Oxa-spirocycles: synthesis, properties and applications

Article abstract of DOI:10.1039/d1sc03615g

A general approach to a new generation of spirocyclic molecules - oxa-spirocycles - was developed. The key synthetic step was iodocyclization. More than 150 oxa-spirocyclic compounds were prepared. Incorporation of an oxygen atom into the spirocyclic unit dramatically improved water solubility (by up to 40 times) and lowered lipophilicity. More potent oxa-spirocyclic analogues of antihypertensive drug terazosin were synthesized and studiedin vivo.

Full text of DOI:10.1039/d1sc03615g

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Mykhailiuk, A. A. Tolmachev, Y. Dmitriv, A. S. Kuznetsova, K. Shvydenko, V. V. Semeno, A. V. Bolbut, A. I.
Vaskevych, R. I. Vaskevych, V. R. Badlo, R. Iminov, E. Litskan, V. V. Levterov, I. Kovalchuk, V. Meliantsev, O.
Svitlychnyi, T. Diachuk, V. Vilchinskiy, T. Savchuk, D. Granat, V. Ripenko, D. Vysochyn, O. Pavlova, H.
Kuznietsova, I. Pishel and P. Borysko, Chem. Sci., 2021, DOI: 10.1039/D1SC03615G.
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DOI: 10.1039/D1SC03615G
ARTICLE
Oxa-spirocycles: synthesis, properties and applications
Kateryna Fominova,a Taras Diachuk,a Dmitry Granat,a Taras Savchuk,a Vladyslav Vilchinskiy,a
Oleksiy Svitlychnyi,a Vladyslav Meliantsev,a Igor Kovalchuk,a Eduard Litskan,a Vadym V. Levterov,a
Valentyn R. Badlo,a Ruslan I. Vaskevych,b Alla I. Vaskevych,c Andrii V. Bolbut,b Volodymyr V.
Semeno,a Rustam Iminov,a Kostiantyn Shvydenko,b Anastasiia S. Kuznetsova,d Yurii V. Dmytriv,a,c
Daniil Vysochyn,a Vasyl Ripenko,a Andrei A. Tolmachev,a Olexandra Pavlova,e Halyna Kuznietsova,e
Iryna Pishel,e Petro Borysko,e Pavel K. Mykhailiuka*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A general approach to a new generation of spirocyclic molecules - oxa-spirocycles - was developed. The key synthetic step
was iodocyclization. More than 150 oxa-spirocyclic compounds were prepared. Incorporation of oxygen atom into
spirocyclic unit dramatically improved water solubility (up to 40-times), and to lowered lipophilicity. More potent oxa-
spirocyclic analogues of antihypertensive drug Terazosin were synthesized and studied in vivo.
a
Mrs. K. Fominova, Mr. T. Diachuk, Dr. D. Granat, Mr. T. Savchuk, Mr. V.
Vilchinskiy, Mr. O. Svitlychnyi, Mr. V. Meliantsev, Mr. I. Kovalchuk, Mr. E.
Litskan, Mr. V. V. Levterov, Mr. V. R. Badlo, Mr. V. V. Semeno, Mr. R. Iminov, Dr.
Y. V. Dmytriv, Mr. D. Vysochyn, Mr. V. Ripenko, Prof. A. A. Tolmachev, Dr. P. K.
Mykhailiuk. Enamine Ltd; Chervonotkatska 78, 02094 Kyiv (Ukraine),
www.enamine.net, www.mykhailiukchem.org, E-mail:
Pavel.Mykhailiuk@gmail.com
b
c
Mr. R. I. Vaskevych, Dr. A. V. Bolbut, Dr. K. Shvydenko
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Murmanska St. 5, 02094Kyiv (Ukraine).
Mrs. A. I. Vaskevych, Dr. Y. V. Dmytriv
National Technical University of Ukraine, “Igor Sikorsky Kiev Polytechnic
Institute,” Prosp. Peremohy 37, 03056 Kyiv (Ukraine).
d
e
Dr. A. S. Kuznetsova, National Research Tomsk Polytechnic University, Lenin
Ave. 30, 634050 Tomsk (Russia).
Mrs. O. Pavlova, Mrs. H. Kuznietsova, Dr. I. Pishel, Dr. P. Borysko. Bienta,
Chervonotkatska 78, 02094 Kyiv (Ukraine), www.bienta.net.
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DOI: 10.1039/D1SC03615G
New chemical space
Popular substituents
Introduction
Saturated monocyclic units,
[209 hits]
[14 articles]
[65 patents]
[2 hits]
[0 articles]
[1 patent]
- cyclohexane, cyclopentane,
piperidine, etc, - dominated in chemistry and in drug discovery for
a long time.1 The situation started switching at the beginning of
this century. In 2009, Lovering introduced the concept “escape
from flatland,”2 that already changed the way how medicinal
chemists think. Today, scientists tend to use small F(sp3)-rich
molecules in their research.3,4 In 2010, saturated spirocycles were
shown to possess improved physico-chemical characteristics over
common monocyclic counterparts.5 Since that time, spirocyclic
molecules have been playing an important role in chemistry.6,7 In
fact, more than 10.000 research manuscripts and 50.000 patents
on the topic appeared during the last decade (Figure 1).8
O
This work
[450 hits]
[18 articles]
[135 patents]
[1 hit]
[1 article]10
New generation
[0 patents]
O
F
F
F
F
[64 hits]
[3 articles]
[35 patents]
[0 hits]
[0 articles]
[0 patents]
O
Figure 2. Spirocycles and their unexplored oxa-counterparts.
3D-shape
Solubility
Bioisosteres
New generation
Of course, there was some interest to oxa-spirocycles before,
but examples reported in the literature were rare and non-
systematic.11 In 1985, Yohida synthesized two substituted oxa-
spirocycles via iodocyclization (Scheme 1).12 In 2008, Gouverneur
studied an influence of fluorine atom on diastereoselectivity of
the iodocyclization reaction. In this work, one example of the oxa-
spirocyclic core was shown (Scheme 1).13 In 2011, Cernak and co-
workers from Merck employed Grubbs-metathesis reaction to
synthesize oxa-spiropiperidines with reduced lipophilicity (Scheme
1).14 Later, Carreira used the same approach to prepare oxa-
spiroazetidines.15 In 2013, Santini elaborated gold-catalyzed
oxidative cyclization of propargyl alcohols into oxa-spirocyclic
amines (Scheme 1).16 In the same year, Santini also developed an
alternative approach to oxa-spirocyclic amines via oxidative
intramolecular hydroxycyclization of alkenes.17 Subsequently,
Cocotos realized an organocatalytic version of that method
O
(2010)
[this work]
[cyclic]
[spiro]
H
[oxa-spiro]
>50.000 patents since 2010
>10.000 manuscripts
O
2015
Vertex
WO2015/6280
O
N
N
O
O
O
CO2H
OMe
O
Me
F
N
F
O
F
O
O
O
S
N
N N
N
NH
N
H
F
Me
2020
Novartis
WO2020/128786
O
2019
BMS
US2019/185446
Cl
O
Me
O
(Scheme 1).18 In 2018, Cossy developed
a [Rh]-catalyzed
NH
Et
F
Cl
N
cyclization of unsaturated alkoxyamines.19 All these reports
described different topics and contained one to three examples of
the desired oxa-spirocyclic molecules. Only recently, Baik and
Hong developed a [Pd]-mediated directed oxidative synthesis of
sterically hindered oxa-spirocycles (Scheme 1).20 This work had an
excellent scope, but needed an installation and the subsequent
removal of a directing group.
N
N
N
F
Me
N
N
2020
Pfizer
US2020/95239
2017
Jansen
WO2017/1660
Figure 1. Spirocycles and their application in chemistry.
Earlier, we reported on the preparation of oxa-bridged bicycles
via iodocyclization of alkenyl alcohols.9 These compounds were
Presumably, absence of a general method to oxa-spirocycles is a
primary reason why these molecules did not receive a proper
recognition by scientific community.21 An ideal practical method
should (a) employ inexpensive starting reagents; (b) not use
protecting groups;22 and (c) provide oxa-spirocycles with a
functional group that could be easily converted into variety of
other functional substituents: amines, alcohols, carboxylic acids,
sulfonyl chlorides, etc. In this work, we present such an approach.
designed
as
water-soluble
analogues
of
popular
bicyclo[1.1.1]pentanes. The work received a positive feedback
from both academy and industry, and therefore we decided to
expand this tactic onto a new generation of spirocycles - oxa-
spirocycles (Figures 1). Previously, oxa-spirocycles remained
mostly in the shadow. For example, while three representative
spirocyclic substituents (left, Figure 2) are extremely popular in
chemistry, the corresponding oxa-spirocyclic counterparts (right,
Figure 2) remain almost unknown.10
Results and discussion
2 | Chem.Sci., 2021, 00, 1-3
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Yoshida (1985)
Santini (2013)
CH2OH
HO
CH2I
mCPBA
HO
I2
O
[hydroxycyclization]
[3 examples]
NaHCO3
OH
[iodocyclization]
[2 examples]
CH2Cl2, rt
72-83%
O
Et2O, rt
H2O, 93%
1-3
N
1-3
Boc
N
OH
Boc
Gouverneur (2008)
Kokotos (2017)
CH2OH
H2O2
PhCOCF3
F
F
I2
[hydroxycyclization]
[2 examples]
NaHCO3
[iodocyclization]
[1 example]
O
OH
tBuOH
CH3CN, rt
70-85%
CH2Cl2, rt
H2O, 69%
CH2I
O
OH
Cernak (2011), Carreira (2013)
Cossy (2018)
NHTs
[Rh]
[aminocyclization]
[3 examples]
[cleavage of N-Ts]
Grubbs II
Cu(OAc)2
[metathesis]
[2 examples]
O
1-2
DCE, t
DCE, t
20-63%
O
O
1-2
86-93%
NHTs
O
N
N
Boc
Boc
[broad scope]
[installation of DG]
[cleavage of DG]
Santini (2013)
Baik, Hong (2018)
O
PhI(OAc)2
Pd(OAc)2
Au(PPh3)NTf2
[Au-cyclization]
[3 examples]
[glovebox]
O
tBu
DG
O
MsOH, MeCN
Cl2Py-N-oxide
50-63%
HOAc
toluene, t
54-76%
OH
1-2
1-2
O
OH
1-3
O
HN
N
1-3
N
DG
DG
Boc
N
Boc
Scheme 1. Literature precedents to oxa-spirocycles.
Optimization. Based on our experience,9 and literature
precedents,12,13 we studied iodocyclization of model alkene 4
(obtained by alkylation of ester 3 with LDA/allyl bromide;
reduction with LiAlH4) into oxa-spirocyclic core 4a. We decided to
exploit specifically iodocyclization, and not bromocyclization or
hydroxycyclization, because the putative alcohols or bromides
would be much less active in further modifications.
Under the previously developed conditions (Table 1, entry 1)
alkene 4 indeed predominantly afforded iodide 4a, however
formation of side products was also observed. Separation of this
mixture was problematic, especially on a gram scale. Performing
the reaction in diethyl ether (entry 2) or dichloromethane (entry
3) still led to formation of a mixture of compounds. Finally, we
screened solvents and find out that the transformation smoothly
proceeded in acetonitrile to provide iodide 4a in almost
quantitative yield (entry 7). Formation of side products was not
observed in this experiment. Other inorganic bases also worked
well, while pyridine and triethylamine gave moderate yields
(entries 10-13). It is worth noting that N-iodosuccinimide could
also be used although with a bit lower efficiency (entry 14).
Importantly, using the optimized conditions we could easily
synthesize iodide 4a on 26 g scale. The product was isolated from
the reaction mixture by simple distillation and no additional
purification was needed.
Previously9
I+
I
I2, NaHCO3
tBuOMe/H2O
rt, 78%
[bridged]
OH
O
HO
via
1
2
This work
F
F
I2
F
F
F
F
NaHCO3
CH3CN, rt
1h, 91%
[oxa-spiro]
I
CO2Et
O
OH
3
4
4a
Scope. Having an optimized procedure in hand, we studied next
its scope. Indeed, various five-membered oxa-spirocyclic iodides
5a-31a were easily prepared in 45-96% yield following the
optimized protocol (Scheme 2). Among them were N-Boc-
protected azetidines (8a, 16a, 21a), pyrrolidines (10a) and
piperidines (14a, 17a, 29a). Labile ketal (7a) and ester groups
(19a) were also compatible with the reaction conditions. Three
(5a) to eight (31a)-membered cycles were incorporated into oxa-
spirocyclic cores. Importantly, popular oxetane ring23 was also
successfully incorporated without decomposition (20a). Next, we
decided to construct the oxetane ring via iodocyclization. The
corresponding products 32a and 33a were obtained, although in
low yields of 21-24% because the reaction was not selective.
a,b
deviations from literature
4a
(%)
entry
NMR yield
1
2
3
4
5
6
7
8
9
tBuOMe/H2O as a solvent
Et2O as a solvent
CH2Cl2 as a solvent
CHCl3 as a solvent
dioxane as a solvent
THF as a solvent
CH3CN as a solvent
DMF as a solvent
DMSO as a solvent
71
67
65
69
49
55
96 (91)c
41
34
10
11
12
13
14
15
Na2CO3 as a base
KHCO3 as a base
NEt3 as a base
Py as a base
NIS instead of I2
NBS instead of I2
83
91
57
42
85
83 (Br)
a 2 mmol. b Yield determined by 1H NMR with CH2Br2 as an internal standard.
cIsolated yield. NIS = N-iodosuccinimide, NIS = N-bromosuccinimide.
Table 1. Optimization of the synthesis of compound 4a.
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F
F
F
· >40 examples
(i) NaN3
F
F
F
DMSO, 85 o
C
· FGs compatibility
· available SMs
· 3-8-memb. cycles
· gram-scale
I2
(ii) Pd/H2
MeOH, rt
CH3CN, rt
[oxa-spiro]
4a 48a
-
NH2
CH2I
O
O
OH
4b 44b
( - )
(
)
· metal-free
4b
4
4a
F
OMe
[tetrahydrofuranes]
5-membered
Boc
MeO
N
F
NH2
NH2
NH2
NH2
NH2
NH2
O
O
O
O
O
O
9a
9b
(93%)
(87%)
5a
5b
6a
6b
4a
4b
7a
7b
8a
8b
(82%)
(56%)
(92%)
(90%)
(91%)
(77%)
(75%)
(89%)
(83%)
(95%)
b
F
Boc
O
F
N
BocN
NH2
NH2
NH2
NH2
NH2
NH2
O
O
O
O
O
O
(91%)
(88%)
10a
10b
11a
11b
12a
12b
13a
13b
14a
14b
15a
15b
(82%, d.r.=5:1)
(81%, d.r.=5:2)
(95%)
(80%)
(93%)
(95%)
(87%)
(78%)
(59%)
(90%)
NBoc
NBoc
NH2
NH2
NH2
BocN
O
NH2
NH2
O
O
NH2
O
O
O
O
OtBu
O
16a
16b
17a
17b
18a
19a
19b
20a
20b
21a
21b
(63%)
(79%)
(71%)
(75%)
(87%)
(90%)
(69%, d.r.=5:1)
(76%, d.r.=5:1)
(45%)
(90%)
(74%)
(79%)
18b
NH2
(d.r.=1:1)
NH2
NH2
NH2
NH2
Me
Me
F
O
O
O
O
O
O
F
25a
22a
22b
23a
23b
24a
24b
25b
26a
26b
(92%),
(95%)
NH2
(81%),
(74%)
(90%),
(87%)
(85%),
(72%)
NH2
(88%),
(69%)
NH2
NH2
NH2
7
8
O
O
O
O
O
O
BocN
O
27a
27b
28a
28b
29a
29b
30a
30b
31a
31b
(81%)
(88%)
(79%, d.r.=1:1)
(73%, d.r.=1:1)
(94%)
(91%)
(95%)
(78%)
(96%)
(90%)
4-, 6-membered
[oxetanes]
[tetrahydropyranes]
Boc
N
Boc
NH2
NH2
O
N
O
BocN
NH2
O
O
NH2
O
NH2
NH2
O
O
(60%)
(86%)
O
(63%)
(79%)
a
a
a
a
32a
32b
33a
33b
34a
34b
35a
35b
36a
36b
37a
37b
(24%)
(45%)
(21%)
(32%)
(48%)
(89%)
(61%)
(84%)
b
b
NH2
O
NH2
NH2
NH2
NH2
O
O
O
O
O
N
Boc
N
O
Boc
OtBu
a
a
a
a
a
38a
38b
39a
39b
40a
40b
41a
41b
42a
42b
(47%)
(94%)
(45%, d.r.=5:1)
(51%)
(87%)
(56%, d.r.=1:1)
(92%, d.r.=1:1)
(64%)
(84%)
(93%, d.r.=5:1)
[dioxanes]
[morpholines]
O
O
Bn
N
Bn
N
Bn
N
Bn
N
Me
I
O
O
N
Boc
O
NH2
O
O
N
O
NH2
a
N
Boc
I
Boc
O
I
a
I
43a
43b
44a
44b
(58%)
(72%)
(63%)
(78%)
a
a
a
a
45a
46a
47a
48a
(72%)
(53%)
(58%)
(67%)
Scheme 2. Scope of iodocyclization step into oxa-spirocycles. Iodocyclization conditions: alkene (1 equiv), NaHCO3 (3 equiv), I2 (3 equiv),
CH3CN, rt, 1h. aalkene (1 equiv), K2CO3 (4 equiv), I2 (4 equiv), CH3CN, rt, 48h. Synthesis of amines, conditions: (i) iodide (1 equiv), NaN3
(1.5 equiv), DMSO, 85 °C. (ii) H2/Pd, MeOH, rt. b(ii) PPh3 (1.5 equiv), H2O/THF, 50 °C.
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We also tried iodocyclization to construct the six-membered
tetrahydropyrane ring. Under the standard conditions, however,
incomplete conversions were observed. The reaction was slow,
and some starting material remained. After optimization, we
found that an excess of molecular iodine and a prolonged reaction
time was needed. As a result, products 34a-42a were obtained in
45-64% yield (Scheme 2). Furthermore, the developed conditions
were also used to synthesize dioxanes 43a, 44a in 58-63% yield
and morpholines 45a-48a in 53-72% yield (Scheme 2).
Limitations. The developed protocol was not without
limitations, however. While alcohols 32 and 33 provided the
needed oxetanes 32a and 33a in low yields (Scheme 2, Scheme 3),
the corresponding azetidine-containing alcohol 49 unexpectedly
afforded pyrrolidine 50 as a single stereoisomer in 92% yield
(Scheme 3).24 Structure of the product was confirmed by X-Ray
analysis.25 Presumably, close proximity of a nitrogen atom and an
iodonium moiety in the initially formed intermediate 51 led to an
intramolecular nucleophilic attack providing another strained
intermediate 52. Ring-opening of the azetidine ring in 52 with
iodide anion gave the observed pyrrolidine 50.
(Scheme 4). Using that simple three-step strategy, seventeen
other acids were synthesized. Especially worth noting unusual
amino acids from Scheme 4 – that type of structures play an
important role in drug discovery programs.26
a) KOAc, DMSO, t
b) EtONa, EtOH, rt
X
X
c
]
[via alcohol
c) TEMPO, PhI(OAc)2
18 examples
[carboxylic acids]
CH2I
CO2H
CO2H
O
O
O
F
F
CO2H
CO2H
O
O
5d
6d
4d
(40%)
(53%)
(47%)
F
F
CO2H
(51%)
CO2H
(41%)
O
O
CO2H
(50%)
O
12d
9d
11d
O
CO2H
(52%)
CO2H
O
O
I
I
O
I2
CO2H
(46%)
BocN
O
13d
BocN
23d
(d.r. = 1:1)
NaHCO3
CH3CN
O
18d
(43%)
O
OH
33
33a
(21%)
27d 34d 36d
additional examples:
,
,
(please, see SI)
I+
[amino acids]
CO2H
CO2H
CO2H
CO2H
BocN
O
O
OH
O
O
via
I
N
N
Boc
21d
N
N
I2
Boc
40d
(42%)
Boc
35d
Boc
OH
BocN
NaHCO3
CH3CN
N
8d
(54%)
(46%)
(44%)
Boc
I
OH
O
X-Ray
49
50
(92%)
I+
O
CO2H
(58%)
I+
I+
O
CO2H
I
BocN
BocN
I-
BocN
51
42d
44d
(47%)
N
Boc
52
Boc N
OH
OH
OH
I-
Scheme 4. Synthesis of oxa-spirocyclic carboxylic acids and amino
acids 4d-6d, 8d, 9d, 11d-13d, 18d, 21d, 23d, 27d, 34d-36d, 40d,
42d and 44d.
Scheme 3. Unexpected synthesis of pyrrolidine 50.
Modifications. Several representative modifications of iodides
4a-48a were undertaken using standard chemical transformations
to provide numerous oxa-spirocyclic derivatives. First, a simple
reaction of iodides 4a-44a with sodium azide followed by
reduction with either H2/Pd or PPh3 gave amines 4b-44b in 32-
95% yield. Among them were not only monofunctional
compounds, but also linkers with two functional groups: amino
acids 19b, 39b and valuable diamines for medicinal chemistry 8b,
10b, 14b, 16b, 17b, 21b, 29b, 33b, 35b, 37b, 40b, 42b, 44b
(Scheme 2).
Next, synthesis of some aliphatic sulfonyl chlorides, - popular
reagents for making bioactive sulfonamides27 - was undertaken.
Reaction of iodide 16a with potassium thioacetate in
dimethylsulfoxide at room temperature, followed by a direct
oxidation of the formed intermediate with N-chlorosuccinimide in
methanol gave aminosulfonyl chloride 16e (Scheme 5). Using this
two-step strategy, sixteen other sulfonyl chlorides and
aminosulfonyl chlorides - linkers - were easily obtained (Scheme
5).
Reaction of iodide 5a with potassium acetate in
dimethylsulfoxide under heating, followed by hydrolysis of the
ester group with sodium ethoxide, and the subsequent oxidation
of the formed alcohol with PhI(OAc)2/TEMPO gave acid 5d
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View Article Online
DOI: 10.1039/D1SC03615G
X
X
X
a) KCN, DMSO, t
b) KOH, EtOH, t
a) KSAc, DMSO, rt
b) NCS, MeOH, rt
X
SO2Cl
14 examples
CO2H
O
17 examples
[sulfonyl chlorides]
CH2I
[
acids]
homo-
CH2I
O
O
O
F
F
CO2H
CO2H
SO2Cl
CO2H
O
9f
(68%)
SO2Cl
O
SO2Cl
(88%)
O
O
O
O
5f
6f
(73%)
(70%)
O
5e
6e
4e
(78%)
(77%)
O
O
CO2H
CO2H
(72%)
CO2H
SO2Cl
SO2Cl
(92%)
SO2Cl
SO2Cl
(83%)
SO2Cl
O
O
13f
O
O
11e
O
18f
34f
(75%)
(80%)
9e
13e
(80%)
SO2Cl
O
CO2H
O
O
O
O
CO2H
O
O
36f
38f
(84%)
18e
22e
23e
(82%)
(69%)
(85%)
(72%, d.r.=1:1)
(please, see SI)
24e 27e 30e 36e 38e
additional examples:
,
,
,
,
[amino acids]
CO2H
CO2H
CO2H
O
[amino-SO2Cl]
SO2Cl
SO2Cl
O
O
O
O
O
SO2Cl
8f
(66%)
21f
(56%)
40f
(70%)
N
Boc
N
Boc
N
Boc
8e
(84%)
16e
(86%)
21e
(77%)
N
Boc
N
Boc
N
Boc
CO2H
CO2H
CO2H
O
CO2H
O
O
O
O
Scheme 5. Synthesis of oxa-spirocyclic sulfonyl chlorides 4e-6e,
8e, 9e, 11e, 13e, 16e, 18e, 21e-24e, 27e, 30e, 36e, 38e.
35f
(67%)
14f
(48%)
29f
Boc
(62%)
44f
N
N
N
Boc
N
Boc
Boc
(69%)
Synthesis of several substituted acetic acids, homologues of
carboxylic acids, was also performed. For example, reaction of
iodide 40a with potassium cyanide, followed by alkali hydrolysis of
the intermediate nitrile gave amino acid 40f (Scheme 6). Likewise,
thirteen other mono- and bifunctional derivatives were obtained
(Scheme 6).
Recently, methylation was shown to have a profound impact
onto activity of bioactive compounds – a “magic methyl” effect.28
On the other hand, in recent years substituted azetidines gained a
lot of popularity in medicinal chemistry.29 In this context, we
reduced C-I bond in compounds 8a, 35a with hydrogen using
palladium on charcoal and after acidic N-Boc cleavage obtained
interesting methyl azetidines 8g and 35g in 85-88% yield (Scheme
7). Morpholine, in turn, is one of the most popular rings in
drugs.1,30 Reduction of the C-I bond in iodides 45a-48a,31 followed
by a Pd-catalyzed hydrogenative cleavage of N-benzyl group
afforded methyl-substituted morpholine-containing diamines 45g-
48g in 68-85% yield (Scheme 7).
Scheme 6. Synthesis of oxa-spirocyclic homoacids 5f, 6f, 8f, 9f,
13f, 18f, 21f, 29f, 34f-36f, 40f, 44f.
Me
Me
I
O
O
O
a) H2/Pd
MeOH, rt
and
b) 5N HCl
dioxane
N
N
Boc
8a 35a
N
H
[magic methyls]
H
35g
8g
,
(88%)
(85%)
Boc
N
O
Me
O
Me
I
a) H2/Pd
MeOH, rt
b) AgNO3
X
O
N
H
N
H
45g
46g
48g
(85%)
(68%)
c) H2/Pd
MeOH
N
Bn
60 o
Boc
C
O
N
Me
Me
45a-48a
O
Me
O
[magic methyls]
N
H
N
H
47g
(73%)
(81%)
Scheme 7. Synthesis of methyl-azetidines 8g, 35g and methyl-
morpholines 45g-48g.
Reaction of iodide 6a with potassium cyanide in
dimethylsulfoxide under heating, followed by reduction of the
nitrile group with Raney nickel alloy gave amine 6h in 78% yield
(Scheme 8) – a homologue of amine 6b (Scheme 2). Using the
6 | Chem.Sci., 2021, 00, 1-3
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View Article Online
DOI: 10.1039/D1SC03615G
O
same tactic, amines 18h and 36h were also obtained. In addition,
reduction of C-I bond in compound 7a followed by acidic cleavage
of the ketal moiety gave methyl ketone 7i in 63% yield (Scheme 8).
a) DIC
HO
N
Me
Me
CH2Cl2
O
Me
Me
O
B
18f
(via
-NHPI, 89%)
CO2H
O
H2N
H2N
b)
B2Pin2 (3 equiv.)
Cu(acac)2 (30 mol%)
LiOH (15 equiv.)
MgBr2*Et2O (1.5 equiv.)
dioxane/DMF (4/1); 0.14M
O
O
18f
18j
(58%)
[decarboxylative
borylation]
O
X
O
a) KCN
DMSO, t
6h
18h
(78%)
(80%)
NH2
I
b) MeOH-NH3
Ra-Ni, 50 atm
Boc
O
O
O
N
[
-amines]
homo
6a 18a 36a
,
,
BPin
BPin
-NHPI (79%)
BPin
O
O
O
O
36h
(72%)
14f
34f
36f
-NHPI (88%)
-NHPI (81%)
14j
34j
36j
(22%)
(24%)
(39%)
O
OMe
a) H2/Pd
MeOH, rt
MeO
O
a) DIC
HO
CH2Cl2
b) aq. HCl
[ketones]
N
I
Me
O
O
O
7a
21f
(via
-NHPI, 71%)
7i
H
(63%)
CO2H
N
b)
B2Pin2 (3 equiv.)
O
N
Boc
O
Boc
Scheme 8. Synthesis of oxa-spirocyclic homoamines 6h, 18h, 36h
and ketone 7i.
Cu(acac)2 (30 mol%)
LiOH (15 equiv.)
MgBr2*Et2O (1.5 equiv.)
21f
21j
(31%)
[sterically bulky]
dioxane/DMF (4/1); 0.14M
All modifications of oxa-spirocyclic iodides depicted on Schemes
4-8 represent (2e)-reactions. In this work, we also wanted to show
that oxa-spirocyclic molecules are also compatible with radical
(1e) modifications. Recently, Blackmond and Baran developed a
practical [Cu]-catalyzed decarboxylative borylation of carboxylic
acid derivatives.32 We used that radical transformation to convert
oxa-spirocyclic acetic acids 14f, 18f, 21f, 34f, 36f into the
corresponding BPin-products (Scheme 9).33 In fact, three mono-
(18j, 34j, 36j), and one bifunctional 14j organoboron compounds
were obtained via the N-hydroxyphtalimide (NHPI) esters. Acid
21f, however, under identical conditions, gave reduced product
21j, presumably due to a steric hindrance around the reaction
center.
Scheme 9. Decarboxylative borylation of oxa-spirocyclic acids.
In short summary, straightforward two to three step
modifications of iodides 4a-48a using common (2e) and radical
(1e) reactions allowed rapid synthesis of >150 novel or previously
hardly accessible oxa-spirocyclic molecules. All products contained
one or two appropriately protected functional groups – amino
acids, diamines, aminosulfonyl chlorides, amino boronates –
suitable for the direct use in medicinal chemistry programs. In
terms of diversity and efficiency, this is the most useful method to
access oxa-spirocyclic cores so far.
5b
.
a) Synthesis of oxa-spiroamine
[Rh]/[Cu]
H2, Pd
[Previous]
no product
NHTs
[H+]
BuLi
MeO2C
O
O NHTs
55
LiAlH4
"traces"
tBuOH
56
Cl
LDA
OH
I2
O
Pd/H2
[Current]
NH2 3 steps (46%)
[20 g scale]
I
(alkylation)
53
54
-
[N3
]
O
5b
29f
b) Synthesis of oxa-spiropiperidine
H2, Pd
.
[Previous]
6 steps (34%)
CO2H
[OH-]
DIBAL
[H+]
O
O
P
CF3
BuLi
MeO2C
N
MeO
MeO
CO2Me
NaH
O
N
3 steps
N
H
O
N
Ref. 34
N
CO2H
N
Boc
Boc
[OH-]
I2
29f
58
57
[CN-]
DGAT1 inhibitor (Merck)
MgBr
[Current]
IC50 = 18nM
4 steps (62%)
Scheme 10. Synthesis of oxa-spiroamine 5b and oxa-spiropiperidine 29f: literature approaches vs this work.
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Application in organic synthesis. The synthetic approach to oxa-
spirocycles described here not only provides entry into novel
chemical space, but also significantly simplifies preparation of
known molecules. For example, in 2018, [Rh]-catalyzed cyclization
of unsaturated alkoxyamines was developed (Scheme 1).19 In this
project, the authors attempted [Rh]-catalyzed cyclization of
substrate 55, but observed only “traces” of the needed N-tosyl
intermediate 56. (Scheme 10). Alternatively, our approach allowed
rapid preparation of the N-deprotected oxa-spiroamine 5b from the
same starting alkene 54 in only three steps. Moreover, the
synthesis was easily scaled up to 20 g amount.
Compound 58 was recently discovered as a potent DGAT1
inhibitor (Scheme 10).34 Synthesis of its key intermediate 29f was
undertaken in six steps from the commercially available N-Boc
piperidone 55 in 34% yield.14,35 On the contrary, our approach
allowed the preparation of oxa-spiropiperidine 29f in four steps
from N-Boc piperidone in 62% yield.
pK :
[spirocycles]
[oxa-spirocycles]
DOI: 10.1039/D1SC03615G
a
View Article Online
CO2H
4.6
CO2H
O
3.5
59
60
5d
CO2H
CO2H
4.6
Acidity
Acidity
O
6d
3.7
pKa = -1
F
F
F
F
CO2H
4.3
CO2H
O
3.4
61
4d
*HCl
*HCl
NH2
NH2
10.1
8.9
O
5b
62
Characterization. Acidity/basicity of functional groups.
Incorporation of oxygen atom into organic molecules changes
significantly acidity/basicity of the neighboring functional groups.36
For this reason, we experimentally measured pKa values of
spirocyclic (59-61) and oxa-spirocyclic (4d-6d) carboxylic acids;
spirocyclic (62-64) and oxa-spirocyclic (4b-6b) amine hydrochlorides
(Figure 3). Incorporation of oxygen atom into acids 59-62 increased
their acidity by ca. one order of a magnitude: pKa (59-62) = 4.3-4.6
vs pKa (4d-6d) = 3.4-3.7. Incorporation of oxygen atom into amines
62-64 reduced their basicity also by ca. one order of a magnitude:
pKa (62*HCl-64*HCl) = 10.1-10.3 vs pKa (4b*HCl-6b*HCl) = 8.9-9.5.
Similar ΔpKa effect on acidity/basicity can be explained in terms of
-(I)-inductive effect of the oxygen atom. In carboxylic acids 4d-6d,
the ether oxygen atom and the carboxylic oxygen atom are
separated by three single bonds. Similarly, in amines 4b-6b, the
ether oxygen atom and the basic nitrogen atom are also separated
by three single bonds. Hence an effect of incorporation of the
oxygen atom on acidity and basicity is similar.
*HCl
*HCl
NH2
NH2
Basicity
10.6
9.5
O
pKa = 1
63
6b
F
*HCl NH2
*HCl
F
F
NH2
10.3
9.2
O
F
64
4b
Figure 3. Experimental pKa values of acids 59-61, 4d-6d; and
conjugated amines 62·HCl-64·HCl, 4b·HCl-6b·HCl.
To study an effect of incorporation of oxygen atom on water
solubility and lipophilicity of spirocyclic structures, we first
synthesized model compounds 65-73 by standard amide coupling
(Table 2).
Water solubility (Sol.). Replacement of the cycloalkane ring in
compounds 65, 68, 71 with the spirocyclic bioisosteres 66, 69, 72
only slightly increased water solubility (Table 2)5. However,
incorporation of oxygen atom into spirocyclic unit led to dramatic
improvement in water solubility (Table 2). For example, oxa-
spirocyclic compound 67 was ca. 40-times (!) more soluble than
spirocycle 66: 9 µM (66) vs 360 µM (67) (Table 2). Similar, but less
profound, effect was observed in pairs 69/70 and 72/73: 7 µM (69)
vs 118 µM (70); <5 µM (72) vs 34 µM (73).
Lipophilicity (logD7.4). Incorporation of oxygen atom into the
spirocyclic unit also decreased lipophilicity. Lipophilicity index (logD)
of oxa-spirocyclic models 67, 70, 73 was ca. one order of a
magnitude lower than that of spirocyclic models 66, 69, 72: 4.5 (66)
vs 3.6 (67); 4.9 (69) vs 4.0 (70); 4.4 (72) vs 3.6 (73).
In brief summary, oxa-spirocylic compounds have (a) dramatically
higher solubility (up to 40-times), and (b) lower lipophilicity (ΔlogD
= ca. 1) than common spirocycles.
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Table 2. Experimental lipophilicity (logD) and water solubility of library was also analyzed, as it was previously showVnietwoArctioclrerOelnalitnee
with success in drug discovery projects.2 The average F(sp3) index
DOI: 10.1039/D1SC03615G
model compounds 65-73.
was 0.79 which is significantly higher than that of a random
Model compound
LogD(7.4)a Sol(7.4)b
molecule from the ZINC database (0.33).38
O
65
66
67
3.6
4.5
<5
9
N
H
O
N
H
O
3.6
360
O
N
H
O
68
4.4
4.9
<5
7
N
H
O
69
70
N
H
O
Figure 4. Distribution of virtual molecules, logP(y)-MW(x), obtained by
decoration of amines 4b, 32b, 43b, 8g, 45g in LLAMA software.
Chemical structure of a representative derivative of 4b is shown.
4.0
118
O
N
H
O
F
F
71
72
4.0
4.4
<5
<5
N
H
F
F
O
N
H
F
F
O
73
3.6
34
O
N
H
aExperimental n-octanol/water distribution coefficient (log) at pH
7.4; bKinetic aqueous solubility (uM) in 50 mM phosphate buffer
(pH 7.4).
Lead-likeness and molecular shape. To analyze lead-likeness and
molecular shape of virtual compound libraries that could be
synthesized from oxa-spirocyclic molecules described here, we used
a free online software LLAMA.37 We selected five representative
amines with different structural motifs to achieve maximal
diversity: primary - tetrahydrofurane 4b, oxetane 32b, dioxane 43b
(Scheme 1); and secondary - azetidine 8g, morpholine 45g (Scheme
8). Next, we decorated them with a default set of capping reagents
using five standard transformations: (a) amide synthesis; (b)
sulfonylation; (c) urea synthesis; (d) reductive amination and (e)
Buchwald-Hartwig amination. As a result, a virtual library of 130
molecules was generated. Important to mention that 126 molecules
(>96%) lied in the lead-like space: MW< 350; clogP < 3 (Figure 4). The
mean lead-likeness index of all 130 compounds was 0.68. To assess the
three-dimensionality of the library, the principal moments of inertia
(PMI) plot was generated (Figure 5). This plot confirmed that many
of these lead-like compounds also showed significant shape
diversity. The fraction of sp3-hybridised carbons, F(sp3), in the
Figure 5. Principal moments of inertia (PMI) plot of virtual molecules,
obtained by decoration of amines 4b, 32b, 43b, 8g, 45g in LLAMA
software. Chemical structure of a representative derivative of 45g is
shown.
Incorporation into bioactive compound. After elaboration of a
general method to oxa-spirocycles and their physico-chemical
characterization, we wanted to experimentally show that these
compounds indeed can be used in medicinal chemistry projects. We
chose Terazosin (74) for modifications, because it is a popular
antihypertensive drug (Figure 6). In 2018, it was the 198th most
commonly prescribed medication in the US, with almost three
million prescriptions.39,40 We synthesized its analogues 75-79 where
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Chemical Science
the tetrahydrofuran ring was replaced with oxa-spirocyclic cores
(Figure 6). The synthesis was realized via standard amide coupling
of carboxylic acids 5d, 6d, 13d, 18d, 27d with the corresponding N-
substituted piperazine.
View Article Online
Systolic Blood Pressure lowering
DOI: 10.1039/D1SC03615G
time (min)
15
60
120
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
NH2
*HCl
Terazosin 74
( )
Antihypertensive drug
MeO
MeO
N
N
N
N
O
O
this work
NH2
N
*HCl
O
MeO
MeO
Saline
Captisol
74 (Terazosin)
75
76
77
78
79
N
N
N
Figure 7. The dynamics of systolic blood pressure in SHR rats at
different time-points after single PO administration of Vehicle
(saline or 20% captisol) or test substances at dose 3 mg/kg.
Compounds were dissolved in saline (74, 76-79) or 20% captisol in
water (75). Data are expressed as means ± SEM.
O
O
O
75
O
O
O
76
77
NH2
N
*HCl
MeO
MeO
N
N
Diastolic Blood Pressure lowering
O
N
O
time (min)
120
15
60
O
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
O
78
79
O
Figure 6. Antihypertensive drug Terazosin (74) and oxa-spiro-
substituted analogues 75, 76, 77, 78, 79.
Finally, we measured and compared biological activity of
Terazosin (74) and all its analogues 75-79. Studies were conducted
using 7.5-month-old spontaneously hypertensive (SHR) male rats
with the average body weight of 329±30 g and basal systolic blood
pressure not less than 185 mmHg.41 The compounds were dissolved
in Saline (74, 76-79), or water containing 20% captisol (75). Animals
received 3 mg/kg compound in 5 ml/kg vehicle per os once. Five
animals per group were assigned. Systolic and diastolic blood
pressure (BP)42 were measured in 15, 60, 120, 180 and 240 min
after the dosing (Figures 7, 8).
Saline
Captisol
74 (Terazosin)
75
76
77
78
79
Terazosin (74) and its oxa-spirocyclic analogues 76, 77, 78 had
similar biological profile in vivo - all compounds caused significant
systolic and diastolic BP lowering compared with Saline treated
groups after 15 min and 60 min, and with no statistical difference
between them (Figures 7, 8). At the same time, after 120 min
treatment, the BP lowering effect of most tested analogues was still
statistically significant, in contrast to the original Terazosin (74). This
effect may suggest that the used modification may contribute to
the prolongation of the drug action.
It is important also to mention that cyclopropane-containing
analogue 75 after 15 min of treatment behaved much better in
both systolic and diastolic BP lowering (Figures 7, 8) than all other
analogues including the original drug Terazosin (74).
Figure 8. The dynamics of diastolic blood pressure in SHR rats at
different time-points after single PO administration of Vehicle (20%
captisol) or test substances at dose 3 mg/kg. Compounds were
dissolved in saline (74, 76-79) or 20% captisol in water (75). Data
are expressed as means ± SEM.
Conclusions
During recent decade, oxa-spirocycles undeservedly remained in
the shadow compared to the more popular spirocyclic analogues
(Figure 2). The key reason was an absence of a general practical
approach to them. In this work, we developed such an approach.
Oxa-spirocycles were easily synthesized through the iodocyclization
reaction. Using common (2e) and radical (1e) modifications, the
obtained iodides 4a-48a were easily converted into >150 oxa-
spirocyclic derivatives with appropriately protected functional
groups, that could be directly used in medicinal chemistry projects.
Incorporation of oxygen atom into spirocyclic unit was shown to
dramatically increase its solubility (up to 40 times: 66 vs 67, Table 1)
10 | Chem. Sci., 2021, 00, 1-3
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Gianatassio, J. M. Lopchuk, J. Wang, C.-M. Pan, L. R. Malins, L.
and lower lipophilicity. The developed protocol not only gave access
to novel molecules, but also significantly simplified the synthesis of
the known ones (Scheme 10). In addition, five oxa-spirocyclic
analogues 75-79 of the antihypertensive drug Terazosin (74) were
prepared. Analogue 75 showed significantly higher potency in vivo
than the original drug (Figures 7,8).
We believe that with this general simple approach to oxa-
spirocyclic iodides and procedures for their modifications (Schemes
4-9), oxa-spirocycles will soon become very popular in chemistry.
Prieto, T. A. Brandt, M. R. Collins, G. M. GallegVoie,wNA.rtWicle. OSanlcinhe,
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Data availability
Supporting data for this article have been uploaded as part of
the ESI material.
Author contributions
Conceptualization – PKM; investigation and methodology – KF, TD,
DG, TS, VV, OS, VM, IK, EL, VVL, VRB, RIV, AIV, AVB, VVS, RI, KS, ASK,
YVD, DV, VR, OP, HK; supervision – IP, PB, AAT, PKM; writing,
original draft – PKM; writing, reviewing & editing – ASK, AAT, OP,
HK, IP, PB, PKM.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Authors are grateful to Enamine Ltd for financial support. AK
acknowledges financial support by Tomsk polytechnic university
competitiveness enhancement program (project CEP-SAMT-
208/2020). Authors are also grateful to Dr. A. Zhemera and Dr. D.
Panov for the synthesis of model compounds 65-73. PM is grateful
to Mrs. I. Sadkova for the help with the preparation of the
manuscript, and to Dr. E. Rusanov (IOC) for X-ray analysis of
compound 50.
Notes and references
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39. https://clincalc.com/DrugStats/Top300Drugs.aspx
40. https://clincalc.com/DrugStats/Drugs/Terazosin
41. Study design, animal selection, handling and treatment were in
accordance with Bienta Animal Care and Use Guidelines, and
European Union directive 2010/63/EU.
42. Blood pressure (BP) was measured by Tail-Cuff MeVtiehwodA.rtiWcleeOunsliende
Coda Non-invasive Blood-Pressure SDyOstIe:m10.1(0K3e9n/Dt 1SSCc0ie3n6t1i5fiGc
Corporation, CT, USA).
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