Concise Syntheses of bis-Strychnos Alkaloids (?)-Sungucine, (?)-Isosungucine, and (?)-Strychnogucine B from (?)-Strychnine

Article abstract of DOI:10.1002/chem.201602663

The first chemical syntheses of complex, bis-Strychnos alkaloids (?)-sungucine (1), (?)-isosungucine (2), and (?)-strychnogucine B (3) from (?)-strychnine (4) is reported. Key steps included (1) the Polonovski–Potier activation of strychnine N-oxide; (2) a biomimetic Mannich coupling to forge the signature C23?C5’ bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH₃CN-mediated reduction to fashion the ethylidene moieties in 1–3. DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners.

Full text of DOI:10.1002/chem.201602663

A Journal of
Accepted Article
Title: Concise Syntheses of Bis-Strychnos Alkaloids (−)-Sungucine, (−)-
Isosungucine, and (−)-Strychnogucine B from (−)-Strychnine
Authors: Senzhi Zhao; Christiana Teijaro; Heng Chen; Gopal Sirasani; Shivaiah
Vaddypally; Michael Zdilla; Graham Dobereiner; Rodrigo Andrade
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To be cited as: Chem. Eur. J. 10.1002/chem.201602663
Link to VoR: http://dx.doi.org/10.1002/chem.201602663
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COMMUNICATION
Concise Syntheses of Bis-Strychnos Alkaloids ()-Sungucine, ()-
Isosungucine, and ()-Strychnogucine B from ()-Strychnine
Senzhi Zhao, Christiana N. Teijaro, Heng Chen, Gopal Sirasani, Shivaiah Vaddypally, Michael J. Zdilla,
Graham E. Dobereiner, and Rodrigo B. Andrade*
Abstract: We report the first chemical syntheses of complex, bis-
Strychnos alkaloids ()-sungucine (1), ()-isosungucine (2), and ()-
strychnogucine B (3) from ()-strychnine (4). Key steps included (1)
the PolonovskiPotier activation of strychnine N-oxide; (2)
a
biomimetic Mannich coupling to forge the signature C23C5’ bond
that joins two monoterpene indole monomers; and, (3) a sequential
Scheme 2. Syntheses of Northern fragment 5 and Southern fragment 9 from ()-strychnine (4).
HBr/NaBH3CN-mediated reduction to fashion the ethylidene moieties
in 13. DFT calculations were employed to rationalize the
regiochemical course of reactions involving strychnine congeners.
The chemical synthesis of complex natural products
remains a vibrant and dynamic enterprise within the rich field of
organic chemistry. Many natural products are represented in our
current pharmacopeia, including those in the bis-indole alkaloid
class.1 ()-Sungucine (1) was isolated by Angenot and co-
workers in 1979 from the roots of Strychnos icaja, a liana native
only to central Africa (Scheme 1).2 The structure of 1 was
rigorously established by single-crystal X-ray analysis.3
Reinvestigation of Strychnos icaja by Frédérich and co-workers
in the 1990s resulted in the discovery of novel sungucine
congeners ()-isosungucine (2) and ()-strychnogucine B (3).4
with inexpensive, commercially available ()-strychnine (4).
Scheme 1. Structures of ()-sungucine (1), ()-isosungucine (2), ()-
strychnogucine B (3) and retrosynthetic analysis leading to northern and
southern synthons derived from ()-strychnine (4).
The structurally unique bis-Strychnos alkaloids 13 feature
a common C23C5’ bond yet differ in oxidation states at C18
and C18’ (Scheme 1). ()-Sungucine (1) possesses anticancer
activity in the low M range, as confirmed through NCI’s in vitro
60 human tumor cell line screen.5 Pharmacological evaluation of
1 revealed it induced apoptosis in both leukemia and colon
cancer cells via a p53-independent mechanism.6 In addition, 2
and 3 were found to possess potent and selective anti-
plasmodial activities against Plasmodium falciparum strains.4,7
Herein, we report the first enantiospecific chemical syntheses of
bioactive, bis-Strychnos alkaloids ()-sungucine (1), ()-
As outlined in Scheme 2, our syntheses of bis-Strychnos
alkaloids 13 began with the construction of northern fragment 5
(i.e., TBS-protected isostrychnine). In order to readily access 5
on a multi-gram scale, we needed a reliable and effective
method for converting strychnine into isostrychine. While
literature reports of this transformation are known,8 we were not
satisfied with the results. Ultimately, we found that when ()-
strychnine
(4)
was
first
treated
with
1,8-diazabi-
cyclo[5.4.0]undecene (DBU) at 200 °C in N-methyl-2-pyrrolidone
(NMP) then TBSCl and imidazole at rt, we routinely isolated 5 in
50% overall yield, in addition to minor regioisomer 6 (26% yield)
on gram scale. Experimental results were consistent with DFT
calculations inasmuch as only 5 and 13-epi-isostrychnine (6)
were isolated out of the three possible products (see Table S1).
isosungucine (2), and ()-strychnogucine
B
(3) from
commercially available and inexpensive ()-strychnine (4).
In our retrosynthetic analysis (Scheme 1), we envisioned
()-sungucine (1) and ()-isosungucine (2) could be synthesized
from ()-strychnogucine B (3) by base-mediated ring-opening
and deoxygenation of the ethylidene moieties. To make ()-3 in
a convergent manner, one can logically disconnect the C23C5’
bond, which could arise from the biomimetic Mannich coupling of
a northern C23-synthon with a southern C5’-synthon. As both
synthons are structurally homologous to strychnine (4), we
reasoned the most step-efficient syntheses of 13 must start
[a]
S. Zhao, C. N. Teijaro, H. Chen, G. Sirasani, S. Vaddypally, M. J.
Zdilla, G. E. Dobereiner, R. B. Andrade
Department of Chemistry
Temple University
1901 N. 13th St. Philadelphia, Pa 19122
E-mail: randrade@temple.edu
Supporting information for this article is given via a link at the end of
the document.

Chemistry - A European Journal
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COMMUNICATION
Scheme 2. Syntheses of Northern fragment 5 and Southern fragment 9 from ()-strychnine (4).
The next stage of the synthesis enlisted the venerable
PolonovskiPotier reaction9 to regioselectively generate and trap
C5N4 iminium ion I (Figure 1) to access southern fragment 9
(Scheme 2). Thus, ()-4 was oxidized with H2O2 to afford
strychnine N-oxide in 98% yield. Reaction with trifluoroacetic
anhydride (TFAA) then KCN gave an intractable mixture of
regioisomers. Replacing KCN with NaHCO3 (aq.) furnished
pseudostrychnine (7) and regioisomeric carbinolamine 8 in a
2.2:1 ratio, respectively, and 71% yield. The structure of 7 was
confirmed by single-crystal X-ray analysis. The use of more
basic and nucleophilic KOH was able to invert the ratio of
products and delivered the desired regioisomer 8 in 52% yield,
Further DFT analysis afforded the minimized structure of
parent N-acyloxyammonium ion IV (Table S2). IV lacks a
hydrogen anti-periplanar to the NOacyl bond (Figure S1AC), a
strict prerequisite for the E2 pathway expected in the
PolonovskiPotier mechanism. The stereochemistry between
C5Hb and N4Oacyl bonds (i.e., HbC5N4O dihedral=148.3°,
Figures S1A and 2) are closest to being anti-periplanar. The
formation of 8 may follow an E2-like mechanism via elimination
from IV to I.
A natural population analysis (NPA)11 of IV (Figure 2)
indicates that C7 is the least negative carbon bound to N4 (C7,
0.00445; C5,  21717; C21, 0.24162), and the charge on
C7H (+0.30252) is more positive than those on C5 and C21
protons. To the extent that pKa and natural charge (QA, QH) are
correlated,12 NPA suggests that C7H, which is syn-coplanar to
the NOacyl bond (11.5°), has the lowest pKa of the CH bonds
adjacent to N4 (Figures 2 and S1B). Thus, reaction at C7 of IV
to form iminium II could occur through an E1-like or E1cb-like
transition state by means of the paired TFA.13 An alternative to
the bimolecular pathway would be the entropically favored syn
elimination arising from the intramolecular deprotonation of
C7H by the pendant N-trifluoroacetyl moiety.
1
along with 40% of 7. Spectral (i.e., H NMR) analysis of major
carbinolamine 8 revealed it was a mixture of epimers at C5.
Treatment of this mixture with 10% MeOH/CH2Cl2 effected N,O-
aminal ether equilibration to afford the requisite southern
fragment 9 in quantitative yield. The structure of 9 was rigorously
established by single-crystal X-ray analysis (Scheme 2).
To rationalize the regiochemical course of the
PolonovskiPotier reaction, we employed DFT analysis
(mPW1PW91/cc-pvdz) to determine relative free energies of
three iminium cations that may form upon trifluoroacetate
elimination (Figure 1). The carbinolamine derived from the
lowest-energy iminium considered III was not observed in
experiment; meanwhile, isolated regioisomer 7 was derived from
the highest-energy iminium II. Besides the error inherent in the
chosen DFT method, the effects of ion pairing10 may dictate the
stability of IIII. Nonetheless, at this stage the experimental
results cannot be understood solely by comparing the relative
computed energies of IIII.
Figure 2. Charges on C and H from the natural population analysis of N-
acyloxyammonium ion IV.
The mechanistic nuances between the classical Polonovski
reaction (acetic anhydride, Ac2O) and the more reactive Potier
variant (TFAA) prompted us to to investigate the effect of both
acylating agent and temperature on the regioselective
functionalization of strychnine N-oxide.13 The results of those
experiments are summarized in Table 1.
Figure 1. Relative DFT energies for iminium ions IIII.
Reactions with TFAA (entries 13) were less sensitive to
temperature such that both percent conversion and ratios of 8 to

Chemistry - A European Journal
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COMMUNICATION
N
N
H
H
H
H
H
H
16
17
N
N
OH
1.) LDA
0 °C, THF
OTBS
23
X-ray
X-ray
Cs2CO3
HF·pyridine
H
H
H
5
O
H
O
H
pyridine
THF
0 °C to rt
N
t-BuOH
85 °C, 5 h
2.) 9, BF3·OEt2
[Mannich Reaction]
N
H
H
H
(70%)
(67% overall)
(88%)
H
H
O
O
N
N
H
H
H
H
O
O
10
11
11: Southern Perspective
11: Northern Perspective
N
H
N
N
H
H
1.) DBU
H
(10 equiv)
NMP
reflux
H
H
H
18
1.) 33% HBr
in AcOH
AcOH
H
H
H
H
H
H
CH3
N
O
N
O
N
OH
OAc
X-ray
30 min
H
H
O
2.) Ac2O
DMAP
CH2Cl2, rt
2.) NaBH3CN
DMF, rt, 24 h
N
N
N
H
H
H
H
H
H
(40²50% overall)
H
(63² 70%
overall)
H
18'
H
H
H
CH3
O
16'
23'
N
N
N
16'
OAc
H
17'
17'
H
23'
1: (²)-sungucine
O
O
O
3: (² )-strychnogucine B
3: (²)-strychnogucine B
12: 13 (! 16',17') = 1:2
2: (²)-isosungucine (! 16',17'
)
(ratio of 1:2 = 1:2)
Scheme 3. Syntheses of ()-sungucine (1), ()-isosungucine (2), and ()-strychnogucine B (3).
7
remained fairly constant. This can be rationalized by
lithium enolate (Scheme 3). Addition thereof to the iminium
derived from BF3Et2O-treatment of 9 smoothly delivered 10 as
a mixture of diastereomers at C23.15 Subsequent treatment of
10 with HFPyridine served to remove the TBS group and effect
equilibration at C23 to afford 11 as a single diastereomer;
moreover, X-ray analysis of 11 confirmed the stereo- and
regiochemical course of the transformations.
considering the nucleofugacity of trifluoroacetate, which greatly
favors iminium ion formation.13
On the other hand, reactions with Ac2O (entries 46) gave
higher ratios of desired carbinolamine 8 to 7. Moreover, they
proceeded at a slower rate and required higher temperature for
the conversion of starting material to products. The highest ratio
of 8 to 7 (3.1:1) was obtained at 35 °C for 4 h (entry 6). These
results are consistent with an E2 mechanism whereby the more
basic acetate can remove the anti-periplanar C5 Hb from an N-
acyloxyammonium strychnine intermediate (Figure 1) to afford
the desired carbinolamine 8.
The synthesis of ()-strychnogucine B (3) required olefin
isomerization from the trisubstituted C16C17 position into
conjugation with the carbonyl. Fortuitously, Magnus had
reported a similar reaction during early synthetic studies toward
strychnine.16 Thus, treatment of 11 with Cs2CO3 in deaerated
tert-butanol at 85 °C furnished ()-strychnogucine B (3) in 70%
yield. Spectral data for 3 (e.g., 1H and 13C NMR, IR) were in
complete agreement with those reported in the literature.4b
The syntheses of ()-sungucine (1) and ()-isosungucine
(2) from ()-3 required two tasks: (1) rupture of the oxepene ring
in the southern portion of ()-strychnogucine B and (2) global
deoxygenation of the attendant hydroxyethylidene moieties. The
first task was addressed by employing tactics used for northern
fragment 5. Successful execution thereof would deliver two
alkene regioisomers (i.e., conjugated and nonconjugated) that
map onto 1 and 2, respectively. In the event, ()-strychnogucine
B (3) was first treated with DBU in NMP at 200 °C to afford two
bis-diols as a mixture of alkene regioisomers. Subsequent
acetylation of this mixture with acetic anhydride to facilitate
purification yielded 12 and 13 in a ratio of 1:2 (6370% overall
yield).
Table 1. Effect of reagent and temperature on the formation of 7 and 8.
Acylating
Agent[a]
Temperature Time
Percent
Ratio of
Entry
7 to 8[d]
(°C)
(hours)[b] Conversion[c]
1
2
3
4
5
6
TFAA
TFAA
TFAA
Ac2O
Ac2O
Ac2O
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
23
35
0
23
35
[a] Two equivalents of the reagent were used using CH2Cl2 as solvent.
[b] Iminium ion was trapped with aqueous KOH after 2 or 4 hours.
[c] Percent conversion calculated by 1H NMR.
Endgame for the syntheses of 12 called for adjusting the
oxidation states at C18 and C18’ in 1213. We screened a
battery of deoxygenation protocols (e.g., Pd-catalyzed
[d] Ratio of 7 to 8 determined by 1H NMR.
With both northern and southern fragments in hand, we
deoxygenation,17
MsCl/LiEt3BH,18
thiocarbonyl
di-
focused on forging the characteristic C23C5’ bond in 13 using
a
experimentation with various metalation conditions of 5 and
screening Lewis acids, we were pleased to find favorable
conditions for the Mannich-mediated fragment coupling of 5 and
9. In the event, 5 was first treated with LDA to generate the
imidazole/Bu3SnH),19 but none yielded satisfactory results.
Success was ultimately realized by first converting the allylic
acetates into their corresponding bromides under acidic
conditions and subsequent reduction with NaBH3CN in DMF.20
Thus, a mixture of 12 and 13 was treated sequentially with 33%
biomimetic Mannich reaction.14 After considerable

Chemistry - A European Journal
10.1002/chem.201602663
COMMUNICATION
[4]
a) M. Frederich, M.-C. De Pauw, G. Llabres, M. Tits, V. Brandt, J.
Penelle, P. De Mol, L. Angenot. Planta. Med. 2000, 66, 262; b) M.
Frederich, M.-C. De Pauw, C. Prosperi, M. Tits, V. Brandt, J. Penelle,
M.-P. Hayette, P. De Mol, L. Angenot. J. Nat. Prod. 2001, 64, 12.
A. Lansiaux, C. Bailly, C. Houssier, P. Colson, M. C. De Pauw-Gillet, M.
Frederich, M. Tits, L. Angenot. Planta. Med. 2002, 68, 591.
a) M. Frederich, M. Bentires-Ali, M. Tits, L. Angenot, E. Heinen, M. C.
De Pauw-Gillet. Naunyn-Schmiedebergs Arch. Pharmacol. 2003, 367,
260; b) M. Frederich, M. Tits, L. Angenot. Chem. Nat. Compd. 2003, 39,
513.
HBr followed by NaBH3CN to furnish ()-sungucine (1) and ()-
isosungucine (2) in 4050% overall yield following
1
chromatographic separation. Spectra data for 1 and 2 (e.g., H
and 13C NMR, IR) were in complete agreement with the reported
values.1,4
[5]
[6]
In summary, we have completed the first syntheses of ()-
sungucine (1), ()-isosungucine (2), and ()-strychnogucine B
(3) from commercially available ()-strychnine (4). Key steps
included (1) a DBU-mediated synthesis of isostrychnine from 4;
(2) the PolonovskiPotier reaction of strychnine N-oxide; (3) a
[7]
M. Frederich, M. J. Jacquier, P. Thepenier, P. De Mol, M. Tits, G.
Philippe, C. Delaude, L. Angenot, M. Zeches-Hanrot. J. Nat. Prod. 2002,
65, 1381.
BF3Et2O-mediated, biomimetic Mannich coupling; (4)
a
Cs2CO3-mediated alkene isomerization; and, (5) a NaBH3CN-
mediated reduction of allylic bromides intermediates to install the
requisite ethylidene moieties found in targets 13.
[8]
[9]
G. F. Smith in The Alkaloids: Chemistry and Physiology, Vol. 8 (Ed: R.
H. F. Manske), Academic Press, 1965, pp. 591671.
A. Ahond, A. Cave, C. Kan-Fan, P. H. Husson, J. De Rostolan, P.
Potier. J. Am. Chem. Soc. 1968, 90, 5622.
Acknowledgements
[10] E. Clot. Eur. J. Inorg. Chem. 2009, 2009, 2319.
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735.
This research was supported by the NSF (CHE-1111558, CHE-
1362461, CNS-09-58854, DEG-12262 awarded to C.N.T.). We
thank Prof. Michel Frédérich (Université de Liège) 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. Finally, we kindly dedicate
this paper to Prof. Stephen F. Martin on the occasion of his 70th
birthday.
[12] P. G. Seybold in Advances in Quantum Chemistry, vol. 64 (Eds: R. S.
John, J. B. Erkki), Academic Press, 2012, pp. 83104.
[13] S. K. Bur in Comprehensive Organic Synthesis II (Second Edition) (Ed:
P. Knochel), Elsevier, 2014, pp. 755801.
[14] M. Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed. 1998, 37,
1044; Angew. Chem. 1998, 110, 1096.
[15] Attempts to determine the exact diastereomeric ratio by 1H NMR was
unsuccessful due to the configurational lability at C23.
[16] P. Magnus, M Giles, R. Bonnert, G. Johnson, L. McQuire, M. Deluca, A.
Merritt, C. S. Kim, N. Vicker, J. Am. Chem. Soc. 1993, 115, 8116.
[17] J. Tsuji, T. Mandai, Synthesis, 1996, 1996, 1.
Keywords: sungucine • bis-Strychnos alkaloids •
PolonovskiPotier • biomimetic synthesis • strychnine
[18] N. Kogure, Y. Suzuki, Y. Wu, M. Kitajima, R. Zhang, H. Takayama,
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[19] K. C. Nicolaou, C. K. Hwang, A. L. Smith, S. V. Wendebom, J. Am.
Chem. Soc. 1990, 112, 7416.
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Crystallogr. Sect. B-Struct. Sci. 1980, 36, 1669.

Chemistry - A European Journal
10.1002/chem.201602663
COMMUNICATION
COMMUNICATION
Senzhi Zhao, Christiana N. Teijaro,
Heng Chen, Gopal Sirasani, Shivaiah
Vaddypally, Michael J. Zdilla, Graham E.
Dobereiner, and Rodrigo B. Andrade*
Page No. – Page No.
Concise Syntheses of Bis-Strychnos
Alkaloids ()-Sungucine, ()-
Isosungucine, and ()-Strychnogucine B
from ()-Strychnine
Text for table of contents
[a]
S. Zhao, C. N. Teijaro, H. Chen, G. Sirasani, S. Vaddypally,
Zdilla, G. E. Dobereiner, R. B. Andrade
Department of Chemistry
Temple University
1901 N. 13th St. Philadelphia, Pa 19122
E-mail: randrade@temple.edu
Supporting information for this article is given via a link at th
the document.