A Unified Approach for the Assembly of Atisine- and Hetidine-type Diterpenoid Alkaloids: Total Syntheses of Azitine and the Proposed Structure of Navirine C

Article abstract of DOI:10.1002/anie.201803018

A tetracyclic dinitrile was synthesized in twelve steps from cyclohex-2-en-1-one by using a chelation-triggered conjugate addition to a γ-hydroxy-substituted α,β-unsaturated nitrile and an oxidative dearomatization/Diels–Alder cycloaddition cascade as the key steps. The first total synthesis of azitine (in 17 steps) was achieved through a simple reductive cyclization of this intermediate and subsequent transformations while the total synthesis of the proposed structure of navirine C (in 19 steps) was accomplished by a hydrogen-atom-transfer reaction of the tetracyclic dinitrile, Pd/C-catalyzed reductive cyclization, and subsequent functional group manipulation.

Full text of DOI:10.1002/anie.201803018

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: A unified approach for the assembly of atisine- and hetidine-type
diterpenoid alkaloids: Total syntheses of azitine and the proposed
structure of navirine C
Authors: Dawei Ma and Jie Liu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803018
Angew. Chem. 10.1002/ange.201803018
Link to VoR: http://dx.doi.org/10.1002/anie.201803018
http://dx.doi.org/10.1002/ange.201803018

10.1002/anie.201803018
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
0((Catch Phrase))
A Unified Approach for the Assembly of Atisine- and Hetidine-Type
Diterpenoid Alkaloids: Total Syntheses of Azitine and the Proposed
Structure of Navirine C
Jie Liu, and Dawei Ma*
Abstract: A tetracyclic dinitrile was synthesized in 12 steps from
cyclohex-2-en-1-one by using a chelation-triggered conjugate
addition to γ-hydroxy α,β-unsaturated nitrile and oxidative-
dearomatization/Diels-Alder cycloaddition as the key steps. The first
total synthesis of azitine (in 17 steps) was achieved through a simple
reductive cyclization of this intermediate and subsequent
transformations, while total synthesis of the proposed structure of
navirine C (in 19 steps) was accomplished via a HAT reaction of the
tetracyclic dinitrile, Pd/C-catalyzed reductive cyclization and
subsequent functional group manipulation.
synthesizing hetidine-type alkaloids, only a non-natural product,
dihydronavirine (3), was synthesized by Sarpong’s group over 27
steps,[9] while Baran’s[4] and Qin’s[5] attempts only led to the
formation of some advanced intermediates. As a result, there is
plenty of room for developing more concise total synthetic routes
towards atisine- and hetidine-type alkaloids. Herein, we wish to
report a short and efficient approach for assembling a tetracyclic
dinitrile compound. Through this common intermediate, we
achieved the first total synthesis of azitine (7), an anti-leishmanial
atisine-type diterpenoid alkaloid that was first isolated from
Consolida hellespontica;[10] and proposed structure of navirine C (2),
a hetidine-type alkaloid that was isolated from Aconitum naviculare,
used in traditional Nepalese medicine against cold, fever and
headache.[11]
Owing to their caged and polycyclic ring systems, the C20-
diterpenoid alkaloids (Figure 1) are recognized among the most
architecturally complex natural products, and have elicited
considerable interest from the synthetic community over the past
several decades.[1] This synthetic campaign has culminated with the
completion of the formal and total syntheses of a subset of C20-
diterpenoid alkaloids namely nominine (1),[2] atisine (4),[3] isoatisine
(5),[4] isoazitine (6),[3g] dihydroajaconine,[5,6] gymnandine,[5]
spiramines C and D,[6] and cochlearenine.[7] However, most of their
synthetic routes require a large number of steps and are restricted to
a very particular structure.[1d] Two notably short and elegant routes
include Gin’s total synthesis of nomine (16 steps),[2] and Baran’s
semi-synthesis of isoatisine (13 steps from (-)-steviol).[4] Some
fundamental challenges still exist for synthesizing the remaining
C20-diterpenoid alkaloids. For example, all early attempts for
synthesizing atisine-type alkaloids only arrived at Pelletier’s
intermediate,[3a-3g] whose transformation to atisine still required six
more steps.[8] Particularly, from this advanced intermediate only
isoazitine (6) with a higher oxidation state at the C19 position could
be obtained.[3g] It could not be used for directly synthesizing azitine
(7) that possesses a higher oxidation state at the C20 position. For
hetisine-type
atisine-type
OH
Me
OH
17
3
1
OH
2
Me
11
5
9
10
20
Me
16
15
12
7
4
18
6
8
19
N
N
O
O
N
13
14
1
( )
nominine
5
( )
isoatisine
4
( )
atisine
6 steps
OH
OH
Me
O
Me
hetidine-type
Me
2 steps
N
N
6
isoazitine
Pelletier's
intermediate
Ac
( )
N
R
R'
OH
Me
navirine C
=
NMe2
:
=
Me, R' H)
2
R
(
N
dihydronavirine
:
=
=
R'
OH)
3 R
7
azitine
H,
(
( )
Figure 1. Structures of some atisane-class C20-diterpenoid alkaloids.
Structural diversity of C20-diterpenoid alkaloids stems from the
different bond connections at C20, which demands our strategy to
put an isolated oxidation state at this position. Considering the
practical and divergent transformations of nitriles, we decided to
undertake the retrosynthetic analysis as shown in Figure 2. Based on
Sarpong's method to install the hordenine part,[9b] we envisioned that
navirine C (2) could arise from the hetidine skeleton 8, which could
be generated via the reductive cyclization of the imine 10. Another
target molecule, azitine could be assembled through the functional
group manipulation of imine 9. Next we anticipated that both the
imines 9 and 10 could be derived from the tetracyclic dinitrile 11
through a reductive cyclization of its two cyano groups, and a HAT
(hydrogen atom transfer) reaction[12] between the olefin part and the
C20 cyano group, respectively. The further bond disconnection
revealed that tetracyclic dinitrile 11 could be assembled from the
tetracycle 12, which could be obtained through oxidative
dearomatization of phenol 13 and subsequent Diels-Alder
cycloaddition. Notably although oxidative dearomatization/Diels-
[∗]
Mr. J. Liu and Prof. Dr. D. Ma
State Key Laboratory of Bioorganic & 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 Lu, Shanghai 200032, China
E-mail: madw@sioc.ac.cn
[∗∗] The authors grateful to Chinese Academy of Sciences
(supported by the Strategic Priority Research Program,
grant XDB20020200 & QYZDJ-SSW-SLH029) and the
National Natural Science Foundation of China (grant
21132008) for their financial support.
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the author.
This article is protected by copyright. All rights reserved.

10.1002/anie.201803018
Angewandte Chemie International Edition
Alder cycloaddition strategy has been used in the synthesis of
diterpenoid alkaloids by several groups,[13] their substrates all
contained the azabicyclo[3.3.1]nonane moiety, which gave high
stereoselectivity during cycloaddition. In comparison, our phenol 13
seemed less favored for this strategy. If this crucial cycloaddition
proceeded well, we would be able to install some intermediates with
isolated oxidative states at C4 and C20, which would be of benefit
for the divergent synthesis. For preparing the phenol 13, we planned
to elaborate the intermediate 14 by applying a chelation-controlled
conjugate addition between γ-hydroxy-α,β-unsaturated nitrile 15
and Grignard reagent 16. This methodology was developed by
Fleming and coworkers about 20 years ago,[14] but has never been
used in natural product synthesis.
marium(II) iodide[18] followed by ketone protection gave a ketal
intermediate, which was treated with Dibal-H to remove the acetate
group, and then subjected to Swern oxida-tion to provide tetracyclic
ketone 22, whose structure was confirmed by X-ray crystallographic
analysis of its precursor (see supporting information).[19] To install
the C4 quaternary stereocenter, ketone 22 was converted into the
nitrile 23 via a Van Leusen reaction,[20] which was treated with
LDA/MeI to furnish the tetracyclic dinitrile 11 in 68% yield.
OTBS
OMe
OTBS
OMe
SOCl2
toluene, 60 o
THF
,
pyridine
Mg,
90 o
16
C
C
HO
81%
Cl
19
18
CN
CN
THF, -78 o
C
NaBH4 CeCl
,
t-
3
BuMgCl,
then
Me
O
,
-78 o
16
MeOH,
C
reagent
r.t.
C
Grignard
OH
-78 o to
97%
N
Me
O
OH
17
15
Me
O
N
then
AcCl
then
NaBH4 MeOH
,
NMe2
CN
2
navirine C
OMe
OTBS
OMe
OTBS
7
azitine
( )
( )
61%
Mg
O
OAc
CN
21
O
O
20
Me
Me
Me
O
O
OH
PIDA, MeOH
NaHCO3
Martin's sulfurane
CH2Cl2
N
N
OMe
OMe
OH
9
8
H
OAc
OAc
OAc
then toluene
then TBAF
74%
reductive
OTBS
reductive
CN
14
cyclization
cyclization
CN
13
105 o 88%
C,
O
O
Me
reaction
HAT
O
O
rt
1. SmI2 MeOH, THF,
,
CN
CN
HN
CN
11
OMe
O
O
2.
OH)2 TMSCl,
MS, CH Cl
,
(CH2
Å
O
10
rt
4
,
2
2
oxidative
dearomatization/
Diels-Alder
O
3. Dibal-H, CH2Cl2
Swern
OMe
CN
CN
12
CN
4.
oxidation
steps)
OMe
22
OMe
O
88%
(4
cycloaddition
OH
OAc
OMe
CN
12
O
O
O
OAc
TosMic
t-BuOK
LDA
MeI
NC
Me
13
O
68% for
2 steps
t
DME
-BuOH,
40 o
CN
AcCl
CN
CN
CN
OH
CN
C
OTBS
chelation-controlled
11
23
OMe
addition
MeO
conjugate
OTBS
Scheme 1. Construction of the tetracyclic dinitrile 11. PIDA =
phenyliodonium diacetate; Dibal-H = diisobutylaluminum hydride;
ClMg
OH
OAc
16
15
14
TosMic
=
toluenesulfonylmethyl isocyanide; LDA
=
lithium
diisopropylamide.
Figure 2. Retrosynthetic analysis of azitine and navirine C
With multigrams of 11 in hand, we next attempted to assemble
azitine (7) via reductive cyclization between two cyano groups
(Scheme 2). In the previous total synthesis of isoazitine (6),[3g]
amine 24 that came from the Pelletier’s intermediate was selected as
the advanced intermediate, whose oxidation only occurred at the less
sterically hindered C19 position and therefore afforded 6 as a single
product. We speculated that reduction of dinitrile 11 should took
place at the less sterically hindered cyano group first, and the
resultant amine unit would attack another cyano group to form an
amidine, which could be used for synthesizing azitine. Accordingly,
we screened a number of reduction conditions and found that
reduction of 11 with LAH in ether at 50 oC could provide the
desired amidine 25 in almost quantitative yield. Due to steric
hindrance, the amidine moiety in 25 was inert toward hydrolysis or
amine protection. After some experimentations, we were pleased to
find that using Li/NH3(l)[21] as the reductant could transform 25 into
imine 26 (path a in Scheme 2). Interestingly, over-reduction product
9 was also isolated from the reaction mixture and the ratio of 9 and
26 was about 2:1. We tried to tune the amount of reductant from 130
During the studies on conjugate addition of unsaturated nitriles,
Fleming and coworkers discovered that γ-hydroxyl group in an α,β-
unsaturated nitrile could prompt the conjugate addition via chelation
with the Grignard reagent.[14] Based on this result, we commenced
our total synthesis as depicted in Scheme 1. Luche reduction of
oxonitrile 17[15] gave alcohol 15, which was subjected to
deprotonation with t-BuMgCl, and further reaction with a Grignard
reagent generated from chloride 19 (prepared from known alcohol
18[16]) to afford the adduct 20. Quenching this reaction with acyl
chloride produced β-keto nitrile 21, which was directly reduced in
one-pot with NaBH4 to give the alcohol 14 in 61% yield.
Dehydration of 14 utilizing Martin’s sulfurane[17] and subsequent
deprotection with TBAF delivered the phenol 13. To our delight,
after oxidative dearomatization of 13, Diels-Alder cycloaddition
proceeded smoothly at 105 oC in toluene to give the desired
tetracycle 12 in 88% yield. Prior to the creation of the C4 quaternary
center, we planned to simplify the bicyclo[2.2.2]octane part first.
Thus, reductive removal of two methoxy group in 12 with sa-
This article is protected by copyright. All rights reserved.

10.1002/anie.201803018
Angewandte Chemie International Edition
equiv to 10 equiv, but found the ratios of 9 and 26 were only slightly
decreased, which implying that the olefin unit was not directly
reduced by Li/NH3(l). As a possible mechanism depicted in Scheme
2, after reduction of the C-N double bond, the resultant radical
species might attack C-C double bond to form intermediate 28 (path
b), in which the rigid structure forced the newly formed C-C bond to
disconnect to give amidine 29. As a result, further reduction of 29
led to the formation of the imine 9. Deprotection of the ketal group
in 9 followed by a Wittig reaction gave the exocyclic alkene 30. The
final step of the synthesis involved allylic oxidation of 30 using
SeO2 to afford the azitine (7), whose spectral data was identical to
those reported.[10a,22]
product 10, respectively. The next problem for us is to reduce the
imine 10 to construct the N-heterocycle. After failures in using
Dibal-H, LAH, NaBH4 and NaCNBH3 as reductants, we found that
Pd/C-catalyzed hydrogenation under acidic conditions could make
this transformation possible. The resultant reaction mixture was
directly treated with HCHO and NaCNBH3 in one-pot to afford
tertiary amine 32, which was more conveniently isolated from the
Pd/C catalyst than its precursor. Deprotection of the ketal group in
32 provided the ketone 33 in 72% yield, whose structure was
confirmed by X-ray analysis of its HCl salt (see SI). Finally, we
incorporated the hordenine part according to Sarpong’s
procedures.[9b] Treatment of ketone 33 with LiHMDS and Comins’
reagent furnished the corresponding triflate,[25] which underwent Pd-
catalyzed Stille coupling[26] with (tributylstannyl)-methanol to give
the allylic alcohol 34 in a moderate yield. Activation of the hydroxyl
group with MsCl, followed by treatment of NaH and hordenine
succeeded to establish the proposed structure of navirine C (2).[11]
However, the spectrum differed from the reported data. Further
studies on structural elucidation were hampered by the loss of the
original sample and spectra of navirine C (2).[27] Unveiling the
structural mystery of navirine C (2) has to rely on re-isolation of the
sample from nature.
OH
OH
Me
Me
Hg(OAc)2
dioxane, 60 o
65%
C
N
N
H
24
6
( )
isoazitine
O
O
Me
Me
LAH, Et
2O
O
O
50 o
C
CN
CN
N
NH
25
H
11
O
Me
THF/i
-PrOH,
-78 o
C
Li/NH
3(l),
O
b
path
O
O
Mn(dpm)3
TBHP
26
9
24%
46%
for
for
steps)
yield
yield
N
Me
Me
a e-
H
NHLi
O
O
path
i-PrOH
PhSiH3
,
(2
CN
HN
CN
27
CN
10
a
11
(68% yield)
O
b
path
O
path
H
Pd/C,
MeOH, HOAc
,
2
Me
O
then HCHO, NaCNBH3
+
O
Me
O
O
Me
Me
N
NHLi
H
O
O
N
CN
26
CN
31
28
N
(30% yield)
32
TsOH,
72%
Me
O
further
reduction
O
40 o
C
Me
acetone, H
2O,
10
Me
O
from
O
yield
O
N
N
NH
H
Me
Me
1. LiHMDS, THF, then Comins'
65%
reagent,
9
29
2.
LiCl, THF, Bu SnCH OH, 75 o
C
,
Pd(PPh3)4
3
2
1. TsOH, acetone, H
40 o
C
2O,
N
60%
2. PPh3MeBr, BuLi, THF, 70 oC
91%
n-
Me
33
(X-ray)
OH
OH
Me
O
Me
Me
TBHP
SeO2
,
1. MsCl, Et3N
N
CH2Cl2
56%
N
azitine
N
2. NaH
hordenine
41%
N
Me
7
30
Me
( )
NMe2
2
34
Scheme 2. Total synthesis of azitine (7). LAH = lithium aluminium
hydride.
O
O
O
Me
Me
HMn(dpm)2
11
O
CN
CN
CN
N
35
36
Guided by our retrosynthetic analysis, we turned our attention to
building up the C20-C14 bond via functionalization of alkene
utilizing metal-hydrid species (HAT reaction), which has recently
become a powerful and practical method in the synthesis of natural
products (Scheme 3).[12] Although no report has appeared for cyano
group being used as the radical acceptor in the HAT reaction,[12] its
performance in cascade radical cyclization[23] prompted us to try a
new type of HAT reaction. Fortunately, HAT reaction of dinitrile 11
under Shenvi’s conditions (Mn(dpm)3/silane/TBHP)[24] worked well
to provide the desired cyclization product 10 in a satisfactory yield,
although simple reduction product 31 still formed. In this
transformation, HAT reaction of the olefin 11 with HMn(dpm)2 that
generated by reduction of Mn(dpm)3 with PhSiH3 might occur first
to afford intermediate 35,[12a] in which the radical might attack C-N
triple bond to produce intermediate 36. Reduction of radicals 35 and
36 could give simple reduction product 31 and radical cyclization
HMn(dpm)2
31
HMn(dpm)2
10
Scheme 3. Total synthesis of the proposed structure of navirine C (2).
TBHP = t-butyl hydroperoxide.
In this communication, we have described a unified approach
towards the atisane-class C20-diterpenoid alkaloids, exemplified by
accomplishing the first total syntheses of azitine (in 17 steps from
cyclohex-2-en-1-one) and the proposed structure of navirine C (in
19 steps from cyclohex-2-en-1-one). The synthesis features a
number of key transformations including: (a) chelation-trigged
conjugate addition to control the continuous three stereogenic
centers in the cyclohexane unit; (b) oxidative dearomatization/Diels-
This article is protected by copyright. All rights reserved.

10.1002/anie.201803018
Angewandte Chemie International Edition
[9] a) A. M. Hamlin, F. de Jesus Cortez, D. Lapointe, R. Sarpong,
Angew. Chem. 2013, 125, 4954-4957; Angew. Chem. Int. Ed. 2013,
52, 4854-4857. b) A. M. Hamlin, D. Lapointe, K. Owens, R.
Sarpong, R. J. Org. Chem. 2014, 79, 6783-6800.
[10] a) H. K. Desai, B. S. Joshi, S. W. Pelletier, B. Sener, F. Bingöl, T.
Baykal. Heterocycles 1993, 36, 1081-1089. b) P. González, C.
Marín, I. Rodríguez-González, A. B. Hitos, M. J. Rosales, M.
Reina, J. G. Díaz, A. González-Coloma, M. Sánchez-Moreno, Int.
J. Antimicrob. Agents 2005, 5, 136-141.
[11] S. Dall’Acqua, B. B. Shrestha, M. B. Gewali, P. K. Jha, M.
Carrara, G. Innocenti, Nat. Prod. Commun. 2008, 3, 1985-1989.
[12] For a recent review, see: a) S. W. M. Crossley, C. Obradors, R. M.
Martinez, R. A. Shenvi, Chem. Rev. 2016, 116, 8912-9000; for a
recent report regarding cyclization of alkene-tethered ketones initiated
by HAT, see: b) M. Saladrigas, C. Bosch, G. V. Saborit, J. Bonjoch, B.
Bradshaw, Angew. Chem. 2018, 130, 188-192; Angew. Chem., Int.
Ed. 2018, 57, 182-186.
Alder cycloaddition to forge the crucial bicyclo[2.2.2]octane moiety
with a free cyano group at C20; (c) reduction of dinitrile
intermediate to form N-heterocycle with the oxidation state at the
C20 position; and (d) first HAT reaction between olefin and cyano
units for constructing the C20-C14 bond. As one can expect, if other
Grignard reagents with oxidation state at C6/7 and functionalized
α,β-unsaturated nitriles are employed to perform the chelation-
controlled conjugate addition, more functionalized diterpenoid
alkaloids would be able to be assembled with ease. Thus, the present
synthetic strategy provides a reliable and efficient approach for
diverse synthesis of diterpenoid alkaloids and their analogues.
[1] For reviews, see: a) F.-P. Wang, Q.-H. Chen, X.-Y. Liu, Nat. Prod.
Rep. 2010, 27, 529-570. b) E. C. Cherney, P. S. Baran, Isr. J.
Chem. 2011, 51, 391-405. c) A. M. Hamlin, J. K. Kisunzu, R.
Sarpong, Org. Biomol. Chem. 2014, 12, 1846-1860. d) X.-Y. Liu,
Y. Qin, Asian J. Org. Chem. 2015, 4, 1010-1019.
[13] For a recent review, see: X.-Y. Liu, Y. Qin, Nat. Prod. Rep. 2017,
34, 1044-1050
[14] a) F. F. Fleming, J. Guo, Q. Wang, D. Weaver, J. Org. Chem. 1999,
64, 8568-8575. b) F. F. Fleming, Q. Wang, O. W. Steward, Org.
Lett. 2000, 2, 1477-1479. c) F. F. Fleming, Q. Wang, Z. Zhang, O.
W. Steward, J. Org. Chem. 2002, 67, 5953-5956. d) F. F. Fleming,
Z. Zhang, Q. Wang, O. W. Steward, Angew. Chem. 2004, 116,
1146-1149; Angew. Chem., Int. Ed. 2004, 43, 1126-1129.
[15] J. A. Lujan-Montelongo, F. F. Fleming, Org. Synth. 2013, 90, 229-
239.
[16] J. Gong, H. Chen, X-Y. Liu, Z.-X. Wang, W. Nie, Y. Qin. Y. Nat.
Commun. 2016, 7, 12183-12.
[17] J. C. Martin, R. J. Arhart, J. A. Franz, E. F. Perozzi, L. J. Kaplan,
Org. Synth. 1977, 57, 22-26.
[2] a) H. Muratake, M. Natsume, Angew. Chem. 2004, 116, 4746-
4749; Angew. Chem., Int. Ed. 2004, 43, 4646-4649. b) H.
Muratake, M. Natsume, H. Nakai, Tetrahedron 2006, 62, 7093-
7112. c) K. M. Peese, D. Y. Gin, J. Am. Chem. Soc. 2006, 128,
8734-8735. d) K. M. Peese, D. Y. Gin, Chem. Eur. J. 2008, 14,
1654-1665.
[3] a) W. Nagata, T. Sugasawa, M. Narisada, T. Wakabayashi, Y.
Hayase, Y. J. Am. Chem. Soc. 1963, 85, 2342-2343. b) S.
Masamune, J. Am. Chem. Soc. 1964, 85, 86, 291-292. c) R. W.
Guthrie, Z. Valenta, K. Wiesner, Tetrahedron Lett. 1966, 7, 4645-
4654. d) W. Nagata, T. Sugasawa, M. Narisada, T. Wakabayashi,
Y. Hayase, J. Am. Chem. Soc. 1967, 89, 1483-1499. e) M. Ihara,
M. Suzuki, K. Fukumoto, T. Kametani, C. Kabuto, J. Am. Chem.
Soc. 1988, 110, 1963-1964. f) M. Ihara, M. Suzuki, K. Fukumoto,
C. Kabuto, J. Am. Chem. Soc. 1990, 112, 1164-1171. g) X.-Y. Liu,
H. Cheng, X.-H. Li, Q.-H. Chen, L. Xu, F.-P. Wang, Org. Bioml.
Chem. 2012, 10, 1411-1417..
[18] J.-T. Hwang, C-C. Liao, Tetrahedron Lett. 1991, 32, 6583-6586.
[19] CCDC 1829100 and 1829101 contain the supplementary
crystallographic data for the precursor of 22 and the compound 33,
respectively. The data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[20] O. H. Oldenziel, D. Van Leusen, A. M. Van Leusen, J. Org. Chem.
1977, 42, 3114-3118.
[21] K. M. Allan, B. M. Stoltz, J. Am. Chem. Soc. 2008, 130, 17270-
17271.
[4] E. C. Cherney, J. M. Lopchuk, J. C. Green, P. S. Baran, J. Am.
Chem. Soc. 2014, 136, 12592-12595.
[5] X.-H. Li, M. Zhu, Z.-X. Wang, X.-Y. Liu, H. Song, D. Zhang, F.-P.
Wang, Y. Qin, Angew. Chem. 2016, 128, 15896-15900; Angew.
Chem. Int. Ed. 2016, 55, 15667-15671.
[22] J. G. Díaz, J. G. Ruiz, G. de la Fuente, J. Nat. Prod. 2000, 63,
1136-1139.
[23] a) B. B. Snider, B. O. Buckman, J. Org. Chem. 1992, 57, 322-326.
b) C. P. Ting, G. Xu, X. Zeng, T. J. Maimone, J. Am. Chem. Soc.
2016, 138, 14868-14871.
[24] K. Iwasaki, K. K. Wan, A. Oppedisano, S. W. M. Crossley, R. A.
Shenvi, J. Am. Chem. Soc. 2014, 136, 1300-1303.
[25] D. L. Comins, A. Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
6302.
[26] W. J. Scott, J. K. Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-
3040.
[6] H. Cheng, F.-H. Zeng, X. Yang, Y. -J. Meng, L. Xu, F.-P. Wang,
Angew. Chem. 2016, 128, 400-404; Angew. Chem., Int. Ed. 2016,
55, 392-396.
[7] a) K. G. M. Kou, B. X. Li, J. C. Lee, G. M. Gallego, T. P. Lebold,
A. G. DiPasquale, R. Sarpong, J. Am. Chem. Soc. 2016, 138,
10830-10833. b) K. G. M. Kou, S. Kulyk, C. J. Marth, J. C. Lee, N.
A. Doering, B. X. Li, G. M. Gallego, T. P. Lebold, R. Sarpong, J.
Am. Chem. Soc. 2017, 139, 13882-13896.
[8] a) S. W. Pelletier, W. A. Jacobs, J. Am. Chem. Soc. 1956, 78,
4144-4145. b) S. W. Pelletier, P. C. Parthasarathy, Tetrahedron
Lett. 1963, 1339-1342.
[27] Personal communication with Prof. Dall'Acqua.
This article is protected by copyright. All rights reserved.

10.1002/anie.201803018
Angewandte Chemie International Edition
((Catch Phrase))
A readily available tetracyclic
dinitrile is found to be a valuable
intermediate for assembly of azitine
and the proposed structure of
navirine C.
O
OH
5 steps
Jie Liu and Dawei Ma*
Me
Me
O
CN
12 steps
CN
N
azitine
7 steps
Me
_______ Page – Page
O
N
proposed
structure
of navirine C
Me
A Unified Approach for the Assembly of
Atisine- and Hetidine-Type Diterpenoid
Alkaloids: Total Syntheses of Azitine
and the Proposed Structure of Navirine
C
O
NMe2
This article is protected by copyright. All rights reserved.