Asymmetric Total Synthesis of Arcutinidine, Arcutinine, and Arcutine

Article abstract of DOI:10.1021/jacs.9b05818

We have accomplished the asymmetric total synthesis of arcutinidine, arcutinine, and arcutine, three arcutine-type C20-diterpenoid alkaloids. A pentacyclic intermediate was rapidly assembled by using two Diels-Alder reactions. We developed a cascade seque

Full text of DOI:10.1021/jacs.9b05818

Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES
Communication
Asymmetric Total Synthesis of Arcutinidine, Arcutinine, and Arcutine
Shupeng Zhou, Kaifu Xia, Xuebing Leng, and Ang Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05818 • Publication Date (Web): 05 Jul 2019
Downloaded from http://pubs.acs.org on July 5, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Asymmetric Total Synthesis of Arcutinidine, Arcutinine, and
Arcutine
Shupeng Zhou,† Kaifu Xia,† Xuebing Leng,‡ and Ang Li*,†
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
†State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences
Supporting Information Placeholder
Wang and Liang recognized the arcutine skeleton as a
rearrangement product of the hetidine or hetisine skeleton.1a
More specifically, Sarpong and colleagues proposed
ABSTRACT: We have accomplished the asymmetric total
synthesis of arcutinidine, arcutinine, and arcutine, three
a
arcutine type C20-diterpenoid alkaloids.
A pentacyclic
Wagner−Meerwein type 1,2-alkyl shift (Figure 1; key bonds
highlighted in red) responsible for the biogenesis of the
arcutine skeleton from the hetidine skeleton, and carried out
DFT calculations to support this insightful hypothesis.16
Indeed, tongolinine (5) bearing a tertiary alcohol may serve
as a precursor of the carbocation species required for
initiating the Wagner−Meerwein pathway. Our experience17
with Prins reaction suggested an opportunity to generate a
carbocation species at the end of this powerful C–C bond
forming reaction.18 Herein, we report the asymmetric total
synthesis of arcutinidine, arcutinine, and arcutine.19
intermediate was rapidly assembled by using two
Diels−Alder reactions. We developed a cascade sequence of
Prins cyclization and Wagner−Meerwein rearrangement to
construct the core of arcutinidine, which was then
elaborated into an oxygenated pentacycle through a scalable
route. Chemoselective reductive amination followed by
spontaneous imine formation furnished the pyrroline motif
at a final stage. We clarified the S configuration of the α-
carbon of the acyl group within arcutine through chemical
synthesis and crystallographic analysis.
HO
RO
H
H
HO
OH
N
The C20-diterpenoid alkaloids1 have long been attractive
targets for chemical synthesis from the structural and
biological perspectives.2 Among them, members from the
atisine,3 hetisine,4 denudatine,5 veatchine,6 napelline,7 and
hetidine8,9 subclasses have been conquered by synthetic
chemists. Nearly two decades ago, Bassonova and co-workers
reported the discovery of two intricate C20-diterpenoid
alkaloids arcutine (the structure of which was originally
described as 1, Figure 1) and arcutinine (2) and their
presumed biogenetic precursor arcutinidine (3).10 Their
scaffold contains two doubly fused bicyclo[2.2.2]octane
moieties (Figure 1; highlighted in blue) and a congested
pyrroline motif.10 Of note, a non-alkaloidal natural product
atropurpuran (4) relevant to 1–3 was later discovered by
Wang and colleagues.11 Compared to the alkaloids,
diterpenoid 4 has drawn considerable attention from the
synthesis community.12–14 Suzuki et al. first disclosed an
inspiring approach for construction of the core of 4,12a and
the Qin13 and Xu14 groups recently accomplished elegant
syntheses of this molecule in a racemic form, respectively.
Obviously, the pyrroline and tertiary alcohol within the
alkaloids pose an additional challenge for chemical synthesis.
Right before our submission of this paper, Qin and co-
workers disclosed a beautiful enantioselective synthesis of
arcutinidine and arcutinine.15 During the course of our
synthesis of hetidine type alkaloids,9 we were intrigued by
the relationship between the hetidine and arcutine skeletons.
OH
Me
H
H
Me
Me
N
CHO O
1
4
5
: tongolinine
: the originally described
structure of arcutine;
R = (R)-s-BuCO
: atropurpuran
2
3
: arcutinine; R = i-PrCO
: arcutinidine; R = H
10
10
Me
5
5
N
20
20
Me
N
the hetidine skeleton
the arcutine skeleton
1,2-alkyl shift
Me
Me
N
N
Figure 1. The structures of representative arcutine type
alkaloids (1–3) and related natural products [atropurpuran
(4) and tongolinine (5)] and the postulated biogenetic
relationship between the hetidine and arcutine skeletons.
We first undertook a retrosynthetic analysis of 1 (Figure 2).
Disassembly of the pyrroline within 1 gave diketoaldehyde 6;
chemoselective reductive amination of the aldehyde
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
functionality of 6 could be a challenge at a late stage of the
vinyllithium addition and MOM protection afforded allylic
ether 15 in 85% yield as a single detectable diastereomer.
Exposure to aq. HClO4 resulted in selective hydrolysis of the
ketal followed by C═C bond migration, furnishing α,β-
unsaturated enone 9 in 72% yield. Following from our
experience with the anionic [4+2]-cycloaddition,9 we
subjected 9 to deprotonation with LiHMDS. The resultant
1,3-dienolate underwent an intramolecular Diels−Alder
reaction at 22 °C, and subsequent desilylation of the
cycloadduct with TBAF provided alcohol 16 in 84% overall
yield. Of note, complete removal of O2 in the reaction system
by the freeze−pump−thaw cycling was crucial to the success
of this anionic cycloaddition. X-ray crystallographic analysis
of 16 (Scheme 1) confirmed the stereochemical outcomes of
the two Diels−Alder reactions. Dehydration of 16 with
SOCl2/pyridine gave trisubstituted olefin 8 in 76% yield.17a
Indeed, 8 could also serve as a versatile intermediate for the
synthesis of hetidine type alkaloids.
synthesis.9 Compound 6 may arise from less oxygenated
intermediate 7. Position-selective C–H oxidation of the latter
would furnish the corresponding lactone, and the quaternary
C4 could be constructed through α-methylation. A key
retrosynthesis step from 7 to compound 8 bearing a
simplified hetidine framework relied on the design of a
cascade sequence of Prins cyclization and Wagner−Meerwein
rearrangement.20 The MOM group of 8 was expected to serve
as a precursor of the oxonium ion species that would initiate
the 6-endo-trig cyclization. Upon formation of the C−C bond
highlighted in blue (Figure 2), the resultant tertiary
carbocation at C5 should induce the 1,2-alkyl shift to
construct the C−C bond highlighted in red (Figure 2). On the
basis of our experience of septedine synthesis,9 the
bicyclo[2.2.2]octane moiety of 8 could be assembled through
an anionic Diels−Alder cycloaddition. Therefore, α,β-
unsaturated enone 9 was considered a suitable precursor of 8.
Further simplification led to aldehyde 10, which may result
from an intermolecular Diels–Alder reaction21 of known
diene 1122 and dienophile 12. The latter was traced back to
known enantioenriched alcohol 13 that was readily available
through lipase-mediated resolution.23
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Construction of Pentacyclic Intermediate 8
a) TBDPSCl,
imidazole
b) t-BuLi; DMF
Br
Br
CHO
93%
91%
OH
OTBDPS
OTBDPS
12
O
HO
reductive
amination
H
H
decagram scale
decagram scale
HO
HO
14
13
4
11
c) , BF3•OEt2
5
68%
H
H
Me
Me
gram scale
N
CHO O
3
: arcutinidine
6
d) vinyllithium;
MOMCl
OTBDPS
OTBDPS
H
H
O
O
O
Prins/Wagner
Meerwein
O
85%
MOMO
H
CHO
10
O
decagram scale
O
15
5
O
MeO
e) aq. HClO4
H
72%
O
gram scale
8
7
f) LiHMDS; TBAF
anionic DielsAlder
OTBDPS
OH
OTBDPS
O
H
H
OTBDPS
84%
O
MOMO
MOMO
H
H
gram scale
O
9
16
O
CHO
MOMO
O
9
10
g) SOCl2, pyr
O
O
76%
gram scale
DielsAlder
O
O
11
Br
CHO
MOMO
O
+
16
8
ORTEP of
OH
OTBDPS
12
Table 1. Conditions for the Cationic Cascade Reaction
11
13
With a large quantity of 8 in hand, we investigated the
conditions for its conversion into 7; the results are
summarized in Table 1. In the presence of a suitable,
Figure 2. Retrosynthetic analysis of 3.
The synthesis commenced with scalable preparation of
pentacyclic intermediate (Scheme 1). Silylation of
8
stoichiometric acid promoter,
8
should undergo
a
enantioenriched alcohol 13 (>99% ee) provided compound 14
in 93% yield. Treatment of 14 with t-BuLi generated the
alkenyl lithium species, which was quenched by DMF to give
aldehyde 12 in 91% yield. We then examined a variety of
conditions for the intermolecular Diels–Alder reaction of 11
and 12; acid lability of the ketal group of the former turned
out to be a problem. To our delight, BF3•OEt2 was found to
be an effective promoter for the cycloaddition at –78 °C, and
compound 10 was obtained in 68% isolated yield. One-pot
Prins/Wagner−Meerwein cascade to give 7 bearing an
arcutine scaffold, presumably via the intermediacy of two
cationic species 17 and 18. To our delight, exposure of 8 to
TFA gave 7 in 22% yield (entry 1), despite a significant
amount of the alcohol resulting from MOM deprotection.
TESOTf caused severe substrate decomposition (entry 2).
BF3•OEt2 slightly increased the yield of 7 (entry 3), while
TiCl4 preferentially led to MOM removal (entry 4). SnCl4 was
then found to be an optimal promoter for the cascade
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
reaction, and 7 was obtained in 63% yield on a gram scale
underwent one-pot Wittig methylenation and silylation to
give compound 20 in 87% yield. α-Methylation of this
lactone turned out to be a challenge; MeI was ineffective
under various conditions. To our delight, MeOTf proved to
be a more powerful reagent in this case.26 The lithium
enolate of 20 was methylated smoothly in the presence of
HMPA, and desilylation with TBAF furnished alcohol 21 in
one pot with good overall efficiency. The stereochemistry at
C4 was secured by the rigid polycyclic system. Oxidation of
21 with SeO2/TBHP gave allylic alcohol 22 in 81% yield as an
undesired diastereomer, which was then subjected to a
sequence of LiAlH4 reduction and CrO3•2pyr oxidation.27
Thus, diketoaldehyde 6 was obtained in 58% overall yield.
We expected to address the stereochemical issue at C15 by
face-selective ketone reduction at a final stage of the
synthesis.
1
2
3
4
5
6
7
8
(entry 5). We briefly explored the possibility of trapping the
post-rearrangement carbocation species with an oxygen
nucleophile (TMSOAc); however, proton elimination
(leading to olefin 7) remained the predominant reaction
pathway (entry 6).
O
H
conditions
O
MOMO
9
H
O
8
7
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
acid
WagnerMeerwein
Prins
O
O
O
O
Scheme 3. Completion of the Synthesis of 3 and 2
17
18
HO
O
H
conditionsa
yield (%)
H
entry
H
HO
a) NH2OH•HCl,
NaOAc; NaBH4
HO
1
TFA, 0 °C, 24 h
22
16
2
3
4
5
6
TESOTf, 0 °C, 1 h
BF3•OEt2, −15 °C, 6 h
TiCl4, −15 °C, 1 h
SnCl4, −15 °C, 1 h
SnCl4, TMSOAc, −15 °C, 1 h
H
Me
Me
O
65%
CHO O
37
24
63
55
N
6
OH 23
b) TiCl3, NaBH3CN
71%
a 1.0 equiv. acid. Reactions performed in CH2Cl2.
HO
RO
H
H
H
HO
HO
Scheme 2. Preparation of Oxygenated Pentacycle 6
H
Me
Me
O
O
H
N
O
a) Mn(acac)2, O2,
PhSiH3, 82%
H
O
HO
H2N
3
2
24
: arcutinidine; R = H
: arcutinine; R = i-PrCO
c) i-PrCO2H, DCC,
DMAP, 77%
b) RuCl3•3H2O,
NaIO4, 70%
H
H
O
O
7
19
gram scale
c) Ph3P=CH2;
TMSOTf, Et3N
87%
gram scale
3
2
ORTEP of
ORTEP of
H
H
HO
TMSO
d) LDA, MeOTf; TBAF
Completion of the synthesis of 3 and 2 relied on
4
differentiating the reactivity of the three carbonyls of 6
(Scheme 3). Chemoselective condensation of the aldehyde
with NH2OH followed by face-selective 1,2-reduction of the
α,β-unsaturated enone with NaBH4 afforded compound 23 as
a single diastereomer in 65% yield. The most hindered
carbonyl group remained untouched through this reaction
sequence. Exposure of 23 to TiCl3 led to reductive cleavage of
the N−O bond.28 The resultant aldimine intermediate was
further reduced in situ by NaBH3CN to form primary amine
24,28 which underwent spontaneous cyclization upon
aqueous workup to give 3 in 71% yield. More than 200 mg of
3 have been prepared in total. Acylation of the allylic alcohol
(i-PrCO2H, DCC, DAMP) provided 2 in 77% yield. The
structures of 2 and 3 were verified by X-ray crystallographic
analysis (Scheme 3).
H
73%
gram scale
H
Me
O
O
O
O
21
20
e) SeO2, TBHP
81%
gram scale
19
ORTEP of
H
15
O
f) LiAlH4
g) CrO3•2pyr
HO
H
HO
OH
H
Me
58% (2 steps)
O
H
Me
CHO O
gram scale
O
22
6
We then developed a robust route from 7 to oxygenated
pentacycle (Scheme 2). Face-selective Mukaiyama
6
hydration of the trisubstituted olefin followed by position-
selective C−H oxidation using the Sharpless protocol24
(RuCl3•3H2O, NaIO4) afforded alcohol 19, the structure of
which was confirmed by X-ray crystallographic analysis
(Scheme 2). Of note, Mn(acac)225 was superior to Co(acac)2 as
a precatalyst for this particular olefin hydration. The alcohol
Finally, we directed our attention to the synthesis of
arcutine (Scheme 4). Under the esterification conditions
used for preparing 2, arcutinidine (3) reacted with
commercially available (R)-s-BuCO2H to form the originally
described structure of arcutine (1). However, the crystal
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
structure of synthetic 1 (Scheme 4) differed from that of
of Frontier Sciences QYZDB-SSW-SLH040), Shanghai
Science and Technology Commission (17XD1404600), and
the K. C. Wong Education Foundation.
authentic arcutine presented in the isolation paper,10a with
regard to the acyl groups. We then checked the X-ray
crystallographic data of authentic arcutine (CCDC 1150924)
and realized that the configuration of the α-carbon of the
acyl group was S. The description of this crucial
configuration in the literature10a was incorrect. To our delight,
acylation of arcutinidine (3) with commercially available (S)-
s-BuCO2H afforded arcutine (25) in 74% yield; the crystal
structures of synthetic 25 (Scheme 4) and authentic arcutine
were identical.
1
2
3
4
5
6
7
8
REFERENCES
(1) (a) Wang, F.-P.; Liang, X.-T. C20-Diterpenoid Alkaloids. In The
Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Elsevier Science:
New York, 2002; Vol. 59, pp 1–280. (b) Wang, F.-P.; Chen, Q.-H.;
Liang, X.-T. Diterpenoid alkaloids. Nat. Prod. Rep. 2010, 27, 529.
(2) (a) Cherney, E. C.; Baran, P. S. Terpenoid-alkaloids: their
biosynthetic twist of fate and total synthesis. Isr. J. Chem. 2011, 51,
391. (b) Hamlin, A. M.; Kisunzu, J. K.; Sarpong, R. Synthetic
strategies toward hetidine and hetisine-type diterpenoid alkaloids.
Org. Biomol. Chem. 2014, 12, 1846. (c) Liu, X.-Y.; Qin, Y. Ongoing
pursuit of diterpenoid alkaloids: a synthetic view. Asian J. Org. Chem.
2015, 4, 1010. (d) Zhu, G.-L.; Liu, R.; Liu, B. Total synthesis of atisane-
type diterpenoids and related diterpenoid alkaloids. Synthesis 2015,
47, 2691. (e) Liu, X.-Y.; Qin, Y. Enabling syntheses of diterpenoid
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Completion of the Synthesis of Arcutine and
the Originally Described Structure of Arcutine
Me
(R)
Me
O
HO
O
a) (R)-s-BuCO2H,
DCC, 4-DMAP
H
H
alkaloids
and
related
diterpenes
by
an
oxidative
HO
HO
dearomatization/Diels–Alder cycloaddition strategy. Nat. Prod. Rep.
2017, 34, 1044.
74%
(3) (a) Pelletier, S. W.; Jacobs, W. A. The aconite alkaloids. XXXI. A
partial synthesis of atisine, isoatisine and dihydroatisine. J. Am.
Chem. Soc. 1956, 78, 4144. (b) Pelletier, S. W.; Parthasarathy, P. C.
The diterpene alkaloids: a partial synthesis of atisine. Tetrahedron
Lett. 1963, 4, 205. (c) Nagata, W.; Sugasawa, T.; Narisada, M.;
Wakabayashi, T.; Hayase, Y. Stereospecific total synthesis of dl-
atisine. J. Am. Chem. Soc. 1963, 85, 2342. (d) Masamune, S. Total
syntheses of diterpenes and diterpene alkaloids. V. atisine. J. Am.
Chem. Soc. 1964, 86, 291. (e) Guthrie, R. W.; Valenta, Z.; Wiesner, K.
Synthesis in the series of diterpene alkaloids VI. A simple synthesis
of atisine. Tetrahedron Lett. 1966, 7, 4645. (f) Nagata, W.; Sugasawa,
T.; Narisada, M.; Wakabayashi, T.; Hayase, Y. Total synthesis of dl-
atisine. J. Am. Chem. Soc. 1967, 89, 1483. (g) Ihara, M.; Suzuki, M.;
Fukumoto, K.; Kametani, T.; Kabuto, C. Stereoselective total
synthesis of (±)-atisine via intramolecular double Michael reaction. J.
Am. Chem. Soc. 1988, 110, 1963. (h) Ihara, M.; Suzuki, M.; Fukumoto,
K.; Kametani, T.; Kabuto, C. Asymmetric total synthesis of atisine via
intramolecular double Michael reaction. J. Am. Chem. Soc. 1990, 112,
1164. (i) Liu, X.-Y.; Cheng, H.; Li, X.-H.; Chen, Q.-H.; Xu, L.; Wang,
H
H
Me
Me
N
N
3
1
: arcutinidine
: the originally described
structure of arcutine
b) (S)-s-BuCO2H,
DCC, DMAP
74%
Me
(S)
Me
H
O
O
1
ORTEP of
HO
H
Me
N
25
25
ORTEP of
: arcutine
In summary, we have accomplished the asymmetric total
synthesis of arcutinidine (3), arcutinine (2), and arcutine (25).
F.-P.
Oxidative
dearomatization/intramolecular
Diels–Alder
An expeditious and scalable route to
a pentacyclic
cycloaddition cascade for the syntheses of (±)-atisine and (±)-
isoazitine. Org. Biomol. Chem. 2012, 10, 1411. (j) Cherney, E. C.;
Lopchuk, J. M.; Green, J. C.; Baran, P. S. A unified approach to ent-
atisane diterpenes and related alkaloids: synthesis of (–)-methyl
atisenoate, (–)-isoatisine, and the hetidine skeleton. J. Am. Chem.
Soc. 2014, 136, 12592. (k) 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. (l) 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. (m)
Liu, J.; Ma, D. Total syntheses of azitine and the proposed structure
of navirine C. Angew. Chem., Int. Ed. 2018, 57, 6676.
(4) (a) Muratake, H.; Natsume, M. Total synthesis of (±)-nominine, a
heptacyclic hetisine-type aconite alkaloid. Angew. Chem., Int. Ed.
2004, 43, 4646. (b) Muratake, H.; Natsume, M. Synthetic study of
hetisine-type aconite alkaloids. Part 1: preparation of tetracyclic
intermediate containing the C14–C20 bond. Tetrahedron 2006, 62,
7056. (c) Muratake, H.; Natsume, M. Synthetic study of hetisine-type
aconite alkaloids. Part 2: preparation of hexacyclic compound
lacking the C-ring of the hetisan skeleton. Tetrahedron 2006, 62,
7071. (d) Muratake, H.; Natsume, M.; Nakai, H. Synthetic study of
hetisine-type aconite alkaloids. Part 3: total synthesis of (±)-
nominine. Tetrahedron 2006, 62, 7093. (e) Peese, K. M.; Gin, D. Y.
Efficient synthetic access to the hetisine C20-diterpenoid alkaloids. A
concise synthesis of nominine via oxidoisoquinolinium-1,3-dipolar
and dienamine-Diels−Alder cycloadditions. J. Am. Chem. Soc. 2006,
128, 8734. (f) Peese, K. M.; Gin, D. Y. Total synthesis of (+)-nominine.
intermediate with hetidine features was established. A
bioinspired Prins/Wagner−Meerwein cascade was then
developed for conversion of the hetidine core structure into
an arcutine core structure. These endeavors may facilitate
studies of the biology of arcutine and hetidine type alkaloids.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and spectroscopic data of
compounds, NMR spectra of compounds, CIF files
AUTHOR INFORMATION
Corresponding Author
*ali@sioc.ac.cn
ACKNOWLEDGMENT
This paper is dedicated to Prof. Qing-Yun Chen on the
occasion of his 90th birthday. We thank Prof. Richmond
Sarpong, Shelby McCowen, and Xiang Zhang for discussions.
This work was supported by National Natural Science
Foundation of China (21525209, 21621002, 21772225, and
21761142003), Chinese Academy of Sciences (Strategic Priority
Research Program XDB20000000 and Key Research Program
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
Chem. Eur. J. 2008, 14, 1654. (g) Zhang, Q.-Z.; Zhang, Z.-S.; Huang, Z.;
(13) Gong, J.; Chen, H.; Liu, X.-Y.; Wang, Z.-X.; Nie, W.; Qin, Y. Total
synthesis of atropurpuran. Nat. Comm. 2016, 7, 12183.
Zhang, C.-H.; Xi, S.; Zhang, M. Stereoselective total synthesis of
hetisine-type C20-diterpenoid alkaloids: spirasine IV and XI. Angew.
Chem., Int. Ed. 2018, 57, 937. (h) Kou, K. G. M.; Pflueger, J. J.; Kiho,
T.; Morrill, L. C.; Fisher, E. L.; Clagg, K.; Lebold, T. P.; Kisunzu, J. K.;
1
2
3
4
5
6
7
8
(14) Xie, S.; Chen, G.; Yan, H.; Hou, J.; He, Y.; Zhao, T.; Xu, J. 13-Step
total synthesis of atropurpuran. J. Am. Chem. Soc. 2019, 141, 3435.
(15) Nie, W.; Gong, J.; Chen, Z.; Liu, J.; Tian, D.; Song, H.; Liu, X.-Y.;
Qin, Y. Enantioselective total synthesis of (–)-arcutinine. J. Am.
Chem. Soc. 2019, 141, 9712.
(16) Weber, M.; Owens, K.; Sarpong, R. Atropurpuran–missing
biosynthetic link leading to the hetidine and arcutine C20-
diterpenoid alkaloids or an oxidative degradation product?
Tetrahedron Lett. 2015, 56, 3600.
Sarpong, R.
A benzyne insertion approach to hetisine-type
diterpenoid alkaloids: synthesis of cossonidine (davisine). J. Am.
Chem. Soc. 2018, 140, 8105.
(5) (a) Nishiyama, Y.; Han-ya, Y.; Yokoshima, S.; Fukuyama, T. Total
synthesis of (–)-lepenine. J. Am. Chem. Soc. 2014, 136, 6598. (b) Kou,
K. G. M.; Li, B. X.; Lee, J. C.; Gallego, G. M.; Lebold, T. P.; DiPasquale,
A. G.; Sarpong, R. Syntheses of denudatine diterpenoid alkaloids:
9
(17) (a) Sun, Y.; Li, R.; Zhang, W.; Li, A. Total synthesis of indotertine
A and drimentines A, F, and G. Angew. Chem., Int. Ed. 2013, 52, 9201.
(b) Sun, Y.; Chen, P.; Zhang, D.; Baunach, M.; Hertweck, C.; Li, A.
Bioinspired total synthesis of sespenine. Angew. Chem., Int. Ed. 2014,
53, 9012. (c) Lu, Z.; Yang, M.; Chen, P.; Xiong, X.; Li, A. Total
synthesis of hapalindole-type natural products. Angew. Chem., Int.
Ed. 2014, 53, 13840. (d) Deng, J.; Zhou, S.; Zhang, W.; Li, J.; Li, R.; Li,
A. Total synthesis of taiwaniadducts B, C, and D, J. Am. Chem. Soc.
2014, 136, 8185. (e) Lu, Z.; Li, H.; Bian, M.; Li, A. Total synthesis of
epoxyeujindole A. J. Am. Chem. Soc. 2015, 137, 13764. (f) Li, H.; Chen,
Q.; Lu, Z.; Li, A. Total syntheses of aflavazole and 14-
hydroxyaflavinine, J. Am. Chem. Soc. 2016, 138, 15555. (g) Sun, Y.;
Meng, Z.; Chen, P.; Zhang, D.; Baunach, M.; Hertweck, C.; Li, A. A
concise total synthesis of sespenine, a structurally unusual indole
terpenoid from Streptomyces. Org. Chem. Front. 2016, 3, 368.
(18) (a) Gahman, T. C.; Overman, L. E. Stereoselective synthesis of
carbocyclic ring systems by pinacol-terminated Prins cyclizations.
Tetrahedron 2002, 58, 6473. (b) Pennington, L. D.; Overman, L. E.
Strategic use of pinacol-terminated Prins cyclizations in target-
oriented total synthesis. J. Org. Chem. 2003, 68, 7143. (c) Velthuisen,
E.; J.; Overman, L. E. Scope and facial selectivity of the Prins–pinacol
synthesis of attached rings. J. Org. Chem. 2006, 71, 1581.
(19) For the original version of this paper, see ChemRxiv Preprint
2019, doi: 10.26434/chemrxiv.8202242. Sarpong and co-workers
disclosed an elegant synthesis of (±)-arcutinidine, as we disclosed
this study.
(20) For recent examples, see: (a) Andrez, J.-C.; Giroux, M.-A.;
Lucien, J.; Canesi, S. Rapid formation of hindered cores using an
oxidative Prins process. Org. Lett. 2010, 12, 4368. (b) Reddy, B. V. S.;
Muralikrishna, K.; Yadav, J. S.; Babu, N. J.; Sirisha, K.; Sarma, A. V. S.
Tandem Prins/Wagner/Ritter process for the stereoselective
cochlearenine,
N-ethyl-1α-hydroxy-17-veratroyldictyzine,
and
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
paniculamine. J. Am. Chem. Soc. 2016, 138, 10830. (c) Kou, K. G. M.;
Kulyk, S.; Marth, C. J.; Lee, J. C.; Doering, N. A.; Li, B. X.; Gallego, G.
M.; Lebold, T. P.; Sarpong, R. A unifying synthesis approach to the
C18-, C19-, and C20-diterpenoid alkaloids. J. Am. Chem. Soc. 2017,
139, 13882. Also see ref. 3l.
(6) (a) Masamune, S. Total syntheses of diterpenes and diterpene
alkaloids. IV. Garryine. J. Am. Chem. Soc. 1964, 86, 290. (b) Nagata,
W.; Narisada, M.; Wakabayashi, T.; Sugasawa, T. Total synthesis of
dl-garryine and dl-veatchine. J. Am. Chem. Soc. 1964, 86, 929. (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. (d) Nagata, W.; Narisada, M.;
Wakabayashi, T.; Sugasawa, T. Total synthesis of dl-veatchine and dl-
garryine. J. Am. Chem. Soc. 1967, 89, 1499. (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.
(7) (a) Wiesner, K.; Ho, P.; Tsai, C. S. J.; Lam, Y. The Total synthesis
of racemic napelline. Can. J. Chem. 1974, 52, 2355. (b) Sethi, S. P.;
Atwal, K. S.; Marini-Bettolo, R. M.; Tsai, T. Y. R.; Wiesner, K. A
stereospecific synthesis of napelline. Can. J. Chem. 1980, 58, 1889.
(8) For recent synthetic studies, see: (a) Hamlin, A. M.; Cortez, F. J.;
Lapointe, D.; Sarpong, R. Gallium(III)-catalyzed cycloisomerization
approach to the diterpenoid alkaloids: construction of the core
structure for the hetidines and hetisines. Angew. Chem., Int. Ed. 2013,
52, 4854. (b) Hamlin, A. M.; Lapointe, D.; Owens, K.; Sarpong, R.
Studies on C20-diterpenoid alkaloids: synthesis of the hetidine
framework and its application to the synthesis of dihydronavirine
and the atisine skeleton. J. Org. Chem. 2014, 79, 6783. (c) Zhu, M.; Li,
X.-H.; Song, X.; Wang, Z.-X.; Liu, X.-Y.; Song, H.; Zhang, D.; Wang,
F.-P.; Qin, Y. Studies towards bioinspired synthesis of hetidine-type
C20-diterpenoid alkaloids. Chin. J. Chem. 2017, 35, 991. Also see ref. 3j,
l, m.
synthesis
of
(3-oxabicyclo[4.2.0]octanyl)amide
and
(1-(5-
aryltetrahydrofuran-3-yl)cyclobutyl)amide derivatives. Org. Biomol.
Chem. 2015, 13, 5532. For a conceptually relevant example from our
group, see ref. 17b, g.
(9) Zhou, S.; Guo, R.; Yang, P.; Li, A. Total synthesis of septedine and
7-deoxyseptedine. J. Am. Chem. Soc. 2018, 140, 9025.
(21) Carreño, M. C., Urbano, A.; Di Vitta, C. Enantioselective
Diels−Alder approach to C3-oxygenated angucyclinones from (SS)-2-
(p-tolylsulfinyl)-1,4-naphthoquinone. Chem. Eur. J. 2000, 6, 906.
(22) For strategically inspiring examples: see: (a) Bergmann, E. D.;
Becker, A. Diels–Alder reactions with 1-formylcyclohexene and 1-
formylcyclopentene. J. Am. Chem. Soc. 1959, 81, 221. (b) Stoltz, B. M.;
Kano, T.; Corey, E. J. Enantioselective total synthesis of
nicandrenones. J. Am. Chem. Soc. 2000, 122, 9044. (c) Jung, M. E.;
Lui, R. M. Studies toward the total syntheses of cucurbitacins B and
D. J. Org. Chem. 2010, 75, 7146. (d) Tartakoff, S. S.; Vanderwal, C. D.
A synthesis of the ABC tricyclic core of the clionastatins serves to
corroborate their proposed structures. Org. Lett. 2014, 16, 1458.
(23) We developed an improved resolution protocol using the
Candida antarctica lipase (see the SI). For a relevant example, see: Li,
J.; Zhang, W.; Zhang, F.; Chen, Y.; Li, A. Total synthesis of
daphniyunnine C (longeracinphyllin A). J. Am. Chem. Soc. 2017, 139,
14893.
(24) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. A
greatly improved procedure for ruthenium tetroxide catalyzed
oxidations of organic compounds. J. Org. Chem. 1981, 46, 3936. For a
recent application by our group, see ref. 17d.
(25) See, Y. Y.; Herrmann, A. T.; Aihara, Y.; Baran, P. S. Scalable C–H
oxidation with copper: synthesis of polyoxypregnanes. J. Am. Chem.
Soc. 2015, 137, 13776.
(10) (a) Tashkhodzhaev, B.; Saidkhodzhaeva, S. A.; Bessonova, I. A.;
Antipin, M. Y. Arcutine-a new type of diterpene alkaloids. Chem.
Nat. Compd. 2000, 36, 79. (b) Saidkhodzhaeva, S. A.; Bessonova, I.
A.; Abdullaev, N. D. Arcutinine, a new alkaloid from Aconitum
arcuatum. Chem. Nat. Compd. 2001, 37, 466.
(11) Tang, P.; Chen, Q.-H.; Wang, F.-P. Atropurpuran, a novel
diterpene with an unprecedented pentacyclic cage skeleton, from
Aconitum hemsleyanum var. atropurpureum. Tetrahedron Lett. 2009,
50, 460.
(12) (a) Suzuki, T.; Sasaki, A.; Egashira, N; Kobayashi, S. A synthetic
study of atropurpuran: construction of a pentacyclic framework by
an intramolecular reverse-electron-demand Diels–Alder reaction.
Angew. Chem. Int. Ed. 2011, 50, 9177. (b) Hayashi, R.; Ma, Z. X.;
Hsung, R. P. A tandem 1,3-H-shift–6pelectrocyclization–cyclic 2-
amido-diene intramolecular Diels–Alder cycloaddition approach to
BCD-ring of atropurpuran. Org. Lett. 2012, 14, 252. (c) Chen, H.;
Zhang, D.; Xue, F.; Qin, Y. Synthesis of the atropurpuran A-ring via
an organocatalytic asymmetric intramolecular Michael addition.
Tetrahedron 2013, 69, 3141. (d) Chen, H.; Li, X.-H.; Gong, J.; Song, H.;
Liu, X.-Y.; Qin, Y. Synthetic approach to the functionalized tricyclic
core of atropurpuran. Tetrahedron 2016, 72, 347. (e) Jarhad, D. B.;
Singh, V. π4s
+
π2s Cycloaddition of spiroepoxycyclohexa-2,4-
dienone, radical cyclization, and oxidation−aldol−oxidation cascade:
synthesis of BCDE ring of atropurpuran. J. Org. Chem. 2016, 81, 4304.
(26) Uenishi, J.; Tatsumi, Y.; Kobayashi, N.; Yonemitsu, O. Highly
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
stereoselective alkylation at neopentyl position on β,β-dialkyl
substituted γ-butyrolactone ring. Tetrahedron Lett. 1995, 36, 5909.
(27) Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H. Selective
oxidation of a primary hydroxyl in the presence of secondary one.
Tetrahedron Lett. 1981, 22, 1605.
(28) Leeds, J. P.; Kirst, H. A. A mild single-step reduction of oximes
to amines. Synth. Commun. 1988, 18, 777.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
The graphic entry for the TOC
1
2
3
4
RO
H
HO
5
6
7
8
H
Me
N
9
arcutinidine; R = H
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
arcutinine; R = i-PrCO
arcutine; R = (S)-s-BuCO
7
ACS Paragon Plus Environment