Biomimetic total syntheses of (-)-leucoridines A and C through the dimerization of (-)-dihydrovalparicine

Article abstract of DOI:10.1002/anie.201505198

Concise biomimetic syntheses of the Strychnos-Strychnos-type bis-indole alkaloids (-)-leucoridine A (1) and C (2) were accomplished through the biomimetic dimerization of (-)-dihydrovalparicine (3). En route to 3, the known alkaloids (+)-geissoschizoline (8) and (-)-dehydrogeissoschizoline (10) were also prepared. DFT calculations were employed to elucidate the mechanism, which favors a stepwise aza-Michael/spirocyclization sequence over the alternate hetero-Diels-Alder cycloaddition reaction. Concise biomimetic syntheses of the Strychnos-Strychnos-type bis-indole alkaloids (-)-leucoridine A and C were accomplished through the biomimetic dimerization of (-)-dihydrovalparicine. DFT calculations were used to elucidate the mechanism, which favors a stepwise aza-Michael/spirocyclization sequence over the alternate hetero-Diels-Alder cycloaddition reaction.

Full text of DOI:10.1002/anie.201505198

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201505198
German Edition: DOI: 10.1002/ange.201505198
Natural Product Synthesis
Biomimetic Total Syntheses of (À)-Leucoridines A and C through the
Dimerization of (À)-Dihydrovalparicine
Praveen Kokkonda, Keaon R. Brown, Trevor J. Seguin, Steven E. Wheeler, Shivaiah Vaddypally,
Michael J. Zdilla, and Rodrigo B. Andrade*
In memory of Grant R. Krow
Abstract: Concise biomimetic syntheses of the Strychnos-
Strychnos-type bis-indole alkaloids (À)-leucoridine A (1) and
C (2) were accomplished through the biomimetic dimerization
of (À)-dihydrovalparicine (3). En route to 3, the known
alkaloids (+)-geissoschizoline (8) and (À)-dehydrogeissoschi-
zoline (10) were also prepared. DFT calculations were
employed to elucidate the mechanism, which favors a stepwise
aza-Michael/spirocyclization sequence over the alternate
hetero-Diels–Alder cycloaddition reaction.
and vincristine-resistant KB/VJ300 cells (IC50 values of 2.39
and 11.80 mgmLÀ1, respectively). While the biological activ-
ities of these congeners justifies their study, we were
particularly drawn to the complex molecular architectures
of 1 and 2 and hypothesized that these natural products are
most likely formed through a highly stereoselective dimeri-
zation of (À)-dihydrovalparicine (3).[2] Spirocyclization to
form the epimeric C16 congener would be precluded on steric
grounds by the rigid and bulky (S)-2-ethyl-4-azatricy-
clo[5.3.3.04,8] undecane nucleus.[4] Over the years, we have
developed synthetic methods for the concise syntheses of
various Strychnos alkaloids.[5] Accordingly, we sought to test
our biogenetic hypothesis that 1 and 2 could be synthesized
through the dimerization of (À)-dihydrovalparicine (3).
Further consideration of our biogenetic hypothesis led us
to propose two mechanistic pathways by which 3 could
dimerize (Scheme 1). On the one hand, 1 could be assembled
through a stepwise aza-Michael addition of the indolenine
nitrogen of one monomer to the electrophilic C16-C22 alkene
C
omplex natural products continue to spark the creativity of
synthetic organic chemists, and the indole alkaloids are an
excellent example.[1] In 2010, Kam and co-workers isolated
(À)-leucoridines A (1) and C (2), complex Strychnos-Strych-
nos alkaloids from the stem-bark extracts of Leuconotis
griffithii (Figure 1).[2] Cursory inspection of 2 suggests it can
be readily prepared through the hydrolysis of the indolenine
nucleus in 1, which itself appears to be a dimer of the
monoterpene indole alkaloid (À)-dihydrovalparicine (3).[3]
Bis-indoles 1 and 2 showed moderate cytotoxicity against
KB cells (IC50 values of 0.57 and 10.91 mgmLÀ1, respectively)
Scheme 1. The two possible mechanisms for the biomimetic dimeriza-
tion of (À)-leucoridine A (1) from (À)-dihydrovalparicine (3): stepwise
aza-Michael/spirocyclization and hetero-Diels–Alder reaction.
Figure 1. Structures of leucoridine A (1), B (2), and the proposed
biogenetic precursor dihydrovalparicine (3).
of another, followed by diastereoselective spirocyclization
onto an activated C16’-C22’ alkene.[6] On the other hand,
a concerted and highly diastereoselective hetero-Diels–Alder
reaction could be envisioned.[7]
[*] P. Kokkonda, K. R. Brown, Dr. S. Vaddypally, Dr. M. J. Zdilla,
Dr. R. B. Andrade
Department of Chemistry, Temple University
Philadelphia, PA 19122 (USA)
To distinguish between these two mechanistic possibilities,
we first turned to computational quantum chemistry. A search
for transition states (TSs) corresponding to the two pathways
was performed at the SMD-M06-2X/6-31 + G(d) level of
theory.[8] Computations were based primarily on the reaction
of 3 with another monomer of 3 protonated at the indolenine
nitrogen atom, which corresponds to the most likely acid-
E-mail: randrade@temple.edu
Homepage: https://www.cst.temple.edu/~randrade
T. J. Seguin, Dr. S. E. Wheeler
Department of Chemistry, Texas A & M University
College Station, TX 77843 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505198.
12632
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12632 –12635

Angewandte
Chemie
catalyzed pathway (see below). An extensive search failed to
locate a transition state corresponding to a concerted hetero-
Diels–Alder cycloaddition, thus suggesting that such a path-
way is not viable. Instead, we identified a stepwise aza-
Michael/spirocyclization pathway with the free energy profile
(298 K) given in Figure 2. The reaction proceeds through
initial formation of a pre-reaction complex followed by the
aza-Michael addition via TS1, with a free energy barrier of
22.0 kcalmolÀ1. The resulting adduct undergoes rotation
To test our biogenetic hypothesis, we focused on an
expedient synthesis of dihydrovalparicine (3). Accordingly,
we began with tetracycle (À)-4, which was prepared in four
operations from commercial N-tosyl indole 3-carboxaldehyde
(Scheme 2).[5e] Removal of the N-Boc group in 4 with TFA
followed by site-selective N-alkylation with (Z)-2-iodo-2-
butenyl bromide[9] afforded 5 in 75% yield over two steps.[5d]
To install the fifth ring in 3, we employed a tactic developed
by Rawal,[10] namely the intramolecular Heck reaction, which
furnished (À)-akuammicine (6)[5d] in 70% yield.
À
about the formed C N bond, followed by cyclization via
TS2, which lies 28.5 kcalmolÀ1 higher in free energy than the
separated reactants. This yields the conjugate acid of leucor-
idine A (1), which is 12.7 kcalmolÀ1 lower in free energy than
the separated reactants.
At this stage, stereoselective hydrogenation of the ethyl-
idene moiety in 6 under the agency of Adamsꢀs catalyst
delivered (À)-dihydroakuammicine (7)[11] in 82% yield. With
7 in hand, we made use of Kuehneꢀs conditions (i.e.,
NaBH3CN in AcOH) to reduce the vinylogous carbamate,
which afforded a separable mixture of C16 diastereomers (a/
b = 7:1) in 79% yield.[12] Reduction of the carbomethoxy
group in the requisite major diastereomer with LiAlH4 gave
the known indole alkaloid (+)-geissoschizoline (8) in 80%
yield.[13] Moreover, we were able to obtain a single-crystal X-
ray structure of 8 to confirm the stereochemical course of
both reduction reactions.
We also considered the non-acid-catalyzed dimerization
of 3 at the same level of theory. Initially, we considered the
dimerization of 2-vinyl-3H-indole as a model for the non-
acid-catalyzed dimerization of 3. In this case, we located TS
structures for both stepwise and concerted pathways. The
barrier for the concerted pathway is predicted to be 1.6 kcal
molÀ1 higher in free energy than that for the stepwise
pathway. However, for the non-acid-catalyzed dimerization
À
of 3, a systematic scan over the formation and breaking of C
The conversion of (+)-geissoschizoline (8) into (À)-
dihydrovalparicine (3) required 1) chemoselective indoline-
to-indolenine oxidation in the presence of the primary C22
hydroxyl group and 2) dehydration of the latter to install the
C16-C22 olefin. Execution of the first task proved problem-
atic and TES protection of the C22 carbinol with TESOTf and
Et3N had to be employed (79% yield). Screening various
oxidation conditions revealed Pb(OAc)4 buffered with Et3N
to be the best approach, furnishing indolenine 9 in 48%
yield.[14] Gratifyingly, we were able to perform single-crystal
À
C and C N bonds revealed that only a stepwise pathway
exists on this potential energy surface (see the Supporting
Information).
In this non-acid-catalyzed stepwise pathway, the cyclo-
addition step is rate limiting, lying 5.8 kcal mol-1 higher in
free energy than the initial aza-Michael addition. Thus,
regardless of whether this process proceeds via protonation
of the indolenine nitrogen, computations support a stepwise
aza-Michael/spirocyclization mechanism.
Figure 2. Free-energy profile of the acid-catalyzed stepwise aza-Michael/spirocyclization pathway (298 K).
Angew. Chem. Int. Ed. 2015, 54, 12632 –12635
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12633

.
Angewandte
Communications
Scheme 2. Synthesis of (À)-dihydrovalparicine (3) and its biomimetic dimerization to form (À)-leucoridines A (1) and C (2).
X-ray analysis on 9 to unambiguously confirm its structure.
The second task began with removal of the TES group with
HF·Pyr in 82% yield, which gave the known alkaloid (À)-
dehydrogeissoschizoline (10).[13] Dehydration of the C16
carbinol was best realized with trifluoroacetic acid (TFA),
a tactic initially reported by Vanderwal and co-workers.[15] In
the event, we obtained a 78% yield of (À)-dihydrovalparicine
(3) following careful purification over neutral alumina.
With (À)-dihydrovalparicine (3) in hand, we proceeded to
test our biogenetic hypothesis. Attempts to effect the
dimerization reaction under neutral conditions by heating
solutions of 3 in various solvents (e.g., THF, 1,4-dioxane,
toluene, DMF, diglyme) at temperatures up to 1458C (sealed
tube) for 16–48 h resulted in either decomposition or
recovered starting material. We reasoned that the dimeriza-
tion reaction would proceed more readily under acidic
conditions (i.e., electrophilic activation) through protonation
of the indolenine nitrogen. To this end, we screened a variety
of conditions and ultimately found that heating a solution of 3
in toluene at 1058C for 16 h in the presence of 25 mol% TFA
afforded (À)-leucoridine A (1) in 40% yield of isolated
product (Scheme 2). While we were delighted to have
prepared the targeted natural product, a more efficient
process for the dimerization of 3 was sorely needed. The
sensitive nature of 3 suggested that bypassing its isolation
would surely increase the yield of 1; moreover, sequestration
of water would drive the equilibrium toward dimerization.
After extensive experimental optimization, we discovered
that when (À)-dehydrogeissoschizoline (10) was treated with
2.1 equivalents of TFA and 4 Š molecular sieves in CH2Cl2
for 24 h, we obtained (À)-leucoridine A (1) in a satisfactory
73% yield (Scheme 2).[16]
the indolenine to deliver (À)-leucoridine C (2) in 47% yield.
Spectroscopic data for synthetic (À)-1 and (À)-2 (e.g., 1H and
13C NMR, IR, HRMS, optical rotation) were in complete
agreement with those reported by Kam and co-workers.[2,17] In
summary, we have accomplished the first asymmetric total
syntheses of the Strychnos-Strychnos alkaloids (À)-leucoridi-
nes A (1) and C (2) by employing a biomimetic dimerization
reaction of (À)-dihydrovalparicine (3). We optimized the
syntheses of 1 and 2 by preparing 3 in situ by dehydrating (À)-
dehydrogeissoschizoline (10) with TFA in the presence of 4 Š
molecular sieves. Finally, we employed DFT calculations to
elucidate the mechanism of dimerization, and the results
suggest that a stepwise aza-Michael/spirocyclization sequence
is operative as opposed to the alternative hetero-Diels–Alder
pathway.
Acknowledgements
Financial support from NSF (CHE-1111558) and the Welch
Foundation (A-1775) is gratefully acknowledged. We thank
Dr. Charles DeBrosse (Director of NMR Facilities at Temple
Chemistry) for assistance with NMR experiments and Dr.
Richard Pederson (Materia, Inc.) for catalyst support, as well
as the Texas A&M Supercomputing Facility for computa-
tional resources.
Keywords: biomimetic synthesis · indole alkaloids ·
natural products · reaction mechanisms · total synthesis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12632–12635
Angew. Chem. 2015, 127, 12823–12826
Finally, we found that the addition of 12N HCl to
a solution of 1 in THF for 24 h resulted in ring-opening of
12634 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12632 –12635

Angewandte
Chemie
[8] a) A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B
[1] a) M. Somei, F. Yamada, Nat. Prod. Rep. 2005, 22, 73 – 103; b) M.
Ishikura, T. Abe, T. Choshi, S. Hibino, Nat. Prod. Rep. 2013, 30,
694 – 752; c) M. Ishikura, K. Yamada, T. Abe, Nat. Prod. Rep.
2010, 27, 1630 – 1680; d) M. Ishikura, K. Yamada, Nat. Prod.
Rep. 2009, 26, 803 – 852.
[2] C. Y. Gan, T. Etoh, M. Hayashi, K. Komiyama, T. S. Kam, J. Nat.
Prod. 2010, 73, 1107 – 1111.
[3] K. H. Lim, Y. Y. Low, T. S. Kam, Tetrahedron Lett. 2006, 47,
5037 – 5039.
2009, 113, 6378 – 6396; b) Y. Zhao, D. G. Truhlar, Theo. Chem.
Acc. 2008, 120, 215 – 241.
[9] W. Y. Yin, M. S. Kabir, Z. J. Wang, S. K. Rallapalli, J. Ma, J. M.
Cook, J. Org. Chem. 2010, 75, 3339 – 3349.
[10] V. H. Rawal, C. Michoud, Tetrahedron Lett. 1991, 32, 1695 –
1698.
[11] M. Amat, M. D. Coll, J. Bosch, E. Espinosa, E. Molins,
Tetrahedron: Asymmetry 1997, 8, 935 – 948.
[12] M. E. Kuehne, F. Xu, J. Org. Chem. 1998, 63, 9427 – 9433.
[13] J. C. P. Steele, N. C. Veitch, G. C. Kite, M. S. J. Simmonds, D. C.
Warhurst, J. Nat. Prod. 2002, 65, 85 – 88.
[4] J. Bonjoch, N. Casamitjana, J. Quirante, M. Rodriguez, J. Bosch,
J. Org. Chem. 1987, 52, 267 – 275.
[5] a) G. Sirasani, R. B. Andrade, Org. Lett. 2009, 11, 2085 – 2088;
b) G. Sirasani, T. Paul, W. Dougherty, Jr., S. Kassel, R. B.
Andrade, J. Org. Chem. 2010, 75, 3529 – 3532; c) G. Sirasani,
R. B. Andrade, Org. Lett. 2011, 13, 4736 – 4737; d) G. Sirasani,
R. B. Andrade in Strategies and Tactics in Organic Synthesis,
Vol. 9 (Ed.: M. Harmata), Elsevier Academic Press, San Diego,
2013, pp. 1 – 44; e) S. Z. Zhao, G. Sirasani, S. Vaddypally, M. J.
Zdilla, R. B. Andrade, Angew. Chem. Int. Ed. 2013, 52, 8309 –
8311; Angew. Chem. 2013, 125, 8467 – 8469; f) S. Munagala, G.
Sirasani, P. Kokkonda, M. Phadke, N. Krynetskaia, P. H. Lu, F. J.
Sharom, S. Chaudhury, M. D. M. Abdulhameed, G. Tawa, A.
Wallqvist, R. Martinez, W. Childers, M. Abou-Gharbia, E.
Krynetskiy, R. B. Andrade, Bioorg. Med. Chem. 2014, 22, 1148 –
1155; g) C. N. Teijaro, S. Munagala, S. Z. Zhao, G. Sirasani, P.
Kokkonda, E. V. Malofeeva, E. Hopper-Borge, R. B. Andrade, J.
Med. Chem. 2014, 57, 10383 – 10390.
[14] E. Wenkert, M. J. Pestchanker, J. Org. Chem. 1988, 53, 4875 –
4877.
[15] D. B. C. Martin, L. Q. Nguyen, C. D. Vanderwal, J. Org. Chem.
2012, 77, 17 – 46.
[16] Shortly after publication of this article as an Angewandte Chemie
Early View, it was brought to our attention that leucoridine A
had been prepared earlier this year via semisynthesis from
natural geissoschizoline by Evanno and co-workers by using
TFA: S. Benayad, M. A. Beniddir, L. Evanno, E. Poupon, Eur. J.
Org. Chem. 2015, 1894—1898.
[17] Proton chemical shift differences for H3 in synthetic and isolated
2 (i.e., 3.75 and 3.79 ppm, respectively) are likely the result of
concentration differences or protonation states. We thank the
reviewers for pointing this out.
[6] K. Kuzuya, N. Mori, H. Watanabe, Org. Lett. 2010, 12, 4709 –
4711.
Received: June 7, 2015
[7] L. F. Tietze, G. Kettschau, Stereoselective Heterocyclic Synthesis
I 1997, 189, 1 – 120.
Revised: July 23, 2015
Published online: August 28, 2015
Angew. Chem. Int. Ed. 2015, 54, 12632 –12635
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12635