Synthesis of Functionalized 1,4-Dioxanes with an Additional (Hetero)Aliphatic Ring

Article abstract of DOI:10.1055/s-0037-1610195

An approach to the preparation of 2-mono-, 2,2- and 2,3-disubstituted 1,4-dioxane derivatives is described. The reaction sequence commences from readily available epoxides, in most cases prepared via the Corey-Chaikovsky reaction of the corresponding aldehydes and ketones. The key step of the method is epoxide ring opening with ethylene glycol monosodium salt, followed by further cyclization of the diols obtained. The utility of the approach was demonstrated by multigram preparation of novel functionalized 1,4-dioxanes bearing additional cycloalkane, piperidine or pyrrolidine rings, mostly spirocyclic compounds, which are advanced building blocks for medicinal chemistry.

Full text of DOI:10.1055/s-0037-1610195

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
paper
A
en
A. V. Bondarenko et al.
Paper
Synthesis
Synthesis of Functionalized 1,4-Dioxanes with an Additional
(Hetero)Aliphatic Ring
Andriy V. Bondarenkoa
Andrey A. Tolmacheva,b
Bohdan V. Vashchenkoa,b
Oleksandr O. Grygorenko*a,b
0
0
0
0
0-
0
0
2
6-
0
3
6
5-
8
5
9
a Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094,
Ukraine
www.enamine.net
b National Taras Shevchenko University of Kyiv, Volodymyrska
Street, 60, Kyiv 01601, Ukraine
gregor@univ.kiev.ua
Received: 04.04.2018
Accepted after revision: 30.05.2018
Published online: 20.07.2018
solubility, or bioavailability of the target molecules.1–7 In
particular, 1,4-dioxane-containing scaffolds have proven
their importance for organic synthesis and medicinal
chemistry because of their occurrence in a number of natu-
ral products and pharmaceutical agents.8–12 The 1,4-diox-
ane motif can be used as a bioisosteric replacement of car-
bocycles, as well as piperidine, piperazine or morpholine
fragments in order to alter the number and strength of hy-
drogen-bond acceptors and overall hydrophilicity of the
compound.
Examples of biologically active 1,4-dioxanes include
spectinomycin (1; Figure 1),13,14 a marketed antibiotic used
for more than half a century, c-Met kinase inhibitor MK-
2461 (2) with in vivo anticancer effect,15 non-receptor tyro-
sine-protein kinase TYK2 inhibitor 3,16 inhibitors of epider-
mal growth factor-activated receptor (EGFR) 4,17 muscarin-
ic receptor antagonists (e.g., 5),18–21 and antiviral agent 6.22
Another feature of the 1,4-dioxane six-membered ring
is its conformational restriction as compared to flexible
open-chain counterparts or even structurally related 1,3-
dioxolane analogues. Given this, C-substituted 1,4-dioxanes
DOI: 10.1055/s-0037-1610195; Art ID: ss-2018-t0230-op
Abstract An approach to the preparation of 2-mono-, 2,2- and 2,3-
disubstituted 1,4-dioxane derivatives is described. The reaction se-
quence commences from readily available epoxides, in most cases pre-
pared via the Corey–Chaikovsky reaction of the corresponding alde-
hydes and ketones. The key step of the method is epoxide ring opening
with ethylene glycol monosodium salt, followed by further cyclization
of the diols obtained. The utility of the approach was demonstrated by
multigram preparation of novel functionalized 1,4-dioxanes bearing ad-
ditional cycloalkane, piperidine or pyrrolidine rings, mostly spirocyclic
compounds, which are advanced building blocks for medicinal chemis-
try.
Key words oxygen heterocycles, 1,4-dioxane, spiro compounds,
building blocks, oxirane
Among recent tendencies in drug discovery, the shift
from aromatic rings dominating in existing drugs towards
compounds derived from saturated heterocycles has be-
come popular because of the improving pharmacokinetics,
HN
N
NH
O
N
O
H
OH
F
H
O
N
O
N
HO
O
O
Me
N
S
H
H
N
O
O
O
O
N
N
H
O
N
N
H
H
NC
OH
O
spectinomycin (1), antibiotic
MK-2461 (2), c-Met kinase inhibitor
3, TYK2 inhibitor
F
X
O
OEt
Me
Ph
O
O
O
O
HN
N
Ph2P
Ph2P
O
Ph
O
N
O
O
Me
OEt
N
O
N
O
O
5, mAChR antagonist
6, antiviral agent
7, ligand for asymmetric
4, EGFR inhibitors; X = H, Cl
hydrogenation
Figure 1 Some representatives of biologically active (1–6) and synthetically useful (7) 1,4-dioxane derivatives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

B
A. V. Bondarenko et al.
Paper
Synthesis
can serve as useful chiral auxiliaries in asymmetric synthe-
sis, for example, in the ligand 7, which is widely used in
asymmetric hydrogenation.23
strates of our interest. Therefore, we have considered basic
reaction conditions; i.e., oxirane ring opening with ethylene
glycol monosodium salt, followed by intramolecular diol
cyclization.
Known methods for the synthesis of 1,4-dioxanes with
aliphatic substituents can be divided into two large groups:
those based on C–H bond modification24–26 and on the con-
struction of the heterocyclic ring. The most renowned ap-
proach falling into the latter category relies on intramolec-
ular cyclizations of 1,2-diol derivatives 8–10 bearing an
electrophilic moiety at the appropriate position (Scheme 1,
pathways A,18,27–32 B,33–35 and C19,36–39). A variation of this
strategy includes the oldest method in this series, namely
dimerization of epichlorohydrin40,41 and other epoxides,42
as well as Lewis acid mediated reaction of epoxides with β-
halohydrins43–46 or 1,2-diols47 (D), followed by intramolec-
ular cyclization. Alternatively, intermediates of the type 8
could be generated by reaction of 1,2-diols and 1,2-dielec-
trophiles48–51 or via dimerization of β-halohydrins.52 Other
methods included iodo-35,53 or selenocyclization54 of
alkenes 11 (E), gold-promoted cyclization of allenyl epox-
ides 12 (F),55 and recyclization of other oxygen-containing
O
O
O
O
NH
NH
NH
NH
O
16
O
O
NH
O
17a
18
17b
17c
O
O
O
O
NH
NH
NH
O
O
O
O
17d
19b
20
O
O
O
O
O
O
O
O
NH
O
21
25
22
23
27
24
O
O
O
O
O
O
O
O
NH
O
O
O
CN
NH2
CO2H
O
26
28
Figure 2 Target compounds of this work (relative configurations are
shown)
heterocycles 13–15 (G,22
H
56–58 and I20,21,59).
To our knowledge, this approach was not described pre-
viously; hence, we have tested this idea for the preparation
of spirocyclic 1,4-dioxanes 17a–d, as well as compound 18
(Scheme 2 and Scheme 3).
O
X
Ri = various alkyl or aryl groups
EWG = electron-withdrawing group
X = OH, Hal
OH
X
Ri
O
D
O
Ri
9
OH
X
EWG
OH
O
Me3S(O)+I–
ONa
n
HO
(CH2OH)2
60 °C
Nn
m
n
O
N
B
PG
O
PG
N
m
t-BuOK
DMSO, rt
Ri
m
HO
31a–d
O
PG
A
C
8
Ri
O
HO
29a–d
10
a: m = n = 1, PG = Bn
b: m = 1, n = 2, PG = Bn
c: m = 2, n = 1, PG = Bn
d: m = n = 2, PG = Boc
Hal
1. t-BuOK, THF
2. TsCl, THF
3. t-BuOK, THF
36–84%
(from 29)
Ri
OH
O
I
E
O
Ri
O
1. H2, Pd-C, MeOH, rt
2. HCl, dioxane (33a–c)
OH
O
Ri
O
Cl–
O
O
n
n
11
15
+
H
N
F
or HCl, dioxane, reflux
(33d)
NH2
O
m
O
m
PG
O
·
33a–d
17a–d·HCl
91–97%
Ri
O
O
G
N–
N+
O
O
C
Ri
Scheme 2 Synthesis of spirocyclic 1,4-dioxanes 17a–d·HCl
H
O
12
14
HO
O
Ri
13
HO
O
O
O
Scheme 1 Known approaches to the construction of the substituted
1,4-dioxane ring
O
HO
O
O
Cl–
ONa
1. t-BuOK, THF
HCl
HO
(CH2OH)2
60 °C
dioxane
reflux
88%
2. TsCl, THF
3. t-BuOK, THF
45% (from 30)
In this work, we have aimed at the preparation of func-
tionalized 1,4-dioxanes with additional fused, spiro-con-
nected or isolated (hetero)aliphatic rings (compounds 16–
24 Figure 2), which are promising advanced building blocks
for use in medicinal chemistry. Given that the correspond-
ing oxiranes are more or less readily available, we have
turned to the pathway D+A shown in Scheme 1 as a general
strategy to achieve this goal.
N
N
N
H2
+
N
Boc
Boc
Boc
18.HCl
30
32
34
Scheme 3 Synthesis of 4-(1,4-dioxan-2-yl)piperidine 18·HCl
We started with synthesis of oxiranes 29a–d and 30 us-
ing the reported method, namely a Corey–Chaikovsky reac-
tion of the corresponding N-protected amino carbonyl com-
pounds.60–63 It was found that formation of the correspond-
ing diols 31a–d and 32 from oxiranes 29a–d and 30
The reported procedures for such transformations in-
volved the use of Lewis acids as the reaction promoter for
step D, which was not compatible with functionalized sub-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

C
A. V. Bondarenko et al.
Paper
Synthesis
proceeded smoothly at 60 °C in ethylene glycol as the sol-
vent. The products 31a–d and 32 were not obtained in pure
form. Given their high hydrophilicity, they were not isolat-
ed by extractive methods; instead, solvent removal was
performed by vacuum distillation. The crude 31a–d and 32
were subjected to the next step, including tosylation and t-
BuOK-mediated cyclization, which gave Boc or Bn deriva-
tives 33a–d and 34 in 36–85% overall yield. Notably, this re-
action sequence could be easily performed in a one-pot
manner, without isolation of the corresponding O-monoto-
sylate intermediate. The use of tetrahydrofuran as the sol-
vent was found to be optimal to achieve short reaction
times (1–3 h), convenient work-up of the reaction mixture,
and good yield of the product. Removal of the protective
group in the molecules 33a–d and 34 gave the target 1,4-
dioxanes 17a–d·HCl and 18·HCl (88–97% yield).
stants in their 1H NMR spectra. It should be noted that other
spectral data (including results of 2D NMR experiments)
were not informative for the stereochemistry assignment
because of the symmetry of both molecules 19a·HCl (C2 ax-
is) and 19b·HCl (plane of symmetry). In the case of 19a, the
3
values of JH–H coupling constants observed for the protons
of the 5(7)-CH2 groups and 4a(7a)-CH were 10.6 Hz and 6.8
Hz, which might be characteristic for the relatively rigid
trans-hydrindane system (Figure 3).65 For 19b, the corre-
sponding values were 5.3 Hz and 3.9 Hz, which might be
expected for the more flexible cis-fused bicyclic ring sys-
tem.
H
7
H
Cl–
Cl–
O
H
+
7a
NH2
7
+H2N
H
2
7a
2
7a O
2
7
O
O
10.56 Hz
H
4a
O
H
5
O
4a
3
+
H
3
NH2
4a
3
Cl–
H
H
It should be noted that aliphatic spirocyclic 1,4-diox-
anes have not been reported to date (although the synthesis
of related 2,3-dihydro[1,4]dioxino[2,3-b]pyridine deriva-
tives was described64).
5.3, 3.9 Hz
H
5
H
6.8 Hz
H
19a·HCl
19b·HCl
Figure 3 Informative 3JH–H coupling constants in 1H NMR spectra of
19a·HCl and 19b·HCl
Being inspired by these results, we introduced oxirane
35 into the reaction sequence described above for the syn-
thesis of the known 1,4-dioxane 19 (Scheme 4).43 Unfortu-
nately, the key reaction sequence of the method gave mod-
est yield of the corresponding N-Boc derivative 36 (ca. 6% by
1H NMR). The target product 19 could be obtained at in-
creased scale (starting from 116 g of 35) after removal of
the Boc protective group in 36 as ca. 9:1 mixture of diaste-
reomers 19a·HCl and 19b·HCl. The major stereoisomer
(19a·HCl) was isolated in 4.5% yield after recrystallization.
The minor isomer (19b·HCl) could be obtained in trace
amounts as a 1:1 mixture with 19a·HCl from the mother li-
quor (0.5% total yield). Relative configuration assignment
for 19a and 19b was based on analysis of 3JH–H coupling con-
We believe that these results can be addressed to the
relative strain observed in the transition state leading to the
trans-fused bicyclic ring system of 36a, which makes cy-
clization of the primary tosylate 37a unfavorable. Instead,
intermolecular reactions occur with 37a, which presum-
ably lead to the formation of unidentified oligo- and poly-
meric products. Formation of cis-isomer 19b·HCl can be ex-
plained by participation of secondary tosylate 37b (a minor
product of the tosylation step), which undergoes cyclization
with inversion of the configuration at the C-4 atom of the
pyrrolidine ring.
Nevertheless, the developed method was effective with
non-symmetric oxirane 38 (Scheme 5).66 Reaction of 38
with ethylene glycol monosodium salt resulted in the for-
mation of a mixture, presumably containing trans-diols 39
and 40. It was not separated but subjected to the cyclization
step, which gave the expected Boc derivative 41 (41% yield).
The target 1,4-dioxane 20·HCl was obtained after the subse-
quent deprotection step (94% yield). Relative trans-configu-
ration of 20·HCl was proven by NOESY experiment (Figure
ONa
(CH2OH)2
O
HO
N
Boc
O
N Boc
HO HO
35
60 °C
1. t-BuOK, THF
2. TsCl, THF
O
O
N
N
Boc
Boc
+
+
N
Boc
Boc
TsO HO
HO TsO
37a
37b
t-BuOK, THF
O
O
ONa
(CH2OH)2
O
O
O
HO
NBoc
NBoc
+
O
N
NBoc
HO
HO
HO
HO
O
60 °C
38
39
40
36a
36b
1. t-BuOK, THF
2. TsCl, THF
3. t-BuOK, THF
HCl, dioxane
reflux
41%
(from 38)
Cl–
Cl–
Cl–
O
O
O
O
O
O
+
NH2
NBoc
HCl
+
+
NH2
NH2
+
dioxane
reflux
94%
O
O
20.HCl
41
19a·HCl; 4.5% (from 35)
19b·HCl
Scheme 4 Synthesis of fused bicyclic 1,4-dioxanes 19·HCl (relative
Scheme 5 Synthesis of fused bicyclic 1,4-dioxane derivative 20·HCl
configurations are shown)
(relative configurations are shown)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

D
A. V. Bondarenko et al.
Paper
Synthesis
4). In this case, trans fusion of two six-membered rings is
favorable and does not result in the steric strain of the bicy-
clic system.
yield, as hydrochloride). It should be noted that isolation of
lactam 21 as the hydrochloride salt is unusual but not un-
precedented.68
O
O
O
O
RuCl3
NaIO4
H
H
O
O
O
O
Boc2O
H
H
Cl–
HCl
H
H
Strong
·HCl
O
O
O
correlation
Et3N
EtOAc–H2O
73%
+
dioxane
reflux
99%
H
H
NH2
quant
Cl–
N
H2
+
17c·HCl
N
N
O
N
Boc
Boc
H
H
Weak
correlation
49
50
21·HCl
H
H
H
Scheme 7 Synthesis of spirocyclic 1,4-dioxane 21
Figure 4 Representative correlations in NOESY spectrum of 20·HCl
The remaining spirocyclic building blocks 22–28 were
prepared through a common synthetic intermediate – ke-
tone 23. In turn, synthesis of 23 commenced from the
known dispirocyclic oxirane 5169 and followed the method-
ology described above using ethylene glycol monosodium
salt (Scheme 8). Compound 23 was obtained from 51 in
three steps and 33% overall yield.
For the preparation of the homologues 22 and 24, classi-
cal ring contraction/expansion reaction sequences were en-
visaged. To prepare 22, the cyclohexanone ring in 23 was
subjected to the oxidative cleavage with a NaNO2/O2/TFA
system. Dicarboxylic acid 54 thus obtained (93% yield) was
transformed into diester 55 (90% yield), which was intro-
duced into the Dieckmann cyclization, followed by hydroly-
sis and decarboxylation. Unfortunately, the product 22
could not be obtained using this method.
For the synthesis of 24, the Tiffeneau–Demjanov rear-
rangement of the corresponding amino alcohol 56 was used
as the key step. Compound 56 was obtained by using a stan-
dard method involving TMS cyanohydrin 57 formation in
quantitative yield and its subsequent reduction with LiAlH4
(78% yield). Treatment of 56 with NaNO2 in AcOH/H2O gave
the target spirocyclic cycloheptanone 24 in 58% yield.
An alternative approach to the ring expansion in the
molecule of 23 was also tested; namely, Beckmann type re-
arrangement of the corresponding oxime 58 (in turn ob-
tained from 23 in 92% yield, using the standard protocol).
The method included tosylation of 58, followed by base-
catalyzed rearrangement, and led to the spirocyclic capro-
lactam analogue 25 (75% yield).
The oxime 58 was reduced to the corresponding prima-
ry amine 26 in methanolic solution over Raney nickel under
100 bar hydrogen (45% yield, isolated as hydrochloride).
Compound 26 was obtained as ca. 2:1 mixture of diastereo-
mers. Notably, using LiAlH4 for this conversion was found to
be ineffective because of the low yield of the product 26
(14%).
A slightly different approach was used for the prepara-
tion of azetidine-containing 1,4-dioxane 16. The reaction
sequence commenced from 1,3-bis(benzyloxy)propan-2-
one (42)67 as a convenient starting material with reason-
able lipophilicity (Scheme 6). Compound 42 was converted
into the corresponding oxirane 43 (55% yield) by using the
Corey–Chaikovsky reaction. Further transformations fol-
lowed the standard synthetic scheme described above; they
included oxirane ring opening with ethylene glycol mono-
sodium salt, tosylation and t-BuOK-mediated cyclization,
and gave the 1,4-dioxane 45 in 69% overall yield. Subse-
quent debenzylation of 45 led to the corresponding 1,3-diol
46 (77% yield). The distilled diol 46 was subjected to the tri-
flation step, which gave bis(trifluoromethanesulfonate)
47in 98% yield. Construction of the azetidine ring was
achieved through the double alkylation of benzylamine
(81% yield), which gave 48. The target spirocyclic 1,4-diox-
ane 16 was obtained after the catalytic hydrogenolysis of 48
(63% overall yield, as hydrochloride).
OH
Me3S(O)+I–
t-BuOK
O
O
O
O
ONa
1. t-BuOK, THF
O
HO
OH
DMSO, rt
55%
(CH2OH)2
60 °C
2. TsCl, THF
3. t-BuOK, THF
69%
OBn OBn
OBn OBn
OBn OBn
OBn OBn
42
43
44
45
(from 43)
H2, Pd/C
MeOH
77%
O
45 °C
O
O
O
1. H2, Pd/C
BnNH2
O
MeOH, rt
Tf2O, py
CH2Cl2
O
DIPEA
O
O
2. HCl
dioxane
63%
MeCN
reflux
81%
N
Cl
N
OTf OTf –5 °C
OH OH
46
H2
Bn
16
48
47
(from 46)
Scheme 6 Synthesis of 5,8-dioxa-2-azaspiro[3.5]nonane (16·HCl)
1,4-Dioxane-containing piperidone 21 was also pre-
pared (Scheme 7). To achieve this, Boc derivative 49 (ob-
tained from hydrochloride 17c·HCl in quantitative yield)
was oxidized with RuCl3 to give imide 50 (73% yield). Subse-
quent deprotection of 50 gave the target compound 21 (99%
Finally, for the preparation of carboxylic acid 28, ketone
23 was converted into the target nitrile 27 by treatment
with tosylmethyl isocyanide (TosMIC) in 83% yield (Scheme
9). Alkaline hydrolysis of 27 gave the target compound 28 in
72% yield as ca. 1.2:1 mixture of diastereomers.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

E
A. V. Bondarenko et al.
Paper
Synthesis
OH
O
O
O
1. H2, Raney Ni
MeOH, 60 °C
100 bar
O
O
O
O
O
O
O
OH
O
O
O
Me3S(O)+I–
1. t-BuOK, THF
1. TsCl, THF
ONa
HO
t-BuOK
DMSO, rt
57%
2. TsCl, THF
3. t-BuOK, THF
2. KOH
aq THF
75%
(from 23)
(CH2OH)2
60 °C
2. HCl, dioxane
45%
(from 23)
O
O
O
O
NH
25
87% (from 51)
Cl
O
O
NH3
N
O
OH
26·HCl
51
52
53
58
aq HCl
66%
NH2OH·HCl
K2CO3
MeOH-H2O
reflux
O
O
O
O
O
O
O
O
1. LiAlH4
O
O
O
O
O
O
O
NaNO2, O2
MeOH
Me3SiCN
THF,5 °C
NaNO2
H2SO4
90%
AcOH–H2O
58%
ZnI2
CH2Cl2
2. HCl
dioxane
78%
TFA
93%
CO2Me
CO2H
CO2H
Cl
CO2Me
O
HO
NH3
Me3SiO CN
O
23
(from 23)
22
24
55
54
57
56·HCl
Scheme 8 Synthesis of spirocyclic 1,4-dioxanes 22–26
In conclusion, recyclization of oxiranes upon reaction
with ethylene glycol monosodium salt is an efficient proto-
col for the preparation of 2-mono-, 2,2- and 2,3-disubsti-
tuted 1,4-dioxanes. The scope of the method covers sub-
strates bearing functional groups (i.e., protected amine or
ketone), as well as 1,4-dioxanes with an additional fused,
spiro-connected or isolated (hetero)aliphatic rings. It is
shown that the products obtained can be subjected to some
typical transformations, including ring contractions/expan-
sions, which allows the scope of the approach to be extend-
ed to other functionalized 1,4-dioxanes (i.e., carboxylic ac-
ids and lactams). The target compounds are advanced
building blocks for drug discovery; they can be prepared on
a multigram scale and can therefore be considered as being
readily available to organic and medicinal chemistry com-
munity.
mental analyses were performed at the Laboratory of Organic Analy-
sis, Department of Chemistry, National Taras Shevchenko University
of Kyiv. Mass spectra were recorded with an Agilent 1100 LCMSD SL
instrument (chemical ionization (APCI), electrospray ionization (CI))
and Agilent 5890 Series II 5972 GCMS instrument (electron impact
ionization (EI)). The purity of the prepared compounds was checked
by GCMS with chemical ionization or by LCMS.
Ethylene Glycol Monosodium Salt
Ethylene glycol (300 g, 4.83 mol) and solid powdered NaOH (176 g,
4.39 mol) were mixed in xylenes (3 L) and stirred under reflux with a
Dean–Stark trap until H2O separation ceased (ca. 20 h). The mixture
was cooled to r.t. and the precipitate was filtered, washed with xy-
lenes (3 × 100 mL) and t-BuOMe (3 × 125 mL), dried in vacuo and
stored under argon.
Yield: 390 g (96%); white powder.
Preparation of Epoxides 29d and 43; General Procedure
t-BuOK (80.0 g, 0.713 mol) was added in one portion to a stirred satu-
rated solution of Me3SO+I– (196 g, 0.892 mol) in DMSO (600 mL) un-
der argon atmosphere, and the mixture was stirred at r.t. until homo-
geneous (ca. 1 h). A solution of the corresponding ketone (0.594 mol)
in THF (600 mL) was added dropwise to the stirred mixture at 15 °C
for 1 h, then the mixture was stirred for 0.5 h, diluted with H2O (1.5 L)
and extracted with t-BuOMe (4 × 750 mL). The organic layer was
washed with cold H2O (4 × 250 mL), dried over Na2SO4 and evaporat-
ed in vacuo. The residue was dissolved in hexanes (750 mL) and
washed with cold brine (4 × 150 mL). The organic phase was separat-
ed and evaporated in vacuo to give the corresponding oxiranes.
O
O
O
1. aq KOH
reflux
O
O
O
TsCH2NC
2. aq HCl
72%
t-BuOK
EtOH, DME
83%
CO2H
O
CN
23
27
28
Scheme 9 Synthesis of target compounds 27 and 28
tert-Butyl 1-Oxa-6-azaspiro[2.6]nonane-6-carboxylate (29d)
Yield: 71.6 g (53%); yellowish liquid.
The solvents were purified according to the standard procedures. Ox-
iranes 29a–c, 30, 35, 38 and 51 were prepared according to the re-
ported methods. All other reagents and starting materials were ob-
tained from commercial sources. Melting points were measured with
a MPA100 OptiMelt automated melting point system. Analytical TLC
was performed using Polychrom SI F254 plates. 1H and 13C NMR spec-
tra were recorded with a Bruker 170 Avance 500 spectrometer (at
499.9 MHz for 1H and 124.9 MHz for 13C) and Varian Unity Plus 400
spectrometer (at 400.4 MHz for 1H and 100.7 MHz for 13C) in CDCl3 or
DMSO-d6 solutions. Chemical shifts (δ) are given in ppm downfield
from TMS as an internal standard. J values are reported in Hz. Ele-
The compound existed as ca. 1:1 mixture of rotamers.
1H NMR (400 MHz, CDCl3): δ = 3.67–3.47 (m, 2 H), 3.36–3.24 (m, 2 H),
2.69–2.52 (m, 2 H), 1.99–1.81 (m, 2 H), 1.79–1.62 (m, 4 H), 1.45 (s,
9 H).
13C NMR (125 MHz, CDCl3): δ = 154.8, 78.9, 58.8 and 58.6, 54.6 and
54.3, 47.1 and 46.2, 42.8 and 42.6, 36.0 and 35.5, 33.3 and 33.1, 28.0,
23.6 and 23.3.
LC/MS (EI): m/z = 227 [M]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

F
A. V. Bondarenko et al.
Paper
Synthesis
Anal. Calcd for C12H21NO3: C, 63.41; H, 9.31; N, 6.16. Found: C, 63.05;
H, 9.13; N, 5.83.
9-Benzyl-1,4-dioxa-9-azaspiro[5.5]undecane (33c)
Yield: 98.9 g (84%); yellowish solid; mp 52–54 °C.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.22 (m, 5 H), 3.74–3.68 (m, 2 H),
3.68–3.62 (m, 2 H), 3.52 (d, J = 4.3 Hz, 2 H), 3.46 (d, J = 4.3 Hz, 2 H),
2.58–2.47 (m, 2 H), 2.38 (t,J= 10.2 Hz, 2 H), 1.91 (d, J = 13.4 Hz, 2 H),
1.64–1.51 (m, 2 H).
2,2-Bis((benzyloxy)methyl)oxirane (43)
Yield: 92.9 g (55%); yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.22 (m, 10 H), 4.58 (d, J = 4.3 Hz,
4 H), 3.71 (d, J = 3.6 Hz, 4 H), 2.82 (d, J = 3.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 138.4, 129.2, 128.2, 127.0, 74.7, 69.1,
13C NMR (125 MHz, CDCl3): δ = 138.0, 128.4, 127.8, 127.7, 73.5, 70.1,
57.8, 48.8.
67.1, 63.1, 59.8, 48.6, 31.2.
LC/MS (CI): m/z = 248 [M + 1]+.
LC/MS (EI): m/z = 284 [M]+.
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 73.24;
H, 8.88; N, 5.79.
Anal. Calcd for C18H20O3: C, 76.03; H, 7.09. Found: C, 75.75; H, 7.42.
tert-Butyl 1,4-Dioxa-9-azaspiro[5.6]dodecane-9-carboxylate (33d)
Yield: 46.5 g (36%); yellowish oil.
Preparation of 33a–d, 34, 36, 41, 45, and 53; General Procedure
Ethylene glycol monosodium salt (40.0 g, 0.476 mol) was suspended
in ethylene glycol (400 mL), and the corresponding oxirane (0.366
mol) was added in one portion under argon atmosphere. The mixture
was heated at 60 °C overnight. H2O (300 mL) and NH4Cl (19.6 g, 0.366
mol) were added and the mixture was stirred for 1 h. Then most of
H2O was evaporated in vacuo, the residue was diluted with CHCl3
(700 mL), stirred at r.t. for 1 h, and the precipitate was filtered off. The
solvents were removed in vacuo, the residue was dissolved in CHCl3
(500 mL), and the precipitate was filtered off once more. The solvent
was evaporated in vacuo.
The compound existed as ca. 1:1 mixture of rotamers.
1H NMR (500 MHz, CDCl3): δ = 3.60–3.55 (m, 1 H), 3.54–3.45 (m, 4 H),
3.45–3.32 (m, 1 H), 3.26 (d, J = 11.4 Hz, 1 H), 3.23 (d, J = 11.4 Hz, 1 H),
3.20–3.09 (m, 1 H), 3.04 (t, J = 12.8 Hz, 1 H), 2.16 (dd, J = 14.7, 6.9 Hz,
1 H), 1.82–1.66 (m, 2 H), 1.62–1.52 (m, 1 H), 1.44–1.35 (m, 1 H), 1.34
(s, 9 H), 1.23–1.11 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 154.9, 78.5, 74.2, 71.8 and 71.7, 66.2,
59.7 and 59.5, 46.0 and 45.1, 39.8 and 39.5, 35.6 and 35.1, 29.7 and
29.3, 27.9, 19.9 and 19.2.
The residue was dissolved in THF (500 mL), and a THF solution (250
mL) of t-BuOK (39.4 g, 0.351 mol) was added in portions at r.t., and
the mixture was stirred at r.t. for 1 h. Then a THF solution (400 mL) of
TsCl (66.9 g, 0.351 mol) was added in one portion, and the mixture
was stirred at r.t. for an additional 2 h. Then a THF solution (325 mL)
of t-BuOK (49.3 g, 0.439 mol) was added and the resulting suspension
was stirred for 1 h. H2O (3.29 mL, 0.183 mol) was added, and most of
THF was removed in vacuo. The residue was extracted with benzene
(500 mL) and washed with cold brine (3 × 100 mL). The combined or-
ganic phases were dried over anhydrous Na2SO4 and evaporated in
vacuo.
LC/MS (EI): m/z = 271 [M]+.
Anal. Calcd for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C, 62.09;
H, 9.10; N, 5.52.
tert-Butyl 4-(1,4-Dioxan-2-yl)piperidine-1-carboxylate (34)
Yield: 58.1 g (45%); yellowish oil.
1H NMR (400 MHz, CDCl3): δ = 7.33 (s, 2 H), 4.09 (s, 2 H), 3.89–3.42
(m, 4 H), 3.37–3.24 (m, 1 H), 2.76–2.51 (m, 2 H), 1.97–1.74 (m, 1 H),
1.68–1.53 (m, 1 H), 1.54–1.47 (m, 1 H), 1.43 (s, 9 H), 1.30–1.12 (m,
2 H).
13C NMR (100 MHz, CDCl3): δ = 154.5, 79.1, 78.4, 69.3, 66.8, 66.5, 38.2,
28.3, 27.8, 27.4.
LC/MS (EI): m/z = 271 [M]+.
2-Benzyl-6,9-dioxa-2-azaspiro[4.5]decane (33a)
Yield: 92.2 g (83%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.21 (m, 5 H), 3.70–3.59 (m, 6 H),
3.57 (s, 1 H), 3.52–3.42 (m, 1 H), 2.83 (d, J = 9.8 Hz, 1 H), 2.62 (t, J =
6.6 Hz, 2 H), 2.52 (d, J = 9.8 Hz, 1 H), 1.97–1.75 (m, 2 H).
Anal. Calcd for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C, 61.73;
H, 9.46; N, 5.50.
13C NMR (125 MHz, CDCl3): δ = 138.2, 128.2, 127.8, 126.5, 80.0, 72.9,
65.9, 62.1, 61.4, 59.8, 52.2, 33.9.
LC/MS (CI): m/z = 234 [M + 1]+.
trans-tert-Butyl Hexahydro[1,4]dioxino[2,3-c]pyridine-6(7H)-car-
boxylate (41)
Yield: 47.5 g (41%); yellowish oil.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.32;
H, 8.01; N, 6.04.
1H NMR (500 MHz, CDCl3): δ = 4.15–3.80 (m, 2 H), 3.59 (s, 4 H), 3.11–
3.02 (m, 1 H), 3.03–2.94 (m, 1 H), 2.64–2.28 (m, 2 H), 1.62 (d,J =
12.0 Hz, 1 H), 1.36–1.29 (m, 1 H), 1.27 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 153.8, 79.2, 78.2, 75.7, 66.6, 66.3, 45.6
and 44.9, 42.2 and 41.3, 28.9, 27.7.
8-Benzyl-1,4-dioxa-8-azaspiro[5.5]undecane (33b)
Yield: 74.2 g (63%); yellowish oil.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.22 (m, 5 H), 3.75–3.65 (m, 2 H),
3.65–3.58 (m, 4 H), 3.58–3.55 (m, 1 H), 3.51–3.45 (m, 1 H), 2.57–2.37
(m, 3 H), 2.37–2.29 (m, 1 H), 1.73 (d, J = 6.1 Hz, 2 H), 1.60–1.43 (m,
2 H).
LC/MS (EI): m/z = 243 [M]+.
Anal. Calcd for C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 58.99;
H, 8.78; N, 6.01.
13C NMR (125 MHz, CDCl3): δ = 138.2, 128.9, 128.1, 127.0, 72.6, 70.3,
67.0, 63.1, 60.4, 57.9, 54.0, 30.9, 21.8.
2,2-Bis((benzyloxy)methyl)-1,4-dioxane (45)
Yield: 107.9 g (69%); clear yellow oil.
LC/MS (CI): m/z = 248 [M + 1]+.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.20 (m, 10 H), 4.56 (s, 4 H),
3.81–3.69 (m, 4 H), 3.70–3.59 (m, 4 H), 3.57 (d, J = 9.6 Hz, 2 H).
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.63;
H, 8.72; N, 5.92.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

G
A. V. Bondarenko et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 138.3, 128.4, 127.7, 127.6, 73.8, 73.6,
1,4-Dioxa-9-azaspiro[5.5]undecane Hydrochloride (17c·HCl)
69.1, 68.5, 66.7, 60.9.
LC/MS (EI): m/z = 328 [M]+.
Yield: 56.4 g (97%); white crystals; mp 191–193 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.23 (s, 2 H), 3.62 (s, 2 H), 3.55 (s,
2 H), 3.39 (s, 2 H), 3.05 (d, J = 12.3 Hz, 2 H), 2.90 (t, J = 11.7 Hz, 2 H),
1.98 (d, J= 13.9 Hz, 2 H), 1.66 (t, J = 13.1 Hz, 2 H).
Anal. Calcd for C20H24O4: C, 73.15; H, 7.37. Found: C, 73.37; H, 7.28.
1,4,9,12-Tetraoxadispiro[4.2.58.25]pentadecane (53)
13C NMR (125 MHz, DMSO-d6): δ = 73.7, 67.4, 66.6, 59.9, 38.9, 27.6.
LC/MS (CI): m/z = 158 [M + 1]+.
Yield: 88.7 g; yellowish oil. Used in the next step without purifica-
tion.
1H NMR (400 MHz, CDCl3): δ = 3.94–3.75 (m, 4 H), 3.66–3.49 (m, 4 H),
Anal. Calcd for C8H16ClNO2: C, 49.61; H, 8.33; N, 7.23; Cl, 18.30.
Found: C, 49.89; H, 7.99; N, 6.97; Cl, 18.37.
3.39–3.23 (m, 2 H), 1.99–1.67 (m, 4 H), 1.55–1.30 (m, 4 H).
13C NMR (125 MHz, CDCl3): δ = 108.9, 74.6, 69.8, 67.0, 64.3, 62.1, 60.8,
Preparation of 17d, 18, 19, and 20; General Procedure
29.5, 28.7.
10% HCl in 1,4-dioxane (95 mL) was added in one portion to the cor-
responding N-Boc derivative (0.170 mol), and the mixture was heated
at reflux upon stirring for 15 min. Then the solvent was removed in
vacuo, and the residue was recrystallized from acetone or ace-
tone/CHCl3 (1:1).
Preparation of 16 and 17a–c; General Procedure
10% Pd/C (7.50 g) was added in portions to the corresponding N-ben-
zyl derivative (0.300 mol) in 10% HCl in 1,4-dioxane (120 mL) at r.t.
The mixture was stirred at r.t. for 30 min, the solvent was evaporated
in vacuo to dryness. The resulting hydrochloride was dissolved in
MeOH (750 mL) and the mixture was stirred vigorously under 1 atm
of H2 until the reaction was complete (monitored by 1H NMR). The
catalyst was filtered off, 10% HCl in 1,4-dioxane (150 mL) was added,
and the mixture was evaporated in vacuo. The residue was triturated
with t-BuOMe (500 mL) and filtered to give the target product as hy-
drochloride. If necessary, the product was recrystallized from i-PrOH
or acetone/CHCl3 (1:1).
1,4-Dioxa-9-azaspiro[5.6]dodecane Hydrochloride (17d·HCl)
Yield: 32.1 g (91%); white crystals; mp 156–158 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.34 (s, 1 H), 9.26 (s, 1 H), 3.62–
3.40 (m, 4 H), 3.33 (d, J = 11.4 Hz, 1 H), 3.27 (d, J = 11.4 Hz, 1 H), 3.17–
2.89 (m, 4 H), 2.16–1.99 (m, 1 H), 1.96–1.62 (m, 4 H), 1.62–1.47 (m,
1 H).
13C NMR (125 MHz, DMSO-d6): δ = 73.6, 72.3, 66.5, 59.9, 45.6, 39.1,
33.2, 29.5, 18.9.
LC/MS (CI): m/z = 172 [M + 1]+.
5,8-Dioxa-2-azaspiro[3.5]nonane Hydrochloride (16·HCl)
Yield: 31.3 g (63%); grayish solid; mp 173–175 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.59 (br s, 2 H), 3.83 (s, 4 H), 3.76
Anal. Calcd for C9H18ClNO2: C, 52.05; H, 8.74; N, 6.74; Cl, 17.07.
Found: C, 51.94; H, 8.80; N, 6.71; Cl, 17.07.
(s, 2 H), 3.64–3.61 (m, 2 H), 3.56–3.53 (m, 2 H).
4-(1,4-Dioxan-2-yl)piperidine Hydrochloride (18·HCl)
13C NMR (125 MHz, DMSO-d6): δ = 71.6, 69.9, 65.7, 62.8, 53.6.
LC/MS (CI): m/z = 130 [M + 1]+.
Yield: 31.1 g (88%); white crystals; mp 177–179 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.29 (s, 1 H), 9.01 (s, 1 H), 3.71 (d,
J = 8.9 Hz, 2 H), 3.61 (d, J = 11.2 Hz, 1 H), 3.53 (t, J = 11.2 Hz, 1 H), 3.40
(t, J = 11.2 Hz, 1 H), 3.29–3.11 (m, 4 H), 2.76 (d, J = 11.2 Hz, 2 H), 1.85
(d, J = 13.2 Hz, 1 H), 1.62 (d, J = 11.2 Hz, 2 H), 1.55–1.38 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 77.8, 68.9, 66.7, 66.3, 43.2, 43.0,
35.5, 24.5, 24.4.
Anal. Calcd for C6H12ClNO2: C, 43.51; H, 7.30; N, 8.46; Cl, 21.40.
Found: C, 43.72; H, 7.33; N, 8.35; Cl, 21.39.
6,9-Dioxa-2-azaspiro[4.5]decane Hydrochloride (17a·HCl)
Yield: 51.7 g (96%); yellowish crystals; mp 102–104 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.16–9.42 (m, 2 H), 3.73–3.49 (m,
6 H), 3.34–3.03 (m, 4 H), 2.13–1.99 (m, 1 H), 1.94–1.78 (m, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 80.1, 70.6, 66.3, 62.1, 50.5, 43.6,
LC/MS (CI): m/z = 172 [M + 1]+.
Anal. Calcd for C9H18ClNO2: C, 52.05; H, 8.74; N, 6.74; Cl, 17.07.
Found: C, 52.18; H, 9.04; N, 6.98; Cl, 17.47.
32.5.
LC/MS (CI): m/z = 144 [M + 1]+.
trans-Hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole Hydrochloride
Anal. Calcd for C7H14ClNO2: C, 46.80; H, 7.86; N, 7.80; Cl, 19.73.
Found: C, 46.41; H, 7.88; N, 8.10; Cl, 19.66.
(19a·HCl)
Obtained by recrystallization of the crude product from acetone/CH-
Cl3.
1,4-Dioxa-8-azaspiro[5.5]undecane Hydrochloride (17b·HCl)
Yield: 4.35 g (4.5% from oxirane 35); yellowish crystals; mp 235–
Yield: 54.6 g (94%); white crystals; mp 160–162 °C.
237 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.89 (br s, 1 H), 8.47 (s, 1 H), 3.74
(m, 1 H), 3.67–3.46 (m, 4 H), 3.40 (d, J = 13.3 Hz, 1 H), 3.33 (d, J =
11.7 Hz, 1 H), 3.07 (d, J = 11.7 Hz, 1 H), 2.88 (t, J = 11.2 Hz, 1 H), 2.75
(m, 1 H), 1.87–1.67 (m, 2 H), 1.66–1.37 (m, 2 H).
1H NMR (400 MHz, DMSO-d6): δ = 9.78 (s, 2 H, NH2+), 3.85 (dd, J =
11.2, 8.4 Hz, 2 H, 2- and 3-CHH), 3.67 (dd, J = 11.2, 8.4 Hz, 2 H, 2- and
3-CHH), 3.61–3.51 (m, 2 H, 4a- and 7a-CH), 3.39 (dd, J = 10.6, 6.8 Hz,
2 H, 5- and 7-CHH), 2.88 (t, J = 10.6 Hz, 2 H, 5- and 7-CHH).
13C NMR (125 MHz, DMSO-d6): δ = 71.9, 68.0, 66.6, 60.0, 45.1, 43.4,
28.3, 17.5.
13C NMR (125 MHz, DMSO-d6): δ = 76.5 (2- and 3-CH2), 66.9 (4a- and
7a-CH2), 42.6 (5- and 7-CH2).
LC/MS (CI): m/z = 158 [M + 1]+.
LC/MS (CI): m/z = 130 [M + 1]+.
Anal. Calcd for C8H16ClNO2: C, 49.61; H, 8.33; N, 7.23; Cl, 18.30.
Found: C, 49.31; H, 8.72; N, 7.30; Cl, 18.62.
Anal. Calcd for C6H12ClNO2: C, 43.51; H, 7.30; N, 8.46; Cl, 21.40.
Found: C, 43.28; H, 7.21; N, 8.49; Cl, 21.46.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

H
A. V. Bondarenko et al.
Paper
Synthesis
cis- and trans-Hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole Hydro-
chlorides (19b·HCl and 19a·HCl)
mixture was evaporated in vacuo, the residue was dissolved in t-
BuOMe (450 mL) and washed with brine (3 × 100 mL). The organic
phase was separated, dried over anhydrous Na2SO4 and evaporated in
vacuo.
A 1:1 mixture of 19a·HCl and 19b·HCl was obtained from the mother
liquor after recrystallization of the crude product 19·HCl.
Yield: 3.88 g (81%); clear yellowish oil.
Yield: 483 mg (0.5% from oxirane 35); white crystals; mp 183–185 °C.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.18 (m, 5 H), 3.79 (s, 2 H), 3.70
(s, 2 H), 3.63 (s, 4 H), 3.46 (d, J = 8.7 Hz, 2 H), 2.98 (d, J = 8.7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 137.7, 128.4, 128.4, 127.2, 71.9, 70.7,
1H NMR (400 MHz, DMSO-d6): δ (only for 19b·HCl) = 9.83 (s, 2 H),
4.30–4.16 (m, 2 H), 3.78–3.71 (m, 2 H), 3.39–3.35 (m, 2 H), 3.28 (dd,
J = 11.9, 3.9 Hz, 2 H), 3.21 (dd ,J = 11.9, 5.3 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ (only for 19b·HCl) = 71.9, 61.9, 44.5.
LC/MS (CI): m/z = 130 [M + 1]+.
66.2, 63.5, 62.9, 62.0.
LC/MS (CI): m/z = 220 [M + 1]+.
Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.41;
H, 7.79; N, 6.56.
Anal. Calcd for C6H12ClNO2: C, 43.51; H, 7.30; N, 8.46; Cl, 21.40.
Found: C, 43.24; H, 6.97; N, 8.77; Cl, 21.37.
tert-Butyl 1,4-Dioxa-9-azaspiro[5.5]undecane-9-carboxylate (49)
trans-Octahydro-[1,4]dioxino[2,3-c]pyridine Hydrochloride
(20·HCl)
Boc2O (27.4 mL, 0.119 mol) was added dropwise to a stirred solution
of amine hydrochloride 17c (22.4 g, 0.116 mol) and Et3N (31.8 mL,
0.228 mol) in MeOH (300 mL) at r.t. The mixture was stirred for an
additional 30 min, and the solvent was evaporated in vacuo. The resi-
due was dissolved in benzene (400 mL) and washed with H2O (3 × 75
mL). The organic layer was separated, dried over anhydrous Na2SO4
and evaporated in vacuo.
Yield: 28.7 g (94%); white crystals; mp 174–176 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.82–9.45 (m, 2 H), 3.75 (t,
J = 7.3 Hz, 2 H), 3.69–3.57 (m, 2 H), 3.56–3.46 (m, 1 H), 3.42–3.30 (m,
1 H), 3.21 (t, J = 11.5 Hz, 2 H), 3.01–2.87 (m, 1 H), 2.81–2.66 (m, 1 H),
1.88 (d, J = 12.3 Hz, 1 H), 1.70 (qd,J = 13.2, 4.1 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 75.9, 73.7, 67.0, 66.9, 44.4, 42.3,
26.6.
Yield: 29.8 g (quant); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 3.61–3.54 (m, 2 H), 3.54–3.51 (m, 2 H),
3.49–3.46 (m, 2 H), 3.25 (s, 2 H), 2.97 (t, J = 11.4 Hz, 2 H), 1.72 (d, J =
13.6 Hz, 2 H), 1.28 (s, 9 H), 1.26–1.19 (m, 2 H).
LC/MS (CI): m/z = 144 [M + 1]+.
Anal. Calcd for C7H14ClNO2: C, 46.80; H, 7.86; N, 7.80. Found: C, 46.61;
H, 7.96; N, 7.63.
13C NMR (126 MHz, CDCl3): δ = 154.1, 78.6, 73.9, 68.5, 66.3, 59.3, 30.4,
27.8.
(1,4-Dioxane-2,2-diyl)dimethanol (46)
LC/MS (EI): m/z = 257 [M]+.
10% Pd-C (2.58 g) was added to a solution of 45 (12.9 g, 39.3 mmol) in
MeOH (150 mL). The mixture was vigorously stirred under 1 atm of
H2 at 45 °C until the reaction was complete. The catalyst was filtered
off and the mixture was evaporated in vacuo.The crude product was
distilled in vacuo.
Anal. Calcd for C13H23NO4: C, 60.68; H, 9.01; N, 5.44. Found: C, 60.63;
H, 9.39; N, 5.73.
tert-Butyl 8-Oxo-1,4-dioxa-9-azaspiro[5.5]undecane-9-carboxyl-
ate (50)
Yield: 4.48 g (77%); clear colorless oil; bp 138–141 °C/1 mmHg.
RuCl3 (0.24 g, 1.16 mmol) in H2O (5 mL) was added in one portion to a
mixture of 49 (29.4 g, 0.114 mol) and NaIO4 (53.8 g, 0.251 mol) in H2O
(500 mL) and EtOAc (1.5 L) at r.t. The resulting mixture was stirred for
2 d, then additional EtOAc (900 mL) was added to the solution, the
organic phase was separated, dried over Na2SO4 and evaporated in
vacuo. The residue was recrystallized from pentane.
1H NMR (400 MHz, CDCl3): δ = 3.72–3.62 (m, 6 H), 3.59–3.53 (m, 4 H),
3.53–3.47 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 73.9, 67.9, 66.5, 61.6, 60.8.
LC/MS (EI): m/z = 148 [M]+.
Anal. Calcd for C6H12O4: C, 48.64; H, 8.16. Found: C, 48.78; H, 8.39.
Yield: 22.6 g (73%); white solid; mp 112–114 °C.
(1,4-Dioxane-2,2-diyl)bis(methylene) Bis(trifluoromethanesul-
fonate) (47)
1H NMR (500 MHz, CDCl3): δ = 3.63–3.59 (m, 4 H), 3.57 (d, J = 4.8 Hz,
2 H), 3.38 (d, J = 4.4 Hz, 2 H), 2.69–2.61 (m, 1 H), 2.37 (d, J = 16.6 Hz,
1 H), 1.64 (dt, J = 15.2, 8.0 Hz, 1 H), 1.42 (s, 9 H), 1.37–1.34 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 168.2, 151.6, 82.4, 72.5, 69.9, 66.0,
60.0, 41.7, 41.1, 28.2, 27.4.
A solution of Tf2O (8.75 mL, 52.0 mmol) in CH2Cl2 (50 mL) was added
dropwise to a stirred solution of 1,3-diol 46 (3.50 g, 23.6 mmol) and
pyridine (4.75 mL, 59.1 mmol) in CH2Cl2 (30 mL) at –5 °C. The mixture
was stirred for 2 h, then the solution was washed with brine (3 × 25
mL). The organic phase was separated, dried over anhydrous Na2SO4
and evaporated in vacuo at r.t. The crude product was used in the
next step without thorough characterization.
LC/MS (EI): m/z = 271 [M]+.
Anal. Calcd for C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C, 57.71;
H, 7.95; N, 5.34.
Yield: 9.54 g; pinkish amorphous solid.
1H NMR (400 MHz, CDCl3): δ = 4.70 (d, J = 10.5 Hz, 2 H), 4.48 (d, J =
10.5 Hz, 2 H), 3.83 (s, 2 H), 3.73 (s, 2 H), 3.67 (s, 2 H).
1,4-Dioxa-9-azaspiro[5.5]undecan-8-one Hydrochloride (21 HCl)
10% HCl in 1,4-dioxane (45 mL) was added in one portion to N-Boc-
amide 50 (22.1 g, 81.5 mmol), and the mixture was heated at reflux
for 1 h. Then the solvent was removed in vacuo to give 21 as the hy-
drochloride.
2-Benzyl-5,8-dioxa-2-azaspiro[3.5]nonane (48)
A solution of bis(trifluoromethanesulfonate) 47 (9.04 g, 21.9 mmol),
benzylamine (2.82 g, 26.3 mmol) and DIPEA (9.55 mL, 54.8 mmol) in
acetonitrile (225 mL) was heated at reflux upon stirring for 2 d. The
Yield: 13.8 g (99%); white crystals; mp 152–154 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

I
A. V. Bondarenko et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 11.73 (br s, 1 H), 7.86 (s, 1 H), 3.69–
3.48 (m, 4 H), 3.44 (d, J = 11.4 Hz, 1 H), 3.33 (d, J = 11.4 Hz, 1 H), 3.24–
3.12 (m, 1 H), 3.12–3.03 (m, 1 H), 2.31–2.18 (m, 2 H), 2.19–2.09 (m,
1 H), 1.66–1.51 (m, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 169.7, 72.8, 70.2, 66.4, 60.3, 38.9,
37.1, 26.2.
LC/MS (CI): m/z = 246 [M]+.
Anal. Calcd for C11H18O6: C, 53.65; H, 7.37. Found: C, 53.61; H, 7.56.
9-((Trimethylsilyl)oxy)-1,4-dioxaspiro[5.5]undecane-9-carboni-
trile (57)
TMSCN (7.30 mL, 58.4 mmol) was added dropwise to a stirred solu-
tion of cyclohexanone 23 (6.62 g, 38.9 mmol) and ZnI2 (3.74 g, 11.7
mmol) in CH2Cl2 (75 mL) at 5 °C. The mixture was stirred overnight at
r.t. and evaporated in vacuo. The residue was diluted with t-BuOMe
(250 mL) and filtered. The filtrate was evaporated in vacuo and the
crude product was used in the next step without further characteri-
zation.
GC/MS (EI): m/z = 171 [M]+.
Anal. Calcd for C8H14ClNO3: C, 46.27; H, 6.80; N, 6.75; Cl, 17.07.
Found: C, 46.45; H, 6.72; N, 6.80; Cl, 17.26.
1,4-Dioxaspiro[5.5]undecan-9-one (23)
37% aq HCl (0.45 mL) was added to a solution of ketal 53 (86.5 g, 0.404
mol) in acetone (500 mL). The mixture was heated at reflux for 1 h,
then cooled to r.t. and evaporated in vacuo. The residue was distilled
in vacuo to give pure ketone.
Yield: 10.5 g; yellowish liquid.
1H NMR (500 MHz, CDCl3): δ = 3.67 (s, 2 H), 3.62 (s, 2 H), 3.47 (s, 2 H),
2.07 (d, J = 13.0 Hz, 2 H), 1.99–1.78 (m, 4 H), 1.41 (t, J = 10.1 Hz, 2 H),
0.19 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 121.7, 74.6, 71.9, 68.6, 67.3, 59.8, 33.6,
28.1, 1.5.
Yield: 45.4 g (66%); clear yellowish oil; bp 87–89 °C/1 mmHg.
1H NMR (400 MHz, DMSO-d6): δ = 3.72–3.63 (m, 2 H), 3.63–3.54 (m,
2 H), 3.43 (s, 2 H), 2.48–2.35 (m, 2 H), 2.21–2.01 (m, 4 H), 1.66 (td, J =
13.7, 4.8 Hz, 1 H).
9-(Aminomethyl)-1,4-dioxaspiro[5.5]undecan-9-ol Hydrochloride
(56·HCl)
13C NMR (125 MHz, DMSO-d6): δ = 210.9, 73.5, 69.6, 66.7, 60.3, 36.0,
30.2.
Cyanohydrin derivative 57 (7.50 g) from the previous step was added
in small portions to a vigorously stirred suspension of LiAlH4 (2.11 g,
55.7 mmol) in THF (150 mL) at 5 °C. The mixture was stirred over-
night at r.t., then 10% aq KOH (12.5 g, 0.223 mmol) was added drop-
wise. The resulting mixture was filtered, 10% HCl in 1,4-dioxane (200
mL) was added to the combined filtrates, and the solution was evapo-
rated in vacuo. The residue was recrystallized from acetone.
GC/MS (EI): m/z = 170 [M]+.
Anal. Calcd for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.11; H, 8.58.
3-(2-(Carboxymethyl)-1,4-dioxan-2-yl)propanoic Acid (54)
Ketone 23 (9.91 g, 58.2 mmol) was dissolved in TFA (100 mL), and Na-
NO2 (16.1 g, 0.233 mol) was added in small portions to the stirred
solution under air continuous flow. The mixture was stirred at 25 °C
for 4 h and evaporated in vacuo. The residue was diluted with EtOAc
(250 mL), insoluble inorganic compounds were filtered off, and the
solvent was evaporated in vacuo.
Yield 5.16 g (78% from 23); white powder; mp 172–174 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.01 (br s, 3 H), 4.99 (s, 1 H), 3.61–
3.55 (m, 2 H), 3.53–3.48 (m, 2 H), 3.41–3.37 (m, 2 H), 2.77 (d, J =
4.4 Hz, 2 H), 1.72–1.62 (m, 2 H), 1.60–1.52 (m, 2 H), 1.51–1.44 (m,
2 H), 1.44–1.40 (m, 2 H).
Yield: 11.3 g (93%); yellowish solid.
1H NMR (400 MHz, DMSO-d6): δ = 12.17 (s, 2 H), 3.66 (d, J = 8.4 Hz,
1 H), 3.58–3.48 (m, 3 H), 3.42 (d, J = 11.5 Hz, 1 H), 3.33 (s, 1 H), 2.60–
2.51 (m, 1 H), 2.48–2.41 (m, 1 H), 2.30–2.18 (m, 2 H), 2.08–1.85 (m,
1 H), 1.81–1.68 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 174.9, 172.1, 72.3, 72.1, 66.4, 60.3,
38.3, 28.6, 27.8.
13C NMR (100 MHz, DMSO-d6): δ = 72.8, 70.4, 68.7, 66.7, 61.2, 59.7,
46.4, 30.5, 29.7, 27.7.
LC/MS (CI): m/z = 202 [M + 1]+.
Anal. Calcd for C10H20ClNO3: C, 50.53; H, 8.48; N, 5.89; Cl, 14.91.
Found: C, 50.19; H, 8.80; N, 5.94; Cl, 14.90.
LC/MS (CI): m/z = 217 [M – 1]–.
1,4-Dioxaspiro[5.6]dodecan-9-one (24)
Anal. Calcd for C9H14O6: C, 49.54; H, 6.47. Found: C, 49.48; H, 6.29.
Amino alcohol 56·HCl (4.25 g, 17.9 mmol) was dissolved in 50% aq
AcOH (210 mL), and NaNO2 (1.27 g, 18.4 mmol) in H2O (19.0 mL) was
added dropwise at 0 °C with stirring. The reaction mixture was
warmed to r.t. upon stirring overnight, then diluted with CHCl3 (500
mL), washed with H2O (3 × 75 mL) and saturated aq NaHCO3 (3 × 50
mL). The organic phase was separated, dried over anhydrous Na2SO4,
and the solvent was evaporated in vacuo to give crude 24, which was
purified by distillation in vacuo. Microanalytical sample was obtained
by reverse-phase HPLC (Poroshell 120 SBC18, 4.6 × 30 mm column,
gradient MeCN/H2O as eluent).
Methyl 3-(2-(2-Methoxy-2-oxoethyl)-1,4-dioxan-2-yl)propanoate
(55)
96% H2SO4 (0.5 mL, 4.63 mmol) was added to a solution of dicarboxyl-
ic acid 54 (10.1 g, 46.3 mmol) in anhydrous MeOH (100 mL). The solu-
tion was stirred for 2 h and evaporated in vacuo. The residue was di-
luted with CHCl3 (350 mL) and washed with saturated aq NaHCO3
(3 × 50 mL). The organic phase was separated, dried over Na2SO4 and
evaporated in vacuo.
Yield: 1.91 g (58%); clear yellowish oil; bp 135–137 °C/1 mmHg.
Yield: 10.3 g (90%); brownish liquid; bp 126–127 °C/1 mmHg.
1H NMR (400 MHz, CDCl3): δ = 3.62 (m, 4 H), 3.38 (d, J = 2.5 Hz, 2 H),
2.77 (t, J = 12.7 Hz, 1 H), 2.55–2.46 (m, 1 H), 2.41 (m, 1 H), 2.30 (d, J =
6.8 Hz, 1 H), 2.25 (d, J = 6.2 Hz, 1 H), 2.19–2.11 (m, 1 H), 1.94–1.87 (m,
1 H), 1.68–1.62 (m, 1 H), 1.55–1.50 (m, 1 H), 1.24 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 214.2, 75.0, 71.9, 66.8, 60.2, 43.5, 36.2,
35.8, 28.2, 17.1.
1H NMR (500 MHz, CDCl3): δ = 3.78–3.72 (m, 1 H), 3.69–3.61 (m,
10 H), 3.51 (dd, J = 11.5, 1.8 Hz, 1 H), 2.72 (dd, J = 14.3, 1.9 Hz, 1 H),
2.62 (dd, J = 14.3, 1.9 Hz, 1 H), 2.45–2.36 (m, 2 H), 2.24–2.13 (m, 1 H),
1.94–1.83 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 173.8, 170.6, 72.3, 72.2, 66.6, 60.6,
51.7, 51.7, 38.1, 28.4, 27.6.
LC/MS (CI): m/z = 184 [M]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

J
A. V. Bondarenko et al.
Paper
Synthesis
Anal. Calcd for C10H16O3: C, 65.19; H, 8.75. Found: C, 65.18; H, 8.87.
LC/MS (CI): m/z = 172 [M + 1]+.
Anal. Calcd for C9H18ClNO2: C, 52.05; H, 8.74; N, 6.74; Cl, 17.07.
Found: C, 52.03; H, 9.02; N, 6.51; Cl, 16.97.
1,4-Dioxaspiro[5.5]undecan-9-one Oxime (58)
A mixture of 23 (80.0 g, 0.470 mol), hydroxylamine hydrochloride
(49.0 g, 0.705 mol), and K2CO3 (77.9 g, 0.564 mol) in MeOH/H2O (1:1
v/v, 600 mL) was heated at reflux overnight. Most of the MeOH was
evaporated in vacuo, additional H2O (300 mL) was added to residue,
which was extracted with CHCl3 (900 mL). The organic phase was
separated, dried over Na2SO4, and the solvent was evaporated in vac-
uo. The crude product was recrystallized from hexanes and used
without further purification.
1,4-Dioxaspiro[5.5]undecane-9-carbonitrile (27)
Ketone 23 (70.0 g, 0.411 mmol), tosylmethyl isocyanide (TosMIC)
(96.4 g, 0.494 mmol) and anhydrous EtOH (28.8 mL, 0.494 mmol)
were dissolved in 1,2-dimethoxyethane (1.4 L). t-BuOK (60.0 g, 0.535
mmol) was added carefully in small portions at 0 °C with vigorous
stirring (CAUTION! Exothermic reaction is observed). The reaction
mixture was stirred at 0 °C for an additional 30 min, and then at 50 °C
for 30 min and at r.t. overnight. Most of 1,2-dimethoxyethane was
evaporated in vacuo, the residue was triturated with t-BuOMe (600
mL), and insoluble precipitate was filtered off. The filtrate was evapo-
rated in vacuo, and the product was purified by flash chromatography
on silica gel (t-BuOMe as eluent).
Yield: 79.2 g; yellowish oil.
1H NMR (400 MHz, CDCl3): δ = 8.47 (s, 1 H), 3.76–3.68 (m, 2 H), 3.68–
3.64 (m, 2 H), 3.16 (d, J = 18.8 Hz, 1 H), 3.07–2.95 (m, 1 H), 2.44–2.34
(m, 1 H), 2.20–2.09 (m, 3 H), 1.95–1.49 (m, 2 H), 1.42–1.31 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 158.8, 99.5, 74.1, 69.7, 66.5, 59.5, 47.1,
27.2, 26.5.
Yield: 61.8 g (83%); yellowish liquid.
The compound was obtained as ca. 1.2:1 mixture of diastereomers.
LC/MS (CI): m/z = 186 [M + 1]+.
1H NMR (400 MHz, CDCl3): δ = 3.63 (br s, 4 H), 3.42 (s, 0.55 × 2 H),
3.36 (s, 0.45 × 2 H), 2.91–2.84 (m, 0.45 × 1 H) and 2.44–2.37 (m,
0.55 × 1 H), 2.07 (d, J = 13.6 Hz, 1 H), 1.98–1.80 (m, 4 H), 1.78–1.70
(m, 1 H), 1.59–1.50 (m, 1 H), 1.22–1.10 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 129.4, 121.7 and 121.4, 113.9, 74.2,
69.0 and 68.4, 66.4, 59.5 and 59.4, 29.2 and 27.1, 27.3 and 26.5, 23.6
and 22.7.
1,4-Dioxa-9-azaspiro[5.6]dodecan-10-one (25)
TsCl (27.2 g, 0.142 mol) was added to a vigorously stirred solution of
oxime 58 (26.9 g) from the previous step and KOH (29.4 g, 0.523 mol)
in THF/H2O (3:1, 1.2 L) at 0 °C. The mixture was warmed to r.t. upon
stirring overnight. Then, most of THF was evaporated in vacuo, and
the residue was extracted with CHCl3 (600 mL). The organic phase
was separated, dried over anhydrous Na2SO4 and the solvent was
evaporated in vacuo. The obtained crude product was recrystallized
from hexanes.
LC/MS (CI): m/z = 181 [M]+.
Anal. Calcd for C10H15NO2: C, 66.27; H, 8.34; N, 7.73. Found: C, 66.27;
H, 8.70; N, 8.10.
Yield: 20.2 g (75% from 23); white crystals; mp 107–109 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.42 (s, 1 H), 3.71–3.45 (m, 4 H),
3.44–3.18 (m, 2 H), 2.90–2.74 (m, 1 H), 2.60 (t, J = 13.0 Hz, 1 H), 2.12–
2.00 (m, 1 H), 2.00–1.81 (m, 2 H), 1.37 (t, J = 13.4 Hz, 1 H), 1.29 (t, J =
13.4 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 177.1, 74.7, 71.3, 66.7, 59.5, 35.3,
35.1, 29.2, 27.8.
1,4-Dioxaspiro[5.5]undecane-9-carboxylic Acid (28)
Nitrile 27 (29.9 g, 0.165 mmol) was heated at reflux in H2O (190 mL)
media in the presence of KOH (37.0 g, 0.660 mmol) for 4 h. The alka-
line solution was diluted with toluene (350 mL), the organic phase
was separated and discarded. The aqueous phase was acidified with
10 M aq HCl (80 mL) and extracted with EtOAc (3 × 250 mL). The com-
bined organic extracts were dried over Na2SO4 and evaporated in vac-
uo.
GC/MS (EI): m/z = 185 [M]+.
Anal. Calcd for C9H15NO3: C, 58.36; H, 8.16; N, 7.56. Found: C, 58.37;
H, 7.81; N, 7.31.
Yield: 23.8 g (72%); yellowish crystals; mp 107–109 °C.
The compound was obtained as ca. 1.2:1 mixture of diastereomers.
1H NMR (400 MHz, CDCl3): δ = 10.91 (br s, 1 H), 3.74–3.67 (m, 1 H),
3.67–3.61 (m, 3 H), 3.49 (s, 0.45 × 2 H) and 3.38 (s, 0.55 × 2 H), 2.55–
2.43 (m, 0.45 × 1 H) and 2.36–2.22 (m, 0.55 × 1 H), 2.10 (d, J = 13.8 Hz,
1 H), 1.96–1.84 (m, 1 H), 1.85–1.73 (m, 3 H), 1.73–1.52 (m, 2 H), 1.20–
1.07 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 181.6 and 181.4, 75.29, 73.0, 70.7,
69.6, 67.0 and 69.9, 60.2 and 59.8, 42.7 and 40.9, 30.1 and 29.9, 23.5
and 22.8.
1,4-Dioxaspiro[5.5]undecan-9-amine Hydrochloride (26·HCl)
Oxime 58 (35.0 g) from the previous step was dissolved in MeOH (1.2
L), and Raney nickel (15 g) was added to the resulting solution in an
autoclave. The mixture was heated at 100 bar of H2 and 60 °C for 8 h.
Then the reaction mixture was cooled, the catalyst was filtered off,
and the combined filtrates were evaporated in vacuo. 10% HCl in 1,4-
dioxane (30 mL) was added to the residue, and the mixture was evap-
orated to dryness. The residue was recrystallized from acetone.
LC/MS (CI): m/z = 199 [M – 1]–.
Yield: 17.7 g (45% from 23); white powder; mp 190–192 °C.
The compound was obtained as ca. 2:1 mixture of diastereomers.
Anal. Calcd for C10H16O4: C, 59.98; H, 8.05. Found: C, 60.08; H, 8.08.
1H NMR (400 MHz, DMSO-d6): δ = 8.15 (br s, 0.33 × 3 H) and 8.09 (br
s, 0.67 × 3 H), 3.69–3.46 (m, 4 H), 3.43 (s, 0.33 × 2 H) and 3.29 (s,
0.67 × 2 H), 3.20–3.09 (m, 0.33 × 1 H) and 3.02–2.86 (m, 0.67 × 1 H),
2.06–1.62 (m, 4 H), 1.59–1.09 (m, 4 H).
Funding Information
The work was funded by Enamine Ltd.
)(
13C NMR (125 MHz, DMSO-d6): δ = 74.6, 72.1, 70.1, 69.0, 66.8 and
66.7, 59.9 and 59.6, 49.5, 48.1, 28.8 and 28.0, 25.2 and 25.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

K
A. V. Bondarenko et al.
Paper
Synthesis
Acknowledgment
(21) Piergentili, A.; Quaglia, W.; Del Bello, F.; Giannella, M.; Pigini,
M.; Barocelli, E.; Bertoni, S.; Matucci, R.; Nesi, M.; Bruni, B.; Di
Vaira, M. Bioorg. Med. Chem. 2009, 17, 8174.
(22) Yang, W.; Sun, J. Angew. Chem. Int. Ed. 2016, 55, 1868.
(23) Li, W.; Waldkirch, J. P.; Zhang, X. J. Org. Chem. 2002, 67, 7618.
(24) Gu, Z.; Tang, Y.; Jiang, G.-F. J. Org. Chem. 2017, 82, 5441.
(25) Wang, Q.; Lou, J.; Wu, P.; Wu, K.; Yu, Z. Adv. Synth. Catal. 2017,
359, 2981.
The authors thank Prof. Andrey A. Tolmachev for his encouragement
and support and UOSLab (www.en.uoslab.com) for providing high-
pressure reactors.
Supporting Information
(26) Wang, J.; Mou, X.-Q.; Zhang, B.-H.; Liu, W.-T.; Yang, C.; Xu, L.; Xu,
Z.-L.; Wang, S.-H. Tetrahedron Lett. 2016, 57, 1239.
(27) Sawant, R. T.; Stevenson, J.; Odell, L. R.; Arvidsson, P. I. Tetrahe-
dron: Asymmetry 2013, 24, 134.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610195.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(28) Ghosh, A. K.; Gemma, S.; Takayama, J.; Baldridge, A.;
Leshchenko-Yashchuk, S.; Miller, H. B.; Wang, Y.-F.; Kovalevsky,
A. Y.; Koh, Y.; Weber, I. T.; Mitsuya, H. Org. Biomol. Chem. 2008,
6, 3703.
(29) Wilkinson, M. C.; Bell, R.; Landon, R.; Nikiforov, P. O.; Walker, A.
J. Synlett 2006, 2151.
(30) Stewart, G. W.; Brands, K. M. J.; Brewer, S. E.; Cowden, C. J.;
Davies, A. J.; Edwards, J. S.; Gibson, A. W.; Hamilton, S. E.; Katz, J.
D.; Keen, S. P.; Mullens, P. R.; Scott, J. P.; Wallace, D. J.; Wise, C.
S. Org. Process Res. Dev. 2010, 14, 849.
(31) Schafroth, M. A.; Rummelt, S. M.; Sarlah, D.; Carreira, E. M. Org.
Lett. 2017, 19, 3235.
(32) Astle, M. J.; Jacobson, B. E. J. Org. Chem. 1959, 24, 1766.
(33) Vishnuvajjala, B. R.; Swain, W. E.; Rector, D. H.; Cook, C. E.;
Petrow, V.; Reel, J. R.; Allen, S. K. M.; Levinel, S. G. J. Med. Chem.
1983, 26, 426.
(34) Holmberg, L.; Lindberg, B.; Lindqvist, B. Carbohydr. Res. 1995,
268, 47.
(35) Del Bello, F.; Barocelli, E.; Bertoni, S.; Bonifazi, A.; Camalli, M.;
Campi, G.; Giannella, M.; Matucci, R.; Nesi, M.; Pigini, M.;
Quaglia, W.; Piergentili, A. J. Med. Chem. 2012, 55, 1783.
(36) Gu, Q.; You, S. L. Org. Lett. 2011, 13, 5192.
(37) Košiová, I.; Šimák, O.; Panova, N.; Buděšínský, M.; Petrová, M.;
Rejman, D.; Liboska, R.; Páv, O.; Rosenberg, I. Eur. J. Med. Chem.
2014, 74, 145.
(38) Tietze, L. F.; Heins, A.; Soleiman-Beigi, M.; Raith, C. Heterocycles
2009, 77, 1123.
(39) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi, C.;
Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2003, 14,
1095.
(40) von Richter, V. Ber. Dtsch. Chem. Ges. 1877, 10, 679.
(41) von Richter, V.; Hofferichter, P. J. Prakt. Chem. 1879, 20, 188.
(42) Kohler, E. P.; Tishler, M.; Potter, H.; Thompson, H. T. J. Am. Chem.
Soc. 1939, 61, 1057.
(43) Zhang, J. Q.; Luo, Y. J.; Xiong, Y. S.; Yu, Y.; Tu, Z. C.; Long, Z. J.; Lai,
X. J.; Chen, H. X.; Luo, Y.; Weng, J.; Lu, G. J. Med. Chem. 2016, 59,
7268.
(44) Vermote, A.; Brackman, G.; Risseeuw, M. D. P.; Coenye, T.; Van
Calenbergh, S. Eur. J. Med. Chem. 2017, 127, 757.
(45) Veliev, M. G.; Shatirova, M. I.; Askerov, O. V. Chem. Heterocycl.
Compd. 2009, 45, 1190.
(46) Hachiya, I.; Matsumoto, T.; Inagaki, T.; Takahashi, A.; Shimizu,
M. Heterocycles 2010, 82, 449.
(47) Hiessböck, R.; Kratzel, M. J. Heterocycl. Chem. 1999, 36, 1295.
(48) Kotha, S.; Ravikumar, O.; Sreevani, G. Tetrahedron 2016, 72,
6611.
(49) Fedorov, B. S.; Golovina, N. I.; Smirnov, S. P.; Firkin, A. I.;
Atovmyan, L. O. J. Chem. Res. 2002, 38, 450.
References
(1) Leeson, P. D.; St-Gallay, S. A.; Wenlock, M. C. MedChemComm
2011, 2, 91.
(2) Ritchie, T. J.; Macdonald, S. J. F.; Peace, S.; Pickett, S. D.;
Luscombe, C. N. MedChemComm 2012, 3, 1062.
(3) Lovering, F. MedChemComm 2013, 4, 515.
(4) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.
(5) Vo, C.-V. T.; Bode, J. W. J. Org. Chem. 2014, 79, 2809.
(6) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301.
(7) Aldeghi, M.; Malhotra, S.; Selwood, D. L.; Chan, A. W. E. Chem.
Biol. Drug Des. 2014, 83, 450.
(8) Kim, H. Y.; Patkar, C.; Warrier, R.; Kuhn, R.; Cushman, M. Bioorg.
Med. Chem. Lett. 2005, 15, 3207.
(9) Kim, H. Y.; Kuhn, R. J.; Patkar, C.; Warrier, R.; Cushman, M.
Bioorg. Med. Chem. 2007, 15, 2667.
(10) Katz, J. D.; Jewell, J. P.; Guerin, D. J.; Lim, J.; Dinsmore, C. J.;
Deshmukh, S. V.; Pan, B. S.; Marshall, C. G.; Lu, W.; Altman, M.
D.; Dahlberg, W. K.; Davis, L.; Falcone, D.; Gabarda, A. E.; Hang,
G.; Hatch, H.; Holmes, R.; Kunii, K.; Lumb, K. J.; Lutterbach, B.;
Mathvink, R.; Nazef, N.; Patel, S. B.; Qu, X.; Reilly, J. F.; Rickert, K.
W.; Rosenstein, C.; Soisson, S. M.; Spencer, K. B.; Szewczak, A.
A.; Walker, D.; Wang, W.; Young, J.; Zeng, Q. J. Med. Chem. 2011,
54, 4092.
(11) Mutlib, A. E.; Cheung, H. T. A.; Watson, T. R. J. Steroid Biochem.
1987, 28, 65.
(12) Weiland, J.; Ritzau, M.; Megges, R.; Schön, R.; Watson, T. R.;
Repke, K. R. H. Eur. J. Med. Chem. 1995, 30, 763.
(13) McCormack, W. M.; Finland, M. Ann. Intern. Med. 1976, 84, 712.
(14) Salmon, S. A.; Watts, J. L. Avian Dis. 2015, 44, 85.
(15) Pan, B.-S.; Chan, G. K. Y.; Chenard, M.; Chi, A.; Davis, L. J.;
Deshmukh, S. V.; Gibbs, J. B.; Gil, S.; Hang, G.; Hatch, H.; Jewell, J.
P.; Kariv, I.; Katz, J. D.; Kunii, K.; Lu, W.; Lutterbach, B. A.;
Paweletz, C. P.; Qu, X.; Reilly, J. F.; Szewczak, A. A.; Zeng, Q.;
Kohl, N. E.; Dinsmore, C. J. Cancer Res. 2010, 70, 1524.
(16) Masse, C. E.; Greenwood, J. R.; Romero, D. L.; Harriman, G. C.;
Wester, R. T.; Shelley, M.; Kennedy-Smith, J. J.; Dahlgren, M.;
Mondal, S. Patent WO 2017040757, 2017.
(17) Zhang, J.; Zhang, Y.; Zhang, W.; Liu, B.; Zhang, J.; Liu, J.; Zhang, L.
Patent WO 2013071697, 2013.
(18) Del Bello, F.; Bonifazi, A.; Giorgioni, G.; Petrelli, R.; Quaglia, W.;
Altomare, A.; Falcicchio, A.; Matucci, R.; Vistoli, G.; Piergentili,
A. Eur. J. Med. Chem. 2017, 137, 327.
(19) Del Bello, F.; Bonifazi, A.; Quaglia, W.; Mazzolari, A.; Barocelli,
E.; Bertoni, S.; Matucci, R.; Nesi, M.; Piergentili, A.; Vistoli, G.
Bioorg. Med. Chem. Lett. 2014, 24, 3255.
(20) Piergentili, A.; Quaglia, W.; Giannella, M.; Del Bello, F.; Bruni, B.;
Buccioni, M.; Carrieri, A.; Ciattini, S. Bioorg. Med. Chem. 2007,
15, 886.
(50) Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J. Org. Chem.
1996, 61, 5280.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

L
A. V. Bondarenko et al.
Paper
Synthesis
(51) Bagnoli, L.; Scarponi, C.; Rossi, M. G.; Testaferri, L.; Tiecco, M.
Chem. Eur. J. 2011, 17, 993.
(62) Weng, Z.; Wei, W.; Dong, X.; Hu, Y.; Huang, S.; Liu, T.; Xie, X.
Monatsh. Chem. 2012, 143, 303.
(52) Derzhinskii, A. R.; Kalugin, V. E.; Konyushkin, L. D.; Prilezhaeva,
E. N. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1983, 32, 641.
(53) Yu, Q.; Carlsen, P. Molecules 2008, 13, 2962.
(54) Potapov, V. A.; Kurkutov, E. O.; Musalov, M. V.; Amosova, S. V.
Russ. J. Org. Chem. 2016, 52, 1719.
(63) Someya, H.; Kondoh, A.; Sato, A.; Ohmiya, H.; Yorimitsu, H.;
Oshima, K. Synlett 2006, 3061.
(64) Soukri, M.; Lazar, S.; Pujol, M. D.; Akssira, M.; Leger, J. M.; Jarry,
C.; Guillaumet, G. Tetrahedron 2003, 59, 3665.
(65) Lightner, D. A.; Gurst, J. E. Organic Conformational Analysis and
Stereochemistry from Circular Dichroism Spectroscopy; Wiley-
VCH: Weinheim, 2000.
(55) Tarselli, M. A.; Zuccarello, J. L.; Lee, S. J.; Gagné, M. R. Org. Lett.
2009, 11, 3490.
(56) Muthusamy, S.; Krishnamurthi, J.; Suresh, E. Chem. Commun.
2007, 861.
(66) Dang, Z.; Yang, Y.; Ji, R.; Zhang, S. Bioorg. Med. Chem. Lett. 2007,
17, 4523.
(57) Brogan, J. B.; Zercher, C. K.; Bauer, G. B.; Rogers, R. D. J. Org.
Chem. 1997, 62, 3902.
(67) Keeling, S. P.; Campbell, I. B.; Coe, D. M.; Cooper, T. W. J.; Hardy,
G. W.; Jack, T. I.; Jones, H. T.; Needham, D.; Shipley, T. J.; Skone,
P. A.; Sutton, P. W.; Weingarten, G. A.; Macdonald, S. J. F. Tetra-
hedron Lett. 2008, 49, 5101.
(68) Winkler, F. K.; Dunits, J. D. Acta Cryst. Sect. B 1975, B31, 270.
(69) Ciaccio, J. A.; Drahus, A. L.; Meis, R. M.; Tingle, C. T.; Smrtka, M.;
Geneste, R. Synth. Commun. 2003, 33, 2135.
(58) Oku, A.; Murai, N.; Baird, J. J. Org. Chem. 1997, 62, 2123.
(59) Duclos, R. I.; Makriyannis, A. J. Org. Chem. 1992, 57, 6156.
(60) Gadekar, P. K.; Roychowdhury, A.; Kharkar, P. S.; Khedkar, V. M.;
Arkile, M.; Manek, H.; Sarkar, D.; Sharma, R.; Vijayakumar, V.;
Sarveswari, S. Eur. J. Med. Chem. 2016, 122, 475.
(61) Balsamo, A.; Giorgi, I.; Lapucci, A.; Lucacchini, A.; Macchia, B.;
Macchia, F.; Martini, C.; Rossi, A. J. Med. Chem. 1987, 30, 222.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L