Efficient access to sp3-rich tricyclic amine scaffolds through Diels-Alder reactions of azide-containing silyloxydienes

Article abstract of DOI:10.1016/j.tet.2016.03.016

The preparation of sp³-rich scaffolds to obtain more natural product-like libraries for incorporation into screening decks is challenging. Here, we describe the use of a Diels-Alder reaction between an enone and an azide-containing silyloxydiene to gain efficient access to complex tricyclic amine scaffolds. Derivatization of these scaffolds provided a library of 80 amines, amides, sulfonamides, quinolines and indolenines, all in >20 mg quantities and >90% purities. These library compounds displayed properties more similar to alkaloid natural products than to drugs and commercial drug-like libraries, as shown by a high proportion of sp³ carbon centers.

Full text of DOI:10.1016/j.tet.2016.03.016

Accepted Manuscript
3
Efficient access to sp -rich tricyclic amine scaffolds through Diels-Alder reactions of
azide-containing silyloxydienes
Michael C. McLeod, Jeffrey Aubé
PII:
S0040-4020(16)30148-X
10.1016/j.tet.2016.03.016
TET 27556
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 January 2016
Revised Date: 1 March 2016
Accepted Date: 2 March 2016
3
Please cite this article as: McLeod MC, Aubé J, Efficient access to sp -rich tricyclic amine scaffolds
through Diels-Alder reactions of azide-containing silyloxydienes, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.03.016.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered
Efficient access to sp3-rich tricyclic amine
scaffolds through Diels-Alder reactions of
azide-containing silyloxydienes
Leave this area blank for abstract info.
Michael C. McLeod and Jeffrey Aubé*
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047

ACCEPTED MANUSCRIPT
Efficient access to sp3-rich tricyclic amine scaffolds
through Diels-Alder reactions of azide-containing
silyloxydienes
Michael C. McLeod and Jeffrey Aubé*,‡
The University of Kansas Center of Excellence in Chemical Methodologies and Library
Development (KU-CMLD), 2034 Becker Drive, Del Shankel Structural Biology Center,
Lawrence, Kansas 66047, United States.
‡Current address: UNC Eshelman School of Pharmacy, 125 Mason Farm Road, CB 7363,
University of North Carolina, Chapel Hill, NC, 27599-7363
KEYWORDS: Parallel synthesis; Diels-Alder cycloaddition; polycyclic heterocycles
ABSTRACT: The preparation of sp3-rich scaffolds to obtain more natural product–like libraries
for incorporation into screening decks is challenging. Here, we describe the use of a Diels-Alder
reaction between an enone and an azide−containing silyloxydiene to gain efficient access to
complex tricyclic amine scaffolds. Derivatization of these scaffolds provided a library of 80
amines, amides, sulfonamides, quinolines and indolenines, all in >20 mg quantities and >90%
purities. These library compounds displayed properties more similar to alkaloid natural products
1

ACCEPTED MANUSCRIPT
than to drugs and commercial drug-like libraries, as shown by a high proportion of sp3 carbon
centers.
2

ACCEPTED MANUSCRIPT
1. Introduction
A growing movement in the drug discovery community has been the introduction of compounds
with greater sp3 character into screening collections.1 Such compounds exhibit higher structural
complexity than more planar analogs, thereby making them more akin to natural products and
better able to probe different regions of chemical space.2 As natural products are extensively
employed as drugs, the creation of more drug-like libraries has been proposed to increase the
likelihood of finding biological hits.3 In order to create such sp3−rich collections of molecules,
methodology needs to be developed to allow the efficient synthesis of these relatively complex
scaffolds. Common approaches to this challenge includes the use of natural products themselves
as starting points for diversification,4 through diverted total synthesis where advanced
intermediates in the synthesis of natural products are repurposed to create analogs of the target
molecule,5 and by diversity orientated synthesis.6 We have recently described an approach to
diverse scaffolds that contain similar structural features to biologically active alkaloid natural
products.7
During this work, we developed a number of enabling technologies to allow access to these
complex scaffolds, including a Diels−Alder/Schmidt domino reaction. This combines the most
prevalent method for carbocycle formation with a useful method of nitrogen insertion and ring
expansion, and allows efficient access to polycyclic amides and lactams.8 This methodology
permitted the efficient construction of 5,6,7-tricyclic lactam scaffolds 2 through a Lewis acid-
promoted Diels-Alder/Schmidt reaction of azidoenone 1 with a number of silyloxydienes
(Scheme 1a).7b By simply tethering the azide to the diene rather than the dienophile, the
structurally similar, but 3-dimensionally rather different, lactams 4 were obtained (Scheme
1b).7a,9 In the latter Diels–Alder/Schmidt reaction, an excess (2.5 to 3 equiv) of Lewis acid is
3

ACCEPTED MANUSCRIPT
required for the lactam formation. However, by reducing the Lewis acid loading to 1 equiv, the
domino reaction can be interrupted so that the Diels−Alder cycloaddition step occurs without
subsequent alkyl azide Schmidt reaction (Scheme 1c). This was previously employed to
synthesize a small (23 member) library of amines and amides, the biological testing of which
identified a number of compounds as potent and selective Sigma-1 inhibitors (Ki ≥2 nM).7a This
promising biological data, as well the as the under-representation of this scaffold in the literature
prompted us to revisit this chemistry with the goal of creating a ca. 100 member library
containing greater structural diversity. In particular, we wanted to obtain scaffolds with different
substituents at C-5, and to prepare library compounds containing functional groups other than
amines and amides.
4

ACCEPTED MANUSCRIPT
Scheme 1. Routes to tricyclic N-containing scaffolds
O
TBSO
O
N
R
library of ~350
compounds
(a)
N3
TiCl4
O
H
R
1
2
O
N3
O
H
N
library of ~100
compounds
H
R
(b)
2.5−3.0 equiv
Lewis acid
O
H
TMSO
R
3
4
O
N3
NH
H
H
H
O
H
library of 23
compounds
(21 amines
& 2 amides)
3 steps
(c)
3
5
1.0 equiv
Lewis acid
O
H
O
Et
H
Et
5
6
NH
Under-represented scaffold
- 24 hits in SciFinder (rings locked)
- 15 hits in PubChem
2. Results and Discussion
2. 1 Scaffold preparation
Our synthetic route to tricyclic amine scaffolds 6a-d is outlined in Scheme 2, and represents an
improved protocol over the previously reported synthesis of 6b (R = Et).7a
Horner−Wadsworth−Emmons reaction of β-ketophosphonates 7a-d with 3-azidopropanal and
treatment of the resulting enone with TMSOTf and Et3N afforded silyloxydienes 3a-d. The key
Diels–Alder reaction of cyclohexenone with 3a-d was then carried out using 1 equiv of
BF3•OEt2 in the presence of flame-dried molecular sieves to afford the cycloadducts 5a-d as a
5

ACCEPTED MANUSCRIPT
mixture of diastereoisomers. The C-5 chiral center can be epimerized in later transformations,
and so this diastereomeric mixture was directly subjected to an aza-Wittig reaction with
triphenylphosphine. Reductive amination of the resulting primary amine forms the desired
tricyclic scaffold, again as a mixture of diastereoisomers. Under the acid conditions employed,
tautomerization of the imine intermediate to its enamine form results in inversion of the C-8a
center. Finally, epimerization of the C-5 stereocenter with NaOMe followed by purification by
silica gel chromatography allowed the isolation of diastereomerically pure (>9:1 dr) amines 6b-d
in multigram (up to 5.0 g) quantities. Compared to the previous route, this method is
advantageous as the difficult separation of isomeric azides 5 is avoided, and epimerization of the
C-5 center is carried out prior to scaffold diversification. This chemistry can also be used to
install alternative R groups at C-5. The sequence where R = H was not as synthetically useful
due to consistently low-yielding steps (mainly caused by difficulties in purification/instability to
silica gel), nonetheless 800 mg of 6a could be obtained along with a diastereoisomer (see
Supporting Information).
Scheme 2. Preparation of scaffolds
6

ACCEPTED MANUSCRIPT
(i)
N3
O
NaH, THF
-50 °C to rt
O
O
P
OTMS
R
R
OMe
OMe
N3
(ii) TMSOTf, Et3N
CH2Cl2, -30 to 0 °C
7a R = H
3a 35%
b 47%
c 47%
d 56%
b
c
d
Et
Bn
CH2-4-MeOC6H4
O
N3
(i) PPh3, THF, rt
NH
(ii) Na(OAc)3BH
AcOH, CH2Cl2, rt
H
H
H
H
O
H
BF3•OEt2
CH2Cl2
-78 to 0 °C
(iii) NaOMe
MeOH, rt
O
R
5
O
H
R
6a 11% c 42%
b 49% d 34%
(over 4 steps)
5a-d
2. 2 Library synthesis
During our first foray into tricyclic amine scaffolds 6, we found that only compounds containing
a basic amine displayed significant activity against the Sigma receptors, corresponding amides
being inactive at these targets. We therefore wished to add further amines to our screening deck
to probe the effect of changing the amine substituent and the R1 group on the biological activity
(Scheme 3). However, we were also interested in the activity of these scaffolds against other
biological targets, and so the secondary amine of 6 was also decorated with different functional
groups to provide libraries of amides and sulfonamides, thereby expanding the volume of
chemical space covered by this collection. We also wanted to incorporate aromatic heterocycles
into these scaffolds as not only are such moieties extensively employed in drug molecules,10 but
quinolines derived from related tricyclic scaffolds have been shown to be active at the Sigma-2
receptor.7a
A library of tertiary amines was prepared by reductive amination with scaffolds 6b-d with ten
aldehydes 8 to afford 25 amines 9b-d (Scheme 3). Of these library members, 20 passed our
7

ACCEPTED MANUSCRIPT
quality hurdles (>20 mg quantities, >90% purity) after mass-directed purification. Scaffold 6a,
along with its diastereoisomer (see Supporting Information) was reacted with propionaldehyde to
afford two more amines.
Scheme 3. Synthesis of tertiary amine libraries
NH
H
N
R2
R2
O
H
H
H
H
H
8{1-10}
AcOH, Na(OAc)3BH
CH2Cl2, rt, 48 h
O
O
H
H
R1
R1
6a-d
9a-d{1-10}
8{1} R2 = Et
8{6} R2 = 4-ClC6H4
8{2} R2 = thiazol-2-yl
8{3} R2 = N-methylimidazol-2-yl
8{4} R2 = (CH2)2Ph
8{5} R2 = Ph
8{7} R2 = 4-MeOC6H4
8{8} R2 = 4-MeC6H4
8{9} R2 = 2-O2NC6H4
8{10} R2 = 2-F3CC6H4
A library of amides was prepared by an EDC-promoted coupling of scaffolds 6b-d with 12
carboxylic acids (Scheme 4). We were able to employ acyclic and cyclic aliphatic, and aromatic
acids in this reaction, to afford 28 new compounds (25 of which passed our quality controls after
mass-directed purification).
Scheme 4. Synthesis of amide libraries
O
H
O
R2
NH
H
N
R2
HO
H
H
H
H
H
H
10{1-12}
EDC, DMAP
CH2Cl2, rt, 48 h
O
O
R1
R1
6b-d
11b-d{1-13}
5{1} R2 = Ph
5{7} R2 = nBu
5{8} R2 = cyclobutyl
5{9} R2 = cyclohexyl
5{10} R2 = thiophen-3-ylmethyl
5{11} R2 = pyridin-3-yl
5{12} R2 = phenylethynyl
5{2} R2 = 4-ClC6H4
5{3} R2 = 4-MeOC6H4
5{4} R2 = 4-MeC6H4
5{5} R2 = 3,4-Cl2C6H3
5{6} R2 = 3-Me2NC6H4
8

ACCEPTED MANUSCRIPT
Reaction of scaffolds 6b-d with various sulfonyl chlorides afforded a library of 28 aromatic and
heteroaromatic sulfonamides, of which 22 were isolated in >20 mg quantities and >90% purities
after mass-directed purification (Scheme 5). We also attempted to incorporate aliphatic
sulfonamides into our library by treatment with methylsulfonyl chloride, however this reaction
proved unsuccessful, with no desired product isolated. Although we did not carefully examine
this, it is possible that mesyl chloride underwent base-mediated elimination before it could react
with the relatively hindered amine partner.
Scheme 5. Synthesis of sulfonamide libraries
O O
S
O O
S
R2
Cl
R2
NH
H
N
H
H
H
H
H
H
H
12{1-12}
Et3N, CH2Cl2, rt, 48 h
O
O
R1
R1
6b-d
13b-d{1-13}
7{1} R2 = Ph
7{7} R2 = 4-FC6H4
7{2} R2 = 4-ClC6H4
7{3} R2 = 4-MeOC6H4
7{4} R2 = 4-MeC6H4
7{5} R2 = 3,5-Cl2C6H3
7{6} R2 = 4-F3CC6H4
7{8} R2 = 4-nBuC6H4
7{9} R2 = 2,4-(NO2)2C6H3
7{10} R2 = benzyl
7{11} R2 = naphthyl
7{12} R2 = N-methylimidazol-2-yl
To prepare compounds containing an indole or quinoline moiety, the synthesis of library member
4b{2} was scaled up to provide 3 g of this tertiary amine. Fisher indole synthesis of 4b{2}with
aryl hydrazines and para-toluenesulfonic acid (PTSA) afforded a library of six indolenines 15 as
single diastereoisomers (5/6 in >20 mg and >90% purity, Scheme 6), the relative stereochemistry
of which was assigned by consideration of the electrocyclization transition state (Figure 1). A
small library of 6 quinolines 17 was also prepared using a one-pot modified Friedländer
quinoline synthesis protocol.11 Each 2-nitrobenzaldehyde 16 was reduced in situ with Fe0
9

ACCEPTED MANUSCRIPT
powder before addition of ketone scaffold 4b{2} and KOH to provide quinolines 17, all in >20
mg quantities and >90% purities after mass-directed purification.
Scheme 6. Synthesis of indolenine and quinoline libraries
CHO
(i)
R2
NO2
16{1-6}
R2
nPr
H
NH2
N
H
nPr
H
nPr
H
N
H
H
H
N
Fe0, HCl
N
H
H
H
H
H
H
14{1-6}
EtOH, 85 °C, 3 h
R2
N
(ii) ketone 4b, KOH
PTSA, EtOH
85 °C, 18 h
N
Et
O
EtOH, 85 °C, 18 h
Et
Et
R2
15{1-6}
4b{2}
17{1-6}
14{1} R2 = H
16{1} R2 = H
14{2} R2 = 4-iPr
14{3} R2 = 4-OMe
14{4} R2 = 2,5-Cl2
14{5} R2 = 2-Cl
14{6} R2 = 4-Cl
16{2} 1-nitro-2-naphthaldehyde
16{3} R2 = 4,5-(-OCH2O-)
16{4} R2 = 5-Cl
16{5} R2 = 3-OMe
16{6} R2 = 4-CF3
Figure 1. Proposed transition state of electrocyclization leading to indolenine 17{1}
H
N
N
HN
nPr
nPr
N
N
Et
Et
17{1}
2.3 Cheminformatic analysis
In total, 95 library members were prepared, of which 80 (84%) were isolated in >20 mg
quantities and >90% purities. As the compounds are to be included in screening decks, it was
desirable to gain an insight as to their expected bioavailability properties. To this effect, the
molecular weight (m/w), XlogP, number hydrogen bond donors (HBD) and acceptors (HBA),
number of rotatable bonds (rotB) and topological polar surface area (tPSA) were calculated
10

ACCEPTED MANUSCRIPT
(mean values shown Table 1; see Supporting Information for details). For comparison, the
equivalent properties for a set of drugs, natural products (NPs), alkaloid natural products and
commercial drug-like libraries are also displayed in Table 1.7b,12 The scaffolds and library
compounds were all found to be Veber-compliant, while 59% of library members and 100% of
scaffolds met all four of Lipinski’s rules. Non-compliance of Lipinski’s rules for the library
compounds was predominantly caused by high XlogP values (average 4.5), presumably arising
from the extensive use of aromatic rings used to decorate the scaffolds; the average XlogP of the
scaffolds themselves was considerably lower (average 2.5). The XlogP aside, our library
compounds were more similar to alkaloid natural products than to the other classes of molecules.
In particular they were more rigid and possessed a smaller polar surface area (RotB 4.2, tPSA
43.0) than drugs (6.3, 68.9), and were more akin to alkaloids (2.8, 53.7).
The average degree of carbon atom saturation (fraction sp3 (Fsp3))1a for the scaffolds and library
compounds was found to be 0.78 and 0.60 respectively. These values are similar to the reference
set of natural products (0.64) and alkaloids (0.65) and considerably higher than those of drugs
(0.41) and commercial drug-like libraries (0.23).
Table 1. Bioavailability properties and Fsp3 analysis
Drugs
NPs
Commercial Alkaloid NPs Scaffolds Library Cmpds
m/w
361
2.7
1.5
5.4
85
629
1.5
414
2.4
1.5
6.8
95
319
2.0
1.3
4.4
90
253
2.5
396
4.5
0.0
3.1
59
XlogP
HBD
4.9
1.0
HBA
10.8
42
2.3
% Pass Lipinski (4/4)
% Pass Lipinski (3/4)
RotB
100
100
1.5
98
53
100
5.7
98.3
95
100
2.8
53.7
95
100
4.2
43.0
99
6.3
68.9
88
9.7
tPSA
183.2
33
31.4
100
% Pass Veber (2/2)
11

ACCEPTED MANUSCRIPT
Fsp3
0.41
0.64
0.23
0.65
0.78
0.60
12

ACCEPTED MANUSCRIPT
3. Conclusion
We have prepared a library of 95 previously unreported compounds from four tricyclic amine
scaffolds, of which 80 were obtained in useful quantities (>20 mg) and purities (>90%) for
incorporation into multiple screening decks. The chemical properties of these compounds were
found to be more similar to natural products, in particular alkaloid natural products, than to drugs
and commercial drug-like libraries, due to their relatively small polar surface area, rigid structure
and high proportion of sp3 carbon centers. One global lesson from our studies and those of
similarly minded laboratories4a,13 is that complex-looking molecules, prepared by total synthesis,
need not be considered beyond the reach of chemists in studying the biological properties of such
molecules. Conversely, we are convinced that the continuing need for precisely targeted
compounds represents an important contemporary motivation for continued advances in
synthetic methodology.
These compounds will be screened against the Sigma 1 and 2 receptors and/or deposited with the
NIH MLSMR (molecular libraries small molecule repository), and their biological activities will
be reported in due course.
4. Experimental Section
4.1 General experimental
Unless stated, all solvents and reagents were used as supplied from commercial sources.
Dichloromethane and tetrahydrofuran were dried by being passed through two packed columns
of neutral ammonia using a commercial solvent purification system prior to use. Parallel library
syntheses were performed on a Bohdan Miniblock XT parallel solution phase syntheziser
13

ACCEPTED MANUSCRIPT
obtained from Mettler-Toledo Auto Chem. Parallel evaporation was performed on a GeneVac
EZ-2 plus evaporation system. Purification of the libraries was performed by mass-directed
preparative HPLC: the HPLC analysis was carried out using a Waters Acquity system with UV
and mass detection with a linear gradient of 5% acetonitrile in pH 9.8 buffered aqueous
NH4HCO2 to 100% MeCN at a flow rate of 0.6 mL/min. Preparative reverse-phase purification
was carried out using a Waters 2767 preparative system with UV detection (Waters 2996 PAD)
and mass detection (Waters Micromass ZQ) with a Waters X-Bridge C18 column (19 x 150 mm,
with 19 x 10 mm guard column) eluting with a water (or pH 9.8 aqueous NH4OH)/ acetonitrile
gradient with a flow rate of 20 mL/min, and sample dilution in DMSO. Flash chromatography
was performed using Sorbent Technologies standard grade silica gel (40-63 ꢀm particle size, 230
Å 400 mesh). Automated column chromatography was performed on a Teledyne CombiFlashRf
system with pre-packed RediSepRf columns for normal phase, and RediSepRf C18 high
performance Gold columns for reverse phase separations. Infrared spectra were acquired on a
PerkinElmer Spectrum 100 FT-IR spectrophotometer. NMR spectra were recorded at the
frequencies stated using a Bruker AM 400 or Bruker 500 MHz AVIII with 13C-observe
cryogenically-cooled probe spectrometer. Chemical shifts were referenced to δ 7.26 and 77.0
ppm from chloroform for 1H and 13C respectively. The multiplicities of 1H signals are designated
by the following abbreviations: s = singlet; d = doublet; t = triplet; m = multiplet; br = broad. All
13C NMR spectra were acquired using broadband decoupled mode and assignments were
determined using DEPT sequences. Mass spectra were obtained by electrospray ionization in
positive ion mode.
14

ACCEPTED MANUSCRIPT
4.2 Experimental procedures for scaffold synthesis
4.2.1 Amine scaffolds 6a and S1
BF3ꢁOEt2 (4.60 mL, 37.1 mmol) was added to a solution of cyclohexenone (3.60 mL,
37.1 mmol) in anhydrous CH2Cl2 (300 mL) with 4Å MS (~8.5 g) at −78 °C under argon. The
mixture was stirred at −78 °C for 5 min, then a solution of silyloxydiene 3a 9 (11.8 g, 55.6 mmol)
in CH2Cl2 (50 mL) was added over 10 min. The reaction was allowed to warm from −78 °C to rt
and stirred for 18 h. The reaction was quenched with H2O (200 mL) and extracted with CH2Cl2
(3 x 100 mL). The combined organics were dried (Na2SO4) and concentrated to afford a brown
oil. The crude product was purified by automated chromatography (2 x 40 g silica columns, 0 to
10% MeOH in CH2Cl2 over 20 min). All of the fractions containing the correct mass were
combined to afford an orange oil (4.00 g).
The diastereomeric mixture of above azides was dissolved in anhydrous THF (200 mL)
and PPh3 (8.90 g, 34.0 mmol) added. The reaction mixture was stirred at rt for 18 h, then 2M
NaOH (50 mL) added and the mixture extracted with EtOAc (3 x 100 mL). The combined
organics were dried (Na2SO4) and concentrated to afford a brown oil. The residue was dissolved
in CH2Cl2 (200 mL) and acetic acid (970 ꢀL, 17.0 mmol) added, followed by sodium
triacetoxyborohydride (7.20 g, 34.0 mmol). The reaction was stirred at rt for 18 h, then quenched
with 2M NaOH (50 mL) and extracted with CH2Cl2 (3 x 100 mL). The combined organics were
dried (Na2SO4) and concentrated to afford a brown solid. The crude product was purified by
15

ACCEPTED MANUSCRIPT
chromatography (silica gel, 90:9:1 CH2Cl2:MeOH:NH4OH) to afford the title compound (800
mg, 7% from diene 3a, inseparable mixture of diastereoisomers) as a brown oil.
4.2.2 Amines 9a{1} and S2
Propionaldehyde (450 ꢀL, 6.21 mmol) was added to a solution of the diastereomeric
mixture of amines 6a and S1 (800 mg, 4.14 mmol) in anhydrous CH2Cl2 (30 mL) at rt under
argon. Acetic acid (240 ꢀL, 4.14 mmol) was then added, followed by sodium
triacetoxyborohydride (1.75 g, 8.28 mmol). The reaction mixture was stirred at rt for 18 h, then
quenched with 2 M NaOH (10 mL) and extracted with CH2Cl2 (3 x 20 mL). The combined
organics were dried (Na2SO4) and concentrated to afford a brown oil (850 mg). The crude
product was purified by automated reverse-phase chromatography (50 g C18 column, 10%
MeCN in basic H2O to 100% over 20 min), to afford 9a{1} (286 mg, 29%) and S2 (152 mg,
16%) as pale yellow solids. 9a{1}: IR 2926, 1711 cm-1; δH (500 MHz, CDCl3) 2.95 – 2.90 (m,
1H), 2.66 – 2.58 (m, 1H), 2.45 – 2.38 (m, 1H), 2.33 – 2.24 (m, 3H), 2.12 – 2.00 (m, 3H), 1.88 –
1.77 (m, 2H), 1.65 – 1.59 (m, 2H), 1.51 – 1.26 (m, 6H), 1.18 – 1.04 (m, 3H), 0.82 (t, J = 7.4 Hz,
3H); δC (125 MHz, CDCl3) 210.2 (C), 63.8 (CH), 55.1 (CH2), 52.6 (CH2), 50.5 (CH), 48.5 (CH2),
48.4 (CH2), 41.01 (CH), 40.99 (CH), 33.8 (CH2), 33.3 (CH2), 30.0 (CH2), 24.5 (CH2), 17.5
(CH2), 12.0 (CH3); m/z (ESI+) found [M+H]+ 236.2001. C15H26NO+ requires 236.2009. S2: IR
2926, 1710 cm-1; δH (500 MHz, CDCl3) 2.96 – 2.90 (m, 1H), 2.60 – 2.53 (m, 2H), 2.49 – 2.37
(m, 2H), 2.28 – 2.21 (m, 2H), 2.19 – 1.99 (m, 5H), 1.75 – 7.64 (m, 2H), 1.62 – 1.50 (m, 2H),
16

ACCEPTED MANUSCRIPT
1.48 – 1.24 (m, 5H), 1.14 (ddd, J = 16.5, 12.5, 4.0 Hz, 1H), 0.85 (t, J = 7.4 Hz, 3H); δC (125
MHz, CDCl3) 211.5 (C), 59.2 (CH), 54.4 (CH2), 53.1 (CH2), 48.6 (CH2), 47.6 (CH2), 45.1 (CH),
39.1 (CH), 34.9 (CH2), 32.6 (CH), 29.7 (CH2), 28.1 (CH2), 19.8 (CH2), 17.1 (CH2), 12.0 (CH3);
m/z (ESI+) found [M+H]+ 236.1999. C15H26NO+ requires 236.2009.
4.2.3 Amine scaffold 6c
BF3ꢁOEt2 (5.20 mL, 42.4 mmol) was added to a solution of cyclohexenone (4.10 mL,
42.4 mmol) in anhydrous CH2Cl2 (350 mL) with 4Å MS (~20 g) at −78 °C under argon. The
mixture was stirred at −78 °C for 5 min, then a solution of silyloxydiene 3c 9 (17.9 g, 59.4 mmol)
in CH2Cl2 (50 mL) was added over 10 min. The reaction was allowed to warm from −78 °C to rt
and stirred for 18 h. The reaction was quenched with H2O (200 mL) and extracted with CH2Cl2
(3 x 100 mL). The combined organics were dried (Na2SO4) and concentrated to afford a brown
oil (19.5 g). The crude product was purified by automated chromatography (40 g silica column, 0
to 10% MeOH in CH2Cl2 over 20 min). All of the fractions containing the correct mass were
combined to afford an orange oil (6.60 g).
The diastereomeric mixture of above azides was dissolved in anhydrous THF (400 mL)
and PPh3 (10.6 g, 40.6 mmol) added. The reaction mixture was stirred at rt for 18 h, then 2M
NaOH (60 mL) added and the mixture extracted with EtOAc (3 x 200 mL). The combined
organics were dried (Na2SO4) and concentrated to afford a brown oil. The residue was dissolved
in CH2Cl2 (350 mL) and acetic acid (1.20 mL, 20.3 mmol) added, followed by sodium
triacetoxyborohydride (8.60 g, 40.6 mmol). The reaction was stirred at rt for 18 h, then quenched
with 2M NaOH (70 mL) and extracted with CH2Cl2 (3 x 100 mL). The combined organics were
dried (Na2SO4) and concentrated to afford a brown oil. The crude product was purified by
17

ACCEPTED MANUSCRIPT
chromatography (silica gel, 90:9:1 CH2Cl2:MeOH:NH4OH) to afford the title compound (3.30 g,
20% from diene 3c, mixture of diastereoisomers) as a brown oil.
The diastereomeric mixture was dissolved in MeOH (150 mL) and K2CO3 (7.20 g, 52.4
mmol) added. The reaction was stirred at rt for 18 h, then concentrated to a brown oil, which was
dissolved in CH2Cl2 (100 mL) and H2O (30 mL). The aqueous layer was extracted with CH2Cl2
(4 x 100 mL). The combined organics were dried (Na2SO4) and concentrated to afford the title
compound (2.44 g, 74%, >9:1 dr) as a yellow solid foam. δH (500 MHz, CDCl3) 7.26 – 7.12 (m,
5H), 3.11 – 3.05 (m, 2H), 2.79 (dd, J = 14.5, 2.6 Hz, 1H), 2.72 (ddd, J = 12.2, 12.2, 2.7 Hz, 1H),
2.43 (ddd, J = 10.8, 8.1, 1.9 Hz, 1H), 2.37 (dd, J = 12.8, 3.8 Hz, 1H), 2.31 – 2.22 (m, 1H), 2.18 –
2.12 (m, 2H), 1.89 – 1.83 (m, 2H), 1.81 – 1.76 (m, 1H), 1.66 (ddd, J = 12.9, 5.9, 2.5 Hz, 1H),
1.58 – 1.49 (m, 1H), 1.42 – 1.23 (m, 4H), 1.19 – 1.05 (m, 2H); δC (125 MHz, CDCl3) 209.9 (C),
141.5 (C), 129.3 (CH), 128.2 (CH), 125.7 (CH), 59.9 (CH), 58.0 (CH), 52.3 (CH), 48.9 (CH2),
46.2 (CH2), 46.0 (CH), 41.5 (CH), 34.3 (CH2), 33.2 (CH2), 31.9 (CH2), 31.2 (CH2), 24.3 (CH2);
m/z (ESI+) found [M+H]+ 284.1991. C19H26NO+ requires 284.2009.
4.2.4 Dimethyl (4-(4-methoxyphenyl)-2-oxobutyl)phosphonate 7d
n-Butyllithium (2.5 M in hexanes, 22.0 mL, 55.1 mmol) was added slowly to a solution
of dimethyl methylphosphonate (6.00 mL, 55.1 mmol) in anhydrous THF (100 mL) at −78 °C
under argon. The reaction mixture was stirred at −78 °C for 1 h, then a solution methyl 3-(4-
methoxyphenyl)propanoate14 (10.7 g, 55.1 mmol) in THF (50 mL) was added dropwise. The
mixture was stirred at −78 °C for 5 min, then at rt for 30 min, after which the reaction was
quenched with saturated aqueous NH4Cl (100 mL) and extracted with Et2O (3 x 100 mL). The
combined organics were dried (Na2SO4) and concentrated to afford a pale yellow oil (15.8 g).
18

ACCEPTED MANUSCRIPT
The crude product was purified by chromatography (silica gel, 100% EtOAc) to afford the title
compound (9.00 g, 57%) as a colourless oil. IR 2956, 1712 cm-1; δH (400 MHz, CDCl3) 7.23 –
7.06 (m, 2H), 6.93 – 6.76 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.09 (d, J = 22.7 Hz,
2H), 2.98 – 2.84 (m, 4H); δC (100 MHz, CDCl3) 201.1 (C, d, J = 6.1 Hz), 158.0 (C), 132.6 (C),
129.3 (CH), 113.9 (CH), 55.3 (CH3), 53.1 (CH3), 53.0 (CH3), 45.8 (CH2), 41.5 (CH2, d, J = 128
Hz), 28.6 (CH2); m/z (ESI+) found [M+H]+ 287.1049. C13H20O5P+ requires 287.1043.
4.2.5 (E)-7-Azido-1-(4-methoxyphenyl)hept-4-en-3-one S3
Sodium hydride (60% dispersion in oil, 1.54 g, 38.6 mmol) was added portionwise to a
solution of 7d (8.50 g, 29.7 mmol) in anhydrous THF (100 mL) at −50 °C under argon. The
resulting suspension was warmed from −78 °C to 0 °C over 2.5 h, then cooled to −10 °C and a
solution of 3-azidopropanal15 (3.82 g, 38.6 mmol) in THF (20 mL) was added over 5 min. The
reaction mixture was stirred between 0 and −10 °C for 1 h, then at rt for 45 min. Water (50 mL)
was then added and extracted with Et2O (2 x 50 mL). The combined organics were washed with
brine (50 mL), dried (Na2SO4) and concentrated to afford a brown oil (10.1 g). The crude
product was purified by automated chromatography (2 x 40 g columns, 0 to 25% EtOAc in
hexanes over 15 min) to afford the title compound (4.5 g, 58%) as a yellow oil. IR 2935, 2094,
1511 cm-1; δH (400 MHz, CDCl3) 7.17 – 7.05 (m, 2H), 6.86 – 6.81 (m, 2H), 6.76 (dt, J = 15.9,
6.9 Hz, 1H), 6.19 (dt, J = 15.9, 1.5 Hz, 1H), 3.79 (s, 3H), 3.42 (t, J = 6.7 Hz, 2H), 3.04 – 2.80
(m, 4H), 2.49 (dtd, J = 6.9, 6.9, 1.5 Hz, 2H); δC (100 MHz, CDCl3) 199.1 (C), 158.0 (C), 142.0
(CH), 133.1 (C), 132.3 (CH), 129.3 (CH), 113.9 (CH), 55.3 (CH3), 49.7 (CH2), 42.2 (CH2), 31.8
+
(CH2), 29.1 (CH2); m/z (ESI+) found [M+H]+ 260.1421. C14H18N3O2 requires 260.1394.
19

ACCEPTED MANUSCRIPT
4.2.6 (((2Z,4E)-7-azido-1-(4-methoxyphenyl)hepta-2,4-dien-3-yl)oxy)trimethylsilane 3d
TMSOTf (4.65 mL, 25.7 mmol) was added dropwise to a solution of azide S3 (4.45 g,
17.2 mmol) and Et3N (7.18 mL, 51.5 mmol) in anhydrous CH2Cl2 (150 mL) at −30 °C under
argon. The resulting yellow solution was stirred at −30 °C for 15 min then at 0 °C for 15 min,
then quenched with sat. aq. NaHCO3 (50 mL) and extracted with CH2Cl2 (2 x 50 mL). The
combined organics were dried (Na2SO4) and concentrated to afford a brown oil, which was
dissolved in 4:1 hexanes: EtOAc and passed through a Florisil plug with 4:1 hexanes: EtOAc
washings. The filtrate was concentrated to afford the title compound (5.50 g, 96%) as a yellow
oil that was used immediately in the next step. δH (400 MHz, CDCl3) 6.93 – 6.88 (m, 2H), 6.65 –
6.60 (m, 2H), 5.80 (d, J = 15.4 Hz, 1H), 5.55 (dt, J = 15.0, 7.1 Hz, 1H), 4.71 (t, J = 7.1 Hz, 1H),
3.58 (s, 3H), 3.20 (d, J = 7.1 Hz, 2H), 3.12 (t, J = 7.1 Hz, 2H), 2.19 (dt, J = 7.1, 7.1 Hz, 2H),
0.05 (s, 9H).
4.2.7 Amine scaffold 6d
BF3ꢁOEt2 (1.47 mL, 11.9 mmol) was added to a solution of cyclohexenone (1.15 mL,
11.9 mmol) in anhydrous CH2Cl2 (100 mL) with 4Å MS (~5 g) at −78 °C under argon. The
mixture was stirred at −78 °C for 5 min, then a solution of silyloxydiene 3d (5.50 g, 16.6 mmol)
in CH2Cl2 (20 mL) was added over 10 min. The reaction was allowed to warm from −78 °C to rt
and stirred for 18 h. The reaction was quenched with H2O (50 mL) and extracted with CH2Cl2 (3
x 50 mL). The combined organics were dried (Na2SO4) and concentrated to afford a brown oily
solid (5.72 g). The crude product was purified by automated chromatography (40 g silica
column, 0 to 10% MeOH in CH2Cl2 over 20 min). All of the fractions containing the correct
mass were combined to afford a brown oil (4.85 g).
20

ACCEPTED MANUSCRIPT
The diastereomeric mixture of above azides was dissolved in anhydrous THF (200 mL)
and PPh3 (7.16 g, 27.3 mmol) added. The reaction mixture was stirred at rt for 18 h, then 2M
NaOH (50 mL) added and the mixture extracted with EtOAc (3 x 100 mL). The combined
organics were dried (Na2SO4) and concentrated to afford a brown oil. The residue was dissolved
in CH2Cl2 (200 mL) and acetic acid (780 ꢀL, 13.6 mmol) added, followed by sodium
triacetoxyborohydride (5.79 g, 27.3 mmol). The reaction was stirred at rt for 18 h, then quenched
with 2M NaOH (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organics were
dried (Na2SO4) and concentrated to afford a brown oil (15 g). The crude product was purified by
chromatography (silica gel, 90:9:1 CH2Cl2:MeOH:NH4OH) to afford the title compound (1.70 g,
46% from silyloxydiene 3d, 4:1 dr) as a brown oil.
The diastereomeric mixture was dissolved in MeOH (50 mL) and K2CO3 (3.37 g, 24.4
mmol) added. The reaction was stirred at rt for 18 h, then concentrated to a brown oil, which was
dissolved in CH2Cl2 (100 mL) and H2O (30 mL). The aqueous layer was extracted with CH2Cl2
(4 x 100 mL). The combined organics were dried (Na2SO4) and concentrated to afford the title
compound (1.65 g, 97%, 9:1 dr) as a brown solid foam. IR2925, 1707, 1511 cm-1; δH (400 MHz,
CDCl3) 7.12 – 7.07 (m, 2H), 6.81 – 6.75 (m, 2H), 3.77 (s, 3H), 3.32 (d, J = 12.4 Hz, 1H), 2.96
(dd, J = 14.3, 7.9 Hz, 1H), 2.88 – 2.78 (m, 2H), 2.65 – 2.58 (m, 1H), 2.49 – 2.39 (m, 2H), 2.25 –
2.07 (m, 3H), 1.94 – 1.87 (m, 1H), 1.80 – 1.52 (m, 5H), 1.42 – 1.26 (m, 2H), 1.24 – 1.13 (m,
1H); δC (100 MHz, CDCl3) 208.4 (C), 157.7 (C), 132.6 (C), 130.2 (CH), 113.7 (CH), 59.0 (CH),
57.4 (CH), 55.2 (CH3), 48.0 (CH), 47.7 (CH2), 45.2 (CH), 43.7 (CH2), 39.5 (CH), 30.9 (CH2),
30.1 (CH2), 30.1 (CH2), 29.7 (CH2), 23.8 (CH2); m/z (ESI+) found [M+H]+ 314.2137.
+
C20H28NO2 requires 314.2115.
21

ACCEPTED MANUSCRIPT
4.2.8 Amine 9b{1}
Propionaldehyde (1.22 mL, 16.8 mmol) was added to a solution of amine 6b (2.48 g, 11.2
mmol) in anhydrous CH2Cl2 (100 mL) at rt under argon. Acetic acid (640 ꢀL, 11.2 mmol) was
then added, followed by sodium triacetoxyborohydride (4.75 g, 22.4 mmol). The reaction
mixture was stirred at rt for 48 h, then quenched with 2 M NaOH (50 mL) and extracted with
CH2Cl2 (3 x 50 mL). The combined organics were dried (Na2SO4) and concentrated to afford the
title compound (2.94 g, 100%) as a yellow oil, which was used without further purification. IR
2929, 1711 cm-1; δH (400 MHz, CDCl3) 3.04-2.99 (1H, m), 2.74-2.66 (1H, m), 2.58-2.51 (1H,
m), 2.40-2.32 (2H, m), 2.17-1.87 (6H, m), 1.70-1.41 (7H, m), 1.36-1.19 (4H, m), 1.10-1.00 (1H,
m), 0.87 (3H, t, J 7.2), 0.85 (3H, t, J 7.6); δC (100 MHz, CDCl3) 210.8 (C), 63.9 (CH), 56.1
(CH), 54.8 (CH2), 52.4 (CH2), 50.4 (CH), 48.8 (CH2), 44.7 (CH), 41.4 (CH), 32.9 (CH2), 31.2
(CH2), 29.5 (CH2), 24.6 (CH2), 17.9 (CH2), 17.1 (CH2), 12.0 (CH3), 11.2 (CH3); ); m/z (ESI+)
found [M+H]+ 264.2314. C17H30NO+ requires 264.2322.
4.2.9 Alcohol S4
L-Selectride (1 M in THF, 8.10 mL) was added dropwise to a solution of 9b{1} (850 mg,
3.23 mmol) in anhydrous THF (20 mL) at −78 °C under argon. The reaction mixture was
allowed to warm slowly to rt and stirred for 18 h, then quenched with 30% aq H2O2 (5.1 mL) and
2 M NaOH (6.8 mL). The mixture was stirred at rt for 1 h, then extracted with CH2Cl2 (3 x 20
mL). The combined organics were dried (Na2SO4) and concentrated to afford a yellow oil. The
crude product was purified by chromatography (silica gel, 90:9:1 CH2Cl2:MeOH:NH4OH) to
afford the title compound (825 mg, 96%) as a yellow oil. δH (500 MHz, CDCl3) 4.03 (br s, 1H),
2.93 (ddd, J = 11.3, 3.8, 3.8 Hz, 1H), 2.70 – 2.56 (m, 1H), 2.55 – 2.40 (m, 1H), 2.32 (ddd, J =
22

ACCEPTED MANUSCRIPT
12.0, 12.0, 2.5 Hz, 1H), 2.14 – 2.00 (m, 1H), 1.96 – 1.76 (m, 4H), 1.68 – 1.60 (m, 1H), 1.53
(ddd, J = 12.6, 2.7, 2.7 Hz, 1H), 1.50 – 1.40 (m, 3H), 1.41 – 0.94 (m, 7H), 0.94 – 0.87 (m, 3H),
0.84 (t, J = 7.4 Hz, 3H), 0.81 – 0.71 (m, 2H); δC (125 MHz, CDCl3) 66.5 (CH), 63.5 (CH), 55.3
(CH2), 52.7 (CH2), 51.4 (CH), 47.6 (CH), 40.3 (CH2), 38.6 (CH), 33.3 (CH), 32.8 (CH2), 29.9
(CH2), 29.8 (CH2), 24.5 (CH2), 21.4 (CH2), 17.1 (CH2), 12.0 (CH3), 11.7 (CH3); m/z (ESI+)
found [M+H]+ 266.2480. C17H32NO+ requires 266.2478
4.3. Experimental procedures for library synthesis
4.3.1 General procedure for the preparation of amines.
Each reaction tube of a 24-position Bohdan Miniblock XT was flushed with argon, then
a solution of the amine scaffold 6b-d (70 mg) in anhydrous dichloromethane (2 mL) was added,
followed by the appropriate aldehyde (1.5 equiv), acetic acid (1 equiv) and Na(OAc)3BH (2
equiv). The reactions were shaken at 500 rpm at rt for 48 h, then 2 M NaOH (1 mL) added. The
reactions were passed through Isolute® hydrophobic phase separator tubes, which allowed the
halogenated solvent layer to pass through. The aqueous layers were extracted with
dichloromethane (2 x 2 mL). The combined organics were evaporated in a Genevac EZ-2 Plus
parallel evaporator and subjected to mass-directed preparative HPLC purification to afford
amines 9b-d{1-10} in average yields of 43% (range 4–76%) and purities of 97.9% (range 94.1–
100%), excluding three compounds that did not meet quantity or purity requirements (9b{9},
9d{2}, and 9d{5}). Full data are provided in Supporting Information.
4.3.2 General procedure for the preparation of amides.
Each reaction tube of a 24-position Bohdan Miniblock XT was flushed with argon, then a
solution of the amine scaffold 6b-d (70 mg) in anhydrous dichloromethane (2 mL) was added,
23

ACCEPTED MANUSCRIPT
followed by the appropriate acid (1.2 equiv), EDC (1.2 equiv) and DMAP (1.2 equiv). The
reactions were shaken at 500 rpm at rt for 48 h, then water (2 mL) added. The reactions were
passed through Isolute® hydrophobic phase separator tubes, which allowed the halogenated
solvent layer to pass through. The aqueous layers were extracted with dichloromethane (2 x 2
mL). The combined organics were evaporated in a Genevac EZ-2 Plus parallel evaporator and
subjected to mass-directed preparative HPLC purification to afford pure amides 11b-d{1-13} in
average yields of 39% (range 20–57%) and purities of 97.3% (range 85.9–100%), excluding two
compounds that did not meet quantity or purity requirements (11b{9} and 11b{11}). Full data are
provided in Supporting Information.
4.3.3 General procedure for the preparation of sulfonamides.
Each reaction tube of a 24-position Bohdan Miniblock XT was flushed with argon, then a
solution of the amine scaffold 6b-d (70 mg) in anhydrous dichloromethane (2 mL) was added,
followed by the appropriate sulfonyl chloride (1.5 equiv) and Et3N (1.5 equiv). The reactions
were shaken at 500 rpm at rt for 48 h, then water (2 mL) added. The reactions were passed
through Isolute® hydrophobic phase separator tubes, which allowed the halogenated solvent layer
to pass through. The aqueous layers were extracted with dichloromethane (2 x 2 mL). The
combined organics were evaporated in a Genevac EZ-2 Plus parallel evaporator and subjected to
mass-directed preparative HPLC purification to afford pure sulfonamides 13b-d{1-13} in
average yields of 39% (range 6–63%) and purities of 98.0% (range 87.8–100%), excluding three
compounds that did not meet quantity or purity requirements (13b{9}, 13c{8}, and 13c{9}). Full
data are provided in Supporting Information.
24

ACCEPTED MANUSCRIPT
4.3.4 General procedure for the preparation of 3H-indoles
PTSA (510 mg, 2.3 mmol) was added to a solution of amine scaffold 4b{2} (60 mg, 0.23
mmol) in EtOH (1.5 mL) in a microwave vial, followed by the appropriate hydrazine
(hydrochloride) (2.5 equiv). The vial was sealed then heated in an oil bath at 90 oC for 4 h, then
cooled to rt, 2 M NaOH (2 mL) added and the mixture extracted with CH2Cl2 (3 x 5 mL). The
combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residues
were subjected to mass-directed preparative HPLC purification to afford pure 3H-indoles 15{1-
6} in average yields of 40% (range 27–57%) and purities of 99.4% (range 87.8–100%),
excluding compound 15{4}, which was not obtained in sufficient purity for screening. Full data
are provided in Supporting Information.
4.3.5 General procedure for the preparation of quinolines.
Fe0 powder (77 mg, 1.4 mmol) was added to a solution of nitrobenzaldehyde 16{1-6}
(0.35 mmol) in ethanol (1 mL) in a microwave vial, followed by 0.1 M HCl (180 ꢀL). The vial
o
was sealed, then heated in an oil bath at 85 C until complete by TLC (~2 h). The mixture was
cooled to rt, then a solution of ketone scaffold 4b{2} (0.27 mmol) in EtOH (2 mL) added,
followed by powdered KOH (18 mg, 0.32 mmol). The mixture was heated at 85 oC for 18 h, then
cooled to rt, passed through a celite plug and eluted with dichloromethane, and concentrated
under reduced pressure. The residues were subjected to mass-directed preparative HPLC
purification to afford pure quinolines 17{1-6} in average yields of 42% (range 26–62%) and
purities of 97.0% (range 91.7–100%). Full data are provided in Supporting Information.
25

ACCEPTED MANUSCRIPT
4.4. Characterization for representative library examples
4.4.1 Amine 9b{2}
δH (500 MHz, CDCl3) 7.72 (d, J = 3.3 Hz, 1H), 7.26 (d, J = 3.3 Hz, 1H), 4.23 (d, J = 15.8
Hz, 1H), 3.94 (d, J = 15.8 Hz, 1H), 3.05 – 2.93 (m, 1H), 2.53 – 2.40 (m, 1H), 2.34 (dd, J = 13.1,
3.3 Hz, 1H), 2.30 – 2.20 (m, 1H), 2.20 – 2.10 (m, 1H), 2.10 – 1.99 (m, 2H), 1.99 – 1.91 (m, 1H),
1.91 – 1.82 (m, 1H), 1.70 – 1.45 (m, 5H), 1.40 – 1.14 (m, 4H), 1.05 (qd, J = 13.0, 3.6 Hz, 1H),
0.84 (t, J = 7.4 Hz, 3H); δC (125 MHz, CDCl3) 210.7 (C), 170.7 (C), 142.4 (CH), 119.1 (CH),
64.3 (CH), 56.1 (CH), 54.3 (CH2), 53.9 (CH2), 50.9 (CH), 48.7 (CH2), 44.4 (CH), 41.3 (CH),
33.2 (CH2), 31.4 (CH2), 30.3 (CH2), 24.4 (CH2), 17.9 (CH2), 11.1 (CH3); m/z (ESI+) found
[M+H]+ 319.1847. C18H27N2OS+ requires 319.1839.
4.4.2 Amine 9c{1}
δH (500 MHz, CDCl3) 7.26 – 7.11 (m, 5H), 3.08 (dd, J = 14.2, 8.1 Hz, 1H), 2.97 – 2.92
(m, 1H), 2.80 (dd, J = 14.2, 2.6 Hz, 1H), 2.69 – 2.61 (m, 1H), 2.52 – 2.45 (m, 1H), 2.45 – 2.38
(m, 1H), 2.38 – 2.28 (m, 2H), 2.17 – 2.10 (m, 3H), 1.92 – 1.86 (m, 2H), 1.66 – 1.61 (m, 1H),
1.52 – 1.41 (m, 4H), 1.37 – 1.07 (m, 5H), 0.85 (t, J = 7.4 Hz, 3H); δC (125 MHz, CDCl3) 210.1
(C), 141.6 (C), 129.3 (CH), 128.2 (CH), 125.6 (CH), 63.8 (CH), 57.8 (CH), 55.2 (CH2), 52.5
(CH2), 51.2 (CH), 48.9 (CH2), 46.5 (CH), 41.6 (CH), 33.4 (CH2), 32.0 (CH2), 31.2 (CH2), 30.0
(CH2), 24.6 (CH2), 17.4 (CH2), 12.0 (CH3); m/z (ESI+) found [M+H]+ 326.2516. C22H32NO+
requires 326.2478.
4.4.3 Amine 9c{2}
26

ACCEPTED MANUSCRIPT
δH (400 MHz, CDCl3) 7.72 (d, J = 3.3 Hz, 1H), 7.28 – 7.12 (m, 6H), 4.23 (d, J = 15.8 Hz,
1H), 3.94 (d, J = 15.4 Hz, 1H), 3.08 (dd, J = 14.2, 8.1 Hz, 1H), 3.03 – 2.95 (m, 1H), 2.82 (dd, J =
14.2, 2.6 Hz, 1H), 2.51 – 2.40 (m, 2H), 2.37 (dd, J = 12.9, 3.2 Hz, 1H), 2.29 – 2.23 (m, 1H), 2.20
– 2.01 (m, 3H), 1.94 – 1.87 (m, 1H), 1.67 – 1.61 (m, 1H), 1.57 – 1.42 (m, 2H), 1.40 – 1.20 (m,
4H), 1.19 – 1.08 (m, 1H); δC (100 MHz, CDCl3) 209.8 (C), 170.9 (C), 142.5 (CH), 141.4 (C),
129.3 (CH), 128.2 (CH), 125.7 (CH), 119.1 (CH), 64.2 (CH), 57.7 (CH), 54.4 (CH2), 53.9 (CH2),
51.2 (CH), 48.7 (CH2), 46.2 (CH), 41.3 (CH), 33.3 (CH2), 32.0 (CH2), 31.2 (CH2), 30.4 (CH2),
24.4 (CH2); m/z (ESI+) found [M+H]+ 381.2039. C23H29N2OS+ requires 381.1995.
4.4.4 Amine 9d{1}
δH (500 MHz, CDCl3) 7.15 – 7.10 (m, 2H), 6.80 – 6.76 (m, 2H), 3.77 (s, 3H), 3.01 – 2.91
(m, 2H), 2.78 (dd, J = 14.2, 2.5 Hz, 1H), 2.70 – 2.61 (m, 1H), 2.54 – 2.44 (m, 1H), 2.39 – 2.27
(m, 3H), 2.17 – 2.08 (m, 3H), 1.93 – 1.85 (m, 2H), 1.67 – 1.60 (m, 1H), 1.54 – 1.38 (m, 4H),
1.36 – 1.05 (m, 5H), 0.85 (t, J = 7.4 Hz, 3H); δC (125 MHz, CDCl3) 210.2 (C), 157.6 (C), 133.4
(C), 130.3 (CH), 113.5 (CH), 63.8 (CH), 57.9 (CH), 55.21 (CH3), 55.18 (CH2), 52.5 (CH2), 51.1
(CH), 48.9 (CH2), 46.2 (CH), 41.5 (CH), 33.3 (CH2), 31.9 (CH2), 30.2 (CH2), 30.0 (CH2), 24.6
+
(CH2), 17.4 (CH2), 12.0 (CH3); m/z (ESI+) found [M+H]+ 356.2596. C23H34NO2 requires
356.2584.
4.4.5 Amine 9d{4}
δH (500 MHz, CDCl3) 7.32 – 7.28 (m, 2H), 7.23 – 7.18 (m, 3H), 7.15 – 7.12 (m, 2H),
6.81 – 6.77 (m, 2H), 3.78 (s, 3H), 3.01 – 2.95 (m, 2H), 2.84 – 2.77 (m, 2H), 2.65 – 2.53 (m, 3H),
2.40 – 2.32 (m, 3H), 2.18 – 2.04 (m, 3H), 1.97 – 1.74 (m, 4H), 1.67 – 1.62 (m, 1H), 1.61 – 1.41
(m, 2H), 1.39 – 1.08 (m, 5H); δC (125 MHz, CDCl3) 210.1 (C), 157.6 (C), 141.9 (C), 133.3 (C),
27

ACCEPTED MANUSCRIPT
130.3 (CH), 128.4 (CH), 128.3 (CH), 125.9 (CH), 113.5 (CH), 63.9 (CH), 57.8 (CH), 55.2
(CH3), 52.5 (CH2), 52.4 (CH2), 50.8 (CH), 48.7 (CH2), 46.1 (CH), 41.3 (CH), 33.8 (CH2), 33.0
(CH2), 31.8 (CH2), 30.2 (CH2), 29.7 (CH2), 26.0 (CH2), 24.5 (CH2); m/z (ESI+) found [M+H]+
+
432.2902. C29H38NO2 requires 432.2897.
4.4.6 Amine 9d{6}
δH (500 MHz, CDCl3) 7.29 – 7.23 (m, 4H), 7.15 – 7.12 (m, 2H), 6.81 – 6.77 (m, 2H),
4.09 (d, J = 13.7 Hz, 1H), 3.78 (s, 3H), 3.16 (d, J = 13.5 Hz, 1H), 2.98 (dd, J = 14.2, 8.1 Hz, 1H),
2.84 – 2.77 (m, 2H), 2.41 – 2.31 (m, 2H), 2.29 – 2.23 (m, 1H), 2.19 – 2.10 (m, 2H), 2.06 – 2.00
(m, 1H), 1.95 – 1.87 (m, 2H), 1.57 – 1.52 (m, 1H), 1.50 – 1.10 (m, 7H); δC (125 MHz, CDCl3)
210.1 (C), 157.6 (C), 138.1 (C), 132.4 (C), 133.4 (C), 130.3 (CH), 130.2 (CH), 128.3 (CH),
113.5 (CH), 65.2 (CH), 57.9 (CH), 56.7 (CH2), 55.2 (CH3), 52.9 (CH2), 51.1 (CH), 48.8 (CH2),
46.1 (CH), 41.5 (CH), 33.0 (CH2), 32.0 (CH2), 30.6 (CH2), 30.3 (CH2), 24.5 (CH2); m/z (ESI+)
+
found [M+H]+ 438.2191. C27H33ClNO2 requires 438.2194.
4.4.7 Amide 11b{1}
δH (500 MHz, CDCl3) 7.43 – 7.35 (m, 5H), 3.56 – 3.46 (m, 2H), 3.41 (ddd, J = 13.9, 6.1,
4.1 Hz, 1H), 2.46 (dd, J = 13.1, 4.4 Hz, 1H), 2.31 – 2.24 (m, 1H), 2.17 – 2.06 (m, 2H), 2.03 –
1.98 (m, 1H), 1.95 – 1.86 (m, 2H), 1.82 – 1.52 (m, 5H), 1.51 – 1.33 (m, 2H), 1.26 – 1.19 (m,
1H), 1.18 – 1.08 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H); δC (125 MHz, CDCl3) 210.0 (C), 171.7 (C),
137.2 (C), 129.6 (CH), 128.5 (CH), 126.9 (CH), 60.2 (CH), 55.9 (CH), 49.0 (CH2), 46.4 (CH),
45.7 (CH), 43.0 (CH2), 37.0 (CH), 32.1 (CH2), 31.4 (CH2), 29.7 (CH2), 24.7 (CH2), 17.9 (CH2),
+
11.3 (CH3); m/z (ESI+) found [M+H]+ 326.2130. C21H28NO2 requires 326.2115.
4.4.8 Amide 11b{4}
28