β-Hydroxy-tetrahydroquinolines from Quinolines Using Chloroborane: Synthesis of the Peptidomimetic FISLE-412

Article abstract of DOI:10.1002/chem.201701944

A new synthetic protocol provides a simple and direct method to generate functionalized β-hydroxy-tetrahydroquinolines (THQs). Hydroboration of quinolines using chloroboranes followed by oxidation with NaBO₃?H₂O led to the formation of functionalized β-hydroxy THQs. High regio- and diastereoselectivities were observed in α and γ substituted quinolines and the trans diastereomer of the β-hydroxy-THQ was the major isostere. This new protocol was utilized to build the novel antibody-targeted lupus peptidomimetic, FISLE-412.

Full text of DOI:10.1002/chem.201701944

A Journal of
Accepted Article
Title: β-hydroxy-tetrahydroquinolines from quinolines using
chloroborane: Synthesis of the peptidomimetic FISLE-412
Authors: Ahmad Altiti, Yousef Al-Abed, Kai Fan Cheng, and Mingzhu
He
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201701944
Link to VoR: http://dx.doi.org/10.1002/chem.201701944
Supported by

10.1002/chem.201701944
Chemistry - A European Journal
COMMUNICATION
β-Hydroxy-tetrahydroquinolines from quinolines using
chloroborane: Synthesis of the peptidomimetic FISLE-412
Ahmad S. Altiti* [a], Kai Fan Cheng [a], Mingzhu He [a], and Yousef Al-Abed*[a]
Dedication ((We Dedicate this work to Professor Wolfgang Voelter on his 80th birthday))
Abstract: A new synthetic protocol provides a simple and direct
method to generate functionalized β-hydroxy-tetrahydroquinolines
(THQs). Hydroboration of quinolines using chloroboranes followed
by oxidation led to the formation of functionalized β-hydroxy-
tetrahydroquinolines. High regio and diastereoselectivities were
observed in α or γ substituted quinolines and the trans diastereomer
of β-hydroxy-THQ was the major isostere. This new protocol was
utilized to build the novel antibody-targeted lupus peptidomimetic
FISLE-412.
acetylated 1,2-dihydroquinolines using Cu(I) salts and
B2(Pin)2.[6b,6c] Earlier, the reaction of quinoline with BH3.THF or
its salts was limited to the reduction of the pyridine ring in the
quinoline system upon protonolysis.[7] On the other side, Brown
and co-workers demonstrated that chloroboranes are superior to
BH3.THF in terms of reactivity and regio-selectivity.[8] Vedejs and
co-workers also reported the activation of the amine-borane
complexes with halides to improve their reactivity and
regioselectivity; they demonstrated that halide could act as a
good leaving group and facilitate the hydroboration through SN2
like pathway.[9] In the light of these findings, we considered the
use of chloroborane to reduce the quinoline ring with
concomitant borylation of the β-position, which can be readily
oxidized to give the corresponding β–hydroxy THQ. Quinoline is
a polarized heterocyclic moiety where the pyridine ring is
susceptible to hydride nucleuphilic attacks at α or γ positions.[10]
Formation of the quinolinium-borane complex is expected to
facilitate such reduction leaving the resulting dihydroquinoline
prone to further hydroboration under thermodynamic conditions.
Herein, we wish to report that β-functionalized THQ and
especially β-hydroxy THQ could be accessed directly in a one-
step operation using chloroborane reagents followed by
appropriate work up.
1,2,3,4-tetrahydroquinolines (THQ) are abundant scaffolds in
many biologically active natural molecules and pharmaceutical
drugs. Particularly, β-functionalized-THQs play a vital role in
various biologically active compounds (Figure 1).[1] These
compounds are synthetically challenging, they are usually made
through multistep synthesis.[1a,2] Wide varieties of reducing
agents have been used extensively to make THQ,[3] however,
very limited reduction approaches were synchronized with
significant functionalization.[4] Stereoselective silylative reduction
of quinolines using B(C6F5)3 and Et2SiH2 is a good example to
access β-silylated THQs,[4a] which can be used as precursors
for wide range of transformations including β-hydroxy-THQs.
Yet, this reduction system might suffer from undesired reductive-
deoxygenation products.[5]
In an early pursuit of optimal hydroborating agents, we
settled on borane (BH3.THF) and mono-chloroborane
(BH2Cl.THF) reagents as promising leads (see supporting
information). A 1:3 mixture of BCl3/BH3 (4mmol) was capable of
converting the quinoline moiety (1mmol) into β-borylated THQ
after stirring at rt for 48 h; the reaction progress was monitored
by TLC upon simple oxidation of the reaction mixture with
NaBO3. The corresponding hydroxylated product was isolated in
44% yield in addition to the 1,2,3,4-THQ. The commercially
available Me2S.BH2Cl was also effective in obtaining the β-
hydroxy THQ in similar yield under similar conditions. Unlike
mono-chloroboranes, BH3.THF reacted with quinoline sluggishly
at rt and gave much lower yield and slower conversion rate (7
days).[7a] These results are not in a full agreement with the
theoretical calculations that predicted BH3 and BH2Cl to have
similar reactivity as Lewis acids.[11] Hence, we explored the
potential of this reaction as a synthetic tool to access β-
functionalized THQ. In order to cut the reaction time, we
considered repeating the reaction under high temperature.
Interestingly, 1 equiv of Me2S.BH2Cl was enough to induce the
NHCH3
R1
R2
OMe
N
N
O
N
H
HN
HN
2: Vabicaserin
3: Sumanirole
D2 Receptor agonist
1a: R1 = CONH2, R2= Cl
Benzastastatin C
Antipsychotic
1b: R1 = CONH2, R2 = OH
Benzastastatin D
OH
H
Ph
HN
N
N
N
1c: R1 = CO2H, R2 = Cl
Virantmycin
N
H
H
OH
NH2
4a,b: FISLE-412
Figure 1. Important β-functionalized tetrahydroquinolines
Furthermore, activated quinoline systems react readily with
borane reagents to give the 1,2-dihydroquinolines or the 1,2,3,4-
THQs.[1a,6] During the preparation of this report, Ito and co-
workers disclosed a regio- and enantio-enriched borylation of N-
o
reaction when refluxed at 65 C for 4 h; however, the reaction
did not go to completion. The borane transfer process to the β-
carbon under stoichiometric condition indicates that this process
might involve a dissociation event of the B-N bond in the borane-
dihydroquinolinium complex II (eq.1 Scheme 1) especially at
high temperature.[12] We reasoned that such a process could be
facilitated by enamine-imine tautomerism eq.1, Scheme 1).[7e]
When 2 equiv Me2S.BH2Cl were used, a complete conversion of
[a]
Center for Molecular Innovation, The Feinstein Institute for Medical
Research, 350 Commuinty Drive, Manhasset, New York 11030,
United States
Dr. Ahmad Altiti, Dr. Kai Fan Cheng, Dr. Mingzhu He, Professor. Dr.
Yousef Al-abed.
E-mail: aaltiti@northwell.edu, Yalabed@northwell.edu
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10.1002/chem.201701944
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o
the quinoline into products took place in less than 2 h at 65 C.
The borylated intermediate was isolated as a pinacolate ester V
(eq.2, Scheme 1) upon treatment with pinacol, which was
isolated in 31% after purification over basic alumina. Due to the
instability of the pinacol ester under the standard extraction and
purification procedure, we treated V with KHF2 and isolated the
borylated intermediate as trifluorborate salt VI in 41 % from
quinoline, VI was purified by trituration with ether in order to get
rid of the pinacol and the 1,4-butane-diol, a side product that
results from opening the THF ring. Besides the borylated
intermediate, we isolated the 1,2,3,4-THQ IX, which theoretically
might be produced from protonlysis of IV. [7a] We were unable to
isolate any borylated intermediate at the α-position. However,
when the borylated intermediate IV was treated with ice-cold
water and NaBO3, β-hydroxy THQ VII and α-hydroxy THQ VIII
were isolated as major products with ratio of 7:2 respectively in
addition to traces of IX (eq.3, Scheme 1). When the isolated
trifluoroborate compound VI was treated with NaBO3 under the
same work up conditions previously used, only the β-hydroxy
THQ VII was observed. This indicates that the two hydroxylated
products might be formed independently through different
pathways. Next, we subjected the quinoline to various sources
of chloroboranes in an effort to understand the factors that might
affect the ratio of β-hydroxy THQ VII and α-hydroxy THQ VIII
(Table 1).
THQ VII compare to BH3. All the examined monochloroboranes
had similar effect on the quinoline in terms of reactivity and
selectivity, a slight increase in reaction rate was observed when
higher concentrations were applied (Entries 2 and 3). Controlling
the reaction concentration was only possible when Me2S.BH2Cl
was used because it is supplied as a neat reagent.
Table 1. Hydroboration-oxidation of quinoline using mono-chloroborane
OH
1.Hydroboration System
65 oC/time
+
N
N
H
OH
N
H
2.H2O/NaBO3
I
VII
VIII
Conc.
(M)
Time
(h)
Entry
Hydroboration System
BH3.THF (8 equiv)
VII%
48
VIII%
49
1
2
0.13
1.0
16
Me2S.BH2Cl (2 equiv)
1.0
65
18
3
4
5
6
7
8
9
Me2S.BH2Cl (2 equiv)
Me2S.BH2Cl (4 equiv)
Me2S.BH2Cl (8 equiv)
BCl3/BH3 (1equiv+2equiv)
BCl3/BH3 (2equiv+6equiv)
BCl3/BH3 (1equiv+7equiv)
0.5
1.5
2
69
64
61
54
59
70
63
19
32
33
33
31
23
29
0.13
0.13
0.33
0.13
0.13
0.13
2
4
4
4
BR2
BR2
TCCA/BH3 (0.5equiv/8 equiv)
4
eq.1
N
N
N
N
B
R2
BR2
I
IV
In order to account for the substituents effect on the
quinoline system and to avoid the malodorous effect of Me2S,
we settled on the procedure used in entry 8 (Table 1) to test the
scope of this reaction. Using excess borane reagent should not
be a burden at this stage, especially as our target is to access
the β-hydroxy THQ and the oxidative work up is mild and
inexpensive.
III
II
O
B
BR2
BF3K
O
Pinacol
KFF2
eq.2
N
N
H
N
B
H
R2
IV
41%
VI
V
31%
BR2
OH
NaBO3
eq.3
+
+
N
N
OH
N
N
B
H
H
We first explored the scope of quinoline derivatives bearing
substituents at the benzene ring (Table 2). The BCl3/BH3
hydroboration system tolerated quinolines with halide
substituents on the benzene ring (Entry 6), however, halides on
the pyridine ring were susceptible to reduction.[7a] When 2-
chloroquinoline was treated with this reduction system, the β-
hydroxy-THQ VII was isolated as the major product
accompanied with traces of VIII (results not shown), the methoxy
substituent (Entry 5) also survived the BCl3/BH3 reduction
system; the corresponding β-hydroxy-THQ was isolated in 54%
yield. The methyl-substituted quinolines (Entries 3 and 4) gave
good yields of the corresponding β-hydroxy-THQ, on the other
hand carboxylic acid moieties suffered from expected partial
reduction only and gave the corresponding primary alcohols
(Entries 2 and 7); these functionalities can be retained with
simple oxidations after appropriate functional group manipulation.
Interestingly, the unprotected 8-amino quinoline (Entry 8) gave
the corresponding β-hydroxy-THQ in 74% isolated yield; the
borylated intermediate of this quinoline can be elaborated easily
to give the racemic version of Sumanirole (Figure 1).[6c]
Regardless of the modest regioselectivity of some of the
quinolines presented here, we believe this protocol has a
superior synthetic value compared to the traditionally used
H
R2
IX
IV
VII
69%
VIII 19%
(traces)
Scheme 1. Hydroboration of the quinoline system using Me2S.BH2Cl.
Treatment of quinoline I with excess BH3.THF (8 equiv)
resulted in a complete conversion of the starting material into
products after 16 h reflux at 65 oC. The products were
characterized after oxidative work up as VII and VIII with 1:1
ratio. Me2S.BH2Cl (8 equiv) gave VII in 61% (Entry5) in shorter
time (2h). Decreasing the amount of Me2S.BH2Cl to 4 equiv
gave similar results (Entry4), to avoid the malodorous effect of
the Me2S, we considered the preparation of mono-chloroborane
following Brown’s protocol[8c] by simply mixing 1 equiv of 1M
BCl3/hexane with
2 equiv of 1M of BH3.THF. Brown’s
chloroborane mixture (3 equiv) was effective in reducing the
quinoline system, where the β-hydroxy THQ VII was isolated in
54% yield. However, the use of 8 equiv of 1:7 mixture of
BCl3/BH3 gave VII in 70% isolated yield (Entry 8). Increasing the
stoichiometriy of BCl3 did not improve the selectivity or the yield
(Entry 7). We also considered the use of trichloroisocyanuric
acid TCCA as a chlorininating agent (Entry 9).[13] Similarly, VII
and VIII were collected with ratios comparable to the previous
chloroboranes systems. As we see form the results in Table1,
monochloroborane indeed favors the formation of the β-hydroxy
[2]
protocols to access such substrates using multistep synthesis
(vide infra).
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10.1002/chem.201701944
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pathway as a rate-limiting step.[4b] Further, the electron rich γ-
dimethylamino quinoline (Entry9) was expected to form a strong
Lewis acid-Lewis base complex and resist the borane reduction.
Indeed, the corresponding β-hydroxy-THQ was isolated in 6%
yield after 16 h at 65 oC beside the recovered starting material.
Table2. Hydroboration-oxidation of quinolines bearing substituents at the
R
R
1. BCl3/BH3 (1:7)
65 oC/time
R
OH
+
N
H
OH
N
H
N
2.H2O/ NaBO3
Table3. Hydroboration of quinolines bearing substituents at the pyridine ring.
I
VII
VIII
1. BCl3/BH3 (1:7)
65 oC/time
R
R
OH
Entry
1
Substrates
Time (h)
4
VII %
VIII%
21
N
2.H2O/ NaBO3
N
H
70
X
XI
N
trans-(racemic)
Diastereos
elctivity
(cis/trans)
Time
(h)
Isolated
yield%
2
3
3
8
38
73
45
13
N
Entry
1
Substrates
Products*
HO
O
OH
OH
1
94
9:91
N
OH
N
N
H
O
4
5
7
6
68
54
24
13
OH
N
MeO
2
3
4
6
16
8
65
55
82
11:89
11:89
9:91
N
H
N
N
Br
OH
6
7
8
6
6
8
44
47
74
48
38
17
N
H
CF3
N
N
CF3
O
OH
OH
N
H
Ph
N
N
Ph
OH
OH
OH
N
5
6
0.5
16
84
70
> 98 trans
> 98 trans
N
N
NH2
H
benzene ring
OH
N(Bn)2
N
N(Bn)2
N
H
O
Satisfied with the performance of the BCl3/BH3 hydroboration
system in Table 2, we decided to investigate the role of this
system on quinolines bearing varied substituents on the pyridine
ring (Table 3). In general the BCl3/BH3 hydroboration system
gave greater yields and better regio- and diasteroselectivities for
quinolines with substituents on the pyridine ring. The
diastereoselectivity was confirmed by nOe analysis (see
supporting information). As expected, quinolines with available
chelating arm at the α position (Entries 1 and 5) exhibited faster
reactions and higher yields; this behavior can be attributed to an
alcohol directed hydroboration effect, the formation of the
alkoxy-borane complex facilitates the borylation of the β-position
through an intramolecular process.[14] The α-methyl, α-
trifluoromethyl, and α-phenyl-quinolines performed well and
gave good trans-diastereoselectivity (Entries 2, 3, and 4),
however, longer reaction time was required. For example, the α-
phenyl quinoline was very sluggish under the BH3.THF reduction
OH
7
8
16
16
91
46
> 98 trans
> 98 trans
N
N
H
OH
O
OH
OH
OH
OH
N
H
N
N
N
9
24
4
6
> 98 trans
> 98 trans
N
H
N
Ph
Ph
10
72
N
H
N
* The depicted structural formulas do not reflect the absolute stereochemistry
system (result not shown). After
2 days of reflux, the
Next, we turned our attention to explore the utility of this
protocol in asymmetric synthesis by building the novel
hydroxylated products were collected in poor selectivity (1:1
cis/trans) in addition to the recovery of some starting material,
however, when subjected to the BCl3/BH3 reduction system, the
reaction proceeded smoothly and the corresponding β-hydroxy-
THQ was generated with 9:91 cis/trans selectivity. The γ-
substituted quinolines exhibited similar behavior to α-substited
quinolines and gave the β-hydroxy-THQs in good yields and
good trans diastereoselectivity. Though, these compounds
required longer reaction time to achieve full conversion.
Interestingly, the α-hydroxy-THQ was not observed as a side
product in the case of the γ-substituted quinolines. Instead, the
fully reduced 1,2,3,4-THQ was isolated; this indicates that γ-
peptidomimetic FISLE-412;
a
potent polyamine-alcohol
neutralizes anti-dsDNA/NMDAR lupus autoantibodies and
prevents their pathogenic interaction with tissue antigens.[1l, 1m]
This poly amine is very challenging in terms of synthesis,
resolution and purification, the only access to this molecule was
through global reduction of the corresponding peptide
“Saquinavir”, this reduction process was very tedious and gave
an inseparable mixture of FISLE-412 with very low yield after
multiple purifications.[1l] We envisaged the synthesis of the
complex polyamine FISLE-412 through the resolution of the β-
hydroxy THQ moiety XI-1 (Entry 1, Table 3), which could be later
integrated in the synthesis of FISLE-412 through benign
substituted quinolines might undergo
a different reduction
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reductive-amination steps after simple protecting groups
handling.
69% for each (the yield is averaged for both isomers). After
exhausting several attempts to cleave the benzyl groups safely,
we found that the Pd black-formic acid combination under reflux
OH
OH
O
Ph
1. BnBr/NaHCO3
1. EtAlCl2/Et2SiH2
OBn
O
condition in 75% aqueous EtOH cleaved all benzyl groups
O
2.Benzaldehyde-
dimethylacetal/CSA
N
H
N
2.DMP/DCM
58%
N
[17]
Bn
Bn
orthogonally
without affecting the phthalimide group, which
XI-1
88%
5
6
trans (racemic)
trans (racemic)
one pair based on X-ray
was cleaved with hydrazine NH2NH2•H2O under reflux condition
to afford FISLE-412A and FISLE-412B (Scheme4). Both
isomers were isolated as TFA salts after C18 column purification
with approximately 50% yield of each over 3 steps (averaged
yield), the purity of these compounds was confirmed by HPLC
analysis (see supporting information).
trans (racemic)
Scheme 2. Synthesis of the racemic aldehyde 6
Accordingly, the trans diol XI-1 was treated with stoichiometric
amount of BnBr in aq NaHCO3 to give the N-Bn derivative, which
was then treated with benzyladehyde dimethylacetal and
camphorsulphonic acid (CSA) to give only one pair of the
H
N
Ph
O
N
BocHN
OH
racemic acetal
5
in 88% yield over two steps. The
H
N
10
OH
H
N
Ph
stereochemistry was confirmed to be trans based on X-ray
analysis of 5 (see supporting information), which was isolated as
white-needled shaped crystals. Regioselective reductive
opening of the acetal 5 using Et3SiH/EtAlCl2 gave exclusively the
primary alcohol,[15] which was oxidized using Dess Martin
periodinane (DMP) to give the corresponding racemic aldehyde
6 in 58% yield over two steps (Scheme 2).
1. 4 M HCl
2. BH3.THF/
1. 9A,Na(OAc)3BH, DCM, rt
N
H
N
H
N
65 o
C
2. Pd-black/formic acid
3. H2NNH2 H2O/EtOH
OH
Ph
NH
NH2
52% (over 3 steps) 4A
H2N
N
H
N
OH
OH
Ph
H
N
1. 9B,Na(OAc)3BH, DCM, rt
11
N
H
N
H
N
2. Pd-black/formic acid
3. H2NNH2 H2O/EtOH
40% (two steps)
OH
NH2
4B
52% (over 3 steps)
O
HO
BocN
1. DEAD, PPh3, Phthalimide
2. 6 M HCl/EtOH
H2N
Scheme4. Synthesis of the FISLE-412 compounds 4A and 4B
OH
7
NPhth
OBn
Bn
N
8
O
In summary, we have successfully developed a rapid and
inexpensive protocol to access β-hydroxy-THQs. The new
procedure features a hydroboration-oxidation reaction using
chloroboranes. High regio- and trans diastereoselectivies were
observed for the α- and γ-substituted quinolines. This
methodology was used to build an interesting library of β-
hydroxy-1,2,3,4-tetrahydroquinolines. We assert that this
protocol has a superior synthetic value compared with other
synthetic approaches used to build β-hydroxy-1,2,3,4-THQ
scaffolds. We are currently investigating the utility of this method
in the synthesis of other biologically relevant alkaloids of interest.
31%
31%
N
Bn
OBn
O
1. 8, Et3N, Na(OAc)3BH
9A
NPhth
2.benzylaldehyde/AcOH/
Benzene/reflux
3.Na(OAc)3BH/DCM
4. DMP/DCM
N
Bn
OBn
Bn
N
O
6 (trans-racemic)
62% (over 4 steps)
N
Bn
9B
NPhth
Scheme3. Synthesis and resolution of Aldehydes 9A & 9B
Next, we sought a chiral fragment that could resolve the
racemic aldehyde and integrate the THQ moieties in the
synthesis of the complex peptidomimetics FISLE-412. We
chose the homologue of Garner’s alcohol 7 because it could be
converted into the 2,4-diaminobutanol with orthogonal protection
of the distal nitrogen. Alcohol 7 was treated with DEAD, Ph3P,
and phthalimide followed by acidic hydrolysis of the Boc and the
isopropylidene groups using 6 M HCl to give amino alcohol 8 in
89% yield over two steps. Reductive amination on 6 and amino
alcohol 8 followed by selective protection of the nitrogen with
Benzyl group through reductive amination using PhCHO/AcOH
and Na(OAc)3BH afforded two separable alcohols by
Supporting Information
The Supporting Information is available free of charge. Procedures for
reactions and characterization of isolated products, NMR spectra and X-
Ray analysis are available in PDF format files.
AUTHOR INFORMATION
Corresponding Authors
* E-mail: aaltiti@northwell.edu; yalabed@northwell.edu
conventional
chromatography. The resulting diasteromeric
alcohols were oxidized respectively using DMP to give
aldehydes 9A/9B in roughly 60% total yield over 4 steps (yield is
averaged for both diastereomers because the absolute
stereochemistry is not assigned yet) (Scheme 3).
Amino-alcohol 11 was accessed from the known
decahydroisoquinoline (DIQ) fragment 10,[16] which was reduced
with BH3.THF upon the deprotection of the Boc group to furnish
11 in 40% yield. Reductive-amination on the amino-alcohol 11
and either aldehyde 9A or 9B gave the protected FISLE-412 in
ACKNOWLEDGMENT
This research was supported by grants from NIH
(RO1AR057084) and STTR (R41 AR060620-01). We also thank
Dr. Matthew Devany the director of NMR facility at Hunter
College and Dr. Barney Yoo for collecting the HRMASS data.
Yousef Alabed thanks Dr. Nanette M. Wachter-Jurcsak,
Professor of Chemistry at Hofstra University.
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Keywords: Quinoline • β-hydroxy-1,2,3,4 tetrahydroquinoline •
Hydroboration of quinolines •Monochloroborane• β-borylated
tetrahydro quinolines.
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10.1002/chem.201701944
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
R4
R4
1. Chloroborane/65 o
C
OH
R2
A. Altiti*, K.C.Cheng, M.He, Y. Al-abed*
R
R
2. NaBO3
N
H
N
R2
Page No. – Page No.
H
N
OH
OH
OH
Ph
H
N
N
H
N
H
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N
β-Hydroxy-tetrahydroquinolines from
quinolines using chloroborane: Synthesis
of the peptidomimetic FISLE-412
Reductive Amination
OH
NH2
FISLE-412
This article is protected by copyright. All rights reserved.