Enantioselective Total Synthesis of (-)-Arcutinine

Article abstract of DOI:10.1021/jacs.9b04847

The first total synthesis of an arcutine-type C₂₀-diterpenoid alkaloid arcutinine has been achieved in both racemic and asymmetric forms. Construction of the C4 quaternary center and the pyrrolidine E ring in an early stage proved to be important for achieving the successful synthesis of the target alkaloid. Strategically, an asymmetric conjugate addition/aldol cascade and a decarboxylative allylation reaction allowed the establishment of the vicinal all-carbon quaternary stereocenters at C4 and C5. Furthermore, a sequence consisting of an intramolecular aza-Wacker cyclization, an oxidative dearomatization/intramolecular Diels-Alder cycloaddition cascade, and a ketyl-olefin cyclization enabled the assembly of the core structure and led to the total synthesis of arcutinine.

Full text of DOI:10.1021/jacs.9b04847

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Article
Enantioselective Total Synthesis of (–)-Arcutinine
Wei Nie, Jing Gong, Zhihao Chen, Jiazhen Liu, Di Tian, Hao Song, Xiao-Yu Liu, and Yong Qin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04847 • Publication Date (Web): 28 May 2019
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Journal of the American Chemical Society
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Enantioselective Total Synthesis of (–)-Arcutinine
Wei Nie,† Jing Gong,† Zhihao Chen, Jiazhen Liu, Di Tian, Hao Song, Xiao-Yu Liu, and Yong Qin*
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Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory
for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of
Pharmacy, Sichuan University, Chengdu 610041 (P. R. China)
Supporting Information Placeholder
ABSTRACT: The first total synthesis of an arcutine-type C20-diterpenoid alkaloid arcutinine has been achieved in both racemic
and asymmetric forms. Construction of the C4 quaternary center and the pyrrolidine E ring in an early stage proved to be important
for achieving the successful synthesis of the target alkaloid. Strategically, an asymmetric conjugate addition/aldol cascade and a
decarboxylative allylation reaction allowed the establishment of the vicinal all-carbon quaternary stereocenters at C4 and C5.
Furthermore, a sequence consisting of an intramolecular aza-Wacker cyclization, an oxidative dearomatization/IMDA cascade, and
a ketyl-olefin cyclization enabled the assembly of the core structure and led to the total synthesis of arcutinine.
A
HO
10
B

INTRODUCTION
RO
H
HO
Me
OR
H
Me
N
B
C
A
HO
4
8
D
5
F
E
The diterpenoid alkaloids, found within various plants of the
genera Aconitum, Delphinium, and Spiraea, represent a large
family of natural products that exhibit rich biological activities
and fascinating chemical structures.1 Architecturally, these
molecules could be classified into three categories, namely,
the C20-, C19-, and C18-diterpenoid alkaloids,2 possessing 20,
19, and 18 carbon atoms in their scaffolds, respectively.
Among them, the C20-subfamily contains the most diverse
skeletal types, which have attracted significant attention from
synthetic chemists for decades.2a,3–9
20
N
R
H
H
arcutine-type
Me
N
s
1
arcutine ( ), R = (R)- BuCO
arcutinine ( ), R = PrCO
arcutinidine ( ), R = H
i
2
3
C20(105)
rearrangement
H2O
H
HO
H
OH
Me
N
OH
Me
A
10
20
Me
B
5
C
E
OHC
D
F
OH
OH
aconicarmicharcutinium A ( )
H
N
O
H
R
hetidine-type
5
atropurpuran ( )
4
The arcutine-type C20-diterpenoid alkaloids (Figure 1) are
Figure 1. (A) Biogenetic relationship between the arcutine and
hetidine diterpenoid alkaloids; (B) structures of arcutine
diterpenoid alkaloids (1–4) and related diterpene atropurpuran (5).
structurally characterized by
framework, including
tetracyclo[5.3.3.04,9.04,12]tridecane ring system (BCDF rings,
highlighted with blue bonds) and unique
a
congested hexacyclic
a
challenging
a

RESULTS AND DISCUSSION
azabicyclo[4.3.0]nonane unit (AE rings), as well as three all-
carbon quaternary stereogenic centers (C4, C5, and C8).2a
Biogenetically, the arcutine alkaloids could be derived from
the hetidine core through a C20 (10→5) rearrangement event
(Figure 1A).2a,10 The representative arcutine-type molecules (1
and 2, Figure 1B) were first isolated by Saidkhodzhaeva and
co-workers from Aconitum arcuatum,11 while arcutinidine (3)
was obtained as a saponification product through chemical
In 2016, our group realized the total synthesis of the diterpene
(±)-atropurpuran (5).14c As shown in Scheme 1, highlights of
the
synthesis
involved
1)
an
oxidative
dearomatization/intramolecular Diels-Alder cycloaddition
(IMDA) cascade to form the bicyclo[2.2.2]octane unit (6), 2) a
sequential aldol addition and ketyl-olefin cyclization that
established the pentacyclic framework (8), and 3) careful
investigations of late-stage transformations that allowed
completion of the synthesis of the target molecule.
Considering the structurally relevance between the arcutine-
type alkaloids (1–3) and their diterpenoid counterpart
(atropurpuran, 5),10 we explored access to the corresponding
alkaloid natural products by making use of intermediates
possessing the entire carbocyclic core (i.e., 8), which met
without success. First, modifications at the C19 and C20
positions in the presence of the C4 quaternary stereocenter and
C1–C10 alkene were challenging probably due to the sterically
hindered circumstance and conformational strain of A ring in
associated structures. For instance, subjection of aldehyde 9 to
reductive amination conditions [e.g., NaBH3CN with NH3 (g),
transformation from
1
and 2.11b More recently,
aconicarmicharcutinium A (4) was reported by Shi et al from
Aconitum carmichaelii.12 The related diterpene congener of
arcutine alkaloids, namely, atropurpuran (5), was isolated by
the Wang group from Aconitum hemsleyanum var.
atropurpureum in 2009.13 While syntheses of the members
from most C20-diterpenoid alkaloid types and structurally
related diterpenes have been accomplished in the synthetic
community,3–9,14 the total synthesis of an arcutine-type alkaloid
remains unsolved. As our continuous interest in the synthesis
of complex diterpenoids and related alkaloids,3c,e,4j,14c here we
report the first total synthesis of arcutinine (2) in both racemic
and asymmetric forms.
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H
HO
O
O
O
OMe
OMe
Me
A
or HCO2NH4, or NH4HCO3] to introduce the crucial N-atom
was unfruitful.15 Second, late-stage installation of the C4
quaternary center (i.e., 9) via -methylation of corresponding
aldehyde suffered from unsatisfactory efficacy (ca. 40% yield,
3:1~5:1 d.r., a similar result was also observed by Xu et al in
their recent synthesis of atropurpuran),14c,d which prevented
extensive studies because of insufficient materials. Most
importantly, preliminary inspections revealed that an
asymmetric oxidative dearomatization/IMDA cascade16 to
access enantioenriched 6 would be difficult to achieve, thereby
leading us to seek new solutions to an enantioselective total
synthesis of the arcutine-type C20-diterpenoid alkaloids.
OR
Me
N
Me
C
B
1
2
3
4
5
6
7
8
F
D
E
OMe
OH
oxidative
ketyl-olefin
cyclization
N
N
dearomatization/
IMDA cascade
H
Ts
H
Ts
H
10
11
2
)
arcutinine (
R = iPrCO
aza-Wacker
O
O
Me
decarboxylative
allylation
O
O
O
OMe
OMe
OMe
OMOM
14
5
4
O
NH
Ts
4
OMOM
Me
MOM
CN
Me
CN
Me
13
12
9
conjugate
addition
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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58
59
60
O
O
O
OMe
OMOM
O
18
Scheme 1. Our Previous Synthesis of (±)-Atropurpuran (5)
and Attempted Access to the Arcutines
OMe
OMOM
15
OMe
OMOM
4
reductive
Knoevenagel
Me
O
OR
16
17
H
1
OMe
10
10 OTBDPS
9
carbonate 14 to 13 and installation of the C5 quaternary
carbon center. The enol derivative 14 would be accessible via
an asymmetric conjugate addition of cyanide to enone 15 by
establishing the initial chiral quaternary stereocenter at C4. In
turn, enone 15 could be prepared by a reductive Knoevenagel
condensation20 between 1,3-cyclohexanedione (17) and
aldehyde 1821 followed by addition of a methyl group to the
resultant ketone 16 and acidic hydrolysis.
O
4
O
5
O
OMe
19
OHC
O
O
O
20
20
TBSO
H
O
H
H
6
7
H
8
ca.40% yield
3:1~5:1 d.r.
H
H
H
HO
OH
OR
Me
4
Me
Me
OHC
4
OHC
19
20
"involvement
of N-atom"
N
O
O
H
H
H
5
)
(±)-atropurpuran (
9
1
3
)
arcutines (
–
Construction of the C4 and C5 Vicinal All-Carbon
Quaternary Stereogenic Centers. According to the synthetic
plan, we initiated our study with the preparation of a key
intermediate containing C4 and C5 vicinal quaternary
stereogenic centers (Scheme 3). A reductive Knoevenagel
condensation20 between 1,3-cyclohexanedione (17) and
aldehyde 1821 was performed in the presence of Hantzsch ester
and L-proline in CH2Cl2, which was followed by methylation
using Me2SO4, providing enol ether 19 in 84% yield. Addition
of MeLi to the carbonyl group in 19 with acidic aqueous
work-up smoothly delivered enone 15 (78% yield). Enone 15
then underwent conjugate addition employing TMSCN and
BF3•OEt2 at 80 ºC to give silyl enol ether 20 (85% yield) with
the desired C4 quaternary stereogenic center. Despite the
failure of preliminary investigations on the asymmetric
conjugate addition of cyanide to enone 15,22 we were eager to
examine the subsequent synthetic strategy that sets the vicinal
C4 and C5 quaternary centers and thus continued the synthesis
with racemic 20. Ether 20 was then sequentially reacted with
MeLi and ClCO2Allyl/HMPA at –20 ºC to furnish dicarbonate
21 (84% yield). The decarboxylative allylic alkylation of 21
with Pd(PPh3)4 at 80 ºC, followed by masking of the resultant
phenol as a MOM ether with MOMCl/DIPEA, afforded the
key intermediate 13 with high diastereoselectivity (13:1 d.r. at
C5, inseparable) and 55% yield.23 Consequently, the two
important vicinal all-carbon quaternary stereogenic centers at
C4 and C5 were secured in compound 13, which was obtained
in decagram quantities.
Retrosynthetic Analysis. The retrosynthetic analysis of
arcutinine (2) is illustrated in Scheme 2. Unlike our previous
synthesis of atropurpuran that generated the C4 quaternary
center at late-stage,14c asymmetric construction of the C4
quaternary center followed by assembly of the pyrrolidine E
ring in 2 prior to forming its complete carbocyclic core would
be feasible for achieving a successful enantioselective
synthesis of the target alkaloid. Thus, two late-stage key steps
involving a ketyl-olefin cyclization17 for the assembly of B
ring (10 to 2) and an oxidative dearomatization/IMDA
cascade3e to establish C/D/F rings (11 to 10) were envisaged to
be conducted with the presence of the azabicyclo[4.3.0]nonane
moiety (AE rings) and the C4 quaternary center. An
intramolecular palladium-catalyzed aza-Wacker reaction18
would secure the formation of the pyrrolidine E ring in
compound 11 from the internal alkene 12, and the latter could
be obtained via functional group manipulations of 13. At this
stage, the focus of our retrosynthetic analysis was on how to
enantioselectively generate the two vicinal all-carbon
quaternary stereogenic centers at C4 and C5 in compound 13.
A palladium-catalyzed decarboxylative allylation19 reaction
would enable the conversion of
Scheme 2. Retrosynthetic Analysis of Arcutinine (2)
Scheme 3. Preparation of the Key Intermediate 9 with C4
and C5 Vicinal Quaternary Stereogenic Centers
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Me
CN
O
O
PdCl2(MeCN)2
PhMe, 110 ºC;
Hantzsch ester
L-proline, CH2Cl2;
1) LiAlH4, 50 ºC
2) TsCl, Et3N, 0 ºC
O
O
1
2
3
4
OMe
OMe
OMOM
18
OMe
OMOM
+
O
OMe
then MOMCl
DIPEA
OMOM
84%
Me2SO4, K2CO3
84%
OMOM
OMe
O
two steps
CN
Me
19
Me
17
75%
22
13
MeLi, THF
78%
0 ºC
5
6
7
8
Me
MeLi; then
ClCO2Allyl
HMPA, –20 ºC
R = H
Pd(OAc)2, DAF
PhMe, O2, 50 ºC
OTMS
O
10 H
O
H
Me
OR
BF3•OEt2
TMSCN, 80 ºC
OMe
OMe
OMOM
15
E
10
OMe
OMe
NH OMOM
Me Ts
23
O
20
OTMS
N
85%
84%
CN
Me
Me
82%, 1:1.5 d.r.
Ts
MOM
(inseparable)
20
O
24a b
/
DAF
9
, R = H
DMAP, Et3N
TMSOTf, 96%
or TBSOTf, 88%
O
26
, R = TMS
27
1) DMP, NaHCO3
2) TFA, CH2Cl2
3) PhI(OAc)2
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
or , R = TBS
N
N
O
O
O
Pd(PPh3)4, PhMe, 80 ºC;
MeOH, reflux
OMe
OMe
OMOM
Pd(OAc)2, DAF
PhMe, O2, 50 ºC
5
4
O
O
then MOMCl, DIPEA
55%
CN
CN
Me
R = TMS (2.5:1 d.r.)
Me
O
OAllyl
28a
28b
26
(-H20, 54% from
(-H20, 22% from
)
13
O
21
OMe
Me
R
Me
10
26
)
O
H
OMe
H
H
N
E
R = TBS (3:1 d.r.)
OMe
Synthesis of the Hexacyclic Core Structure. Our next task
was to explore the assembly of the hexacyclic core structure of
the target molecule 2. As depicted in Scheme 4, isomerization
of the terminal olefin in 13 to an internal olefin occurred in the
presence of PdCl2(MeCN)2 in toluene at 110 ºC,24 under which
the MOM group was also cleaved. After filtration of the
reaction suspension, the filtrate was re-subjected to
MOMCl/DIPEA and produced E-alkene 22 in 75% yield.
Reduction of the cyano and carbonyl groups in 22 with
LiAlH4, followed by selective protection of the resulting
primary amine with TsCl in the presence of Et3N, furnished 23
as a single diastereomer in 84% yield over two steps. The
stage was then set for a palladium-catalyzed aza-Wacker
reaction to form the pyrrolidine E ring. As a result, according
to Stahl’s protocol,18b treatment of sulfonamide 23 with
Pd(OAc)2/DAF/PhMe/O2 at 50 ºC led to the formation of N–
C20 bond, giving 24a/b as a pair of inseparable diastereomers
(1:1.5 d.r.at C20) in 82% combined yield. Since the C20
configurations would be eliminated by converting into a sp2
carbon (an imine moiety) in the target molecule, theoretically
both diastereomers could be useful for subsequent synthesis.
Thus, subjection of the inseparable mixture (24a/b) to a three-
step sequence, including 1) oxidation of the C10 alcohol to
ketone with DMP, 2) removal of the MOM group with TFA,
and 3) oxidative dearomatization/IMDA cascade of the
resulting phenol, generated separable cycloadducts 10 (25%
yield) and 25 (39% yield), respectively. The structures of both
pentacyclic products were unambiguously determined by X-
ray crystallographic analysis. Of note, the Diels-Alder
cycloaddition of both diastereomers proceeded with exclusive
endo selectivity, and only the isomer bearing an -H20
yielded the desired cycloadduct (10) with the correct C14
configuration.
14
20
O
20
N
29a
29b
27
)
(-H20, 56% from
(-H20, 18% from
Ts
Ts
MOM
27
)
25
24a b
/ )
(39% from
[X-ray, see the
Supporting Information]
61% overall
28b
(from
)
+
1) TBAF, 0 ºC
O
O
OMe
OMe
2) DMP, NaHCO3
3) TFA, CH2Cl2
4) PhI(OAc)2
Me
H
N
MeOH, reflux
20
14
H
Ts
59% overall
(from
10
24a b
/ )
(25% from
[X-ray]
28a
)
10
ORTEP of (±)-
yield the desired product with -H at C20. Various silyl
protecting groups were investigated for this purpose. As
expected, after installing a TMS group at the C10 hydroxyl
group in 23 with TMSOTf/DMAP/Et3N, the resultant 26 was
subjected to the same aza-Wacker conditions and generated
allylic sulfonamides 28a and 28b as a pair of separable
diastereomers (2.5:1 d.r.) in 76% combined yield. Use of a
TBS protecting group for this cyclization reaction was trivial
to further improve the diastereoselectivity (27 to 29a and 29b,
3:1 d.r.). However, deprotection of TBS group in the next step
failed under various attempted conditions (e.g., TBAF,
HF•Pyr., TASF) presumably due to steric factors. Installation
of other bulky substituents (e.g., TES, TIPS, TBDPS) at the
C10 hydroxyl group in compound 23 was unsuccessful, which
once again demonstrated the sterically hindered circumstance
of this position. Meanwhile, we determined the configurations
at the newly generated C20 stereocenter in 28a and 28b by
converting them to the corresponding Diels-Alder
cycloadducts (10 and 25) via a four-step transformation,
respectively. The major diastereomer 28a of the aza-Wacker
reaction with -H20 was confirmed to deliver the desired
pentacyclic intermediate 10 and was ready for accessing the
core of the target molecule. Similarly, the minor isomer 28b
with -H20 yielded the undesired pentacyclic compound 25
bearing the incorrect C14 configuration.
In this context, we turned back to investigate the aza-
Wacker cyclization in hoping of improving the
diastereoselectivity of this key transformation. It was supposed
that a bulky substitution group rather than a hydroxyl group at
C10 in 23 would provide a steric hindrance environment to
force the resultant vinyl group far away from the C10
substituent and
Next, compound 10 was treated with SmI2 in THF/MeOH
for 10 min to firstly remove the two methoxy groups and
produce diketone 30 (91% yield, Scheme 5). According to our
previous study,14c the crucial ketyl-olefin cyclization of 30
occurred in the presence of SmI2 and HMPA in THF/tBuOH to
give diol 31, under which the C15 carbonyl group was also
reduced. The intermediate 31 was inseparable from HMPA
and was thus directly subjected to oxidation employing DMP,
affording ketone 32 in 50% yield over two steps. Pleasingly,
we later found that exposure of diketone 10 to
Scheme 4. Synthesis of the Key Intermediate 10
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H
HO
H
HO
SmI2/THF/MeOH in the absence of HMPA with prolonged
reaction time (12 h) was able to remove the two methoxy
groups and trigger the expected ketyl-olefin cyclization in one
pot, leaving the C15 ketone unreduced, thereby forming the
complete skeleton of arcutinine and delivering 32 in 85%
yield.
O
Me
CH2(NMe2)2
Ac2O, DMF, 100 ºC
O
Me
NaBH(OMe)3
THF/MeOH, –30 ºC
1
2
3
4
H
N
H
N
70%
77%
H
H
Ts
Ts
32
33
O
Me
Me
H
HO
1) iPrCO2H, EDCI
DMAP, CH2Cl2
OH
15
Me
H
HO
5
O
Me
6
7
8
9
H
N
2) Li/naphthalene
THF, –78 ºC
76% overall
Scheme 5. Construction of the Hexacyclic Core
H
H
O
Ts
N
35
34
H
H
O
O
O
15
O
15
OMe
Me
Me
SmI2, THF/MeOH
10 min, 91%
Me
Me
PhIO oxidation
Temp.(ºC)
OMe
10
H
N
H
HO
H
N
OR
2 36
Me
Sol.
:
H
HO
14
14
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
O
Me
H
Ts
CH2Cl2
CH2Cl2
CDCl3
PhMe
0
1:2
1:1
5:3
5:1
H
Ts
30
25
50
110
+
H
N
N
SmI2, THF/MeOH
12 h, 85%
SmI2, HMPA
THF/tBuOH
H
2
H
, (±)-arcutinine
NaOMe
70%
(R = iPrCO, 71%)
36
(14%)
H
H
3
, (±)-arcutinidine (R = H)
HO
HO
OH
15
O
Me
Me
15
DMP, NaHCO3
H
N
H
N
30
)
Enantioselective Total Synthesis of (–)-Arcutinine.
Having established a successful synthetic approach to the
arcutine-type C20-diterpenoid alkaloid (±)-arcutinine (2) in
racemic form in 18 steps, we sought to further complete its
asymmetric total synthesis. Installing the initial C4 stereogenic
center in compound 20 (Scheme 3) enantioselectively would
allow us to achieve the asymmetric synthesis of (–)-arcutinine
in a substrate-controlled fashion. As direct asymmetric
conjugate addition of cyanide to enone 15 to access
enantioenriched 20 was unfruitful (Scheme 3), we envisioned
to prepare a simpler chiral intermediate 39 (i.e., a precursor of
20, Scheme 7A) that possessed the desired C4 quaternary
center by conjugate addition of a cyano group to 3-
methylcyclohex-2-enone (37) or of a methyl group to 3-
50% (from
H
H
31
Ts
Ts
32
Total Synthesis of (±)-Arcutinine. Having the core
structure 32 secured, the total synthesis of (±)-arcutinine (2)
was completed in a few steps (Scheme 6). Performing an -
methylenation of ketone 32 using CH2(NMe)2 and Ac2O in
DMF at 100 ºC yielded enone 33 (70%).25 Reduction of the
carbonyl group in 33 took place efficiently with
NaBH(OMe)3,14c giving diol 34 as the major product in 77%
yield (see reference 26 for discussion).26 Subsequent
installation of the isobutyryl group at C15 secondary alcohol
in 34 with isobutyric acid and removal of the N-Ts protecting
group with Li/naphthalene provided 35 (76% overall yield).
The only remaining step to arcutinine (2) was to generate an
imine functionality at the C20 position. To this end, PhIO was
found to be an appropriate oxidant and the oxidation took
place in CH2Cl2 at 0 ºC to give the desired imine 2 and its
regioisomer 36 with 1:2 ratio in an initial experiment. Further
investigations revealed that the reaction temperature played an
important role in determining the ratio of the two regioisomers.
Ultimately, oxidation of the secondary amine in 35 employing
PhIO/PhMe at 110 ºC furnished (±)-arcutinine (2) in 71%
yield, along with the regioisomer 36 (14% yield).
oxocyclohex-1-enecarbonitrile (40).
A
known catalytic
asymmetric conjugate addition of cyanide to enone 37 was
described by Shibasaki et al harnessing a chiral Gd-complex,22
producing 39 in 70% yield and 25% ee.27 Because of the low
ee value, the Shibasaki’s protocol for asymmetric installation
of the C4 quaternary center was abandoned. In this context, we
then examined the asymmetric conjugate addition of enones
37 and 40 employing Alexakis’s approach that has proved to
be useful for installing quaternary stereocenters.28 However,
when 37 was subjected to cyanide addition with Et2AlCN and
the phosphoramidite ligand 38, the adduct 39 was only
obtained in racemic form either at –30 ºC (<30% conv.) or at 0
ºC (61% yield). In addition, an attempted methyl group
addition to 40 in the presence of Me3Al and 38 resulted in no
reaction.
Spectroscopic data of the synthetic arcutinine (2) were
identical to those reported for the natural product, expect for
the carbon chemical shift of the carbonyl group in the
isobutyryl moiety (synthetic: C176.98 vs reported: C
175.80).11b In the isolation paper, the natural products arcutine
(1) and arcutinine (2) were isolated as an inseparable mixture
in 2:1 ratio.11 However, the carbon chemical shift of both the
carbonyl groups in 1 and 2 were assigned to be the same (C
175.80). We suspected that the reported data might belong to
the major component (1) and the one from the minor (2) was
neglected. After saponification of the synthetic arcutinine (2)
to arcutinidine (3) using NaOMe/MeOH (70% yield), the
NMR data of the obtained 3 completely matched those
reported in the literature,11b which thus further confirmed the
structure of our synthetic arcutinine (2) (see the Supporting
Information for more details).
A cyano group at C4 proved to be important for ensuring
the desired relative stereochemistry of the vicinal C4 and C5
stereocenters in the palladium-catalyzed decarboxylative
allylation step (21 to 13, Scheme 3). The failure of direct
enantioselective installation of the C4 quaternary center with a
cyano group (e.g., 39) promoted us to design a substrate
containing an O-functionalized group for the asymmetric
conjugate addition, which could be converted to a cyano group
later. Thus, enone 4129 with a pivalate at C19 was examined
for the asymmetric conjugate addition according to Alexakis’s
method.28 Specifically, as shown in Scheme 7B, treatment of
enone 41 with AlMe3 and copper(I) thiophene-2-carboxylate
(CuTC) in the presence of the chiral ligand 38 at –30 ºC
afforded the aluminum enolate intermediate 42. Gratifyingly,
such a protocol succeeded in generating the C4 quaternary
stereocenter in enantioselective manner. The enantioselectivity
Scheme 6. Completion of the Total Synthesis of (±)-
Arcutinine (2)
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Scheme 7. (A) Unsuccessful Asymmetric Conjugate
Additions and (B) Preparation of the Enantioenriched
Intermediate 20
Although not as straightforward as the racemic synthesis,
the established synthetic route to the enantioenriched
intermediate 20 was able to be performed on multigram scales,
providing us sufficient materials for the enantioselective total
1
2
3
4
A
O
O
O
38
, CuTC, Me3Al
synthesis of (–)-arcutinine (2). As
a
result, using
38
, CuTC, Et2AlCN
Et2O, –30 to 0 ºC
Et2O, –30 ºC or 0 ºC
enantioenriched 20 as the starting material, we went through
the remaining synthetic route as that described for the
synthesis of racemic 2 and completed the total synthesis of
(–)-arcutinine and (–)-arcutinidine (see the Supporting
Information for details). Key intermediates are shown in
Scheme 8, and the structures of (+)-10 and (–)-32 were again
verified through X-ray crystallographic methods.
5
6
7
8
–30 ºC: <30% conv., 0% ee
0 ºC: 61% yield, 0% ee
No reaction
Me
CN
Me
CN
39
37
40
OTMS
Ph
OMe
OTMS
20
O
O
9
P
N
CN
Me
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
Ph
38
B
Scheme 8. Enantioselective Total Synthesis of (–)-
Arcutinine and (–)-Arcutinidine
O
O
OAl
K2CO3, MeOH, reflux
71% yield, 92% ee
38
AlMe3, , CuTC
4
OH
43
–30 ºC
OPiv
19
OTMS
Me
TMS
O
Me
Me
OPiv
41
42
O
H
OMe
OTMS
18
then
45% from
OMe
OMOM
OMe
41
O
N
CN
Me
CN
Me
Ts
MOM
13
(+)-
20
28a
(–)-
O
OH
O
1) Burgess
reagent, 60 ºC
OMe
OMe
OPiv OMOM
19
H
HO
2) Pd/C, H2
OPiv OMOM
H
HO
OR
O
O
O
OMe
OMe
Me
Me
Me
Me
Me
76%, two steps
1) LiAlH4
2) DMP
45
44
H
N
H
N
3) NH2OH•HCl
4) Burgess reagent
N
H
H
Ts
H
Ts
2
(–)- , (–)-arcutinine
32
(–)-
10
(+)-
(R = iPrCO)
O
OTMS
43%
R
3
(–)- , (–)-arcutinidine
10
overall
1) TsOH, 78%
(R = H)
OMe
OMOM
OMe
OTMS
1
5
46a 46b
= 1:1.5
:
2) TMSCl, LiI,
HMDS, 65%
CN
Me
CN
Me
20
46a
, R = -H
DBU, 58%
(96% brsm)
46b
, R = -H
32
ORTEP of (–)-
10
ORTEP of (+)-
(92% ee) of this transformation was determined after
converting 42 into the ketone 43 with K2CO3/MeOH at reflux.
Directly adding a solution of aldehyde 1821 in Et2O to the
reaction mixture of 42 provided the hydroxyl ketone 44 (45%
yield) through an asymmetric conjugate addition/aldol cascade
reaction. The inseparable diastereomeric mixtures of 44 were
then subjected to dehydration with Burgess reagent and
hydrogenation of the resultant alkene to give ketone 45 as a
pair of inseparable diastereomers in 76% combined yield.
Next, the C19 pivalate in 45 was switched to a cyano
functionality by a four-step sequence including LiAlH4
reduction of both the pivaloyl and C10 carbonyl groups to
diol, oxidation of the diol to the keto-aldehyde with Dess-
Martin periodinane (DMP), conversion of the aldehyde to
oxime with hydroxylamine hydrochloride, and dehydration of
the resulting oxime to a nitrile with Burgess reagent, providing
46 as a pair of separable diastereomers with 43% overall yield
and 1:1.5 d.r. value.30 Unfortunately, subjecting both 46a and
46b to various conditions for enol silane formation led to the
undesired regioselectivity at C1 rather than C5. After much
experimentation, we were delighted to observe that the
intermediate with a free phenol group resulted from 46b by
deprotection of the MOM group (with TsOH) was able to
generate the desired enol silane 20 predominately by treating
with TMSCl/LiI/HMDS in 65% yield. By contrast, treating the
free phenol compound obtained from the minor isomer 46a
under the similar conditions led to the undesired C1 enol
silane. Fortunately, epimerization of 46a to 46b proceeded
using DBU with 58% yield (96% brsm) and allowed recycling
of the material.

CONCLUSION
In summary, we have achieved the first total synthesis of the
arcutine-type C20-diterpenoid alkaloid arcutinine (2) in both
racemic and asymmetric formats. Several key features of the
synthesis deserve to be highlighted. Initial installation of the
vicinal chiral all-carbon quaternary stereocenters at C4 and C5
was secured through an asymmetric conjugate addition
reaction and a palladium-catalyzed decarboxylative allylation
reaction, respectively. Early stage construction of the
pyrrolidine E ring by taking advantage of an intramolecular
aza-Wacker cyclization proved to be critical for realizing the
successful
synthesis.
In
addition,
an
oxidative
dearomatization/IMDA cascade and a ketyl-olefin cyclization
allowed
access
to
the
remaining
tetracyclo[5.3.3.04,9.04,12]tridecane ring system (BCDF rings)
and assembly of the complete arcutine skeleton. We anticipate
the synthetic approach disclosed here will be helpful to probe
the biological profiles of related alkaloids.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, characterization data, and NMR spectra
(PDF)
X-ray crystallographic data for (±)-10 (CIF)
X-ray crystallographic data for (±)-25 (CIF)
X-ray crystallographic data for (+)-10 (CIF)
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Page 6 of 8
ent-atisane diterpenes and related alkaloids: synthesis of (−)-methyl
X-ray crystallographic data for (–)-32 (CIF)
atisenoate, (−)-isoatisine, and the hetidine skeleton. J. Am. Chem. Soc.
2014, 136, 12592–12595. (i) Cheng, H.; Zeng, F.-H.; Yang, X.; Meng,
Y.-J.; Xu, L.; Wang, F.-P. Collective total syntheses of atisane-type
diterpenes and atisine-type diterpenoid alkaloids: (±)-spiramilactone
B, (±)-spiraminol, (±)-dihydroajaconine, and (±)-spiramines C and D.
Angew. Chem., Int. Ed. 2016, 55, 392–396. (j) Li, X.-H.; Zhu, M.;
Wang, Z.-X.; Liu, X.-Y.; Song, H.; Zhang, D.; Wang, F.-P.; Qin, Y.
Synthesis of atisine, ajaconine, denudatine, and hetidine diterpenoid
alkaloids by a bioinspired approach. Angew. Chem., Int. Ed. 2016, 55,
15667–15671. (k) Liu, J.; Ma, D. A unified approach for the assembly
of atisine- and hetidine-type diterpenoid alkaloids: total syntheses of
azitine and the proposed structure of navirine C. Angew. Chem., Int.
Ed. 2018, 57, 6676–6680.
(5) Syntheses of veatchine-type diterpenoid alkaloids: (a)
Masamune, S. Total syntheses of diterpenes and diterpene alkaloids.
IV. Garryine. J. Am. Chem. Soc. 1964, 86, 290–291. (b) Nagata, W.;
Narisada, M.; Wakabayashi, T.; Sugasawa, T. Total synthesis of dl-
garryine and dl-veatchine. J. Am. Chem. Soc. 1964, 86, 929–930. (c)
Valenta, Z.; Wiesner, K.; Wong, C. M. Synthesis in the diterpene
alkaloid series - II. A total synthesis of the garrya alkaloids.
Tetrahedron Lett. 1964, 5, 2437–2442. (d) Nagata, W.; Narisada, M.;
Wakabayashi, T.; Sugasawa, T. Total synthesis of dl-veatchine
and dl-garryine. J. Am. Chem. Soc. 1967, 89, 1499–1504. (e) Wiesner,
K.; Uyeo, S.; Philipp, A.; Valenta, Z. Synthesis in the series of
diterpene alkaloids. IX. A new simple synthesis of veatchine.
Tetrahedron Lett. 1968, 9, 6279–6282.
1
2
3
4
5
6
7
8
AUTHOR INFORMATION
Corresponding Author
*yongqin@scu.edu.cn
Author Contributions
†W.N. and J.G. contributed equally.
9
Notes
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
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by the National Natural Science
Foundation of China (21732005), the Drug Innovation Major
Project (2018ZX09711003-015 and 2018ZX09711001), and
Fundamental Research Funds for the Central Universities
(2012017yjsy103). We would like to thank Dr. Daibing Luo at the
Analytical & Testing Center of Sichuan University for X-ray
crystallographic structure determination.
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(30) The configurations of C5 in 46a and 46b were determined by
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O
TMS
Me
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decarboxylative
allylation
O
O
O
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OMe
OMe
O
O
NH
Ts
O
Me
MOM
CN
Me
OAllyl
aza-Wacker;
oxidative
dearomatization/
IMDA cascade
H
HO
OR
Me
N
O
ketyl-olefin
cyclization
O
OMe
OMe
Me
H
N
(–)-arcutinine
H
Ts
R = iPrCO
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