Lithium bis-catechol borate as an effective reductive quencher in photoredox catalysis

Article abstract of DOI:10.1016/j.tet.2018.04.053

The use of lithium bis-catechol borate (LiB(cat)₂) as a reductive quencher for the photoredox mediated intermolecular C–H functionalization of various heteroaromatics with bromopyrroloindolines is described. LiB(cat)₂ offers a financial benefit over state-of-the-art quenchers currently in use while eliminating the side reactions that typically plague these couplings. The advantage of this methodology is highlighted by the synthesis of C3–C2’ (?) gliocladin C. Furthermore, additional examples of reactivity with various bromopyrroloindolines sets the stage for expedient routes towards other pharmaceutically active hexahydropyrroloindoline alkaloids and their analogues.

Full text of DOI:10.1016/j.tet.2018.04.053

Accepted Manuscript
Lithium bis-catechol borate as an effective reductive quencher in photoredox catalysis
Martin J. Sevrin, Laura Furst, John D. Nguyen, James L. Collins, III, Corey R.J.
Stephenson
PII:
S0040-4020(18)30442-3
10.1016/j.tet.2018.04.053
TET 29468
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 January 2018
Revised Date: 13 April 2018
Accepted Date: 17 April 2018
Please cite this article as: Sevrin MJ, Furst L, Nguyen JD, Collins III JL, Stephenson CRJ, Lithium bis-
catechol borate as an effective reductive quencher in photoredox catalysis, Tetrahedron (2018), doi:
10.1016/j.tet.2018.04.053.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Lithium bis-catechol borate as an effective reductive quencher in photoredox catalysis
Martin J. Sevrin, Laura Furst, John D. Nguyen, James L. Collins III and Corey R. J. Stephenson*
Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor, MI 48109,
USA; Email: crjsteph@umich.edu
Abstract The use of lithium bis-catechol borate (LiB(cat)2) as a reductive quencher for the
photoredox mediated intermolecular C–H functionalization of various heteroaromatics with
bromopyrroloindolines is described. LiB(cat)2 offers a financial benefit over state-of-the-art
quenchers currently in use while eliminating the side reactions that typically plague these
couplings. The advantage of this methodology is highlighted by the synthesis of C3–C2’ (–)
gliocladin C. Furthermore, additional examples of reactivity with various bromopyrroloindolines
sets the stage for expedient routes towards other pharmaceutically active
hexahydropyrroloindoline alkaloids and their analogues.
1. Introduction
In recent years, visible light-mediated catalysis has been extensively studied to develop an array
of novel organic transformations.1–3 Of the myriad methods centered around photo-induced
single electron transfer (SET) chemistry, our research program has been particularly interested in
the reduction of activated and unactivated C–X bonds.4,5 Using a photoredox catalyst, an
efficient method for the intramolecular radical arylation of electron-rich heterocycles was
developed.6 Traditionally, chemists have employed trialkyl amines as sacrificial reductive
quenchers for photocatalytic reactions. However, several unavoidable side reactions can limit the
potential of photocatalysis. Of these undesired pathways, hydrogen atom abstraction from
trialkyl amine 1 by radicals (2) lead to premature reduction of activated halides (3) (Figure 1).
Importantly, the rate of unwanted hydrogen atom transfer is competitive with the desired
trapping with a heterocycle or activated alkene. In the case of bromopyrroloindolines, which our
group has been interested in coupling with heterocycles for natural product syntheses, trialkyl
amines reactivity had so far limited their use.
This undesired reactivity initially hampered our efforts to develop redox neutral coupling
protocol. We, therefore, introduced commercially available 4-methoxy-N,N-diphenylaniline 4 as
a novel reductive quencher in photoredox catalysis.7 In the absence of α-protons, the formed N-
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centered radical cation is unable to act as a hydrogen atom donor. Due to the high cost of this
reductive quencher,8 we envisioned employing a less expensive alternative that still avoided the
deleterious side reactions seen with trialkyl amines. Similar to trialkyl amines, the redox
potential of the novel quencher would have to be in the electrochemical window required for
reductive quenching of photocatalysts such as Ru(bpy)32+ (E1/2II*/I = +0.77 V vs SCE)9 as well as
be inexpensively procured. Finally, the new reductive quencher and its oxidized state need to be
innocent species in the desired reaction.
The indole aromatic scaffold is ubiquitous in both bioactive natural products and
pharmaceuticals,1 and tremendous effort has been expended to develop methods for the robust
and efficient functionalization of the heteroaromatic skeleton. In the same vein, reliable
investigation of the bioactivity of the natural frameworks has often relied upon de novo synthesis
to supply the necessary quantities for study. Indole alkaloids functionalized at both the 2- and 3-
carbons of the aromatic scaffold, such as undulifoline,2 actinophyllic acid,3 vinblastine and
vincristine,4 piqued our interest into radical indole alkylation as they pose both strategic and
methodological challenges (Figure 1).
Figure 1. Off-cycle reactivity with trialkyl amine reductive quenchers
2. Results and discussion
Given the previous success of tertiary amines as reductive quenchers, we began looking for other
commercially available amines capable of undergoing reductive SET without resulting in
premature reduction. Our search proved unfruitful; no amine unable to undergo H-atom donation
was financially competitive or a productive quencher. In 2006, lithium bis-catechol borate 5
(LiB(cat)2) was reported as a reductive quencher of photoexcited ruthenium polypyridyl
complexes (Figure 2).10
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Figure 2. Comparison of reductive quenchers
Although not directly available for purchase, borate complexes can readily be synthesized from
abundantly-available commodity chemicals: boric acid and catechol. Furthermore, once
oxidized, the borate complex is no longer ionic and thus can easily diffuse from the iridium or
ruthenium photocatalyst, inhibiting the unproductive back electron transfer process.11 Detailed
herein, this low-cost, inert sacrificial reductant has been shown to operate effectively in our
reductive, formal C–H functionalization of electron-rich heterocycles while also enabling a
universal method to couple bromopyrroloindolines with electron-rich or electron-poor
heterocycles.
The reaction conditions can be varied based on the availability of either coupling partner. If the
heterocycle is more precious than the reagents, an excess of halide can be used. Using less than
two equivalents of diethyl bromomalonate led to slow reactions and/or poor conversions to the
product. Moderate to good yields were observed for electron-rich and electron-poor indoles
(Scheme 1, 6–8). Pyrroles and even azaindole were also compatible with this method (9–10).
The starting material was fully consumed within 3 hours. It should be noted that in the case of
more electron rich heterocycles such as thianaphthene, only decomposition of starting materials
was observed (11).
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Scheme 1. Malonate coupling scope
The radical coupling with bromopyrroloindolines with various heterocycles was also attempted
(Scheme 2). Coupling with indole 12 occurred in 60% isolated yield. The use of LiB(cat)2
enabled a shorter reaction time and a reduced excess of indole compared to trialkyl amine
quenchers which was critical to achieve a 50% improvement in yield as the product was prone to
decomposition under reaction conditions (Figure 3). Notably, indole-2-carbaldehyde, 13, led to
isolation of the product in 91% yield, a significant improvement of the key step towards the
synthesis of the natural product (+)-gliocladin C. Previous efforts required five equivalents of
indole, longer reaction times and resulted in a lower yield (Figure 3).12 N-Boc tryptophan was
isolated in good yields (14, 57%). Pyrrole (15) and furan (16) were also compatible with our
optimized reaction protocol. Lastly, quenching the bromopyrroloindolines radical with butyl
vinyl ether afforded the target aldehyde in good yields (17, 71%). The resulting aldehyde
provides a simple yet useful handle for further transformation. For example, this aldehyde could
be used to revisit syntheses of (–)-flustramine B and (+)-nocardiozines.13 Interestingly, we did
not observe poor mass recovery in cases with electron-rich heterocycles, a dramatic
improvement compared to our coupling of di-ethyl bromomalonate with said substrates.
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Scheme 2. Bromopyrroloindoline coupling scope
Figure 3. Improved key step towards gliocladin C and its analogues
Having demonstrated the versatility of the new reductive quencher, we decided to apply this
method towards the synthesis of a gliocladin C analogue. Natural gliocladin C is a
hexahydropyrroloindoline alkaloid14 containing a C3-C3’ bisindole motif. Along other natural
products of this class of alkaloids, gliocladin C exhibits potent cytotoxic properties against
lymphocytic leukemia cell lines (ED50 = 240 ng mL-1).15 Novel analogues of gliocladin C are
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highly desired due to their potential as new anti-cancer therapy leads. Given our previous re-
port,12 we sought to synthesize the C3-C2’ gliocladin C, 18, in a quick and efficient manner
(Scheme 3). Starting from bromopyrrolindoline 19, C3-C2’ coupling with indole proceeded
smoothly with the catechol borate quencher to isolate 12 in good yield (60 %). Boc-deprotection
with TMSI followed by N-acylation led to the desired triketopiperazine 20 after an unexpected
second N-acylation occurring during silica gel chromatography. Finally, Pd/C dehydrogenation
provided 21 and a Lewis acid-mediated deprotection delivered the C3–C2’ unnatural gliocladin
C (18) in 97% yield.
Scheme 3. Total synthesis of C3-C2’ unnatural gliocladin C 18
We propose that a reductive quenching cycle is occurring in this reaction (Figure 4). Ir(III) is
excited by visible light irradiation to form Ir(III)*, which is then reductively quenched by
LiB(cat)2 to form the highly reducing Ir(II) species and 22. Reductive dehalogenation
regenerates Ir(III) and malonyl radical 23 that adds to the desired heterocycle, such as 3-methyl
indole (24). Multiple mechanisms can be suggested for the re-aromatization of 25 to form
product 6. We propose 23 can oxidize 25, which after deprotonation would yield 6. With re-
aromatization as a potent driving force to 6, deprotonation occurring before electron-transfer
cannot be excluded. Given the short reaction times of this protocol, a chain propagation
mechanism in which 25 is deprotonated is also possible.16
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Figure 4. Proposed mechanism
3. Conclusions
In summary, we have introduced a novel reductive quencher, catechol borate, that can be
synthesized on scale in a single step from inexpensive commercial reagents. Employing
LiB(cat)2 as a quencher in reductive photoredox dehalogenation was found to eliminate
undesired hydrogen atom abstraction observed with trialkyamines. The protocol can
accommodate cases in which either substrates may be used in excess, lending desired flexibility
in multistep routes towards a chemical agent. Notably, this method achieves a long-standing goal
of using photoredox catalysis with non-commercially available and precious
bromopyrroloindolines which thus far had not shown to be universally compatible or reactive in
photoredox methods. Access to this reactivity unlocks new routes towards
hexahydropyrroloindoline alkaloids and their analogues, as shown in our synthesis of unnatural
C3–C2’ (–)-gliocladin C, which was prepared in 6 steps (11% overall yield).
4. Experimental Section
4.1. General experimental methods
Chemicals were used as received. All reactions were performed using common inert atmosphere
techniques. Reactions were monitored by TLC and visualized by a dual short wave/long wave
UV lamp and stained with an ethanolic solution of potassium permanganate or p-anisaldehyde.
Flash column chromatography was performed using 230–400 mesh silica gel. NMR spectra were
recorded on Varian Unity Plus 400, Varian MR400, Varian vnmrs 500, Varian Inova 500, Varian
1
Mercury 500, and Varian vnmrs 700 spectrometers. Chemical shifts for H NMR were reported
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as δ, parts per million, relative to the signal of CHCl3 at 7.26 ppm or CD3OD at 4.78 ppm.
13
Chemical shifts for C NMR were reported as δ, parts per million, relative to the center line
signal of the CDCl3 triplet at 77.0 ppm or the center line signal of the CD3OD septet at 49.15
19
ppm. Chemical shifts for F NMR were reported as δ, parts per million, relative to the center
line signal of the C6H5CF3 triplet at –63.78 ppm. The abbreviations s, br. s, d, dd, br. d, ddd, t, q,
br. q, qi, m, and br. m stand for the resonance multiplicity singlet, broad singlet, doublet, doublet
of doublets, broad doublet, doublet of doublet of doublets, triplet, quartet, broad quartet, quintet,
multiplet and broad multiplet, respectively. IR spectra were recorded on a Perkin-Elmer
Spectrum BX FT-IR spectrometer. Mass spectra were recorded at the Mass Spectrometry
Facility at the Department of Chemistry of the University of Michigan in Ann Arbor, MI on an
Agilent Q-TOF HPLC-MS with ESI high resolution mass spectrometer. UV/Visible spectra were
recorded at the Analytical Instruments Facility at the Department of Chemistry of the University
of Michigan in Ann Arbor, MI on a Shimadzu UV-1601 UV-Vis spectrometer. Concentration
refers to removal of solvent under reduced pressure (house vacuum at ca. 20 mmHg). LED lights
and the requisite power box and cables were purchased from Creative Lighting Solutions
(http://www.creativelightings.com) with the following item codes: CL-FRS5050-12WP-12V
(4.4W blue LED light strip), CL-FRS5050WPDD-5M-12V-BL (72 W LED strip), CL-PS94670-
25W (25 W power supply), CL-PS16020-150W (150 W power supply), CL-PC6FT-PCW
(power cord), CL-TERMBL-5P (terminal block). The 300 W 2500 lumen white LED work light
was purchased from Home Depot Model # WL2540LP.
Synthesis of lithium bis-catechol borate
To a 100 mL round bottom flask equipped with rubber septum and magnetic stir bar was added
catechol (17.8 g, 162 mmol, 2.0 equiv) and methanol (35 mL). Lithium hydroxide monohydrate
(3.40 g, 81 mmol, 1.0 equiv) was added and the reaction was stirred until homogeneous (mild
heat can be used to speed up the process). Boric acid (5.00 g, 81 mmol, 1.0 equiv) was added
and the reaction was allowed to stir at 60 °C for 1 hour. Methanol was removed via rotary
evaporation and the reaction mixture was dissolved in THF (80 mL). Stir bar was removed and
hexanes (~100 mL) was slowly added to precipitate the desired product. Crystals were collected
via vacuum filtration and washed with hexanes, then ether until white. Product was further dried
overnight over phosphorus pentoxide under reduced pressure. Spectroscopic data in agreement
with previous report.1
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Note: Lithium bis-catechol borate should be kept in a desiccator checked for quality if stored for
a period longer than one month. To check for decomposition, dissolve a sample of LiBCat2 in
THF. If a green color is observed, the batch should be discarded. Cause of green color is
hypothesized to be semi-quinone species generated via partial O2 oxidation.
Couplings with diethyl bromomalonate
General Procedure A: A flame dried 25 mL round bottom flask equipped with a rubber septum
and magnetic stir bar was charged with Ir(ppy)2(dtbbpy)PF6 (0.01 equiv), diethyl bromomalonate
(0.5–2.0 equiv), bis-catechol borate lithium salt (2.0 equiv) and corresponding indole or olefin (1
equiv). The flask was purged with a stream of argon and dry DMSO was added. The resultant
mixture was degassed by argon sparging for 20 min and placed at a distance of ~2 cm from a
blue LED strip. After the reaction was complete (as judged by TLC analysis), the mixture was
poured into a separatory funnel containing 75 mL of EtOAc and 75 mL of sat. Na2CO3 (aq). The
layers were separated and the aqueous layer was extracted with EtOAc (2 X 50 mL). The
combined organic layers were dried (over Na2SO4) and concentrated. The residue was purified
by chromatography on SiO2, using the solvent system indicated, to afford the desired product.
Diethyl 2-(3-methyl-1H-indol-2-yl)malonate (6)
According to General Procedure A, 3-methyl indole (70 mg, 0.53 mmol), LiB(cat)2 (0.26 g, 1.1
mmol), diethyl bromomalonate (182 ꢀL, 1.1 mmol, 2.0 equiv) and Ir(ppy)2(dtbbpy)PF6 (4.9 mg,
10.0 ꢀmol) in dry DMSO (5.0 mL) afforded 6 (105 mg, 68%) as a white solid after purification
by chromatography on SiO2 (10-35% EtOAc/hexanes) (3 h reaction time). Spectroscopic data in
agreement with previous report.2 1H NMR (400 MHz): δH 8.93 (br. s., 1 H), 7.55 (dd, J = 7.8, 1.2
Hz, 1 H), 7.42-7.30 (m, 1H), 7.23- 7.16 (m, 1 H), 7.16-7.04 (m, 1 H), 4.38-4.13 (m, 4 H), 2.39-
2.21 (m, 3 H), 1.36-1.20 (m, 6 H).
Diethyl 2-(2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl)malonate (7)
According to General Procedure A, 1-methylindole-2-carboxylate (175 mg, 1.0 mmol), LiB(cat)2
(0.47 g, 2.0 mmol), diethyl bromomalonate (0.36 ꢀL, 5.0 mmol, 5.0 equiv) and
Ir(ppy)2(dtbbpy)PF6 (9.1 mg, 10.0 ꢀmol) in dry DMSO (10.0 mL) afforded 7 (0.22 g, 42%) as a
white solid after purification by chromatography on SiO2 (10-35% EtOAc/hexanes) (3 h reaction
time). Spectroscopic data in agreement with previous report.2 1H NMR (400 MHz): δH 7.78-7.64
(m, 1 H), 7.43-7.30 (m, 2 H), 7.20-7.10 (m, 1 H), 5.75 (s, 1 H), 4.32-4.15 (m, 4 H), 4.02 (s, 3 H),
3.94 (s, 3 H), 1.24 (t, J = 7.1 Hz, 6 H).
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Diethyl
(S)-2-(3-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-indol-2-
yl)malonate (8)
According to General Procedure A, methyl (2S)-2-(tert-butoxycarbonylamino)-3-(1H-indol-3-
yl)propanoate (0.200 g, 0.63 mmol), LiB(cat)2 (0.308 g, 1.3 mmol), diethyl bromomalonate (214
ꢀL, 1.3 mmol, 2.0 equiv) and Ir(ppy)2(dtbbpy)PF6 (5.7 mg, 6.0 ꢀmol) in dry DMSO (10.0 mL)
afforded 8 (0.14 g, 47%) as a beige solid after purification by chromatography on SiO2 (10-35%
EtOAc/hexanes) (3 h reaction time). Spectroscopic data in agreement with previous report.2 1H
NMR (400 Mhz): δH 8.93 (br. s., 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.17
(td, J = 7.5, 1.2 Hz, 1 H), 7.12-7.04 (m, 1 H), 5.24 (d, J = 8.0 Hz, 1 H), 4.96 (s, 1 H), 4.70-4.57
(m, 1 H), 4.33-4.13 (m, 4 H), 3.59 (s, 3 H); 3.26 (d, J = 5.9 Hz, 2 H), 1.39 (s, 6 H), 1.27 (td, J =
7.1, 1.5 Hz, 6 H).
Diethyl 2-(3-acetyl-1-methyl-1H-pyrrol-2-yl)malonate (9)
According to General Procedure A, 1-(1-methylpyrrol-3-yl)ethanone (88 mg, 0.711 mmol),
LiB(cat)2 (0.17 g, 0.71 mmol), diethyl bromomalonate (53.5 ꢀL, 0.36 mmol, 2.0 equiv) and
Ir(ppy)2(dtbbpy)PF6 (3.2 mg, 4.0 ꢀmol) in dry DMSO (3.5 mL) afforded 9 (100 mg, 57%) as a
white solid after purification by chromatography on SiO2 (15% EtOAc/hexanes) (16 h reaction
time). Spectroscopic data in agreement with previous report.2 1H NMR (300 MHz): δH 6.61 (s, 1
H), 6.53 (dd, J = 15.3, 2.9 Hz, 1 H), 4.38-4.05 (m, 4 H), 3.63 (s, 3 H), 2.40 (s, 3 H), 1.27 (t, J =
7.1 Hz, 6 H).
Diethyl 2-(5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)malonate (10)
According to General Procedure A, 5-bromo-1-methyl-pyrrolo[2,3-b]pyridine (75 mg, 0.36
mmol), LiB(cat)2 (0.175 g, 0.74 mmol), diethyl bromomalonate (121 ꢀL, 0.71 mmol, 2.0 equiv)
and Ir(ppy)2(dtbbpy)PF6 (3.2 mg, 4.0 ꢀmol) in dry DMSO (5.7 mL) afforded 10 (55 mg, 42%) as
a yellow oil after purification by chromatography on SiO2 (10-35% EtOAc/hexanes) (3 h
reaction time). Spectroscopic data in agreement with previous report.2 1H NMR (500 MHz): δH
8.25 (d, J = 2.2 Hz, 1 H), 7.89 (dd, J = 2.2, 0.5 Hz, 1 H), 6.44 (s, 1 H), 4.84 (s, 1 H), 4.30 – 4.11
(m, 4 H), 3.73 (s, 3 H), 1.22 (t, J = 7.1 Hz, 6 H).
Couplings with bromopyrroloindolines
General Procedure B: A flame dried 25 mL round bottom flask equipped with a rubber septum
and magnetic stir bar was charged with Ir(ppy)2(dtbbpy)PF6 (10 µmol, 0.01 equiv), the
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corresponding bromopyrroloindoline (1.0 mmol, 1.0 equiv), bis-catecholborate lithium salt (2.0
mmol, 2.0 equiv) and corresponding indole or olefin (2.0–10.0 equiv). The flask was purged with
a stream of argon and 10 mL of dry DMSO was added. The resultant mixture was degassed by
argon sparging for 20 min and placed at a distance of ~2 cm from a blue LED strip. After the
reaction was complete (as judged by TLC analysis), the mixture was poured into a separatory
funnel containing 75 mL of EtOAc and 75 mL of sat. Na2CO3 (aq). The layers were separated
and the aqueous layer was extracted with EtOAc (2 X 50 mL). The combined organic layers
were dried (over Na2SO4) and concentrated. The residue was purified by chromatography on
SiO2, using the solvent system indicated, to afford the desired product.
(2R,3aR,8aS)-8-benzyl-1-tert-butyl-3a-(1H-indol-2-yl)-2-(methylcarbamoyl)-3,3a-
dihydropyrrolo[2,3-b]indole-1,8(2H,8aH)-dicarboxylate (12)
According to General Procedure B, bromopyrroloindoline 19 (0.53 g, 1.0 mmol), LiB(cat)2 (0.47
g, 2.0 mmol), indole (1.2 g, 10.0 mmol, 10.0 equiv) and Ir(ppy)2(dtbbpy)PF6 (9.1 mg, 10.0 ꢀmol)
in dry DMSO (10.0 mL) afforded 12 (0.34 g, 60%) as a white solid after purification by
chromatography on SiO2 (1:1 hexanes/EtOAc) (3 h reaction time). Excess indole was recovered
25
upon purification and re-used. Rf (1:1 hexanes/EtOAc): 0.32; [α]
= -45.3° (c 0.7, CHCl3); IR
D
(neat): 3359, 2975, 1715, 1667, 1555, 1482, 1456, 1407, 1366, 1323, 1283, 1216, 1157, 1026,
914, 750 cm-1; 1H NMR (500 MHz, CDCl3) δH 7.69 (d, J = 7.69 Hz, 1 H), 7.33 - 7.45 (m, 5 H),
7.14 - 7.23 (m, 7 H), 7.06 (t,J=7.05 Hz,1 H), 6.30 (br. s., 2 H), 5.94 (br. s., 1 H), 5.32 (d, J =
12.47 Hz, 1 H), 5.10 (d, J = 12.47 Hz, 1 H), 4.28 (br. s., 1 H), 2.98 (dd, J = 4.89 Hz, 1 H), 2.92
13
(d, J = 4.89 Hz, 3 H), 2.81 - 2.85 (m, 1 H), 1.41 (s, 9 H); C NMR (126 MHz, cdcl3) δ 173.34,
153.54, 141.36, 138.44, 137.16, 135.96, 129.35, 128.60, 128.14, 127.75, 127.54, 124.71, 124.63,
122.21, 120.43, 119.82, 118.04, 111.40, 101.99, 82.52, 81.86, 67.69, 60.84, 56.22, 38.21, 28.38,
+
28.30, 28.24, 26.66, 26.52; HRMS (ESI) m/z calculated for C33H34N4NaO5 ([M+Na]+)
589.2427, found 589.2424.
(2R,3aR,8aS)-8-benzyl-1-tert-butyl-3a-(2-formyl-1H-indol-3-yl)-2-(methylcarbamoyl)-3,3a-
dihydropyrrolo[2,3-b]indole-1,8(2H,8aH)-dicarboxylate (13)
According to General Procedure B, bromopyrroloindoline 19 (0.53 g, 1.0 mmol), LiB(cat)2 (0.47
g, 2.0 mmol), indole-2-carboxaldehyde (0.29 g, 2.0 mmol, 2.0 equiv) and Ir(ppy)2(dtbbpy)PF6
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(9.1 mg, 10.0 ꢀmol) in dry DMSO (10.0 mL) afforded 13 (0.54 g, 91%) as a white solid after
purification by chromatography on SiO2 (7:3 hexanes/acetone) (6 h reaction time). Rf (3:2
hexanes/acetone): 0.30. Spectroscopic data in agreement with previous report.3 1H NMR
(CDCl3, 400 MHz) δH 9.32 (s, 1 H), 8.22 (s, 1 H), 8.05 (d, J = 6.8 Hz, 1 H), 7.71 (br. s, 1 H),
7.42-7.34 (m, 4 H), 7.21-7.04 (m, 7 H), 6.64 (s, 1 H), 6.06 (s, 1 H), 5.25 (d, J = 12.4 Hz, 1 H),
4.97 (d, J = 12.0 Hz, 1 H), 4.00 (dd, J = 9.6, 7.2 Hz, 1 H), 3.40 (dd, J = 12.8, 10.0 Hz, 1 H), 2.95
(dd, J = 12.8, 6.8 Hz, 1 H), 2.86 (d, J = 4.8 Hz, 3 H), 1.37 (s, 9 H).
(2R,3aR,8aS)-8-benzyl-1-tert-butyl-2-methyl-3a-(3-((S)-2-((tert-butoxycarbonyl)amino)-3-
methoxy-3-oxopropyl)-1H-indol-2-yl)-3,3a-dihydropyrrolo[2,3-b]indole-1,2,8(2H,8aH)-
tricarboxylate (14)
According to General Procedure B, bromopyrroloindoline 19 (1.1 g, 2.0 mmol), LiB(cat)2 (0.93
g, 4.0 mmol), Boc-tryptophan methyl ester (6.3 g, 20 mmol, 10 equiv) and Ir(ppy)2(dtbbpy)PF6
(18 mg, 20 ꢀmol) in dry DMSO (20.0 mL) afforded 14 (0.88 g, 57%) as a white solid after
purification by chromatography on SiO2 (0:100→1:99 MeOH/CH2Cl2) (12 h reaction time). Rf
25
(8:2, hexanes/EtOAc): 0.16; [α]
= +1.3° (c 0.0048, CHCl3); IR (neat): 3385, 3360, 2980,
D
1
1719, 1482, 1456, 1437, 1409, 1367, 1332, 1285, 1214, 1156, 1064, 1021, 752 cm-1; H NMR
(500 MHz, CDCl3) δH 7.81 (br. s., 1 H), 7.64 (d, J = 7.6 Hz, 1 H), 7.59 (br. s., 1 H), 7.53 (d, J =
7.3 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 1 H), 7.16-7.35 (m, 9 H), 6.58 (s, 1 H), 5.45 (d, J = 12.5 Hz, 1
H), 5.15 (d, J = 8.1 Hz, 2 H), 4.69 (d, J = 7.6 Hz, 1 H), 4.16 (m, 1 H), 3.90 (s, 3 H), 3.63 (s, 3 H),
3.27-3.35 (m, 2 H), 3.14 (dd, J = 12.7, 6.6 Hz, 1 H), 3.01 (d, J = 10.8 Hz, 1 H), 1.47 (d, J= 31.8
18 H); 13C NMR (126 MHz) δC172.95, 172.47, 154.94, 153.23, 141.51, 134.63, 130.05, 129.33,
128.44, 128.02, 127.49, 124.05, 122.41, 119.90, 119.03, 110.94, 107.72, 82.50, 81.56, 79.70,
67.71, 60.39, 59.80, 54.17, 52.40, 52.15, 38.09, 28.57, 28.21, 21.03, 14.20; HRMS (ESI) m/z
calculated for C42H48N4NaO10+ ([M+Na]+) 791.3268, found 791.3254.
(2R,3aR,8aS)-8-benzyl-1-tert-butyl-3a-(3-acetyl-1-methyl-1H-pyrrol-2-yl)-2-
(methylcarbamoyl)-3,3a-dihydropyrrolo[2,3-b]indole-1,8(2H,8aH)-dicarboxylate (15)
According to General Procedure B, bromopyrroloindoline 19 (0.53 g, 1.0 mmol), LiB(cat)2 (0.47
g, 2.0 mmol), 1-methyl-3-acetylpyrrole (0.59 ꢀL, 5.0 mmol, 5.0 equiv) and Ir(ppy)2(dtbbpy)PF6
(9.1 mg, 10.0 ꢀmol) in dry DMSO (10.0 mL) afforded 15 (0.34 g, 60%) as a white solid after
12

ACCEPTED MANUSCRIPT
purification by chromatography on SiO2 (1:1 hexanes/EtOAc) (12 h reaction time). Rf (1:1
25
hexanes/EtOAc): 0.16; [α]
= −83.1° (c 0.0081, CHCl3); IR (neat): 3393, 2978, 2930, 1710,
D
1645, 1547, 1483, 1406, 1378, 1359, 1324, 1284, 1263, 1213, 1151, 1134, 1080, 1065, 1021,
926, 864, 750 cm-1; 1H NMR (500 MHz, CDCl3) δH 7.59 (br. s., 1 H), 7.32-7.37 (m, 2 H), 7.06-
7.19 (m, 4 H), 6.55 (br. s., 1 H), 6.42 (s, 1 H), 6.21 (br. s., 1 H), 5.30 (d, J = 12.2 Hz, 1 H), 5.04
(br. s., 1 H), 3.83 (t, J = 7.8 Hz, 1 H), 2.81-2.84 (m, 4 H), 2.69-2.73 (m, 1 H), 2.66 (s, 3 H), 2.41
13
(s, 3 H), 1.30 (s, 9 H); C NMR (126 MHz, cdcl3) δ 194.84, 173.50, 153.33, 142.55, 136.56,
134.35, 132.53, 130.48, 128.65, 128.53, 128.36, 127.90, 127.44, 126.92, 125.34, 124.26, 122.61,
118.69, 112.69, 83.93, 81.07, 67.43, 63.69, 39.11, 29.82, 29.50, 28.35, 28.30, 26.25; HRMS
+
(ESI) m/z calculated for C32H36N4NaO6 ([M+Na]+) 595.2533, found 595.2537.
(2R,3aS,8aS)-8-benzyl-1-tert-butyl-3a-(furan-2-yl)-2-(methylcarbamoyl)-3,3a-
dihydropyrrolo[2,3-b]indole-1,8(2H,8aH)-dicarboxylate (16)
According to General Procedure B, bromopyrroloindoline 19 (0.53 g, 1.0 mmol), LiB(cat)2 (0.47
g, 2.0 mmol), furan (0.36 ꢀL, 5.0 mmol, 5.0 equiv) and Ir(ppy)2(dtbbpy)PF6 (9.1 mg, 10.0 ꢀmol)
in dry DMSO (10.0 mL) afforded 16 (0.22 g, 42%) as a white solid after purification by
chromatography on SiO2 (7:3, hexanes/acetone) (5 h reaction time). Rf (7:3, hexanes/acetone):
25
0.27; [α]
= +9.6° (c 0.0065, CHCl3); IR (neat): 3309, 2980, 1713, 1664, 1562, 1481, 1464,
D
1407, 1367, 1353, 1327, 1287, 1269, 1215, 1157, 1081, 1052, 1028, 980, 910, 857, 750 cm-1; 1H
NMR (500 MHz, CDCl3) δH 7.60 (br. s., 1 H), 7.23-7.30 (m, 8 H), 7.05-7.08 (m, 1 H), 6.40 (s, 1
H), 6.15 (s., 2H), 5.77 (s, 1 H), 5.38 (d, J = 12.5 Hz, 1 H), 5.11 (d, J = 12.5 Hz, 1 H), 3.84-3.87
13
(m, J =, 1 H), 2.75 (s, J = 4.9 Hz, 5 H), 1.35 (s, 9 H); C NMR (126 MHz, cdcl3) δ 172.22,
153.47, 152.70, 142.76, 141.54, 136.05, 133.03, 129.29, 128.47, 128.03, 127.71, 124.37, 123.72,
118.03, 110.20, 107.05, 81.24, 80.88, 67.59, 61.35, 55.32, 37.10, 28.17, 28.12, 26.30, 26.26;
+
HRMS (ESI) m/z calculated for C29H31N3NaO6 ([M+Na]+) 540.2111, found 540.2109.
(2R,3aS,8aS)-8-benzyl-1-tert-butyl-2-(methylcarbamoyl)-3a-(2-oxoethyl)-3,3a-
dihydropyrrolo[2,3-b]indole-1,8(2H,8aH)-dicarboxylate (17)
According to the General Procedure B, bromopyrroloindoline 19 (0.53 g, 1.0 mmol), LiB(cat)2
(0.47 g, 2.0 mmol), butyl vinyl ether (0.65 ꢀL, 5.0 mmol, 5.0 equiv) and Ir(ppy)2(dtbbpy)PF6
13

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(9.1 mg, 10.0 ꢀmol) in dry DMSO (10.0 mL) afforded 17 (0.35 g, 71%) as a white solid after
purification by chromatography on SiO2 (7:3, hexanes/acetone) (12 h reaction time). Rf (7:3,
25
hexanes/acetone): 0.17; [α]
= +33.9° (c 0.0073, CHCl3); IR (neat): 3347, 2980, 2930, 1716,
D
1
1559, 1481, 1464, 1409, 1355, 1330, 1269, 1213, 1154, 1035, 912, 752 cm-1; H NMR (500
MHz, CDCl3) δH 9.59 (s, 1 H), 7.60 (d, J= 7 Hz, 1 H), 7.35 (d, J= 7.2 Hz, 2 H), 7.33-7.39 (m, 4
H), 7.24-7.28 (m, 4 H), 7.07 (t, J = 7.5 Hz, 1 H), 6.17 (s, 1 H), 5.77 (br. s., 1 H), 5.41 (d, J = 12.2
Hz, 1 H), 5.22 (d, J = 12.0 Hz, 1 H), 3.81 (dd, J = 9.7, 7.0 Hz, 1 H), 2.77-2.89 (m, 3 H), 2.32 (dd,
13
J = 13.0, 10.0 Hz, 1 H), 1.37 (s, 9 H); C NMR (126 MHz, cdcl3) δ 199.14, 172.84, 153.61,
141.06, 136.04, 134.35, 129.20, 128.65, 128.60, 128.41, 128.31, 128.10, 124.39, 123.98, 117.77,
81.36, 67.96, 61.31, 52.32, 49.84, 37.71, 28.25, 26.34; HRMS (ESI) m/z calculated for
+
C27H31N3NaO6 ([M+Na]+) 516.2111, found 516.2.108.
C3–C2' (–)-gliocladin C Synthesis
(5aS,10bR,11aR)-benzyl-10b-(1H-indol-2-yl)-2-methyl-1,3,4-trioxo-3,4,5a,10b,11,11a-
hexahydro-1H-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-6(2H)-carboxylate (20)
Trimethylsilyl iodide (0.19 mL, 1.4 mmol, 2.0 equiv) was added dropwise to a solution of 19
(0.37 g, 0.68 mmol, 1.0 equiv) in MeCN (10 mL) at 0 °C. The reaction mixture was stirred for 45
min at 0 °C and then quenched with sat NaHCO3(aq) and stirred for an additional 0.5 h at 23 °C,
followed by extraction with CH2Cl2 (3 X 25 mL). Combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered and were concentrated under reduced pressure. The
residue was purified by flash column chromatography on SiO2 (3:7 hexanes/EtOAc) to yield the
2° amine (300 mg, 95%) as yellow solid. Rf (1:1, hexanes/EtOAc): 0.17. The 2˚ amine (0.33 g,
0.71 mmol, 1.0 equiv) was dissolved in CH2Cl2 and cooled to 0 ˚C. To this was added Et3N (0.3
mL, 2.1 mmol, 3.0 equiv) and ClCOCO2Et (0.16 mL, 1.4 mmol, 2.0 equiv). The mixture was
stirred 1 h before quenching with 10 mL 1 N HCl. The mixture was extracted 4 X with CH2Cl2
and the combined organic phases were washed with 40 mL sat. NaHCO3 (aq), dried over
anhydrous Na2SO4, filtered, and were concentrated. Two major products are observed on TLC
(6:4 hexanes/EtOAc), a non-polar compound (Rf = 0.31) and a polar compound (Rf = 0.06). Upon
flash chromatography on SiO2 (6:4 hexanes/EtOAc) the polar compound converts to the more
non-polar compound to yield 20 (0.21 g, 57%) as a yellow solid upon one additional flash.
14

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25
[α]
= +120.0° (c 0.00027, CHCl3); IR (neat): 3346, 3058, 2917, 2849, 1691, 1600, 1482,
D
1
1455, 1417, 1396, 1366, 1316, 1277, 1205, 1149, 1051, 1024, 752 cm-1; H NMR (400 MHz,
CDCl3) δH 8.69 (br. s., 1 H), 7.84 (d, J = 7.83 Hz, 1 H), 7.7.47 (d, J = 7.63 Hz, 1 H), 7.29 - 7.38
(m, 3 H), 7.16-7.26 (m, 5H), 7.02-7.10 (m, 3H), 6.83 (s, 1 H), 6.28 (s, 1 H), 5.18 (d, J = 11.93
Hz, 1 H), 5.03 (d, J = 11.93 Hz, 1 H), 4.37 (dd, J = 10.76, 6.46 Hz, 1 H), 3.23 (s, 3 H), 3.09 -
13
3.12 (m, 2 H); C NMR (126 MHz, cdcl3) δ 166.89, 157.72, 152.55, 151.00, 142.45, 137.10,
136.96, 135.58, 130.71, 130.44, 128.91, 128.73, 128.59, 128.48, 127.78, 124.93, 124.91, 122.73,
120.68, 120.38, 116.36, 111.33, 101.67, 81.49, 68.41, 59.73, 54.38, 43.40, 27.51; HRMS (ESI)
+
m/z calculated for C30H24N4NaO5 ([M+Na]+) 543.1644, found 543.1652.
(5aS,10bR)-benzyl-10b-(1H-indol-2-yl)-2-methyl-1,3,4-trioxo-3,4,5a,10b-tetrahydro-1H-
pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-6(2H)-carboxylate (21)
Triketopiperazine 20 (0.11 g, 0.22 mmol, 1.0 equiv) and 10 wt.% Pd/C (0.11 g) were refluxed in
toluene (3.0 mL) for 5 d. The mixture was filtered over Celite and purified by flash
chromatography on SiO2 (6:4 hexanes/EtOAc) to yield 21 (63 mg, 56%) as a white solid. Rf (8:2,
25
hexanes/EtOAc): 0.32; [α]
= -57.5° (c 0.0007, CHCl3); IR (neat): 3338, 3063, 2925, 2852,
D
1
1719, 1685, 1599, 1480, 1455, 1409, 1335, 1309, 1230, 1155, 1083, 1052, 1027, 752 cm-1; H
NMR (400 MHz, CDCl3) δH 7.95 d, J= 8.22 Hz, 1H), 7.85 (br. s., 1 H), 7.55 (d, J= 7.9 Hz, 1 H),
7.39 - 7.43 (m, 3 H), 7.27-7.30 (m, 3 H), 7.10-7.24 (m, 5 H), 6.84 (s, 2H), 6.37 (s, 1H), 5.25-5.36
13
(m, 2 H), 3.33 (s, 3 H); C NMR (176 MHz, cdcl3) δ 156.90, 156.28, 152.87, 149.40, 141.64,
136.79, 135.31, 135.00, 132.87, 130.54, 130.36, 129.13, 128.70, 128.66, 128.06, 125.29, 124.75,
124.35, 123.29, 121.03, 120.84, 117.85, 111.36, 102.61, 102.60, 84.61, 69.22, 59.16, 27.65;
HRMS (ESI) m/z calculated for C30H22N4O5 ([M+H]+) 519.1668, found 519.1663.
+
(5aR,10bR)-10b-(1H-indol-2-yl)-2-methyl-5a,6-dihydro-1H-pyrazino[1',2':1,5]pyrrolo[2,3-
b]indole-1,3,4(2H,10bH)-trione (C3–C2' (–)-gliocladin C, (18)
Cbz-amine 22 (50 mg, 96 ꢀmol, 1.0 equiv) was placed in a flame dried round bottom flask,
dissolved in CH2Cl2 (19 mL), and cooled to −78 °C. To this solution was added a solution of 1M
BCl3 in CH2Cl2 (0.29 mL 0.29 mmol, 3.0 equiv). The reaction mixture was stirred for 12 h
(during the reaction time the flask was allowed to warm to room temperature) and then quenched
15

ACCEPTED MANUSCRIPT
with. sat. NaHCO3 (aq). To this solution was added 75 mL of CHCl3 and the mixture was stirred
for an additional 12 h at rt. The suspension was extracted (2 X 25 mL CHCl3) and washed with
brine, dried over anhydrous Na2SO4, filtered and was concentrated under reduced pressure. The
residue was purified by flash column chromatography on SiO2 (7:3 hexanes/EtOAc), providing
25
18 (37 mg, 97%) as yellow solid. Rf (1:1, hexanes/EtOAc): 0.35; [α]
= -17.0° (c 0.005,
D
CHCl3); IR (neat): 3340, 2958, 1735, 1682, 1638, 1602, 1483, 1455, 1429, 1345, 1310, 1250,
1
1144, 1113, 1066, 1023, 748 cm-1; H NMR (500 MHz, acetone-d6) δH 10.18 (br. s., 1 H), 7.51
(d, J = 7.83 Hz, 1 H), 7.31 (dd, J = 14.06, 7.95 Hz, 2 H), 7.14 (t, J = 7.58 Hz, 1 H), 7.08 (t, J =
7.46 Hz, 1 H), 6.96 - 7.04 (m, 1 H), 6.90 (s, 1 H), 6.73 - 6.85 (m, 2 H), 6.58 (br. s., 1 H), 6.34
13
(dd, J = 10.88, 2.08 Hz, 2 H), 3.25 (s, 3 H); C NMR (101 MHz, acetone-d6) δC 158.5, 158.0,
150.8, 150.3, 139.5, 138.3, 133.7, 130.3, 129.2, 129.1, 125.8, 125.0, 122.7, 121.2, 120.5, 120.0,
+
112.2, 111.0, 101.3, 84.8, 61.8, 27.2; HRMS (ESI) m/z calculated for C22H16N4O3 ([M+H]+)
385.1301, found 385.1311.
Acknowledgements
The authors thank Dr. Joel Beatty, and Dr. Irene Bosque for their helpful discussions and
suggestions. This work was partially funded by the Boston University Undergraduate Research
Opportunities Program. Financial support for this research from the NIH-NIGMS (R01-
GM096129), the Camille Dreyfus Scholar Award Program, Eli Lilly, Novartis, Boston
University and the University of Michigan is gratefully acknowledged.
Supplementary data
1
13
Copies of H and C NMR spectra for all products. Supplementary data associated with this
article can be found, in the online version, at http://dx.doi.org/xxxxxxxxxxxxxxxx.
References and Notes
(1) T. P. Yoon, M. A. Ischay and J. Du, Nat. Chem., 2010, 2, 527–532.
(2) J. M. R. Narayanam and C. R. J. Stephenson, Chem. Soc. Rev., 2010, 40, 102–113.
(3) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322–5363.
(4) J. D. Nguyen, J. W. Tucker, M. D. Konieczynska and C. R. J. Stephenson, J. Am. Chem.
Soc., 2011, 133, 4160–4163.
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(5) C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner and C. R. J. Stephenson, J. Am. Chem. Soc.,
2012, 134, 8875–8884.
(6) J. W. Tucker, J. M. R. Narayanam, S. W. Krabbe and C. R. J. Stephenson, Org. Lett., 2010,
12, 368–371.
(7) L. Furst, B. S. Matsuura, J. M. R. Narayanam, J. W. Tucker and C. R. J. Stephenson, Org.
Lett., 2010, 12, 3104–3107.
(8) $9609/mol–Sigma Aldrich catalog 646121 .
(9) K. Kalyanasundaram, Coord. Chem. Rev., 1982, 46, 159–244.
(10) Yarasik, A. Investigation of the Suitability of the biscatecholborate. M.S. Dissertation, The
University of Texas at Arlington, Arlington, TX, 2006.
(11). Attration between the radical anion of quinones and polypyridyl complexes has been
reported to form a stable complex that promotes back electron transfer: J. Chem. Soc., Faraday
Trans., 1981, 77, 373.
(12) L. Furst, J. M. R. Narayanam and C. R. J. Stephenson, Angew. Chem. Int. Ed., 2011, 50,
9655–9659.
(13) (a) Austin, J. F.; Kim, S. G.; Sinz, J.; Xian, W. J.; MacMillan, D. W. C. Proc. Nat. Acad.
Sci. 2004, 101, 5482–5487 (b) Wang, M.; Feng, X.; Cai, L.; Xu, Z.; Ye, T. Chem. Comm. 2012,
48, 4344–4346 (c) Wang, H,; Reisman, S. E. Angew. Chem. Int. Ed. 2014, 53, 6206–6210.
(14) Ruiz-Sanchis, P.; Savina, S. A; Albericio, F.; Álvarez, M. Chem. Eur. J. 2011, 17, 1388.
(15) (a) Usami, Y.; Yamaguchi, J.; Numata, A. Heterocycles 2004, 63, 1123. (b) Bertinetti, B.
V.; Rodriguez, M. A.; Godeas, A. M.; Cabrera, G. M. J. Antibiot. 2010, 63, 681.
(16) Studer, A.; Curran, D. P. Angew. Chem. Int. Ed. 2016, 55, 58–102.
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