Synthesis of Benzannulated Medium-ring Lactams via a Tandem Oxidative Dearomatization-Ring Expansion Reaction

Article abstract of DOI:10.1002/chem.201802880

Medium-ring natural products exhibit diverse biological activities but such scaffolds are underrepresented in probe and drug discovery efforts due to the limitations of classical macrocyclization reactions. We report herein a tandem oxidative dearomatization-ring-expanding rearomatization (ODRE) reaction that generates benzannulated medium-ring lactams directly from simple bicyclic substrates. The reaction accommodates diverse aryl substrates (haloarenes, aryl ethers, aryl amides, heterocycles) and strategic incorporation of a bridgehead alcohol generates a versatile ketone moiety in the products amenable to downstream modifications. Cheminformatic analysis indicates that these medium rings access regions of chemical space that overlap with related natural products and are distinct from synthetic drugs, setting the stage for their use in discovery screening against novel biological targets.

Full text of DOI:10.1002/chem.201802880

A Journal of
Accepted Article
Title: Synthesis of Benzannulated Medium-ring Lactams via a Tandem
Oxidative Dearomatization-Ring Expansion Reaction
Authors: Tezcan Guney, Todd A. Wenderski, Matthew W. Boudreau,
and Derek S. Tan
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To be cited as: Chem. Eur. J. 10.1002/chem.201802880
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Synthesis of Benzannulated Medium-ring Lactams via a Tandem
Oxidative Dearomatization–Ring Expansion Reaction
[
a,†]
[a,†]
[b]
[a,c]
Tezcan Guney,
Todd A. Wenderski,
Matthew W. Boudreau, and Derek S. Tan*
Abstract: Medium-ring natural products exhibit diverse biological
activities but such scaffolds are underrepresented in probe and drug
discovery efforts due to the limitations of classical macrocyclization
reactions. We report herein a tandem oxidative dearomatization–
ring-expanding rearomatization (ODRE) reaction that generates
benzannulated medium-ring lactams directly from simple bicyclic
substrates. The reaction accommodates diverse aryl substrates
a) Tandem ODRE reaction
Oxidative
Ring-Expanding
rearomatization
Dearomatization
ketone
O
O
N
O
MeO
MeO
N
H
PhI(TFA)2
N
OH
)n
MeO
OH
Ar OR
HetAr
O
Ar OR
HetAr
Ar OR
HetAr
Y
(
( )n
Z
( )n
Y
Z
Y
Z
(
haloarenes, aryl ethers, aryl amides, heterocycles) and strategic
diverse substrates
medium-ring scaffolds
incorporation of a bridgehead alcohol generates a versatile ketone
moiety in the products amenable to downstream modifications.
Cheminformatic analysis indicates that these medium rings access
regions of chemical space that overlap with related natural products
and are distinct from synthetic drugs, setting the stage for their use
in discovery screening against novel biological targets.
b) Stepwise ODRE sequence
OD
RE
olefin isomers &
solvent adducts
X
(
m
TsOH
OR Cu(BF4)2
m
( )
m
)
Me
)n
( )
X
X
Me
PhI(OAc)2
OR Tf O
2
Me
(
O
( )n
cyclohexadienone
RO
( )n
HO
phenol
substrates
medium-ring scaffolds
Introduction
c) Strategic reversal of electron flow in tandem vs. stepwise ODRE
[
1]
“
Normal” reactivity in stepwise ODRE sequence
Medium-ring structures (8–11-membered rings) are found in
[
2]
Nu
Nu
Nu
diverse biologically-active natural products and are attractive
OD
RE
[
3-16]
scaffolds for use in discovery libraries.
Such scaffolds have
[
17-19]
RO
also been leveraged in structure-based drug design.
The
HO
O
cyclic constraint imparts conformational restriction that is
associated with favorable pharmacological properties, including
-
flow
- flow
e
e
[
20]
[21,22]
increased binding affinity,
cell permeability,
However, medium rings remain severely
underrepresented in screening collections and approved
and oral
Umpolung reactivity in tandem ODRE reaction
[
23]
bioavailability.
E
E
E
OD
RE
Ar OR
HetAr
Ar OR
HetAr
[
24]
drugs,
accessing these structures.
approaches to medium rings are highly substrate-dependent
likely due to the well-known synthetic challenges in
Y
[
25]
Y
Y
Conventional cyclization-based
[
26-
e- flow
e- flow
2
9]
and suffer from the lowest cyclization rates among all ring
[
25]
sizes due to unfavorable transannular interactions.
To
Figure 1. Oxidative dearomatization–ring-expanding rearomatization
ODRE) approaches to medium ring synthesis. (a) Tandem ODRE provides
(
address this synthetic challenge, we have been developing
alternative synthetic approaches based on ring expansion to
medium-ring scaffolds from bicyclic substrates having an electron-rich
aromatic ring. (b) Stepwise ODRE sequence is limited to phenol substrates
and provides mixtures of products. (c) Umpolung reversal of electron flow
enables new tandem ODRE reaction.
[
15,16]
access medium-ring and macrocyclic structures.
Herein, we
[
[
a]
b]
Dr. T. Guney, Dr. T. A. Wenderski, Prof. Dr. D. S. Tan
Chemical Biology Program, Sloan Kettering Institute
Memorial Sloan Kettering Cancer Center
report a new tandem oxidative dearomatization–ring expansion
(ODRE) reaction that provides efficient access to a wide range
of medium-ring lactams in a single step from readily available
bicyclic substrates (Fig. 1a). We demonstrate the scope of this
tandem ODRE across 31 substrates, and downstream reactions
of the resulting scaffolds to introduce additional functionalities.
Cheminformatic analysis confirms that the resulting medium-ring
compounds access regions of chemical space that overlap with
related natural products and are distinct from synthetic drugs
and conventional drug-like libraries.
1275 York Avenue, Box 422, New York, New York, 10065, USA
E-mail: tand@mskcc.org
M. W. Boudreau
Gerstner Sloan Kettering Summer Undergraduate Research
Program
Memorial Sloan Kettering Cancer Center
1275 York Avenue, Box 422, New York, New York, 10065, USA
[
c]
†]
Prof. Dr. D. S. Tan
Tri-Institutional Research Program
Memorial Sloan Kettering Cancer Center
1275 York Avenue, Box 422, New York, New York, 10065, USA
In recent years, there has been growing interest in
developing creative synthetic strategies to access medium-ring
[
These authors contributed equally to this work
[
30-33]
Supporting information for this article is given via a link at the end of
the document.
compounds.
Tandem
cyclization/ring
expansion
[
34-40]
approaches
are particularly useful as they offer greater
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Chemistry - A European Journal
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a)
efficiency and flexibility compared to conventional direct
cyclization methods. However, despite these advances, several
limitations are commonly observed, such as tedious multistep
substrate preparation and narrow tolerance of functional groups
and ring sizes found in natural products and bioactive
O
MeO
O
α
N
H
O
β
PhI(TFA)2
M1 eNO2
MeO
Me
Me
MeO
N
N
1
γ
Me
δ´
δ
Y
Y
Y
Y
[
41-43]
pharmacophores.
We recently reported
sequence to access
benzannulated medium rings (Fig. 1b).
1
a-1d
2a-2d
3a-3d
a
biomimetic, stepwise ODRE
regioselectivity
yield (β,γ / γ,δ / γ,δ´)
diverse,
natural
product-based
This synthetic
[
16]
3
a
Br 65%
91 : 0 : 9
87 : 10 : 3
approach was inspired by Barton’s seminal proposal for the
3b Cl 66%
[
44]
3c
I
72% 100 : 0 : 0
biosynthesis of the alkaloid protostephanine, which was later
3
d
F
40%
79 : 12 : 9
[
45-49]
reduced to practice in several biomimetic syntheses.
Initial
oxidative dearomative of a bicyclic phenol substrate forms an
electrophilic cyclohexadienyl cation intermediate, which is then
attacked by a side chain nucleophile to generate a tricyclic
cyclohexadienone. This intermediate is then activated with a
Brønsted acid, Lewis acid, or triflic anhydride to induce ring
expansion with rearomatization of the phenol ring. While this
stepwise ODRE sequence provided a variety of ring linkages
found in medium-ring natural products, including aryl ethers,
diaryl ethers, lactones, and biaryls, it was restricted to phenolic
substrates and often led to mixtures of olefin isomers and
solvent adducts, arising from various termination reactions of a
penultimate tertiary carbocation intermediate.
O
b)
a)
NaNO2
CuBr, HBr
c)
b)
LiHMDS
MeONH2
AlMe
3
O
O
EtO
OH
H
N
Br
Br
2
4
a
5a
6a
O
O
O
N
d)
MeO
N
H
PhI(TFA)2
MeO
MeO
OH
OH
N
O
1
MeNO2
Br
Br
Br
7
a
8a
9a
To overcome these limitations, we envisioned
a new
Figure 2. Tandem ODRE reactions of haloaromatic substrates to form
medium-ring lactam products. (a) Synthesis of 10-membered ring
haloaromatics 3a–3d (major isomer shown). Reagents and conditions:
umpolung approach in which the initial oxidative dearomatization
step would instead proceed via attack of an electron-rich
[
50-56]
aromatic ring on an electrophilic side chain (Fig. 1c).
This
PhI(TFA)
membered ketolactam 9a. Reagents and conditions: a) NaNO
CuBr (2.2 equiv), HBr (aq), 85%. b) LiHMDS (3.0 equiv), EtOAc (3.0 equiv),
THF, –78 ºC, 3 h, 93%. c) AlMe (3.0 equiv), NH (OMe)·HCl (3.0 equiv), THF,
ºC to 24 ºC, 16 h, 96%. d) PhI(TFA) (1.5 equiv), MeNO , 0 ºC to 24 ºC, 1 h,
2
(2.0 equiv), MeNO
2
, 0 ºC to 24 ºC, 14 h. (b) Synthesis of 9-
2
(1.1 equiv),
would allow a wider range of non-phenolic substrates to be used
and might also allow direct ring expansion from the nascent
reactive intermediate in a tandem reaction (Fig. 1a). This
umpolung ODRE strategy would also allow installation of a
tertiary alcohol in the substrate to terminate the cationic cascade
via formation of a ketone product, avoiding various other
termination pathways as well as providing a versatile handle for
further functionalization. Notably, Kikugawa has leveraged
hypervalent iodine activation of N-methoxyamides as nitrenium
3
2
0
2
2
73%. HMDS = hexamethyldisilazide; TFA = trifluoroacetate; THF = tetra-
hydrofuran.
could then undergo spontaneous ring-expanding rearomatization
to form a C1 tertiary carbocation, providing the olefin 3a after E1
[
16]
[
54]
elimination.
We recognized that a potential undesired
electrophiles in such umpolung reactivity, which was used by
pathway could involve solvolysis of the bromonium intermediate
Wardrop
in
ipso-cyclization
reactions
to
synthesize
[
57-59]
2a to form a stable cyclohexadienone intermediate that would
spirolactams.
Thus, we set out to investigate the utility of
[
16,60]
not be expected to undergo spontaneous ring expansion.
such N-methoxyamide side chains in an ODRE approach to
Moreover, the penultimate C1 tertiary carbocation could also
form other endo- and exocyclic olefin regioisomers or solvent
medium-ring synthesis.
[
16]
adducts.
Treatment of bromotetralin 1a with (diacetoxyiodo)benzene
Results and Discussion
in trifluoroethanol led to a mixture of olefin regioisomers
(
70 : 28 : 2 β,γ / γ,δ / γ,δ´) for the desired medium-ring lactam
Development of tandem ODRE with haloaromatic substrates
In initial studies, we investigated the reactivity of
bromotetralin 1a to access medium-ring lactam 3a (Fig. 2a).
The phenol in the original substrate system (Fig. 1b) was
product 3a. Use of PhI(TFA) in trifluoroethanol improved the
2
ratio of olefin isomers (75 : 18 : 7). Moreover, changing the
solvent to nitromethane provided 3a in 65% yield as a 91:9
mixture of β,γ and γ,δ´ olefin regioisomers, without formation of
[
60,61]
replaced with an aryl bromide
activation of the phenol.
to avoid competing oxidative
Indeed, Ciufolini has reported
2
the γ,δ isomer. Similarly, PhI(TFA) -mediated tandem ODRE of
chlorotetralin 1b, iodotetralin 1c, and fluorotetralin 1d afforded
the corresponding medium-ring lactams 3b, 3c, and 3d in
modest to good yields, with varying regioselectivity favoring
endocyclic β,γ olefins.
extensive studies of such oxidative dearomatization reactions of
phenols in the presence of nitrogen nucleophiles under the
[
62-65]
‘
normal’ polarity reaction manifold.
We postulated that
umpolung oxidative dearomatization would provide
a
[
60]
cyclohexadienyl bromonium intermediate 2a in situ, which
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yielda
yielda
substrate
product
substrate
product
aryl halides
aryl amide
O
O
MeO
O
MeO
O
N
H
9a (Y = Br): 73%
9b (Y = Cl): 72%
N
H
OH
MeO
OH
MeO
57%
O
O
N
[9]
N
[9]
9
9
c (Y = I): 75%
d (Y = F): 81%
Y
Y
AcHN
AcHN
7
a–d
9a–d
24
25
O
O
aryl sulfonamide
MeO
MeO
O
N
MeO
O
N
H
b
b
b
b
H
11a (Y = F): 46%
1b (Y = Cl): 51%
1c (Y = Br): 37%
11d (Y = I): 41%
OH
MeO
OH
N
O
88%
[9]
1
1
N
[
8]
Y
Y
O
O
N
N
Ts
27
Ts
1
0a–d
11a–d
2
6
O
heteroarenes
O
MeO
Y
O
N
H
OH
MeO
MeO
O
MeO
[10]
N
H
1
1
1
3a (Y = F): 90%
7%
3c (Y = Br): 79%
N
OH
OH
MeO
30 (G = O): 57%
[9]
O
3b (Y = Cl):
7
N
3
1 (G = S): 61%
Y
G
G
1
2a–c
13a–c
28,29
30,31
O
O
OMe
O
N
O
N
H
MeO
Y
OH
MeO
N
H
O
N
[9]
53%
O
15a (Y = F): 74%c
Y
d
1
5b (Y = Cl): 70%
[
11]
N
N
Ts
Ts
1
4a,b
15a,b
32
33
O
aryl ethers
MeO
O
N
H
O
OH
OH
OH
MeO
MeO
O
[9]
O
68%
N
N
H
OH
MeO
O
86%e
N
[9]
N
N
Ts
Ts
MeO
MeO
34
35
1
6
17
O
MeO
Ts
O
N
H
O
MeO
O
O
Ts MeO
N N
[9]
O
67%
N
H
N
OH
MeO [10]
N
7%e
8
MeO
MeO
3
6
37
1
8
19
O
MeO
O
O
O
N
H
MeO
O
MeO
N
H
N
66%
OH
MeO
O
21a (Y = H): 89%
1b (Y = F): 86%
[10]
N
[9]
2
N
N
O
Ts
Ts
Y
O
Y
3
8
39
OMe
2
0a,b
21a,b
O
O
MeO
N
H
N
O
MeO
O
OH
N
H
OH
MeO
O
60%
O
N
N
O
[9]
82%
Ts
[11]
N
O
Ph
Ph
Ts
2
2
23
40
41
a
b
Figure 3. Scope of tandem ODRE reaction. Reagents and conditions: PhI(TFA)
2
(1.0–1.5 equiv), MeNO
2
, 0 ºC to 24 ºC, 0.5–2 h. Remainder indene
1
c
byproducts resulting from dehydration of 10a–d and unidentified side products, based on H-NMR analysis of crude product. Isolated as a mixture of amide
d
e
rotamers (3:2 E/Z). Isolated as a mixture of amide rotamers (2:1 E/Z). Reaction performed in MeOH at 0 °C.
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Strategic installation of tertiary alcohol to generate ketone
products
3
Notably, subjecting 16 to the same conditions in CD OD did not
result in deuterium incorporation in the methyl ether moiety of
the product 17, suggesting that methanol may undergo a 1,4-
addition to the O-methyloxocarbenium intermediate, followed by
elimination during, or en route to, anisole rearomatization
(Supplementary Fig. 1b).
Next, to avoid formation of mixtures of olefin regioisomers, we
replaced the C1-methyl group in the tetralin substrate with a
hydroxyl group, that would lead to a single ketone product
(
Fig. 2b). We reasoned that the lone-pair electrons of the
hydroxyl group would also potentiate the ring-expanding
rearomatization step, by analogy to previous biomimetic
syntheses of protostephanine and related alkaloids, in which an
endocyclic amine nitrogen likely plays a similar role in driving
In contrast, chromanone-derived substrates 20a,b and
flavanone derivative 22, both having an endocyclic ether moiety,
did not suffer from the dealkylation pathway in nitromethane,
and proceeded to the medium-ring products 21a,b and 23,
respectively, in excellent yields (82–89%). Similarly, acetanilide
substrate 24 and quinolone derivative 26 provided the
corresponding acetamidoaryl lactam and sulfonamidoaryl lactam
products 25 and 27 respectively, under the standard reaction
[
45-49]
ring-expanding rearomatization.
Moreover, the resulting
ketone motif would serve as a versatile handle for further
chemical diversification of the medium-ring scaffolds. Notably,
this approach was not feasible in the original stepwise ODRE
[
16]
sequence with phenolic substrates
due to competing Adler–
conditions.
hypervalent
Sulfanilides have been used previously in
iodine-induced oxidative dearomatization
[
66,67]
Becker oxidation.
Thus, reversing the electron flow in the
oxidative dearomatization step of this umpolung tandem ODRE
reaction was critical to this approach.
spirocyclization reactions under the ‘normal’ polarity reaction
[
69]
manifold.
Accordingly, bromotetralol 7a was prepared from
commercially available 6-amino-1-tetralone (4a) in 3 steps and
We next sought to extend the tandem ODRE reaction to
heteroaromatic ring systems found in natural products and drug
pharmacophores. Commercially available furano-, thiopheno-,
and pyrrolocyclohexanones were transformed into the
corresponding b-hydroxy-N-methoxyamide substrates 28, 29,
and 32, respectively, then converted via tandem ODRE to 9-
membered ring lactam products 30, 31, and 33 in serviceable
yields. Hypervalent iodine-induced oxidative dearomatization
reactions have been reported under the ‘normal’ polarity reaction
7
6% overall yield.
nitromethane then afforded the desired β-ketolactam 9a in 73%
yield. The corresponding chloro-, iodo-, and fluorotetralol
Treatment of 7a with PhI(TFA)
2
in
substrates 7b-d were also obtained using the same scalable,
efficient synthetic sequence and converted via tandem ODRE to
medium rings 9b-d in good yields (Fig. 3). The aryl fluoride
product 9d was obtained in the highest yield in this series (81%),
consistent with improved “back-donation” of the fluorine lone
[
70,71]
manifold for furans
and under the umpolung reaction
[
60,68]
[72,73]
pairs into the cyclohexadienyl halonium intermediate.
manifold for thiophenes and pyrroles.
Further, indoles 34
and 36 proved to be reactive as nucleophiles at both the C3-
and C2-positions, respectively, providing the corresponding
regioisomeric indole products 35 and 37. Hypervalent iodine-
induced oxidative dearomatization reactions of indoles with
nitrogen nucleophiles or electrophiles have been reported under
Scope of the tandem ODRE reaction
We next investigated the effects of varying ring size in the
substrates (Fig. 3). In tandem ODRE reactions of haloindanol
substrates 10a–d, the corresponding 8-membered ring lactam
products 11a–d were recovered in moderate 37–51% yields.
This decreased efficiency may be attributed to competing
formation of indene side products via dehydration of the indanol
substrates, or poor orbital overlap of the scissile bond with the
[
74,75]
[76-78]
the ‘normal’
and umpolung
reaction manifolds,
respectively. The larger indole-fused 7- and 8-membered ring
substrates 38 and 40, readily accessed from the corresponding
cyclic ketones via Fischer indole synthesis followed by a DDQ
oxidation sequence, were also converted to the corresponding
10- and 11-membered lactam products 39 and 41 in good yields.
Taken together, these results demonstrate the excellent scope
of the tandem ODRE reaction in providing access to a wide
variety of benzannulated medium-ring lactam products.
[
16]
nascent aromatic p-system in the rearomatization reaction.
In
contrast, the corresponding halobenzosuberanols 12a-c and
halobenzocyclooctanols 14a,b afforded 10- and 11-membered
benzannulated lactams 13a-c and 15a,b, respectively, in 70–
9
0% yields.
Next, we explored the use of aryl ether substrates in the
tandem ODRE. Anisoles have been used previously in such
umpolung oxidative dearomatization spirocyclization reactions of
Mechanistic proposal
A proposed mechanism for the tandem ODRE reaction
[
57-59]
N-methoxyamides.
However, reaction of the anisole 16 led
involves initial PhI(TFA)
2
activation of the N-methoxyamide side
to only a 15% yield of the desired medium-ring lactam 17. From
this complex mixture, we also recovered a cyclohexadienone
byproduct (≈20%), presumably resulting from hydrolysis or
demethylation of the corresponding O-methyl oxocarbenium
intermediate (Supplementary Fig. 1a). We posited that this
unproductive pathway could be avoided by stabilizing the O-
methyloxocarbenium intermediate with a temporary nucleophile.
Thus, when the reactions were conducted in methanol instead of
nitromethane, the 9- and 10-membered medium-ring products
chain in 42, in the presence of the charge-stabilizing solvent
[
57,79-81]
nitromethane, to form a nitrenium ion intermediate
44
(Fig. 4). Ensuing intramolecular electrophilic substitution
through ipso-attack of the tethered arene generates a cationic
tricyclic intermediate 45 poised for ring expansion.
Rearomatization of the arene then drives spontaneous C–C
bond cleavage, facilitated by the lone-pair electrons on the
C1-hydroxyl group, to afford the benzannulated medium ring-
lactam product 46.
1
7 and 19 were obtained in 86% and 87% yields, respectively.
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Chemistry - A European Journal
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MeO
NH
MeO
Ph
O
Me Me
a)
OMe
N
N
I
O
a)
MeI, K CO
O
O
O
HO
+ PhI(TFA)2
HO
2
3
MeO
O
O
CF3
N
O
–
TFA
– PhI
TFA
Br
–
Y
Y
Br
4
2
43
13c
47
Y = heteroatom
c)
b)
ArB(OH)2
Pd(II)
d)
Zn
AcOH
H
Ph
MeO
O
N
MeO
O
Pd(0), Cu(I)
N
N
Me Me
HO
OD
MeO
RE
OH
O
OMe
O
O
1
O
H
N
MeO
Y
O
N
O
N
Y
Y
O
O
4
4
45
46
Br
Ar
Ph
Figure 4. Proposed mechanism of tandem ODRE reaction.
5
2
49 (Ar = 3-CO2MePh)
48
5
5
0 (Ar = Ph)
1 (Ar = (E)-styrenyl)
Functionalization of medium-ring scaffolds
b)
With access to
a
variety of medium-ring scaffolds
e)
MeI
KOt-Bu
OMe
N
g)
BnNH2
NaBH(OAc)3
OMe
established, we next investigated downstream synthetic
modifications to introduce additional structural diversity. Thus,
bromoaryllactam 13c and methoxyaryllactam 53 were scaled up
to explore these transformations (Fig. 5a). The acidity of the
O
N
O
1
9
O
H
N
MeO
Me
MeO
Bn
Me
5
3
5
5
1
,3-dicarbonyl methylene protons in 13c enabled conversion to
[
82]
h)
α,α-dimethylketone 47 in a one-pot geminal dimethylation.
f)
LiHMDS
OMe
N
Sonogashira coupling of the aryl bromide moiety in 47 with
L-Selectride
p-NO2PhCHO
O
[
83]
phenyl acetylene then afforded aryl alkyne 48 in 65% yield.
From the parent aryl bromide 13c, several boronic acids were
OH
MeO
OMe
Me
[
84]
OH
also coupled under standard Suzuki–Miyaura conditions
to
N
O
provide cross-coupling products 49–51 in good yields.
Reductive cleavage of the N–O bond in 13c with zinc metal
afforded corresponding secondary lactam 52 without affecting
OH ≡
MeO
Me
[
85]
54
56
NO2
the bromide.
In a second series, β-ketolactam 19 (Fig. 5b) was first
converted to α-methyl-β-ketolactam 53 using potassium tert-
butoxide and methyl iodide. The ketone moiety of 53 was then
reduced to afford anti-α-methyl-β-hydroxylactam 54 in 94% yield
Figure 5. Downstream modification reactions of medium-ring scaffolds
3c and 53. Reagents and conditions: a) MeI (4.0 equiv), K CO (4.0 equiv),
DMF, 24 ºC, 48 h, 68%. b) phenylacetylene (10.0 equiv), Pd(PPh (20
1
2
3
3 4
)
mol%), CuI (25 mol%), Et N, DMF, 60 ºC, 16 h, 65%. c) ArB(OH) (1.1 equiv),
3
2
[
86]
and >99:1 dr.
The stereochemical configuration of 54 was
Pd(OAc)
2
(20 mol%), K
2
CO
3
(2.5 equiv), TBAB (1.1 equiv), H
2
O, 70 ºC, 2 h,
6
5–77%. d) Zn (40.0 equiv), AcOH/H
equiv), KOt-Bu (1.05 equiv), THF, 0 ºC, 4 h, 72%. f) L-Selectride (2.0 equiv),
THF, 0 ºC to 24 ºC, 3 h. 94%, >99:1 dr anti/syn. g) BnNH (1.1 equiv), AcOH
2
O (1:1), 24 ºC, 24 h, 85%. e) MeI (3.0
assigned based on X-ray crystallographic analysis (see
Electronic Supplementary Information). Analogously, reductive
amination of the ketone in scaffold 53 with benzyl amine
provided β-aminolactam 55 in 76% yield and 94:6 dr, favoring
the anti diastereomer, assigned based on extensive 2D NMR
2
(1.0 equiv), 4Å MS, toluene, 90 ºC, 2 h, then NaBH(OAc) (4.0 equiv), DCE, 24
3
ºC, 16 h, 76%, 94:6 dr anti/syn. h) LiHMDS (3.0 equiv), THF, –78 ºC, 1 h;
2
then p-NO PhCHO (2.5 equiv), –78 ºC to 24 ºC, 16 h, 59%, 99:1 dr. DCE =
[
87]
dichloroethane; DMF = N,N-dimethylformamide; L-Selectride = lithium tri-s-
butylborohydride; TBAB = tetrabutylammonium bromide.
studies.
Finally, a one-pot aldol–Tishchenko reaction
generated anti-1,3-diol 56 in good yield as a single diastereomer
[
88]
with four contiguous stereocenters.
Relative stereochemistry
was assigned via conversion to the corresponding acetonide
and 1D and 2D NMR studies (see Electronic Supplementary
Information).
analyzed each compound based on our established set of 20
structural and physicochemical parameters, then used principal
component analysis (PCA) to identify correlations between
parameters, reducing the dimensionality of the complete 20-
Cheminformatic analysis of medium-ring scaffolds
dimensional dataset to enable convenient visualization
To assess the structural features of the tandem ODRE
products, we carried out a cheminformatic analysis of these 41
compounds in comparison to 47 accessed by the original
stepwise ODRE sequence, 20 benzannulated medium-ring
natural products, and our previously established reference sets
of 60 diverse natural products, 40 top-selling brand-name drugs,
[89]
(
(
Supplementary Fig. 2).
The first three principal components
PC1–PC3) accounted for 75% of the variance represented in
the complete 20-dimensional dataset.
In this analysis, visualization of the first two principal
components (PC1, PC2) was insufficient to differentiate the
medium-ring ODRE libraries and natural products clearly from
the synthetic drugs and drug-like libraries. In contrast, the
[
15,16,89,90]
and 20 commercial drug-like library compounds.
We
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Chemistry - A European Journal
10.1002/chem.201802880
FULL PAPER
reference set of 60 diverse natural products occupied a larger,
distinct region of the plot. Examination of component loadings
variety of downstream modifications. Cheminformatic analysis
indicates that the tandem ODRE library overlaps with medium-
ring natural products and is distinct from conventional synthetic
drugs and drug-like libraries, accessing regions of chemical
space that are underrepresented in probe and drug discovery.
Notably, related benzannulated medium-ring lactam scaffolds
have also been used in structure-based designed of
(
Supplementary Fig. 3) indicated that positioning along PC1
was dominated by parameters that correlate with molecular size
e.g., molecular weight, van der Waals surface area). Along
(
PC2, parameters that correlate with hydrophobicity (logP, logD)
shifted molecules down (negative) while those that correlate with
polarity (logS, relative polar surface area) shift molecules up
[
17-19]
angiotensin-converting enzyme inhibitors.
While the
(
positive). Thus, the overlap of the medium-ring and drug/drug-
immediate applications of these molecules lie in efforts to
discover novel biological probes, both β-ketolactam and
N-alkoxyamide motifs are found in approved and investigational
drugs, suggesting that these motifs are also compatible with
like sets is likely due to their relatively small and hydrophobic
nature. Further, the broader range of this plot covered by the
diverse natural product reference set is primarily due to the
larger size of these molecules and, in some cases, high polarity.
In contrast, when PC3 was plotted, the medium-ring libraries
and natural products diverged from the synthetic drugs and
drug-like libraries. Along PC3, parameters that correlate with
[
96-100]
eventual translational applications.
Biological evaluation of
this tandem ODRE library is ongoing and will provide insights
into its utility in identifying novel probes and therapeutic leads.
3
three-dimensional structure (stereochemical density, sp
content) shifted molecules positively while aromatic ring content
Experimental Section
shifted molecules negatively.
Thus, the relatively three-
dimensional structures of the medium-ring compounds
effectively differentiated them from the relatively flat, highly
aromatic structures of the drugs and drug-like molecules.
Notably, the former parameters have been associated with
See Supporting Information for complete experimental protocols and
analytical data, as well as PCA and X-ray crystallographic datafiles.
General procedure for tandem ODRE reaction
[
91]
increased target specificity
preclinical and clincial development
been associated with preclinical toxicity.
and progression through
[
92,93]
while the latter has
Moreover, both of
The β-hydroxy-N-methoxyamide substrate (0.32 mmol, 1.0 equiv) was
[
94,95]
dissolved in nitromethane (3.2 mL) and cooled to 0 °C.
[
Bis(trifluoroacetoxy)iodo]benzene (0.48 mmol, 1.5 equiv) was added as
the ODRE libraries overlapped well with bonafide medium-ring
natural products across all three principal components.
a solid at 0 °C and the reaction was slowly warmed to 24 °C and stirred
for 0.5–2 h and monitored by TLC until complete consumption of the
starting material was observed. The reaction was then quenched with
satd aq NaHCO
3
.
The mixture was extracted with CH
2
Cl
2
(4 ´ 10 mL).
SO ),
Conclusions
The combined organic extracts were washed with brine, dried (Na
2
4
filtered, and concentrated by rotary evaporation to afford the crude
product. Purification by silica flash chromatography (0% → 5% MeOH in
Despite their prevalance in natural products and attractive
pharmacological properties, medium-ring structures are
underrepresented in current discovery libraries due to the
challenges associated with classical cyclization-based synthetic
approaches. To address this limitation, we have developed a
novel tandem ODRE reaction that provides flexible, efficient
access to diverse medium-ring scaffolds in 3 steps from readily
available cyclic ketone precursors. In contrast to our previously
2 2
CH Cl ) provided the corresponding medium-ring lactam. In the case of
anisole-tethered β-hydroxy-N-methoxyamides, the general procedure
was modified by using methanol instead of nitromethane as the solvent
and keeping the reaction at 0 °C.
Principal component analysis
PCA of the 41 resulting benzannulated medium-ring lactams, 47
medium-ring products synthesized previously by the stepwise ODRE
[
16]
reported stepwise ODRE sequence,
this tandem reaction
[
16]
provides medium-ring scaffolds directly from simple bicyclic
precursors through an umpolung strategy. Conceptual reversal
of electron flow in the initial oxidative dearomatization step leads
to a cationic tricyclic intermediate that undergoes spontaneous
sequence, and our previously established reference sets of 40 drugs,
20 commercial drug-like library members, and 60 natural products was
[
89]
conducted using R, an open-source statistical computing package.
A
set of 20 physicochemical descriptors (Supplementary Table 3) for all
compounds was obtained from PubChem and/or calculated using
ring-expanding rearomatization.
Moreover, this umpolung
[101]
cheminformatics tools (Instant JChem and VCCLab ) or ChemDraw
strategy enables strategic installation of an adjacent hydroxyl
group to prevent formation of olefin regioisomers and other
cation termination products, while also providing a versatile
ketone motif for further transformations. This was not feasible in
the original stepwise ODRE sequence due to competing Adler–
Becker reaction of phenolic substrates. Finally, the umpolung
strategy enables use of a much wider array of arene substrates
to provide haloaryl, aryl ether, acetanilide, aryl sulfonamide and
heteroaromatic medium-ring products found in numerous natural
and synthetic pharmacophores. The resulting natural product-
based medium ring scaffolds are amenable to scale-up and a
and uploaded to R for the study. The first three principal components
(
PC1–PC3) were obtained using R, which accounted for 74.6% of the
cumulative variance in the complete data set. They were then plotted on
newly generated, unitless, orthogonal axes (principal components) based
on linear combinations of the original 20 parameters (Supplementary
Table 3 and Supplementary Data Set 1). The PCA graphs shown in
Supplementary Fig. 2 were generated using the data visualization
software Prism.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201802880
FULL PAPER
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Chemistry - A European Journal
10.1002/chem.201802880
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Tezcan Guney, Todd A. Wenderski,
Matthew W. Boudreau, and Derek S.
Tan*
Page No. – Page No.
Synthesis of Benzannulated Medium-
ring Lactams via a Tandem Oxidative
Dearomatization–Ring Expansion
Reaction
East River Reactivity: Reversal of electron flow during a tandem oxidative
dearomatization–ring-expanding rearomatization reaction (left) was inspired by the
East River in New York City, a tidal estuary that reverses direction with each tide
(
right). The tandem reaction provides rapid and efficient access to a wide range of
medium-ring products that probe natural product-like regions of chemical space.
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