Synthesis of bis-strychnos alkaloids (–)-sungucine, (–)-isosungucine, and (–)-strychnogucine B from (–)-strychnine

Article abstract of DOI:10.21577/0103-5053.20180217

It was developed a concise synthetic route resulting in the first syntheses of bis-Strychnos alkaloids (–)-sungucine, (–)-isosungucine, and (–)-strychnogucine B from commercially available (–)-strychnine. Employing a highly convergent synthetic strategy, it was demonstrated that both Strychnos monomers could be efficiently prepared from commercially available (–)-strychnine. The venerable Mannich reaction was enlisted to join the two Strychnos monomers in a biomimetic fashion. Subsequent epimerization and olefin isomerization yielded (–)-strychnogucine B. Functional group manipulation transformed (–)-strychnogucine B into (–)-sungucine and (–)-isosungucine. Computational chemistry was employed to rationalize the regiochemical course of key steps en route to the bis-Strychnos targets.

Full text of DOI:10.21577/0103-5053.20180217

http://dx.doi.org/10.21577/0103-5053.20180217
J. Braz. Chem. Soc., Vol. 30, No. 3, 436-453, 2019
Printed in Brazil - ©2019 Sociedade Brasileira de Química
Account
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and
(–)-Strychnogucine B from (–)-Strychnine
Senzhi Zhao,a Christiana N. Teijaro,a Heng Chen,a Gopal Sirasani,a
Shivaiah Vaddypally,a Owen O’Sullivan,a Michael J. Zdilla,a Graham E. Dobereiner
and Rodrigo B. Andrade *,a
a
aDepartment of Chemistry, Temple University, 19122 Philadelphia-PA, USA
It was developed a concise synthetic route resulting in the first syntheses of bis-Strychnos
alkaloids (–)-sungucine, (–)-isosungucine, and (–)-strychnogucine B from commercially available
(–)-strychnine. Employing a highly convergent synthetic strategy, it was demonstrated that both
Strychnos monomers could be efficiently prepared from commercially available (–)-strychnine.
The venerable Mannich reaction was enlisted to join the two Strychnos monomers in a biomimetic
fashion. Subsequent epimerization and olefin isomerization yielded (–)-strychnogucine B.
Functional group manipulation transformed (–)-strychnogucine B into (–)-sungucine and
(–)-isosungucine. Computational chemistry was employed to rationalize the regiochemical course
of key steps en route to the bis-Strychnos targets.
Keywords: bis-Strychnos alkaloids, biomimetic synthesis, sungucine, Mannich
1. Introduction
alkaloids beginning with natural (–)-strychnine (4), which
was purchased from Sigma-Aldrich for approximately
$2 per gram. Our rationale for this, as opposed to a fully
synthetic route, included the following reasons. First, it was
reported that isostrychnine and strychnine were isolated
from S. icaja along with 1-3.4,5 Moreover, it is reasonable
to hypothesize strychnine is involved in the biosynthesis of
these bis-Strychnos congeners due to structural similarity,
particularly strychnogucine B whose Southern monomer
is a C5-α-substituted strychnine unit! Third, strychnine is
commercially available, inexpensive, and would greatly
expedite any preparation of 1-3 since it represents an
advanced intermediate. Finally, a semi-synthetic approach
from (–)-4 would guarantee an enantiospecific preparation
of the targets, which is a prerequisite for biological
evaluation.
The retrosynthetic analysis of 1-3 is shown in Scheme 1.
We envisioned (–)-sungucine (1) and (–)-isosungucine (2)
could be synthesized from (–)-strychnogucine B (3)
via base-mediated ring-opening and deoxygenation at
the C18 and C18’ positions. For the retrosynthesis of
(–)-3, we disconnected at the C23–C5’ bond, which
could arise from the late-stage biomimetic coupling
of a Northern C23-anionic synthon with a Southern
C5’-cationic synthon. Both synthons would ultimately
be prepared from the putative biosynthetic precursor,
(–)-strychnine (4).
Since the first isolation of the infamous indole alkaloid
strychnine from the African plant Strychnos icaja by
Sandberg et al.,1 many other mono- and dimeric indole
alkaloids have been isolated from the roots of this African
Strychnos species.2-6 Among them, the unsymmetric dimeric
Strychnos alkaloids (–)-sungucine (1),3,4 (–)-isosungucine
(2),4 and (–)-strychnogucine B (3)5 captured our attention
owing to their potential anticancer and antiplasmodial
activities4-9 in addition to structural complexity (Figure 1).
As part of our research program aimed at developing
and applying novel synthetic methods for efficiently
accessing complex indole alkaloids over the past decade,10-20
we recently communicated the first enantiospecific
syntheses of bis-Strychnos alkaloids 1-3.21 Herein, we
provide a full account of our synthetic efforts, from failure
to success, employed in the preparation of these unique
natural products.
2. Results and Discussion
2.1. Synthetic strategy and retrosynthetic analysis
Weproposedasemi-syntheticroutetothesebis-Strychnos
*e-mail: randrade@temple.edu

Vol. 30, No. 3, 2019
Zhao et al.
437
Figure 1. Structures of bis-Strychnos alkaloids (–)-sungucine (1), (–)-isosungucine (2), and (–)-strychnogucine B (3).
Scheme 1. Retrosynthetic analysis of (–)-1, (–)-2 and (–)-3 ultimately arriving at biosynthetic precursor (–)-strychnine (4).
2.2. Synthesis of the Southern fragment
Subjection of these α-amino nitriles to Lewis or Brønsted
acids regenerates the iminium ions, which can subsequently
engage in reactions with suitable nucleophiles. Excellent
examples include Husson and co-workers’27-30 application of
For the synthesis of the Southern fragment, the main
challenge to be addressed was the regioselective synthesis
of the desired iminium ion from (–)-4. Even though
the direct oxidation of amines to iminium ions seems
attractive, most of the reported amine oxidation methods
suffer from limited substrate scope, low functional group
compatibility, high cost and toxicity.22-24 On the other hand,
the Polonovski-Potier reaction is a well-established method
for the preparation of iminium ions via the activation of
tertiary amine N-oxides with trifluoroacetic anhydride
(TFAA).25,26 Furthermore, the in situ-formed iminium ions
are often trapped with cyanide to access the corresponding
α-amino nitriles, which can be isolated and characterized.
3
2-cyano-Δ -piperidines in the synthesis of the corynanthe-
type indole alkaloids and Lounasmaa’s31 synthesis of the
indoloquinolizidine-type indole alkaloids.
To apply the Polonovski-Potier reaction in the synthesis
of the Southern fragment, strychnine N-oxide (5) was first
prepared from the hydrogen peroxide-mediated oxidation
of (–)-strychnine (4). However, subjection of 5 to TFAA
followed by trapping with KCN led to an intractable
mixture of α-amino nitriles regioisomers (Scheme 2).
Activation of the mixture with Lewis acids (e.g.,
AgBF4,27,28,30,32,33 BF3OEt2,31,34 and TiCl4)35 or Brønsted acid

438
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine J. Braz. Chem. Soc.
Scheme 2. The Polonovski-Potier reaction of N-oxide (5) and trapping with KCN.
(i.e., HCl),36 followed by addition of various nucleophiles
(e.g., Grignard reagents, silyl enol ethers, ketone enolates
and amide enolates) yielded no coupling product.
Likewise, all the efforts to directly apply the mixture as the
Southern fragment for the next coupling step with various
nucleophiles generated no satisfactory result.
While exploring the regioselectivity of the Polonovski-
Potier reaction, we carried out the reaction in the
presence of Et3N. However, this led to the formation of
the vinylogous trifluoromethyl amide 6,37,38 the structure
of which was confirmed by single crystal X-ray analysis
(Scheme 3). The formation of 6 presumably arises
via a stepwise process including (i) regioselective
C5–N4 iminium formation; (ii) base-promoted imine-
enamine tautomerism; (iii) nucleophilic attack of TFAA;
and finally, (iv) elimination to furnish vinylogous
trifluoroacetamide 6.
At this juncture, we were aware that the iminium salt
generated from the Polonovski-Potier reaction of 5 with
TFAA might be stable enough to be isolated without
being trapped with KCN. By following Lounasmaa and
Hanhinen31 procedure, the Polonovski-Potier reaction was
carried out with NaHCO3 workup. The crude product was
then subjected to flash column chromatography on basic
Al2O3 with EtOAc and hexanes as mobile phase solvents.
The only isolated product from the reaction mixture was
Scheme 3. The fate of the Polonovski-Potier reaction of N-oxide (5) depending on the base employed.

Vol. 30, No. 3, 2019
Zhao et al.
439
Figure 2. Relative DFT energies for iminium ions I-III.
pseudo-strychnine (7) whose structure was confirmed by
single crystal X-ray analysis (Scheme 3).
Interestingly, when the Polonovski-Potier reaction
of 5 was followed by addition of an aqueous solution of
KOH, a more basic and nucleophilic base, the desired
carbinolamine 8 was isolated in 52% yield as a mixture of
two epimers at C5, together with regioisomeric pseudo-
strychnine (7) in 40% yield (Scheme 3).
To rationalize the regiochemical course of the
Polonovski-Potier reaction, density functional theory
(DFT) analysis (mPW1PW91/cc-pvdz) was employed
to determine relative free energies of the three iminium
cations that may form upon trifluoroacetate elimination
(Figure 2). It seems that the comparison of the relative
calculated energies I-III cannot account for all the
experimental results. For example, the carbinolamine
derived from the lowest-energy iminium III was not
obtained. However, the carbinolamine 7 derived from the
highest-energy iminium II was isolated in 40% yield, as
shown in Scheme 3. Other factors are believed to be at
play to dictate the formation of the iminium ions. We then
conducted further DFT analysis to determine the minimized
structure of parent N-acyloxyammonium ion IV.21 Based on
the minimized structure of IV, C5–Hb bond and N4–Oacyl
bond are closest to be anti-coplanar (i.e., Hb–C5–N4–O
dihedral = 148.3°), the prerequisite for the E2 reaction
pathway. Thus, the formation of 8 may result from the
elimination of IV to I via an E2-like mechanism.21
A natural population analysis (NPA)39 of IV suggests
that since the C7–H has the more positive charge (+0.30252)
than those on C5 and C21, and it is syn-coplanar to the
N‑Oacyl bond, the iminium ion II is likely to be formed via
the elimination of C7–H through an E1-like or E1cb-like
transition state by means of the paired TFA (Figure 3).40,41
Another possibility is that the formation of II could be from
the intramolecular deprotonation of C7–H by the pendant
N-trifluoroacetyl moiety.21
Figure 3. Natural population analysis of IV.
Potier variant, we also conducted experimental studies
to investigate the effect of both acylating agent and
temperature on the regioselective functionalization of
strychnine N-oxide.41 As shown in Table 1, the reactions
with TFAA (entries 1-3) were less sensitive than the ones
withAc2O (entries 4-6) in terms of both percent conversion
and ratios of 8 to 7. These results can be attributed to the
high nucleofugacity of trifluoacetate.41 The highest ratio of
8 to 7 was obtained at 35 °C for 4 h whenAc2O was used as
acylating reagent (entry 6). These results are in line with an
E2 mechanism, whereby the more basic acetate favors the
formation of the desired carbinolamine 8 via the removal
of the anti-periplanar C5–Hb from an N-acyloxyammonium
strychnine intermediate.
With the desired carbinolamine 8 in hand, we were able
to test the feasibility of the Mannich coupling reaction.42
Treatment of 8 with BF3OEt243 followed by addition of
silyl ketene acetal 944 produced the ester 10 in 59% yield
(Scheme 4). Single crystal X-ray analysis of 10 confirmed
the stereochemical course of the Mukaiyama-Mannich
reaction and the regioselectivity of the Polonovski-Potier
reaction of 5.
Later, when we tried to get a better chromatographic
separation of 8 from 7, the crude reaction mixture from the
sequential Polonovski-Potier reaction and KOH trapping
was loaded on a neutral Al2O3 column for the column
chromatography purification. Carbinolamine 7 was quickly
eluted off the column with 50% acetone in ethyl acetate.
However, 8 remained on the column even when eluted
To explore the mechanistic differences between
the classic Polonovski reaction and the more active

440
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine J. Braz. Chem. Soc.
Table 1. Effect of acylating agent and temperature on the formation of 7 and 8
entry
Acylating agenta
TFAA
Temperature / °C
timeb / h
Conversionc / %
7/8d
1
2
3
4
5
6
0
2
2
2
4
4
4
49
58
52
21
41
62
1:1.6
1:1.4
1:1.9
1:1.3
1:2.7
1:3.1
TFAA
23
35
0
TFAA
Ac2O
Ac2O
23
Ac2O
35
aTwo equivalents of the reagent were used with CH2Cl2 as a solvent; biminium ion was trapped with aqueous KOH after 2 or 4 h; cpercent conversion was
calculated by 1H NMR spectroscopy; dratio of 7 to 8 was determined by 1H NMR spectroscopy.
Scheme 4. A model Mukaiyama-Mannich reaction of 8 with silyl ketene acetal 9.
with 100% acetone. Switching acetone to 5% methanol
in dichloromethane resulted in the isolation of a new
compound, whose 1H nuclear magnetic resonance (NMR)
showed the presence of only one single isomer. Similarly,
when 8 was treated with 5% methanol in dichloromethane
in the presence of silica gel, the same single isomer was also
obtained. To rationalize this observation, we hypothesized
that the new product might be formed from the addition
of methanol to the corresponding iminium ion 11, which
was generated in the presence of Al2O3 or silica gel.45 The
quantitative conversion of 8 to N,O-acetal 12 was achieved
when carbinolamine 8 was stirred in 5% methanol in
dichloromethane. The stereochemistry of 12 was confirmed
by single crystal X-ray analysis (Scheme 5).
Scheme 5. Synthesis of N,O-acetal 12 from carbinolamine 8.

Vol. 30, No. 3, 2019
Zhao et al.
441
The stereoselectivity of this conversion can be
attributable to the steric hindrance. Specifically, during
the attack of methanol on iminium ion 11, the presumed
intermediate, methanol would experience more steric
interactions on the β-face of C5–N4 double bond (concave
side) than on the α-face (convex side). The same explanation
is also applicable to the selective formation of ester 10 as a
single diastereomer from the Mukaiyama-Mannich reaction
of 8 with silyl ketene acetal 9. Considering the acidic
proton in carbinolamine 8 may complicate the Mannich
coupling reaction with the Northern fragment, we selected
N,O-acetal 12 as the Southern fragment.
that bases used in the previous protocols might not be just
promoters of the elimination of the ether oxygen but also
perpetrators of the lactam opening. For example, strychnine
was found to be easily converted to strychnic acid (14)
under relatively mild alkaline conditions (e.g., NaOEt at
50 °C).50-52 However, the use of more vigorous conditions
(e.g., aqueous barium hydroxide at 140 °C53 or NaOH in
boiling amyl alcohol)54 led to the formation of isostrychnic
acid (15), as shown in Scheme 7.
In light of these experimental facts, we believed
that a bulky non-nucleophilic base would minimize the
side reactions relating to the lactam ring-opening. The
non-nucleophilic amidine base 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) has been utilized in a variety of base-
mediated transformations including eliminations and alkene
isomerizations.55 Moreover, since only water was used in
Pictet’s synthesis of isostrychnine, it would be interesting to
know what effect DBU would have on the reaction if it was
added to a water suspension of strychnine.46 Some of the
results are presented in Table 2. However, the conversion of
strychnine was very low at 110 or 150 °C, even with up to
10 equivalents of DBU (Table 2, entries 1-2). Replacement
of water with dimethyl sulfoxide (DMSO) did not improve
the conversion. Conversely, another aprotic polar solvent,
dimethylformamide (DMF), allowed for the formation of
isostrychnine (13) in 29% yield after stirring strychnine (4)
with 10 equivalents of DBU at 160 °C for 24 h (Table 2,
entry 5). Further extension of the reaction time or increased
temperature did not benefit the reaction.
2.3. Synthesis of the Northern fragment
Our retrosynthetic plan of (–)-sungucine (1),
(–)-isosungucine (2) and (–)-strychnogucine B (3) included
the Northern fragment as an isostrychnine monomer with
a suitably protected C18 hydroxyl moiety. A survey of the
literature46-48 showed the synthesis of isostrychnine from
strychnine (i.e., degradation studies) had been long known
with selected examples shown in Scheme 6. However, each
protocol had its drawbacks such that in order to reliably
access the Northern fragment on a multigram scale, we
needed to develop a new protocol for converting strychnine
(4) into isostrychnine (13).
Generally, the conversion of strychnine to isostrychnine
consists of two seemingly simple steps.49 The first step is
an acid- or base-mediated elimination of the ether oxygen
at the β-position of the lactam carbonyl group. The
second step involves the isomerization of the conjugated
double bond in the α,β-position into a trisubstituted, non-
conjugated double bond in the β,γ-position.
Owing to the instability of DMF56 or DMSO57 at high
temperatures, we opted for using a more stable, aprotic
polar solvent with a higher boiling point. N-Methyl-
2-pyrrolidinone (NMP) has been known to have advantages
over both DMF and DMSO for nucleophilic displacement
reactions due to its greater stability,58 and its higher boiling
point (202 °C) certainly was advantageous. Moreover, the
In order to develop a new protocol for the preparation
of isostrychnine from strychnine, we realized that a
prudent choice of a base was paramount. It was observed
Scheme 6. Prior art regarding the chemical transformations of strychnine (4).

442
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine J. Braz. Chem. Soc.
Scheme 7. Reported lactam ring-opening of strychnine with different bases.
Table 2. Screening the conditions for the conversion of (–)-4 to (–)-13 with DBU
entry
Solvent
H2Oa
Temperature / °C
DBU / equivalent
Reaction time / h
Yieldb / %
c
1
2
3
4
5
6
7
8
9
110
150
150
160
160
120
120
120
160
3
44
36
16
15
24
24
32
45
24
–
H2Oa
5
–
c
DMSOa
DMFa
DMFa
NMP
NMP
NMP
NMP
10
10
10
10
10
10
10
–
c
25
29
25
28
13
24
aThe reaction was carried out in a sealed tube; bisolated yields; cthe product was not isolated due to low conversion.
formation of its conjugate base would be possible due to
the acidity of its hydrogens (β to the lactam group), which
then could serve as a potential source of base.59,60 Our
preliminary experiments showed the best yield was 28%
when NMP was used as solvent (Table 2, entry 7). We also
found longer reaction times and high temperatures were
detrimental to the reaction (Table 2, entry 8).
Finally, upon treatment of a deaerated NMP solution
of 4 with DBU at 200 °C for 40 min, a mixture of the
expected isostrychnine (13) and 13-epi-isostrychnine (16)
was obtained in a 2:1 ratio in 61% yield (Scheme 8). It
should be noted that the formation of 16 was also observed
in the previous screening, but its characterization was not
complete due to the difficulties with its purification (e.g., its
high polarity and the presence of other polar byproducts).
The plausible reaction pathways of strychnine upon
treatment with DBU are presented in Scheme 9. Anion 17
was assumed to be the product from the deprotonation step,
whether or not the mechanism for the first step is E2 or
E1cb. If 17 is stable enough during the reaction, it would
give rise to the formation of 18. On the other hand, proton
transfer of 17 would produce anion 19, from which all three
alcohols (13, 16 and 18) could be formed.
To explain why only 13 and 13-epi-isostrychnine (16)
were isolated from the three possible products, we turned
to computational analysis using DFT. Calculations were

Vol. 30, No. 3, 2019
Zhao et al.
443
Scheme 8. The synthesis of isostrychnine (–)-13 and 13-epi-isostrychnine (–)-16 from (–)-strychnine (4) with DBU in NMP.
Scheme 9. Plausible reaction pathways for the DBU-mediated conversion of strychnine into regioisomeric alkenes 13 and 16.
performed at the mpw1pw91/cc-pvdz level of theory.
Computational data were consistent with experimental
findings wherein 18 is 7 kcal mol-1 higher in free energy
than 16 and 6.5 kcal mol-1 higher in free energy than 13.
To facilitate the purification of 13 and 16, we treated
the reaction mixture from the DBU-mediated reaction of
strychnine with TBSCl (tert-butyldimethylsilyl chloride)
and imidazole. The resulting products, TBS-protected
isostrychnine (20) and TBS-protected 13-epi-isostrychnine
(21), were isolated in 50 and 26% yields, respectively
(Scheme 10). Thus, we developed a one-pot synthesis
of the Northern fragment 20 from (–)-strychnine 4. With
the synthetic routes to Northern and Southern fragments
established, we turned to the task of joining the two via a
biomimetic Mannich reaction.
2.4. The Mannich coupling reaction of the Northern and
Southern fragments
The Mannich reaction is the preeminent method for
making C–C bonds between nucleophilic Cα–H acidic (i.e.,
carbonyl) compounds and electrophilic imines or iminium
salts.42,61-63 To forge the characteristic C23–C5’bond in bis-
Strychnos alkaloids 1-3, the reaction of the amide enolate
derived from 20 with iminium ion 11 would be desirable.
However, a survey of the literature regarding the reaction

444
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine J. Braz. Chem. Soc.
Scheme 10. One-pot synthesis of Northern fragment 20 from (–)-strychnine 4.
of amide enolates with iminium salts is surprisingly
limited.42 Presumably, the challenges stem not only from
the difficulties with the generation of amide enolates, but
also from the higher basicity of the amide enolates. In
particular, the use of strong bases to generate the amide
enolates might not be compatible with the conditions for
the generation of the iminium ions. Furthermore, the strong
basic conditions could cause other side reactions with the
iminium ions such as isomerization to the corresponding
enamines in the presence of strong bases.31
One way to circumvent such problems would be to
employ the silyl enol derivative of 20, which would then
be used in a separate Mukaiyama-Mannich reaction using
in situ generated iminium ion 11. However, the conversion
of 20 to its silyl enol derivative turned out to be unsuccessful
in our hands (e.g., LHMDS/LiCl followed by trapping with
TMSCl).64,65 Thus, this approach was abandoned.
At this stage, our attention returned to the generation of
the amide enolate of 20.We were encouraged by a literature66
example wherein ketone lithium enolates were reacted with
trimethylorthoformate in the presence of BF3OEt2 to give
the dimethoxymethylated ketone, suggesting this Lewis
acid was compatible with lithium enolates. In addition,
it was found that Grignard reagents were employed for
nucleophilic addition reactions with iminium ions, which
indicated the isomerization of iminium ions to enamines
in the presence of Grignard reagents could be avoided.67,68
Based on this information, we planned to employ
the magnesium amide enolate of 20 for the Mannich
coupling owing to its weaker basicity compared to that
of a Li variant. Moreover, the Lewis acidity of Mg has
been leveraged for the generation of iminium ions from
N,O-acetals.69 The Mg amide enolate in turn could be
obtained from the Li amide enolate via transmetallation
with MgBr2OEt2.70,71 For the generation of iminium ion 11
from the Southern fragment 12, BF3OEt2 was employed
because of its successful reaction with carbinolamine 8
in our model Mukaiyama-Mannich studies (Scheme 4).
Since both 20 and 12 contain several Lewis basic sites, an
excess of BF3OEt2 was employed to ensure the productive
generation of 11.
The reaction results are summarized in Table 3.
Lithiation of 20 with lithium di(isopropyl)amide (LDA)
and subsequent transmetallation with MgBr2OEt2 afforded
the Mg amide enolate, which was added dropwise to a
solution of 12 followed by treatment with BF3OEt2 to
afford Mannich base 22 as a mixture of epimers at C5’.
For each entry in Table 3, the ratio of the epimers was not
determined due to the instability of one epimer, which was
slowly converted to the other isomer during isolation by
silica gel chromatography.
As shown in Table 3, it was interesting to observe
that increasing the equivalents of MgBr2OEt2 had a
negative effect on the reaction yields (Table 3, entries 1-4).
Finally, the highest yield (67%) of 22 was obtained with
1.1 equivalents of LDA with no addition of MgBr2OEt2
(Table 3, entry 6)! We attribute the increase in yield of 22
to the increased nucleophilicity of the Li enolate vis-à-vis
the Mg enolate.
Nevertheless, the first Mannich reaction was
accomplished between a Li amide enolate and N,O-acetal
in the presence of BF3OEt2, and the successful formation
of the key C23–C5’ bond enabled the synthesis of
bis-Strychnos alkaloids 1-3. Next, attention was turned to
the synthesis of (–)-strychnogucine B (3).
2.5. Synthesis of (–)-strychnogucine B (3)
The synthesis of (–)-strychnogucine B (3) from 22
required two steps. The first step was the removal of the
primary TBS ether. To our delight, treatment of 22 with
HFpyridine in tetrahydrofuran (THF) buffered with

Vol. 30, No. 3, 2019
Zhao et al.
445
Table 3. The Mannich reaction to couple Northern fragment 20 with Southern fragment 12 to afford bis-Strychnos intermediate 22a
entry
LDA / equiv.
MgBr2OEt2 / equiv.
BF3OEt2 / equiv.
Temperature / °C
0 to rt
Yieldb / %
1
2
3
4
5
6
2.2
2.2
2.2
2.2
2.2
1.1
3
2
5
5
5
5
9
9
24
36
36
52
0 to rt
1
0 to rt
0.5
0
0 to rt
c
0 to rt
–
0
0 to rt
67
aThe typical reaction conditions are as follows: 19 (1 equiv., 0.2 mmol) in tetrahydrofuran (THF, 2 mL) with in situ generated lithium di(isopropyl)amide
(LDA, 1.2 equiv.) in THF (2 mL), 0 °C, 1 h; then, MgBr2•OEt2, THF (2 mL), 0 °C, 1 h; then, 12 (1.5 equiv.) in THF (2 mL) and BF3•OEt2, 0 °C to room
temperature (rt), 16 h; bisolated yields; cnot determined due to low conversion.
pyridine72-74 not only removed the TBS group but also
effected epimerization at C23 to furnish 23 as a single
isomer, the structure of which was further confirmed by
X-ray analysis (Scheme 11).
The confirmation of the structure of 23 made us believe
that the Mannich reaction of 20 with 12 might be under
kinetic control and the more stable isomer of 22 should
have the same stereochemistry at C23, although it is not
the major isomer. To lend support to this assumption, a
deuterium quench experiment was performed, in which
treatment of 20 with LDA at 0 °C was followed by
quenching with d-MeOD to give a crude product that was
directly used for NMR analysis. The 1H NMR of the crude
product showed only one isomer 20-D, with the deuterium
on the β side of C23, which was considered to be the kinetic
product (Scheme 12).
Regarding the Mannich reaction of 20, it was assumed
that iminium ion 11, generated from N,O-acetal 12, would
attack Li amide enolate 20-Li from the β face to give the
kinetic product 22-1. Since the latter is not the more stable
epimer, it would undergo epimerization at C23 to give the
thermodynamic epimer 22-2 (Scheme 13). As previously
Scheme 11. Deprotection and epimerization of Mannich product 22.

446
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine J. Braz. Chem. Soc.
Scheme 12. Deuterium quenching of the lithium enolate derived from 20.
Scheme 13. Proposed pathway for the Mannich reaction of 20 with 12.
mentioned, the conversion of 22-1 to 22-2 was observed
during the chromatographic purification.
The last step for the synthesis of (–)-strychnogucine B (3)
required the isomerization of the C16–C17 double bond in
23 to conjugation with the lactam carbonyl (i.e., C23‑C17).
To realize this transformation, we drew on a crucial
discovery made by Magnus et al.75 when attempting to
improve the conversion of isostrychnine to strychnine.

Vol. 30, No. 3, 2019
Zhao et al.
447
Specifically, they found that treating isostrychnine (13) with
cesium carbonate in refluxing tert-butyl alcohol isomerized
the olefin into conjugation with the lactam carbonyl,
affording 13-epi-isostrychnine (16) (Scheme 14).75
After inspecting the structure of 23, we were confident
that the isomerization of 23 to strychnogucine B would
take place, because the isomerized double bond not only
is in conjugation with the lactam carbonyl group but is
also trisubstituted one and therefore thermodynamically
more favorable. To our delight, treatment of 23 with
Cs2CO3 in deaerated tert-butanol at 85 °C for 3 h furnished
(–)-strychnogucine B (3) in 70% yield. Spectral data
for 3 (e.g., 1H NMR, 13C NMR and infrared (IR)) were in
complete agreement with those reported in the literature.5
The structure of 3 was further confirmed by X-ray analysis
(Scheme 15).
successful application of this strategy would deliver two
alkene regioisomers with the newly formed C=C double
bond at different positions (i.e., conjugated and non-
conjugated). Both regioisomers were important as bis-
deoxygenation thereof would furnish (–)-sungucine (1)
and (–)-isosungucine (2), respectively. The second step
required deoxygenation site-specifically at C18 (Northern
monomer) and C18’ (Southern monomer).
Given that numerous deoxygenation methods can
be found in the literature,76-89 we were confident this
task could be accomplished. Unfortunately, most
modern deoxygenation conditions (e.g., Pd-catalyzed
reduction with various hydride sources,84 MsCl/LiBEt3H,89
thiocarbonyl diimidazole/Bu3SnH)81 did not work in our
hands. Finally, promising results were obtained when we
conducted model studies of deoxygenation on O-acetyl
isostrychnine (24), which was readily prepared from 13
with standard conditions (Scheme 16).
2.6.Syntheses of (–)-sungucine (1) and (–)-isosungucine (2)
When 24 was subjected to 33% HBr in HOAc, the
corresponding allylic bromide HBr salt 25 was obtained
(Table 4), which was subsequently treated with various
hydride source to afford deoxygenated isostrychnine (26).
Among the hydride sources screened [e.g., LiAlH4, LiBEt3H
(Super-Hydride),89 NaB(OMe)3H, and NaBH3CN],90
Super-Hydride was found to give the best result (Table 4,
entry 2). The success of this protocol was attributed to the
protection of the tertiary amine in 26 as HBr salt, since
With (–)-strychnogucine B (3) in hand, a critical stage
was reached for testing the projected conversion of 3 to
(–)-sungucine (1) and (–)-isosungucine (2). We envisaged
the conversion would be performed in two steps. The first
step required the elimination of the allylic ether oxygen
with concomitant ring-opening of the Southern oxepane
F-ring, which could be accomplished by applying tactics
used in the synthesis of Northern fragment 20. The
Scheme 14. Magnus’s Cs2CO3-mediated isomerization of isostrychnine (13).
Scheme 15. Synthesis of (–)-strychnogucine B (3) using Magnus’s conditions.

448
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine J. Braz. Chem. Soc.
Scheme 16. Synthesis of O-acetyl isostrychnine (24) from isostrychnine (13) as a model substrate for deoxygenation reactions.
Table 4. Deoxygenation of model substrate 24a
entry
Reducing reagent
LAH
Solvent
THF
Temperature / °C
Yieldb (overall) / %
1
2
3
4
–78
–78
70
57
84
36
47
LiBEt3H (Super-Hydride)
NaBH(OMe)3
THF
HMPA
HMPA
NaBH3CN
70
aTypical reaction conditions: 24 (1 equiv., 0.01 mmol) in HOAc (2 mL) with HBr (33% in HOAc, 0.1 mL), 10 °C to room temperature (rt), 24 h; the reaction
mixture was concentrated in vacuo; then, reducing reagent (3 to 8 equiv.) in solvent, 1-2 h; bisolated yields.
other attempts to directly activate the hydroxyl group in
isostrychnine (13) for deoxygenation were not successful.
Having established a reliable deoxygenation method
on a closely related model system, we proceed to apply
those conditions on (–)-strychnogucine B (3) to access
(–)-sungucine (1) and (–)-isosungucine (2). First, subjection
of 3 to the conditions employed for the synthesis of Northern
fragment 20 (i.e., DBU, NMP, reflux) afforded two diols as
a mixture of regioisomeric alkenes. Subsequent acetylation
thereof with Ac2O yielded a mixture of bis-acetates 27-1
and 27-2 in a 1:2 ratio in 63-70% overall yield (Scheme 17).
Significantly, we required the bis-acetates as substrates for
our two-step deoxygenation protocol (vide supra).
With bis-acetates 27-1 and 27-2 in hand, we subjected
the mixture to 33% HBr in HOAc to generate the
corresponding allylic bromides (as HBr salts). After
considerable optimization, we discovered that NaBH3CN
as hydride source in DMF at room temperature (rt) for
24 h delivered (–)-sungucine (1) and (–)-isosungucine (2)
as a separable 1:2 mixture, respectively, in 40-50% overall
yield (Scheme 18). Curiously, Super-Hydride was inferior
to NaBH3CN in the deoxygenation of bis-acetates 27-1
Scheme 17. Synthesis of bis-acetates from (–)-strychnogucine B (3).

Vol. 30, No. 3, 2019
Zhao et al.
449
Scheme 18. Syntheses of (–)-sungucine (1) and (–)-isosungucine (2).
and 27-2, further illustrating the limitations associated
was performed on 60 F254 silica gel plates. Detection was
performed using UV light, KMnO4 stain, phosphomolybdic
acid (PMA) stain and subsequent heating. Infrared
spectra were measured on a Fourier transform infrared
with model studies in natural product total synthesis.
1
Spectral data for 1 and 2 (e.g., H NMR, 13C NMR and
IR) were in complete agreement with those reported in
the literature.4,5,91
1
spectrometer (FTIR). H and 13C NMR spectra were
recorded on a 500 MHz instrument in CDCl3 at 298 K.
Chemical shifts are indicated in parts per million (ppm) and
internally referenced to residual solvent signals. Splitting
patterns are abbreviated as follows: s (singlet), d (doublet),
bs (broad singlet), bd (broad doublet), t (triplet), q (quartet)
and m (multiplet). High-resolution mass spectra (HRMS)
were obtained on a time-of-flight (TOF) mass spectrometer
using an electrospray ionization (ESI) source.
3. Conclusions
In summary, the first syntheses of bis-Strychnos
alkaloids (–)-strychnogucine B, (–)-sungucine and
(–)-isosungucine have been successfully accomplished from
inexpensive and commercially available (–)-strychnine.
Key steps in the syntheses include the following: (i) a
DBU-mediated conversion of strychnine into isostrychnine;
(ii) a Polonovski-Potier reaction of strychnine N-oxide
for regioselective Southern fragment activation; (iii) a
stereoselective BF3OEt2-mediated Mannich reaction
for the coupling of Northern and Southern fragments;
(iv) a Cs2CO3-mediated olefin isomerization reaction; and
(v) a NaBH3CN-mediated reduction of allylic bromide
intermediates to install the requisite ethylidene moieties
in the bis-Strychnos targets.
(–)-(4aR,4a1R,5aS,8aS,8a1S,15aS)-8-(2,2,2-Trifluoroacetyl)-
2,4a,4a1,5,5a,8a1,15,15a-octahydro-14H-4,6-methano-
indolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one
(6)
To a stirred clear solution of strychnine N-oxide 5
(50 mg, 0.143 mmol), KCN (47 mg, 0.72 mmol) and
Et3N (0.12 mL, 0.86 mmol) in CH2Cl2 (2 mL) was added
TFAA (0.1 mL, 0.71 mmol) at 0 °C. The resulting mixture
was allowed to warm to rt and stirred overnight. The
reaction was quenched with addition of saturated aqueous
NaHCO3 (5 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (1 × 10 mL). The
combined organic layers were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography eluting with 30%
EtOAc in CH2Cl2 to afford 32 mg (52%) of vinylogous
4. Experimental
All reactions containing moisture- or air-sensitive
reagents were performed in oven-dried glassware under
nitrogen or argon. Tetrahydrofuran, diethyl ether and
dichloromethane were passed through two columns of
neutral alumina prior to use. All other reagents were
purchased from commercial sources and used without
further purification. All solvents for work-up procedures
were used as received. Flash column chromatography
was performed according to the procedure of Still et al.92
using 60 Å silica gel with the indicated solvents. For all
ring-closing metathesis reactions, CH2Cl2 was deaerated by
bubbling argon (1 min mL-1). Thin layer chromatography
trifluoromethyl amide 6 as a pale yellow foam.
–691.8
(c 2.1, CHCl3); IR (neat) ν / cm-1 2980, 2883, 1645, 1545,
1480, 1393, 1286, 1160, 1136, 969, 918, 754, 720; 1H NMR
(500 MHz, CDCl3) d 8.13 (d, J 7.9 Hz, 1H), 7.31-7.22 (m,
2H), 7.22 (s, 1H), 5.95 (m, 1H), 4.53 (s, 1H), 4.25 (dt,
J 8.5, 3.2 Hz, 1H), 4.18 (dd, J 13.9, 7.1 Hz, 1H), 4.09 (dd,
J 14.1, 1.2 Hz, 1H), 4.05-4.00 (m, 2H), 3.58 (d, J 14.1 Hz,

450
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine J. Braz. Chem. Soc.
1H), 3.23 (s, 1H), 3.10 (dd, J 17.3, 8.5 Hz, 1H), 2.61 (dd,
J 17.2, 3.2 Hz, 1H), 2.52 (dt, J 14.8, 4.3 Hz, 1H), 1.66 (d,
J 14.7 Hz, 1H), 1.38 (dt, J 10.3, 3.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 173.0 (q, J 34.4 Hz), 167.3, 155.7 (q,
J 4.5 Hz), 144.3, 140.8, 129.3, 128.6, 126.9, 123.7, 123.6,
122.4, 116.7 (q, J 290 Hz), 116.3, 77.4, 64.6, 63.9, 62.3,
58.6, 51.0, 50.9, 42.6, 31.5, 26.1; HRMS (ESI) calcd. for
C23H19F3N2O3 + H = 429.1426, found 429.1416.
200 °C for 40 min under inert atmosphere. The resultant
reaction mixture was cooled to rt and purified by flash
column chromatography eluting with MeOH/DCM
(1:100 to 20:100) to afford 0.8 g (40%) of 13 as a white
foam.
–22.2 (c 0.98, CHCl3); IR (neat) ν / cm-1
3383, 2931, 1653, 1595, 1483, 1397, 1150, 1076, 1013,
1
919, 757, 731; H NMR (500 MHz, CDCl3) d 8.15 (d,
J 8.0 Hz, 1H), 7.26-7.23 (m, 1H), 7.21-7.18 (m, 1H),
7.09 (td, J 7.5, 1.0 Hz, 1H), 5.87-5.84 (m, 1H), 5.59 (t,
J 6.5 Hz, 1H), 4.31-4.24 (m, 3H), 3.68-3.66 (m, 1H),
3.61-3.58 (m, 2H), 3.21 (ddd, J 11.1, 7.8, 5.3 Hz, 1H),
3.12 (dd, J 17.4, 6.7 Hz, 1H), 3.05-2.98 (m, 1H), 2.94
(d, J 14.4 Hz, 1H), 2.89 (dt, J 11.1, 7.1 Hz, 1H), 2.28
(dt, J 13.1, 7.7 Hz, 1H), 2.21 (dd, J 13.1, 6.1 Hz, 1H),
2.18-2.12 (m, 1H), 1.47 (dt, J 14.0, 2.3 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 168.5, 142.1, 141.3, 137.5, 134.5,
128.4, 126.7, 124.2, 122.5, 120.5, 114.6, 67.2, 63.3, 58.1,
53.9, 52.8, 52.2, 46.1, 36.8, 34.6, 25.7; HRMS (ESI) calcd.
for C21H22N2O2 + H = 335.176, found 335.1768.
(–)-Methyl 2-((4aR,4a1R,5aS,7R,8aR,8a1S,15aS)-
14-oxo-2,4a,4a1,5,5a,7,8,8a1,15,15a-decahydro-
14H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]
pyrrolo[2,3-h]quinolin-7-yl)acetate (10)
To a stirred clear solution of secondary amino alcohols
8 (44 mg, 0.126 mmol), and ketene silyl acetal (55 mg,
0.378 mmol) in THF (4 mL) was added BF3OEt2 (62 µL,
0.5 mmol) at 0 °C. The resulting mixture was allowed to
warm to rt and stirred overnight. The reaction was quenched
with addition of MeOH (1 mL) and saturated aqueous
NaHCO3 (5 mL). The resulting mixture was diluted with
CH2Cl2 (5 mL) and H2O (1 mL). The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
(1 × 10 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography
eluting with 50% acetone in EtOAc to afford 30 mg (59%)
(–)-(3aS,5R,5aS,5a1S,13bR,E)-14-(2-Hydroxyethylidene)-
1,2,3a,4,5a,5a1-hexahydro-5H,8H-3,5-ethanopyrido
[1,2,3-lm]pyrrolo[2,3-d]carbazol-8-one (16)
The same procedure was followed as the one for the
synthesis of isostrychnine (13). The residue was purified
by flash column chromatography eluting with MeOH/
DCM (1:100 to 20:100) to afford 0.42 g (21%) of 16 as a
of ester 10 as a white foam.
–50.2 (c 1.3, CHCl3); IR
(neat) ν / cm-1 2981, 2883, 1733, 1596, 1479, 1458, 1389,
1169, 1049, 958, 758; 1H NMR (500 MHz, CDCl3) d 8.07
(d, J 7.9 Hz, 1H), 7.26-7.22 (m, 1H), 7.16 (d, J 6.8 Hz,
1H), 7.08 (td, J 7.4, 0.9 Hz, 1H), 5.92 (m, 1H), 4.28 (dt,
J 8.4, 3.3 Hz, 1H), 4.14 (dd, J 13.8, 6.9 Hz, 1H), 4.07-4.01
(m, 2H), 3.93 (d, J 10.5 Hz, 1H), 3.67 (s, 3H), 3.64 (d,
J 15.0 Hz, 1H), 3.43-3.35 (m, 1H), 3.17-3.07 (m, 2H), 2.77
(d, J 15.0 Hz, 1H), 2.67 (dd, J 17.4, 3.3 Hz, 1H), 2.64-2.60
(m, 1H), 2.46 (dd, J 14.9, 7.6 Hz, 1H), 2.33 (dt, J 14.4,
4.3 Hz, 1H), 2.16 (dd, J 12.7, 5.7 Hz, 1H), 1.67 (dd, J 12.7,
11.5 Hz, 1H), 1.43 (d, J 14.4 Hz, 1H), 1.27-1.24 (m, 1H);
13C NMR (125 MHz, CDCl3) d 172.1, 169.3, 142.1, 140.5,
132.2, 128.6, 127.3, 124.2, 122.2, 116.2, 77.4, 64.5, 60.6,
60.3, 58.3, 52.2, 51.6, 51.1, 49.3, 47.8, 42.4, 40.5, 31.4,
26.9; HRMS (ESI) calcd. for C24H26N2O4 + H = 407.1971,
found 407.1973.
white foam.
–317.8 (c 0.9, CHCl3); IR (neat) ν / cm-1
3383, 2981, 2884, 1664, 1591, 1481, 1424, 1146, 1075,
1
1010, 812, 756; H NMR (500 MHz, CDCl3) d 8.24 (d,
J 8.0 Hz, 1H), 7.29-7.22 (m, 2H), 7.12 (td, J 7.5, 1.0 Hz,
1H), 6.79 (dd, J 9.8, 6.5 Hz, 1H), 6.01 (dd, J 9.8, 1.0 Hz,
1H), 5.52 (t, J 6.5 Hz, 1H), 4.26 (d, J 6.5 Hz, 1H), 4.20
(dd, J 6.5, 2.5 Hz, 2H), 3.63 (d, J 15.3 Hz, 1H), 3.30 (d,
J 15.3 Hz, 1H), 3.27-3.20 (m, 2H), 3.06 (ddd, J 10.5, 8.1,
6.4 Hz, 1H), 2.74 (m, 1H), 2.63-2.59 (m, 1H), 2.58-2.52 (m,
1H), 2.15 (dt, J 13.3, 5.9 Hz, 1H), 1.87-1.83 (m, 1H), 1.75
(ddd, J 14.3, 4.7, 2.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 161.6, 144.3, 142.4, 141.3, 135.4, 128.4, 124.5, 123.7,
123.3, 122.3, 116.4, 65.2, 64.4, 57.9, 53.9, 52.5, 51.9, 38.1,
37.0, 31.4, 23.2; HRMS (ESI) calcd. for C21H22N2O2 + Na
= 357.1579, found 357.1571.
(–)-(3aS,5S,5a1S,7R,13bR,E)-14-(2-((tert-Butyl-
dimethylsilyl)oxy)ethylidene)-1,2,3a,4,5a1,7-hexahydro-
5H,8H-3,5-ethanopyrido[1,2,3-lm]pyrrolo[2,3-d]carbazol-
8-one-7-d (20-D)
(–)-(3aS,5S,5a1S,13bR,E)-14-(2-Hydroxyethylidene)-
1,2,3a,4,5a1,7-hexahydro-5H,8H-3,5-ethanopyrido
[1,2,3-lm]pyrrolo[2,3-d]carbazol-8-one (13)
A stirred suspension of (–)-strychnine 4 (2.0 g,
5.98 mmol) and DBU (8.9 mL, 60 mmol) in N-methyl-
2-pyrrolidone (40 mL) was deaerated by bubbling argon
(1 min mL-1) for 1 h. The reaction mixture was stirred at
To a stirred solution of (i-Pr)2NH (7.5 µL, 0.054 mmol)
in THF(1 mL) was added n-BuLi (2.35 M solution in
hexanes, 20.9 µL, 0.049 mmol) at 0 °C. The mixture
was stirred at 0 °C for 30 min, followed by addition of a

Vol. 30, No. 3, 2019
Zhao et al.
451
solution of Northern fragment 20 (20 mg, 0.045 mmol)
in THF (1 mL). The mixture was stirred at 0 °C for 1 h
and the reaction was quenched by addition of MeOD
(0.5 mL). The resulting mixture was extracted with EtOAc
(2 × 5 mL) and the combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced
pressure to give 19 mg (95%) of 20-D as a gray foam.
–21.4 (c 1.0, CHCl3); IR (neat) ν / cm-1 2954, 2924,
(–)-(3aS,5S,5a1S,13bR,E)-14-Ethylidene-1,2,3a,4,5a1,7-
hexahydro-5H,8H-3,5-ethanopyrido[1,2,3-lm]pyrrolo[2,3-d]
carbazol-8-one (26)
To a stirred solution of 24 (35 mg, 0.093 mmol) in
HOAc (2 mL) was added HBr (33% in HOAc, 0.1 mL)
at 10 °C. The cooling bath was removed and the reaction
mixture was stirred at rt for 24 h. The solvent was then
removed under reduced pressure. The crude residue was
dissolved in THF (3 mL) and cooled to –78 °C. A solution
of lithium triethylborohydride (1 M in THF, 0.744 mL,
0.744 mmol) was added dropwise, and the reaction mixture
was stirred at –78 °C for 1 h. The reaction was quenched
by addition of water (2 mL) at –78 °C. The resulting
mixture was diluted with EtOAc (10 mL) and washed
with brine (5 mL). The organic layer was separated, dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was first purified by flash
column chromatography eluting with MeOH/CH2Cl2
(5:100 to 10:100) to afford 25 mg (84%) of 26 as a white
2885, 2855, 1671, 1483, 1461, 1393, 1254, 1105, 1063,
1
836, 777, 754; H NMR (500 MHz, CDCl3) d 8.14 (d,
J 7.9 Hz, 1H), 7.25-7.18 (m, 2H), 7.08 (td, J 7.5, 0.8 Hz,
1H), 5.80-5.78 (m, 1H), 5.50 (t, J 5.5 Hz, 1H), 4.30-4.23
(m, 3H), 3.71 (s, 1H), 3.61 (d, J 14.4 Hz, 1H), 3.50 (s, 1H),
3.24-3.18 (m, 1H), 3.10-3.07 (m, 1H), 2.92 (d, J 14.4 Hz,
1H), 2.89-2.85 (m, 1H), 2.29-2.23 (m, 1H), 2.18-2.11
(m, 2H), 1.44 (d, J 14.1 Hz, 1H), 0.90 (s, 9H), 0.07 (s,
6H); 13C NMR (125 MHz, CDCl3) d 168.4, 142.0, 141.4,
135.5, 134.5, 128.3, 127.9, 124.1, 122.5, 120.2, 114.6,
66.9, 63.0, 59.1, 53.7, 52.6, 52.3, 45.9, 36.5 (t, J 18 Hz),
34.8, 25.9, 25.4, 18.3, –5.1, –5.2; HRMS (ESI) calcd. for
C27H35DN2O2Si + Na = 472.2507, found 472.2516.
foam.
–41.0 (c 1.1, CHCl3); IR (neat) ν / cm-1 2924,
2851, 1666, 1595, 1482, 1392, 1313, 1284, 1149, 1106,
1080, 932, 754, 733; 1H NMR (500 MHz, CDCl3) d 8.16
(d, J 8.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.21-7.18 (m, 1H),
7.09 (td, J 7.5, 1.0 Hz, 1H), 5.85-5.82 (m, 1H), 5.47-5.42
(m, 1H), 4.29-4.25 (m, 1H), 3.67 (m, 1H), 3.57-3.54 (m,
2H), 3.18 (ddd, J 11.1, 7.8, 5.3 Hz, 1H), 3.11 (dd, J 17.3,
6.6 Hz, 1H), 3.06-2.99 (m, 1H), 2.90-2.84 (m, 2H), 2.26
(dt, J 13.4, 7.7 Hz, 1H), 2.21-2.17 (m, 1H), 2.16-2.11 (m,
1H), 1.68 (d, J 6.9 Hz, 3H), 1.46 (dt, J 13.9, 2.3 Hz, 1H);
13C NMR (125 MHz, CDCl3) d 168.7, 142.1, 141.4, 135.5,
135.0, 128.2, 124.0, 122.5, 121.2, 120.0, 114.5, 67.4, 63.6,
54.2, 52.8, 52.3, 46.3, 36.8, 34.3, 25.8, 12.8; HRMS (ESI)
calcd. for C21H22N2O + H = 319.181, found 319.1821.
(–)-(E)-2-((3aS,5S,5a1S,13bR)-8-Oxo-1,2,3a,4,5a1,7-hexa-
hydro-5H,8H-3,5-ethanopyrido[1,2,3-lm]pyrrolo[2,3-d]
carbazol-14-ylidene)ethyl acetate (24)
To a stirred suspension of (–)-isostrychnine (13)
(100 mg, 0.3 mmol) and 4-dimethylaminopyridine
(18.3 mg, 0.15 mmol) in CH2Cl2 (5 mL) was added Ac2O
(66 µL, 0.66 mmol) at rt. The resulting mixture was stirred
at rt overnight. The reaction was quenched by addition of
saturated aqueous NH4Cl (5 mL). The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
(2 × 10 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography
eluting with acetone/EtOAc (50 to 70%) to afford 86 mg
Supplementary Information
(76%) of 24 as a white foam.
–10.0 (c 1.15, CHCl3);
Supplementary information (1H and 13C NMR spectra
for 6, 10, 13, 16, 20-D, 24 and 26) is available free of charge
at http://jbcs.sbq.org.br as PDF file.
Crystallographic data, including instructions file, atomic
coordinates, and intensity data of 6 and 10 are available for
download in CIF format at http://jbcs.sbq.org.br.
IR (neat) ν / cm-1 2937, 1733, 1667, 1596, 1483, 1461,
1394, 1232, 1150, 1023, 757; 1H NMR (500 MHz, CDCl3)
d 8.14 (d, J 7.8 Hz, 1H), 7.25-7.21 (m, 1H), 7.20-7.17 (m,
1H), 7.08 (td, J 7.5, 1.0 Hz, 1H), 5.89-5.87 (m, 1H), 5.50
(t, J 6.4 Hz, 1H), 4.74-4.62 (m, 2H), 4.29-4.24 (m, 1H),
3.66 (m, 1H), 3.58 (d, J 14.6 Hz, 2H), 3.19 (ddd, J 11.1,
7.8, 5.3 Hz, 1H), 3.12 (dd, J 17.4, 6.7 Hz, 1H), 3.05-2.97
(m, 1H), 2.93 (d, J 14.6 Hz, 1H), 2.87 (dt, J 11.1, 7.1 Hz,
1H), 2.29-2.23 (m, 1H), 2.22-2.12 (m, 2H), 2.06 (s, 3H),
1.47 (dt, J 14.0, 2.3 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 170.8, 168.4, 141.9, 141.4, 140.7, 134.6, 128.3, 124.1,
122.4, 120.9, 120.8, 114.6, 67.2, 63.3, 59.8, 53.9, 52.9,
52.3, 46.2, 36.9, 34.8, 25.7, 20.9; HRMS (ESI) calcd. for
C23H24N2O3 + H = 377.1865, found 377.1863.
Acknowledgments
This research was supported by the National
Science Foundation (CHE-1111558, CHE-1362461,
CHE-1665145, CNS-09-58854, DEG-12262 awarded
to C. N. T.). Support for the NMR facility at Temple
University by a CURE grant from the Pennsylvania
Department of Health is gratefully acknowledged. We

452
Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine J. Braz. Chem. Soc.
thank Prof Michel Frédérich (Université de Liége) for
kindly providing natural samples of (–)-1-3. We thank
Prof Scott Bur (Gustavus Adolphus College), Prof David
Dalton (Temple University), and Prof Jeffrey Winkler
(University of Pennsylvania) for helpful discussions.
Synthesis, vol. 9; Michael, H., ed.; Academic Press: London,
2013, p. 1.
14. Zhao, S.; Andrade, R. B.; J. Am. Chem. Soc. 2013, 135, 13334.
15. Zhao, S.; Sirasani, G.; Vaddypally, S.; Zdilla, M. J.; Andrade,
R. B.; Angew. Chem., Int. Ed. 2013, 52, 8309.
16. Teijaro, C. N.; Munagala, S.; Zhao, S.; Sirasani, G.; Kokkonda,
P.; Malofeeva, E.V.; Hopper-Borge, E.;Andrade, R. B.; J. Med.
Chem. 2014, 57, 10383.
Rodrigo B. Andrade was born
in Rio de Janeiro, Brazil and
received his primary and secondary
education in the United States. He
17. Teijaro, C. N.; Zhao, S.; Kokkonda, P.;Andrade, R. B.; Synthesis
2015, 47, 1547.
obtained a BA degree in Biophysics
in 1996 from the Johns Hopkins
University. In 2001, he obtained his
18. Kokkonda, P.; Brown, K. R.; Seguin, T. J.; Wheeler, S. E.;
Vaddypally, S.; Zdilla, M. J.; Andrade, R. B.; Angew. Chem.,
Int. Ed. 2015, 54, 12632.
PhD in organic chemistry from MIT
with Prof Peter Seeberger. He was
19. Zhao, S.; Sirasani, G.; Vaddypally, S.; Zdilla, M. J.; Andrade,
R. B.; Tetrahedron 2016, 72, 6107.
an NIH Postdoctoral Fellow with Prof Stephen Martin at
UT-Austin from 2003-2006. In August 2006, he began his
independent research career at Temple University in the
Department of Chemistry and was promoted to Associate
Professor in 2012. His research interests include natural
products synthesis and methods development.
20. Zhao, S.; Andrade, R. B.; J. Org. Chem. 2017, 82, 521.
21. Zhao, S.; Teijaro, C. N.; Chen, H.; Sirasani, G.;Vaddypally, S.;
Zdilla, M. J.; Dobereiner, G. E.; Andrade, R. B.; Chem. - Eur.
J. 2016, 22, 11593.
22. Murahashi, S.-I.; Angew. Chem., Int. Ed. 1995, 34, 2443.
23. Murahashi, S.-I.; Zhang, D.; Chem. Soc. Rev. 2008, 37, 1490.
24. Schümperli, M. T.; Hammond, C.; Hermans, I.; ACS Catal.
2012, 2, 1108.
References
25. Polonovski, M.; Polonovski, M.; Bull. Soc. Chim. Fr. 1727, 41,
1190.
1. Sandberg, F.; Roos, K.; Ryrberg, K. J.; Kristiansson, K.;
Tetrahedron Lett. 1968, 9, 6217.
26. Ahond, A.; Cave, A.; Kan-Fan, C.; Husson, H. P.; De Rostolan,
J.; Potier, P.; J. Am. Chem. Soc. 1968, 90, 5622.
27. Grierson, D. S.; Harris, M.; Husson, H. P.; J. Am. Chem. Soc.
1980, 102, 1064.
2. Kambu, K.; Coune, C.;Angenot, L.; Planta Med. 1979, 37, 161.
3. Lamotte, J.; Dupont, L.; Dideberg, O.; Kambu, K.; Angenot,
L.; Tetrahedron Lett. 1979, 20, 4227.
28. Grierson, D. S.; Vuilhorgne, M.; Lemoine, G.; Husson, H. P.;
J. Org. Chem. 1982, 47, 4439.
4. Frédérich, M.; De Pauw, M.-C.; Llabrès, G.; Tits, M.; Hayette,
M.-P.; Brandt, V.; Penelle, J.; De Mol, P.; Angenot, L.; Planta
Med. 2000, 66, 262.
29. Guibe, F.; Grierson, D. S.; Husson, H.-P.; Tetrahedron Lett.
1982, 23, 5055.
5. Frédérich, M.; De Pauw, M.-C.; Prosperi, C.; Tits, M.; Brandt,
V.; Penelle, J.; Hayette, M.-P.; De Mol, P.; Angenot, L.; J. Nat.
Prod. 2001, 64, 12.
30. Grierson, D. S.; Harris, M.; Husson, H.-P.; Tetrahedron 1983,
39, 3683.
31. Koskinen,A.; Lounasmaa, M.; J. Chem. Soc., Chem. Commun.
1983, 821; Koskinen, A.; Lounasmaa, M.; Tetrahedron Lett.
1983, 24, 1951; Jokela, R.; Karvinen, E.; Tolvanen, A.;
Lounasmaa, M.; Tetrahedron 1988, 44, 2367; Lounasmaa,
M.; Jokela, R.; Tirkkonen, B.; Tamminen, T.; Tetrahedron
1989, 45, 7615; Lounasmaa, M.; Karvinen, E.; Tetrahedron
1991, 47, 6371; Lounasmaa, M.; Hanhinen, P.; Tetrahedron
1996, 52, 15225; Hanhinen, P.; Putkonen, I.; Lounasmaa, M.;
Heterocycles 1999, 51, 1827.
6. Frederich, M.; Tits, M.;Angenot, L.; Chem. Nat. Compd. 2003,
39, 513.
7. Lansiaux, A.; Bailly, C.; Houssier, C.; Colson, P.; De Pauw-
Gillet, M. C.; Frédérich, M.; Tits, M.;Angenot, L.; Planta Med.
2002, 68, 591.
8. Frédérich, M.; Jacquier, M. J.; Thepenier, P.; De Mol, P.; Tits,
M.; Philippe, G.; Delaude, C.;Angenot, L.; Zeches-Hanrot, M.;
J. Nat. Prod. 2002, 65, 1381.
9. Frederich, M.; Bentires-Ali, M.; Tits, M.;Angenot, L.; Heinen,
E.; De Pauw-Gillet, M. C.; Naunyn-Schmiedeberg’s Arch.
Pharmacol. 2003, 367, 260.
32. Lounasmaa, M.; Miettinen, J.; Hanhinen, P.; Jokela, R.;
Tetrahedron Lett. 1997, 38, 1455.
33. Agami, C.; Couty, F.; Evano, G.; Org. Lett. 2000, 2, 2085.
34. Deiters, A.; Chen, K.; Eary, C. T.; Martin, S. F.; J. Am. Chem.
Soc. 2003, 125, 4541.
10. Sirasani, G.; Andrade, R. B.; Org. Lett. 2009, 11, 2085.
11. Sirasani, G.; Paul, T.; Dougherty, W.; Kassel, S.; Andrade, R.
B.; J. Org. Chem. 2010, 75, 3529.
35. Passarella, D.; Martinelli, M.; Llor, N.; Amat, M.; Bosch, J.;
Tetrahedron 1999, 55, 14995.
12. Sirasani, G.; Andrade, R. B.; Org. Lett. 2011, 13, 4736.
13. Sirasani, G.;Andrade, R. B. In Strategies and Tactics in Organic

Vol. 30, No. 3, 2019
Zhao et al.
453
36. Bonjoch, J.; Casamitjana, N.; Bosch, J.; Tetrahedron 1988, 44,
1735.
63. Noble, A.; Anderson, J. C.; Chem. Rev. 2013, 113, 2887.
64. Nishimoto, Y.;Yasuda, M.; Baba, A.; Org. Lett. 2007, 9, 4931.
65. McLeod, M. C.; Wilson, Z. E.; Brimble, M. A.; J. Org. Chem.
2012, 77, 400.
37. Wenkert, E.; Chauncy, B.; Wentland, S. H.; Synth. Commun.
1973, 3, 73.
38. Kende, A. S.; Liu, K.; Jos Brands, K. M.; J. Am. Chem. Soc.
1995, 117, 10597.
66. Suzuki, M.;Yanagisawa,A.; Noyori, R.; Tetrahedron Lett. 1982,
23, 3595.
39. Reed, A. E.; Weinstock, R. B.; Weinhold, F.; J. Chem. Phys.
1985, 83, 735.
67. Shono, T.; Matsumura, Y.; Inoue, K.; Ohmizu, H.; Kashimura,
S.; J. Am. Chem. Soc. 1982, 104, 5753.
40. Seybold, P. G.; Adv. Quantum Chem. 2012, 64, 83.
41. Bur,S.K.InComprehensiveOrganicSynthesisII,2nd ed.;Knochel,
P.; Molander, G. A., eds.; Elsevier: Amsterdam, 2014, p. 755.
42. Arend, M.; Westermann, B.; Risch, N.; Angew. Chem., Int. Ed.
1998, 37, 1044.
68. Overman, L. E.; Lesuisse, D.; Hashimoto, M.; J. Am. Chem.
Soc. 1983, 105, 5373.
69. Llacet, C.; Couturier, J.; Bull. Soc. Chim. Fr. 1962, 2097.
70. Lau, P. W. K.; Chan, T. H.; Tetrahedron Lett. 1978, 19, 2383.
71. Eisch, J. J.; Galle, J. E.; J. Org. Chem. 1979, 44, 3279.
72. Trost, B. M.; Caldwell, C. G.; Murayama, E.; Heissler, D.; J.
Org. Chem. 1983, 48, 3252.
43. Enders, D.; Ward, D.; Adam, J.; Raabe, G.; Angew. Chem., Int.
Ed. 1996, 35, 981.
73. Evans, D. A.; Gage, J. R.; Leighton, J. L.; J. Am. Chem. Soc.
1992, 114, 9434.
44. Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M.; J. Am. Chem.
Soc. 2006, 128, 7164.
74. Carreira, E. M.; Du Bois, J.; J. Am. Chem. Soc. 1995, 117, 8106.
75. Magnus, P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.;
Deluca, M.; Merritt, A.; Kim, C. S.; Vicker, N.; J. Am. Chem.
Soc. 1993, 115, 8116.
45. Litinskii,A. O.; Gokhberg, P.Y.; Shatkovskaya, D. B.; Bolotin,
A. B.; Litinskaya, N. N.; Popov, G. P.; Theor. Exp. Chem. 1984,
19, 450.
46. Bacovescu, A.; Pictet, A.; Ber. Dtsch. Chem. Ges. 1905, 38,
2787.
76. Wenkert, E.; Sklar, R.; J. Org. Chem. 1966, 31, 2689.
77. Kutney, J. P.; Fuller, G. B.; Heterocycles 1975, 3, 197.
78. Keinan, E.; Greenspoon, N.; Tetrahedron Lett. 1982, 23, 241.
79. Hartwig, W.; Tetrahedron 1983, 39, 2609.
80. Tabuchi, T.; Inanaga, J.;Yamaguchi, M.; Tetrahedron Lett. 1986,
27, 601.
47. Leuchs, H.; Nitschke, R.; Ber. Dtsch. Chem. Ges. 1922, 55,
3171.
48. Wieland, H.; Jennen, R. G.; Justus Liebigs Ann. Chem. 1940,
545, 99.
49. Smith, G. F. In The Alkaloids: Chemistry and Physiology, vol. 8;
Manske, R. H. F., ed.; Academic Press: New York-London,
1965, p. 591.
81. Nicolaou, K. C.; Hwang, C. K.; Smith, A. L.; Wendeborn, S.
V.; J. Am. Chem. Soc. 1990, 112, 7416.
82. Tedesco, R.; Fiaschi, R.; Napolitano, E.; J. Org. Chem. 1995,
60, 5316.
50. Tafel, J.; Justus Liebigs Ann. Chem. 1891, 264, 33.
51. Tafel, J.; Justus Liebigs Ann. Chem. 1892, 268, 229.
52. Tafel, J.; Justus Liebigs Ann. Chem. 1898, 301, 285.
53. Oesterlin, M.; Imoudsky, G.; Ber. Dtsch. Chem. Ges. 1943, 76,
172.
83. Kuehne, M. E.; Wang, T.; Seraphin, D.; J. Org. Chem. 1996,
61, 7873.
84. Tsuji, J.; Mandai, T.; Synthesis 1996, 1996, 1.
85. Fernandes, L.; Bortoluzzi, A. J.; Sá, M. M.; Tetrahedron 2004,
60, 9983.
54. Boit, H.-G.; Chem. Ber. 1951, 84, 16.
55. Savoca, A. C.; Urgaonkar, S. In Encyclopedia of Reagents for
Organic Synthesis; John Wiley & Sons, Ltd: New York, 2001.
DOI: 10.1002/047084289X.rd011.pub2.
86. Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M.
R.; Wood, J. L.; J. Am. Chem. Soc. 2005, 127, 12513.
87. Utsugi, M.; Miyano, M.; Nakada, M.; Org. Lett. 2006, 8, 2973.
88. Kim, H. J.; Su, L.; Jung, H.; Koo, S.; Org. Lett. 2011, 13, 2682.
89. Kogure, N.; Suzuki, Y.; Wu, Y.; Kitajima, M.; Zhang, R.;
Takayama, H.; Tetrahedron Lett. 2012, 53, 6523.
90. Jung, M. E.; Usui, Y.; Vu, C. T.; Tetrahedron Lett. 1987, 28,
5977.
56. Juillard, J.; Pure Appl. Chem. 1977, 49, 885.
57. Head, D. L.; McCarty, C. G.; Tetrahedron Lett. 1973, 14, 1405.
58. Trapencieris, P.; Pigza, J. A. In Encyclopedia of Reagents for
Organic Synthesis; John Wiley & Sons, Ltd: New York, 2001.
DOI: 10.1002/047084289X.rm240.pub2.
59. Heathcock, C. H.; Henderson, M. A.; Oare, D. A.; Sanner, M.
A.; J. Org. Chem. 1985, 50, 3019.
91. Newman, D. J.; Cragg, G. M.; J. Nat. Prod. 2007,
70, 461.
60. Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock, C.
H.; J. Org. Chem. 1990, 55, 132.
92. Still, W. C.; Kahn, M.; Mitra,A.; J. Org. Chem. 1978, 43, 2923.
61. Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L.
M.; Rutjes, F. P. J. T.; Chem. Soc. Rev. 2008, 37, 29.
62. Kobayashi, S.; Mori,Y.; Fossey, J. S.; Salter, M. M.; Chem. Rev.
2011, 111, 2626.
Submitted: July 28, 2018
Published online: November 6, 2018
This is an open-access article distributed under the terms of the Creative Commons Attribution License.