Structural Simplification of a Tetrahydroquinoline-Core Peptidomimetic μ-Opioid Receptor (MOR) Agonist/δ-Opioid Receptor (DOR) Antagonist Produces Improved Metabolic Stability

Article abstract of DOI:10.1021/acs.jmedchem.9b00219

We have previously reported a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands to serve as potential nonaddictive opioid analgesics. These ligands have been shown to be active in vivo, do not manifest withdrawal syndromes or reward behavior in conditioned-place preference assays in mice, and do not produce dependence. Although these attributes are promising, these analogues exhibit poor metabolic stability in mouse liver microsomes, likely due to the central tetrahydroquinoline scaffold in this series. As such, a structure-activity relationship (SAR) campaign was pursued to improve their metabolic stability. This resulted in a shift from our original bicyclic tetrahydroquinoline core to a monocyclic benzylic-core system. By eliminating one of the rings in this scaffold and exploring the SAR of this new core, two promising analogues were discovered. These analogues (5l and 5m) had potency and efficacy values at MOR better or comparable to morphine, retained their DOR-antagonist properties, and showed a 10-fold improvement in metabolic stability.

Full text of DOI:10.1021/acs.jmedchem.9b00219

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Article
Structural Simplification of a Tetrahydroquinoline Core
Peptidomimetic µ-Opioid-Receptor (MOR) Agonist/ #-Opioid
Receptor (DOR) Antagonist Produces Improved Metabolic Stability
Sean Henry, Thomas M. Fernandez, Jessica P. Anand,
Nicholas Griggs, John R. Traynor, and Henry I. Mosberg
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b00219 • Publication Date (Web): 29 Mar 2019
Downloaded from http://pubs.acs.org on March 29, 2019
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Structural Simplification of a Tetrahydroquinoline Core Peptidomimetic µ-Opioid Receptor (MOR)
Agonist/ δ-Opioid Receptor (DOR) Antagonist Produces Improved Metabolic Stability
Sean P. Henry, Thomas J. Fernandez, Jessica P. Anand, Nicholas W. Griggs,b, c John R. Traynor,a, b, c
a
b
b, c
Henry I. Mosberg* a, c
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aDepartment of Medicinal Chemistry, College of Pharmacy, University of Michigan, 428 Church Street,
Ann Arbor, MI 48109, United States
bDepartment of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI 48109, United
States
cEdward F Domino Research Center, University of Michigan, Ann Arbor, MI 48109, United States
Abstract:
We have previously reported a series of µ-opioid receptor (MOR) agonist/ δ-opioid receptor
(
DOR) antagonist ligands to serve as potential nonaddictive opioid analgesics. These ligands have been
shown to be active in vivo, do not manifest withdrawal syndromes or reward behavior in conditioned-
place preference assays in mice, and do not produce dependence. While these attributes are promising,
these analogs exhibit poor metabolic stability in mouse liver microsomes, likely due to the central
tetrahydroquinoline scaffold in this series. As such, an SAR campaign was pursued to improve their
metabolic stability. This resulted in a shift from our original bicyclic tetrahydroquinoline core to a
monocyclic benzylic core system. By eliminating one of the rings in this scaffold and exploring the SAR
of this new core, two promising analogs were discovered. These analogs (5l and 5m) had potency and
efficacy values at MOR better or comparable to morphine, retain their DOR antagonist properties, and
showed a 10-fold improvement in metabolic stability.
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Introduction:
Mu-opioid analgesics, such as morphine and oxycodone, are the most clinically relevant drugs
used for the treatment of chronic pain. Despite their widespread use, tolerance develops to their analgesic
actions and patients suffer from undesirable side effects, such as dependence, addiction, constipation, and
respiratory depression. A growing body of pre-clinical evidence has emerged suggesting that compounds
that stimulate the µ-opioid receptor (MOR) in conjunction with antagonism at the δ-opioid receptor
(DOR) can produce the desired analgesic effects without producing analgesic tolerance or dependence.
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For instance, rats given morphine and co-treated with the DOR-antagonists TIPP[Ψ] or naltrindole
displayed antinociception with significantly diminished chronic antinociceptive tolerance and dependence
as measured by reduced withdrawal symptoms. These trends are supported by experiments wherein DOR
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knockout mice did not develop chronic tolerance to the analgesic effects of morphine. Furthermore, mice
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treated with antisense DOR oligodeoxynucleotide did not develop acute dependence or chronic tolerance
to the analgesic effects of morphine.
Many ligands have been synthesized that possess this MOR-agonist/DOR-antagonist profile,6,7
and some small molecule bifunctional MOR-agonist/DOR-antagonists have been reported that show
reduced side-effect profiles (Figure 1). Some of these are based on the classical morphinan scaffold
(Figure 1A, I and II), and show attenuated chronic tolerance and dependence.8–10 Mitragynine
pseudoindoxyl (Figure 1B, III), derived from the kratom alkaloid mitragynine, was found to elicit
reduced withdrawal and respiratory depression, and does not produce conditioned-place preference.11
Others still are derived from opioid peptides (Figure 1C-D). DIPP[Ψ]-NH (Figure 1C, IV), an
2
endomorphin derivative, produces antinociception in murine models without acute tolerance and chronic
physical dependence.12 AAH8 (Figure 1C, V) has also been shown to produce antinociception in murine
models without developing tolerance to antinociceptive effects, physical dependence, nor does it evoke
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conditioned-place preference, suggesting it does not have reward properties. While a large number of
derivatives of this last compound have been reported,14–20 these ligands show poor metabolic stability in
mouse liver microsomes (MLM) (T ~5 min), suggesting they will be too short acting in vivo for clinical
1
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development. We therefore sought to improve their metabolic stability while maintaining the desired
bifunctional opioid profile.
A)
B)
III=
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HO
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II=
I=
OH
O
OH
N
N
HO
H
N
Cl
O
O
O
HO
N
O
O
SoRI 9409
UMB 425
D)
Mitragynine
Pseudoindoxyl
C)
O
IV=
V=
O
O
HN
H
N
N
NH2
H N
2
N
OH
H
O
NH2
OH
N
O
DIPP[]-NH2
AAH8
Figure 1: Notable structures that exhibit a MOR-agonist/DOR-antagonist profile. Some of these compounds utilize
the morphinan scaffold shared by many opioids (A), or is a derivative of kratom alkaloids (B), while others are
derived from endomorphins (C), or cyclic opioid peptides (D).
With this goal in mind, we sought to identify regions that would be most amenable to
modifications aimed at improving metabolic stability. Here, we used our original lead peptidomimetic
KSKPP1E (Figure 2A, A)21 as a reference point on which to base our initial design choices.
Tetrahydroquinolines (THQ) have been shown to aromatize upon action by CYP2A6 enzymes,22
commonly found in mouse liver microsomes. This aromatization could in part explain the metabolic
instability of our peptidomimetic series, an instability that persists for almost all compounds that contain a
bicyclic core akin to the THQ system. Given the role of the THQ core as linker for the 2’6’-
dimethyltyrosine (DMT) and benzyl pharmacophores, an SAR campaign aimed at transforming this core
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into a more stable form was pursued. Initially, we sought to remove the aliphatic ring of the THQ system,
producing more conformationally flexible ligands while removing the metabolically labile cycle (Figure
2
B). We were encouraged by other opioids that relied on similar strategies to connect these two
pharmacophore elements together, such as a urea,23 piperidine or piperazine,24 pyrazinone,25–28 alkyl
diamine,29,30 or long alkyl chains. Herein, we describe our initial SAR study that eliminates the bicyclic
system of the THQ core to both produce our desired MOR-agonist/DOR-antagonist profile and to
improve metabolic stability.
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A)
O
HN
NH2
OH
A=
Tyrosine Pharmacophore Mimic,
Very Sensitive to Modification
N
H
Phenylalanine Pharmacophore
Mimic, Sensitive to Modification
Tetrahydroquinoline linker, Least Sensitive to Modification,
Known to Aromatize with CYP 2A6
B)
O
HN
NH2
R1
OH
R2
Maintain Sensitive Tyrosine Mimic
Maintain Sensitive Phenylalanine Mimic
Convert Linker to More Stable Monocyclic Form
and Maintain MOR-agonist/DOR-antagonist Profile
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a: R =H, R =H
5e: R =H, R =Cl
5i: R =H, R =NHCOEt 5m: R =H, R =OnPr
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2
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2
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b: R =Me, R =H
5f: R =H, R =OH
5j: R =H, R =OMe
5n: R =H, R =OCPM
1
2
1
2
1
2
1
2
c: R =Et, R =H
5g: R =H, R =NHAc
5k: R =H, R =OCF
5o: R =H, R =OBn
3
1
2
1
2
1
2
1
2
d: R =H, R =Me
5h: R =H, R =NHEt
5l: R =H, R =OEt
5p: R =Me, R =OMe
Figure 2: A.) Pharmacophore and linker elements of our peptidomimetic lead.19,21 The pharmacophore elements
include 2’,6’-dimethyltyrosine and benzyl pendants that are sensitive to modification, and the linker consists of a
tetrahydroquinoline (THQ) core. B.) New analogs lacking the THQ core.
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Results:
General Chemistry: All of the described monocyclic compounds were synthesized according to Scheme
. Before engaging in the main route of synthesis, the ethers and the anilines were diversified at the
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beginning. To synthesize functionalized anilines, 2-amino-5-bromobenzaldehyde was subjected to
acylation using the appropriate neat anhydride at 100 °C, producing the acetyl and propionyl anilines 1g
and 1i respectively. To produce aromatic ethers, 5-bromo-2-hydroxybenzaldehyde was functionalized
using an alkyl bromide or iodide, producing the methyl, ethyl, n-propyl, cyclopropyl methyl, and benzyl
ethers 1j, l-o. The exceptions here are trifluoromethoxy ether 1k, which was purchased, and 1p, which
used 1-(5-bromo-2-hydroxyphenyl)ethan-1-one as starting material instead of 5-bromo-2-
hydroxybenzaldehyde. The functionalized aromatic bromo ketone or aldehydes 1a-e, g, i-p were then
reduced through imine formation with an Ellman’s chiral sulfonamide and subsequent reduction with
sodium borohydride, producing compounds 2a-e, g, i-p. The Ellman’s chiral sulfonamide both enables
enantioselective amine formation (if applicable) as used previously,18 and protects the amine during
subsequent Suzuki coupling to generate compounds 3a-e, g, i-p. This was followed by Ellman
deprotection using concentrated HCl and dioxane to produce 4a-e, g, i-p. The exception here being the
synthesis of the 6-phenol (4f) which utilized BBr to both remove the Ellman’s chiral sulfonamide and
3
cleave the 6-position ether 3l. The ethyl aniline analog 4h was synthesized by reduction of the acetyl
aniline 4g with borane-dimethylsulfide complex (BH *Me S). Finally, Boc-protected DMT was coupled
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2
to the free primary amine of structures 4a-p using PyBOP, followed by removal of the Boc groups using
trifluoroacetic acid to yield the final peptidomimetics 5a-p.
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Scheme 1: Synthesis of Substituted Monocyclic Core Analogs 5a-p
O
S
O
S
O
R
O
HN
X
NH3
HN
HN
Br
Br
R1
A
B
Bn
C for 4a-e, g, i-p Bn
G for 3l to 4f
R1
R1
Bn
1NH
3
R1
D
OH
O
R2
2
R2
R2
a-p
R
R2
1
a-e, g, i-p
2a-e, g, i-p
O
CF3
3
a-e, g, i-p
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5a-p
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R =H, R =NH
1
2
2
R =H, R =NHAc
4g
E
1
2
H
R =H, R =NHAcyl
1
2
R =H, R =NHEt 4h
1
g, i
1
1
2
1
2
1
2
1
2
2
1-5a: R =H, R =H
1-5e: R =H, R =Cl
1-5i: R =H, R =NHCOEt 1-5m: R =H, R =OnPr
R =H or Me R =OH
1
2
1
2
1
2
1
2
F
1
2
1-5b: R =Me, R =H
4-5f: R =H, R =OH
1-5j: R =H, R =OMe
1-5n: R =H, R =OCPM
R =H or Me R =OAlk
1
2
1
2
1
2
1
2
1-5c: R =Et, R =H
1-5g: R =H, R =NHAc 1-5k: R =H, R =OCF
3
1-5o: R =H, R =OBn
1
j-p
1
2
1
2
1
2
1
2
1
-5d: R =H, R =Me
4-5h: R =H, R =NHEt 1-5l: R =H, R =OEt
1-5p: R =Me, R =OMe
A) 1. (R)-(+)-2-methyl-propane-2-sulfinamide, Ti(OEt)
:1 Acetone:Water, 80-100 °C. C) HCl conc., Dioxane. D) 1. DiBocDMT, DIEA, PyBOP, 6-Cl-HOBt, DMF. 2.
TFA, DCM. E) Neat acyl anhydride, 100 °C. F) MeI or Alk-Br, K CO , DMF. G) BBr , DCM. H) BH *Me S, THF,
5 °C.
4 4 2 3 2
, THF, 75 °C 2. NaBH . B) BnBPin, K CO , Pd(dppf)Cl ,
3
2
3
3
3
2
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SAR: Our studies began by first probing the structural components of the aliphatic ring of the THQ core.
These studies focused on binding affinity, efficacy, and potency at MOR and DOR, though the κ-opioid
receptor (KOR) was also examined to determine compound selectivity. The binding affinity data can be
found in Table 1, whereas the efficacy and potency data can be found in Table 2 (see footnotes of each
table for how these values were measured). Initially, all substituents and functional groups comprising
this aliphatic ring were removed, yielding 5a. This conversion had little effect on binding affinity
compared to the original lead A, but had a significant effect on efficacy. Indeed, 5a did not stimulate any
of the three classical opioid receptors. We then began to restore different portions of the original aliphatic
ring to elucidate the importance of each component. The incorporation of short linear alkyl chains (5b-c)
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on the benzylic position (R ) connecting the aromatic core to the DMT pharmacophore partially restored
MOR agonism (41 % stimulation for compound 5b). In this case, the methyl group (5b) was superior to
an ethyl group (5c), however MOR efficacy was less than that of morphine (57 % stimulation), which
serves here as a benchmark for MOR activity. It should be noted that morphine’s intrinsic activity of 57
%
should not be interpreted as poor MOR efficacy, only that the standard agonist DAMGO in this assay
has exceptional efficacy. DOR affinity was found to decrease when these alkyl chains are incorporated,
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though these compounds still did not stimulate DOR. KOR binding improved with increasing chain size,
and weak KOR agonism was observed with both alkyl groups.
In parallel with the analogs described above, an assortment of compounds was made with
functional groups at the 6-position, corresponding to that of the THQ nitrogen. Initially, a few simple
substituents were incorporated at this position. These included methyl, chloro, and hydroxy groups (5d-f).
Each of these managed to restore MOR agonism to between 17 % and 39 %, but much less than that seen
with the parent compound. None of these ligands produced agonism at DOR, though the hydroxy (5f)
significantly reduced the binding at DOR compared to 5a.
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A small number of nitrogen containing substituents were also incorporated at the 6-position,
resulting in ethyl, acetyl, and propionyl anilines (5g-i). These were made to mimic the substituents of the
original THQ core without ring cyclization, or to mimic some N-acyl compounds that had utility in our
1
6
previously reported THQ series. These ligands were all weak partial MOR agonists and had reduced
binding affinity at DOR compared to 5a. The ethyl aniline also displayed reduced affinity at MOR.
Several ethers were examined due to their synthetic accessibility, their ability to be rapidly
diversified, and to probe the effect of hydrogen bond acceptors at the 6-position. The alkyl ethers included
methyl, trifluoromethyl, ethyl, n-propyl, cyclopropyl methyl (CPM), and benzyl (5j-o). Here, an activity
maximum was observed between the ethyl ether (5l), and the n-propyl ether (5m). Both ethers proved to
be more potent than morphine and displayed similar levels of efficacy to morphine at MOR. This, in
combination with the high DOR affinity and the lack of DOR efficacy of these two compounds,
demonstrates that these monocyclic core compounds can retain our desired in vitro profile.
1
2
A final compound was synthesized to determine if a combination of R and R substituents could
1
2
yield additive effects. To this end, 5p was synthesized, in which R =-Me and R =-OMe. These
substituents were selected as they have the same number of large atoms as the original THQ core, while
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O
R
HN
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5
3
1NH2
Binding Affinity, K
(nM)
Selectivity
i
OH
6
4
R2
Name
-R1
-CH
-R2
CH NH-
MOR
DOR
KOR
MOR:DOR:KOR
1:43:309
1:27:9.7
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A
2
2
0.22±0.02a
6.3±2.5b
1.0±0.2
1.1±0.3
3.2±0.6
5.2±0.9
5.6±0.8
9.48±0.50
7.9±1.1
23.5±6.5
4.2±1.1
3.58±0.10
1.4±0.5
2.8±0.5
0.91±0.06
2.7±0.6
8.0±1.5
8.0±0.8
9.4±0.8a
171±19b
14.7±0.6
46±10
68±2a
61±17b
Morphine
-
-
5
5
a
b
H
Me
Et
H
H
H
410±47
201±36
49.5±1.7
360±60
528±49
307±34
1550±130
408±54
1090±290
610±100
370±83
1180±120
390±150
319±51
575±80
330±150
1:15:410
1:42:180
1:19:15
5
c
H
61±10
5
d
Me
Cl
33.9±4.9
38.1±3.9
175±26
387±31
63.8±5.2
108±27
21.5±4.5
7.3±0.5
23.8±3.3
5.3±1.0
13.9±1.8
70.4±5.4
6.8±1.1
1:6.5:69
5
e
H
1:6.8:94
5
f
H
OH
1:18:32
5
g
H
NHAc
NHEt
1:49:200
1:2.7:17
5
h
H
5i
H
NHCOEt
OMe
1:26:260
1:6.0:170
1:5.2:260
1:8.5:420
1:5.8:430
1:5.1:120
1:8.8:71
5j
H
5k
H
OCF
3
5
l
H
OEt
5
m
H
OnPr
OCPM
OBn
5
n
H
5
5
o
p
H
Me
OMe
1:0.85:41
i
Table 1: Affinity of the benzylic core compounds at MOR, DOR, and KOR. Binding affinities (K ) were obtained
3
by competitive displacement of radiolabeled [ H] diprenorphine in membrane preparations. Included are morphine
and the original lead peptidomimetic (A) for comparison. All data were from three separate experiments, performed
in duplicate. These data are reported as the average ± standard error of the mean. Selectivity was calculated by
a
dividing the K
i
of each receptor by the K
i
at MOR for a given compound. DNS=Does Not Stimulate. From
2
1
b
32
Reference . From Reference .
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O
HN
1
2
5
3
NH2
R1
Potency, EC50 (nM)
Efficacy, (% Stimulation)
OH
6
4
R2
Name
-R1
-R2
MOR
1.6±0.3a
194±21b
DNS
DOR
110±6a
ND
KOR
540±72a
DNS
MOR
DOR
16±2a
ND
KOR
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A
-CH
2
CH
2
NH-
-
81±2a
22±2a
DNS
DNS
>40
Morphine
-
H
57±5b
5
5
a
b
H
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
DNS
Me
Et
H
H
44.4±7.5
158±17
111±29
250±24
552±90
117±13
156±20
84±26
>1700
2200±500
DNS
41±12
5
c
H
15.0±2.6
21.9±5.3
39.2±1.0
17.0±1.1
32.5±2.6
25.9±5.8
28.7±7.1
37.2±1.7
45.0±6.1
65.9±5.2
54.9±4.0
37.5±1.3
34.7±3.8
20.2±1.4
26.6±3.0
DNS
DNS
DNS
DNS
>40
5
d
Me
Cl
5
e
H
DNS
5
f
H
OH
DNS
5g
5h
5i
H
NHAc
NHEt
NHCOEt
OMe
DNS
H
>2440
>4000
DNS
H
>35
5
j
H
264±21
342±80
77±10
DNS
DNS
DNS
DNS
DNS
DNS
DNS
5
k
H
OCF
OEt
3
DNS
5
l
H
DNS
5
m
H
OnPr
OCPM
OBn
68±10
DNS
5
n
H
71±13
DNS
5
5
o
p
H
107±19
296±69
DNS
Me
OMe
DNS
Table 2: Efficacy and potency of the benzylic core compounds at MOR, DOR, and KOR. Efficacy and potency data
35
were obtained using agonist induced stimulation of [ S] GTPγS binding. Potency is represented as EC50 (nM) and
efficacy as percent maximal stimulation relative to standard agonist DAMGO (MOR), DPDPE (DOR), or U69,593
(KOR) at 10 μM. Included are morphine and the original lead peptidomimetic (A) for comparison. All data were
from three separate experiments, performed in duplicate. These data are reported as the average ± standard error of
a
19
b
33
the mean. DNS=Does Not Stimulate. ND =Not Determined. From Reference . From Reference .
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5
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5
5
5
5
5
6
also utilizing the more desirable ethers. When compared to 5b, this compound appears to have reduced
binding affinity, efficacy, and potency at MOR. DOR binding, however, shows a modest improvement
over 5b and retains an antagonist profile at DOR.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
With regards to KOR, most of the ligands express reduced binding affinity at this receptor
compared to A, with the exception of 5c. Similarly, only 5c, 5h, and 5i were shown to have weak, partial
efficacy at KOR; the rest have no efficacy at this receptor. Since we were interested in balancing the
binding affinity between MOR and DOR, and since we were screening KOR for selectivity, we calculated
binding ratios between MOR, DOR, and KOR normalized to MOR. Most of these ligands show an
improved balance between MOR and DOR compared to the lead compound A, the exception of 5g. The
2
greatest balance can be found with various functional groups at the R -position, namely the methyl (5d),
chloro (5e), ethyl aniline (5h), and all the ethers (5j-p). When comparing MOR and KOR for selectivity,
only the unfunctionalized compound 5a, and the ethyl (5l) and n-propyl (5m) ethers contained greater
selectivity than A.
Antagonist Potency of Representative Analogs: Finally, while analogs displaying reasonably high DOR
affinity (~20 nM or less) and no DOR efficacy are presumptive DOR antagonists, this was tested
explicitly for 5l, 5m, and 5n. DOR antagonism was confirmed for all three analogs, which effected
rightward shifts in the EC of the standard DOR agonist DPDPE that equated to K values of 20.2 nM,
5
0
e
7
.4 nM, and 20.5 nM, respectively (calculated as described in Methods).
Metabolic Stability: In tandem with the SAR described above, the metabolic stability of these monocyclic
core compounds was characterized in mouse liver microsomes (MLM) (Table 3) using verapamil as the
positive control. Because of the variability between the measures of metabolic half-life for verapamil
(from 13.8 to 22.6 min) in the different assay preparations, the ratio of T1/2 for the compound and
verapamil was calculated as a stability ratio. This was to ensure consistent comparisons between different
analogs.
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Name
R1
CH
H
R2
NH
T
1/2 (min)
Verapamil T1/2 (min)
14.7±2.0
14.6±1.0
22.6±1.4
13.8±1.6
22.6±1.4
22.6±1.4
14.4±1.0
14.4±1.0
22.6±1.4
13.8±1.6
14.6±1.0
14.6±1.0
19.6±2.3
22.6±1.4
22.6±1.4
14.6±1.0
Stability Ratio
0.21±0.03
0.89±0.19
0.38±0.04
0.29±0.04
0.54±0.03
0.72±0.12
1.1±0.1
cLogP
3.74
4.30
4.61
5.14
4.75
5.01
3.58
2.45
4.33
4.22
5.33
4.75
5.28
5.19
5.99
4.53
A
2
CH
2
3.1±0.1
13.0±2.6
8.5±0.8
5
5
a
b
H
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
Et
H
5
c
H
4.1±0.2
5
d
Me
12.2±0.0
16.3±2.5
15.4±1.3
10.2±0.4
12.1±1.5
19.7±2.0
5.7±0.0
5
e
H
Cl
5
f
H
OH
NHAc
NHEt
OMe
5
g
H
0.71±0.06
0.54±0.07
1.4±0.2
5
h
H
5
j
H
5k
5l
H
OCF
OEt
3
0.39±0.03
1.6±0.4
H
23.7±5.9
33.1±2.8
56.3±10.1
15.6±0.1
4.3±0.0
5m
H
OnPr
1.7±0.2
5
n
H
OCPM
OBn
2.5±0.5
5
5
o
p
H
0.69±0.04
0.30±0.02
Me
OMe
Table 3: Metabolic stability of monocyclic compounds in MLM. Included are the compound half-life
1/2), the half-life of the positive control verapamil, and the stability ratio between the compound and the positive
control. The stability ratio was calculated by dividing the half-life of the analog of interest by the half-life of the
(T
positive control in that assay. Individual compounds were tested once, with errors representing the SE in the decay
curve regressed onto the data collected in 15 minute intervals. Finally, the cLogP of these analogs are included and
were calculated using PerkinElmer’s ChemDraw® Professional Software.
To evaluate the improvement in stability of these compounds, the original lead compound A is
included in Table 3. This compound displays the poorest metabolic stability, with a ratio of 0.21
compared to verapamil and is characteristic of the other THQ containing analogs in our previously
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reported series. Stripping away all the substituents that make up the aliphatic portion of the
tetrahydroquinoline ring (5a) improves the ratio 4-fold to 0.89. However, introducing alkyl chains off this
1
benzylic position (R , 5b-c) reduces the stability of these compounds back to that of A.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
Next, we examined our analogs at the 6-position (R ). The small substituents at this position (5d-
f) did not improve the stability of these compounds, even though some of these modifications are polar
3
4
(
which would reduce cLogP ) or are electron withdrawing groups (which would inhibit free radical
formation during the CYP catalytic cycle). This also extends to the acetyl and ethyl anilines (5g-h), in
which no improvements were observed.
The ethers (5j-o), generally produced significant improvements in metabolic stability. This is
particularly true for cyclopropyl methyl ether (5n), which was 2.5 fold more stable than verapamil,
reflecting a half-life of 56 minutes. This was not true of all the ethers however, as the trifluoromethyl
ether (5k) showed lower stability levels than 5a. Finally, the hybrid analog 5p had low stability, similar to
compound 5b.
Discussion and Conclusions:
SAR: Using A as a baseline, it appears that moving to 5a causes a loss in MOR agonism and affinity. This
may in part be explained by increased conformational flexibility that occurs upon elimination of the
aliphatic portion of the tetrahydroquinoline ring. This activity can be partially regained through the
introduction of small alkyl chains at the benzylic position (5b-c), likely due to restoring interactions that
favor interaction with the active state of the receptor.
Introducing the methyl, chloro, or hydroxy group to the 6-position of the benzylic core (5d-f)
produced partial MOR agonism compared to 5a. The hydroxyl group (5f) was the least potent and
efficacious of the three, suggesting that either an electron donating group on the benzylic core or a
hydrogen bond donor at the 6-position interferes with the ability of substituents at this position to activate
MOR. This trend is also seen with binding affinity at DOR, as the hydroxy substituent possesses the
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lowest affinity. The chloro substituent (5e) is similar to the methyl (5d) substituent in its activity at the
three receptors, and differed only from 5d in that it had twice the efficacy at MOR. This reinforces the
electronics argument, as the chloro group is more electron withdrawing than the methyl group due to
induction.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The 6-position ethers produced some of the most promising ligands in this series. These ligands
generally had high MOR and DOR affinity, except for the benzyl ether at DOR (5o). However, the
potency and efficacy of these compounds at MOR vary greatly. The optimum here appears to be with the
ethyl (5l) and n-propyl (5m) ethers, which proved comparable to morphine in efficacy and potency. This
is particularly interesting when these data are compared to the 6-anilines (5g-i) and the 6-hydroxyl (5f), as
they suggest that the hydrogen bond donor present in these latter compounds is detrimental for MOR
efficacy, rather than the presence of electron donating groups. The orientation of the hydrogen bond
donor may be important, as the lead compound A displays high MOR efficacy. From the data illustrated
in compounds 5g-i, it appears that orientating the hydrogen bond donor toward the DMT pendant is
detrimental to MOR agonism. Since these ethers also antagonize DPDPE, these data suggest that the
small chain ethers are best for producing our desired MOR-agonist/DOR-antagonist profile.
It should be noted that the ethers 5l and 5m do not possess the potency or efficacy at MOR of the
original lead compound A. Since we are ultimately interested in determining if MOR-agonist/DOR-
antagonist ligands are suitable for use as opioid analgesics without abuse liabilities, the stability
improvements of 5l and 5m represents a necessary developmental step toward this end. This is
particularly true considering the instability of the THQ core compounds such as A. However, 5l and 5m
have improved potency and similar efficacy at MOR compared to morphine, which is the classic opioid
analgesic. As such, sacrificing some potency and efficacy at MOR to improve pharmacokinetic
parameters is worthwhile, especially if they still perform better than morphine in vitro.
The hybrid compound 5p is also notable due to its poor MOR efficacy and potency. While the
potency of this compound was akin to the simple 6-OMe precursor (5j), the efficacy here was less than
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
either precursor analog 5b and 5j. This suggests that steric effects within the ligand may be detrimental to
activation of MOR, a problem that vanishes when these two groups are tied together in the bicyclic ring
of the original THQ core.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
With regard to selectivity, two notable trends can be observed. Selectivity for MOR over KOR
can be reduced compared to our original lead A through two different means. Extending alkyl chains off
1
the benzylic position (R , 5b-c) do this largely through improving KOR binding which peaks with the
ethyl group (5c) in this series, whereas some substituents containing a hydrogen bond donor off the 6-
2
position (R ), namely the hydroxyl (5f) and ethyl aniline (5h) do this through reduced MOR binding.
Conversely, the ethyl and n-propyl ethers (5l-m) show the best selectivity over KOR, largely due to
reduced KOR binding compared to A. While almost all of the compounds show improved MOR/DOR
affinity balance, possibly due to elimination of the bicyclic ring system, all of the ethers (5j-p) have
among the best balance. Overall, the ethers 5l and 5m show the best selectivity over KOR, and are among
the compounds that best balance MOR and DOR affinities.
Metabolic Stability: Stripping away all the components of the THQ core (5a) produced a 4-fold
improvement in metabolic stability over A. When incorporating alkyl chains onto the benzylic position
(5b-c, and 5p), this improvement is lost, suggesting that this benzylic position in both this series and in
the original THQ series is a metabolic hot spot. This is consistent with the mechanism of CYP
metabolism, namely that the benzylic methyne present in compounds 5b-c, and 5p can greater stabilize
the radical formed upon interaction with the enzyme than can the methylene alone. Simple chloro (5e)
and hydroxyl (5f) functional groups at the 6-position were no different than the unfunctionalized system
(5a). The ethers (5j-o), apart from the trifluoro (5k) and benzyl (5o) ethers, displayed the greatest levels
of stability, reaching stability ratios of 2.5 and half-lives near an hour, as determined for 5n.
Interestingly, these ethers were more stable than the functionalized anilines, despite their greater
cLogP, which is commonly associated with reduced stability.34 Amines are better electron donating
substituents than ethers. As such, they may further stabilize metabolism at the adjacent benzylic positions
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on the aromatic ring. Notably, the most stable ether contained a cyclopropyl moiety. This can likely be
attributed to a combination of steric effects and ring strain, as the cyclopropyl group can both block
metabolism at adjacent positions and the ring strain destabilizes free radical formation on the cyclopropyl
group itself.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Fortunately, the SAR regarding the restoration of our MOR-agonist/DOR-antagonist profile
overlapped with the SAR aimed at improving metabolic stability. This suggests that these 6-position
ethers are a promising new direction for the development of these peptidomimetics. As such, our future
derivatization of these analogs will follow the lead provided by these promising ethers.
Conclusion: Addiction to prescription opioids remains a major challenge for millions of Americans. This
problem is driven largely by the widespread use of opioids to treat chronic pain. Consequently, there is a
growing need for potent analgesics that lack these abuse liabilities. To this end, agonism at MOR with
simultaneous antagonism at DOR may be able to produce analgesia without these side effects. Our
previously reported peptidomimetics and their bicyclic analogs display such a profile, however their
metabolic instability represents a major hurdle in their development. The results presented here show that
the metabolically labile THQ core can be changed to a monocyclic core to improve metabolic stability.
Initial modification of the simplified benzyl core yielded analogs (5l and 5m) which display similar
potency and efficacy as morphine at MOR, are antagonists at DOR, possess a more balanced affinity
between MOR and DOR, are more selective over KOR, and show improved metabolic stability in mouse
liver microsome assays compared to our original THQ core ligands. These monocyclic compounds
represent an attractive new direction through which more stable MOR-agonist/DOR-antagonist ligands
may be developed.
Experimental:
Chemistry
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General Methods: All reagents and solvents were obtained commercially and were used without further
purification. Intermediates were purified by flash chromatography using a Biotage Isolera One
instrument. Most purification methods utilized a hexanes/ethyl acetate solvent system in a Biotage SNAP
KP-Sil column, with a linear gradient between 0 and 100% ethyl acetate. Reverse phase column
chromatography using a linear gradient of 0 % to 100 % solvent B (0.1 % TFA in acetonitrile) in solvent
A (0.1 % TFA in water) using a Biotage SNAP Ultra C18 column was utilized for some intermediate
amine salts. Purification of final compounds was performed using a Waters semipreparative HPLC with a
Vydac protein and peptide C18 reverse phase column, using a linear gradient of 0 % to 100 % solvent B
in solvent A at a rate 1 % per minute, monitoring UV absorbance at 230 nm. The purity of final
compounds was assessed using a Waters Alliance 2690 analytical HPLC instrument with a Vydac protein
and peptide C18 reverse phase column. A linear gradient (gradient A) of 0 % to 70 % solvent B in solvent
A in 70 min, measuring UV absorbance at 230 nm was used to determine purity. All final compounds
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used for testing were ≥95 % pure, as determined by analytical HPLC. H NMR and C NMR data were
obtained on a 500 or 400 MHz Varian spectrometer using CDCl or CD OD solvents. The identities of
3
3
final compounds were verified by mass spectrometry using an Agilent 6130 LC–MS mass spectrometer in
the positive ion mode, or an Agilent 6230 TOF HPLC-MS in the positive ion mode. Suzuki couplings
using microwave irradiation were performed on a Discover S-class (CEM) microwave in a closed vessel
with maximum power input of 300 W and temperature set to 100 °C for 30 min under the standard
method using their Synergy software.
General Procedure for Ellman Reductions (Procedure A): A flamed-dried round bottom flask containing 1
equivalent of aldehyde or ketone and 3 equivalents of (R)-(+)-2-methyl-propane-2-sulfinamide was
attached to a reflux condenser and flushed with argon. 4 mL of THF was added and cooled to 0 °C. 6 or
7
.5 equivalents of titanium (IV) ethoxide was added, followed by an additional 4 mL of THF. The
solution was stirred and heated to 75 °C overnight with TLC monitoring until all ketone or aldehyde was
consumed. A separate flame-dried flask containing 6 equivalents of sodium borohydride was flushed with
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argon. 4 mL of THF was added, at which point the solution was cooled to -78 °C. The solution containing
Ellman adduct was cooled to room temperature and slowly transferred to the sodium borohydride solution
via syringe. This final solution was then allowed to warm to room temperature and stirred for 2 hours, at
which point the reaction mixture was quenched with methanol to consume the sodium borohydride,
followed by DI water to precipitate the titanium. The solution was vacuum filtered, and the precipitate
was washed with ethyl acetate. The filtrate was then concentrated in vacuo and purified via column
chromatography (0-100 % EtOAc in Hexanes).
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General Procedure for Suzuki Couplings Using Microwave Irradiation (Procedure Ba): To a microwave
vessel containing the protected amine was added 2 equivalents of benzylboronic acid pinacol ester, 3
equivalents of potassium carbonate, and 0.1 equivalents of 1,1′-Bis(diphenylphosphino)ferrocene]
dichloropalladium. The vessel was purged with argon and 2.5 mL of degassed 3:1 Acetone:Water was
added. The vessel was then subject to microwave irradiation to a temperature of 100 °C for 30 min. The
solution was cooled, partitioned between brine and ethyl acetate, and extracted with ethyl acetate. The
organic layer was then dried with magnesium sulfate, filtered, and concentrated in vacuo. Column
chromatography was then performed (0-100 % ethyl acetate in hexanes), yielding the desired Suzuki
coupled derivatives.
General Procedure for Suzuki Couplings without Microwave Irradiation (Procedure Bb): To a round
bottom flask containing protected amine, 2 equivalents of potassium carbonate, and 0.1 equivalents of
1
,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium was added 2.5 equivalents of benzylboronic
acid pinacol ester. The flask was equipped with a reflux condenser, purged with argon, and 5 mL of
degassed 3:1 Acetone:Water was added. The vessel was then heated to a temperature of 80 °C overnight.
The solution was cooled, partitioned between brine and ethyl acetate, and extracted with ethyl acetate.
The organic layer was then dried with magnesium sulfate, filtered, and concentrated in vacuo. Column
chromatography was then performed (0-100 % ethyl acetate in hexanes), yielding the desired Suzuki
coupled derivatives.
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General Procedure for Removal of Ellman’s chiral sulfonamide (Procedure C): To a flask containing
Ellman protected amine was added 2 mL of Dioxane and 0.2 mL concentrated HCl. The solution was
stirred at room temperature for 1 minute and concentrated in vacuo. The ensuing salt was then purified via
one of two methods. If the product is insoluble in diethyl ether, it was triturated with diethyl ether, and the
precipitate was concentrated in vacuo to dryness, yielding the product as an HCl salt. If the product was
soluble in diethyl ether, it was purified using a reverse phase chromatography (0-100% B in A), yielding
the product as a TFA salt.
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General Procedure for the Coupling of 2’,6’-Dimethyltyrosine to Functionalized Amine Salt (Procedure
D): To a dried flask containing the amine salt under argon was added 3 mL of DMF and 10 equivalents of
Hunig’s base. 1 equivalent of PyBOP and 1 equivalent of 6-Cl-HOBt was added, followed by 1
equivalent of N-Boc-O-Boc-2’,6’-dimethyl-L-tyrosine in 1.5 mL DMF. The solution was stirred
overnight at room temperature and concentrated in vacuo. 2 mL of TFA and 2 mL of DCM were then
added, and the solution was stirred for an additional hour. The reaction mixture was concentrated in vacuo
and purified via semipreparative reverse phase HPLC (0.1% TFA in water: 0.1% TFA in acetonitrile).
The product was concentrated in vacuo and lyophilized overnight to yield the final peptidomimetic.
General procedure for the acylation of 2-amino-5-bromobenzaldehyde (Procedure E): To a dried flask
containing 2-amino-5-bromobenzaldehyde under argon was added neat acyl anhydride. The reaction was
stirred overnight at 100 °C and concentrated in vacuo. The product was then partitioned between sat.
NaHCO and DCM. The compound was extracted with DCM, filtered, and concentrated in vacuo yielding
3
the desired acylated compound.
General Procedure for the Synthesis of 6-position Ethers (Procedure F): To a flame dried flask containing
phenolic aldehyde or ketone was added 3 equivalents of potassium carbonate. The flask was purged with
argon and 4 mL of DMF was added. 3 equivalents of an alkyl iodide or bromide was then added, and the
solution was stirred at room temperature overnight. The solution was then concentrated in vacuo,
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partitioned between ethyl acetate and saturated sodium bicarbonate, and extracted with ethyl acetate. The
organic layers were combined, dried with magnesium sulfate, filtered, and concentrated in vacuo, yielding
the desired ether.
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General procedure for the Cleavage of Phenolic Ethers (Procedure G): To a flame dried flask containing 1
equivalent of phenolic ether under argon was added 5 mL DCM and 3.02 equivalents of 1M BBr in DCM
3
was added dropwise. The solution was stirred at room temperature for 4 hours and quenched with
methanol. The solution was concentrated in vacuo, suspended in diethyl ether, and filtered. The
precipitate was then dissolved in methanol and filtered. The product in methanol was then concentrated in
vacuo, yielding the desired phenol.
General procedure for the Reduction of Acyl Anilines (Procedure H): To a dried flask containing the
desired acyl aniline under argon was added 2M BH *Me S in THF and additional THF. The solution was
3
2
heated to 75 °C for 3 hours, at which point the solution was quenched with methanol and stirred an
additional 15 minutes at 75 °C. The solution was cooled, concentrated in vacuo, yielding the reduced
alkyl aniline.
N-(4-bromo-2-formylphenyl)acetamide (1g): See Procedure E: 74 mg (0.37 mmol) of 2-amino-
5
-bromobenzaldehyde, and 3 mL of acetic anhydride. The compound was purified after aqueous workup
via column chromatography (0-10% ethyl acetate in hexanes) to produce compound 1g (59 mg, 65.9 %
1
yield) which was isolated as an orange solid. H NMR (500 MHz, Chloroform-d) δ 11.00 (br s, 1H), 9.84
1
3
(
s, 1H), 8.65 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 9.0, 2.4 Hz, 1H), 2.24 (s, 3H). C
NMR (126 MHz, Chloroform-d) δ 194.22, 169.53, 139.84, 138.80, 137.98, 122.78, 121.70, 114.91, 25.38.
N-(4-bromo-2-formylphenyl)propionamide (1i): See Procedure E: 98 mg (0.49 mmol) of 2-
amino-5-bromobenzaldehyde, and 3 mL of propionic anhydride. Compound 1i (113 mg, 90.1 % yield)
1
was isolated as an orange solid. H NMR (500 MHz, Chloroform-d) δ 11.00 (s, 1H), 9.81 (s, 1H), 8.65 (d,
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J = 9.0 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.64 (dd, J = 9.0, 2.4 Hz, 1H), 2.46 (q, J = 7.6 Hz, 2H), 1.24 (t,
13
J = 7.6 Hz, 3H). C NMR (126 MHz, Chloroform-d) δ 194.21, 173.28, 139.94, 138.75, 137.95, 122.83,
1
21.70, 114.71, 31.48, 9.33.
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-bromo-2-methoxybenzaldehyde (1j): See Procedure F: 157 mg (0.78 mmol) of 5-
bromosalicylaldehyde, 320 mg (2.3 mmol, 3.0 eq.) of K CO , 150 µL (342 mg, 2.4 mmol, 3.1 eq) of MeI,
2
3
1
3 mL of DMF. Compound 1j (170 mg, Quantitative Yield) was isolated as a yellow solid. H-NMR
(400MHz, CDCl ) δ 10.34 (s, 1H), 7.86 (d, J=2.3 Hz, 1H), 7.58 (dd, J=8.9, 2.3 Hz, 1H), 6.86 (d, J=8.9
3
13
Hz, 1H) 3.89 (s, 3H); C-NMR (101 MHz, CDCl ) δ 183.3, 169.7, 138.3, 130.9, 126.0, 113.7, 113.4,
3
5
6.0.
5
-bromo-2-ethoxybenzaldehyde (1l): See Procedure F: 451 mg (1.5 mmol) of 5-
bromosalicylaldehyde, 608 mg (4.4 mmol, 3.0 eq.) of K CO , 330 µL (482 mg, 4.4 mmol, 3.0 eq.) of
2
3
1
EtBr, 4 mL of DMF. Compound 1l (495 mg, 96.3 % yield) was isolated as a white solid. H NMR (400
MHz, Chloroform-d) δ 10.36 (s, 1H), 7.85 (d, J = 2.6 Hz, 1H), 7.55 (dd, J = 8.8, 2.6 Hz, 1H), 6.83 (d, J =
1
3
8
.9 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H). C NMR (101 MHz, Chloroform-d) δ
188.4, 160.2, 138.2, 130.7, 126.0, 114.5, 113.2, 64.6, 14.5.
5-bromo-2-propoxybenzaldehyde (1m): See Procedure F: 123 mg (0.61 mmol) of 5-
bromosalicylaldehyde, 251 mg (1.8 mmol, 3.0 eq.) of K CO , 160 µL (217 mg, 1.8 mmol, 2.9 eq.) of
2
3
1
nPrBr, 4 mL of DMF. Compound 1m (155 mg, Quantitative Yield) was isolated as a white waxy solid. H
NMR (400 MHz, Chloroform-d) δ 10.41 (s, 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.58 (dd, J = 8.9, 2.6 Hz, 1H),
1
3
6
.86 (d, J = 8.9 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H), 1.86 (h, J = 7.3 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). C
NMR (101 MHz, Chloroform-d) δ 188.4, 160.4, 138.2, 130.7, 126.1, 114.5, 113.2, 70.4, 22.4, 10.5.
-bromo-2-(cyclopropylmethoxy)benzaldehyde (1n): See Procedure F: 99 mg (0.49 mmol) of
-bromosalicylaldehyde, 204 mg (1.5 mmol, 3.0 eq.) of K CO , 140 µL (195 mg, 1.4 mmol, 2.9 eq.) of
5
5
2
3
(bromomethyl)cyclopropane, 3 mL of DMF. Compound 1n (128 mg, Quantitative Yield) was isolated as
1
a white solid. H NMR (500 MHz, Chloroform-d) δ 10.42 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.9 Hz, 1H),
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.82 (d, J = 8.7 Hz, 1H), 3.89 (d, J = 6.6 Hz, 2H), 1.27 (m, 1H), 0.65 (m, 2H), 0.36 (m, 2H). C NMR
126 MHz, Chloroform-d) δ 188.5, 160.3, 138.2, 130.7, 126.3, 114.9, 113.3, 73.7, 10.0, 3.2.
-(benzyloxy)-5-bromobenzaldehyde (1o): See Procedure F: 401 mg (2.0 mmol) of 5-
bromosalicylaldehyde, 828 mg (6.0 mmol, 3.0 eq.) of K CO , 710 µL (1021 mg, 6.0 mmol, 3.0 eq.) of
(
2
2
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BnBr, 5 mL of DMF. Compound 1m (569 mg, 97.9 % yield) was isolated as a white solid. H NMR (500
MHz, Chloroform-d) δ 10.46 (s, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.60 (dd, J = 8.9, 2.6 Hz, 1H), 7.45 – 7.33
(m, 5H), 6.95 (d, J = 8.9 Hz, 1H), 5.18 (s, 2H). 13C NMR (126 MHz, Chloroform-d) δ 188.2, 159.9,
138.2, 135.5, 131.0, 128.8, 128.5, 127.3, 126.5, 115.2, 113.8, 70.9.
1
-(5-bromo-2-methoxyphenyl)ethan-1-one (1p): See Procedure F: 198 mg (0.92 mmol) of 1-(5-
bromo-2-hydroxyphenyl)ethan-1-one, 380 mg (2.8 mmol, 3.0 eq.) of K CO , 0.170 mL (388 mg, 2.7
2
3
mmol, 3.0 eq.) of MeI, 3 mL of DMF. Compound 1p (205 mg, 97.2 % yield) was isolated as a white
1
solid. H NMR (500 MHz, Chloroform-d) δ 7.77 (d, J = 2.7 Hz, 1H), 7.48 (dd, J = 8.8, 2.6 Hz, 1H), 6.81
1
3
(
d, J = 8.9 Hz, 1H), 3.86 (s, 3H), 2.55 (s, 3H). C NMR (126 MHz, Chloroform-d) δ 198.1, 157.9, 136.0,
32.8, 129.5, 113.6, 113.0, 55.8, 31.7.
R)-N-(3-bromobenzyl)-2-methylpropane-2-sulfinamide (2a): See Procedure A: 90 mg (0.49
1
(
mmol) of 3-bromobenzaldehyde, 179 mg (1.5 mmol, 3.0 eq.) of (R)-(+)-2-methyl-propane-2-sulfinamide,
600 µL (653 mg, 2.9 mmol, 5.9 eq.) of Ti(OEt) , and 4+4 mL THF. 115 mg (3.0 mmol, 6.3 eq.) of sodium
4
1
borohydride in 4 mL THF. Compound 2a (111 mg, 78.6 % yield) was isolated as a white solid. H NMR
(
500 MHz, Chloroform-d) δ7.47 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 7.1 Hz, 1H), 7.19 (t, J = 7.7
Hz, 1H), 4.30 (dd, J = 14.2, 5.1 Hz, 1H), 4.22 (dd, J = 14.2, 7.5 Hz, 1H), 3.56 (t, J = 6.3 Hz, 1H), 1.23 (s,
1
3
9
H). C NMR (126 MHz, Chloroform-d) δ 140.8, 131.1, 130.7, 130.2, 126.6, 122.6, 56.0, 48.7, 22.7.
R)-N-((R)-1-(3-bromophenyl)ethyl)-2-methylpropane-2-sulfinamide (2b): See Procedure A:
55 mg (0.78 mmol) of 3’-bromoacetophenone, 261 mg (2.2 mmol, 2.8 eq.) of (R)-(+)-2-methyl-propane-
-sulfinamide, 1.00 mL (1.09 g, 4.8 mmol, 6.1 eq.) of Ti(OEt) , and 4+4 mL THF. 179 mg (4.7 mmol, 6.1
(
1
2
4
eq.) of sodium borohydride in 4 mL THF. Compound 2b (125 mg, 62.5 % yield) was isolated as a white
1
solid. H NMR (400 MHz, Chloroform-d) δ 7.46 (t, J = 1.8 Hz, 1H), 7.39 (ddd, J = 7.8, 2.0, 1.2 Hz, 1H),
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.26 (dt, J = 7.8, 1.4 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 4.48 (qd, J = 6.6, 3.1 Hz, 1H), 3.41 (d, J = 3.2 Hz,
13
H), 1.48 (d, J = 6.6 Hz, 3H), 1.21 (s, 9H). C NMR (101 MHz, Chloroform-d) δ 146.3, 130.9, 130.4,
29.6, 125.4, 122.7, 55.6, 53.6, 22.8, 22.6.
(R)-N-((R)-1-(3-bromophenyl)propyl)-2-methylpropane-2-sulfinamide (2c): See Procedure A:
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06 mg (0.50 mmol) of 1-(3-bromophenyl)propan-1-one, 185 mg (1.5 mmol, 3.1 eq.) of (R)-(+)-2-
methyl-propane-2-sulfinamide, 800 µL (870 mg, 3.8 mmol, 7.7 eq.) of Ti(OEt) , and 4+4 mL THF. 111
4
mg (2.9 mmol, 5.9 eq.) of sodium borohydride in 4 mL THF. Compound 2c (125 mg, 78.9 % yield) was
1
isolated as a white solid. H NMR (500 MHz, Chloroform-d) δ 7.43 (t, J = 1.8 Hz, 1H), 7.39 (dt, J = 7.6,
1
.7 Hz, 1H), 7.25 – 7.16 (m, 2H), 4.21 (ddd, J = 8.9, 5.4, 4.1 Hz, 1H), 3.40 (d, J = 4.0 Hz, 1H), 2.01 (dtd,
13
J = 14.7, 7.4, 5.5 Hz, 1H), 1.77 – 1.65 (m, 1H), 1.21 (s, 9H), 0.79 (t, J = 7.4 Hz, 3H). C NMR (126
MHz, Chloroform-d) δ 144.7, 130.9, 130.20, 130.15, 126.1, 122.7, 60.1, 55.8, 29.4, 22.6, 10.0.
(R)-N-(5-bromo-2-methylbenzyl)-2-methylpropane-2-sulfinamide (2d): See Procedure A: 77
mg (0.39 mmol) of 5-bromo-2-methylbenzaldehyde, 143 mg (1.2 mmol, 3.1 eq.) of (R)-(+)-2-methyl-
propane-2-sulfinamide, 490 µL (533 mg, 2.3 mmol, 6.0 eq.) of Ti(OEt) , and 4+4 mL THF. 89 mg (2.4
4
mmol, 6.1 eq.) of sodium borohydride in 4 mL THF. Compound 2d (108 mg, 91.8 % yield) was isolated
1
as a colorless oil that solidified on standing. H NMR (500 MHz, Chloroform-d) δ 7.43 (s, 1H), 7.30 (d, J
= 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.27 (dd, J = 13.9, 3.7 Hz, 1H), 4.16 (dd, J = 13.7, 8.4 Hz, 1H),
1
3
3
.43 (dt, J = 8.4, 3.7 Hz, 1H), 2.26 (s, 3H), 1.22 (s, 9H). C NMR (126 MHz, Chloroform-d) δ 138.4,
1
35.5, 132.1, 131.4, 130.7, 119.5, 56.0, 46.7, 22.7, 18.6.
(R)-N-(5-bromo-2-chlorobenzyl)-2-methylpropane-2-sulfinamide (2e): See Procedure A: 104
mg (0.47 mmol) of 5-bromo-2-chlorobenzaldehyde, 162 mg (1.3 mmol, 2.8 eq.) of (R)-(+)-2-methyl-
propane-2-sulfinamide, 600 µL (653 mg, 2.9 mmol, 6.0 eq.) of Ti(OEt) , and 4+4 mL THF. 107 mg (2.8
4
mmol, 6.0 eq.) of sodium borohydride in 4 mL THF. Compound 2e (134 mg, 87.1 % yield) was isolated
1
as a white solid. H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 2.3 Hz, 1H), 7.33 (dd, J = 8.5, 2.4 Hz,
1H), 7.21 (d, J = 8.5 Hz, 1H), 4.40 (dd, J = 15.0, 5.8 Hz, 1H), 4.28 (dd, J = 15.0, 7.5 Hz, 1H), 3.68 (t, J =
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.7 Hz, 1H), 1.22 (s, 9H). C NMR (126 MHz, Chloroform-d) δ 138.3, 132.7, 132.6, 131.9, 131.0, 120.6,
6.2, 46.9, 22.6.
(
R)-N-(4-bromo-2-(((tert-butylsulfinyl)amino)methyl)phenyl)acetamide (2g): See Procedure
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A: 93 (0.38 mmol) of 1g, 144 mg (1.2 mmol, 3.1 eq.) of (R)-(+)-2-methyl-propane-2-sulfinamide, 600 µL
(653 mg, 2.9 mmol, 7.5 eq.) of Ti(OEt) , and 4+4 mL THF. 87 mg (2.3 mmol, 6.0 eq.) of sodium
4
borohydride in 3 mL THF. This compound was purified using 0-10 % methanol in DCM as the mobile
phase during column chromatography. Compound 2g (130 mg, 97.5 % yield) was isolated as a colorless
1
oil. H NMR (400 MHz, Chloroform-d) δ 8.89 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 8.7, 2.4 Hz,
1
5
1
H), 7.37 (d, J = 2.4 Hz, 1H), 4.22 (dd, J = 13.5, 5.8 Hz, 1H), 4.11 (dd, J = 13.5, 4.5 Hz, 1H), 3.72 (t, J =
1
3
.1 Hz, 1H), 2.19 (s, 3H), 1.23 (s, 9H). C NMR (101 MHz, Chloroform-d) δ 169.53, 135.72, 133.03,
32.03, 130.51, 126.03, 117.34, 56.50, 44.54, 24.08, 22.85.
(
R)-N-(4-bromo-2-(((tert-butylsulfinyl)amino)methyl)phenyl)propionamide
(2i):
See
Procedure A: 84 (0.33 mmol) of 1i, 123 mg (1.0 mmol, 3.1 eq.) of (R)-(+)-2-methyl-propane-2-
sulfinamide, 410 µL (446 mg, 2.0 mmol, 6.0 eq.) of Ti(OEt) , and 4+4 mL THF. 76 mg (2.0 mmol, 6.1
4
eq.) of sodium borohydride in 4 mL THF. Compound 2i (78 mg, 65.8 % yield) was isolated as a colorless
1
oil. H NMR (500 MHz, Chloroform-d) δ 8.70 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 8.7, 2.2 Hz,
1
5
1
H), 7.36 (d, J = 2.4 Hz, 1H), 4.20 (dd, J = 13.4, 5.9 Hz, 1H), 4.08 (dd, J = 13.1, 4.5 Hz, 1H), 3.67 (t, J =
1
3
.1 Hz, 1H), 2.44 (q, J = 7.6 Hz, 2H), 1.22 (m, 12H). C NMR (126 MHz, Chloroform-d) δ 173.14,
35.81, 133.02, 132.07, 130.19, 125.87, 117.15, 56.47, 44.52, 30.22, 22.82, 9.69.
(
R)-N-(5-bromo-2-methoxybenzyl)-2-methylpropane-2-sulfinamide (2j): See Procedure A:
142 mg (0.66 mmol) of 1j, 240 mg (2.0 mmol, 3.0 eq.) of (R)-(+)-2-methyl-propane-2-sulfinamide, 1.00
mL (1.09 g, 4.8 mmol, 7.2 eq.) of Ti(OEt) , and 4+4 mL THF. 152 mg (4.0 mmol, 6.1 eq.) of sodium
4
1
borohydride in 4 mL THF. Compound 2j (159 mg, 75.2 % yield) was isolated as a colorless oil. H NMR
(
400 MHz, Chloroform-d) δ 7.36 (d, J = 2.5 Hz, 1H), 7.33 (dd, J = 8.6, 2.5 Hz, 1H), 6.72 (d, J = 8.6 Hz,
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H), 4.34 (dd, J = 14.4, 5.6 Hz, 1H), 4.11 (dd, J = 14.5, 7.6 Hz, 1H), 3.80 (s, 3H), 3.66 (t, J = 6.9 Hz,
13
H), 1.19 (s, 9H). C NMR (101 MHz, Chloroform-d) δ 156.4, 131.9, 131.4, 129.3, 112.6, 112.0, 55.9,
4.8, 22.6.
(R)-N-(5-bromo-2-(trifluoromethoxy)benzyl)-2-methylpropane-2-sulfinamide (2k): See
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Procedure A: 70 µL (119 mg, 0.44 mmol) of 5-bromo-2-(trifluoromethoxy)benzaldehyde, 163 mg (1.3
mmol, 3.0 eq.) of (R)-(+)-2-methyl-propane-2-sulfinamide, 700 µL (762 mg, 3.3 mmol, 7.5 eq.) of
Ti(OEt) , and 4+4 mL THF. 103 mg (2.7 mmol, 6.1 eq.) of sodium borohydride in 4 mL THF. Compound
4
1
2k (128 mg, 77.1 % yield) was isolated as a white solid. H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J
=
2.4 Hz, 1H), 7.43 (dd, J = 8.7, 2.5 Hz, 1H), 7.11 (dd, J = 8.7, 1.6 Hz, 1H), 4.38 (dd, J = 15.1, 5.8 Hz,
1
H), 4.27 (dd, J = 15.1, 7.4 Hz, 1H), 3.61 (t, J = 6.6 Hz, 1H), 1.22 (s, 9H). 13C NMR (126 MHz,
Chloroform-d) δ 146.2 (q, J = 1.7 Hz), 133.5, 133.0, 132.0, 122.2 (q, J = 1.7 Hz), 121.4, 120.2, 119.3,
6.2, 43.7, 22.6.
R)-N-(5-bromo-2-ethoxybenzyl)-2-methylpropane-2-sulfinamide (2l): See Procedure A: 73
mg (0.32 mmol) of 1l, 116 mg (0.96 mmol, 3.0 eq.) of (R)-(+)-2-methyl-propane-2-sulfinamide, 500 µL
5
(
(544 mg, 2.4 mmol, 7.5 eq.) of Ti(OEt) , and 4+4 mL THF. 74 mg (2.0 mmol, 6.1 eq.) of sodium
4
1
borohydride in 3 mL THF. Compound 2l (97 mg, 91.1 % yield) was isolated as a white solid. H NMR
(500 MHz, Chloroform-d) δ 7.36 (d, J = 2.5 Hz, 1H), 7.30 (dd, J = 8.7, 2.5 Hz, 1H), 6.70 (d, J = 8.7 Hz,
1
6
1
H), 4.35 (dd, J = 14.3, 5.6 Hz, 1H), 4.12 (dd, J = 14.4, 7.9 Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 3.72 (t, J =
13
.8 Hz, 1H,), 1.40 (t, J = 7.0 Hz, 3H), 1.20 (s, 9H). C NMR (126 MHz, Chloroform-d) δ 155.8, 131.8,
31.3, 129.4, 112.8, 112.5, 63.9, 55.9, 45.0, 22.6, 14.8.
(R)-N-(5-bromo-2-propoxybenzyl)-2-methylpropane-2-sulfinamide (2m): See Procedure A:
1
33 mg (0.55 mmol) of 1m, 98 mg (0.81 mmol, 1.5 eq.) of (R)-(+)-2-methyl-propane-2-sulfinamide, 420
µL (457 mg, 2.0 mmol, 3.7 eq.) of Ti(OEt) , and 3+3 mL THF. 121 mg (3.2 mmol, 5.9 eq.) of sodium
4
1
borohydride in 3 mL THF. Compound 2m (169 mg, 88.7 % yield) was isolated as a white solid. H NMR
(500 MHz, Chloroform-d) δ 7.35 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 8.7, 2.5 Hz, 1H), 6.68 (d, J = 8.7 Hz,
1H), 4.33 (dd, J = 14.4, 5.6 Hz, 1H), 4.11 (dd, J = 14.4, 7.8 Hz, 1H), 3.88 (t, J = 6.5 Hz, 2H), 3.72 (dd, J
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=
7.8, 5.6 Hz, 1H), 1.78 (h, J = 7.4 Hz, 2H), 1.18 (s, 9H), 1.01 (t, J = 7.4 Hz, 3H). C NMR (126 MHz,
Chloroform-d) δ 155.8, 131.8, 131.3, 129.4, 112.8, 112.4, 69.8, 55.9, 44.9, 22.6, 22.5, 10.6.
R)-N-(5-bromo-2-(cyclopropylmethoxy)benzyl)-2-methylpropane-2-sulfinamide (2n): See
(
Procedure A: 135 mg (0.53 mmol) of 1n, 197 mg (1.6 mmol, 3.1 eq.) of (R)-(+)-2-methyl-propane-2-
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sulfinamide, 840 µL (914 mg, 4.0 mmol, 7.6 eq.) of Ti(OEt) , and 4+4 mL THF. 115 mg (3.0 mmol, 5.8
4
eq.) of sodium borohydride in 3 mL THF. Compound 2n (165 mg, 86.5 % yield) was isolated as a
1
colorless oil that solidifies to a white solid on standing. H NMR (500 MHz, Chloroform-d) δ 7.36 (d, J =
2.5 Hz, 1H), 7.30 (dd, J = 8.7, 2.5 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 4.39 (dd, J = 14.4, 5.7 Hz, 1H), 4.14
(
dd, J = 14.4, 7.9 Hz, 1H), 3.88 – 3.75 (m, 3H), 1.21 (s, 9H), 0.62 (dt, J = 8.9, 3.2 Hz, 2H), 0.32 (dd, J =
13
4
5
.7, 2.1 Hz, 2H). C NMR (126 MHz, Chloroform-d) δ 155.9, 131.8, 131.3, 129.6, 113.0, 112.5, 73.1,
5.9, 45.3, 22.6, 10.2, 3.24, 3.18.
(
R)-N-(2-(benzyloxy)-5-bromobenzyl)-2-methylpropane-2-sulfinamide (2o): See Procedure A:
4
40 mg (1.5 mmol) of 1o, 558 mg (4.6 mmol, 3.1 eq.) of (R)-(+)-2-methyl-propane-2-sulfinamide, 2.4
mL (2.6 g, 11.4 mmol, 7.6 eq.) of Ti(OEt) , and 5+5 mL THF. 341 mg (9.0 mmol, 6.0 eq.) of sodium
4
1
borohydride in 4 mL THF. Compound 2o (582 mg, 97.2 % yield) was isolated as a white solid. H NMR
(400 MHz, Chloroform-d) δ 7.29 (d, J = 2.5 Hz, 1H), 7.27 – 7.18 (m, 4H), 7.18 – 7.11 (m, 2H), 6.62 (d, J
= 8.7 Hz, 1H), 4.98 (s, 2H), 4.32 (dd, J = 14.6, 5.7 Hz, 1H), 4.18 (dd, J = 14.6, 7.2 Hz, 1H), 4.12 (dd, J =
1
3
7
1
.2, 5.8 Hz, 1H), 1.14 (s, 9H). C NMR (101 MHz, Chloroform-d) δ 155.3, 136.2, 131.7, 131.0, 129.9,
28.5, 128.1, 128.0, 127.2, 126.7, 113.3, 112.8, 70.0, 55.7, 44.5, 22.5.
(
R)-N-((R)-1-(5-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (2p): See
Procedure A: 129 mg (0.59 mmol) of 1p, 193 mg (1.6 mmol, 2.7 eq.) of (R)-(+)-2-methyl-propane-2-
sulfinamide, 720 µL (783 mg, 3.4 mmol, 5.8 eq.) of Ti(OEt) , 4+4 mL THF, 137 mg (3.6 mmol, 6.1 eq.)
4
of sodium borohydride in 4 mL THF. Compound 2p (173 mg, 91.9 % yield) was isolated as a colorless
1
oil. H NMR (500 MHz, Chloroform-d) δ 7.33 (d, J = 2.5 Hz, 1H), 7.26 (dd, J = 8.7, 2.5 Hz, 1H), 6.69 (d,
J = 8.7 Hz, 1H), 4.69 (p, J = 6.5 Hz, 1H), 3.77 (s, 3H), 3.75 (d, J = 5.8 Hz, 1H), 1.40 (d, J = 6.7 Hz, 3H),
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.16 (s, 9H). C NMR (126 MHz, Chloroform-d) δ 155.6, 134.5, 131.1, 129.7, 113.0, 112.6, 55.6, 49.6,
3.6, 22.6, 21.0.
(
R)-N-(3-benzylbenzyl)-2-methylpropane-2-sulfinamide (3a): See Procedure Bb: 55 mg (0.19
mmol) of 2a, 120 µL (118 mg, 0.54 mmol, 2.8 eq.) of benzyl boronic acid pinacol ester, 54 mg (0.39
mmol, 2.1 eq.) of potassium carbonate, 17 mg (0.023 mmol, 0.12 eq.) of 1,1′-
Bis(diphenylphosphino)ferrocene]dichloropalladium, 4 mL of 3:1 Acetone:Water. Compound 3a (38 mg,
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66.5% yield) was isolated as a colorless oil that solidified to a white solid on standing. H NMR (400
MHz, Chloroform-d) δ 7.32 – 7.24 (m, 3H), 7.23 – 7.10 (m, 6H), 4.31 (dd, J = 13.8, 4.6 Hz, 1H), 4.21
13
(
dd, J = 13.8, 7.8 Hz, 1H), 3.98 (s, 2H), 3.45 (dd, J = 7.6, 4.6 Hz, 1H), 1.22 (s, 9H). C NMR (101 MHz,
Chloroform-d) δ 141.6, 140.8, 138.7, 128.9, 128.7, 128.6, 128.5, 128.3, 126.2, 125.8, 55.9, 49.3, 41.8,
2
9
2.7.
(
R)-N-((R)-1-(3-benzylphenyl)ethyl)-2-methylpropane-2-sulfinamide (3b): See Procedure Bb:
8 mg (0.32 mmol) of 2b, 180 µL (176 mg, 0.81 mmol, 2.5 eq.) of benzyl boronic acid pinacol ester, 86
mg (0.62 mmol, 1.9 eq.) of potassium carbonate, 21 mg (0.029 mmol, 0.089 eq.) of 1,1′-
Bis(diphenylphosphino)ferrocene]dichloropalladium, 5 mL of 3:1 Acetone:Water. Compound 3b (58 mg,
1
57.1 % yield) was isolated as a colorless oil. H NMR (500 MHz, Chloroform-d) δ 7.33 – 7.23 (m, 3H),
7.24 – 7.14 (m, 5H), 7.11 (dt, J = 7.7, 1.4 Hz, 1H), 4.51 (qd, J = 6.5, 2.6 Hz, 1H), 3.99 (s, 2H), 3.39 (d, J
1
3
=
2.6 Hz, 1H), 1.49 (d, J = 6.5 Hz, 3H), 1.22 (s, 9H). C NMR (126 MHz, Chloroform-d) δ 144.3, 141.7,
40.8, 128.91, 128.87, 128.5, 128.3, 127.2, 126.1, 124.2, 55.4, 53.8, 41.9, 22.8, 22.6.
R)-N-((R)-1-(3-benzylphenyl)propyl)-2-methylpropane-2-sulfinamide (3c): See Procedure
Ba: 83 mg (0.28 mmol) of 2c, 130 µL (127 mg, 0.58 mmol, 2.1 eq.) of benzyl boronic acid pinacol ester,
16 mg (0.84 mmol, 3.0 eq.) of potassium carbonate, 20 mg (0.027 mmol, 0.098 eq.) of 1,1′-
1
(
1
Bis(diphenylphosphino)ferrocene]dichloropalladium, 2.5 mL of 3:1 Acetone:Water. Compound 3c (81
1
mg, 94.3 % yield) was isolated as a colorless oil. H NMR (500 MHz, Chloroform-d) δ 7.30 – 7.23 (m,
3H), 7.21 – 7.07 (m, 6H), 4.23 (dt, J = 8.5, 4.6 Hz, 1H), 3.98 (s, 2H), 2.02 (dp, J = 13.2, 7.4 Hz, 1H), 1.73
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(
dq, J = 21.7, 7.3 Hz, 1H), 1.20 (s, 9H), 0.77 (t, J = 7.5 Hz, 3H). C NMR (126 MHz, Chloroform-d) δ
42.4, 141.4, 140.9, 128.9, 128.7, 128.5, 128.4, 127.9, 126.1, 124.9, 60.2, 55.7, 41.8, 29.3, 22.6, 10.0.
R)-N-(5-benzyl-2-methylbenzyl)-2-methylpropane-2-sulfinamide (3d): See Procedure Bb: 89
mg (0.29 mmol) of 2d, 200 µL (196 mg, 0.90 mmol, 3.1 eq.) of benzyl boronic acid pinacol ester, 82 mg
0.59 mmol, 2.0 eq.) of potassium carbonate, 22 mg (0.030 mmol, 0.10 eq.) of 1,1′-
1
(
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(
Bis(diphenylphosphino)ferrocene]dichloropalladium, 4 mL of 3:1 Acetone:Water. Compound 3d (65 mg,
1
70.4 % yield) was isolated as a tan solid. H NMR (500 MHz, Chloroform-d) δ 7.30 – 7.26 (m, 2H), 7.19
(t, J = 8.7 Hz, 3H), 7.12 – 7.07 (m, 2H), 7.05 (dd, J = 7.8, 1.9 Hz, 1H), 4.30 (dd, J = 13.3, 3.9 Hz, 1H),
13
4
.18 (dd, J = 13.3, 8.8 Hz, 1H), 3.94 (s, 2H), 3.27 (dd, J = 9.1, 3.9 Hz, 1H), 2.31 (s, 3H), 1.20 (s, 9H). C
NMR (126 MHz, Chloroform-d) δ 141.0, 139.0, 136.2, 134.4, 130.6, 129.4, 128.9, 128.5, 128.3, 126.1,
5.9, 47.4, 41.5, 22.7, 18.6.
R)-N-(5-benzyl-2-chlorobenzyl)-2-methylpropane-2-sulfinamide (3e): See Procedure Bb: 59
mg (0.18 mmol) of 2e, 100 µL (98 mg, 0.45 mmol, 2.5 eq.) of benzyl boronic acid pinacol ester, 47 mg
0.34 mmol, 1.9 eq.) of potassium carbonate, 13 mg (0.018 mmol, 0.098 eq.) of 1,1′-
5
(
(
Bis(diphenylphosphino)ferrocene]dichloropalladium, 4 mL of 3:1 Acetone:Water. Compound 3e (45 mg,
1
73.7 % yield) was isolated as a colorless oil that solidifies to a white solid on standing. H NMR (500
MHz, Chloroform-d) δ 7.30 – 7.24 (m, 3H), 7.21-7.18 (m, 2H), 7.15 (d, J = 7.5 Hz, 2H), 7.05 (d, J = 8.1
Hz, 1H), 4.40 (dd, J = 14.4, 5.1 Hz, 1H), 4.27 (dd, J = 14.3, 7.8 Hz, 1H), 3.93 (s, 2H), 3.60 (t, J = 6.8 Hz,
13
1
1
H), 1.18 (d, J = 1.4 Hz, 9H). C NMR (126 MHz, Chloroform-d) δ 140.3, 136.0, 131.4, 130.5, 129.6,
29.5, 128.9, 128.6, 126.3, 56.1, 47.3, 41.2, 22.6.
(
R)-N-(4-benzyl-2-(((tert-butylsulfinyl)amino)methyl)phenyl)acetamide (3g): See Procedure
Ba: 125 mg (0.36 mmol) of 2g, 140 µL (137 mg, 0.63 mmol, 1.8 eq.) of benzyl boronic acid pinacol ester,
36 mg (0.98 mmol, 2.7 eq.) of potassium carbonate, 29 mg (0.040 mmol, 0.11 eq.) of 1,1′-
1
Bis(diphenylphosphino)ferrocene]dichloropalladium, 3.2 mL of 3:1 Acetone:Water. Compound 3g (94
1
mg, 72.8 % yield) was isolated as a yellow oil H NMR (500 MHz, Chloroform-d) δ 8.72 (s, 1H), 7.79 (d,
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J = 8.3 Hz, 1H), 7.29 – 7.22 (m, 2H), 7.20 – 7.12 (m, 4H), 7.04 (d, J = 2.1 Hz, 1H), 4.20 (dd, J = 13.2, 6.0
Hz, 1H), 4.12 (dd, J = 13.3, 4.4 Hz, 1H), 3.90 (s, 2H), 3.65 (t, J = 5.3 Hz, 1H), 2.18 (s, 3H), 1.21 (s, 9H).
13C NMR (126 MHz, Chloroform-d) δ 169.48, 140.67, 137.91, 134.64, 130.73, 129.71, 128.89, 128.74,
1
28.51, 126.19, 124.72, 56.34, 45.48, 41.28, 24.05, 22.84.
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(R)-N-(4-benzyl-2-(((tert-butylsulfinyl)amino)methyl)phenyl)propionamide
(3i):
See
Procedure Bb: 76 mg (0.21 mmol) of 2i, 120 µL (118 mg, 0.54 mmol, 2.6 eq.) of benzyl boronic acid
pinacol ester, 59 mg (0.43 mmol, 2.0 eq.) of potassium carbonate, 15 mg (0.020 mmol, 0.098 eq.) of 1,1′-
Bis(diphenylphosphino)ferrocene]dichloropalladium, 5 mL of 3:1 Acetone:Water. Compound 3i (68 mg,
1
8
8
4
6.8 % yield) was isolated as a yellow oil. H NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 7.84 (d, J =
.3 Hz, 1H), 7.27 (t, J = 7.3 Hz, 2H), 7.23 – 7.11 (m, 4H), 7.05 (s, 1H), 4.19 (dd, J = 13.1, 6.2 Hz, 1H),
.11 (dd, J = 13.1, 4.3 Hz, 1H), 3.92 (s, 2H), 3.55 (t, J = 5.2 Hz, 1H), 2.44 (q, J = 7.6 Hz, 2H), 1.25 – 1.21
1
3
(
m, 12H). C NMR (126 MHz, Chloroform-d) δ 173.06, 140.73, 137.67, 134.78, 130.73, 129.71, 128.88,
1
28.50, 128.46, 126.18, 124.49, 56.27, 45.47, 41.28, 30.28, 22.83, 9.87.
(R)-N-(5-benzyl-2-methoxybenzyl)-2-methylpropane-2-sulfinamide (3j): See Procedure Bb:
49 mg (0.47 mmol) of 2j, 200 µL (196 mg, 0.90 mmol, 1.9 eq.) of benzyl boronic acid pinacol ester, 193
1
mg (1.4 mmol, 3.0 eq.) of potassium carbonate, 33 mg (0.045 mmol, 0.096 eq.) of 1,1′-
Bis(diphenylphosphino)ferrocene]dichloropalladium, 3 mL of 3:1 Acetone:Water. Compound 3j (98 mg,
1
6
3.5 % yield) was isolated. H NMR (400 MHz, Chloroform-d) δ 7.26 (ddd, J = 7.6, 6.3, 1.3 Hz, 2H),
7
.20 – 7.13 (m, 3H), 7.09 – 7.04 (m, 2H), 6.77 (d, J = 9.0 Hz, 1H), 4.36 (dd, J = 13.8, 5.1 Hz, 1H), 4.10
1
3
(
dd, J = 13.8, 8.0 Hz, 1H), 3.90 (s, 2H), 3.79 (s, 3H), 3.76 (dd, J = 8.0, 5.3 Hz, 1H), 1.17 (s, 9H). C
NMR (101 MHz, Chloroform-d) δ 155.8, 141.3, 133.2, 129.9, 129.0, 128.8, 128.4, 126.9, 126.0, 110.4,
55.9, 55.4, 45.5, 41.0, 22.6.
(R)-N-(5-benzyl-2-(trifluoromethoxy)benzyl)-2-methylpropane-2-sulfinamide
(3k):
See
Procedure Bb: 141 mg (0.38 mmol) of 2k, 110 µL (108 mg, 0.49 mmol, 1.3 eq.) of benzyl boronic acid
pinacol ester, 94 mg (0.68 mmol, 1.8 eq.) of potassium carbonate, 28 mg (0.038 mmol, 0.10 eq.) of 1,1′-
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Bis(diphenylphosphino)ferrocene]dichloropalladium, 5 mL of 3:1 Acetone:Water. Compound 3k (105
1
mg, 72.3 % yield) was isolated as a tan solid. H NMR (500 MHz, Chloroform-d) δ 7.33 – 7.27 (m, 2H),
7
2
.26 (s, 1H), 7.25 – 7.11 (m, 5H), 4.39 (dd, J = 14.5, 5.4 Hz, 1H), 4.26 (dd, J = 14.5, 7.7 Hz, 1H), 3.97 (s,
1
3
H), 3.53 (dd, J = 7.7, 5.4 Hz, 1H), 1.19 (s, 9H). C NMR (126 MHz, Chloroform-d) δ 145.6 (q, J = 1.5
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Hz), 140.2, 140.1, 131.1, 130.5, 129.3, 128.9, 128.6, 126.4, 121.6, 120.6 (q, J = 1.4 Hz), 119.5, 56.03,
4.1, 41.2, 22.5.
(R)-N-(5-benzyl-2-ethoxybenzyl)-2-methylpropane-2-sulfinamide (3l): See Procedure Ba: 119
mg (0.36 mmol) of 2l, 160 µL (157 mg, 0.72 mmol, 2.0 eq.) of benzyl boronic acid pinacol ester, 151 mg
1.1 mmol, 3.1 eq.) of potassium carbonate, 29 mg (0.040 mmol, 0.11 eq.) of 1,1′-
4
(
Bis(diphenylphosphino)ferrocene] dichloropalladium, 2.5 mL of 3:1 Acetone:Water. Compound 3l (87
1
mg, 70.7 % yield) was isolated as a colorless oil. H NMR (500 MHz, Chloroform-d) δ 7.29 – 7.24 (m,
2
H), 7.20 – 7.15 (m, 3H), 7.07 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 8.2, 2.3 Hz, 1H), 6.76 (d, J = 8.3 Hz,
H), 4.39 (dd, J = 13.8, 5.1 Hz, 1H), 4.11 (dd, J = 13.8, 8.1 Hz, 1H), 4.02 (qd, J = 7.0, 1.1 Hz, 2H), 3.91
1
(
s, 2H), 3.76 (dd, J = 8.3, 5.2 Hz, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.18 (s, 9H). 13C NMR (126 MHz,
Chloroform-d) δ 155.2, 141.4, 133.0, 129.9, 129.0, 128.8, 128.4, 127.1, 126.0, 111.2, 63.6, 55.8, 45.6,
41.0, 22.6, 15.0.
(R)-N-(5-benzyl-2-propoxybenzyl)-2-methylpropane-2-sulfinamide (3m): See Procedure Ba:
1
22 mg (0.35 mmol) of 2m, 130 µL (127 mg, 0.58 mmol, 1.7 eq.) of benzyl boronic acid pinacol ester,
35 mg (0.98 mmol, 2.8 eq.) of potassium carbonate, 25 mg (0.034 mmol, 0.098 eq.) of 1,1′-
1
Bis(diphenylphosphino)ferrocene]dichloropalladium, 2.5 mL of 3:1 Acetone:Water. Compound 3m (92
1
mg, 73.1 % yield) was isolated as a yellow oil. H NMR (500 MHz, Chloroform-d) δ 7.26 (dd, J = 8.1,
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.9 Hz, 2H), 7.20 – 7.14 (m, 3H), 7.08 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 8.3, 2.3 Hz, 1H), 6.76 (d, J = 8.3
Hz, 1H), 4.39 (dd, J = 13.8, 5.2 Hz, 1H), 4.12 (dd, J = 13.8, 8.2 Hz, 1H), 3.91 (t, J = 6.5 Hz, 2H), 3.90 (s,
1
3
2
H) 3.76 (dd, J = 8.2, 5.2 Hz, 1H), 1.80 (h, J = 7.2 Hz, 2H), 1.17 (s, 9H), 1.04 (t, J = 7.4 Hz, 3H). C
NMR (126 MHz, Chloroform-d) δ 155.3, 141.4, 133.0, 129.9, 129.0, 128.8, 128.4, 127.1, 126.0, 111.2,
69.6, 55.8, 45.6, 41.0, 22.7, 22.6, 10.7.
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