A unifying synthesis approach to the C18-, C19-, and C20-diterpenoid alkaloids

Article abstract of DOI:10.1021/jacs.7b07706

The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C₁₈, C₁₉, and C₂₀ families depending on the number of contiguous carbon atoms that constitute their central framework. Herein, we detail our efforts to prepare these molecules by chemical synthesis, including a photochemical approach, and ultimately a bioinspired strategy that has resulted in the development of a unifying synthesis of one C₁₈ (weisaconitine D), one C₁₉ (liljestrandinine), and three C₂₀ (cochlearenine, paniculamine, and N-ethyl-1α-hydroxy-17-veratroyldictyzine) natural products from a common intermediate.

Full text of DOI:10.1021/jacs.7b07706

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Article
A Unifying Synthesis Approach to the
C18#, C19#, and C20#Diterpenoid Alkaloids
Kevin G. M. Kou, Svitlana Kulyk, Christopher J Marth, Jack C. Lee, Nicolle A
Doering, Beryl X. Li, Gary M. Gallego, Terry P Lebold, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07706 • Publication Date (Web): 31 Aug 2017
Downloaded from http://pubs.acs.org on August 31, 2017
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A Unifying Synthesis Approach to the C18‒, C19‒, and C20‒Diterpenoid
Alkaloids
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†
‡
§
Kevin G. M. Kou, Svitlana Kulyk, Christopher J. Marth, Jack C. Lee, Nicolle A. Doering, Beryl X. Li,
Gary M. Gallego, Terry P. Lebold and Richmond Sarpong*
¶
‖
Department of Chemistry, University of California, Berkeley, California 94720, United States
KEYWORDS. Diterpenoid alkaloids, total synthesis, unified synthesis, weisaconitine D, liljestrandinine, cochlearenine, N-ethyl-1α-
hydroxy-17-veratroyldictyzine, paniculamine, retrosynthetic analysis, network analysis, Wagner‒Meerwein rearrangement
ABSTRACT: The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C18-, C19-, and C20
-
families depending on the number of contiguous carbon atoms that constitute their central framework. Herein, we detail
our efforts to prepare these molecules by chemical synthesis, including a photochemical approach, and ultimately a bioin-
spired strategy that has resulted in the development of a unifying synthesis of one C18 (weisaconitine D), one C19
(
liljestrandinine), and three C20 (cochlearenine, paniculamine, and N-ethyl-1α-hydroxy-17-veratroyldictyzine) natural
products from a common intermediate.
INTRODUCTION
The diterpenoid alkaloids are complex, bridged, polycy-
clic natural products that possess analgesic, anti-
inflammatory, anti-arrhythmic, and other pharmacological
weisaconitine D (C18, 2), liljestrandinine (C19, 4), cochle-
arenine (C20, 6), N-ethyl-1α-hydroxy-17-veratroyldictyzine
(C20, 7), and paniculamine (C20, 8).
12,13
1
‒3
activities.
The Aconitum, Consolidum, and Delphinium
plants from which these pseudoalkaloids are isolated have
long been used in traditional medicine for the treatment of
pain and cardiovascular diseases. In fact, Guan-fu base A
(
5, Figure 1) is in phase IV clinical trials as an anti-
4
arrhythmic agent in China, while the hydrobromide salt of
lappaconitine (1) is approved and marketed in both China
5
and Russia as a pain and arrhythmia treatment. Perhaps
most intriguing is the ability of some diterpenoid alkaloids
+
+
6
to modulate Na and/or K ion channels. For example,
+
aconitine (3) is a highly toxic Na channel activator with an
estimated lethal dose of 1‒2 mg in humans. However,
structurally related lappaconitine (1) is a Na channel
blocker that has therapeutic value. The potential for these
7
+
6
molecules to act as subtype-selective ion channel modula-
tors has significant implications for treating channelopa-
8,9
thies without significant undesirable side effect profiles.
While over 1200 members make up this class of secondary
metabolites, few have been studied for their function due
to inadequate accessibility. Developing synthesis strategies
that allow access to a variety of these natural products and
related unnatural analogs would facilitate structure-
activity-relationship studies and provide myriad opportu-
nities for clinical applications.
Attracted by the challenges associated with the architec-
tural complexity, and the opportunities to learn about the
biological function of these natural products, we embarked
on a total synthesis campaign targeting members of the
5,10,11
C
18-, C19-, and C20-diterpenoid alkaloids
with varying
substitution and oxygenation patterns decorating their
framework. These efforts have led to the first syntheses of
Figure 1. Examples of diterpenoid alkaloids.
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Scheme 1. Network-analysis-guided retrosynthetic analysis of aconitine-type natural products. The red dots indi-
cate bridging atoms in the network analyses
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RESULTS AND DISCUSSION
In this case, the B-ring contains five bridging atoms, the E-
and F-rings four bridging atoms (F-ring not shown, see SI),
the C-ring contains three bridging atoms, the D-ring three
bridging atoms (not shown), and the A-ring two bridging
atoms (not shown). Having identified the B-ring as the
maximally-bridged ring, we envisioned a bicyclization
transform that effectively simplifies the target to tricyclic
vinyl arene 9. In the forward sense, this operation forges
The assembly of these structurally complex molecules
has challenged synthetic chemists since the 1960’s, begin-
ning with Nagata, Masamune, and Wiesner’s formal syn-
14
15
16,17
theses of C20-members atisine, garryine,
and vi-
1
7,18
atchine.
While lengthy, these contributions set the
stage for the field and provided inspiration even to modern
synthetic approaches, including our own (see Scheme
19,20
28
7).
Recently, the Baran and Xu groups have devised
two bonds and three new rings in a single step. Similarly,
unified strategies toward various diterpenoid alkaloids but
applying network analysis to intermediate 9 yields the
piperidine E-ring as the maximally-bridged system with
four bridging atoms. Since the piperidine ring also contains
a nitrogen atom (a functional group), we reasoned that its
disconnection would provide the greatest simplification,
thus leading back to fused AF ring system 10 that contains
no bridging elements. The protected amine functionality of
10 can arise from a hydration and Hofmann rearrange-
ment sequence on nitrile 11, which in turn can be pre-
pared from vinyl nitrile 12 through a conjugate arylation
reaction and transformation of the methyl ester. This in-
termediate can be further simplified to hydrindenone 13,
which can be accessed in >20 g quantities using a
21,22
particularly natural products within the C20 family.
Our
group demonstrated conversion of the C20 hetidine core to
23,24
the atisine framework,
and the Fukuyama group subse-
quently showed that an advanced intermediate used en-
25
route to the C20 natural product (‒)-lepenine can also be
26
used to synthesize the C19 alkaloid (‒)-cardiopetaline.
Here we describe our studies on an approach that unifies
the syntheses of secondary metabolites belonging to each
of the C18, C19, and C20 families.
Retrosynthesis. For bridged, polycyclic molecules with
complexity as daunting as that of the diterpenoid alkaloids,
27
network analysis, an approach formalized by Corey, pro-
vides an objective starting point and guide for retrosyn-
thetic analyses. In a complex molecular setting containing
a network of fused and bridged-ring systems, the latter are
generally perceived to be more challenging to assemble.
However, significant simplification to the network can be
achieved by iteratively cleaving bonds associated with the
maximally bridged ring(s), which is a key element of net-
work analysis.
13
Diels‒Alder reaction.
Correctly identifying the maximally-bridged ring sys-
tems in complex polycycles manually is inherently time-
2
9,30
consuming.
Therefore, to facilitate the use of network
3
1
analysis in retrosynthetic planning, we developed a com-
puter algorithm that correctly identifies the maximally-
bridged ring(s) for any molecule using the Chemistry De-
1
2,32‒34
velopment Kit software library.
We envision this
In applying network analysis to the hexacyclic aconitine
framework, as exemplified by weisaconitine D (Scheme 1),
each of the individual rings can be analyzed for the number
of bridging atoms (or bridgehead sites) that they contain.
web-based deterministic program to be a useful tool in
both the research laboratory and classroom for retrosyn-
thesis and chemical education.
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ring-opening to furnish diketone 18.36,37 This approach
Scheme 2. Proposed meta-π-arene photocycloaddition
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approach to the BCD ring system
would be unlike the proposed biosynthesis of the lappaco-
nitine and aconitine-type diterpenoid alkaloids that con-
tain the [3.2.1]-CD bicyclic structure, and would provide a
more direct route to the desired carbon framework.
We chose to introduce a methoxy-substituted aromatic
ring (see 14) because the arene oxygens would be native
to many of our target natural products. In addition, elec-
tron-rich methoxy groups direct meta-π-functionalization
to sites ortho to them, which would permit us to take max-
imum advantage of the substituents inherent to the target
structures, thereby streamlining synthesis.
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The synthesis begins with dimethylation of 1,4-
butynediol (19, Scheme 3) followed by NaNH
2
-promoted
elimination/isomerization to generate enyne 20 in 60%
38
yield.
A two-step sequence involving alkylation of the
terminal alkyne with paraformaldehyde and subsequent
Scheme 4. Synthesis of vinyl arene intermediate 31 for
photocycloaddition
Scheme 3. Decagram-scale synthesis of diene 20 and
cycloadducts 22
A photochemical approach to the CD [3.2.1] bicyclic
ring system. Using network analysis, we determined that
a bicyclization reaction to form the BCD ring systems
would be most effective in directly assembling the target
hexacyclic structure. To achieve this, we imagined a late-
stage meta-π-arene photocycloaddition between the al-
kene and arene groups of vinyl arene 14 (Scheme 2). Pho-
toexcitation of the arene component with UV irradiation
was expected to lead to formation of an exciplex where
concerted σ-bond formations would occur to generate
diradical 15. Spontaneous collapse of the diradical inter-
35
mediate would form vinyl cyclopropane 16. Subsequent
oxidation of the alkene to epoxide 17 could be followed by
an acid-mediated cyclopropane fragmentation and epoxide
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Scheme 5. Exploring alkene-arene photocycloadditions
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reduction of the propargyl alkyne with LiAlH
TBS-protection of the primary alcohol yields diene 21,
4
, followed by
the silyl ether, hydration of the nitrile to afford primary
amide 29 proceeds in 65‒75% yield under anhydrous
39
which can be prepared on 54 g scale in a single pass. Heat-
ing a two-equivalent excess of diene 21 with dienophile 22
(prepared from α-selenation of β-ketoester 23, followed by
selenoxide elimination from 24) results in formation of
the desired endo-cycloadduct (13) as the major product in
71% yield, along with the exo-diastereomer in 4% yield.
The alkene group in hydrindenone endo-13 is hydrogen-
ated with Pd/C as the catalyst, and the ketone group con-
verted to the vinyl triflate by treatment with LiHMDS and
conditions employing Wilkinson’s catalyst and acetaldox-
ime as the water-equivalent.
43
Hypervalent iodine-
mediated Hofmann rearrangement of 29 in methanol sol-
vent forms the corresponding methyl carbamate, which is
then subjected to TBAF-mediated deprotection to reveal
alcohol 30 in 94% yield over two steps. Successive activa-
tion of the alcohol as the mesylate and treatment with KH
in DMF results in cyclization to piperidine 31 (88% yield
over two steps), which served as our substrate for photo-
cycloaddition studies.
40
PhNTf in 88% yield over the two steps (Scheme 4). The
2
resulting vinyl triflate is then converted to vinyl nitrile 12
Irradiation of a solution of vinyl arene 31 in C
6
D with
6
in 78% yield by a Pd- and Cu-catalyzed cyanation protocol
254 nm UV light results in the formation of diastereomeric
[2+2]-cycloadducts 32 and 33 (Scheme 5a) via ortho-π-
arene photocycloaddition. Using 310 nm UV light gives a
4
1
using NaCN. Introducing the electron-rich aromatic
group onto the vinyl nitrile is accomplished using a Rh-
catalyzed 1,4-addition reaction developed by the Hayashi
group, providing trans-β-aryl nitrile 25 in 69% yield (78%
1
similar outcome by H NMR analysis. Attempts to isolate
these cycloadducts by silica gel chromatography resulted
in their decomposition to a mixture of hydrolyzed prod-
ucts. However, reconstituting this mixture of 32 and 33 in
methanol with p-TsOH fully converts the bis-enol ether
intermediates to an isomeric mixture of hexacyclic, vinylo-
gous esters 34, 35, and 36 in 12%, 28%, and 8% yields,
4
2
brsm). The ester moiety is selectively reduced to the
primary alcohol with Red-Al, leaving the nitrile intact
(
(
(
77%). The primary hydroxyl is oxidized to aldehyde 26
89%), which is subsequently methylenated to alkene 27
98%). In the presence of acid-labile functionalities such as
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Scheme 7. Wagner‒Meerwein approaches to the
respectively. These cycloadducts were unambiguously
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characterized by single-crystal X-ray crystallography.
Products arising from formation of exciplex 37 and the
desired (3+2) meta-π-arene photocycloaddition pathway
were not observed (e.g., 38). UV irradiation in other non-
polar solvents such as cyclohexane and toluene at room
temperature or 4 ˚C has minimal effect on reactivity, and
the use of methanol as solvent partially facilitates hydroly-
sis of photocycloadducts 32 and 33. The lack of (3+2) reac-
tivity is likely due to the developing strain that is imposed
by tethering the alkene meta to the methoxy-directing
groups, a substitution pattern that has not been demon-
strated to undergo meta-π-arene photocycloaddition. To
help alleviate strain, bicyclic vinyl arenes 27 and 39 (pre-
cursors to alcohol 30) were subjected to 254 nm UV irra-
diation (Scheme 5b). However, reducing strain by not hav-
ing the piperidine ring in place results in no reactivity, like-
ly due to the system being unable to adopt an energetical-
ly-accessible, reactive conformation. Based on similar rea-
soning, a less constrained vinyl arene (40) lacking the
C7‒C17 bond was prepared and irradiated with 254 nm
UV light (Scheme 5c). While reactive, this substrate gives
rise to a complex mixture of products that could not be
easily purified. To test whether the lack of (3+2) reactivity
could be due to a high barrier in forming a strained 6-
membered B-ring, we designed substrate 41 where the
alkene is tethered ortho to the methoxy-group (Scheme
5d). In this case, if a (3+2) photocycloaddition were to oc-
cur through exciplex 42 and diradical 43, a more favorable
5-membered B-ring (highlighted in red) would form. This
hypothesis proved correct, providing (3+2) cycloadduct 44
as the major product in 44% yield. The [2+2] cycloaddition
pathway is also operative to a small extent, affording cy-
clobutene-bearing 47 in 16% yield. This product differs
from the previously observed ortho-photocycloaddition
reactions (cf. Scheme 5a) in that cyclobutene intermediate
[3.2.1]-bicyclic motif (BCD ring system)
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35
4
5 bearing a tertiary methoxy group formed from the ini-
tial photochemical [2+2]-cycloaddition, undergoes sponta-
neous 6π-electrocyclic ring opening to cyclooctatriene 46,
followed by a final photochemical 4π-electrocyclic ring
work involves a [4+2]-cycloaddition between the alkene
and the arene system following oxidative dearomatization
44
closing process to arrive at 47. These products, however,
could not be easily advanced to the target natural prod-
ucts.
(
Scheme 6). The product will contain a bicyclo[2.2.2]-
octane system characteristic of the denudatine-type mole-
cules that will need to be rearranged to give the bicy-
clo[3.2.1] CD-ring system. Since nature employs such an
isomerization in the biosynthesis of numerous diterpenes
A bioinspired Wagner‒Meerwein rearrangement
approach to the BCD ring system. An alternative bicy-
clization disconnection that still retrosynthetically cleaves
the maximally-bridged B-ring of the aconitine-type frame-
by rearranging the diterpene skeleton of denudatine alka-
45‒48
loids to that of the aconite skeleton,
we reasoned that
this approach could offer promising opportunities for de-
veloping a divergent synthesis. In fact, Wagner‒Meerwein-
type rearrangement of a bicyclo[2.2.2]octane to the corre-
sponding bicyclo[3.2.1]octane was first reported in
Scheme 6. Revised retrosynthetic plan
49,50
1949
by Doering et al. and successfully applied to early
51
syntheses of the diterpenoid alkaloids talatisamine and
52
13-desoxydelphonine
by Wiesner and coworkers
(Schemes 7a and 7b). More recently, Fukuyama and
coworkers disclosed an unusual solvolytic rearrangement
of sulfonyloxirane 50, followed by reduction of the result-
ant ketone to alcohol 51 (Scheme 7c). We were particular-
ly interested in implementing a process reported by Xu
53
and Wang in 2012,
in which an oxidative Wag-
ner‒Meerwein-type rearrangement on the
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Scheme 8. Formation of the key hexacyclic intermediate containing [2.2.2]-bicycle
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bicyclo[2.2.2]octene system of 52 furnishes the bicy-
clo[3.2.1] system of 53 with concomitant introduction of a
new oxygen atom (Scheme 7d). The alkene group in 53
also presents additional opportunities for functionaliza-
tion, which we envisioned to be useful for generating di-
versity when planning natural and unnatural product syn-
thesis. We thus targeted hexacycle 54, which exhibits the
denudatine framework, with the intention of rearranging it
to 55, which exhibits the aconitine framework, via an oxi-
dative Wagner‒Meerwein rearrangement (Scheme 7e).
The synthesis of the denudatine framework commences
with the 1,4-arylation of vinyl nitrile 12 using aryl boro-
nate ester 56 to form β-aryl nitrile 57 in 60‒75% yields
the intramolecular [4+2]-cycloaddition to provide the de-
sired hexacycle (63) as a single diastereomer in 77% yield.
Reduction of the ketone carbonyl of 63 occurs exclusively
from the more sterically-encumbered β-face (see the SI),
which is then followed by acid-catalyzed cleavage of the
dimethyl ketal to reveal α-hydroxy ketone 64 in 87% yield.
This secondary hydroxy-group is masked as the MOM-
ether by treatment with NaH and MOMCl, and a NaBH -
4
mediated reduction of the remaining carbonyl group again
occurs exclusively from the β-face, generating α-disposed
alcohol 65 in 87% yield over two steps. Xu and Wang ob-
served a similar β-selective NaBH reduction in their syn-
4
thesis of model substrate 52 (see Scheme 7d); however,
they stated that a rationalization for the observed selectivi-
ty could not be provided. We postulate that the exclusive
approach from the β-face of the molecule arises from a
torsional steering effect: reduction from the seemingly
less-hindered α-face would give rise to an unfavorable
eclipsing interaction in the transition state whereas reduc-
tion from the seemingly more-hindered β-face would lead
directly to an energetically-favorable transition state with
a staggered conformation (Scheme 9).
(
4
Scheme 8). Similar to the sequence illustrated in Scheme
, selective reduction of the methyl ester to its correspond-
ing primary alcohol (81‒87% yields), followed by oxida-
tion (76‒82% yields) and Wittig olefination (85‒95%
yields) provides alkene 58. Subjecting 58 to Rh-catalyzed
nitrile hydration gives the desired primary amide (59) in
70% yield, with the remainder of the mass balance ac-
counted for by unreacted starting material that can be re-
subjected to the same reaction conditions. The primary
amide is effectively converted to its corresponding methyl
carbamate by treatment with PhI(OAc)
the primary alcohol deprotected with TBAF to yield 60 in
6% over the two steps. Mesylation of the alcohol and cy-
clization of the piperidine ring occurs by reacting 60 with
MsCl/Et N and KOt-Bu, respectively, to give tricycle 61 in
3% yield over the two steps. Subsequent cleavage of the
MOM protecting group with HCl and oxidative dearomati-
zation with PhI(OAc) in methanol furnishes dienone 62,
2
in methanol and
Scheme 9. Torsional steering controls NaBH reduction
4
9
3
7
2
the immediate precursor to intramolecular Diels‒Alder
cycloaddition, in 98% yield over two steps. Heating a solu-
tion of 62 in p-xylene to 150 °C in a sealed flask induces
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Scheme 11. Completion of weisaconitine D and confir-
Scheme 10. Wagner‒Meerwein rearrangement and
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
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2
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4
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6
possible mechanisms
mation of chemical structure by X-ray crystallography
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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0
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8
9
0
unambiguous confirmation of its structure and stereo-
chemistry. The alcohol group was alkylated to give epoxy
ether 73 in 78% yield over two steps. A titanium(III)-
mediated epoxide ring opening using water as the hydro-
Activating alcohol 65 with triflic anhydride, and then
heating the newly formed triflate (66) in a mixture of DBU
and DMSO resulted in the formation of allylic alcohol 69 as
the only observable product (Scheme 10). Enone 70, which
was anticipated on the basis of the precedent by Xu and
Wang, was not formed to any appreciable extent. One pos-
sible pathway involves a thermally-induced 1,2-alkyl shift
leading to the formation of tertiary, allylic carbocation 67,
which is trapped by the DMSO solvent, and ultimately af-
fords allylic alcohol 69 through an elimination pathway
58
gen atom source occurs regioselectively, and the hydrox-
yl obtained in this manner was methylated in 66% yield
over two steps with an isomeric ratio of 14:1 (the minor
isomer has the methoxy group at C15, not shown). To in-
troduce the N-ethyl substituent, the carbamate of 74 was
first cleaved by base-mediated hydrolysis, and the un-
veiled piperidine nitrogen acetylated with Ac
2
O and re-
(
Scheme 10a). In contrast, enone 70 would arise through
duced with LiAlH . As discussed later, installing the ethyl
4
an S 2’ addition of DMSO to the less hindered position of
N
group in a more direct fashion would not yield a more effi-
cient synthesis (Scheme 15). A final deprotection with
aqueous HCl cleaved the MOM-protecting group and ac-
complished the first synthesis of weisaconitine D (54%
yield over the last four steps). Derivatizing 2 to p-
nitrobenzoylated 75 allowed us to acquire a single crystal
X-ray structure to support the characterization of the natu-
ral product.
allylic carbocation 67 followed by oxidation of the allylic
hydroxyl. Presumably, the strain imposed by the alkene
group of the enone precludes the formation of 70. Alter-
natively, a dyotropic rearrangement involving simulta-
neous, concerted migration of the alkyl and triflate groups
through the intermediacy of allylic triflate 71, can be in-
voked to explain the observed selectivity for 69 (Scheme
54
55
1
0b).
Synthesis of C19 liljestrandinine.59 All of the C19- and
20-diterpenoid alkaloids contain an additional carbon
atom (C18) at C4 with respect to the C18 natural products
see Figure 1). Using an intermediate (60, Scheme 8) from
Synthesis of C18 weisaconitine D. Allylic alcohol 69,
C
although unanticipated, bears the desired bicyclo[3.2.1]
octene system that can be advanced to weisaconitine D
(
56
(
2). Alcohol 69 also possesses the framework of other C18
the synthesis of weisaconitine D (2), we initially sought to
introduce this one-carbon unit through an enolate alkyla-
tion reaction (Scheme 12a). Thus, alcohol 60 was oxidized
to aldehyde 76 in 95% yield under typical Swern condi-
tions. We expected that exposure of 76 to base and a
and C19 diterpenoid alkaloids such as the lappaconitines,
57
ranaconitines, and aconitines. Epoxidation of 69 yields
epoxy alcohol 72 as a single diastereomer (Scheme 11). X-
ray crystallographic analysis of this intermediate provided
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Scheme 12. α-Alkylation generates only the undesired diastereomer
Page 8 of 16
1
2
3
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5
6
7
8
9
1
1
1
1
1
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0
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5
6
7
8
9
0
methylating agent would effect α-alkylation from the con-
vex face of the bicycle. Treating 76 with excess KOt-Bu
leads to formation of bicyclic enolate 77 with accompany-
ing deprotonation of the methyl carbamate. However, re-
acting this enolate with iodomethane did not result in the
desired alkylation from the convex face to give β-methyl
aldehyde 78, but instead alkylation occurred exclusively
from the concave face of the bicycle to yield α-methyl alde-
hyde 79 in 54% yield. The stereochemistry of α-79 was
confirmed by its conversion to mesylate 80 and acquiring
single crystal X-ray diffraction data. Unfortunately, the
aldehyde of 79 is not correctly disposed for cyclization to
yield the requisite piperidine structure. To gain insight
into the observed alkylation selectivity, we modeled the
intermediate (77) arising from the double deprotonation
of aldehyde 76 by DFT at the B3LYP/6-31+G(d,p) level of
theory (Scheme 12b). In the two views of the minimized
structure, the vinylic proton (shown in blue) protrudes
directly over the reactive p-orbital of the enolate, effective-
ly shielding approach of the methyl electrophile from the
convex face. In contrast, approach of the electrophile from
the concave face is relatively unhindered, providing a ra-
tionale for the exclusive α-selectivity that is observed.
On the basis of this analysis, any type of electrophile
should approach the enolate from the undesired concave
face. Inspired by the precedent of Wiesner, transforming
aldehyde 76 to diol 81 using an aldol-Cannizzaro reac-
plex mixtures of products. In these reactions, the desired
mono-deoxygenated products 82 and 84 were not formed
in significant amounts. We next sought to synthesize bis-
Scheme 13. Alternative attempts at installing the C
methyl group
4
-
60
tion, which we accomplished in 97% yield, obviates the
need for a diastereoselective alkylation (Scheme 13). At-
tempts at selective deoxygenation directly from diol 81
using Morandi’s protocol (Ph
2
SiH
2
/Et
3
SiH and catalytic
61
B(C
6
F
5
)
3
)
or through a more traditional stannane-
6
2
mediated deoxygenation of thiocarbonate 83 gave com-
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for an intramolecular Diels‒Alder reaction. Heating to 150
Scheme 14. Synthesis of C19-diterpenoid alkaloid
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
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5
5
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5
5
5
5
5
6
liljestrandinine
˚C effectively transforms 87 into the Diels‒Alder cycload-
duct, and its ketone carbonyl is reduced stereoselectively
with NaBH to afford hexacyclic alcohol 88 in 60% yield
4
over two steps. The ketal hydrolysis and MOM protection
occurs in 90% yield over two steps. Similar to the protocol
adopted for the synthesis of weisaconitine D (2, Scheme 8),
the ketone group in 89 is stereoselectively reduced to the
corresponding secondary alcohol from the desired β-face,
and the resulting alcohol activated for skeletal rearrange-
ment by triflation. Heating the resultant triflate with DBU
and DMSO affords allylic alcohol 90, which contains the
desired aconitine core, in 62% yield over three steps. A
final four-step sequence involving piperidine deprotection,
N-acetylation, amide reduction, and MOM cleavage was
executed in 57% yield to complete the first synthesis of
liljestrandinine (4).
Synthesis of C20-diterpenoid alkaloids. In developing
syntheses of weisaconitine D (2) and liljestrandinine (4),
we prepared intermediates that possess the denudatine
framework and solvolytically rearranged these scaffolds to
molecules that have the aconitine core structure. We thus
aimed to take advantage of these intermediates to access
denudatine-type natural products. Like liljestrandinine, the
0
1
2
3
4
5
6
7
8
9
0
1
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3
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7
8
9
0
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8
9
0
1
2
3
4
5
6
7
8
9
0
C
20-diterpenoid alkaloids contain a carbon atom at C4, but
in the form of a methyl group (C18, see Figure 1). To install
this carbon, we surmised that a sequence similar to that
used to install the methoxymethyl group of liljestrandinine
(Scheme 14, steps a-f) would be most effective. However,
the low yield (26%) associated with forming the piperidine
ring and transforming the second mesylate needed to be
improved in order for this sequence of reactions to be truly
useful in synthesizing any of the C20-alkaloids.
The formation of the piperidine E-ring was thus reinves-
tigated. In contrast to the mesylation and subsequent KOt-
Bu-mediated cyclization of alcohol 60 (Scheme 8), which
occurs in good yield, the analogous KOt-Bu-mediated cy-
clization of bis-mesylate 85 occurs in a low 30% yield, with
the majority of the mass balance accounted for by free
amine 94, which is isolated in 39% yield (Table 1, entry 1).
A similar cleavage of carbamates using KOt-Bu in THF has
63
been reported in the literature. By switching to KH in
THF, the isolated yield for piperidine 91 increases to 62%.
Under these conditions, exocyclic alkene 92 and oxetane
93 are each produced in 8% yields, while the decar-
bamoylation side product 94 is formed in only trace quan-
tities (LC-MS analysis; entry 2). As a consequence of the
poor solubility of bis-mesylate 85 in THF, elevated tem-
peratures between 50‒60 ˚C are necessary to facilitate
dissolution of the substrate and achieve reactivity. Pre-
sumably, the high temperatures are responsible for some
of the undesired side reactions that were observed. Per-
forming the same reaction with DMF as the solvent at
room temperature results in exclusive formation of de-
sired piperidine 91 in 83% yield (entry 3).
mesylate 85. This was achieved through an optimized
three-step sequence from alcohol 60 in 71% overall yield,
involving Swern oxidation, an aldol-Cannizarro reaction,
and mesylation (Scheme 14). We reasoned that the carba-
mate nucleophile should react selectively with the mesyl-
ate on the same face. Thus, addition of KOt-Bu to 85 results
in displacement of the α-mesylate to form the piperidine
ring and ensuing addition of NaOMe displaces the remain-
ing mesylate to form the methoxymethyl group. However,
these basic conditions also led to undesired cleavage of the
N-carbamoyl group, which was reintroduced by treating
the crude mixture with methyl chloroformate. An acidic
workup procedure ultimately yields tricycle 86 with the
free phenolic group in 26% yield over the three steps (see
Table 1 for an optimization of this process and its applica-
tion to the syntheses of the C20 natural products). Conver-
sion of guaiacol derivative 86 to dienone 87 with hyperva-
lent iodine occurs smoothly in 89% yield and sets the stage
With robust conditions established for installing the pi-
peridine moiety, we next turned our attention to trans-
forming the methylene mesylate group in 91 to a methyl
group (Scheme 15). Attempts to reduce 91 with lithium
triethylborohydride64 and the CuCl
2
∙2H O/Li/catalytic 4,4’-
2
di-t-butylbiphenyl system65 failed, returning only unreact-
ed starting material. The lack of reactivity is presumably
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Table 1. Optimization of E-ring piperidine formation
Page 10 of 16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
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5
5
5
5
6
Entry Conditions
91
92
0%
8%
0%
93
0%
8%
0%
94
39%
trace
0%
0
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2
3
4
5
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7
8
9
0
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9
0
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2
3
4
5
6
7
8
9
0
1
2
3
KOt-Bu (3 equiv), THF, 50 °C
30%
62%
83%
KH (1.6 equiv), THF, 55‒60 °C
KH (1.6 equiv), DMF, rt
Scheme 15. Synthesis of cochlearenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and paniculamine
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Journal of the American Chemical Society
due to the steric congestion at the neopentyl mesylate site.
The desired reduction, however, is accomplished using a
1
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9
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5
5
6
combination of NaI and Zn and holding the reacting mix-
ture at reflux in DME. Successive acidic cleavage of the
MOM protecting group and oxidative dearomatization gen-
erates masked o-benzo-quinone 95 (61% yield over three
steps) which was then heated to 150 ˚C in p-xylene to fur-
nish Diels‒Alder cycloadduct 96 (80‒87% yields). To
complete the C20 denudatine core, a final one-carbon unit
needed to be delivered to the ketone group of 96. We opt-
6
6
ed to use the Corey‒Chaykovsky reagent, which would
provide an epoxide that can be conveniently elaborated to
the target natural products. Contrary to the stereoselectivi-
0
1
2
3
4
5
6
7
8
9
0
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8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Optimized geometries for paniculamine (8) and
its epimer computed at the M06-2X/6-31+G(d,p)/IEFPCM
(
H O) level of theory.
2
ty observed for nucleophilic addition with NaBH
4
(Scheme
9) which we postulate to be governed by torsional steering
respectively, compared to the synthetic material.
The primary hydroxyl (C17 position) of cochlearenine
and results in nucleophilic approach from the β-face, dime-
thylsulfoxonium ylide approaches ketone 96 from the op-
posite, less sterically-demanding α-face to yield epoxide 97
as a single, albeit the undesired, diastereomer in 85%
yield. To obtain the desired epoxide diastereomer that can
be advanced to the C20-targets, 96 was subjected to a Wit-
tig olefination, which after an acidic workup produces
enone 98 in 96% yield. We hypothesized that delivery of
an oxygen atom can occur from the α-face provided a suffi-
ciently large oxidant is used. As postulated, a Weitz-
(6) is veratroylated by exposure to veratroyl chloride and
polymer-supported DMAP to give 7 in 25% yield (34%
brsm). In this case, the acquired spectroscopic data for the
neutral amine bears no resemblance to that reported in the
72
isolation disclosure. An attempt to acidify 7 with anhy-
1
drous HCl in diethyl ether resulted in a species with a H
NMR spectrum that exhibits broad signals differing signifi-
cantly from those reported by Díaz et al. However, titrating
7
with trifluoroacetic acid distinctly converts the neutral
6
7
Scheffer epoxidation with trityl hydroperoxide forges the
desired α-epoxide (99) in 57% yield (64% brsm) as the
sole diastereomer. To cleave the methyl ether and methyl
carbamate, 99 is heated in a mixture of HBr in AcOH under
microwave conditions, and then basified with aqueous
species to its protonated state, 7∙TFA (see SI), the spectro-
scopic data of which is fully consistent with the reported
data. This observation also supports our assignment of
cochlearenine (6).
Finally, paniculamine (8) was prepared as a single dia-
68
NaOH. Ensuing treatment with Ac O and pyridine acety-
2
stereomer in 50% yield by treating 6 with aqueous H
2
O .
2
lates the free amine, and leads to the isolation of elimina-
tion product 100 (~5% yield), fragmentation product 101
1
Because the H NMR data for 8 is only partially reported in
13
the isolation study, and the C NMR data not reported at
(
28% yield), and the desired demethylated products 102
73
all, we used DFT to confirm the identity of our synthetic
and 103 (51% combined yield). LC-MS analyses suggest
that the 1-acetoxy group of 103 is introduced during the
dealkylation step with HBr in AcOH and not during the
1
13
material. The computed H and C spectra for 8 matches
closely our experimental data with CMADs of 0.23 ppm
and 1.5 ppm, respectively. In contrast, larger discrepancies
subsequent acetylation step with Ac
2
O. Epoxide ring-
1
with CMADs of 0.27 ppm for the H NMR data and 2.5 ppm
opening was effected in the presence of KOAc in AcOH,
affording α-hydroxyketone 104. This was followed by hy-
drogenation of the strained alkene using Pd/C and global
13
for the C NMR data were found for N-epi-8 compared to
those of the synthesized compound. Altogether, the results
suggest that the synthesized material is consistent with the
structure of 8. The natural product is also found to be 9.8
kcal/mol lower in energy than its N-epimer, presumably in
large part due to a favorable enthalpic interaction between
the oxygen of the N-oxide and the 1-hydroxy group (Figure
reduction with LiAlH
4
in 63‒77% yield over three steps,
which accomplished the first synthesis of cochlearenine
(6).
We found density functional theory (DFT) to be critical
69
in confirming the structures of the natural products.
2). Thus, the oxidation to form 8 is likely both thermody-
Cochlearenine (6) has been isolated and characterized
namically and kinetically favored, with the 1-hydroxy
group directing oxidation from the back face of the piperi-
dine ring.
Early installation of an N-ethyl substituent. Because
all of the natural products that we have targeted bear an N-
ethyl substituent, the use of the N-carbamate as a protect-
ing group does not provide the most direct approach since
it requires three additional steps (decarbamoylation, acet-
ylation, amide reduction) to transform it into the N-ethyl
group. In addition, hydrolysis of carbamates 74 (Scheme
twice in the literature, albeit with significant discrepancies
7
0,71
between the two sets of data.
The spectroscopic data
obtained by us for synthetic 6 are consistent with those
1
3
reported by Wada et al. apart from one C signal, raising
the concern that the C15-epimer of the natural product
might have formed during the global reduction step
1
13
(
Scheme 15, step l). We thus computed the H and C NMR
data for both cochlearenine (6) and its C15-epimer, and
found that our experimental data closely agree with the
computed data for the natural product with a computed
11, step e) and 90 (Scheme 14, step o) is slow and requires
1
mean absolute deviation (CMAD) of 0.14 ppm for the H
harsh conditions (4 M KOH, 100 ˚C, 60‒120 h). We thus
explored the possibility of introducing the N-ethyl substit-
uent early on. Instead of submitting primary amide 59 to
Hofmann rearrangement conditions in MeOH (Scheme 8),
13
NMR data and 1.5 ppm for the C NMR data (see SI). This
analysis also allowed us to discount the possibility of hav-
ing formed the C15-epimer, which exhibits larger CMADs
1
13
of 0.21 ppm and 2.9 ppm for the H NMR and C NMR data,
performing the reaction in CH CN solvent forms the isocy-
3
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Page 12 of 16
Scheme 16. Studying the feasibility of protecting the E- Surprisingly, the Diels‒Alder reaction of 107 proceeds
1
2
3
4
5
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8
9
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5
5
5
6
ring piperidine with an acetyl group
to yield a mixture of the undesired exo-108 in 35% yield
and the desired endo-108 in 40% yield. This is in stark
contrast to dienones 62 (Scheme 8), 87 (Scheme 14), and
95 (Scheme 16), which all bear carbamate protected piper-
idine structures, and undergo [4+2] cycloadditions with
complete diastereocontrol for the desired endo-
cycloadducts. A possible rationale for this observation is
that the transition state leading to the exo-cycloadduct
experiences substantial repulsive interactions between the
oxygens of the carbamate and the exo-disposed dimethyl
acetal (Figure 3a), an interaction that is absent in the endo
transition state. In the case of the N-acetylated substrate
0
1
2
3
4
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7
8
9
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8
9
0
(
107), its exo-TS, while more sterically-encumbered, can
orient the oxygen atom of the amide away from the dime-
thyl acetal and reduce some of the unfavorable repulsive
interactions (Figure 3b). The endo-TS experiences less of
the unfavorable interactions and is still formed as the ma-
jor product. Regardless, the poor diastereoselectivity ob-
served in this key transformation precluded the use of the
N-acetyl group in the syntheses.
Enantioselective synthesis of endo-Diels‒Alder cy-
cloadduct 13.
To synthesize weisaconitine D (2),
liljestrandinine (4), cochlearenine (6), N-ethyl-1α-
hydroxy-17-veratroyldictyzine (7), and paniculamine (8)
in enantioenriched form, an initial enantioselective
Diels‒Alder cycloaddition to access endo-13 is necessary.
We initially sought to directly combine diene 21 and
dienophile 22 enantioselectively by employing a cationic
ruthenium(II) center coordinated to a chiral, tetradentate
PNNP ligand, (1S,2S)-N,N′-bis[o-(diphenylphosphino)-
74,75
benzylidene]cyclohexane-1,2-diamine,
or a copper(II)
center ligated to a chiral bisoxazoline. When these com-
plexes were applied as catalysts in our system, significant
decomposition of diene 21 and minimal formation of the
desired cycloadduct (13) were observed. The small
anate intermediate that can be trapped with methyl mag-
nesium bromide to form alcohol 104. This material was
advanced to masked ortho-benzoquinone 107, the precur-
sor for the intramolecular Diels‒Alder cycloaddition, using
the same sequence developed for the synthesis of denudat-
ine natural products 6‒8.
Table 2. Exploring reagents for selective imide meth-
anolysis
Entry
1
Reagent
NaOMe
AgOTf
Time (h)
4
R
114/115 c
2:1
no conv.
2.9:1
2.5:1
4.8:1
3.8:1
only 114
no conv.
a
TBS
TBS
TBS
H
TBS
TBS
H
b
2
3
4
5
6
7
8
48
2
b
Cu(OTf)
2
b
Sn(OTf)
Eu(OTf)
2
>48
0.5
0.5
0.5
24
b
3
b
Sm(OTf)
3
b
Ga(OTf)
Yb(OTf)
Bi(OTf)
3
b
3
TBS
H
b
9
a
3
5.5
1:10
b
1
8 equiv NaOMe used, [113] = 0.1 M, 0‒23 ˚C; 10 mol
c
%
Lewis acid used, [113] = 0.1 M, 28 ˚C; ratios deter-
Figure 3. Proposed rationale for selective, intramolecular,
Diels‒Alder cycloaddition.
1
mined by H NMR analysis of the crude reaction mixtures.
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Scheme 17. Development of an enantioselective Diels‒Alder reaction
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
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1
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0
amount of product obtained was of low ee, suggesting in-
adequate binding of the ketoester component of 22 to the
lent Lewis acids were more reactive. Cu(OTf)
2
, Sn(OTf) ,
2
Eu(OTf) , and Sm(OTf) were all capable of transforming
3
3
catalyst. Inspired by the use of β-oxo imides in Cu-
113 to mixtures of products favoring amide 114 over ester
115 in 2.5:1 to 4.8:1 selectivities (entries 3‒6), with
7
6
catalyzed
Mukaiyama‒Michael
additions,
[4+2]-
77
cycloadditions, and Hosomi‒Sakurai reactions, we hy-
pothesized that incorporating the β-oxo imide motif into
our dienophile could enhance binding of the dienophile to
a Lewis-acid catalyst (relative to a β-ketoester) and facili-
tate Diels‒Alder reactivity and selectivity. A scalable syn-
thesis of β-oxo imide containing dienophile 112 was thus
developed starting from vinyl bromide 109 (Scheme 17a).
Lithium-halogen exchange, followed by nucleophilic addi-
tion to ethyl isocyanoformate 110 provides ketal 111 in
62% yield. Ketal hydrolysis using TsOH reveals β-oxo im-
ide 112 in 97% yield. Upon subjecting a mixture of diene
Sn(OTf)
completely favors the formation of 114 and results in de-
protection of the alcohol (entry 7). While Yb(OTf) is unre-
active (entry 8), Bi(OTf) desirably and effectively meth-
2
simultaneously cleaving the silyl group. Ga(OTf)
3
3
3
anolyses the imide at the more hindered carbonyl to yield
ester 115 with complete site selectivity (entry 9). We pos-
tulate that this mode of reactivity may result from coordi-
nation of bismuth to the ketone oxygen and the proximal
“amide carbonyl,” effectively activating it for nucleophilic
substitution. Because this Lewis acid also cleaves the silyl
group, a final step to re-silylate the alcohol group was re-
quired, producing the desired enantioenriched 13 in 63%
yield. This enantioenriched bicycle can be used to access
enantioenriched diterpenoid alkaloids.
21 and dienophile 112 to [Cu-((S,S)-t-Bu-box)](OTf) ca-
2
talysis, enantioselective [4+2]-cycloaddition proceeds to
furnish endo-cycloadduct 113 in 67% yield (>20:1 dr) and
9
2% ee. Related copper catalysts modified with different
BOX-ligands generally resulted in lower yields and ee
CONCLUSION
(
Scheme 17b).
Guided by network analysis, we accomplished a unified
strategy to synthesize natural products belonging to each
of the C18-, C19-, and C20-families of diterpenoid alkaloids.
Specifically, aconitine-type molecules weisaconitine D (2)
and liljestrandinine (4) are synthesized in 30 and 29 steps,
respectively, beginning from the initial Diels‒Alder reac-
tion between diene 21 and dienophile 22. Denudatine-type
To achieve the synthesis of enantioenriched 13, selective
methanolysis of the imide functionality of 113 at the “am-
ide carbonyl” over the “carbamate carbonyl” is necessary.
Methanolysis under standard conditions using NaOMe in
MeOH resulted in a 2:1 mixture of products in favor of the
undesired primary amide (114, Table 2, entry 1). We
turned to Lewis acids with the intention of reversing the
selectivity. AgOTf did not promote methanolysis even after
extended reaction times (entry 2). Oxophilic di- and triva-
cochlearenine
(6),
N-ethyl-1α-hydroxy-17-veratroyl-
dictyzine (7) and paniculamine (8) are synthesized in 25,
26, and 26 steps, respectively, from hydrindenone 13,
ACS Paragon Plus Environment

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which is readily prepared on 30 g scale in a single pass.
Page 14 of 16
S10OD023532. We thank Dr. Kathleen Durkin and Dr. Yinka
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
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2
2
2
2
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4
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5
6
Olatunji-Ojo for assistance with DFT calculations and Dr. An-
tonio DiPasquale and Nicholas Settineri for single crystal X-
ray diffraction studies.
Advanced intermediate 60 is common to the synthesis of
these natural products and is prepared on multigram scale
per run. We have also developed a gram-scale enantiose-
lective approach to 13 that should allow for the prepara-
tion of enantioenriched natural products. In doing so, we
discovered a bismuth-catalyzed methanolysis of imide 113
that exclusively targets the more sterically-encumbered
carbonyl. Motivated by the effectiveness of this network
analysis approach, we have developed a freely accessible
web-based program, that facilitates quick and accurate
application of this concept by anyone in the synthetic
community designing retrosyntheses.
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Department of Chemistry, Pfizer Pharmaceuticals, La Jolla
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ACKNOWLEDGMENT
This project is supported by Award No. R01 GM084906 from
the National Institute of General Medical Sciences. K.G.M.K.
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grateful to the NSF GRFP for graduate fellowships to C.J.M. and
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