Total Synthesis of Paspaline A and Emindole PB Enabled by Computational Augmentation of a Transform-Guided Retrosynthetic Strategy

Article abstract of DOI:10.1021/jacs.8b13127

We report the total syntheses of two indole diterpenoid natural products, paspaline A and emindole PB. Paspaline A is synthesized in a 9-step sequence from commercially available materials. The first total synthesis of emindole PB is accomplished in 13 steps and confirms a previously ambiguous structural assignment. Density functional theory calculations are utilized to interrogate the key carbocationic rearrangement in a predictive capacity to aid in the selection of the most favorable precursor substrate. This work highlights how retrosynthetic design can be augmented with quantum chemical calculations to reveal energetically feasible synthetic disconnections, minimizing time-consuming and expensive empirical evaluation.

Full text of DOI:10.1021/jacs.8b13127

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Communication
Total Synthesis of Paspaline A and Emindole PB Enabled by Computational
Augmentation of a Transform-Guided Retrosynthetic Strategy
Daria E. Kim, Joshua E. Zweig, and Timothy R. Newhouse
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13127 • Publication Date (Web): 09 Jan 2019
Downloaded from http://pubs.acs.org on January 9, 2019
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Total Synthesis of Paspaline A and Emindole PB Enabled by
Computational Augmentation of a Transform-Guided Retrosynthetic
Strategy
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Daria E. Kim, Joshua E. Zweig and Timothy R. Newhouse*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, United States
Supporting Information Placeholder
O
ABSTRACT: We report the total syntheses of two indole
H
Me
Me
Me
diterpenoid natural products, paspaline A and emindole PB.
Paspaline A is synthesized in a 9-step sequence from commercially
available materials. The first total synthesis of emindole PB is
accomplished in 13 steps and confirms a previously ambiguous
structural assignment. Density functional theory calculations are
utilized to interrogate the key carbocationic rearrangement in a
predictive capacity to aid in the selection of the most favorable
precursor substrate. This work highlights how retrosynthetic design
can be augmented with quantum chemical calculations to reveal
energetically feasible synthetic disconnections, minimizing time-
consuming and expensive empirical evaluation.
Me
Me
Me
Me
N
H
Me
N
H
H
OH
Me
Me
3
H
H
H
4
Biosynthesis
H
D
H
A
Me
Me
Me
C
B
Me
Me
E
F
Me
OH
Me
OH
Me
O
O
N
H
Me
Me
H
H
H
H
H
H
N
Me
emindole PB (2)
paspaline A (1)
Me
Chemical Synthesis
H
H
Me
Me
Me
Me
Me
Me
OH
Me
Me
OH
Modern computational tools offer powerful new ways to
augment retrosynthetic analysis.1 One of these approaches is the
development of algorithms to expedite the identification of
strategic bond disconnections.2–6 An underutilized, yet
complementary, strategy is to employ quantum chemical
calculations to rigorously predict the feasibility of the most
challenging and least precedented aspects of synthetic plans.
Herein, we report the application of predictive density functional
theory (DFT) calculations to the concise synthesis of two
biosynthetically related, but structurally distinct indole
diterpenoids, paspaline A (1) and emindole PB (2) (Figure 1). To
the best of our knowledge, this is the first report that demonstrates
that iterative DFT calculations can be used to refine and guide the
retron selection employed in a transform-based strategy.
O
Me
Me
H
4A
H
H
H
4B
H
H
H
N
N
Me
Me
H
H
O
H
Me
H
4C
Me
Me
O
N
H
Figure 1. Computationally guided retrosynthesis. Biosynthesis of
1 and 2 via 3 and 4 suggests several potentially viable cyclization
precursors for chemical synthesis (4A–4C).
due to its role in critical cellular processes like proliferation,
differentiation and migration.12
Previous synthetic strategies towards these indole diterpenoids
have relied on a late-stage indole ring synthesis by annulation onto
an existing five-membered ring motif.7a,b,f,g Inspired by the polyene
cascade that assembles the indole diterpenoid skeleton in the
putative biosynthesis,13,14 we planned to directly incorporate an
indole motif and leverage its innate nucleophilicity to expedite
synthesis of the C-ring (Figure 1). The cascade proceeds through a
notable biosynthetic fork in which the operative carbocation 4 is
thought to give rise to three distinct subclasses of natural products
via Friedel-Crafts cyclization to paspaline A (1), methyl migration
to emindole PB (2), or elimination to give the anthcolorin class of
natural products.15,16
These molecules belong to a class of complex indole diterpenoid
natural products that have been the subject of synthetic
investigations for several decades.7 The hexacyclic architecture of
paspaline A (1), a flagship member of the class, includes a pyran
ring as well as an indole-fused cyclopentane adjacent to two vicinal
quaternary centers.8 Emindole PB (2), a natural product with
multiple reported structural assignments,9,10 has not been the
subject of any reported synthetic efforts. Our interest in these
compounds was motivated by the biological activity of paspaline A
and related natural products, which includes anti-proliferative and
anti-metastatic activity in the MDA-MB-231 mammalian breast
cancer cell line through modulation of the Wnt/–catenin signaling
pathway.11 The Wnt signaling pathway is a target of interest in solid
tumor cancers with high rates of metastasis, such as breast cancer,
We envisioned applying a variant of this transform to enable
divergent access to several structurally distinct members of the
class in a single reaction. Within the framework of this transform-
based strategy, there is flexibility with respect to structural
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Figure 2. Gas-phase computational evaluation of three variations on F-ring structures were investigated using DFT. These calculations
predicted that 4C possess the largest inherent substrate bias (∆∆G‡) favoring C-ring cyclization over the 1,2-methyl shift. (Calculations at
the mPW1PW91/6-31+G(d,p)//B3LYP/6-31G* level of theory, energies of intermediates 5-8 are relative to their respective carbocation 4)
variation of the F-ring, with each of these variants requiring their
own retrosynthetic disconnections. It was our hope that DFT
calculations could be used to select the most energetically favorable
retron for the key carbocationic rearrangement and thereby guide
the remainder of our retrosynthetic search, rather than assist in
selection of specific reaction conditions which are more easily
screened empirically.
Thus, the stepwise pathways were modeled by DFT to assess
which of these three aforementioned substrates would be most
optimal for cyclization rather than methyl shift. When the relative
energies (∆∆G‡) between the gas phase transition states leading to
cyclization and methyl-shift for each carbocationic substrate were
compared at the mPW1PW91/6-31+G(d,p)//B3LYP/6-31G* level
of theory, it was found that 4C possessed the largest energetic bias
(4.5 kcal/mol) towards cyclization via this stepwise pathway.18
A
We identified a set of substructures that would lead to step
efficient routes, yet were structurally distinct enough to elicit
measurable energetic differences with respect to the behavior of the
tertiary carbocation: the acyclic biosynthetic intermediate 4A, a
monocyclic tetrahydropyran 4B, and a bicyclic ketal 4C (Figure 2).
Despite these obvious structural differences, the distal nature of the
modifications made it challenging to predict from first principles
which of these substrates would optimally promote access to both
the cyclization and 1,2-methyl shift. Therefore, we sought to use
DFT calculations to refine our selection of the key carbocationic
rearrangement precursor as a function of F-ring structure by
comparing the energetic barriers for the two possible
diastereomeric cyclizations and the methyl shift.
limitation of this approach is that the degree of error associated with
these calculations is uncertain.
An additional challenge in effecting the desired indole
cyclization reaction to form paspaline is that this ring formation
would need to result in a trans-fused 5-membered ring, despite the
fact that cyclization reactions that form fused 5-membered rings
generally lead to the formation of cis-fused ring systems.19 Both
stereochemical outcomes have been observed in synthetic studies
of other indoloterpenoid scaffolds.20 In one such instance, a study
by Ang Li and co-workers, which involves the formation of vicinal
quaternary centers results in the formation of the cis-fused ring
system.20a Conversely, a report by Dethe and co-workers discloses
the trans-stereoselectivity – though notably to form a different ring
system in the absence of vicinal quaternary centers.20b Fortuitously,
DFT analysis of all four diastereomeric cyclization intermediates
of precursor 4C predicted that our desired stereochemical outcome
(trans-C/D-fusion) was the more energetically favorable pathway
by at least 1.3 kcal/mol (see Supporting Information Figure S2).
In considering which mechanistic pathway to model, we
reasoned that the 1,2-methyl shift could occur via a concerted or
stepwise pathway, however the cyclization to form vicinal
quaternary centers is presumably limited to the carbocationic
pathway.17 As our goal was to select a route rather than predict
exact conditions, our calculations were conducted with a simplified
system (i.e. the gas phase carbocation). Although it would be
interesting to calculate the propensity of the concerted methyl
migration as a function of the substrate, comparison of these results
to the energetics of the stepwise cyclization would be challenging.
This is due to the two pathways requiring different assumptions and
simplifications (e.g. analysis of several leaving groups or
counterions, variable dependence on reagents, etc.), which may
mask the subtle differences that arise due to substrate structural
modification.
With a substrate defined for application of our transform goal, a
subsequent structure-goal strategy identified a Wieland-Miescher
ketone derivative as our starting material. We began our synthesis
with the thermodynamic alkylation of known Wieland-Miescher
ketone derivative 9, which was prepared in one step from
commercial materials by Robinson annulation with homoprenyl
iodide 10, resulting in formation of diketone 11 with a
diastereomeric ratio (d.r.) of 3:1 (Fig. 3).21 Dihydroxylation of the
more exposed alkene gave a separable mixture of diastereomers
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Scheme 1. Total Synthesis of Paspaline A (1) and Emindole PB (2)
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Reagents and conditions: (1) KOtBu (1.2 equiv), THF, 60 ˚C; then 10 (1.3 equiv), THF, 0 ˚C to 23 ˚C, 58% yield, 3:1 d.r. (2) K2OsO4 (2.5
mol%), citric acid (10 mol%), NMO (3.0 equiv), tBuOH:H2O (1:1 v:v), rt, 90% yield, 2:1 d.r. (3) CF3CO2H (1.0 equiv), CH2Cl2, 23 ˚C, 93%
yield. (4) Fe(acac)3 (1.2 equiv), PhSiH3 (3.0 equiv), EtOH, 65% yield. (5) LiHMDS (1.2 equiv), THF, 0 ˚C, then 14 (1.0 equiv); then KOH
(10.0 equiv), EtOH, 80 ˚C, 68% yield and 11% recovered 13. (6) MeLi (4.0 equiv), THF, 0 ˚C, 92% yield, >20:1 d.r. (7) AlCl3 (1.1 equiv),
CH2Cl2, –15 ˚C, 44% yield, 17:18 = 3:1. (8) TiCl4 (1.3 equiv), Et3SiH (2.0 equiv), CH2Cl2, 0 ˚C, 88% yield. (8’) AlMe3 (5.0 equiv), iPr2NH
(6.0 equiv), DCE, 80 ˚C, 92% yield. (9’) m-CPBA (1.2 equiv), THF, 0 ˚C; then Dess-Martin periodinane (4.0 equiv), THF, 23 ˚C, 56% yield.
(10’) HBr (0.5 equiv), THF, 23 ˚C to 40 ˚C, 69% yield. (11’) NaBH4 (4.0 equiv), THF:MeOH (1:1 v:v), 0 ˚C, 96% yield, >20:1 d.r. (12’)
TiCl4 (3.0 equiv), Et3SiH (3.0 equiv), CH2Cl2, 0 ˚C, 63% yield. (13’) Cu(OAc)2 (2.0 equiv), AgTFA (2.0 equiv), Pd(OAc)2 (30 mol%), 2-
methyl-2-butene (30.0 equiv), MeCN, 32% yield.
(2:1 d.r.), the major of which could be ketalized with TFA to
provide 12. Thermodynamic reduction using hydrogen atom
transfer conditions with Fe(acac)3 and PhSiH3 afforded tricycle 13
in 65% yield, as a single detectable diastereomer as confirmed by
X-ray crystallography.22,23 The indole moiety was introduced
through alkylation of 13 with tosyl-protected indole iodide 14,
which was deprotected in situ by the addition of ethanolic KOH.
The key precursor to the biomimetic transformation was obtained
through MeLi addition to 15, yielding the axial tertiary alcohol 16,
as confirmed by X-ray crystallography. The C-ring cyclization to
form the cyclopentane ring was found to proceed under a limited
set of reaction conditions with the optimal result obtained upon
treatment with AlCl3 in CH2Cl2. A mixture of the congeners 17 and
18 was isolated in 44% yield in a ratio of 3:1, favoring the methyl
migration product 17.
Given that related 1,2-methyl migrations have been suggested to
proceed via either stepwise or concerted pathways,17 we anticipate
the diastereomeric alcohol, which cannot undergo the concerted
methyl migration, might provide a higher yield of the cyclization
product 18. Synthesis of the diastereomeric equatorial alcohol was
attempted, but was unsuccessful by either modifying the conditions
used for nucleophilic addition to the ketone 15 or by alternative
strategies, such as alkene hydration or reductive epoxide opening.
Additionally, synthesis and acid-mediated activation of the
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exocyclic alkene did not result in formation of compounds 17 or
18.
To complete the synthesis of paspaline A, cyclization product 18
We gratefully acknowledge Dr. Brandon Mercado for X-ray
crystallography of compounds 11, 14, and 20 and Yingchuan
Zhu for technical assistance.
1
2
was subjected to ionic reduction conditions with TiCl4 and Et3SiH
to give the natural product (1) in 9 steps from commercially
available starting materials, which is approximately one third the
number of steps as either the landmark 25-step Smith or 27-step
Johnson syntheses.
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REFERENCES
[1] Corey, E. J.; Cheng, X. M. The Logic of Chemical Synthesis (Wiley,
New York, 1995)
[2] Corey, E. J.; Wipke, W. T. Computer-assisted Design of Complex
Organic Syntheses. Science 1969, 166, 178–192.
[3] (a) Todd, M. H. Computer-aided organic synthesis. Chem. Soc. Rev.
2004, 34, 247–266. (b) Szymkuc, S.; Gajewska, E. P.; Klucznik, T.;
Molga, K.; Dittwald, P.; Startek, M.; Bajczyk, M.; Grzybowski, B. A.
Computer-Assisted Synthetic Planning: The End of the Beginning.
Angew. Chem. Int. Ed. 2016, 55, 5904–5937.
[4] Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou,
K. G. M.; Qin, J.; Lilien, R.; Sarpong, R. Network-analysis-guided
synthesis of weisaconitine D and liljestrandinine. Nature 2015, 528,
493–498.
In the formation of compound 17, the elimination following the
methyl migration proceeded directly to the undesired
tetrasubstituted alkene. In order to transpose the olefin to the
desired position, enol ether 19 was accessed in 92% yield by
treatment of 17 with (i-Pr2N)AlMe2.24 A Rubottom oxidation of the
enol ether, followed by treatment with Dess-Martin periodinane,
provided a ,-unsaturated ketone. Isomerization of the alkene was
then elicited through treatment with HBr to give 20 in 69% yield.
Removal of the carbonyl functionality could be effected through
reduction of the enone to the allylic alcohol 21, followed by
simultaneous ionic reduction of both the allylic alcohol and ketal to
give 22. Subsequent N-reverse prenylation through a one-step
protocol described by Baran and co-workers provided emindole PB
(2) in greater yield (32%) than the conventional two-step
propargylation and reduction approach (11%).25 The material
obtained by this route produced spectroscopic data which agreed
with that of Kawai and co-workers, and the structure was confirmed
through comparative DFT NMR calculations (See Supporting
Information) and X-ray crystallography of the penultimate
intermediate 22.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[5] Elkin, M.; Newhouse, T. R. Computational chemistry strategies in
natural product synthesis. Chem. Soc. Rev. 2018, 47, 7830–7844.
[6] Tantillo, D. J. Questions in natural product synthesis research that can
(and cannot) be answered using computational chemistry. Chem. Soc.
Rev. 2018, 47, 7845–7850.
[7] (a) Smith, A. B.; Mewshaw, R. Total synthesis of (-)-paspaline. J. Am.
Chem. Soc. 1985, 107, 1769–1771. (b) Smith, A. B.; Leenay, T. L.
Indole diterpene synthetic studies. 5. Development of a unified
synthetic strategy; a stereocontrolled, second-generation synthesis of (-
)-paspaline. J. Am. Chem. Soc. 1989, 111, 5761–5768. (c) Smith, A. B.;
Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. Total synthesis of (+)-
paspalicine and (+)-paspalinine. J. Am. Chem. Soc. 1990, 112, 8197–
8198. (d) Smith, A. B.; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.;
Sunazuka, T. Indole diterpene synthetic studies. 8. The total synthesis
of (+)-paspalicine and (+)-paspalinine. J. Am. Chem. Soc. 1992, 114,
1438–1449. (e) Enomoto, M.; Morita, A.; Kuwahara, S. Total Synthesis
of the Tremorgenic Indole Diterpene Paspalinine. Angew. Chem. Int.
Ed. 2012, 51, 12833–12836. (f) Sharpe, R. J.; Johnson, J. S. A Global
and Local Desymmetrization Approach to the Synthesis of Steroidal
Alkaloids: Stereocontrolled Total Synthesis of Paspaline. J. Am. Chem.
Soc. 2015, 137, 4968–4971. (g) Sharpe, R. J.; Johnson, J. S.
Asymmetric Total Synthesis of the Indole Diterpenoid Alkaloid
Paspaline. J. Org. Chem. 2015, 80, 9740–9766. (h) George, D. T.;
Kuenstner, E. J.; Pronin, S. V. A Concise Approach to Paxilline Indole
Diterpenes. J. Am. Chem. Soc. 2015, 137, 15410–15413. (i) Godfrey,
N. A.; Schatz, D. J.; Pronin, S. V. Twelve-step asymmetric synthesis of
(-)-nodulisporic acid C. J. Am. Chem. Soc. 2018, 140, 12770–12774.
[8] Springer, J. P.; Clardy, J. Paspaline and paspalicine, two indole-
mevalonate metabolites from claviceps paspali. Tetrahedron Lett.
1980, 21, 231–234.
[9] Kawai, K.; Nozawa, K.; Nakajima, S. Structure of a new type of
indoloditerpenoid from Emericella purpurea. J. Chem. Soc. Perkin
Trans. 1 1994, 0, 1675–1674.
[10] Hosoe, T.; Itabashi, T.; Kobayashi, N.; Udagawa, S.; Kawai, K. Three
New Types of Indoloditerpenes, Emindole PA–PC, from Emericella
purpurea. Revision of the structure of emindole PA. Chem. Pharm.
Bull. 2006, 54, 185–187.
[11] Sallam, A. A.; Ayoub, N. M.; Foudah, A. I.; Gissendanner, C. R.;
Meyer, S. A.; El Sayed, K. A. Indole diterpene alkaloids as novel
inhibitors of the Wnt/-catenin pathway in breast cancer cells. Eur. J.
Med. Chem. 2013, 70, 594–606.
[12] Nusse, R. ; Clevers, H. Wnt/-catenin Signaling, Disease, and
Emerging therapeutic Modalities. Cell 2017, 169, 985–999.
[13] Tagami, K.; Liu, C.; Minami, A.; Noike, M.; Isaka, T.; Fueki, S.;
Shichijo, Y.; Toshima, H.; Gomi, K.; Dairi, T.; Oikawa, H.
Reconstitution of Biosynthetic Machinery for Indole-Diterpene
Paxilline in Aspergillus orizae. J. Am. Chem. Soc. 2013, 135, 1260–
1263.
DFT augmented retrosynthesis can assist in selecting substrates
to be prioritized for experimentation and significantly streamline
synthetic workflows. In this manuscript, we demonstrate how
transform-based strategies can be refined through a priori DFT
calculations, and apply this approach to the synthesis of paspaline
A in approximately one third the steps of previous routes as well as
the first synthesis of emindole PB. The limitations and capabilities
of this computational approach are still unexplored, but further
studies in predictive computational evaluation and experimentation
will define the boundaries of this framework.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures, X-ray
diffraction, spectroscopic data for all new compounds including
1H- and 13C-NMR spectra (PDF), Crystallographic data (CIF).
AUTHOR INFORMATION
Corresponding Author
timothy.newhouse@yale.edu
Funding Sources
Financial support for this work was provided by Yale
University, the Sloan Foundation, Amgen and the National
Science Foundation (GRFP to J.E.Z.). We gratefully
acknowledge the National Science Foundation for financial
support in the establishment of the Yale University High
Performance Computing (HPC) Center (CNS 08-21132).
[14] Tang, M. C.; Lin, H. C.; Li, D.; Zou, Y.; Li, J.; Xu, W.; Cacho, R. A.;
Hillenmeyer, M. E.; Garg, N. K.; Tang, Y. Discovery of Unclustered
Notes
Fungal
Indole-Diterpene
Biosynthetic
Pathways
Through
The authors declare no competing financial interest.
Combinatorial Pathway Reassembly in Engineered Yeast. J. Am. Chem.
Soc. 2015, 137, 13724–13727.
ACKNOWLEDGMENT
[15] Nakanishi, K.; Doi, M.; Usami, Y.; Amagata, T.; Minoura, K.; Tanaka,
R.; Numata, A.; Yamada, T. Anthcolorins A–F, novel cytotoxic
4
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metabolites from
a
sea urchin derived Aspergillus versicolor.
[19] Beckwith, A. L. J.; Phillipou, G.; Serelis, A. K. Formation of Some
Tetrahedron 2013, 69, 4617–4623.
Bicyclic Systems by Radical Ring-Closure. Tetrahedron Lett. 1981, 22,
2811–2814.
1
2
3
4
5
6
7
8
[16] (a) Rainer, D. J.; Smith, A. B. Polyene cyclizations to indole
diterpenes. The first synthesis of (+)-emindole SA using a biomimetic
approach. Tetrahedron Lett. 2000, 41, 9419–9423. (b) Clark, S. J.;
Myatt, J.; Wilson, C.; Roberts, L.; Walshe, N. Exploration of the
biomimetic synthesis of indole-diterpene mycotoxins: an unexpected
cascade reaction during the attempted synthesis of emindole SB. Chem.
Commun. 2003, 0, 1546–1547. (c) Clark, S. J.; Myatt, J.; Roberts, L.;
Walshe, N. Investigation of the Biomimetic Synthesis of Emindole SB
Using a Fluorinated Polyene Cyclisation Precursor. Synlett 2005, 4,
697–699. (d) Isaka, T.; Hasegawa, M.; Toshima, H. Biomimetic
Cyclization of Epoxide Precursors of Indole Mono-, Sesqui- and
Diterpene Alkaloids by Lewis Acids. Biosci. Biotechnol. Biochem.
2011, 75, 2213–2222.
[17] Elkin, M.; Scruse, A. C.; Turlik, A.; Newhouse T. R. Computational
and Synthetic Investigation of Cationic Rearrangement in the Putative
Biosynthesis of Justicane Triterpenoids. Angew. Chem. Int. Ed. 2019,
DOI: 10.1002/anie.201810566.
[18] Matsuda, S. P. T.; Wilson, W. K.; Xiong, Q. Mechanistic insights into
triterpene synthesis from quantum mechanical calculations. Detection
of systematic errors in B3LYP cyclization energies. Org. Biomol.
Chem. 2006, 4, 530–543.
[20] (a) Xiong, X.; Zhang, D.; Li, J.; Sun, Y.; Zhou, S.; Yang, M.; Shao, H.;
Li, A. Synthesis of Indole Terpenoid Mimics through a Functionally-
Tolerated Eu(fod)3-catalyzed Conjugate Addition. Chem. Asian J.
2015, 10, 869–872. (b) Dethe, D. H.; Sau, S. K.; Mahapatra, S.
Biomimetic Enantioselective Total Synthesis of (−)-Mycoleptodiscin
A. Org. Lett. 2016, 18, 6392–6395.
[21] Wan, K. K.; Iwasaki, K.; Umotoy, J. C.; Wolan, D. W.; Shenvi, R. A.
Nitrosopurines En Route to Potently Cytotoxic Asmarines. Angew.
Chem. Int. Ed. 2015, 54, 2410–2415.
[22] Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W. M.; Shenvi,
R. A. Simple, Chemoselective Hydrogenation with Thermodynamic
Stereocontrol. J. Am. Chem. Soc. 2014, 136, 1300–1303.
[23] King, S. M.; Ma, X.; Herzon, S. B. A Method for the Selective
Hydrogenation of Alkenyl Halides to Alkyl Halides. J. Am. Chem. Soc.
2014, 136, 6884–6887.
[24] Nicolaou, K. C.; Kubota, S.; Li, W. S. A new synthesis of
dihydroimidazo-compounds. J. Chem. Soc. Chem. Commun. 1989, 0,
512–514.
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[25] Luzung, M. R.; Lewis, C. A.; Baran, P. S. Direct, Chemoselective N-
tert-Prenylation of Indoles by C-H Functionaliztion. Angew. Chem. Int.
Ed. 2009, 48, 7025–7029.
H
H
Me
Me
Me
Me
Me
Me
Me
OH
Me
O
N
O
OH
H
Me
Me
H
Me
H
H
H
H
H
N
Me
paspaline A
(9 steps)
emindole PB
(13 steps)
5
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