Design, Synthesis, and Biological Evaluation of Structurally Rigid Analogues of 4-(3-Hydroxyphenyl)piperidine Opioid Receptor Antagonists

Article abstract of DOI:10.1021/acs.joc.6b01366

In order to gain additional information concerning the active conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1) class of opioid receptor antagonists, procedures were developed for the synthesis of structurally rigid N-substituted-6-(3-hydroxyphenyl)3-azabicyclo[3.1.0]hexane and 3-methyl-4-(3-hydroxyphenyl)-4-azabicyclo[4.1.0]heptanes. Evaluation of the conformationally constrained series in a [³⁵S]GTPγS assay showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to 1. The studies of the rigid compounds also suggested that the 3-methyl group present in compound 1 type antagonists may not be necessary for their pure opioid antagonist properties.

Full text of DOI:10.1021/acs.joc.6b01366

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Article
Design, synthesis, and biological evaluation of structurally rigid
analogues of 4-(3-hydroxyphenyl)piperidine opioid receptor antagonists
Scott P Runyon, Chad M. Kormos, Moses G. Gichinga, Samuel Wayne Mascarella,
Hernán A Navarro, Jeffrey R. Deschamps, Gregory Howard Imler, and Frank Ivy Carroll
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01366 • Publication Date (Web): 27 Jul 2016
Downloaded from http://pubs.acs.org on August 2, 2016
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Design, synthesis, and biological evaluation of structurally rigid analogues of 4ꢀ(3ꢀ
hydroxyphenyl)piperidine opioid receptor antagonists
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Scott P. Runyon†, Chad M. Kormos†, Moses G. Gichinga†, S. Wayne Mascarella†, Hernán A.
Navarro†, Jeffrey R. Deschamps‡, Gregory H Imler§, and F. Ivy Carroll†*1
†Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709ꢀ2194 United
States
‡Naval Research Laboratory, Code 6910, 455 Overlook Avenue, Washington, DC 20375 United
States
§ASEE Postdoctoral Fellow, Washington, DC 20036 United States
*Corresponding author:
Dr. F. Ivy Carroll
Research Triangle Institute
Post Office Box 12194
Research Triangle Park, NC 27709ꢀ2194
Telephone: 919 541ꢀ6679
Fax: 919 541ꢀ8868
Eꢀmail: fic@rti.org
1 ISHC member
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CH3
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NR
CH3
H3C
CH3
NR
NR
HO
HO
CH3
8
OH
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Abstract
In order to gain additional information concerning the active conformation of the Nꢀ
substituted transꢀ3,4ꢀdimethylꢀ4ꢀ(3ꢀhydroxyphenyl)piperidine (1) class of opioid receptor
antagonists, procedures were developed for the synthesis of structurally rigid Nꢀsubstitutedꢀ6ꢀ(3ꢀ
hydroxyphenyl)3ꢀazabicyclo[3.1.0]hexane and 3ꢀmethylꢀ4ꢀ(3ꢀhydroxyphenyl)ꢀ4ꢀ
azabicyclo[4.1.0]heptanes. Evaluation of the conformationally constrained series in a
[35S]GTPγS assay showed that structural rigid compounds having the 3ꢀhydroxyphenyl group
locked in the piperidine equatorial orientation had potencies equal to or better than similar
compounds having more flexible structures similar to 1. The studies of the rigid compounds also
suggested that the 3ꢀmethyl group present in compound 1 type antagonists may not be necessary
for their pure opioid antagonist properties.
Keywords: azabicyclo[3.1.0]hexanes, azabicyclo[4.1.0]heptanes, opioid antagonist, xꢀray
structure
Introduction
Nꢀsubstituted transꢀ3,4ꢀdimethylꢀ4ꢀ(3ꢀhydroxyphenyl)piperidines (1) are a class of pure
opioid receptor antagonists with a novel pharmacophore.1 This pharmacophore has been used to
design and develop several interesting opioid receptor antagonists. A few of the most studied
compounds are LY255582 which was developed as a potential drug to treat obesity, LY246736
(alvimopan; ENTEREG®, a drug on the market that accelerates the time to upper and lower GI
recovery following surgeries that include partial bowel resection with primary anastomosis) and
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JDTic, a potent and selective kappa opioid receptor antagonist as a potential pharmacotherapy
for treating depression, anxiety, and substance abuse that reached phase 1 clinical studies.2 JDTic
also proved highly useful for obtaining the xꢀray structure of the human κ opioid receptor.3
The SAR studies that led to the discovery of LY255582, LY246736, and JDTic all
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involved changes in the Nꢀsubstituent of 1 (Figure 1). We have previously reported the synthesis
of 2, 3, 4, and 5, also in this class.4 In this study we report the development of methods for the
synthesis of Nꢀsubstituted 6ꢀ(3ꢀhydroxyphenyl)ꢀ3ꢀazabicyclo[3.1.0]hexane analogues 6, 7, 8, 9,
10, and 11, and the Nꢀsubstituted 3ꢀmethylꢀ4ꢀ(3ꢀhydroxyphenyl)ꢀ4ꢀazabicyclo[4.1.0]heptanes 12
and 13, and compare their [35S]GTPγS Ke values as opioid receptor antagonists to previously
reported Nꢀsubstituted transꢀ3,4ꢀdimethylꢀ4ꢀ(3ꢀhydrophenyl)ꢀpiperidines (1ꢀ5).
OH
R2
OH
OH
OH
R1
O
HO
N
N
N
O
N
OH
N
R3
H
O
1 R1=R2=CH3
2 R1=R2=H, R3=CH3
3 R1=R3=CH3, R2=H
NH
HO
N
H
4 R1=R2=R3=CH3
LY246736
alvimopan, ENTEREG
5 R1=R2=CH3, R3=2-methylcinnamyl
LY255582
JDTic
OH
OH
OH
OH
R1
R2
N
N
N
N
R3
6 R1=R2=H, R3=CH3
7 R1=R3=CH3, R2=H
8 R1=R2=R3=CH3
9 R1=CH3, R2=H, R3=2-methylcinnamyl
10 R1=R2=CH3, R3=2-methylcinnamyl
11
12
13
Figure 1. Structures of 1ꢀ5, LY255582, JDTic, alvimopan, and 6ꢀ13.
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Results
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Compounds 6, 7, and 8 were synthesized as outlined in Scheme 1.5 Compounds 14a and
14b were condensed with hydrazine hydrate to provide the hydrazones 15a and 15b,
respectively. Oxidation of 15a and 15b with manganese dioxide in dioxane afforded the diazo
compounds, which were reacted directly with the appropriate Nꢀmethylmaleimide to afford the
imides 16a–c. In the presence of boron trifluoride diethyl etherate, sodium borohydride reduced
the imides to provide the amines 17a–c. Demethylation of aryl methyl ethers 17a–c was
achieved using boron tribromide followed by the treatment of the resulting intermediate with
refluxing piperazine to obtain target compounds 6, 7, and 8.
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Scheme 1. Synthesis of Compounds 6–8
OCH3
OCH3
OH
OCH3
OCH3
R1
R2
R1
R2
R1
R2
a
b
c
d
H
H
H
R1
O
R1
NNH2
O
O
N
N
N
CH3
CH3
CH3
14a R1=H
15a R1=H
16a R1=R2=H
17a R1=R2=H
6 R1=R2=H
14b R1=CH3
15b R1=CH3
16b R1=CH3, R2=H
16c R1=R2=CH3
17b R1=CH3, R2=H
17c R1=R2=CH3
7 R1=CH3, R2=H
8 R1=R2=CH3
Reagents: a) NH2NH2•H2O; b) (1) MnO2, dioxane, (2) 1ꢀmethylmaleimide or 1,3ꢀ
dimethylmaleimide, THF, reflux; c) NaBH4, BF3•(OEt)2, THF; d) BBr3, CH2Cl2.
The synthesis of 9 and 10 is outlined in Scheme 2. The diazo intermediate from 15b
(Scheme 1) was reacted with Nꢀbenzylmaleimide 18 to afford the 3ꢀazaꢀ[3.1.0]ꢀbicyclo
compounds 19a and 19b. Diborane reduction of the imides in tetrahydrofuran yielded 20a and
20b. Demethylation of the aryl methyl ethers was effected with boron trichloride and
tetrabutylammonium iodide6 in dichloromethane to afford the phenols 21a and 21b, which were
converted to the phenyl acetates 22a and 22b for ease of handling. Catalytic hydrogenation
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afforded the secondary amines, which were alkylated with transꢀ2ꢀmethylcinnamaldehyde and
sodium cyanoborohydride. Finally, acetate hydrolysis afforded 9 and 10.
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9
Scheme 2. Synthesis of Compounds 9 and 10
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OCH3
OR2
OAc
OH
R1
O
CH3
R1
N
CH3
CH3
R1
CH3
R1
a
b
d
e
H
R1
H
H
H
O
O
O
N
N
N
N
Bn
Bn
Bn
CH3
c
22a R1=H
22b R1=CH3
18a R1=H
18b R1=CH3
19a R1=H
19b R1=CH3
20a R1=H R2=CH3
21a R1=H, R2=H
20b R1=CH3, R2=CH3
21b R1=CH3, R2=H
c
9 R1=H
10 R1=CH3
Reagents: a) 1ꢀ(3ꢀMethoxyphenyl)ꢀdiazoethane, dioxane, reflux; b) NaBH4, BF3•(OEt)2, THF; c)
BCl3, TBAI, CH2Cl2; d) (1) NaOH, (NBu4)2SO4, dioxane or NaH, THF, (2) AcCl; e) (1) Pd/C,
H2, HCl, EtOH, (2) transꢀ2ꢀmethylcinnamaldehyde, NaBH(OAc)3, 1,2ꢀdichloroethane; (3)
K2CO3, CH3OH (aq).
The cyclopropanation reaction, which afforded 19b, was found to produce a small yield of
a competing product 23. The diastereomer 23 was separated by chromatography and carried
forward as shown in Scheme 3. The aryl methyl ether 24a was converted to the phenol 24b,
which was masked as the phenyl mesylate 24c. Hydrogenation afforded the secondary amine
24d, which was reductively alkylated with 2ꢀmethylcinnamaldehyde to afford the penultimate
intermediate 24e. Mesylate hydrolysis afforded the final product 11.
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Scheme 3. Synthesis of Compound 11
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6
OCH3
OR1
OH
7
8
9
CH3
CH3
CH3
CH3
CH3
a
f
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H
CH3
H
H
O
O
N
N
N
Bn
R2
CH3
23
24a R1=CH3, R2=Bn
24b R1=H, R2=Bn
24c R1=Ms, R2=Bn
24d R1=Ms, R2=H
b
c
d
e
24e R1=Ms, R2=(2-Me)-cinnamyl
11
Reagents: a) NaBH4, BF3•(OEt)2, THF; b) BCl3, TBAI, CH2Cl2; c) MsCl, pyridine; d) Pd/C,
EtOH, HCl, H2; e) transꢀ2ꢀmethylcinnamaldehyde, NaBH(OAc)3, 1,2ꢀdichloroethane; f) NaOH,
CH3OH.
A review of the literature confirms cyclopropanation of alternately substituted maleimides
proceeds with high selectivity for the 6ꢀexoꢀproduct where the largest group from the diazo
compound is oriented away from the formed [3.1.0] ring system.7ꢀ9 The groups at the 5ꢀ and 6ꢀ
positions of 16a–c and 19a–b are stereospecifically fixed upon the same face via the 1,3ꢀdipolar
cycloaddition forming the pyrazoline prior to denitrogenation. Xꢀray analysis of 6 (See Figure S1
in Supporting Information) confirms the exo configuration was exclusively obtained in 16a.
Depending on the size of groups involved, a small amount of the competing endoꢀproduct (such
as 23) may also be formed. In the case of 19b and 23, ROESY analysis of the major product 19b
revealed a through space correlation between the δ 1.23 6ꢀendo methyl (assigned by HMBC
correlation with the δ 142.4 aromatic carbon) and the δ 4.61 Nꢀbenzyl methylene. Importantly,
no correlation between the Nꢀbenzyl methylene and the electronꢀrich aromatic protons of the 6ꢀ
exoꢀ(3ꢀmethoxyphenyl) was observed. These observations support the assignment of 19b as the
exoꢀproduct and 23 as the minor, endoꢀproduct.
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The major products 7, 8, 9 and 10 were therefore assigned analogous (1α,5α,6α)
stereochemistry. The relative stereochemistry of the minor product 11 (arising from 23) has been
assigned (1α,5α,6β). As can be seen in Figure 2, this results in the 6ꢀ(3ꢀhydroxyphenyl)
occupying the opposite (β) face of the cyclopropane relative to the 1ꢀmethyl and 3ꢀhydro
substituents on the primary (α) face of the ring. The (1α,5α,6α) geometry of 6, 7, 8, 9, 10
compares favorably to the natural conformation of Nꢀsubstituted transꢀ3,4ꢀdimethylꢀ4ꢀ(3ꢀ
hydroxyphenyl)piperidines (1) such as 4, 5, LY255582 and JDTic (Figure 1).
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CH3
R2
H3C
H3C
NR1
NR1
NR1
HO
HO
CH3
CH3
OH
1
7, 9 R2=H
8, 10 R2=CH3
11
Figure 2. Conformational representation of general structure 1 and the (1α,5α,6α)ꢀcompounds 7ꢀ
10 as compared to the (1α,5α,6β)ꢀ11.
Compounds 12 and 13 were prepared from the corresponding pure enantiomers as shown in
Scheme 4. Demethylation of Nꢀmethylꢀ1,2,3,6ꢀtetrahydropyridine 25a afforded the secondary
amine 25b.10 The amine was converted to the trifluoromethylsulfonamide 25c. Cyclopropanation
with dibromocarbene proceeded stereoselectively on the face opposite the 3ꢀmethyl of 25c to
afford the intermediate 26.11 Reduction of the dibromide proceeded concomitant to the triflamide
hydrolysis yielding the piperidine 27a,12 which was subjected to xꢀray analysis to confirm the
structure and relative stereochemistry (See Figure S2 in Supporting Information). Deprotection
to the phenol 27b and reductive amination with 2ꢀcinnamylaldehyde afforded to final product 12.
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Scheme 4. Synthesis of Compounds 12 and 13
6
7
OiPr
OiPr
OR
OH
OH
8
9
f
c
d
CBr2
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N
R
N
N
N
N
Tf
H
26
27a R=iPr
27b R=H
a
25a R=CH3
25b R=H
25c R=Tf
e
b
12
13
Reagents: a) (1) 1ꢀChloroethyl chloroformate, 1,2ꢀdichloroethane, (2) CH3OH; b) Tf2O, NEt3,
CH2Cl2; c) (1) NaOH, CHBr3, BnNMe3Cl, EtOH, CH2Cl2, (2) O3, CH2Cl2, (3) S(CH3)2; d) Na,
tBuOH, THF, NH3; e) BCl3, CH2Cl2; f) transꢀ2ꢀmethylcinnamaldehyde, NaBH(OAc)3, 1,2ꢀ
dichloroethane.
In this study, we compared the opioid receptor properties of structurally rigid 6, 7, 8, 10,
11, 13, and 12 to the corresponding Nꢀsubstituted transꢀ3,4ꢀdimethylꢀ4ꢀ(3ꢀ
hydroxyphenyl)piperidine analogs 2, 3, 4, and 5 (Table 1).4 Compound 8 has Ke = 18, 244, and
42 nM at the ꢁ, δ, and κ opioid receptors compared to Ke = 29.3, 681, and 134 nM at the ꢁ, δ,
and κ receptors for 4. Thus, the in vitro antagonist activity for 8 is a little bit better than that for 4
at all three opioid receptors. Compound 7 has Ke = 241 and 479 nM at the ꢁ and κ opioid
receptors, compared to Ke = 974 and 479 nM at the ꢁ, and δ receptors for 3. Thus, 7 is also
slightly better than 3 at the ꢁ and κ opioid receptors. Compound 3 was an agonist at the δ
receptor, whereas 7 is an antagonist with Ke = 2390 nM. Both 6 and 2 lack antagonist activity at
the ꢁ and δ opioid receptors and have very little antagonist activity at the κ opioid receptor. The
Nꢀ2ꢀmethylcinnamyl analog 10 has Ke = 0.02, 0.74, and 0.39 nM at the ꢁ, δ, and κ opioid
receptors, respectively, compared to Ke = 0.08, 1.21, and 0.44 nM at the ꢁ, δ, and κ receptors,
respectively, for 5 and thus, has slightly better antagonist activity than 5 at the ꢁ and δ opioid
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receptors (Ke = 0.08 and 1.21 nM) and almost identical antagonism at the κ opioid receptor (Ke =
0.44 nM). In contrast 11 (Ke = 54.6, 85 and IA at the ꢁ, δ, and κ receptors, respectively), which
has the 3,4ꢀdimethyl groups in a cis relationship, is much less potent than 10 and 5, which have
the 3,4ꢀdimethyl groups in a trans relationship. The Nꢀ2ꢀmethylcinnamyl analog 9 which does
not have a 3ꢀmethyl group remains a pure opioid receptor antagonist with Ke = 0.48, 8.8, and 2.9
nM at the ꢁ, δ, and κ opioid receptors, respectively, and thus has a little less antagonist potency
than 5 at all three opioid receptors.
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Table 1. Inhibition of Agonistꢀstimulated [35S]GTPγS Binding in Cloned Human ꢁ, δ, κ
Opioid Receptors
Compound
ꢁ, DAMGO Ke (nM)
241 ± 65
IAa
δ, DPDPE Ke (nM)
2390 ± 440
IAa
κ, U69,593 Ke (nM)
479 ± 130
>8000
7
6
18 ± 6
244 ± 75
8.8 ± 3
42 ± 10
8
0.48 ± 0.02
0.02 ± 0.01
54.6 ± 17
3.5 ± 1
2.9 ± 1
9
0.74 ± 0.3
85 ± 26
0.39 ± 0.2
IAa
10
11
13
12
2b
3b
4b
5
156 ± 90
50.2 ± 14
40.8 ± 15
2700 ± 1300
479 ± 150
134 ± 27
0.44 ± 0.2
0.42 ± 0.02
IAa
89 ± 46
ΙAa
c
974 ± 230
29.3 ± 3
681 ± 240
1.21 ± 0.4
0.08 ± 0.03
a IA = inactive. b Data taken from Ref 4. c 3 was an agonist, ED50 = 8300 ± 2500 with Emax = 6490 ± 590 of DPDPE
max.
Discussion
Synthetic procedures were developed for the synthesis of structurally rigid Nꢀsubstituted 6ꢀ
(3ꢀhydrophenyl)ꢀ3ꢀazabicyclo[3.10]hexane and 3ꢀmethylꢀ4ꢀ(3ꢀhydroxyphenyl)ꢀ4ꢀ
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azabicyclo[4.1.0]heptanes of the 3,4ꢀdimethylꢀ4ꢀ(3ꢀhydroxyphenyl)piperidine class of opioid
receptor antagonists and were used to synthesize analogs 6, 7, 8, 10, 11, 13, and 12.
Results from early NMR studies of trimethylꢀsubstituted 4ꢀ(3ꢀhydroxyphenyl)ꢀpiperidines
suggested that a 3ꢀhydroxyphenyl equatorial piperidine chair conformation mediated the opioid
antagonist properties of the transꢀ3,4ꢀdimethylꢀ4ꢀ(3ꢀhydroxyphenyl)ꢀpiperidine class of opioid
antagonist.13, 14 At this point in time it was also thought that the presence of the 3ꢀmethyl group
on the piperidine ring was necessary for the opioid receptor antagonists’ properties. Evaluation
of the compounds in this study for their opioid properties using an [35S]GTPγS assay showed that
each of the analogs which have the 3ꢀhydroxyphenyl group locked in an equatorial orientation
were opioid receptor antagonist with efficacy at least as good as the corresponding transꢀ1,3ꢀ
dimethylꢀ4ꢀ(3ꢀhydroxyphenyl)piperidine compound and in the case of 10, its antagonist activity
was slightly better than that of the corresponding 5.
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In order to determine the importance of the 1ꢀmethyl group (equivalent to the 3ꢀmethyl in
the 3,4ꢀdimethylpiperidine class of antagonist) of the 1,6ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexane
ring system of 10, we synthesized and evaluated the 1ꢀdesmethyl analog 9. We found that 9,
which also has the 3ꢀhydroxyphenyl group in a locked equatorialꢀlike orientation, was a pure
opioid receptor antagonist with Kes of 0.48, 8.6, and 2.9 nM at the ꢁ, δ, and κ opioid receptors
suggesting that the 3ꢀposition methyl group on 1 may not be needed for its opioid antagonist
receptor of 10. Although functional antagonism was not affected by the lack of a 1ꢀposition
methyl group in the azabicyclo[3.1.0]hexanes series, the absence of a methyl group in this
position did result in a small decrease in potency.
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Melting points were determined using a capillary melting point apparatus and are
uncorrected. Nuclear magnetic resonance (1H NMR and 13C NMR) spectra were obtained on a
500 MHz NMR spectrometer or a 300 MHz NMR spectrometer. Chemical shifts are reported in
parts per million (ppm) with reference to internal solvent. Mass spectra (MS) were conducted on
a mass spectrometer equipped with ESI (turbospray) source. Elemental analyses were performed
by an external laboratory. The purity of the compounds (>95%) was established by elemental
analysis. Optical rotations were measured on an automatic polarimeter. Analytical thinꢀlayer
chromatography (TLC) was carried out using silica gel 60 F254 TLC plates. TLC visualization
was achieved with a UV lamp or in an iodine chamber. Flash column chromatography was done
on a system using prepacked silica gel columns or using silica gel 60A (230–400 mesh). Solvent
system: CMA80 80:18:2 CHCl3:MeOH:conc. NH4OH. Unless otherwise stated, reagentꢀgrade
chemicals were obtained from commercial sources and were used without further purification.
All moistureꢀ and airꢀsensitive reactions and reagent transfers were carried out under dry
nitrogen.
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3ꢀ[(1α,5α,6α)ꢀ3ꢀMethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenol (6). Boron tribromide (1M
solution in CH2Cl2, 5.4 mL) was added dropwise to a solution of 17a (500 mg, 2.5 mmol) in
dichloromethane (25 mL) at –78 °C under N2. The reaction mixture was allowed to warm to
room temperature overnight. The reaction mixture was cooled to –78 °C, treated with MeOH (20
mL), warmed to r.t and stirred 10 min. The methanol was evaporated. The residue was
partitioned between EtOAc and aq. piperazine. The resulting biphasic mixture was heated to
reflux. Upon cooling, the organic layer was separated and concentrated. The residue was
subjected to chromatography on silica gel eluting with a gradient of CMA80 in CH2Cl2 to afford
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6 (59.6 mg, 13%) as white solid. mp 131–132 °C; 1H NMR (500 MHz, CDCl3) δ 7.08 (t, J = 7
Hz, 1H), 6.59 (m, 2H), 6.49 (m, 1H), 3.13 (d, J = 10 Hz, 2H), 2.48 (d, J = 10 Hz, 2H), 2.37 (s,
3H), 2.20 (m, 1H), 1.70 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 156.1, 144.4, 129.4, 112.9, 64.9,
57.7, 41.5, 27.9, 24.9; LRMS (ESIꢀquadrupole) m/z 190.3 (M + H+); Anal. Calcd for C12H15NO:
C, 76.16; H, 7.99; N, 7.40. Found C, 75.74; H, 7.71; N, 7.39.
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racꢀ3ꢀ[(1α,5α,6α)ꢀ1,3ꢀDimethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenol (7). Boron
tribromide (1M solution in CH2Cl2, 4.8 mL) was added dropwise to a solution of 17b (500 mg,
2.3 mmol) in dichloromethane (25 mL) at –78 °C under N2. The reaction mixture was allowed to
warm to room temperature overnight. The reaction mixture was cooled to –78 °C, treated with
MeOH (20 mL), warmed to room temperature and stirred for 10 min. The methanol was
evaporated. The residue was partitioned between EtOAc and aq. piperazine. The resulting
biphasic mixture was heated to reflux. Upon cooling, the organic layer was separated and
concentrated. The residue was subjected to chromatography on silica gel eluting with a gradient
of CMA80 in CH2Cl2 to afford 7 (95.1 mg, 19%) as a white crystalline solid. m.p. 150–152 °C;
1H NMR (300 MHz, CDCl3) δ 7.17 (t, J = 8 Hz, 1H), 6.95 (d, J = 8 Hz, 1H), 6.70 (d, J = 7 Hz,
1H), 6.46 (s, 1H), 3.42 (m 2H), 2.63 (d, J = 10 Hz, 2H), 2.38 (s, 3H), 2.08 (s, 2H), 1.39 (s, 3H);
LRMS (ESIꢀquadrupole) m/z 204.6 (M + H+). Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N,
6.89. Found C, 76.69; H, 8.27; N, 6.95.
racꢀ3ꢀ[(1α,5α,6α)ꢀ1,3,6ꢀTrimethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenol (8). Boron
tribromide (1M solution in CH2Cl2, 1.82 mL) was added dropwise to a solution of 17c (200 mg,
0.86 mmol) in dichloromethane (20 mL) at –78 °C under N2. The reaction mixture was allowed
to warm to room temperature overnight. The reaction mixture was cooled to –78 °C, treated with
MeOH (20 mL), warmed to r.t and stirred for 10 min. The methanol was evaporated. The residue
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was partitioned between EtOAc and aq. piperazine. The resulting biphasic mixture was heated to
reflux. Upon cooling, the organic layer was separated and concentrated. The residue was
subjected to chromatography on silica gel eluting with a gradient of CMA80 in CH2Cl2 to afford
8 as a white solid (68.2 mg, 36%). m.p. 119–121 °C. 1H NMR (300 MHz, CDCl3) δ 7.13 (t, J = 8
Hz, 1H), 6.72 (d, J = 7 Hz, 1H), 6.65 (m, 2H), 3.12 (m, 1H), 2.87 (d, J = 10 Hz, 1H), 2.78 (d, J =
11 Hz, 2H), 2.34 (s, 3H), 1.67 (m, 1H), 1.40 (s, 3H), 0.94 (s, 3H); LRMS (ESIꢀquadrupole) m/z
218.5 (M + H+). Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found C, 77.12; H, 8.75;
N, 6.42.
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3ꢀ{(1α,5α,6α)ꢀ6ꢀMethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀ
azabicyclo[3.1.0]hexꢀ6ꢀyl}phenol oxalate (9). A solution of 22a (860 mg, 2.68 mmol) in EtOH
(35 mL) was added to a Parr hydrogenation bottle under N2. Solid 10% Pd/C (1.0 g) was added
and a 1.0 M solution of HCl in Et2O (2.68 mL, 2.68 mmol) was then added and the solution was
hydrogenated at 40 psi for 8 h. The solution was then filtered through a pad of Celite and
concentrated under reduced pressure to afford 3ꢀ[(1α,5α,6α)ꢀ6ꢀmethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀ
yl]phenyl acetate as the HCl salt (0.92 g, 88%). A solution of transꢀ2ꢀmethylcinnamaldehyde
(80.0 mg, 0.51 mmol) in 1,2ꢀdichloroethane (10 mL) was then added to a suspension of 3ꢀ
[(1α,5α,6α)ꢀ6ꢀmethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenyl acetate (100 mg, 0.43 mmol) and
sodium triacetoxyborohydride (130 mg, 0.65 mmol) in 1,2ꢀdichloroethane (30 mL). The
suspension was allowed to stir at room temperature for 4 h and was diluted with a saturated
solution of NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 50 mL). The resulting extracts
were combined, dried (MgSO4), and concentrated under reduced pressure to afford an oil that
was purified using silica gel chromatography (CHCl3, MeOH, NH4OH; 90:9:1) to provide 3ꢀ
{(1α,5α,6α)ꢀ6ꢀmethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀ
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yl}phenyl acetate (0.065 g, 42 %) as a colorless oil. Solid K2CO3 (120 mg, 0.90 mmol) was
added to a solution of 3ꢀ{(1α,5α,6α)ꢀ6ꢀmethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀ
azabicyclo[3.1.0]hexꢀ6ꢀyl}phenyl acetate in MeOH (5 mL) and H2O (2 mL). The solution was
allowed to stir at room temperature for 2 h and was acidified with 1.0 M HCl, made basic with
NaHCO3 and extracted with EtOAc (3 × 25 mL). The organic extracts were combined, dried
(MgSO4) and concentrated under reduced pressure. The resulting oil was purified on silica gel
chromatography (CHCl3, MeOH, NH4OH; 80:18:2) to afford pure 3ꢀ{(1α,5α,6α)ꢀ6ꢀmethylꢀ3ꢀ
[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl}phenol (0.05 g, 83 %) as
the free base: 1H NMR (300 MHz, MeOD) δ 7.42 (td, J = 2.3, 4.5 Hz, 1H), 7.24–6.96 (m, 4H),
6.82 (d, J = 15.4 Hz, 1H), 6.75–6.64 (m, 2H), 6.56 (dd, J = 2.4, 8.1 Hz, 1H), 6.12 (td, J = 6.5,
15.5 Hz, 1H), 3.38–3.25 (m, 3H), 3.13–3.00 (m, 2H), 2.87 (d, J = 10.5 Hz, 2H), 2.33 (s, 3H),
1.86 (br. s., 2H), 1.44 (s, 3H). The salt was formed by dissolving the free base and 1.1 eq. oxalic
acid in acetone (10 mL) followed by gentle heating and cooling to induce precipitation. The
collected solids were then recrystallized from acetone and EtOAc to afford 9 as a white solid.
m.p. 161–162 °C; Anal. Calcd for C22H25NO•C2H2O4: C, 70.40; H, 6.65; N, 3.42. Found C,
70.18; H, 6.61; N, 3.41.
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racꢀ3ꢀ{(1α,5α,6α)ꢀ1,6ꢀDimethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀ
azabicyclo[3.1.0]hexꢀ6ꢀyl}phenol resorcylate (10). A solution of 22b (1.12 g, 0.0033 mol in
EtOH (30 mL) was added to a Parr hydrogenation bottle under N2. Solid 10% Pd/C (0.20 g) was
added and a 1.0 M solution of HCl in Et2O (3.34 mL, 3.34 mmol) was then added and the
solution was hydrogenated at 40 psi for 8 h. The solution was then filtered through a pad of
Celite and concentrated under reduced pressure to afford racꢀ3ꢀ[(1α,5α,6α)ꢀ1,6ꢀdimethylꢀ3ꢀ
azabicyclo[3.1.0]hexꢀ6ꢀyl]phenyl acetate as the HCl salt (0.92 g, 88%). A solution of transꢀ2ꢀ
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methylcinnamaldehyde (0.66 g, 4.5 mmol) in 1,2ꢀdichloroethane (10 mL) was then added to a
suspension of racꢀ3ꢀ[(1α,5α,6α)ꢀ1,6ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenyl acetate (920
mg, 3.75 mmol) and sodium triacetoxyborohydride (1.19 g, 0.0057 mol) in 1,2ꢀdichloroethane
(30 mL). The suspension was allowed to stir at room temperature for 4 h and was diluted with a
saturated solution of NaHCO3 (30 mL) and extracted with CH2Cl2 (3 × 50 mL). The resulting
extracts were combined, dried (MgSO4), and concentrated under reduced pressure to afford an
oil that was purified using silica gel chromatography (CHCl3, MeOH, NH4OH; 90:9:1) to
provide racꢀ3ꢀ{(1α,5α,6α)ꢀ1,6ꢀdimethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀ
azabicyclo[3.1.0]hexꢀ6ꢀyl}phenyl acetate (0.30 g, 21%) as a colorless oil. Solid K2CO3 (0.64 g,
4.63 mmol) was added to a solution of racꢀ3ꢀ{(1α,5α,6α)ꢀ1,6ꢀdimethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀ
methylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl}phenyl acetate in MeOH (9.5 mL)
and H2O (6.5 mL). The solution was allowed to stir at room temperature for 2 h and was
acidified with 1.0 M HCl, made basic with NaHCO3 and extracted with EtOAc (3 × 25 mL). The
organic extracts were combined, dried (MgSO4) and concentrated under reduced pressure. The
resulting oil was purified on silica gel chromatography (CHCl3, MeOH, NH4OH; 80:18:2) to
afford pure racꢀ3ꢀ{(1α,5α,6α)ꢀ1,6ꢀdimethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀ
azabicyclo[3.1.0]hexꢀ6ꢀyl}phenol (0.14 g, 50%) as the free base: 1H NMR (300MHz, CDCl3) δ
7.48–7.21 (m, 2H), 7.20–7.04 (m, 4H), 6.82–6.56 (m, 4H), 6.14 (td, J = 6.6, 15.4 Hz, 1H), 3.33
(d, J = 6.4 Hz, 2H), 3.21 (dd, J = 5.7, 10.2 Hz, 1H), 2.99–2.85 (m, 2H), 2.82 (d, J = 10.2 Hz,
1H), 2.32 (s, 3H), 1.67 (d, J = 4.9 Hz, 1H), 1.46–1.36 (m, 3H), 0.92 (s, 3H). The salt was formed
by dissolving 1.1 eq. 3,5ꢀdihydroxybenzoic acid in MeOH (1 mL) and adding it to the free base
in MeOH (3 mL) followed by Et2O (10 mL) to induce precipitation. The collected solids were
then recrystallized from MeOH and EtOAc to afford 10 as a white solid. m.p. 136–138 °C; Anal.
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Calcd for C23H27NO•C7H6O4•1.25H2O: C, 70.64; H, 7.01; N, 2.74. Found C, 70.38; H, 6.75; N,
2.63.
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racꢀ3ꢀ{(1α,5α,6β)ꢀ1,6ꢀDimethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀ
azabicyclo[3.1.0]hexꢀ6ꢀyl}phenol resorcylate (11). A 1.0 M solution of NaOH (10 mL) was
added to a solution of 24e (110 mg, 0.27 mmol) in MeOH (25 mL) at 0 °C. The solution was
allowed to warm to room temperature over 4 hours and was made acidic with 1.0 M HCl, made
basic with NaHCO3 and extracted with EtOAc (3 × 25 mL). The organic extracts were
combined, dried (MgSO4), and concentrated under reduced pressure. The resulting oil was
purified on silica gel chromatography (CHCl3, MeOH, NH4OH; 80:18:2) to afford racꢀ3ꢀ
{(1α,5α,6β)ꢀ1,6ꢀdimethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀ
yl}phenol (0.054 g, 60%) as a colorless oil: 1H NMR (300MHz, CDCl3) δ 7.24 (d, J = 3.8 Hz,
1H), 7.20–7.02 (m, 4H), 6.67 (d, J = 7.5 Hz, 1H), 6.62–6.51 (m, 2H), 6.37 (d, J = 15.8 Hz, 1H),
5.62 (td, J = 6.4, 15.8 Hz, 1H), 5.30 (br. s, 1H), 2.92 (dd, J = 3.4, 9.4 Hz, 2H), 2.84 (d, J = 6.0
Hz, 2H), 2.73 (dd, J = 4.3, 9.6 Hz, 1H), 2.51 (d, J = 9.4 Hz, 1H), 2.25 (s, 3H), 1.39 (s, 3H), 1.24
(s, 3H), 1.18 (d, J = 4.5 Hz, 1H). The salt was formed by adding a solution of 1.1 eq. 3,5ꢀ
dihydroxybenzoic acid in MeOH (1 mL) to the free base in MeOH (3 mL) followed by Et2O (10
mL) to induce precipitation. The collected solids were then recrystallized from MeOH and
EtOAc to afford 11 as a white solid. m.p. 126–128 °C; Anal. Calcd for C23H27NO•C7H6O4•H2O:
C, 71.26; H, 6.97; N, 2.77. Found C, 71.17; H, 6.71; N, 2.74.
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3ꢀ{(1R,5R,6S)ꢀ5ꢀMethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀ
azabicyclo[4.1.0]heptꢀ6ꢀyl}phenol resorcylate (12). A solution of transꢀ2ꢀ
methylcinnamaldehyde (150 mg, 0.98 mmol) in 1,2ꢀdichloroethane (5 mL) was then added to a
suspension of 27b (200 mg, 1.06 mmol) and sodium triacetoxyborohydride (250 mg, 1.18 mmol)
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in 1,2ꢀdichloroethane (15 mL). The suspension was allowed to stir at room temperature for 4 h
and was diluted with a saturated solution of NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 50
mL). The resulting extracts were combined, dried (MgSO4), and concentrated under reduced
pressure to afford an oil that was purified using silica gel chromatography using petroleum ether,
Et2O, TEA (10:9:1) as eluents to provide 3ꢀ{(1R,5R,6S)ꢀ5ꢀmethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀ
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methylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀazabicyclo[4.1.0]heptꢀ6ꢀyl}phenol (0.16 g, 56 %) as an oil: 1H
NMR (300 MHz, CDCl3) δ 7.30
6.70 6.61 (m, 3H), 6.53 (dd, J = 8.0, 2.0 Hz, 1H), 6.03 (dt, J = 9.0, Hz Hz, 1H) 3.08 (d, J = 6.6
Hz, 2H), 2.97 (d, J = 11.1 Hz, 1H), 2.66 (dd, J = 11.3, 5.0 Hz, 1H), 2.53 (dd, J = 11.4, 4.5 Hz,
1H), 2.21 (s, 3H), 2.18 – 2.07 (m, 1H), 1.77 (t, J = 10.4 Hz, 1H), 1.32 1.24 (m, 1H), 0.85 0.76
–7.27 (m, 1H), 7.05–7.01 (m, 4H), 6.97 (d, J = 7.8 Hz, 1H),
–
–
–
(m, 2H), 0.58 (d, J = 15.9, 6.6 Hz, 3H). The resorcylate salt was formed by adding a solution of
1.1 eq. 3,5ꢀdihydroxybenzoic acid in MeOH (1 mL) to the free base in MeOH (3 mL) followed
by Et2O (10 mL) to induce precipitation. The collected solids were then recrystallized from
22
MeOH and EtOAc to afford 12 as a white solid. m.p. 155
–
157 °C; [α]D
–14.6 (c 0.11, MeOH;
Anal. Calcd for C23H27NO•C7H6O4•1.25H2O: C, 70.63; H, 7.01; N, 2.75. Found C, 70.74; H,
6.79; N, 2.79.
3ꢀ{(1S,5S,6R)ꢀ5ꢀMethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀ
azabicyclo[4.1.0]heptꢀ6ꢀyl}phenol resorcylate (13). Compound 13 was prepared in manner
analogous to 12. The free base: 1H NMR (300 MHz, CDCl3) δ 7.30–7.27 (m, 1H), 7.05–7.01 (m,
4H), 6.97 (d, J = 7.8 Hz, 1H), 6.70–6.61 (m, 3H), 6.53 (dd, J = 8.0, 2.0 Hz, 1H), 6.03 (dt, J = 9.0,
Hz Hz, 1H) 3.08 (d, J = 6.6 Hz, 2H), 2.97 (d, J = 11.1 Hz, 1H), 2.66 (dd, J = 11.3, 5.0 Hz, 1H),
2.53 (dd, J = 11.4, 4.5 Hz, 1H), 2.21 (s, 3H), 2.18–2.07 (m, 1H), 1.77 (t, J = 10.4 Hz, 1H), 1.32–
1.24 (m, 1H), 0.85–0.76 (m, 2H), 0.58 (d, J = 15.9, 6.6 Hz, 3H). The resorcylate salt: m.p. 152–
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155 °C [α]D22 +14.75 (c 0.19, MeOH). Anal. Calcd for C23H27NO•C7H6O4•H2O: C, 71.26; H,
6.97; N, 2.77. Found C, 71.08; H, 6.75; N, 2.73.
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[(3ꢀMethoxyphenyl)methylidene]hydrazine (15a). Hydrazine hydrate (36.7 g, 0.734 mol)
was added dropwise to cooled mꢀanisaldehyde (14a) (10 g, 0.073 mol). Ethanol (5 mL) was
rinsed through the addition funnel and added to the reaction. The reaction mixture was allowed
to warm to room temperature and stirred overnight. Water (100 mL) was added and the product
extracted with CH2Cl2 (3 × 150 mL). The organic layer was dried (Na2SO4), filtered and
concentrated to afford a quantitative yield of 15a as oil. 1H NMR (300 MHz, CDCl3) δ 7.33 (s,
1H), 7.23 (t, J = 7 Hz, 1H), 7.16 (s, 1H), 7.08 (d, J = 8 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 5.53 (s,
2H), 3.82 (s, 3H).
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[1ꢀ(3ꢀMethoxyphenyl)ethylidene]hydrazine (15b). 3ꢀMethoxyacetophenone (14b) (10 g,
0.067 mol) was slowly added to hydrazine hydrate (33.3 g, 0.67 mol) at room temperature then
the solution was heated to reflux for 30 min. Upon cooling, water (100 mL) was added to the
reaction mixture and the product extracted with CH2Cl2 (3 × 150 mL). The organic layer was
dried (Na2SO4), filtered and evaporated to obtain a quantitative yield of 15b as an oil. 1H NMR
(300 MHz, CDCl3) δ 7.23 (m, 3H), 6.86 (m, 1H), 5.36 (s, 2H), 3.83 (s, 3H), 2.12 (s, 3H).
(1α,5α,6α)ꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀmethylꢀ3ꢀazabicyclo[3.1.0]hexaneꢀ2,4ꢀdione (16a).
Manganese dioxide (15.2 g, 0.17 mol) was added to a solution of 15a (11.0 g, 0.074 mol) in
dioxane (100 mL). The reaction mixture was stirred for 45 min then filtered through Celite and
washed through with dioxane (250 mL). The resulting red solution was treated with 1ꢀmethylꢀ
1Hꢀpyrroleꢀ2,5ꢀdione (9.34 g, 74 mmol). The reaction mixture was stirred at room temperature
for 1 h then heated to reflux overnight. The reaction mixture was cooled, then concentrated. The
residue was subjected to chromatography on silica gel eluting with petroleum ether/acetone
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(90:10) to afford 5.29 g (31%) of 16a as colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J =
8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.63 (m, 2H), 3.80 (s, 3H), 2.92 (s, 3H), 2.76 (s, 2H); 13C
NMR (75 MHz, CDCl3) δ 173.8, 159.9, 137.3, 130.1, 118.4, 113.2, 112.4, 55.4, 38.1, 28.9, 24.5.
racꢀ(1α,5α,6α)ꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ1,3ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexaneꢀ2,4ꢀdione
(16b). Manganese dioxide (14.5 g, 0.17 mol) was added to a solution of 15b (10.9 g, 0.067 mol)
in dioxane (100 mL). The reaction mixture was stirred for 45 min then filtered through Celite
and washed through with dioxane (250 mL). The resulting red solution was treated with 1ꢀ
methylꢀ1Hꢀpyrroleꢀ2,5ꢀdione (7.33 g, 0.067 mol). The reaction mixture was stirred at room
temperature for 1 h then heated to reflux overnight. The reaction mixture was cooled, then
concentrated. The residue was subjected to chromatography on silica gel eluting with petroleum
ether/acetone (90:10) to afford 3.52 g, (22%) of 16b as colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.23 (t, J = 8 Hz, 1H), 6.90 (d, J = 8 Hz, 1H), 6.86 (m, 2H), 3.81 (s, 3H), 2.95 (s, 3H),
2.80 (s, 2H), 1.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.6, 159.9, 144.1, 134.2, 130.1,
119.5, 113.3, 55.4, 42.6, 32.7, 24.1, 17.6.
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racꢀ(1α,5α,6α)ꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ1,3,6ꢀtrimethylꢀ3ꢀazabicyclo[3.1.0]hexaneꢀ2,4ꢀ
dione (16c). Manganese dioxide (14.5 g, 0.166 mol) was added to a solution of 15b (10.9 g,
0.067 mol) in dioxane (100 mL). The reaction mixture was stirred for 45 min then filtered
through Celite and washed through with dioxane (250 mL). The resulting red solution was
treated with 1,3ꢀdimethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione (8.41 g, 0.067 mol). The reaction mixture was
stirred at room temperature for 1 h then heated to reflux overnight. The reaction mixture was
cooled, then concentrated. The residue was subjected to chromatography on silica gel eluting
with petroleum ether/acetone (90:10) to afford 6.3 g (37%) of 16c as colorless oil. 1H NMR (300
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MHz, CDCl3) δ 7.28 (m, 1H), 6.81 (m, 3H), 3.82 (s, 3H), 2.95 (s, 3H), 2.68 (s,H), 1.42 (s, 3H),
1.19 (s, 3H); LRMS (ESI, quadrupole) m/z 260.4 (M + H+).
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(1α,5α,6α)ꢀ6ꢀ(3ꢀMethoxyphenyl)ꢀ3ꢀmethylꢀ3ꢀazabicyclo[3.1.0]hexane (17a). Sodium
borohydride (1.19 g, 31.6 mmol) was added in portions to a solution of 16a (3.52 g, 0.014 mol)
in THF at –5 °C. Boron trifluoride diethyl etherate (5.70 g, 40.1 mmol) was added dropwise to
the mixture leading to the formation of a white precipitate. The reaction mixture was allowed to
warm to room temperature, stirred for 2 h, and then heated at reflux for 3 h. The reaction mixture
was cooled, treated with saturated NaHCO3 (150 mL) then extracted with EtOAc (3 × 150 mL).
The organic layer was dried (Na2SO4), filtered, and concentrated to obtain a white solid which
was subjected to chromatography on silica gel eluting with CH2Cl2 to obtain 2.27 g (78%) of 17a
as a white solid. 1H NMR (300MHz, CDCl3) δ 7.15 (t, J = 7.9 Hz, 1 H), 6.68 (ddd, J = 0.9, 2.5,
8.2 Hz, 1 H), 6.65–6.60 (m, 1 H), 6.60–6.56 (m, 1 H), 3.81–3.74 (m, 3 H), 3.16 (d, J = 9.0 Hz, 2
H), 2.42 (td, J = 1.1, 9.0 Hz, 2 H), 2.36 (s, 3 H), 2.24 (t, J = 3.3 Hz, 1 H), 1.67 (dt, J = 1.1, 2.6
Hz, 2 H); 13C NMR (75MHz, CDCl3) δ 159.6, 144.5, 129.2, 118.1, 111.6, 110.6, 57.6, 55.1, 41.3,
28.0, 24.2; LRMS (ESIꢀquadrupole) m/z 204.6 (M + H+ ).
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racꢀ(1α,5α,6α)ꢀ6ꢀ(3ꢀMethoxyphenyl)ꢀ1,3ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexane (17b).
Sodium borohydride (1.19 g, 31.6 mmol) was added in portions to a solution of 16b (3.52 g,
0.014 mol) in THF at –5 °C. Boron trifluoride diethyl etherate (5.70 g, 0.040 mol) was added
dropwise to the mixture leading to the formation of a white precipitate. The reaction mixture was
allowed to warm to room temperature, stirred for 2 h, and then heated at reflux for 3 h. The
reaction mixture was cooled, treated with saturated NaHCO3 (150 mL) then extracted with
EtOAc (3 × 150 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to obtain
a white solid which was subjected to chromatography on silica gel eluting with CH2Cl2 to obtain
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2.27 g (78%) of 17b as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.23 (t, J = 6 Hz, 1H), 6.78
(m, 3H), 3.81 (s, 3H), 3.59 (m, 1H), 3.12 (m, 2H), 2.73 (m, 3H), 2.65 (m, 1H), 2.30 (m, 1H),
2.23 (m, 1H), 1.46 (s, 2H), 1.37 (s, 1H); LRMS (ESIꢀquadrupole) 217.0 (M + H+).
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racꢀ(1α,5α,6α)ꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ1,3,6ꢀtrimethylꢀ3ꢀazabicyclo[3.1.0]hexane (17c).
Sodium borohydride (885 mg, 23.4 mmol) was added in portions to a solution of 16c (2.76 g,
0.011 mol) in THF at –5 °C. Boron trifluoride diethyl etherate (4.22 g, 0.03 mol) was added
dropwise to the mixture leading to the formation of a white precipitate. The reaction mixture was
allowed to warm to room temperature, stirred for 2 h, and then heated at reflux for 2 h. The
reaction mixture was cooled, treated with saturated NaHCO3 (150 mL) then extracted with
CH2Cl2 (3 × 150 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to obtain
a yellow oil which was subjected to chromatography on silica gel eluting with petroleum
ether/acetone (90:10) to obtain the 1.5 g (76%) of 17c as a white solid. 1H NMR (300MHz,
CDCl3) δ 7.23 (t, J = 7.9 Hz, 1 H), 6.82–6.68 (m, 3 H), 3.80 (s, 3 H), 3.37 (d, J = 13.4 Hz, 1 H),
3.28–3.13 (m, 2 H), 2.88 (dd, J = 1.1, 13.4 Hz, 1 H), 2.80 (s, 3 H), 2.11–2.03 (m, 1 H), 1.45 (s, 3
H), 1.12 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 159.7, 145.6, 129.5, 121.2, 114.9, 111.6, 68.6,
63.4, 55.2, 53.0, 40.2, 36.3, 34.2, 21.0, 18.1; LRMS (ESIꢀquadrupole) 232.6 (M + H+).
(1α,5α,6α)ꢀ3ꢀBenzylꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ6ꢀmethylꢀ3ꢀazabicyclo[3.1.0]hexaneꢀ2,4ꢀ
dione (19a). Manganese dioxide (7.17 g, 82.5 mmol) was added to a solution of 15b (4.95 g,
0.033 mol) in dioxane (80 mL). The reaction mixture was stirred for 45 min then filtered through
Celite and washed through with dioxane (50 mL). The resulting red solution was treated with Nꢀ
benzylmaleimide (18a) (6.17 g, 0.033 mol). The reaction mixture was stirred at room
temperature for 1 h then heated to reflux overnight. The reaction mixture was cooled, then
concentrated. The residue was subjected to chromatography on silica gel eluting with petroleum
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ether/acetone (90:10) to afford 4.15 g (39%) of 19a as a white solid mp. 110–112 °C 1H NMR
(300MHz, CDCl3) δ 7.43 (dd, J = 7.7, 1.7 Hz, 2H), 7.31–7.22 (m, 4H), 6.86 (dd, J = 8.0, 0.8 Hz,
1H), 6.81 (s, 1H), 6.81 (d, J = 2.1 Hz, 1H), 4.60 (s, 2H), 3.78 (s, 3H), 2.76 (s, 2H), 1.26 (s, 3H).
racꢀ(1α,5α,6α)ꢀ3ꢀBenzylꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ1,6ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexaneꢀ
2,4ꢀdione (19b). Manganese dioxide (17.36 g, 0.2 mol) was added to a solution of 15b (10.94 g,
0.067 mol) in dioxane (160 mL). The reaction mixture was stirred for 1 h then filtered through
Celite and washed through with dioxane (150 mL). The resulting red solution was treated with 1ꢀ
benzylꢀ3ꢀmethylꢀ2,5ꢀdihydropyrroleꢀ2,5ꢀdione (13.39 g, 0.067 mol). The reaction mixture was
stirred at room temperature for 2 h then heated at reflux for 2 h. The reaction mixture was
cooled, then concentrated under reduced pressure. The residue was subjected to chromatography
on silica gel eluting with petroleum ether/acetone (90:10) to afford a 7:1 mixture of 19b (2.28 g,
10 %) and 23 (1.82 g, 8 %) as white semisolids. 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 7.29
Hz, 2H), 7.20–7.35 (m, 4H), 6.79 (t, J = 7.55 Hz, 2H), 6.73 (br. s., 1H), 4.54–4.68 (m, 2H), 3.79
(s, 3H), 2.65 (s, 1H), 1.23 (s, 3H), 1.16 (s, 3H); 13C NMR (75MHz, CDCl3) δ 177.0, 174.3,
160.3, 142.4, 136.1, 130.4, 129.7, 129.0, 128.4, 120.8, 114.3, 113.3, 55.7, 46.1, 42.5, 37.0, 35.3,
19.0, 12.5.
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(1α,5α,6α)ꢀ3ꢀBenzylꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ6ꢀmethylꢀ3ꢀazabicyclo[3.1.0]hexane (20a).
Sodium borohydride (0.26 g, 6.9 mmol) was added in portions to a solution of 19a (1.05 g,
0.0033 mol) in THF at –10 °C. Boron trifluoride diethyl etherate (1.30 g, 0.0092 mol) was added
dropwise and the reaction mixture was allowed to warm to room temperature, stirred for 2 h, and
then heated at reflux for 3 h. The reaction mixture was cooled, treated with an aqueous solution
of piperazine hydrate (1.7 g, 19.6 mmol) in H2O (12 mL) then heated at reflux for 18 h. The
solution was cooled to room temperature and extracted with EtOAc (3 × 50 mL). The organic
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extracts were combined, dried (Na2SO4), and concentrated under reduced pressure to obtain a
pale yellow oil which was subjected to chromatography on silica gel eluting with petroleum
ether/acetone (95:5) to obtain the 0.69 g (72%) of 20a as a colorless oil. 1H NMR (300MHz,
CDCl3) δ 7.33–7.08 (m, 6H), 6.82–6.79 (m, 2H), 6.68–6.64 (m, 1H), 3.73 (s, 3H), 3.63 (s, 2H),
3.02 (d, J = 9.3 Hz, 2H), 2.82–2.73 (m, 2H), 1.72 (s, 2H), 1.61 (s, 3H).
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racꢀ(1α,5α,6α)ꢀ3ꢀBenzylꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ1,6ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexane
(20b). Sodium borohydride (0.54 g, 14.3 mmol) was added in portions to a solution of 19b (2.28
g, 0.0068 mol) in THF (150 mL) at –10 °C. Boron trifluoride diethyl etherate (2.70 g, 19.04
mmol) was added dropwise and reaction mixture was allowed to warm to room temperature,
stirred for 2 h, and then heated at reflux for 3 h. The reaction mixture was cooled, treated with an
aqueous solution of piperazine hydrate (3.4 g, 0.039 mol) in H2O (25 mL) then heated at reflux
for 12 h. The solution was cooled to room temperature, diluted with H2O (200 mL) and extracted
with EtOAc (3 × 150 mL). The organic layer was dried (MgSO4), filtered, and concentrated
under reduced pressure to obtain a pale yellow oil which was subjected to chromatography on
silica gel eluting with petroleum ether/acetone (95:5) to obtain the 1.51 g (72%) of 20b as a
colorless oil. 1H NMR (300MHz, CDCl3) δ 7.35–7.12 (m, 6H), 6.82–6.65 (m, 3H), 3.78 (s, 3H),
3.73–3.59 (m, 2H), 3.07 (dd, J = 3.0, 9.4 Hz, 2H), 2.91 (dd, J = 4.9, 9.4 Hz, 1H), 2.60 (d, J = 9.4
Hz, 1H), 1.61 (s, 3H), 1.57 (d, J = 4.9 Hz, 1H), 0.91 (s, 3H).
3ꢀ[(1α,5α,6α)ꢀ3ꢀBenzylꢀ6ꢀmethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenol (21a). A 1.0 M
solution of boron trichloride in CH2Cl2 (10.57 mL, 10.57 mmol) was added dropwise to a
solution of tetrabutylammonium iodide (2.17 g, 0.0059 mol), 20a (690 mg, 2.35 mmol) in
CH2Cl2 (15 mL). The mixture was allowed to warm to room temperature and stirred for 2 h. Ice
and water (50 mL) were added to quench the reaction and the biphasic mixture was allowed to
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stir for 30 min and was extracted with CH2Cl2 (3 × 50 mL). The extracts were combined, dried
(MgSO4), and concentrated under reduced pressure to afford an oil. The oil was purified using
silica gel chromatography with petroleum ether and acetone (9:1) as eluents to afford 21a (0.62
g, 94%) as a colorless semisolid. 1H NMR (300MHz, CDCl3) δ 7.86 (br. s, 1H), 7.35–7.20 (m
5H), 7.04 (t, J = 7.8 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.64–6.57 (m, 2H), 3.66 (s, 2H), 3.03–
2.91 (m, 2H), 2.78 (d, J = 10.2 Hz, 2H), 1.75 (s, 2H), 1.41 (s, 3H); 13CꢀDEPT135 NMR (75
MHz, CDCl3) δ 129.8 (CH), 129.3 (CH), 128.8 (CH), 127.5 (CH), 119.1 (CH), 114.8 (CH),
113.7 (CH), 59.5 (CH2), 53.5 (CH2), 31.0 (CH), 15.18 (CH3).
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racꢀ3ꢀ[(1α,5α,6α)ꢀ3ꢀbenzylꢀ1,6ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenol (21b). A
1.0 M solution of boron trichloride in CH2Cl2 (22 mL, 22 mmol) was added dropwise to a
solution of tetrabutylammonium iodide (4.53 g, 0.0123 mol), 20b (1.51 g, 0.0049 mol) in CH2Cl2
(30 mL). The mixture was allowed to warm to room temperature and stirred for 2 h. Ice and
water (75 mL) were added to quench the reaction and the biphasic mixture was allowed to stir
for 30 min and was extracted with CH2Cl2 (3 × 75 mL). The extracts were combined, dried
(MgSO4), and concentrated under reduced pressure to afford an oil. The oil was purified using
silica gel chromatography with petroleum ether and acetone (9:1) as eluents to afford 21b (1.36
g, 94 %) as a colorless semisolid. 1H NMR (300MHz, CDCl3) δ 7.33–7.21 (m, 5H), 7.06 (t, J =
8.1 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.60 (s, 1H), 6.59 (d, J = 6.3 Hz, 1H), 3.72–3.62 (m, 2H),
3.09–3.03 (m, 1H), 2.88 (d, J = 9.9 Hz, 1H), 2.84 (d, J = 9.9 Hz, 1H), 2.73 (d, J = 9.9 Hz, 1H),
1.56 (d, J = 4.8 Hz, 1H), 1.31 (s, 3H), 0.85 (s, 3H).
3ꢀ[(1α,5α,6α)ꢀ3ꢀbenzylꢀ6ꢀmethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenyl acetate (22a).
Sodium hydroxide (180 mg, 4.47 mmol) was added to a solution of 21a (1.25 g, 0.0045 mol) and
tetrabutylammonium sulfate (0.015 g) in dioxane at 0 °C and allowed to stir for 1 h. Acetyl
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chloride (0.42 g, 5.36 mmol) was then added dropwise and the reaction was allowed to warm to
room temperature over 4 h. The solution was diluted with H2O (50 mL) and extracted with
CH2Cl2 (3 × 50 mL). The extracts were combined, dried (MgSO4), and concentrated under
reduced pressure to afford an oil. The oil was purified using silica gel chromatography eluting
with petroleum ether/acetone (90:10) to obtain 22a (0.86 g, 60%) as a colorless oil. 1H NMR
(300MHz, CDCl3) δ 7.29–7.18 (m 6H), 7.05 (d, J = 7.8 Hz, 1H), 6.86 (s, 1H), 7.03 (d, J = 7.8
Hz, 1H), 3.63 (s, 2H), 3.02 (d J = 9.9 Hz, 2H), 2.82–2.72 (m, 2H), 2.21 (s, 3H), 1.75–1.67 (m,
2H), 1.61 (s, 3H).
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racꢀ3ꢀ[(1α,5α,6α)ꢀ3ꢀbenzylꢀ1,6ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenyl acetate
(22b). A solution of 21b (1.36 g, 0.0046 mol) in THF (20 mL) was added to a solution of NaH
(60%, 210 mg, 5.34 mmol) in THF (50 mL) at 0 ◦C under N2. The suspension was allowed to stir
at 0 ◦C for 1 h. Acetyl chloride (420 mg, 5.34 mmol) was then added dropwise and the solution
was allowed to warm to room temperature. The solution was diluted with H2O (50 mL) and
extracted with CH2Cl2 (3 × 50 mL). The organic extracts were combined, dried (MgSO4) and
concentrated under reduced pressure to afford an oil that was purified on silica gel eluting with
petroleum ether/acetone (95:5) to obtain 22b (1.12 g, 72%) as a colorless oil. 1H NMR
(300MHz, CDCl3) δ 7.31–7.17 (m, 6H), 7.05 (d, J = 7.8 Hz, 1H), 6.91–6.84 (m, 2H), 3.79–3.60
(m, 2H), 3.06 (dd, J = 9.5, 3.2 Hz, 2H), 2.90 (dd, J = 9.5, 5.0 Hz, 1H), 2.60 (d, J = 9.6 Hz, 1H),
2.27 (s, 3H), 1.62 (s, 3H), 1.56 (d, J = 4.8 Hz, 1H), 0.91 (s, 3H).
racꢀ3ꢀ[(1α,5α,6β)ꢀ3ꢀBenzylꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ1,6ꢀdimethylꢀ3ꢀ
azabicyclo[3.1.0]hexaneꢀ2,4ꢀdione (23). Manganese dioxide (17.36 g, 0.2 mol) was added to a
solution of 15b (10.94 g, 0.067 mol) in dioxane (160 mL). The reaction mixture was stirred for 1
h then filtered through Celite and washed through with dioxane (150 mL). The resulting red
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solution was treated with 1ꢀbenzylꢀ3ꢀmethylꢀ2,5ꢀdihydropyrroleꢀ2,5ꢀdione (13.39 g, 0.067 mol).
The reaction mixture was stirred at room temperature for 2 h then heated at reflux for 2 h. The
reaction mixture was cooled, then concentrated under reduced pressure. The residue was
subjected to chromatography on silica gel eluting with petroleum ether/acetone (90:10) to afford
a 7:1 mixture of 19b (2.28 g, 10 %) and 23 (1.82 g, 8 %) as white semisolids. 1H NMR
(300MHz, CDCl3) δ 7.12–7.05 (m, 3H), 7.01 (t, J = 7.9 Hz, 1H), 6.94–6.84 (m, 2H), 6.74 (d, J =
7.5 Hz, 1H), 6.64 (s, 1H), 6.61–6.54 (m, 1H), 4.04 (s, 2H), 3.64 (s, 3H), 2.32 (s, 1H), 1.64 (s,
3H), 1.43 (s, 3H)
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racꢀ3ꢀ[(1α,5α,6β)ꢀ3ꢀBenzylꢀ6ꢀ(3ꢀmethoxyphenyl)ꢀ1,6ꢀdimethylꢀ3ꢀ
azabicyclo[3.1.0]hexane (24a). Sodium borohydride (430 mg, 11.4 mmol) was added in
portions to a solution of 23 (1.82 g, 0.0054 mol) in THF (100 mL) at –10 °C. Boron trifluoride
diethyl etherate (2.15 g, 0.015 mol) was added dropwise and reaction mixture was allowed to
warm to room temperature, stirred for 2 h, and then heated at reflux for 3 h. The reaction mixture
was cooled, treated with an aqueous solution of piperazine hydrate (2.68 g, 0.031 mol) in H2O
(20 mL) then heated at reflux for 12 h. The solution was cooled to room temperature, diluted
with H20 (200 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried
(MgSO4), filtered, and concentrated to obtain a pale yellow oil which was subjected to
chromatography on silica gel eluting with petroleum ether/acetone (95:5) to obtain 24a (0.91 g,
55 %) as a colorless oil. 1H NMR (300MHz, CDCl3) δ 7.23 (t, J = 7.7 Hz, 1H), 7.09–7.00 (m,
3H), 6.81 (dd, J = 2.6, 8.3 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 6.51–6.40
(m, 2H), 3.77 (s, 3H), 3.24 (q, J = 13.6 Hz, 2H), 2.95–2.77 (m, 2H), 2.50 (dd, J = 4.0, 8.9 Hz,
1H), 2.26 (d, J = 9.0 Hz, 1H), 1.36 (s, 3H), 1.26 (s, 3H), 1.12 (d, J = 3.8 Hz, 1H)
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racꢀ3ꢀ[(1α,5α,6β)ꢀ3ꢀBenzylꢀ1,6ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenol (24b). A
1.0 M solution of boron trichloride in CH2Cl2 (12 mL, 12 mmol) was added dropwise to a
solution of tetrabutylammonium iodide (2.47 g, 0.0067 mol) and 24a (820 mg, 2.68 mmol) in
CH2Cl2 (20 mL). The mixture was allowed to warm to room temperature and stirred for 2 h. Ice
and water (50 mL) were added to quench the reaction and the biphasic mixture was allowed to
stir for 30 min and was extracted with CH2Cl2 (3 × 50 mL). The extracts were combined, dried
(MgSO4), and concentrated under reduced pressure to afford an oil. The oil was purified using
silica gel chromatography with petroleum ether and acetone (9:1) as eluents to afford 24b (0.23
g, 30 %) as a colorless semisolid. 1H NMR (300MHz, CDCl3) δ 7.15 (t, J = 7.7 Hz, 1H), 7.10–
7.01 (m, 3H), 6.73 (dd, J = 1.9, 7.9 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.60 (br. s., 1H), 6.53 (d, J
= 3.0 Hz, 2H), 3.33–3.12 (m, 2H), 2.93–2.73 (m, 2H), 2.61 (s, 1H), 2.54 (dd, J = 3.8, 9.0 Hz,
1H), 2.29 (d, J = 9.0 Hz, 1H), 1.38–1.29 (m, 3H), 1.26 (s, 3H), 1.10 (d, J = 3.8 Hz, 1H).
racꢀ3ꢀ[(1α,5α,6β)ꢀ3ꢀBenzylꢀ1,6ꢀdimethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenol methane
sulfonate (24c). Methanesulfonyl chloride (110 mg, 0.94 mmol) was added to a solution of 24b
(230 mg, 0.78 mmol) in pyridine (10 mL) at 0 °C. The solution was allowed to warm to room
temperature over 2 h and H2O (10 mL) was added. The biphasic mixture was extracted with
CH2Cl2 (3 × 25 mL) and the organic extracts were combined, dried (MgSO4) and concentrated
under reduced pressure to afford an oil. The oil was purified on silica gel eluting with petroleum
ether/acetone (95:5) to obtain 24c (0.18 g, 60 %) as a colorless oil. 1H NMR (300MHz, CDCl3) δ
7.42–7.28 (m, 1H), 7.22–7.14 (m, 1H), 7.13–7.00 (m, 5H), 6.46–6.35 (m, 2H), 3.28 (d, J = 13.6
Hz, 1H), 3.17 (d, J = 13.6 Hz, 1H), 2.98 (s, 3H), 2.89 (d, J = 9.4 Hz, 1H), 2.76 (d, J = 9.0 Hz,
1H), 2.53 (dd, J = 3.8, 9.4 Hz, 1H), 2.27 (d, J = 9.4 Hz, 1H), 1.37 (s, 3H), 1.26 (s, 3H), 1.17 (d, J
= 3.4 Hz, 1H).
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racꢀ3ꢀ[(1α,5α,6β)ꢀ1,6ꢀDimethylꢀ3ꢀazabicyclo[3.1.0]hexꢀ6ꢀyl]phenyl methanesulfonate
(24d). A solution of 24c (170 mg, 0.47 mmol) in EtOH (20 mL) was added to a Parr
hydrogenation bottle under N2. Solid 10% Pd/C (0.15 g) was added and then a 1.0 M solution of
HCl in Et2O (0.47 mL, 0.47 mmol) was then added and the solution was hydrogenated at 40 psi
for 8 h. The solution was then filtered through a pad of Celite and concentrated under reduced
pressure to afford 24d (0.18 g, 88%) as a colorless oil. 1H NMR (300MHz, CDCl3) δ 7.38 (t, J =
6.0 Hz, 1H), 7.23–7.06 (m, 3H), 3.13 (s, 3H), 3.02 (d, J = 12 Hz, 1H), 2.91–2.76 (m, 3H), 1.41
(s, 3H), 1.26 (s, 3H), 1.22 (d, J = 3 Hz, 1H).
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racꢀ3ꢀ[(1α,5α,6β)ꢀ1,6ꢀDimethylꢀ3ꢀ[(2E)ꢀ3ꢀ(2ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀyl]ꢀ3ꢀ
azabicyclo[3.1.0]hexꢀ6ꢀyl}phenyl methanesulfonate (24e). A solution of transꢀ2ꢀ
methylcinnamaldehyde (70 mg, 0.50 mmol) in 1,2ꢀdichloroethane (10 mL) was then added to a
suspension of 24d (120 mg, 0.42 mmol) and sodium triacetoxyborohydride (140 mg, 0.63 mmol)
in 1,2ꢀdichloroethane (10 mL). The suspension was allowed to stir at room temperature for 4 h
and was diluted with a saturated solution of NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 20
mL). The resulting extracts were combined, dried (MgSO4), and concentrated under reduced
pressure to afford an oil that was purified using silica gel chromatography (CHCl3, MeOH,
NH4OH; 90:9:1) to provide 24e (0.11 g, 65%) as a colorless oil. 1H NMR (300MHz, CDCl3) δ
7.36–6.99 (m, 8H), 6.32 (d, J = 15.8 Hz, 1H), 5.36 (td, J = 6.4, 15.4 Hz, 1H), 2.97–2.76 (m, 7H),
2.53 (dd, J = 3.6, 9.2 Hz, 1H), 2.33 (d, J = 9.4 Hz, 1H), 2.24 (s, 3H), 1.39 (s, 3H), 1.31–1.22 (m,
3H), 1.19–1.12 (m, 1H).
(3R)ꢀ3ꢀMethylꢀ4ꢀ[3ꢀ(1ꢀmethylethoxy)phenyl]ꢀ1,2,3,6ꢀtetrahydropyridine (25b). 1ꢀ
Chloroethyl chloroformate (29.13 g, 0.2 mol) was added to a solution of 25a15 (10 g, 0.041 mol)
in 1,2ꢀdichloroethane (150 mL) and heated at reflux for 48 h. The solution was allowed to cool to
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room temperature and MeOH (150 mL) was added and the mixture was again heated at reflux for
48 h. The solution was cooled, made basic with saturated NaHCO3, and extracted with CH2Cl2 (3
× 75 mL). The extracts were combined, dried (MgSO4), and concentrated under reduced pressure
to afford an oil that was purified using silica gel chromatography (CHCl3, MeOH, NH4OH;
80:18:2) to provide 25b (7.92 g, 84%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.21 (t, J
= 8.0 Hz, 1H), 6.89–6.84 (m, 2H), 6.77 (dd, J = 8.1, 2.4 Hz, 1H), 5.92 (t, J = 3.3 Hz, 1H), 4.55
(sept., J = 6.0 Hz, 1H), 3.52–3.38 (m, 2H), 3.13 (dd, J = 12.5, 4.7 Hz, 1H), 2.83 (dd, J = 12.3, 4.2
Hz, 1H), 2.72 (br. s, 1H), 1.59 (br. s, 1H), 1.34 (dd, J = 6.0, 2.1 Hz, 6H), 0.99 (d, J = 6.9 Hz,
3H).
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(3R)ꢀ3ꢀMethylꢀ4ꢀ[3ꢀ(1ꢀmethylethoxy)phenyl]ꢀ1ꢀ[(trifluoromethyl)sulfonyl]ꢀ1,2,3,6ꢀ
tetrahydropyridine (25c). Trifluoromethanesulfonic acid anhydride (11.60 g, 0.041 mol) was
added dropwise to a solution of 25b (7.92 g, 0.034 mol) and TEA (4.16 g, 41.07 mmol) in
CH2Cl2 (150 mL) at –78 °C under N2. The solution was allowed to stir at –78 °C for 2 h and then
allowed to warm to room temperature. The solution was then made acidic with 1 M HCl and
extracted with CH2Cl2 (3 × 100 mL). The extracts were combined, dried (MgSO4), and
concentrated under reduced pressure to provide an oil. The oil was purified on silica gel using
petroleum ether and acetone (9.5:0.5) as eluents to afford 25c (9.08 g, 73 %) as a colorless oil.
1H NMR (300 MHz, CDCl3) δ 7.25 (t, J = 8.4 Hz, 1H), 6.88–6.82 (m, 3H), 5.83 (t, J = 3.2 Hz,
1H), 4.57 (sept., J = 6.2 Hz, 1H), 4.24 (d, J = 17.1 Hz, 1H), 4.02 (d, J = 17.4 Hz, 1H), 3.69–3.42
(m, 2H), 2.94 (br. s, 1H), 1.34 (dd, J = 6.0, 2.1 Hz, 6H), 1.09 (d, J = 6.9 Hz, 3H).
(1R,5R,6R)ꢀ7,7ꢀDibromoꢀ5ꢀmethylꢀ6ꢀ[3ꢀ(1ꢀmethylethoxy)phenyl]ꢀ3ꢀ
[(trifluoromethyl)sulfonyl]ꢀ3ꢀazabicyclo[4.1.0]heptane (26). Sodium hydroxide (50%
aqueous, 12.5 mL) was added dropwise to a solution of 25c (9.08 g, 0.025 mol), CHBr3 (13.54 g,
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