Joanna K Loh1,2, Naeem Asad1,2, Thiwanka B Samarakoon1,2, Paul R Hanson1,2. 1. Department of Chemistry, University of Kansas , 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States. 2. Center for Chemical Methodologies and Library Development (KU-CMLD), Delbert M. Shankel Structural Biology Center, The University of Kansas , 2034 Becker Drive, Lawrence, Kansas 66047, United States.
Abstract
The generation of common and stereochemically rich medium-sized benzo-fused sultams via complementary pairing of heretofore-unknown (o-fluoroaryl)sulfonyl aziridine building blocks with an array of amino alcohols/amines in a modular one-pot, sequential protocol using an aziridine ring opening and intramolecular nucleophilic aromatic substitution is reported. The strategy employs a variety of amino alcohols/amines and proceeds with 6 + 4/6 + 5 and 6 + 1 cycloetherification pathways in a highly chemo- and regioselective fashion to obtain skeletally and structurally diverse, polycyclic, 10- to 11- and 7-membered benzo-fused sultams for broad-scale screening.
The generation of common and stereochemically rich medium-sized benzo-fused sultams via complementary pairing of heretofore-unknown (o-fluoroaryl)sulfonyl aziridine building blocks with an array of amino alcohols/amines in a modular one-pot, sequential protocol using an aziridine ring opening and intramolecular nucleophilic aromatic substitution is reported. The strategy employs a variety of amino alcohols/amines and proceeds with 6 + 4/6 + 5 and 6 + 1 cycloetherification pathways in a highly chemo- and regioselective fashion to obtain skeletally and structurally diverse, polycyclic, 10- to 11- and 7-membered benzo-fused sultams for broad-scale screening.
The
development of efficient methods for the generation of medium-
and large-sized heterocycles is an important facet of screening campaigns
for facilitating drug discovery.[1] In particular,
medium and macrocyclic lactams[1,2] constitute an important
class of molecules in compound collections derived from target-oriented
and diversity-oriented[3] synthetic approaches.
Their distinct properties, which include conformational constraint,
reduced polarity, increased proteolytic stability, and potential for
higher target binding and selectivity,[4] are manifested in improved pharmacokinetics and pharmacodynamics,[4] rendering them as attractive lead molecules for
drug development.[5] Taken collectively,
these attributes have inspired production of natural product like[6] medium-sized and macrocyclic ring systems that
are stereochemically rich and enhanced in terms of their fraction
of sp3 carbons,[7] enabling efforts
to address emerging difficult drug targets[5,8] such
as protein–protein interactions[9] and epigenetic targets.[10]Synthetic
medium-sized (8–11 membered)[11] and
macrocyclic lactams have a rich biological profile
and have been shown to exhibit broad activity in a variety of areas
ranging from antitumor,[2a] antifungal,[12] anthelmintic,[13] neutral
endopeptidase inhibitory,[14] and hepatitis
C virus protease inhibitory[15] in drug discovery[16] to insecticidal agents in agriculture (Figure ).[17] In contrast, their sulfonamide-based counterparts (amide
surrogates),[18] medium[19] and macrocyclic sultams, are unnatural and less prevalent
in the literature but have been found to exhibit antiproliferative,[20] anti-HIV activity,[21] inhibitory activity of trypsin-like serine protease Factor XIa involved
in blood coagulation[22] and, more recently,
have been shown to be modulators of lysosomal acidification involved
in critical cellular function (Figure ).[23] Despite advances in
the field,[24] methods to generate functionally
rich, medium- to large-sized lactams and sultams remains a significant
challenge.[25]
Figure 1
Bioactive lactams and
sultams.
Bioactive lactams and
sultams.We herein report a modular approach
utilizing a heretofore-unknown
class of sulfonamide building blocks, namely (o-fluoroaryl)sulfonyl
aziridines, which react with amino alcohols via a process we term
complementary pairing (CP), vide infra, with high chemo- and regioselectivity
enabling access to 10- to 11-membered sultams. Overall, this one-pot
protocol involves sequential aziridine ring opening by the amine component
and intramolecular nucleophilic aromatic substitution (SNAr) via the alkoxy component. In addition, dual reactivity with primary
amines facilitates access to 7-membered sultams. Taken collectively,
the routes reported herein generate a diverse array of polycyclic,
10- to 11- and 7-membered benzo-fused sultam scaffolds.Previously,
our group has reported a strategy termed complementary
ambiphile pairing (CAP)[26,27] for the synthesis of
skeletally diverse 7- and 8-membered benzo-fused sultams in a modular
and efficient fashion. As shown in Figure A, CAP strategies unite a pair of ambiphilic
compounds, possessing both electrophilic and nucleophilic components,
in a synergistic complementary manner [(4 + 3) and (4 + 4) cyclizations].
In contrast, Yudin and co-workers have developed a number of elegant
methods using aziridine aldehydes that contain a nucleophile and electrophile
on the same molecule (Figure B) and which they term as amphoteric molecules.[28]
Figure 2
Complementary ambiphile pairing and amphoteric molecules.
Complementary ambiphile pairing and amphoteric molecules.We have previously investigated
and reported the use of o-haloaryl sulfonyl chlorides
in a number of pairing strategies
including Click, Click, Cyclize[29] to generate
a variety of bridged and benzo-fused sultams (Figure ). Based on these studies, we sought to expand
the scope to another unique class of bis-electrophiles,
namely, heretofore unknown o-fluoroaryl-sulfonyl
aziridines for use in complementary pairing to bis-nucleophilic counterparts,
such as amino alcohols, as well as consecutive coupling with primary
amines.[30] We envisioned CP of activated
sulfonyl aziridines (simple 6-atom bis-electrophilic synthon) via
“chemo- and regioselective” ring opening by the amino
component of the amino alcohol (bis-nucleophiles) and subsequent SNAr cyclization with the alcohol component to furnish unprecedented,
functionally rich, medium-sized benzo-fused sultams in chemoselective
“6 + 4” and “6 + 5” heterocyclization
pathways. Moreover, the method can accommodate the use of (o-fluoroaryl)sulfonyl aziridines to generate 7-membered
benzo-fused sultams via a “6 + 1” atom cyclization sequence
where primary amines are utilized for sulfonyl aziridine ring opening
and the resulting secondary amines cyclize via a subsequent SNAr reaction (Figure ).
Figure 3
Summary of CAP and CP routes to benzo-fused sultams.
Summary of CAP and CP routes to benzo-fused sultams.Historically, intramolecular SNAr cyclizations
have
been utilized to access common-sized rings or macrocycles comprising
5-membered indoles and indolines,[31] macrolactams
such as complestatin (16-membered),[32] vancomycin
(16-membered and their modified derivatives),[33] and cyclopeptide alkaloids.[34] Reports
of intramolecular heteroaryl cyclizations en route to sultams first
surfaced in the 1990s, when Giannotti and co-workers reported Cu-catalyzed
reactions on o-halobenzene-sulfonamides bearing amino
side chains.[35] In 2010, concurrent reports
from several other laboratories detailed SNAr aryletherification
protocols to 7- and 8-membered benzo-fused sultams.[36] Use of intramolecular SNAr to access 10- and
11-membered sultams, however, to the best of our knowledge, is void
in the literature, due to several challenging problems including methods
of macrocyclization (cyclization vs oligomerization) and strain (distortion
of standard bond angles, lengths and unfavorable transannular interactions)
in the macrocyclic products.[37]
Results and Discussion
The titled investigation commenced with the preparation of chiral,
nonracemic aziridines 3 via use of a mild Wenker synthesis[38] from the respective amino alcohols, with all
preparations occurring in good to excellent yields. Sulfonylation
of aziridines with o-fluorobenzenesulfonyl chlorides
and Et3N in CH2Cl2 at −30
°C furnished a variety of 1-((2-fluorophenyl)sulfonyl)aziridines
in good yields (71–94%) (Scheme ).
Scheme 1
Preparation of Aziridines and Sulfonylation To Provide
(o-Fluoroaryl)sulfonyl Aziridines
Studies on the one-pot, sequential process began
with aziridinyl
sulfonamide 4a (aziridine ring opening), which was reacted
with N-methylethanolamine 5a (1.2 equiv)
in DMF at 130 °C, using microwave (μW) irradiation for
30 min (Table , entry
1). The reaction was monitored by TLC, and upon disappearance of starting
material, Cs2CO3 (2.5 equiv) was added to the
crude mixture. The mixture was next subjected to 30 additional minutes
of μW irradiation at 150 °C in order to facilitate the
SNAr reaction and ultimately afford the desired benzo-oxathiadiazecine
1,1-dioxide 6a in moderate yield (43% over two reactions;
66% avg/reaction).
Table 1
Optimization of Reaction Conditions
entryc
conc (i–ii M)
time (i, ii min)
yielda (%)
1
0.3
30, 30
43b
2
0.3
30, 40
50b
3
0.3–0.1
30, 40
58b
4
0.3–0.08
30, 40
66b
5
0.3–0.05
30, 40
34b,d
Final isolated
yield over two reactions
after flash chromatography.
Aziridine opening: 1 (1.0 equiv) and 2 (1.05–1.3
equiv) in DMF at
130 °C. SNAr: Cs2CO3 (2.5 equiv)
in DMF at 150 °C.
Reactions
were monitored by TLC.
Reaction
was run only once at 0.05.
Final isolated
yield over two reactions
after flash chromatography.Aziridineopening: 1 (1.0 equiv) and 2 (1.05–1.3
equiv) in DMF at
130 °C. SNAr: Cs2CO3 (2.5 equiv)
in DMF at 150 °C.Reactions
were monitored by TLC.Reaction
was run only once at 0.05.With this result in hand, optimization of reaction conditions was
carried out. Notably, it was found that solvent concentrations, reaction
time, and temperature were key factors since the aziridine ring opening
and SNAr reactions are inter- and intramolecular pathways,
respectively (Table and Scheme ). In
particular, increased reaction time and temperature were found to
effect reaction decomposition. It should also be noted that the first
reaction (intermolecular aziridine ring opening) was carried out under
relatively high concentrations, while the subsequent intramolecular
SNAr reaction requires dilute concentrations (Table , entries 3–5).
Furthermore, it should also be noted that while aziridine ring opening
proceeds at room temperature, the reaction took 5 days in order to
go to completion, while utilization of μW irradiation allowed
for completion of reaction in 30 min. Efforts to improve this reaction
by screening other bases, for instance, CsF, K2CO3, K3PO4, DBU, and NaH, revealed that Cs2CO3 was optimal (see the Supporting Information for more data). After thorough investigation, the
optimized conditions for this one-pot, sequential aziridine ring opening–SNAr protocol was achieved, whereby arylsulfonyl aziridine 4a and amino alcohol 5a were subjected to μW
irradiation in DMF at 130 °C for 30 min and 150 °C for 40
min, respectively. This led to 10-membered sultam 6a in
good yield (66% over two reactions; 81% avg/reaction) (Table , entry 4). The structure of
sultam 6a was confirmed by X-ray crystallographic analysis
(Figure ). This set
of optimized conditions was also utilized for the synthesis of 7-membered
benzo-fused sultams, with some substrates having a shorter reaction
time for SNAr cyclization.
Scheme 2
“6 + 4”
and “6 + 5” Cyclization to Bi-
and Tricyclic 10- and 11-Membered Sultams
Figure 4
X-ray structures of 6a, 6p, and 8b.
X-ray structures of 6a, 6p, and 8b.With the optimization conditions
in hand, the substrate scope studies
commenced with the synthesis of medium-sized, fused polycyclic and
spirocyclic benzo-fused sultams using several secondary acyclic and
cyclic amino alcohols 5a–e to yield
the corresponding products 6a–p in
average to good overall yields (Scheme ). Notable applications include both (R)- and(S)-prolinol, racemic 2-piperidinemethanol,
and 2-piperidine-ethanol to afford the 6,10,5-fused, 6,10,6-fused,
and 6,11,6-fused tricyclic systems, respectively. During the investigation,
it was determined that by increasing the reaction time for some substrates
slightly higher yields were obtained. Thus, sultam 6b was generated in 70% yield over two reactions (84% avg/reaction)
when the reaction time for SNAr reaction was extended to
50 min while maintaining all other reaction conditions (Scheme ). In addition, two 10-membered
benzo-fused sultams 6g and 6m were synthesized
from sulfonamides derived from spiro-cyclohexylaziridine in good
yields. Finally, it is worth noting that a single diastereomer of
the 6,11,6-fused tricyclic sultam 6p was synthesized,
starting with racemic 2-piperidine-ethanol, suggesting only one diastereomer
intermediate underwent cyclization reaction (or potentially aziridine
ring opening). The relative stereochemistry of 6p was
confirmed by X-ray crystallography (Figure , vide infra). Similar sultams 6n and 6o were also obtained as single diastereomers as
observed by NMR.A proposed plausible mechanism suggests that
in all cases the secondary
amino group reacts in a chemoselective fashion for the aziridine ring
opening reaction, rendering the resulting tertiary amine incapable
of executing the cyclization reaction (SNAr) and thus allowing
the unprotected primary or secondary hydroxyl group to cyclize under
basic conditions to provide the various benzo-oxathiadiazecine 1,1-dioxides.
The resulting products have stereocenters on the core medium-sized
rings, which consequently imparts “non-flatland” architecture.[7]Next, we further investigated the scope
of this one-pot, sequential
procedure by using chiral, nonracemic, substituted secondary amino
alcohols (Scheme ).
Commercially available derivatives of ephedrine, 7a–e, were subjected to the “Click” aziridine ring
opening–SNAr reaction conditions, and to our delight,
the secondary alcohols proceeded smoothly to afford medium-sized sultams
(8a–f) in average to good yields
over two reactions, albeit in lower yield for (1S,2S)-(+)-pseudoephedrine-derived 8c. Sultam 8b was confirmed by X-ray crystallography where
the respective stereocenters (6R,7R) correspond to the structure as shown in Figure . In addition, in all cases studied, both
primary and branched secondary hydroxyl groups were able to undergo
SNAr cyclization to yield their respective sultams. Also,
use of N-(methylamino) cyclohexyl methanol in the
aforementioned method furnished the spiro-benzo-oxathiadiazecine-cyclohexane
1,1-dioxide 8f in 46% yield over two reactions (68% avg/reaction)
(Scheme ).
Scheme 3
Spiro-
and Stereochemically Rich 10-Membered Sultams
It is worth noting that the preferred conformations of
these constrained
structures are governed by stereoelectronic effects innate to sulfonamides,
which place the nitrogen lone pair antiperiplanar to the S–Ar
bond to maximize the σ* orbital delocalization and also bisect
the O=S=O internuclear angle.[39] The bisection of the O=S=O internuclear angle by the
nitrogen lone pair has been confirmed in all X-ray crystallographic
structures taken in this study (Figure ). The consequence of this stereoelectronic effect/preferred
rotomer of the Ar-SO2NR1R2 moiety is that it
renders the core macrocyclic in a unique conformation, whereby the
N–H bond points to the inner core of the macrocycle (see the
circled highlighted area in 8b of Figure ).[40]With
the aforementioned results in hand, the one-pot, sequential
strategy was extended to several primary amines 9, whereby
their ability to have dual reactivity facilitates access to 7-membered
(common-sized) benzo-fused sultams in an overall “6 + 1”
atom cyclization sequence involving consecutive aziridine ring opening
and SNAr reaction (Scheme ). The use of simple alkyl and aromatic amines containing
different substituents furnished benzo-thiadiazepine 1,1-dioxides 10a–e in satisfactory yields (44–53%
over two reactions, 67–73% avg/reaction). Amines with both
cyclic and linear ether moieties were also employed successfully to
provide 7-membered benzo-fused sultams 10f–i in moderate yields (46–56% over two reactions, 68–75%
avg/reactions) (Scheme ). The primary amines proceeded with aziridine ring opening, and
the secondary amines generated from the first reaction were then cyclized
to form cyclic sulfonamides.
Scheme 4
Substrate Scope of “6 + 1”
Cyclization to 7-Membered
Sultams
Similarly, common-sized
benzo-fused sultams 10j–p consisting
of amines having hydroxyl motifs were generated
with different (o-fluoroaryl)sulfonyl aziridines
(cyclohexyl, iPr, and iBu) in albeit slightly
lower yields (12–56% over two reactions, 35–75% avg/reaction).
On the basis of the results, when primary amines with unprotected
hydroxyl groups are used as the nucleophile, the resulting secondary
amines from the aziridine ring opening reaction chemoselectively proceed
to SNAr cyclization in preference to the free hydroxyl
groups. A high degree of chemoselectivity was observed in the majority
of cases, although in some cases formation of an unidentified side
product during the SNAr reaction and some final product
decomposition were seen.A notable feature of these 7-membered
sultams possessing a free
N–H is their ability to undergo an additional facile Mitsunobu
reaction to synthesize bridged [3.2.2] bicyclic benzo-fused sultams.
Hence, sultam 10l was treated with Ph3P and
DIAD in THF at room temperature, stirred overnight, and upon completion,
provided ethanobenzothiadiazepine 1,1-dioxide 11a in
87% yield (Scheme ). The structure of sultam 10m was confirmed by X-ray
crystallography and shown to display an optimal positioning of the
hydroxyl group in order to participate in facile intramolecular Mitsunobu
alkylation to afford sultam 11b bearing a two-carbon
bridgehead. Further demonstration of the intramolecular Mitsunobu
reaction was realized in the production of the spiro-cyclohexyl-containing
[3.2.2] bridged benzo-fused sultam 11c, albeit in a lower
yield of 40%. The structure of 11c was confirmed by X-ray
crystallography (Scheme ). Sultam 10o, on the other hand, was unsuccessful in
yielding the two-carbon bridged sultam after several attempts using
similar reaction conditions. The recovery of starting material and
several side products present in Mitsunobu reactions as well as excess
reagents that were used in the reaction were collected.
Scheme 5
Utilization
of the Mitsunobu Reaction To Access Bridged 7-Membered
Sultams
A key finding during
the studies was the isolation of the intermediate,
aziridine ring opened product, which was observable on 19F NMR (Scheme ).
A major difference between the intermediate and the final product
is the presence of the fluorine atom, and use of 19F NMR
provided a convenient way to monitor the progression of the SNAr reaction. In this experiment, aziridinyl-sulfonamide A was chosen and shown to contain a single resonance (triplet)
in the 19F NMR spectrum (Figure 1a, Supporting Information). Reaction with racemic 2-piperidinemethanol
furnished the ring opened intermediate B, which was detected
as a single resonance (triplet) in the 19F NMR spectrum
(Figure 1b, Supporting Information) but
shifted marginally upfield due to the electronic changes within the
sulfonamide. After SNAr reaction, the 19F NMR
of the desired product C (6n) was obtained
and showed complete disappearance of the fluorine resonance (Figure
1c, Supporting Information).[41]
Scheme 6
19F NMR Studies: Comparison between
Sulfonamide A, Ring-Opened B, and Product C
See the 19F spectra
in the Supporting Information.
19F NMR Studies: Comparison between
Sulfonamide A, Ring-Opened B, and Product C
See the 19F spectra
in the Supporting Information.Encouraged by these results, and in an effort to
further highlight
the efficiency of this modular approach, studies were focused toward
the extension of the method using readily available chiral, nonracemic
building blocks that were obtained in one step (Scheme ). Hence, both (R)- and(S)-benzyl glycidyl ethers were subjected to “Click”
epoxide ring opening[30] with TBS-protected d-alaninol to furnish elaborate amino alcohols 16 and 17. The chiral, nonracemic building blocks were
then utilized in the established aziridine ring opening–SNAr procedure to afford 10-membered sultams 18 and 19 with three stereocenters, along with pendant
free hydroxy group, in moderate yields. In this regard, it should
be noted that the TBS-ether protecting group was removed during the
reaction, presumably by the displaced fluoride anion in the SNAr reaction, thus representing an overall one-pot, sequential
aziridine ring opening–SNAr–desilylation
protocol.
Scheme 7
“Click, Click, Click, Cyclize” to Stereochemically
Rich, 10-Membered Sultams
In summary, we have developed a one-pot CP strategy introducing
(o-fluoroaryl)sulfonyl aziridine building blocks
as versatile bis-electrophilic species for reaction with amino alcohols/amines
for the preparation of common and medium-sized benzo-fused sultams
containing up to three stereocenters. This approach was extended to
the utilization of elaborate chiral, nonracemic building blocks as
well as cyclic and spirocyclic amino alcohols to afford a diverse
array of polycyclic scaffolds. Furthermore, the method is highly modular
and adaptable for the preparation of sultam libraries in a one-pot,
sequential manner. Work in this regard is underway and will be reported
in due course.
Experimental Section
General
Information
All air- and moisture-sensitive
reactions were carried out in flame- or oven-dried glassware under
argon atmosphere using standard gastight syringes, cannula, and septa.
Stirring was achieved with oven-dried, magnetic stir bars. CH2Cl2 was purified by passage through the purification
system employing activated Al2O3.[42] Et3N was purified by passage over
basicalumina and stored over KOH. Flash column chromatography was
performed with SiO2. The crude mixture was also purified
using an automated flash column chromatography system. Thin-layer
chromatography was performed on silica gel plates. Deuterated solvents
were purchased from commercial sources. 1H and 13C NMR spectra were recorded on a 400 MHz spectrometer as well as
a 500 spectrometer operating at 500 MHz and 126 MHz, respectively.
High-resolution mass spectrometry (HRMS) spectra were obtained on
a TOF-MS operating on ESI. Microwave-assisted reactions were carried
out in 1 dram vials utilizing a reaction heating block in an Anton
Paar Synthos 3000 synthesizer and also Biotage Initiator both using
an external calibrated external infrared (IR) sensor. All NMR peak
assignments were assigned on the basis of both COSY and HSQC NMR methods.
General Procedure A: Preparation of (o-Fluoroaryl)sulfonyl
Aziridines
To a round-bottom flask containing a solution
of aziridine (2.2 mmol, 2.0 equiv) in dry CH2Cl2 (0.5 M) was added Et3N (2.2 mmol, 2.0 equiv). The reaction
mixture was cooled to −40 °C and stirred for 10 min, and
sulfonyl chloride (1.1 mmol, 1.0 equiv) was added to the reaction
mixture in a dropwise fashion. The reaction was then stirred for 30
min after which conversion of starting material was monitored by TLC.
Upon completion of the reaction, the mixture was warmed to rt and
quenched with cold water (2.2 mL), and the layers were separated.
The organic portion was washed with cold 10% aqHCl, and the resulting
layers were separated. This partitioning was then repeated with cold
water, cold satd NaHCO3, cold water again, and finally
brine. The final organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the desired aziridinyl
sulfonamide.
General Procedure B: One-Pot, Sequential
(Aziridine Ring Opening
and SNAr)
To a microwave vial containing a solution
of sulfonamide (1.0 equiv) in DMF (0.3 M) was added amine/amino alcohol
(1.05–1.2 equiv). The reaction vessel was capped and heated
in the Biotage Initiator microwave at 130 °C for 30–40
min, after which conversion of starting material was monitored by
TLC. To the crude mixture were added DMF (0.08 M) and Cs2CO3 (2.5 equiv), and the mixture underwent microwave irradiation
again at 150 °C for 30–50 min. Water was added to the
crude mixture, which was extracted with EtOAc (4×). The organic
layer was separated, and the combined organic layers were washed with
water and brine, dried (Na2SO4), and concentrated
under reduced pressure to afford the crude product, which was purified
by an automated flash column chromatography system.
General Procedure
C: One-Pot, Sequential (Aziridine Ring Opening
and SNAr)
To a microwave vial containing a solution
of sulfonamide (1.0 equiv) in DMF (0.3 M) was added amine/amino alcohol
(1.05–1.2 equiv). The reaction vessel was capped and heated
in a Biotage Initiator microwave at 130 °C for 30–40 min,
after which conversion of starting material was monitored by TLC.
To the crude mixture was added Cs2CO3 (2.5 equiv),
and the mixture underwent microwave irradiation again at 150 °C
for 30–50 min. Water was added to the crude mixture, which
was extracted with EtOAc (4×). The organic layer was separated,
and the combined organic layers were washed with water and brine,
dried (Na2SO4), and concentrated under reduced
pressure to afford the crude product, which was purified by the automated
flash column chromatography system.
General Procedure D: Mitsunobu
Reaction
To a flame-dried
round-bottom flask containing a solution of sultam (0.047 mmol, 1.0
equiv) in dry THF (0.05 M) was added triphenylphosphine (0.140 mmol,
3.0 equiv). The reaction mixture was stirred for 10 min, and diisopropyl
azodicarboxylate (0.12 mmol, 2.5 equiv) was added to the mixture in
a dropwise fashion. The reaction was then stirred overnight at rt,
and conversion of starting material was monitored by TLC. The solvent
was removed in vacuo to yield a yellow oil and was purified by an
automated flash column chromatography system.
Authors: Daniel F Veber; Stephen R Johnson; Hung-Yuan Cheng; Brian R Smith; Keith W Ward; Kenneth D Kopple Journal: J Med Chem Date: 2002-06-06 Impact factor: 7.446
Authors: Yang Hu; Kai Lang; Chaoqun Li; Joseph B Gill; Isaac Kim; Hongjian Lu; Kimberly B Fields; McKenzie Marshall; Qigan Cheng; Xin Cui; Lukasz Wojtas; X Peter Zhang Journal: J Am Chem Soc Date: 2019-11-01 Impact factor: 15.419
Authors: Saqib Faisal; Pradip K Maity; Qin Zang; Thiwanka B Samarakoon; Robert L Sourk; Paul R Hanson Journal: ACS Comb Sci Date: 2016-06-14 Impact factor: 3.784
Figure 1
Figure 2
Figure 3
Scheme 1
Scheme 2
Figure 4
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7