Syntheses of Denudatine Diterpenoid Alkaloids: Cochlearenine, N-Ethyl-1α-hydroxy-17-veratroyldictyzine, and Paniculamine

Article abstract of DOI:10.1021/jacs.6b07268

The denudatine-type diterpenoid alkaloids cochlearenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and paniculamine have been synthesized for the first time (25, 26, and 26 steps from 16, respectively). These syntheses take advantage of a common intermediate (8) that we have previously employed in preparing aconitine-type natural products. The syntheses reported herein complete the realization of a unified strategy for the preparation of C₂₀, C₁₉, and C₁₈ diterpenoid alkaloids.

Full text of DOI:10.1021/jacs.6b07268

Subscriber access provided by Northern Illinois University
Communication
Syntheses of Denudatine Diterpenoid Alkaloids: Cochle-arenine,
N-Ethyl-1#-Hydroxy-17-Veratroyldictizine, and Paniculamine
Kevin G. M. Kou, Beryl Xiao Li, Jack Chang Hung Lee, Gary M. Gallego,
Terry P Lebold, Antonio G DiPasquale, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07268 • Publication Date (Web): 15 Aug 2016
Downloaded from http://pubs.acs.org on August 15, 2016
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 free 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 accessible to all
readers and 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.
Journal of the American Chemical Society 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 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Syntheses of Denudatine Diterpenoid Alkaloids: Cochlearenine, N-
Ethyl-1α-Hydroxy-17-Veratroyldictizine, and Paniculamine
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
Kevin G. M. Kou, Beryl X. Li, Jack C. Lee,† Gary M. Gallego,‡ Terry P. Lebold,§ Antonio G.
DiPasquale, and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, CA 94720, United States
Supporting Information Placeholder
Scheme 1. A unified strategy to the C20, C19, and C18
diterpenoid alkaloids
ABSTRACT: The denudatine-type diterpenoid alkaloids cochle-
arenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and panicu-
lamine have been synthesized for the first time (25, 26 and 26
steps from 16, respectively). These syntheses take advantage of a
common intermediate (8) that we have previously employed in
preparing aconitine-type natural products. The syntheses reported
herein complete the realization of a unified strategy for the prepa-
ration of C20, C19, and C18 diterpenoid alkaloids.
Syntheses of architecturally complex secondary metabolites are
not easily accomplished using an iterative approach where a par-
ticular bond construction method (e.g., aldol reaction, cross-
coupling, etc.) features prominently.1−5 For topologically complex
frameworks, the strategy that is adopted for synthesis takes on
added significance. Many highly complex, bioactive, secondary
metabolites often co-occur in the producing organism with conge-
ners that also possess interesting and desirable bioactivity. For
these reasons, unified strategies using a versatile intermediate
often provide the most efficient approach to these topologically
complex, structurally related, compounds.6 The diterpenoid alka-
loids (Figure 1 and Scheme 1) are a family of compounds for
which this context is highly pertinent. These secondary metabo-
lites are isolated from the Aconitum, Consolidum, and Delphinium
genera of plants, which are used in traditional medicine (e.g., in
China) for the treatment of pain and cardiovascular diseases.7−9
Importantly, these natural products are noted for their potential to
modulate Na+ and/or K+ ion channels10 and in some cases may be
subtype-specific.11 This characteristic may allow specific target-
ing of particular ion channel isoforms implicated in channelopa-
thies, and thus may provide new opportunities for developing
therapeutics where side-effects are minimized.12
The over 1200 known diterpenoid alkaloids are categorized in-
to C20, C19, and C18 families depending on the number of contigu-
ous carbon atoms comprising the framework.13–15 These nitrogen-
containing diterpenoids have attracted significant attention from
the synthetic community as a result of their diverse biological
activity and structural complexity.16 The earliest synthetic efforts
focused on the C20 alkaloids, resulting in syntheses of atisine
(1),17,18 garryine,19,20 veatchine,20,21 napelline,22 and nominine
(2).23 Baran et al. demonstrated a unified approach to (−)-methyl
atisenoate, its alkaloidal counterpart (−)-isoatisine (3), and the
hetidine skeleton.24 Similarly, Xu et al. reported the syntheses of
atisine-type dihydroajaconine (4), spiramines C (5) and D (6),
along with the biosynthetically related diterpenes spiramilactone
B and spiraminol, all arising from a common, advanced interme-
diate.25 Fukuyama and coworkers were the first to complete a
synthesis of a denudatine-type alkaloid, lepenine (7).26
While previously reported synthesis strategies either target one
diterpenoid alkaloid or several biogenetically related natural
products within the C20 family, we have focused on a strategy that
would provide access to C20, C19, and C18 congeners. We recently
disclosed a successful approach to the C19 and C18 secondary me-
tabolites liljestrandinine (9) and weisaconitine D (10) using hy-
drindane derivative 8 as a common intermediate.27 Herein, we
demonstrate the extension of this strategy to the syntheses of the
C20 denudatine-type alkaloids cochlearenine (11),28,29 N-ethyl-1α-
hydroxy-17-veratroyldictyzine (12),30 and paniculamine (13)31
Figure 1. Examples of C20 diterpenoid alkaloids
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
(Scheme 1). The seemingly “simpler” framework of 11, 12, and
uct in 83% yield. The methylene O-mesylate group of 22 was
1
2
3
4
5
6
7
8
13 (relative to 9 and 10) belies the challenge that is inherent in
their syntheses. This challenge includes the installation of the C18
methyl group and the orchestration of synthetic steps to achieve
the desired hydroxylation pattern on the bicyclo[2.2.2] structural
motif. From a function standpoint, cochlearenine (11) is especial-
ly interesting because it exhibits a dose-dependent bradycardic
effect in guinea pig atria at doses between 0.1−1.0 mg/mL.32 The
biological function of veratroylated derivative 12 and N-oxide 13
have not been evaluated; we anticipate that their structural simi-
larities to cochlearenine (11) would yield insight into the struc-
ture-activity relationships of the denudatines.
Retrosynthetically, we envisioned 11, 12, and 13 arising from
14 by late-stage manipulation of the functional groups on the
[2.2.2] bicycle (Scheme 2). This bicyclic moiety would be forged
by intramolecular Diels–Alder cycloaddition of tricycle 15, which
can be assembled from 8 by a sequence involving methylation at
C4 to install the C18 methyl group and piperidine ring formation.
In turn, 8 could be obtained in 10 steps (25% overall yield) from
16 using an improved version of our previously established se-
quence (see SI for details).27
reduced to the corresponding methyl group using a combination
of NaI/Zn. In this way, the methyl group that is present in all of
the C20 alkaloids can be stereoselectively introduced. Removal of
the MOM group and oxidative dearomatization of the resulting
phenol with PhI(OAc)2 in MeOH yields dienone 23 in 61% yield
over 3 steps, and sets the stage for an intramolecular Diels–Alder
cycloaddition.
Heating dienone 23 in p-xylene effects clean conversion to
hexacycle 14 in 80−87% yield (Scheme 4). To complete the C20
framework of the denudatine natural products, an additional car-
bon atom is required on the [2.2.2] bicycle (see 26). To this end,
we first investigated a Corey-Chaykovsky epoxidation.37 Using
dimethylsulfonium ylide in THF/DMSO at 0 ˚C resulted in exclu-
sive formation of epoxide 24, which was the undesired diastere-
omer in the context of our target molecules. The diastereomer of
epoxide 24 (i.e., 26) was easily obtained from 14 using a Wittig
methylenation (to give 25; 87% yield) and Weitz-Scheffer epoxi-
dation38 to install an α-epoxide. Of note, the use of hydrogen per-
oxide or tert-butyl hydroperoxide led to poor conversions and to
mixtures of epoxide diastereomers, whereas the use of trityl per-
oxide39 generated epoxy-ketone 26 as a single diastereomer in
57% yield.
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 2. Retrosynthesis of 11, 12, and 13
Scheme 3. Installing the C18 methyl group a
With 8 in hand, we focused on installing the C18 methyl group
(Scheme 3). In preparation for this functionalization, 8 was con-
verted to aldehyde 17 in 95% yield using a Swern oxidation. It
was our expectation that generation of an enolate from 8 (with
accompanying deprotonation of the methyl carbamate) and treat-
ment with a methyl electrophile would result in α-methylation of
the enolate from the convex face of the bicycle.33 In our hands
only the C4 epimer 18, which is unambiguously supported by an
X-ray crystallography study of its derivative, 19, was obtained.
Presumably, approach of the electrophile from the convex face of
the bicycle is disfavored in this case due to steric crowding im-
posed by the axially-disposed vinyl group at the ring junction
through a developing syn-pentane interaction between the electro-
phile and angular vinyl group (see SI for details). To overcome
this challenge, we sought to install an electrophile at C4 that
would obviate the undesired diastereoselectivity that we observe.
Inspired by the studies of Wiesner,34,35 we have shown in our
previous studies27 that an aldol–Cannizzaro sequence on 17 pro-
duces diol 20 (97% yield), which was activated to give dimesylate
21 in 76% yield.
We have previously found that subjecting 21 to KOt-Bu to ef-
fect cyclization to piperidine 22 results in low yields.27 A closer
examination of this reaction revealed that piperidine 22 is formed
in only 30% yield and a significant amount of the mass balance
(39%) is accounted for by KOt-Bu mediated decarbamoylation36
to the corresponding deprotected amine that does not cyclize un-
der the reaction conditions (see SI for details). This challenge was
overcome by using KH as the base. This modification affords
piperidine 22 as the major product (62% yield) along with minor
amounts of side products lacking the mesyl group (16%, see SI)
when conducted in THF as the solvent. Using KH and DMF as the
solvent, cyclization of 21 occurs to give 22 as the exclusive prod-
Drawing inspiration from an observation made by Wang and
coworkers,40 epoxy-ketone 26 was subjected to a solution of
HBr/AcOH at 110 ˚C, which resulted in cleavage of the me thyl
carbamate and the methyl group on the C1 hydroxyl (Scheme 5).
The desired N-acetylated products 27 and 28, along with fragmen-
tation product 29, were formed in a combined 79% yield upon
quenching with NaOH and treating the crude mixture with Ac2O
and pyridine.41
Mono- and diacetylated epoxy-ketones 27 and 28 (51% com-
bined yield from 26) were independently advanced to 11, from
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
Scheme 4. Complementary epoxide formations a
tiary amine to the biological activity of the denudatine-type alka-
loids.
1
2
3
Scheme 5. Accessing denudatine natural products
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
which 12 and 13 were synthesized. This sequence commenced
with epoxide opening using KOAc. The strained alkene group
was hydrogenated using Pd/C as catalyst, and a final, global re-
duction with LiAlH4 produced cochlearenine (11) in 63–77%
yield over the 3 steps. While the spectroscopic data obtained for
the material prepared by us is not consistent with that reported in
the initial isolation disclosure,28 it is consistent with the data re-
ported in a subsequent isolation study,29 with the exception of a
single 13C resonance (see SI for details). Using density functional
ASSOCIATED CONTENT
Supporting Information
1
theory (DFT), we confirmed that the predicted H and 13C NMR
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
data for cochlearenine (11) agrees most closely with our experi-
mental data, and fully support the assignment of the reported
structure.42 Coupling 11 with veratroyl chloride produces N-ethyl-
1α-hydroxy-17-veratroyldictyzine (12) in 25% yield. The litera-
ture data30 reported for this natural product is inconsistent with the
1H and 13C NMR data for the neutral form of the synthetic materi-
al. However, the isolation data is fully consistent with the proto-
nated form (31) that is generated upon treatment with TFA. Final-
ly, treating 11 with H2O2 affords paniculamine (13) in 50%.
In summary, the first total syntheses of cochlearenine (11), N-
ethyl-1α-hydroxy-17-veratroyldictyzine (12) and paniculamine
(13) in racemic form have been accomplished. These syntheses
were achieved in 25, 26, and 26 steps, respectively, from hy-
drindanone 16. This readily available bicycle is prepared in 30 g
in a single pass. Importantly, we have previously reported an en-
antioselective route to 16,27 and so our racemic syntheses of 11,
12 and 13 may be easily rendered enantioselective. From a broad-
er perspective, the completion of the syntheses of these denudat-
ine-type alkaloids represents a realization of a unified synthetic
strategy to the C20, C19, and C18 diterpenoid alkaloids when placed
in the context of our previously reported syntheses of
liljestrandinine and weisaconitine D. Keys to success in preparing
11, 12, and 13 include a stereoselective installation of the C18
methyl group via dimesylate 21, identifying optimal conditions
for the piperidine ring formation, and demethylation of the 1-
methoxy group under acidic conditions. Our syntheses of 11 and
12 should enable a study of the effect of veratroylation as well as
of other acylations on the biological activity of the C20 denudat-
ine-type diterpenoid alkaloids.10,43 Furthermore, access to 13
should facilitate an evaluation of the importance of the basic ter-
AUTHOR INFORMATION
Corresponding Author
*rsarpong@berkeley.edu
Present Addresses
† Worldwide Medicinal Chemistry, Groton Laboratories, Pfizer
Inc. Eastern Point Road, Groton, CT, 06340, USA
‡ Chemistry Department, Pfizer Pharmaceuticals, La Jolla La-
boratories, 10770 Science Center Drive, La Jolla, CA, 92121,
USA
§ Janssen Research & Development, LLC, 3210 Merryfield Row,
San Diego, CA, 92121, USA
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This project was supported by award no. R01 GM084906 from
the National Institute of General Medical Sciences. K. G. M. K.
and T. P. L. are grateful for NSERC postdoctoral fellowships. X-
ray crystallography instrumentation are supported by NIH Shared
Instrumentation Grant S10-RR027172. The AV-600, AV-500,
DRX-500, AVQ-400, and AVB-400 NMR spectrometers are par-
tially supported by NIH grants SRR023679A and
1S10RR016634-01, and NSF grants CHE-9633007 and CHE-
0130862. The 900 MHz NMR instrument is funded by NIH grant
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
(22) (a) Wiesner, K.; Ho, P.-K.; Tsai (Pan), C. S. J.; Lam, Y.-K. Can. J.
GM68933. The Molecular Graphics and Computation Facility is
funded by NSF grant CHE-0840505. We thank Dr. Kathleen
Durkin and Dr. Yinka Olatunji-Ojo for assistance with DFT com-
putations.
Chem. 1974, 52, 2355. (b) Sethi, S. P.; Atwal, K. S.; Marini-Bettolo,
R. M.; Tsai, T. Y. R.; Wiesner, K. Can. J. Chem. 1980, 58, 1889.
(23) (a) Muratake, H.; Natsume, M. Angew. Chem. Int. Ed. 2004, 43, 4646.
(b) Peese, K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 8734. (c)
Peese, K. M.; Gin, D. Y. Chem. Eur. J. 2008, 14, 1654.
(24) Cherney, E. C.; Lopchuk, J. M.; Green, J. C.; Baran, P. S. J. Am.
Chem. Soc. 2014, 136, 12592.
1
2
3
4
5
6
7
8
REFERENCES
(1) For reviews on iterative, solid phase peptide synthesis, see: (a)
Barany, G.; Kneib-Cordonier, N., Mullen, D. G. Int. J. Peptide Proten
Res. 1987, 30, 705. (b) Kimmerlin, T.; Seebach, D. J. Peptide Res.,
2005, 65, 229.
(2) For an iterative synthesis of deoxyoligonucleotides, see: Caruthers, M.
H. Science 1985, 230, 281.
(3) For selected reviews on iterative, automated oligosaccharide synthe-
sis, see: (a) Seeberger, P. H.; Haase, W.-C. Chem. Rev. 2000, 100,
4349. (b) Sears, P.; Wong, C.-H. Science 2001, 291, 2344. (c)
Seeberger, P. H.; Werz, D. B. Nature 2005, 4, 781.
(4) For a recent review on iterative syntheses of polyketides, see: Zheng,
K.; Xie, C.; Hong, R. Front. Chem. 2015, 3, 32.
(5) For an example of an iterative polyene synthesis, see: Woerly, E. M.;
Roy, J.; Burke, M. D. Nature Chem. 2014, 6, 484.
(6) Shimokawa, J. Tetrahedron Lett. 2014, 55, 6156.
(7) Rahman, A.-u; Choudhary, M. I. Nat. Prod. Rep. 1999, 16, 619.
(8) Wang, F.-P.; Chen, Q.-H.; Liu, X.-Y. Nat. Prod. Rep. 2010, 27, 529.
(9) Wang, X.-W.; Xie, H. Drugs Future 1999, 24, 877.
(10) Ameri, A. Prog. Neurobiol. 1998, 56, 211.
(11) Borcsa, B.; Fodor, L.; Csupor, D.; Forgo, P.; Molnár V., A.;
Hohmann, J. Planta Med. 2014, 80, 231.
(12) Stevens, M.; Peigneur, S.; Tytgat, J. Front. Pharmacol. 2011, 2, 71.
(13) Wang, F.-P.; Liang, X.-T. C20-Diterpenoid Alkaloids. In The Alka-
loids: Chemistry and Biology; Cordell, G. A., Ed.; Elsevier Science:
New York, 2002; 59, pp 1–280.
(14) Wang, F.-P.; Chen, Q.-H. The C19-Diterpenoid Alkaloids. In The
Alkaloids: Chemistry and Biology; Cordell, G. A. Ed.; Academic
Press, 2010; 69, pp 1–577.
(15) Wang, F.-P.; Chen, Q.-H.; Liang, X.-T. The C18-Diterpenoid Alka-
loids. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.;
Academic Press, 2009; 67, pp. 1–78.
(16) For reviews on syntheses of diterpenoid alkaloids, see: (a) Zhu, G.;
Liu, R.; Liu, B. Synthesis 2015, 47, 2691. (b) Liu, X.-Y.; Qin, Y.
Asian J. Org. Chem. 2015, 4, 1010.
(17) Pelletier, S. W.; Parthasarathy, P. C. Tetrahedron Lett. 1963, 4, 205.
(18) For examples of early, formal syntheses of atisine, see: (a) Nagata,
W.; Sugasawa, T.; Narisada, M.; Wakabayashi, T.; Hayase, Y. J. Am.
Chem. Soc. 1963, 85, 2342. (b) Nagata, W.; Sugasawa, T.; Narisada,
M.; Wakabayashi, T.; Hayase, Y. J. Am. Chem. Soc. 1967, 89, 1483.
(c) Masamune, S. J. Am. Chem Soc. 1964, 86, 296. (d) Guthrie, R. W.;
Valenta, Z.; Wiesner, K. Tetrahedron Lett. 1966, 7, 4645.
(19) Masamune, S. J. Am. Chem. Soc. 1964, 86, 290.
(20) (a) Nagata, W.; Sugasawa, T.; Narisada, M.; Wakabayashi, T.;
Hayase, Y. J. Am. Chem. Soc. 1963, 86, 929. (b) Nagata, W.; Narisa-
da, M.; Wakabayashi, T.; Sugasawa, T. J. Am. Chem. Soc. 1967, 89,
1499.
(25) Cheng, H.; Zeng, F.-H.; Yang, X.; Meng, Y.-J.; Xu, L.; Wang, F.-P.
Angew. Chem. Int. Ed. 2016, 55, 392.
(26) (a) Nishiyama, Y.; Han-ya, Y.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2014, 136, 6598. (b) A late-stage intermediate with the
denudatine core obtained in ref. 26(a) can be converted to (–)-
cardiopetaline featuring the atisane framework: Nishiyama, Y.; Yoko-
shima, S.; Fukuyama, T. Org. Lett. 2016, 18, 2359.
(27) Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou,
K. G. M.; Qin, J.; Lilien, R.; Sarpong, R. Nature 2015, 528, 493.
(28) Kolak, U.; Öztürk, M.; Özgökçe, F.; Ulubelen, A. Phytochemistry
2006, 67, 2170.
(29) Wada, K.; Kawahara, N. Helv. Chim. Acta 2009, 92, 629.
(30) Díaz, J. G.; Ruiza, J. G.; Herz, W. Phytochemistry 2005, 66, 837.
(31) Yusupova, I. M.; Bessonova, I. A.; Tashkodzhaev, B. Chem. Nat.
Prod. 1995, 31, 228.
(32) Ulubelen, A.; Kolak, U. Chemical and Biological Studies with an
Aconitum and a Delphinium Species. In Innovations in Chemical Bi-
ology; Sener, B., Ed.; Springer Science+Business Media B.V., 2009;
pp 39–49.
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
(33) We anticipated that methylation of the deprotonated carbamate, which
resides on the concave face would be difficult and therefore not sig-
nificantly compete with the desired methylation.
(34) Wiesner, K. Pure Appl. Chem. 1975, 41, 93.
(35) A related, 2-step aldol-reduction sequence was used to install a hy-
droxymethyl group at the C4 position in a study towards acochlearine:
Fujioka, K.; Miyamoto, N.; Toya, H.; Okano, K.; Tokuyama, H. Syn-
lett 2016, 27, 621.
(36) Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M. Tetrahedron Lett.
2004, 45, 905.
(37) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(38) (a) Weitz, E.; Scheffer, A. Ber., 1921, 54, 2327. (b) For a review, see:
Wang, Z. Weitz-Scheffer Epoxidation. In Comprehensive Organic
Name Reactions and Reagents; John Wiley & Sons, Inc, 2010; pp
2975–2979.
(39) For examples that show greater reactivity with trityl peroxide over t-
butyl peroxide, see: (a) Li, C.; Pace, E. A.; Liang, M.-C.; Lobkovsky,
E.; Gilmore, T. D.; Porco, Jr., J. A. J. Am. Chem. Soc. 2001, 123,
11308. (b) McGrath, N. A.; Bartlett, E. S.; Sittihan, S.; Njardarson, J.
T. Angew. Chem. Int. Ed. 2009, 48, 8543.
(40) Tang, P.; Chen, Q.-F.; Wang, L.; Chen, Q.-H.; Jian, X.-X.; Wang, F.-
P. Tetrahedron 2012, 68, 5668.
(41) The 1-acetoxy group of 27 is introduced during HBr/AcOH mediated
dealkylation and not during the subsequent acetylation step.
(42) Willoughby, P. H.; Jansma, M. J.; Hoye, T. R. Nat. Protoc. 2014, 9,
643.
(43) For studies on the effects of acylation on aconitine-type diterpenoid
alkaloids, see: (a) Sata, H.; Yamada, C.; Konno, C.; Ohizumi Y.; En-
do, K.; Hikino, H. Tohoku J. Exp. Med. 1979, 128, 175. (b) Ye, L.;
Yang, X.; Yang, Z.; Gao, S.; Yin, T.; Liu, W.; Wang, F.; Hu, M.; Liu,
Z. Toxicol. Lett. 2013, 216, 86.
(21) (a) Wiesner, K.; Uyeo, S.; Philipp, A.; Valenta, P. Tetrahedron Lett.
1968, 9, 6279. (b) Wiesner, K.; Komlossy, Z. I.; Philipp, A.; Valenta,
Z. Experentia 1970, 26, 471.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
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
5
ACS Paragon Plus Environment