Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

Article abstract of DOI:10.1016/j.chempr.2018.10.017

Recent years have witnessed an increasing focus on saturated substructures within drug development as a result of the pharmacokinetic and toxicological benefits correlated with higher saturation content. However, the synthetic challenges presented by densely functionalized saturated architectures generally prohibit their evaluation. The abundance of anilines within high-throughput screening libraries is demonstrative of these competing needs. Anilines are prone to adverse metabolic processing, commonly necessitating re-engineering of a given drug lead to ameliorate CYP450 inhibition and/or glutathione adduction issues, but the ease with which these systems are prepared outweighs the toxicity risks. This article contributes to the need for aniline bioisosteres through the development of a robust, photochemical methodology that supplies 1-aminonorbornanes, saturated bicyclic ring systems that offer similar spatial occupancy to anilines while improving metabolic stability. The chemistry provided herein details an efficient and flexible route toward architecturally distinctive 1-aminonorbornanes through the use of visible-light photoredox catalysis. The incorporation of readily diversifiable functional handles (e.g., -OH, -CO₂Me, -NHBoc, -NHCbz) illustrates the potential utility of these 1-aminonorbornanes within drug-discovery programs. Additionally, these motifs offer improved metabolic stability relative to that of their aniline congeners (as demonstrated through microsomal stability assays and metabolite identification efforts), indicating applicability of 1-aminonorbornanes as aniline bioisosteres. This report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp³-rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing allowed for efficient operation on the gram scale, providing promise for translation to industrially relevant scales. This methodology only requires low loadings of a commercially available, visible-light-active photocatalyst and a simple salt; thus, it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.

Full text of DOI:10.1016/j.chempr.2018.10.017

Article
Providing a New Aniline Bioisostere through
the Photochemical Production of 1-
Aminonorbornanes
Daryl Staveness, Taylor M.
Sodano, Kangjun Li, Elizabeth A.
Burnham, Klarissa D. Jackson,
Corey R.J. Stephenson
crjsteph@umich.edu
HIGHLIGHTS
Strain-driven homolysis initiates
radical cyclization sequence
toward norbornane core
Robust functional-group
tolerance provides readily
modifiable building blocks
Unique modes of diastereocontrol
afford enantiopure 1-
aminonorbornanes
1-Aminonorbornanes are shown
to offer improved metabolic
stability over anilines
The chemistry provided herein details an efficient and flexible route toward
architecturally distinctive 1-aminonorbornanes through the use of visible-light
photoredox catalysis. The incorporation of readily diversifiable functional handles
(e.g., -OH, -CO2Me, -NHBoc, -NHCbz) illustrates the potential utility of these 1-
aminonorbornanes within drug-discovery programs. Additionally, these motifs
offer improved metabolic stability relative to that of their aniline congeners (as
demonstrated through microsomal stability assays and metabolite identification
efforts), indicating applicability of 1-aminonorbornanes as aniline bioisosteres.
Staveness et al., Chem 5, 1–12
January 10, 2019 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.10.017

Please cite this article in press as: Staveness et al., Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonor-
bornanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.017
Article
Providing a New Aniline Bioisostere
through the Photochemical
Production of 1-Aminonorbornanes
Daryl Staveness,1 Taylor M. Sodano,1 Kangjun Li,2 Elizabeth A. Burnham,2 Klarissa D. Jackson,2
and Corey R.J. Stephenson1,3,
*
SUMMARY
The Bigger Picture
Recent years have witnessed an
increasing focus on saturated
substructures within drug
This report describes the photochemical conversion of aminocyclopropanes into
1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic frag-
mentation of amine radical cation intermediates. Aligning with the modern move-
ment toward sp3-rich motifs in drug discovery, this strategy provides access to a
diverse array of substitution patterns on this saturated carbocyclic framework
while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) neces-
sary for further derivatization. Evaluating the metabolic stability of selected mor-
pholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative
processing and no proclivity toward reactive metabolite formation, suggesting a
potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing
allowed for efficient operation on the gram scale, providing promise for transla-
tion to industrially relevant scales. This methodology only requires low loadings
of a commercially available, visible-light-active photocatalyst and a simple salt;
thus, it stays true to sustainability goals while readily delivering saturated build-
ing blocks that can reduce metabolic susceptibility within drug development
programs.
development as a result of the
pharmacokinetic and
toxicological benefits correlated
with higher saturation content.
However, the synthetic challenges
presented by densely
functionalized saturated
architectures generally prohibit
their evaluation. The abundance
of anilines within high-throughput
screening libraries is
demonstrative of these
competing needs. Anilines are
prone to adverse metabolic
processing, commonly
INTRODUCTION
necessitating re-engineering of a
given drug lead to ameliorate
CYP450 inhibition and/or
The recent discovery that approved drugs are enriched with saturated content (higher
Fsp3) relative to the average high-throughput screening compound1–3 has sparked an
increasing demand for new, saturated building blocks for use in drug discovery
efforts.4 Further incentive arises from the fact that saturated substructures are generally
less susceptible to adverse metabolic processing events than their aromatic conge-
ners5 while also offering more potential sites of diversification. Thus, the introduction
of sp3-rich motifs can not only generate new intellectual property and access unique
chemical space but also promote improved drug safety by reducing the likelihood
of the metabolism-derived toxicities6–8 (e.g., drug-induced liver injury9). However,
these saturated systems tend to require more involved syntheses, a central reason
for the bias toward aromatic systems10 in modern commercial screening libraries.
Diversifying the medicinal chemistry toolbox from its current arene-rich state therefore
requires the development of efficient methods for the preparation of complex, satu-
rated substructures. This work provides one solution to this challenge, generating
the intriguing yet rarely implemented 1-aminonorbornane (1-aminoNB; 2) motif
via an operationally simple, visible-light-mediated transformation.
glutathione adduction issues, but
the ease with which these systems
are prepared outweighs the
toxicity risks. This article
contributes to the need for aniline
bioisosteres through the
development of a robust,
photochemical methodology that
supplies 1-aminonorbornanes,
saturated bicyclic ring systems
that offer similar spatial
occupancy to anilines while
improving metabolic stability.
Interestingly, despite receiving little attention in recent times, 1-aminoNBs were
central to delineating the basic principles of SN1 and SN2 reactivity,11 as illustrated
Chem 5, 1–12, January 10, 2019 ª 2018 Elsevier Inc.
1

Please cite this article in press as: Staveness et al., Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonor-
bornanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.017
A
Common Reactivity Modes
This Work
R'
R'
R'
+
R'
-CO2
-SiR3
N
N
N
N
R''
R
R
O
H
R''
-H+
-
R
R'''
amine
radical cation
amine
radical cation
-iminium
radical
-amino
radical
C-R bond Heterolysis
Strain-Driven Homolysis
B
aminoCP (1)
1-aminoNB (2)
R
New Building Blocks
through Photoredox Catalysis
R
R'
7
1
N
1
N
R
3
R
7
R'
*
3
4
4
Ir(III)
Ir(II)
Ir(III)
Ir(II)
3
a
b
1
R
R
R
R
R
7
1
6-exo
N
5-exo
N
3
R
N
N
R
1
1
3
1
R
R
3
R'
7
3
4
4
3
4
5
6
Figure 1. Generating 1-AminoNBs via Homolytic Fragmentation
(A) Amine radical cation decomposition pathways: heterolytic versus strain-driven homolytic.
(B) Proposed mechanistic pathways.
by the landmark report from Bartlett and Knox12 in which bridgehead-substituted
1-apocamphanes (7,7-dimethylnorbornanes) were used as negative controls for
SN2 reactivity supporting the Walden inversion mechanism.13–15 These classical ac-
counts,16–20 as well as more recent approaches,21–24 largely generate the bridge-
head amine via Hofmann or Curtius rearrangements of C1–CO2H motifs within
terpene derivatives or from downstream products of cyclopentadiene-based
Diels-Alder reactions. One radical-based closure exists from Della and Knill,25 cycliz-
ing a C7-radical into an oxime after traditional tin-based initiation conditions. The
lack of structural diversity available through these strategies has likely contributed
to the minimal utilization of 1-aminoNB-based scaffolds within medicinal chemis-
try,21 yet these substructures aptly address the needs of Fsp3-centric drug discovery.
Notably, these motifs can also be envisioned to serve as aniline bioisosteres, com-
plementing recent work with amine-substituted [1.1.1]bicyclopentanes26 and
cubanes.27 Anilines are prevalent in modern library generation because of their
ease of synthesis, despite their reputation as the most ‘‘notorious’’ of all structural
alerts7 (functional groups known to predispose a lead compound toward meta-
bolism-derived toxicities or risk of adverse drug-drug interactions). This proclivity
for deleterious metabolic susceptibility thus heightens the importance of delivering
saturated systems that can supplant anilines yet be accessed with equivalent
efficiency.28
1Department of Chemistry, University of
Michigan, Ann Arbor, MI 48109, USA
Our approach to the synthesis of 1-aminoNBs sought to generate the norbornane
core through serialized radical cyclizations, initiating from a photochemically
generated amine radical cation intermediate (see Figure 1). Specifically, through
the oxidation of 1-homoallyl-1-aminocyclopropanes (aminoCPs; 129), amine radical
2Department of Pharmaceutical Sciences,
Lipscomb University, Nashville, TN 37204, USA
3Lead Contact
*Correspondence: crjsteph@umich.edu
https://doi.org/10.1016/j.chempr.2018.10.017
cations of form
3 (isoelectronic with a ) would
cyclopropylcarbinyl radical30
2
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bornanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.017
undergo b-scission to generate a b-iminium radical (4), thereby enabling a 6-exo-
trig radical cyclization toward distonic radical cation 5 and subsequent 5-exo-trig
cyclization to forge the norbornane core. Reduction to product 2 closes the cata-
lytic cycle (or propagates the chain) to provide a net redox-neutral transformation.
Single-electron oxidation of amines can be readily achieved through the reductive
quenching of excited state photocatalysts such as [Ru(bpy)3]Cl2, reactivity that was
first observed by Whitten and co-workers in 1977 for both anilines and trialkyl-
amines.31 The groups of Kellogg32 and Mariano33 provided some of the earliest
reports that capitalized on the synthetic utility of the resultant amine radical cat-
ions. The recent rise of photoredox catalysis both in academia34,35 and industry36
has led to a multitude of new methods employing amine radical cations,37–39
including our group’s 2010 report of visible-light-mediated aza-Henry reactions.40
Interestingly, the large majority of these methods still operate through the classi-
cally studied heterolytic mode of decomposition,41,42 fragmenting a-C-R bonds to
access a-amino radicals (or iminium species upon further oxidation). Homolytic
decomposition modes are far less common,43–45 although only small amounts of
ring strain are necessary to drive C–C bond scission as seen in our efforts convert-
ing catharanthine (4.2 kcal/mol ring strain) into Aspidosperma and Iboga alka-
loids.46 Zheng and co-workers have demonstrated the viability of cyclopropane
fragmentations within photoredox catalysis, coupling oxidized anilinocyclopro-
panes with a variety of styrenes,47 arylacetylenes,48 diynes, and enynes.49 The
goal of this work was to harness the unique capabilities of photoredox catalysis
to generate 1-aminoNBs as a means of addressing the need for new, saturated
building blocks in drug discovery. The following describes the optimization,
scope, scalability, and performance in continuous flow of this formal [3 + 2] cyclo-
addition toward 1-aminoNBs, as well as preliminary investigations into the meta-
bolic fate of these 1-aminoNBs.
RESULTS
Initial optimization was performed with 7,7-dimethyl aminoCP 1a, prepared via
Kulinkovich cyclopropanation50 of the corresponding amide (see Supplemental
Information). Heteroleptic Ir(III) photocatalyst [Ir(dF[CF3]ppy)2(dtbbpy)](PF6)51 (7)
in degassed acetonitrile was identified as the best starting point, affording
63% of 1-aminoNB 2a after 12 hr of irradiation (see Figure 2, entry 1). It was
found that simple Lewis acidic salts enhanced conversion to product even at sub-
stoichiometric loadings (20 mol %). LiBF4 and ZnCl2 proved to be the most effec-
tive, yielding 79% and 84% of 1-aminoNB 2a, respectively (Figure 2, entries 2
and 3). The addition of ZnCl2 even enabled partial productivity when employing
the less oxidizing photocatalyst Ru(bpy)3Cl2∙6H2O (Figure 2, entries 10 and 11;
for 8: Ru(II)*/Ru(I) E1/2 = +0.77 V versus SCE;34 for 7: Ir(III)*/Ir(II) E1/2 = +0.89 V
versus SCE51). Other Lewis acids provided little enhancement (NaBF4; entry 4)
or facilitated degradation pathways (Me2AlCl, BF3∙OEt2, MgBr2∙OEt2; entries
5–7), while redox non-innocent metal salts inhibited reactivity (CuBr2, NiCl2; en-
tries 8 and 9); of note, ZnCl2 is not necessarily redox-innocent under these con-
ditions given the efforts of Bernhard and co-workers,52 although only the most
inefficient substrates afforded a gray precipitate that could indicate reduction
to Zn0 (see Supplemental Information). Importantly, this formal [3 + 2] cycloaddi-
tion methodology was readily translated to continuous flow processing (Figure 2;
compare entry 2 and entry 15; 79% and 78%, respectively53), including efforts on
gram scale (entry 16). Of note, the reaction did not proceed to any extent in the
absence of photocatalyst, without light, or under purely thermal conditions (en-
tries 12–14).
Chem 5, 1–12, January 10, 2019
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bornanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.017
O
catalyst,
additive
O
F3C
N
F
F
N
7
1
4
MeCN, rt,
12 hrs,
1
N
tBu
tBu
7
4
blue LEDs
N
N
1a
2a
F
F
Ir
Catalyst Additive Isolated Recov.
Trial
(2 mol%) (20 mol%) Yield
SM[a]
N
1
2
3
4
5
6
7
8
9
7
7
7
7
7
7
7
--
LiBF4
ZnCl2
NaBF4
Me2AlCl
BF3·OEt2
63%
79%
84%
66%
59%
69%
24%
~15%
~8%
19%
20%
~11%
~5%
39%
0%
F3C
[Ir(dF[CF3]ppy)2(dtbbpy)](PF6)
7)
(
2
MgBr2·OEt2 75%
7
7
CuBr2
NiCl2
20%
49%
N
N
N
N
N
8
8
--
7
--
--
0%
34%
0%
0%
0%
10
11
88%
52%
96%
99%
96%
Ru
ZnCl2
ZnCl2
ZnCl2
--
12[b]
N
13
14[c]
15[d] 7 [flow]
LiBF4
LiBF4
78%
13%
[Ru(bpy)3]Cl2·6H2O
(8)
16[d] 7 [flow]
70%[e] ~11%
Voltammetry data (vs. SCE in MeCN)[f]
O
O
N
O
N
N
N
1a
2a
NMM
+1.28 V [g]
+1.11 V
NMP
no add.:
LiBF4:
+1.02 V
+0.98 V
+1.18 V
+1.04 V
+1.06 V
+0.99 V
Figure 2. Optimization of Visible-Light-Mediated Formal [3 + 2] Cycloaddition toward 1-
AminoNBs and DPV Measurements
aRecov. SM = recovered starting material; approximate values indicate that recovered material was
not entirely pure and are provided only for general comparison. bReaction run in the absence of
light. cReaction run in the absence of light at 80ꢀC. dDetailed descriptions of flow and batch setups
f
are provided in the Supplemental Information. eReaction run on a 1 g scale. Values obtained
through DPV versus Ag/AgCl; peak potentials were then converted to DPV versus SCE (VSCE = VAg/
AgCl + [0.241 V À 0.197 V]); see the Supplemental Information for further details and additional DPV
measurements. gMeasured NMM oxidation potential closely compares with the previously
reported value.63
Differential pulse voltammetry (DPV) data suggest that the Lewis acidic salts are
eliciting an effect on reaction outcome through modulation of amine oxidation
potential. Morpholines are unusually difficult to oxidize relative to other N,N-dia-
lkylamines (for N-methylmorpholine (NMM): Ep = +1.28 V versus SCE, for N-meth-
ylpiperidine (NMP): Ep = +1.06 V versus SCE; see Figure 2), thus prior morpholine
oxidation efforts in the field have necessitated the use of an Ir(ppy)3/O2-based
oxidative quenching cycle54 (operating via the Ir(IV) species) or the development
of new Ir(III) photocatalysts with excited state oxidizing power that vastly exceeds
4
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bornanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.017
A
B
F
O
N
R1
R4
R6
O
N
7
N
N
7
N
N
7
O
7
7
7 (2 mol%),
ZnCl2 (20 mol%)
R5
1
N
1
1
1
1
N
7
MeO
1
2(6)
R2
R5
1
7
R1
3(5)
2b
2c
33%
50%
2d
2e
2a
63%
84%
MeCN, rt, 12 hrs
blue LEDs
R2
4
R3
4
38%[a]
R4
no ZnCl2:
12%
39%
R3
R6
68%
1
2
ZnCl2:
31%
85%
C
O
O
O
O
O
O
O
O
7
1
N
7
1
N
Ph
N
2
N
N
7
1
4
7
N
N
7
7
7
N
2
1
1
1
1
7
1
4
N
3
3
3
3
2f
2g
2h
2i
2j
2k
2l
52%
9; [3.2.0]
15%
71%; 4.0:1 dr
21%; 1.5:1 dr
84%; 2.3:1 dr [b]
63%[c]
16%[d]
17%[c]
O
O
O
O
O
O
O
O
O
O
8
8
8
8
CO2Me
7
(S)
(S)
(S)
(S)
7
7
7
TBSO
AcO
BnO
HO
N
N
N
N
N
N
N
N
7
7
7
7
(R)
(R)
(R)
(R)
1
1
1
1
1
1
1
1
early TS
O-donation
drives
2m
71%
2n
76%
2o
77%
2p
2q
2r
2s
7S:61%; 7R:8%
2t
78%[c]
7S:36%; 7R:26%
7S:65%; 7R:13%
7S:75%; 7R:0%
selectivity
C7 Diastereoselectivity
C3 Diastereoselectivity
R
8
O
O
O
O
O
O
H
H
NR2
4
N
N
N
N
N
7
7
7
7
7
1
1
1
1
1
1
vs.
minimized
3
3
8
3
3
3
H
8
A1,3
8
8
8
8
R
R2N
H
(R)
(S)
(S)
(S)
(S)
NHAc
BnO
BocHN
CbzHN
AcHN
O
R2N
7
H
1
2u
2v
2w
82%; >20:1 dr
2x
2y
86%; >20:1 dr
4
78%; >20:1 dr [e]
83%; >20:1 dr
73%; >20:1 dr
3
1
R'
steric clash
Figure 3. Reaction Scope
(A) Generic depiction of aminoCPs converted to 1-aminoNBs; C2/C3 from cyclopropane can also be C6/C5 depending on substitution pattern.
(B) Reaction scope of amine-containing heterocycles. aNo additive trial toward 1-aminoNB 2b was inhibited by the low solubility of the corresponding
aminoCP in MeCN.
(C) Reaction scope of substitution patterns. b84% yield obtained with the anti-C3-Me aminoCP, the syn-C3-Me aminoCP yielded 81% 1-aminoNB 2h,
also in 2.3:1 dr. c24-hr time course. dConditions: 7 (5 mol %), MeCN, room temperature, 72 hr, blue LEDs. e78% corresponds to a 3.3:1 mix of the 3R,4R
and 3S,4S isomers (both axial) from a 4:1 mix of the anti:syn aminoCPs.
that of photocatalyst 7.55 Alternatively, these data appear to show that morpholine
oxidation is more facile in the presence of readily available Lewis acidic salts (for
NMM: DEp = À170 mV56). Intriguingly, the impact of the Lewis acidic salts was
not limited to morpholines, facilitating conversion to product for a variety of
nitrogen heterocycles, i.e., piperidine, piperazine, azetidine, and pyrrolidine
(1-aminoNBs 2b–2e; see Figure 3B; see Supplemental Information for correspond-
ing DPV data). The discrepancy in oxidation potential between aminoCP 1a and
NMM (DEp = À260 mV) can be rationalized by the facile post-oxidation fragmenta-
tion pathway, as single-electron transfer processes with amines are highly influ-
enced by post-oxidation reactivity.41 This effect also suggests a propagative
mechanistic pathway, as there is a clear enthalpic driving force for the reduction
of 1-aminoNB radical cation 6 with an additional equivalent of starting aminoCP
1 (path b in Figure 1) rather than the Ir(II) species (path a);57 the latter is also en-
thalpically feasible but is kinetically unfavorable, requiring the interaction of two
low-concentration species. Interestingly, the quantum yield for the transformation
of aminoCP 1a to 1-aminoNB 2a was determined to be just 0.34.58 The high
quenching efficiency (see Supplemental Information) and the presence of facile
post-oxidation fragmentation (putatively minimizing back-electron transfer) limit
the impact of two common explanations for artificially low quantum yields.59 An
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alternative hypothesis is that the 5-exo-trig cyclization is sufficiently slow relative to
the electron transfer processes that it renders the measured quantum yield < 1
because of photons lost during the lifetime of distonic radical cation 5. Defining
the role of these kinetic idiosyncrasies could have ramifications for a variety of
photochemical transformations beyond this methodology.
In addition to enabling the use of various nitrogen heterocycles, the ZnCl2-assisted
procedure proved effective for generating C7-, C2-, C3-, and C4-substituted sys-
tems (see Figure 3). Presence of C2-substitution led to preferential formation of
the C2-axial isomer as seen with 1-aminoNB 2f. A C2-prenyl substituent was less
well tolerated (toward 2g) as a result of competing cyclization and C–H abstraction
pathways. Selectivity for the equatorial C3-Me 1-aminoNBs 2h was observed when
the methyl substitution arose from a substituted cyclopropane ring, whereas allylic
functionality proceeded with high selectivity for axial C3-substiution (vide infra).
Further annulated 1-aminoNBs were also accessible via this strategy, as evidenced
by C2–C3 (hetero)aryl-fused 1-aminoNBs 2i and 2j as well as C3–C7-propyl-bridged
1-aminoNB 2k. (Hetero)aryl-fused systems necessitated a 24-hr time course likely
attributable to the competing photosensitization of the styrenyl-type functionality
within the aminoCP, whereas the bridged system was low-yielding regardless of irra-
diation time, presumably because of unfavorable torsional strain during the radical
cyclizations. C4-methyl 1-aminoNB 2l was prepared in a modest 52% yield, but the
analogous C4-phenyl system afforded [3.2.0]-bicyclic core 9, preferring an initial
7-endo-trig cyclization over the anticipated 6-exo-trig. Both acrylate- and enone-
based systems were efficiently converted to C7-substituted 1-aminoNBs 2n and
2o (>75% yield). C7-spirofused 1-aminoNB 2p was also produced in good yield after
24 hr (78%).
Importantly, diastereoselective variants of this formal [3 + 2] methodology enable
the preparation of optically pure 1-aminoNBs. One particularly interesting discovery
was the protecting group-dependent control of C7 configuration with C7-(2-hydrox-
yethyl) derivatives 2q–2t. The increasing availability of the oxygen lone pairs (both in
steric and electronic terms; –OH > –OBn > –OAc > –OTBS) was positively correlated
with selectivity for the 7S,8R diastereomer, with the C8-OH system (2t) proceeding
in >20:1 dr. Our hypothesis is that the oxygen lone pairs are donating into the
antibonding orbital of the iminium species in the earliest phases of the transition
state for the formation of the C1–C7 bond, a donation that is readily accomplished
toward the favored 7S epimer but impeded by steric encumbrance en route to the
disfavored 7R epimer. Additionally, C3-(2-hydroxyethyl) and C3-(2-aminoethyl)
aminoCPs cleanly afforded a single isomer of the resultant 1-aminoNBs (2u–2y),
necessarily providing control over the absolute configuration of both C1 and C4.
The divergent axial versus equatorial selectivities of cyclopropane-substituted and
allylic-substituted aminoCPs offers an inherent form of diastereocontrol, thus avoid-
ing the necessity of developing exogenous stereocontrol mechanisms. Significantly,
these two series of aminoCPs also serve to demonstrate the robust functional-group
tolerance of this strategy, proceeding in good to high yields while incorporating
alcohol, ether, acyloxy, amide, and carbamate functionality.
The synthetic flexibility shown above inherently positions the 1-aminoNB motif as a
new option for discovery chemists; demonstrating the feasibility of our aniline
bioisosterism hypothesis would only enhance the potential applicability. A prelim-
inary in silico analysis indicates that the norbornane core will lead to minimal
perturbation of physicochemical parameters relative to the aniline congener (as
well as alternative aniline bioisosteres: [1.1.1]-bicyclopentanes and cubanes). As
6
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Please cite this article in press as: Staveness et al., Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonor-
bornanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.017
seen in Figure 4A, the transition from the arene system to the saturated core(s)
largely maintains the overall lipophilicity. Of note, the pKa of protonated N-alkyl
morpholines is comparable with physiological pH. Thus, supplanting a given mor-
pholine-based aniline with a 1-morpholinonorbornane will likely lead to population
of both protonated and deprotonated forms; this imbues enhanced hydrophilicity
despite an overall increase in carbons, potentially providing further pharmacoki-
netic benefits in specific cases. Other N,N-dialkylamine-based 1-aminoNBs will
be fully protonated under physiological conditions (unlike their direct aniline coun-
terpart), and this would need to be taken into consideration in any drug design or
re-engineering effort. Additionally, the norbornane core does lead to slight depar-
ture from linearity for the C4-substituted form, but given the diversity of substitu-
tion patterns that can be accessed via the above method, these 1-aminoNBs are
well suited for exploring chemical space beyond simple 1,4-substituted arene
modalities.
Preliminary assessment of metabolic susceptibility was achieved through micro-
somal stability assays and identification of prominent metabolites. Selected co-
pounds (see Figure 4B; 10 mM assay concentration) were incubated for 45 min
with either rat or human liver microsomes (RLMs or HLMs, respectively), and the
percent compound retention was determined relative to an untreated control
(see Figure 4C and Supplemental Information for additional details). In general,
the RLMs were more efficient in processing both classes of compounds relative
to the HLMs. Interestingly, aniline stability was highly dependent on the pattern
of methyl substitution (10: H > 12: 3,5-diMe > 11: 4-Me > 13: 2,6-diMe), with
the 2,6-dimethyl system (13) being all but entirely decomposed in both trials.
N-Phenylmorpholine (10) appeared to be the most stable aniline system (at least
in HLMs), likely because of the lack of potential benzylic oxidation sites and
reduced hydrophobicity. The decomposition of 1-aminoNBs was more consistent
overall across the selected substitution patterns, especially in HLMs (all four com-
pounds between 55% and 75% retention). In both RLMs and HLMs, the 1-aminoNB
panel outperformed or was on par with the most robust aniline compounds. One
notable exception was C4-Me 1-aminoNB 2l in the RLM assay, in which it was
entirely decomposed in 45 min. This is presumably an isoform-specific and/or spe-
cies-dependent result given the 58% retention measured in HLMs. CYP450 active
sites tend to be hydrophobic in nature,60 so the trimethylated norbornane core of
2l could be serving as an optimal lipophilic anchor for a specific RLM-derived
CYP450 isoform. Any given 1-aminoNB-based drug lead is likely to have additional
polar functionality that would disrupt this anchoring effect, and unsurprisingly, the
C3-substituted acetamide-based 1-aminoNB 2x offered the best overall retention
profile between the two species (67% and 73%). Importantly, the aniline bio-
isostere concept does not hinge on imbuing complete inertness to metabolic pro-
cessing; rather, the avoidance of reactive metabolite generation is the true goal.
The norbornane core provides no obvious path toward reactive metabolites, and
this analysis was confirmed with metabolite profiling. Through the use of LC-MS/
MS, formamide 15 and a hydroxylated system (generically represented by 16)
were identified as the primary metabolites arising from 1-aminoNB 2a (see Fig-
ure 4D). The identity of the former was confirmed through oxidation of 1-aminoNB
2a with a non-heme iron catalyst developed by White and co-workers for C–H hy-
droxylation,61,62 generating formamide 15 as the major isolable product. No prod-
ucts of core oxidation were directly observed in either system, likely because of the
increased s-character of the norbornane C–H bonds. Addition of glutathione to the
microsomal incubations led to no discernible change in metabolite profile (see
Supplemental Information); thus the 1-aminoNB system shows no inherent
Chem 5, 1–12, January 10, 2019
7

Please cite this article in press as: Staveness et al., Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonor-
bornanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.017
A
Anilines
Alternative Isosteres
This work
*
* *
*
*sites amenable[a]
to diversification
*
*
*
*
*
*
*
*
*
*
*
*
N
N
N
N
[b]
N-C4 distance:
N-C1-C4 angle:
cLogP:
4.20 Å
180°
3.30 Å
180°
1.26
4.02 Å
180°
--xx
3.61 Å
159°
2.25
2.07
B
O
O
O
O
N
N
N
N
10
11
12
13
O
O
O
O
N
N
N
N
NHAc
2m
2a
2l
2x
C
D
Rat or Human
Liver
HO
O
OH
O
Microsomes
N
N
N
H
+
NADPH,
buffer, rt
O
2a
15
16[a]
[Fe(PDP)](SbF6)2
(20 mol%),
AcOH, H2O2,
N
O
OH
H
N
N
NCMe
N
N
Fe
N
NCMe
2SbF6
MeCN, rt
O
2a
<5%
15
[22% RSM]
[Fe(PDP)](SbF6)2
8
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bornanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.017
Figure 4. Metabolic Susceptibility of 1-AminoNBs Relative to Anilines
(A) Fundamental physicochemical parameters of a dimethyl 1-aminoNB relative to congeners of aniline
and related bioisosteres. aDiversification sites for [1.1.1]-bicyclopentanes and cubanes chosen based on
Stepan et al.26 and Chalmers et al.27 bData were calculated with OpenEye software.64
(B) Panel of anilines and 1-aminoNBs evaluated in the microsomal stability assay.
(C) Graphical depiction of compound retention after 45 min of incubation in the presence of either
rat or human liver microsomes. Empty bars, RLMs; filled bars, HLMs; black bars, verapamil∙HCl
(14; positive control); red bars, aniline compounds; green bars, 1-aminoNB compounds. All data
are normalized to a negative control that was not exposed to the incubation period (see
Supplemental Information for more details) and reported as GSEM.
(D) Metabolite profile of 1-aminoNB 2a and synthetic recapitulation of CYP450 reactivity. aThe
location of hydroxylation on the morpholine ring is unknown at this juncture.
propensity to the glutathione adduction issues that can plague aniline-based drug
scaffolds.7
DISCUSSION
This report details the most efficient and flexible access to 1-aminoNBs to date in
an effort to provide the medicinal chemistry community with valuable new saturated
building blocks. Via this visible-light-mediated formal [3 + 2] cycloaddition,
a wide variety of substitution patterns, many incorporating functional handles
for further diversification, have been readily prepared. These include optically
pure 1-aminoNBs via diastereoselective variants, a central requirement for drug
discovery purposes, and bridged, fused, and spiro-fused structures for exploration
of unique chemical space. This methodology operates well in continuous flow,
including gram-scale preparations, suggesting that this chemistry can translate
beyond the discovery scale. Microsomal stability data and preliminary metabolite
profiling indicate a strong potential for these 1-aminoNB building blocks to serve
as aniline bioisosteres. Future investigations will seek to demonstrate the value of
these substructures for generating bioactive leads.
EXPERIMENTAL PROCEDURES
General Procedure of the Photochemical Conversion of 1-Amino-1-
homoallylcyclopropanes (1) to 1-AminoNBs (2)
In a dry vial under inert atmosphere, aminoCP 1 was dissolved in dry MeCN (0.1 M
aminoCP) before the addition of [Ir(dF[CF3]ppy)2(dtbbpy)](PF6) (0.02 equiv) and then
ZnCl2 (1.0 M in ether; 0.2 equiv) in one portion each. The reaction mixture was
degassed with three freeze-pump-thaw cycles. The reaction was stirred at room
temperature (controlled with jacketed water bath; the temperature was maintained
between 18ꢀC and 23ꢀC) while being irradiated with two strips of 4.4 W blue LEDs for
12 hr. The mixture was partitioned between 1:1 saturated NaHCO3 (aq)/1 M NaOH
and 1:1 ether/hexanes. Phases were separated, and the aqueous phase was further
extracted with 1:1 ether/hexanes three times. Combined organics were washed with
brine, dried over anhydrous magnesium sulfate, filtered to remove solids, and
concentrated in vacuo. The crude residue was purified via flash chromatography
over silica to afford the desired 1-aminoNB 2.
For detailed Experimental Procedures and characterization data for all aminoCPs and
1-aminoNBs presented above, see the Supplemental Information and Figures S1–S170.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures and 170
figures and can be found with this article online at https://doi.org/10.1016/j.chempr.
2018.10.017.
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9

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bornanes, Chem (2018), https://doi.org/10.1016/j.chempr.2018.10.017
ACKNOWLEDGMENTS
The authors acknowledge the financial support for this research from the NIH
National Institute of General Medical Sciences (R01-GM127774 to C.R.J.S.), NIH
National Cancer Institute (K01CA190711 to K.D.J.), the Camille Dreyfus Teacher-
Scholar Award Program (C.R.J.S.), and the University of Michigan (C.R.J.S.). T.M.S.
was supported by an Mcubed grant. D.S. was supported by a postdoctoral fellow-
ship, PF-16-236-01-CDD, from the American Cancer Society.
AUTHOR CONTRIBUTIONS
D.S. and T.M.S. performed the synthetic experiments; D.S., K.L., E.A.B., and K.D.J.
performed the microsomal stability and metabolite identification experiments; D.S.,
T.M.S., K.D.J, and C.R.J.S. designed the experiments; D.S., T.M.S., K.D.J., and
C.R.J.S. wrote the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing financial interests.
Received: August 3, 2018
Revised: September 30, 2018
Accepted: October 26, 2018
Published: November 21, 2018
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64. The OpenEye software package was
unable to generate a reasonable cLogP for
cubane-based systems. It is suspected that
the fragment library employed by the
software for calculating these values does
not contain a cubane, leading to an
erroneous value. Chalmers et al.27
provide various ChromLogD values for
cubane versus benzene comparisons,
leading to an average increase of 0.28
units upon introduction of the cubane
motif.
61. Chen, M., and White, M.C. (2007). A
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62. Of note, the addition of strong Bronsted acid
was able to protect the morpholine from
decomposition (in line with the reference that
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