, produced the correct C16-
the newly generated C16-stereochemistry of 19 would epimer.27,28 When 23 was treated with SmI2 in THF/HMPA in
originate from nucleophilic attack of the silyl enol ether from the presence of t-BuOH, -oriented C16-alcohol 24 was
the Si-face of the oxocarbenium ion, which would be fixed by obtained as the major product (22 24 = 1:8). It is noteworthy
the binding of SnCl4 between the oxygen and nitrogen atoms. that the use of H2O or MeOH instead of t-BuOH decreased the
The synthesis of was finalized by functional group stereoselectivity for 24 22
24 = 1.5:1),29 indicating that the
β-oriented C16-alcohol. Conversely, SmI2, a one-
,
α
:
1
(
:
manipulations at the C14 and C16 positions (Scheme 5). The slower protonation of the C16-carbanion intermediate had a
C14-ketone of 19 was stereoselectively reduced from the beneficial effect for generating 24. Lastly, methylation of the
convex face to provide the hydroxy group of 20. Alcohol 20 C16-hydroxy group of 24 provided the targeted puberuline C
was in turn converted to methyl ether 21 by using MeI and t- skeleton 1
with the ten contiguous stereocenters.21
BuOK. Then, the C16-configuration was inverted by an
Scheme 3. (A) Plausible reaction pathway for the radical cascade reaction. (B) Calculated energy diagram for the cascade reaction. The changes in Gibbs free energy from Int-1b
were calculated at the UM06-2X/6-31G(d) level and are shown in kcal/mol (298 K, 1 atm, gas phase). (C) The pink dotted line represents the forming C10-11 bond, and the cyan
dotted
line
represents
the
C14O-C15H
interaction
in
the
TS-1A
and
TS-1B
structures.
4 | Chem. Sci. 2012, 00, 1-3
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13
14
14
H
H
O
TBSO
a) TBSOTf
b) SnCl4
H
H
N
Et
N
Et
BnO
BnO
16
HO
HO
OBn
OBn
CO2Et
CO2Et
17
14a
Bn
O
H
BnO
O
16
14
13
16
SnCl4
NEt
H
H
H
c) NaBH4
13
O 14
N
Et
TBS
HO
19
CO2Et
CO2Et
HO
18
H
H
BnO
HO
16
16
14
f) AZADO
CuCl
R4O
MeO
H
H
H
H
e) H2, Pd/C
N
Et
N
Et
g) NaBH4
HO
HO
CO2Et
CO2Et
20: R4 = H
22
d) MeI
21: R4 = Me
H
H
H
O
R5O
16
16
H
H
H
MeO
MeO
h) SmI2
N
Et
N
Et
HMPA
t-BuOH
Scheme 4. Attempted D-ring formation by the aldol reaction. The relative Gibbs free
energy values were calculated at the UM06-2X/6-31G(d) level (298 K, 1 atm, gas
phase).
HO
HO
CO2Et
CO2Et
23
24: R5 = H
1: R5 = Me
i) MeI
Scheme 5. Synthesis of the hexacyclic ring system of puberuline C. Reagents and
conditions: a) TBSOTf, Et3N, CH2Cl2, 0 °C, 90%; b) SnCl4, CH2Cl2, -78 to 0 °C, 46%; c)
NaBH4, MeOH, 0 °C, 96%; d) MeI, t-BuOK, THF, 0 °C, 93%, e) H2, Pd/C, aq. HCl, MeOH,
95%; f) AZADO (15 mol%), CuCl (15 mol%), 2,2’-bipyridine (15 mol%), DMAP (30 mol%),
CH3CN, air, 82%; g) NaBH4, MeOH, 0 °C, 50%; h) SmI2, t-BuOH, HMPA, THF, 22:24 = 1:8,
75% for 24; i) MeI, t-BuOK, THF, 0 °C, 93%. AZADO = 2-azaadamantane N-oxyl, HMPA =
In summary, we accomplished the expeditious synthesis of
the entire 6/7/5/6/6/6-membered ring system
diterpenoid alkaloid puberuline [18 steps from 2-
(ethoxycarbonyl)cyclohexanone ( )]. The six ABCDEF rings and
1 of the C19-
C
4
the ten stereogenic centers were constructed by a series of
powerful transformations. First, the double Mannich reaction
hexamethylphosphoric
triamide,
TBS
=
tert-butyldimethylsilyl,
Tf
=
trifluoromethanesulfonyl.
cyclized the AE-ring
tetrasubstituted carbons (C4, 11). Second, carbon elongation
from to was realized by nucleophilic addition of and
palladium-catalyzed couplings of and , introducing the C5-
3, with implementation of the two
3
2
C
Acknowledgements
A
B
This research was financially supported by the Funding
Program a Grant-in-Aid for Scientific Research (A) to M.I. (JSPS)
stereocenter and the C-ring structure. Third, the C11-
bridgehead radical reaction of highly unsaturated substrate
and (C) (JSPS) and on Innovative Areas (MEXT) to D.U.
A
11a
underwent
the
7-endo
cyclization/1,5-radical
fellowship from JSPS to K.H. is gratefully acknowledged. We
thank Dr. Kenji Yoza (Bruker AXS) for X-ray crystallographic
analysis.
translocation/6-exo cyclization process to form the B- and F-
rings with establishing the stereochemistries of the two
quaternary (C8, 11) and three tertiary carbons (C9, 10, 17) in a
single step. Forth, the Mukaiyama aldol reaction, followed by
hydride and one-electron reductions, constructed the D-ring
and the C13,14,16-stereocenters. Importantly, detailed DFT-
calculations fully validated the reaction course and the
stereoselective outcome of the salient radical cascade reaction.
Further synthetic studies of puberuline C based on the newly
developed strategy are underway in our laboratory.
Notes and references
1
2
3
F.-P. Wang and Q.-H. Chen, The C19-Diterpene Alkaloids, in
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