High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

Article abstract of DOI:10.3762/bjoc.14.45

Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API's) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient continuous synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous stirred tank reactors for the direct conversion of the starting materials to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global access to hydroxychloroquine for treatment of malaria.

Full text of DOI:10.3762/bjoc.14.45

High-yielding continuous-flow synthesis of antimalarial
drug hydroxychloroquine
Eric Yu‡, Hari P. R. Mangunuru‡, Nakul S. Telang, Caleb J. Kong, Jenson Verghese,
Stanley E. Gilliland III, Saeed Ahmad, Raymond N. Dominey and B. Frank Gupton*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 583–592.
Department of Chemistry and Department of Chemical and Life
Science Engineering, Virginia Commonwealth University, 601 W.
Main St., Richmond, VA 23220, USA
doi:10.3762/bjoc.14.45
Received: 04 November 2017
Accepted: 14 February 2018
Published: 08 March 2018
Email:
B. Frank Gupton* - bfgupton@vcu.edu
This article is part of the Thematic Series "Integrated multistep flow
synthesis".
* Corresponding author ‡ Equal contributors
Keywords:
Guest Editor: V. Hessel
antimalarial; API manufacturing; flow chemistry; hydrogenation;
hydroiodic acid; hydroxychloroquine
© 2018 Yu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API’s) have
been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient contin-
uous synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination
of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process
employs a combination of packed bed reactors with continuous stirred tank reactors for the direct conversion of the starting materi-
als to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global
access to hydroxychloroquine for treatment of malaria.
Introduction
Our research group has been focused on the development of modium falciparum. Hydroxychloroquine (1) is an antimalarial
new synthetic methods for the preparation of a variety of active drug developed for both treatment and prevention of the disease
pharmaceutical ingredients for global health applications by in response to the widespread malaria resistance to chloroquine
employing the principles of process intensification [1-3]. In (2, Figure 1) [5,6].
2016, estimated 212 million cases of malaria, including 429,000
fatalities, were reported worldwide, with the majority of these Additionally, hydroxychloroquine (1, HCQ) is an effective non-
cases occurring in sub-Saharan Africa and Southern Asia [4]. steroidal drug with anti-inflammatory activity for the treatment
The malaria epidemic is particularly difficult to control due to of rheumatoid arthritis (RA) in patients with cardiovascular
the multidrug resistant nature of the malaria parasite Plas- disease [7-9]. The World Health Organization has identified
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Beilstein J. Org. Chem. 2018, 14, 583–592.
HCQ (1) is currently produced via the batch method shown in
Scheme 1. Therefore, continuous-flow chemistry approaches to
synthesizing HCQ (1) offer a great potential to maximize the
efficiency, and thus significantly reduces the overall manufac-
turing costs of this important medicine.
The commercial HCQ synthesis employs a key intermediate,
5-(ethyl(2-hydroxyethyl)amino)pentan-2-one (6), which is a
major cost driver in the process. The protection–deprotection
strategy of chloro-ketone starting material 3 used in the com-
mercial route (Scheme 1a) [21] has been targeted as a signifi-
cant opportunity for optimization. While the recent improved
route (Scheme 1b) by Li and co-workers [21] eliminates the
protection–deprotection steps, its use of a complex multi-transi-
tion-metal-catalyst system to achieve direct SN2 substitution of
the chlorine on 3 by amine 7, is sub-optimal [22,23]. With these
issues in mind, we carried out a retrosynthetic analysis
(Scheme 2) in which 10, an iodo analogue to the starting materi-
al 3, could be generated in a single step via a decarboxylative
ring-opening of α-acetyl butyrolactone 8. The iodo analogue 10
could then be used without isolation to prepare compound 6.
Figure 1: Commercially available antimalarial drugs.
HCQ (1) as an essential antimalarial medication for a basic
healthcare system, but global access to HCQ (1) has been
hindered by high manufacturing costs of the API. Thus, the de-
velopment of cost effective synthetic strategies to increase the
global access to this important global health drug is of great
importance. Effective strategies for accomplishing such objec-
tives often include identifying more cost effective starting mate-
rials and reagents, simplifying the synthetic route in terms of
reducing the total number of steps as well as reducing the cost
and improving the efficiency of individual steps.
It is well known that the direct one-step reductive amination of
Flow chemistry methodologies have been increasingly investi- 6 to give 12 can be accomplished by simple heterogeneous
gated in recent years in the pharmaceutical industry for multi- reduction with H2/Raney-nickel [24]. However, THF is em-
step preparations of highly-complex natural products and APIs ployed in all of our prior flow steps and is a poor choice as a
[10-19]. Advantages include precise control of key reaction pa- solvent for the reductive amination step due to limited solu-
rameters such as heat and pressure, improved heat and mass bility of ammonia in THF. H2/Raney-nickel reductions are often
transfer capabilities for better thermal control, enhanced selec- carried out in alcoholic media where much higher concentra-
tion of kinetically controlled products to potentially maximize tions of ammonia are achievable but would require a solvent
conversion, smaller equipment footprint, and increased safety exchange. There are many reports of continuous-flow chem-
profiles when working with hazardous materials and reaction istry methods for reductive amination of ketones [25-31]; how-
conditions [20]. These advantages often result in flow pro- ever, such processes typically require soluble reductants such as
cesses being significantly more efficient, as well as less costly, diisobutylaluminium hydride (DIBAL-H), superhydrides, or
when compared to batch processes.
supported borohydride species [32-36]. Although these ap-
Scheme 1: Current batch syntheses of the key intermediate 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one (6).
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Beilstein J. Org. Chem. 2018, 14, 583–592.
Scheme 2: Retrosynthetic strategy to hydroxychloroquine (1).
proaches are effective, they are significantly more costly than entries 1–5); however, the use of 55% hydroiodic acid (Table 1,
using simple heterogeneous reduction with H2/Raney-nickel. entries 6–8) was found to give near quantitative conversion. The
Therefore, we explored an alternate strategy: simple conversion reaction profile was monitored using GC–MS and 1H NMR –
of the ketone group of 6 to oxime 11, followed by reduction to no intermediates were observed under these conditions. Optimi-
give 5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane (12). We zation of the flow rate with 55% hydroiodic acid (Table 1,
have found H2/Raney-nickel efficiently reduces 11 to 12 with entries 6–8) revealed that a flow rate of 1.0 mL min−1
THF as the solvent in a continuous stirred tank reactor (CSTR). (tR = 5 min) gave an isolated yield of 89%.
The last step requires the reaction of 12 with 4,7-dichloroquino- Due to the need to use an excess of hydroiodic acid it is impor-
line (13) which when used neat takes 24–48 hours at tant to remove its excess from the eluting reaction stream before
120–140 °C to give 75–80% yield of HCQ (1) [37]. We have telescoping into the next step in flow. The product stream con-
found that this step can be accelerated by employing K2CO3/tri- taining crude 10 was mixed in-line with methyl tert-butyl ether
ethylamine, to facilitate the formation of 1, resulting in a (MTBE) and saturated NaHCO3 before phase separation using a
comparable yield in less than 6 hours. Thus, we have integrated hydrophobic, membrane-based separator (Zaiput) [40]
the continuous preparation of reaction with our new efficient (Scheme 3) to afford purified 10 in the organic phase. A loss of
continuous-flow synthesis of 12 with the final step by using a 5–10% of product to the water layer was observed, however,
CSTR to accommodate the longer reaction time required to this was deemed adequate as it prevented the need for a com-
produce HCQ (1).
plete work-up step in batch.
Results and Discussion
In the next step 6 was reacted with hydroxylamine, which was
Initial optimization efforts to prepare 6 (Scheme 1) revealed facilitated by passing through a packed-bed of K2CO3 to give
poor reactivity of starting material 3, so we pursued the iodo an- oxime 11 (Table 2). As was seen with the reaction to produce 6
alogue of 3, 5-iodopentan-2-one (10) as an alternative. By opti- (Table S1 in Supporting Information File 1), reactant concentra-
mizing the reaction concentration, we have also shown that (see tions also had a dramatic effect on the oxime formation. A
Table S1 in Supporting Information File 1) 10 reacts rapidly series of experiments were conducted to optimize the continu-
and cleanly with 7 under flow conditions to give 6 in high yield ous formation of 11. Reaction yields were modest at lower reac-
(>80%). Furthermore, we have developed and optimized a con- tant concentrations across several temperatures and residence
tinuous synthesis of 10 (Table 1), wherein hydroiodic acid is times (Table 2). Conversion to 11 increased when reactant con-
reacted with neat 3-acetyldihydrofuran-2(3H)-one (8) to provide centrations were increased (9% at 0.1 M to 72% at 1 M,
a rapid route to 10 which is significantly higher in yield than in Table 2, entries 1–6). Optimization of the flow rate with
previously reported syntheses [38,39]. Initial results using 1 M concentrations of each reactant (Table 2, entries 6–8)
diluted hydroiodic acid (20–40%) provided only modest showed that a flow rate of 1.0 mL min−1 (tR = 20 min) was
conversion to product over a range of temperatures (Table 1, optimal, giving an isolated yield of 78% (Table 2, entry 7).
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Table 1: Optimization of the flow process for the synthesis of 10.
entry
HI [aqueous %]
temp (°C)
tR = min
pressure (bar)
conv.a (%)
1
2
3
4
5
6
7
8
20
20
20
40
40
55
55
55
r.t.
40
80
80
80
80
80
80
5
5
1.5
2.0
2.0
2.0
2.5
3.0
3.0
3.0
5
31
5
34
5
43
46
5
5
98 (89%)b
91
2.5
10
92
aConversion determined by GC–MS and 1H NMR. bIsolated yield.
Scheme 3: Schematic representation for continuous in-line extraction of 10.
The reductive amination of 11 performed in the first generation yields of 12 over a broad range of oxime 11 reactant concentra-
batch process was carried out using Raney-nickel at 80 °C tions. An optimum residence time was determined to be
and 10 bar hydrogen pressure for 4–6 h [21-24]. In order 4 hours.
to perform this step in a continuous fashion, a continuous
stirred tank reactor [25,41] was employed (Table 3). Materials After optimizing the individual steps up to compound 12 the en-
were delivered to the CSTR vessel through an HPLC pump tire reaction was telescoped into a continuous reaction process
and were reacted under hydrogen pressure with mechanical that convert 10 and 6 into 12 (Scheme 4) with an overall isolat-
stirring. The dip tube in the CSTR was outfitted with a ed yield of 68% for compound 12.
fritted metal filter, allowing for retention of the heterogeneous
catalyst within the CSTR vessel. Optimization of this With an optimized continuous process for producing the key
CSTR-based flow process (Table 3) showed near quantitative intermediate 12 in-hand the reaction conditions for the conver-
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Table 2: Schematic representation for the continuous telescoped process to synthesize 11.
entry
concentrationa
temp (°C)
tR = min
conv. of 11 (%)b
1
2
3
4
5
6
7
8
0.1 M
0.2 M
0.4 M
0.6 M
0.8 M
1.0 M
1.0 M
1.0 M
100
100
100
100
100
100
100
100
10
10
10
10
10
10
20
40
9
16
34
37
62
72
85 (78)c
76
aConcentration of 10 , 7 and hydroxylamine. bConversion determined by GC–MS and 1H NMR. cIsolated yield.
sion of 12 to HCQ (1) were examined. In the commercial 88% conversion (Table 4, entry 6) to 1, with corresponds to an
process this step is carried out in batch under neat reactant isolated yield of 78%.
conditions and requires a relatively long reaction time of
24–48 h [42-44]. In order to convert this step to a flow chem- Conclusion
istry method, we selected to employ a CSTR (Table 4). This In summary, we have developed a high-yielding continuous-
final step, transforming 13 and 12 into 1, was first investigated flow process for the synthesis of hydroxychloroquine (1, HCQ)
in batch to optimize the conditions before implemented in a by optimizing continuous-flow methods for the synthesis of key
CSTR.
intermediates 6 and 12. Additionally, we have developed and
optimized flow-chemistry conditions for performing reductive
Process optimization for the final step started with the screening amination of 11 using Raney-nickel as catalyst in a continuous
of the effect of solvents and base(s) on the yield of HCQ (1). stirring tank reactor (CSTR) for the synthesis of compound 12,
Screening of different polar–protic and non-protic solvents (see and have incorporated it into a fully continuous telescoped
Table S2 in Supporting Information File 1) demonstrated that process for the synthesis of 12 from lactone 8 and amino-
ethanol is the most effective for this transformation. During the ethanol 7. Feeding the output stream containing 12 from the
screening of bases, the pKa of the amine and alcohol groups above CSTR into a second CSTR in which 12 is converted to
present in compound 12 were given careful consideration in HCQ (1) provides a completely continuous-flow process for
order to minimize C–O bond formation (Table 4). NaOH or producing HCQ (1) from readily available starting materials.
KOH in ethanol gave low (<40%) conversion, whereas using This efficient process has the potential to increase the global
K2CO3 in ethanol gave 82% conversion to HCQ (Table 4, entry access to this strategically important antimalarial drug. We are
3). Attempts with organic bases (Table 4, entries 5 and 6) currently working to demonstrate that this fully integrated con-
resulted in only moderate conversions to the desired product; tinuous-flow process for the synthesis of HCQ (1) can be scaled
however, using a 1:1 mixture of K2CO3/Et3N (1:1) resulted in to commercial operations.
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Table 3: Optimization of the flow process for the reductive amination of 12 using a CSTR.
entry
oxime [concentration]
temp. (°C)
pressure
(bar)
tR = hours
conv. of 12 (%)a
1
2
3
4
5
6
0.05 M
0.25 M
0.5 M
2.0 M
2.0 M
2.0 M
80
80
80
80
80
80
10
10
10
10
10
10
4
4
4
4
2
1
94%
96%
97%
98% (89%)b
56%
46%
aConversion determined by GC–MS and 1H NMR. bIsolated yield.
Scheme 4: Optimization of the flow process for the synthesis of 12.
Experimental
spectra were recorded using 600 MHz spectrometers. Chemical
General information
shift (δ) values are given in ppm, and coupling constants (J) are
All reactions for the preparation of substrates were performed in given in Hz. The 7.26 ppm resonance of residual CHCl3 (or
standard, dry glassware under an inert atmosphere of nitrogen 0 ppm of TMS) for proton spectra and the 77.23 ppm reso-
or argon unless otherwise described. All starting materials and nance of CDCl3 for carbon spectra were used as internal refer-
reagents were purchased from commercial sources and were ences. Continuous-flow experiments were carried out using the
used as received unless otherwise noted. 1H and 13C NMR E-series flow reactor instrument purchased from Vapourtec Ltd.
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Table 4: Optimization of the reaction conditions for the preparation of hydroxychloroquine (1).a
entry
base
solvent
temp. (°C)
conv. to 1 (%)b
1
2
3
4
5
6
NaOH
KOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
125
125
125
125
125
125
30
35
K2CO3
Et3N
82
61
DIPEA
55
K2CO3/Et3N
88 (78)c
aReaction conditions: 4,7-dichloroquinoline (13, 1.0 equiv), base (1.0 equiv), amine 12 (1.2 equiv). bConversion determined by HPLC and 1H NMR,
cIsolated yield.
PFA tubing (1/16 OD × 1 mm ID) was used for all reactor coils (t, J = 6.9 Hz, 2H), 2.17 (s, 3H), 2.06 (quin, J = 7.0 Hz, 2H);
in flow experiments. Most of the reagents and starting materi- 13C NMR (125 MHz, CDCl3) δ 207.4, 44.0, 30.3, 27.2, 6.7.
als were purchased from commercial sources and used as Spectra were obtained in accordance with those previously re-
received. All HPLC chromatograms were recorded on an ported [3].
Agilent Technologies 1260 Infinity instrument with a Poroshell
120 EC-C18 column (4.6 × 50 mm, 2.7 micron). Continuous Synthesis of 5-(ethyl(2-hydroxyethyl)amino)pentan-
flow hydrogenation was performed using a FlowCAT instru- 2-one (6)
ment.
Synthesis of 5-iodopentan-2-one (10)
Telescope of compound 6: Prior to the start of the experiment,
the flow reactor unit was rinsed with dry THF and flushed with
nitrogen gas. At room temperature, the stock solutions of
Two solutions, 2-acetylbutyrolactone (8, 1.176 mL, 5-iodopentan-2-one (10, 1.0 M) and 2-(ethylamino)ethan-1-ol
10.35 mmol, 1.0 equiv) and hydroiodic acid (55% aqueous solu- (7) in THF solution (1.0 M) were streamed in at 0.5 mL min−1
tion) were pumped at 1.0 mL min−1 using peristaltic pumps via a T-piece into a 10 mL reactor coil (tR = 10 min) and passed
through a 10 mL coil (residence time, tR = 5 min) at 80 °C. The through a packed bed reactor of potassium carbonate at 100 °C.
completion of the reaction was monitored using GC–MS. Com- The output solution was collected and quenched with a satu-
plete consumption of starting material was observed. The reac- rated solution of ammonium chloride. The aqueous phase was
tion mixture was cooled to room temperature and sodium extracted by DCM (3 × 50 mL) and the organic layers were
hydrogencarbonate was added until neutralized at pH 7. The combined, dried over sodium sulfate, and evaporated in vacuo
crude mixture was extracted with hexanes/MTBE and the to give a light brown liquid (14.05 g, 86%). 1H NMR
combined organic phase was dried over anhydrous sodium (600 MHz, CDCl3) δ 3.53 (t, J = 5.2 Hz, 2H), 2.58 (m, 3H),
sulfate and evaporated in vacuo to dryness yielding the desired 2.53 (m, 2H), 2.45 (t, J = 6.7 Hz, 4H), 2.59 (t, J = 6.9 Hz, 2H),
product as a light brown liquid (14.72 g, 89%). 1H NMR 2.17 (s, 3H), 2.07 (quin, J = 7.0 Hz, 2H); 13C NMR (125 MHz,
(600 MHz, CDCl3) δ 3.22 (t, J = 6.9 Hz, 2H), 2.59 CDCl3) δ 208.9, 58.6, 55.0, 52.4, 47.2, 41.3, 30.0, 21.2, 11.7.
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Beilstein J. Org. Chem. 2018, 14, 583–592.
Spectra were obtained in accordance with those previously re- couple measured the temperature at approximately 150 mL
ported [38,39].
reactor volume. When the two thermocouples were within 3 °C,
the level control ‘opened’ the exit stream dip tube to allow
products to exit the reactor, or ‘closed’ the exit stream dip tube
to allow the reactor to fill when the temperature difference be-
tween the two thermocouples was greater than 3 °C. The prod-
uct was collected after a full reaction volume of material
(150 mL) had passed through the CSTR indicating that steady-
state was reached. The reaction was monitored by liquid chro-
matography and 1H NMR. The reaction mixture was filtered
Synthesis of (E)-5-(ethyl(2-hydroxyethyl)amino)-
pentan-2-one oxime (11)
Flow: Prior to the start of the experiment, the flow reactor unit through a celite pad and dried under reduced pressure. The solu-
was rinsed with dry THF and flushed with nitrogen gas. At tion was extracted with water (10 mL) and dichloromethane
room temperature, the stock solutions of 5-iodopentan-2-one (3 × 20 mL). The organic layers were combined, washed with
(10, 1.0 M) and 2-(ethylamino)ethan-1-ol (7) in THF solution brine and dried over sodium sulfate and evaporated in vacuo.
(1.0 M) were streamed in at 0.5 mL min−1 via a T-piece into a The resulting oil was fractionally distilled to give a colorless
10 mL reactor coil (tR =10 min) and passed through a packed liquid (16.83 g, 84%). 1H NMR (600 MHz, CDCl3) δ 3.53
bed reactor of potassium carbonate. The output solution was (t, J =5.3 Hz, 2H), 2.89 (sx, J = 6.4 Hz, 1H), 2.57 (t, J = 5.5 Hz,
streamlined with hydroxylamine (1.0 M) at 1.0 mL min−1 via a 2H), 2.55 (t, J = 7.0 Hz, 2H), 2.45 (t, J = 7.0 Hz, 2H), 1.55–1.44
T-piece into a 10 mL reactor coil (tR =10 min) and passed (m, 2H), 1.36–1.27 (m, 2H), 1.22 (t, J = 7.1 Hz, 2H), 1.07
through a packed bed reactor of potassium carbonate at 100 °C. (d, J = 7.1 Hz, 2H), 1.00 (t, J = 7.1 Hz, 2H); 13C NMR
The reaction mixture was then concentrated in vacuo, taken up (125 MHz, CDCl3) δ 58.2, 54.9, 53.2, 46.9, 46.7, 36.6, 23.8,
in dichloromethane (3 × 20 mL) and concentrated under 22.4, 10.6. Spectra were obtained in accordance with those pre-
reduced pressure to yield 11 as light brown liquid. The viously reported [38,39].
crude product was used in the next step without further purifica-
tion.
Synthesis of 2-((4-((7-chloroquinolin-4-yl)amino)-
pentyl)(ethyl)amino)ethan-1-ol (1)
Synthesis of 2-((4-aminopentyl)(ethyl)amino)ethan-
1-ol (12)
Flow: The synthesis of compound 12 was performed in a HEL
continuous stirred tank reactor (CSTR) with a reaction volume Batch: In a CSTR reactor, to a mixture of 4,7-dichloroquino-
of 150 mL. The reaction vessel was first charged with Raney- line (200 mg, 1.0 mmol), compound 12 (208 mg, 1.2 mmol), tri-
nickel (1.0 g). The Raney-nickel catalyst was retained in the ethylamine (0.069 mL, 0.5 mmol, 0.5 equiv) and potassium
CSTR by the 2 µm metal filter frit on the dip tube of the exit carbonate (69 mg, 0.5 mmol, 0.5 equiv) was added ethanol
stream. The reaction mixture, consisting of compound 11 (1.0 mL). The ethanol was distilled off from the reaction mix-
(0.05–2.0 M) in THF, was pumped by a HPLC pump set at a ture and kept under nitrogen atmosphere (15 psi). The reaction
flow rate of 0.6–2.5 mL min−1 into the reaction vessel. The was left at 125 °C in the nitrogen atmosphere for 6 h. After
reaction pressure was set to 10 bar of hydrogen supplied by cooling, the mixture was transferred into a separatory funnel
hydrogen gas (ultrahigh purity) at a flow rate of 0.5 mL min−1. using 1 M aqueous sodium hydroxide (5 mL) and dichloro-
The reaction temperature was set to 80 °C which was con- methane (2 × 20 mL). The organic phases were separated and
trolled by a thermocouple positioned in the reaction mixture. the aqueous phase was re-extracted with dichloromethane
The reaction was stirred with mechanical stirring (750 rpm) to (2 × 10 mL). The organic layers were combined and dried over
provide proper mixing. Two thermocouples were used to sodium sulfate and evaporated in vacuo. The crude material was
control the reaction volume in the reactor by setting a level purified using flash chromatography with DCM/Et3N/MeOH
control of −3 °C. The lower thermocouple constantly measured 95:3:2 to give a white solid (0.263 g, 78%). 1H NMR
and controlled the reaction temperature and the upper thermo- (600 MHz, CDCl3) δ 8.48 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 5.4
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Beilstein J. Org. Chem. 2018, 14, 583–592.
11.Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2015, 11,
1194–1219. doi:10.3762/bjoc.11.134
Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 8.8, 7.3 Hz,
1H), 6.39 (d, J = 5.4 Hz, 1H), 4.96 (d, J = 7.5 Hz, 1H), 3.70 (sx,
J = 6.8 Hz, 1H), 3.55 (m, 2H), 2.57 (m, 5H), 2.49 (m, 2H),
1.74–1.62 (m, 1H), 1.65–1.53 (m, 3H), 1.31 (d, J = 6.9 Hz, 3H),
1.24 (d, J = 7.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 152.2,
149.5, 149.2, 135.0, 129.0, 125.4, 121.2, 117.4, 99.4, 58.6, 54.9,
53.18, 48.5, 47.9, 34.5, 24.1, 20.6, 11.9. Spectra were obtained
in accordance with those previously reported [38,39].
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Supporting Information
Supporting Information File 1
Additional experimental descriptions and NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-45-S1.pdf]
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Acknowledgements
This work was supported by The Defense Advanced Research
Projects Agency (DARPA) (W911NF-16-2-0023). We thank all
members of the two teams (Prof. B. Frank Gupton and Prof.
Thomas Roper) for their discussions and kind help.
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