The cyclic nitronate route to pharmaceutical molecules: Synthesis of GSK's potent PDE4 inhibitor as a case study

Article abstract of DOI:10.3390/molecules25163613

An efficient asymmetric synthesis of GlaxoSmithKline's potent PDE4 inhibitor was accomplished in eight steps from a catechol-derived nitroalkene. The key intermediate (3-acyloxymethyl-substituted 1,2-oxazine) was prepared in a straightforward manner by tandem acylation/(3,3)-sigmatropic rearrangement of the corresponding 1,2-oxazine-N-oxide. The latter was assembled by a (4 + 2)-cycloaddition between the suitably substituted nitroalkene and vinyl ether. Facile acetal epimerization at the C-6 position in 1,2-oxazine ring was observed in the course of reduction with NaBH3CN in AcOH. Density functional theory (DFT) calculations suggest that the epimerization may proceed through an unusual tricyclic oxazolo(1,2)oxazinium cation formed via double anchimeric assistance from a distant acyloxy group and the nitrogen atom of the 1,2-oxazine ring.

Full text of DOI:10.3390/molecules25163613

molecules
Article
The Cyclic Nitronate Route to Pharmaceutical
Molecules: Synthesis of GSK’s Potent PDE4 Inhibitor
as a Case Study
Evgeny V. Pospelov 1,2, Ivan S. Golovanov 1 , Sema L. Ioffe 1 and Alexey Yu. Sukhorukov 1,3,
*
1
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia;
evpos00@mail.ru (E.V.P.); cell-25@yandex.ru (I.S.G.); iof@ioc.ac.ru (S.L.I.)
Department of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia
Department of Innovational Materials and Technologies Chemistry,
2
3
Plekhanov Russian University of Economics, 117997 Moscow, Russia
*
Correspondence: sukhorukov@ioc.ac.ru; Tel.: +7-499-135-53-29
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Nagatoshi Nishiwaki
Received: 3 July 2020; Accepted: 4 August 2020; Published: 8 August 2020
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: An efficient asymmetric synthesis of GlaxoSmithKline’s potent PDE4 inhibitor was
accomplished in eight steps from a catechol-derived nitroalkene. The key intermediate
3-acyloxymethyl-substituted 1,2-oxazine) was prepared in a straightforward manner by tandem
(
acylation/(3,3)-sigmatropic rearrangement of the corresponding 1,2-oxazine-N-oxide. The latter
was assembled by a (4 + 2)-cycloaddition between the suitably substituted nitroalkene and vinyl
ether. Facile acetal epimerization at the C-6 position in 1,2-oxazine ring was observed in the
course of reduction with NaBH CN in AcOH. Density functional theory (DFT) calculations suggest
3
that the epimerization may proceed through an unusual tricyclic oxazolo(1,2)oxazinium cation
formed via double anchimeric assistance from a distant acyloxy group and the nitrogen atom of the
1
,2-oxazine ring.
Keywords: C–H functionalization; total synthesis; pyrrolidines; anchimeric assistance; epimerization;
PDE4 inhibitors
1
. Introduction
Cyclic nitronates (1,2-oxazine-N-oxides
the synthesis of complex nitrogen containing scaffolds due to their versatile reactivity as 1,3-dipoles
and accessibility from nitroalkenes (Scheme 1a) [ 10]. Denmark’s group extensively exploited the
inter- and intramolecular (3 + 2)-cycloaddition reactions with six-membered cyclic nitronates to
construct various bi- and polycyclic nitroso acetal frameworks , which were then converted into
fused pyrrolidine derivatives by an intramolecular reductive amination (Scheme 1b) [ 11]. Using
this strategy, total syntheses of numerous pyrrolizidine and indolizidine alkaloids [12 14], as well as
5.5.5.5)- and (5.5.5.4)-azafenestanes [15,16], were accomplished.
Our group has a long-term interest in developing another approach towards the modification
of cyclic nitronates, which utilizes C–H functionalization of the position next to the nitronate group
-C-atom, Scheme 1c) [17]. Some time ago, we demonstrated that upon silylation, cyclic nitronates
and are transformed into N-siloxyenamines , in which the double bond is shifted to the exocyclic
-position [18]. Enamines exhibit umpolung reactivity and react with nucleophiles in the presence
of Lewis acids (LA) to give -substituted cyclic oxime ethers (1,2-oxazines or isoxazolines) via
SN’ substitution of TMSO-group (Scheme 1c). Using this approach, nucleophilic halogenation [19],
oxygenation [20 22], azidination [23] of cyclic nitronates were performed (route 1). Although we
succeeded in using this methodology in the total synthesis of some pharmaceutical molecules, in
1 and isoxazoline-N-oxides 2) are useful intermediates in
1–
1
3
1,
–
(
(α
1
2
4
α
4
α
5
–
Molecules 2020, 25, 3613; doi:10.3390/molecules25163613
www.mdpi.com/journal/molecules

Molecules 2020, 25, 3613
2 of 13
the case of nitronates having acid-sensitive groups (e.g., acetals), it proved to be not very efficient
(vide infra) [20,24,25].
Scheme 1. Approaches towards modification of cyclic nitronates. (a) Synthesis of cyclic nitronates
from nitroalkenes; (
) C-H functionalization of cyclic nitronates via N-siloxyenamines (route 1); (
of cyclic nitronates via [3,3]-rearrangement of N-acyloxyenamines (route 2).
b
) 1,3-Dipolar addition with cyclic nitronates and its application in total synthesis;
(
c
d) C-H functionalization
Recently, we designed another strategy for the site-selective functionalization of cyclic nitronates
and via acylation with acyl halides/Et N (Scheme 1d) [26]. The initially formed N-acyloxyenamines
undergo a spontaneous (3,3)-rearrangement to give -acyloxy-substituted cyclic oxime ethers 7
1
6
2
3
α
(route 2). This tandem C–H oxygenation process could be performed under very mild conditions.
At present, we are testing the scope and limitation of this method in the total synthesis of some model
target molecules to compare its efficacy with our previous C–H functionalization methods. In this
study, a potent GlaxoSmithKline’s phosphodiesterase 4 (PDE4) inhibitor CMPO [27–29], which was
previously synthesized using route 1 [24,30], was chosen as a target molecule.
Scheme 2 depicts our previous synthetic route to CMPO. The fused pyrrolidine core was prepared
by carbamylation of a trans-3-aryl-substituted prolinol 15. The latter was accessed in our strategy by
the reductive contraction of the 1,2-oxazine ring in the intermediate 14, which was prepared by the
stereoselective hydride reduction of the 5,6-dihydro-4H-1,2-oxazine 13
[24]. This intermediate was
synthesized by the reduction of the ONO -group in the corresponding nitroxy-substituted 1,2-oxazine
2
1
2
. Introduction of the nitroxy-group was accomplished by the LA-assisted functionalization of the
methyl group in the N-oxide 10 using route 1 described above (see Scheme 1c). The required N-oxide

Molecules 2020, 25, 3613
3 of 13
1
0
was assembled in a stereoselective manner by the (4 + 2)-cycloaddition of nitroalkene
8
with the
vinyl ether 9 bearing Whitesell’s chiral auxiliary group ((+)-trans-2-phenyl-1-cyclohexanol ether).
O
Ph
OMe
OMe
O
O
O
OMe
9
O
SnCl4
DCM
C-H
NaBH3CN
AcOH
H
functionalization
X
6
6
N
O
N
O
X = OH
O
separation from
C-6 epimer
o
O
-
94 C
8
2 %
Ph
Ph
NO2
d.r. 13 : 1
(
from 11)
7
5%
8
10
X = Br, 11
AgNO , acetone
3
X = ONO , 12
2
Zn, AcOH, 24 h
X = OH, 13
OMe
OMe
OMe
O
O
O
2
5 bar H2
Ra-Ni
OH
Im CO
2
H
MeOH, rt
NH
O
O
DCM
N
N
OH
O
H
Ph
7
7 % from 14
OH
O
1
5
Ph
(
-)-CMPO
1
4
Scheme 2. Previous asymmetric synthesis of (−)-CMPO.
Oxygenation of the methyl group in the N-oxide 10 proved to be challenging, and several methods
were tested (Scheme 3). N-Siloxy,N-oxyenamine 16 was generated from the N-oxide 10 under mild
conditions and then subjected to the LA-assisted nucleophilic addition of the bromide anion [24,25].
However, the desired 3-bromomethyl-1,2-oxazine 11, which served as a precursor to nitrate 12, was
formed in moderate yields (best results are shown in Scheme 3a). Another issue was the epimerization
0
of the sensitive C-6 acetal stereocenter leading to a mixture of 4,6-trans/4,6-cis-diastereomers 11 and 11
which had to be separated by column chromatography (Scheme 3a,b). Unfortunately, the epimer 11
,
0
could not be used in the synthesis of CMPO as it produced the undesired 3,4-cis-stereoisomer upon
the reduction of the C=N bond in 5,6-dihydro-4H-1,2-oxazine ring on the later stages of the synthesis
(
Scheme 3c) [25].
The reason for the epimerization may lie in the mechanism of the LA-promoted reaction of
N-oxyenamines with nucleophiles, which involves heterolytic cleavage of the N–O bond (Scheme 3b).
Experimental [20 22] and computational data [22] suggest that the S ’ substitution of the TMSO-group
may proceed through an epimerizable N-vinyl,N-oxynitrenium cation C1. In our later study, we were
able to optimize the epimerization ratio to 6: 1 by using Cr(NO ) as both a mild Lewis acid and the
,
N
3
3
source of the nitrate anion [20]. However, the yield of nitroxy-derivative 12 was still not very high
ca. 40% from nitronate 10, Scheme 3a). Thus, further optimization of the C–H functionalization stage
was reasonable.
(

Molecules 2020, 25, 3613
4 of 13
a. Functionalization of cyclic nitronate 10
OMe
OMe
OMe
O
O
O
O
TMSBr, Et N
conditions
3
4
4
X
6
6
N
O
o
N
O
DCM, -78 C
N
O
G*O
G*O
OTMS
G*O
8
8 %
X = Br (trans-11, cis-11')
X = ONO (trans-12, cis-12')
1
0
16
2
conditions
X
yield
4,6-trans/cis
ref.
o
G*O =
TMSBr, DCM, -50 C
CoBr , THF-DCM, rt
Br
Br
36 %
45 %
46 %
traces
3.4 : 1.0
1.0 : 1.9
6.1 : 1.0
-
[24, 25]
unpubl.
[20]
O
Ph
2
Cr(NO ) , THF-DCM, rt
ONO2
OAc
3
3
AcOH, DCM
unpubl.
b. Mechanism of epimerization at C-6
Ar
Ar
Ar
Ar
LA
4
4
4
6
6
N
O
6
N
N
N
G*O
G*O
O
OTMS
G*O
O
G*O
O
LAOTMS
C1
c. Hydride reduction of 4,6-cis-1,2-oxazines
Ar
Ar
Ar
NaBH3CN
AcOH
4
X
4
X
3
3
4
X
6
6
NH
NH
6
N
G*O
O
G*O
O
G*O
O
minor, desired
major, undesired
Scheme 3. Problems associated with C-6 epimerization in the LA-assisted functionalization of cyclic
nitronate 10. ( ) Functionalization of cyclic nitronate 10; ( ) Mechanism of epimerization at C-6;
c) Hydride reduction of 4,6-cis-1,2-oxazines.
a
b
(
2
. Results
We speculated that the pericyclic (3,3)-rearrangement of N-acyloxyenamine intermediate I1
generated by the acylation of nitronate 10 may proceed without any epimerization of the C-6 stereogenic
center. To test this idea, cyclic nitronate 10 was treated with pivaloyl chloride/Et N (1.5/2.0 equiv.)
3
◦
under conditions previously optimized for model 1,2-oxazine-N-oxides (MeCN,
−
30 C, 2 h) [26].
The desired pivalate 17 was formed in a 61% yield together with some amount of unreacted N-oxide
. After a short optimization of conditions, we found that the use of a bigger access of the PivCl/Et N
1
0
3
system (2.0/2.5 equiv.) and prolonged reaction time (18 h) at lower temperature resulted in an increase
in the yield up to 76% (Scheme 4). Gratifyingly, no noticeable epimerization at the C-6 position was
observed under these conditions.
We further investigated whether pivalate 17 could be used in the synthesis of CMPO
Hydrogenolysis of the pivalate group in 17 (to give alcohol 13) prior the reduction is challenging
since 5,6-dihydro-4H-1,2-oxazines are known to undergo fragmentation via a retro-[4+2]-cycloaddition
process under the action of bases [31]. Therefore, pivalate 17 was subjected to the hydride reduction
.
with NaBH CN in acetic acid (Scheme 5). Surprisingly, the reaction produced two separable isomeric
3
0
products 18 and 18 in 3: 1 ratio (62% combined yield, 91% based on converted 17). From the
coupling constants in H-NMR spectra, it was deduced that both isomers had trans-arrangement of the
1

Molecules 2020, 25, 3613
5 of 13
substituents at the C-3 and C-4 atoms, while the configuration of the C-6 stereocenter was different.
Thus, the C-6 acetal moiety underwent epimerization in the course of the reduction (see Discussion
0
section). The amount of 4,6-cis-isomer 18 increased with time, demonstrating that the isomerization
took place in the reduced product 18 and not in the starting compound 17. This is also confirmed by
0
the fact that stereisomers 18 and 18 had same configuration of the newly formed C-3 stereocenter.
0
If the epimerization preceded the reduction, the C-6 epimerized 5,6-dihydro-4H-1,2-oxazine 17 would
also give the reduced product with the 3,4-cis-disposition of substituents (see Scheme 3c).
Scheme 4. Tandem acylation/(3,3)-rearrangement of nitronate 10.
Scheme 5. Cyanoborohydride reduction of 3-hydroxymethyl 1,2-oxazine 13 and its pivalate 17.
0
Isomers 18 and 18 could be almost equally used in the reductive contraction of the 1,2-oxazine
ring [32], since both produced the same amino aldehyde intermediate I3 upon cleavage of the N–O
bond followed by fragmentation of the hemiacetal I2 (Scheme 6). Subsequent intramolecular reductive
amination in the intermediate I3 and protection with the Boc-group afforded the desired prolinol ester
0
1
9
. Hence, the separation of epimers 18 and 18 was not required and a mixture could be converted into
the product 19 in a 61% yield. The chiral auxiliary alcohol (trans-2-phenylcyclohexanol) was recovered
at this stage in 77% yield.

Molecules 2020, 25, 3613
6 of 13
0
Scheme 6. Conversion of 1,2-oxazines 18 and 18 into target PDE4 inhibitor (−)-CMPO.
On the next step, careful saponification of the pivalate moiety in pyrrolidine 19 with KOH in
aqueous methanol gave Boc-prolinol 20 in 84% yield (Scheme 6). It is noteworthy that hydrolysis of
the Boc-group was also observed to some extent under these conditions. For this reason, the reaction
mixture was treated with Boc O after neutralization to convert the unprotected prolinol into the
2
N-Boc-derivative 20, which was isolated by column chromatography.
Finally, deprotection of the N-Boc moiety with TFA and treatment of the resulting prolinol
trifluoroacetate with Im CO/Et N afforded the desired PDE4 inhibitor CMPO (Scheme 6). Thus,
2
3
the asymmetric synthesis of PDE4 inhibitor CMPO was completed in seven steps from a known
nitroalkene in 8% overall yield. Chiral HPLC analysis revealed the enantiomeric purity of the
8
product >97% ee. The racemic sample of CMPO for HPLC analysis was prepared according to the
same synthetic sequence starting from the racemic trans-2-phenylcyclohexanol.
3
. Discussion
Epimerization of the acetal moiety in the course of the hydride reduction of
,6-dihydro-4-H-1,2-oxazine 17 is of special note. In the previously reported hydride reduction
5
of 1,2-oxazine 13 possessing a free hydroxymethyl group, no epimerization at the C-6 atom was
observed (cf. data in Scheme 2; Scheme 5) [24]. We hypothesized that such a difference in the behavior
of 3-hydroxymethyl- and 3-acyloxymethyl-substituted 1,2-oxazines 13 and 17 may be attributed to
an anchimeric assistance from the carbonyl group, which stabilizes the intermediate cation C2 [33]
by forming a bridged system with an eight-membered ring (cation C3). In carbohydrates, a similar
anchimeric assistance of the acyloxy group from the distant 1,4-position has been proposed, yet it was
not confirmed unambiguously by experimental data [34
DFT) calculations at the MN15/Def2TZVP level of theory (see Supplementary material for details)
revealed that the bridged cation C3 is much less stable compared to the initial monocyclic cation C2
–37]. In our case, density functional theory
(
.
Interestingly, the formation of a third ring between the nitrogen atom and the acyloxy group may lead
to a tricyclic cation C4, which is predicted to be much more stable than the mono- or bicyclic structures
C2 and C3 (Scheme 7). The formation of such a stable tricyclic cation as an intermediate or a resting
state may account for the observed facile epimerization of pivalate 18. The higher thermodynamic

Molecules 2020, 25, 3613
7 of 13
0
stability of the 4,6-cis-isomer 18 over the 4,6-trans-isomer 18, as shown by DFT calculations, is likely to
be the driving force for the epimerization at the C-6 atom.
Scheme 7.
Ar
Plausible mechanism of the epimerization at the C-6 position in 1,2-oxazine
4-methoxy-3-cyclopentyloxyphenyl, G*—trans-2-phenylcyclohexyl. DFT calculations:
1
8.
−
MN15/Def2TZVP (AcOH, smd), LA was not included in the calculations.
Another remarkable observation was that 1,2-oxazine 18 (as well as its precursor 17) did not
0
undergo epimerization in acetic acid (rt, 2 h). Isomerization to the cis-isomer 18 was observed
only in the presence of NaBH CN. Hence, the fragmentation of the acetal moiety is most likely
3
promoted by some Lewis acidic boron species generated from NaBH CN in acidic medium. Indeed,
3
slow epimerization of 1,2-oxazine 18 was observed upon treatment of 18 with B(OBu) or BF3
acetic acid.
·
Et O in
2
3
It is noteworthy that an anchimeric-assisted epimerization in 1,2-oxazine series has not been
reported previously. Moreover, to our knowledge, this is the first reported example of a remote
neighboring group participation from the 1,4-position in a six-membered ring confirmed by DFT
calculations [38–40]. The formation of an eight-membered ring in this case may be driven by an
unusual secondary anchimeric interaction involving the nitrogen atom of the 1,2-oxazine ring leading
to an unusual tricyclic oxazolo(1,2)oxazinium cation C4.
4
. Materials and Methods
◦
All reactions were carried out in oven-dried (150 C) glassware. NMR spectra (Bruker AM
00 spectrometer, Karlsruhe, Germany) were recorded at room temperature (if not stated otherwise)
3
with residual solvents peaks as an internal standard. Peak multiplicities are indicated by s (singlet),
d (doublet), t (triplet), dd (doublet of doublets), q (quartet), quint (quintet), ddd (doublet of doublets
of doublets), tt (triplet of triplets), tdd (triplets of doublets of doublets), m (multiplet), br (broad).
The numeration of atoms used in the assignment of NMR spectra is given in Figure 1.
HRMS were measured on the electrospray ionization (ESI) (Bruker MicroTOF, Karlsruhe, Germany)
instrument with a time-of-flight (TOF) detector. Concentrations c in optical rotation angles are given in
−
1
2
−1
g/100 mL. [
Kieselgel (Merck, Germany) 40–60
on silica gel plates with QF 254. Visualization was accomplished with UV light and solution of
anisaldehyde/H SO in ethanol. Chiral HPLC analysis was performed on a chromatograph with a
α
]D values are given in 10 deg cm g . Column chromatography was performed using
µm 60A. Analytical thin-layer chromatography was performed
2
4
UV-VIS photodiode array detector (Shimadzu LC-20, Shimadzu, Japan). All reagents were commercial
grade and used as received. Et N, dichloromethane (DCM), and MeCN were distilled over CaH prior
3
2
to the experiments; MeOH, hexane and ethyl acetate were distilled without drying agents.

Molecules 2020, 25, 3613
8 of 13
Figure 1. Numeration of atoms in products 17–20.
(
+)-(4S,6S)-4-(3-(Cyclopentyloxy)-4-methoxyphenyl)-3-methyl-6-(((1S,2R)-2-phenylcyclohexyl)oxy)-5,
-dihydro-4H-1,2-oxazine 2-oxide (+)-10 and the corresponding racemate rac-10 were synthesized
according to the previously reported procedure from nitroalkene and vinyl ether 9 [25]. In most
6
8
experiments, very similar yields in enantiomeric and racemic series were obtained. In Schemes and
Procedures, the best yields among two series are given if not otherwise stated.
Oxygenation of nitronate 10. Enantipure or racemic nitronate 10 (347 mg, 0.72 mmol) was
dissolved in dry acetonitrile (1.7 mL) in a Schlenk tube under argon atmosphere, and then Et N (251
µ
L,
3
◦
1
.8 mmol) was added. The solution was cooled to
−
40 C and pivaloyl chloride (174
40 C for 2 h and then kept in a freezer (ca. −25 C
µ
L, 1.41 mmol)
◦
◦
was added. The reaction mixture was stirred at ca.
−
)
overnight. The mixture was diluted with EtOAc (5 mL) and transferred into a separating funnel
containing EtOAc (20 mL) and 0.25 M aq. NaHSO solution (20 mL). The aqueous layer was extracted
4
with EtOAc (20 mL), the combined organic layers were washed with water (30 mL) and brine (30 mL),
dried over anhydrous Na SO and concentrated under reduced pressure. The residue was subjected to
2
4
a column chromatography on silica gel (Hexane/EtOAc = 10/1) to give 311 mg (76%) of enantiopure or
racemic pivalate 17.
(
1S,2R,4S,6S)- and (1S*,2R*,4S*,6S*)-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-6-((2-phenylcyclohexyl)
1
oxy)-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl pivalate (17). R = 0.44 (hexane/EtOAc = 3/1). H-NMR
f
(300 MHz, COSY, HSQC, CDCl3)
δ
7.41–7.13 (m, 5H, H14, H15, H16), 6.75 (d, J = 8.2 Hz, 1H, H23),
6
H
3
.57 (dd, J = 8.2, 2.1 Hz, 1H, H22), 6.53 (d, J = 2.2 Hz, 1H, H26), 5.36 (dd, J = 2.7, 2.5 Hz, 1H,
0
eq6), 4.71 (m, 1H, H28), 4.08 (d, J = 13.5 Hz, 1H, H17 ), 4.02 (ddd, J = 10.3, 10.2, 4.0 Hz, 1H, Hax7),
0
.98 (d, J = 13.5 Hz, 1H, H17 ’), 3.80 (s, 3H, H27), 2.92 (dd, J = 11.9, 7.7 Hz, 1H, Hax4), 2.61 (ddd, J = 11.1
,
1
0.3, 3.6 Hz, 1H, Hax8), 2.37 (m, 1H, H12), 2.01 (ddd, J = 13.0, 7.7, 2.7 Hz, 1H, Heq5), 1.98–1.73
0 0
(m, 10H,
H
ax5, H9 , H10, H29, H30 ), 1.70–1.52 (m, 3H, H9”, H30”), 1.50–1.28 (m, 3H, H11, Heq12),
13
1
.10 (s, 9H, H20)
.
C-NMR (75 MHz, HSQC, CDCl3) δ 177.4 (C18), 155.3 (C3), 149.3 and 147.9 (C24 and
C25), 144.4 (C13), 131.1 (C21), 128.0 and 127.8 (2 C14 and 2 C15), 125.9 (C16), 120.7 (C22), 114.9 (C26)
,
1
3
2
12.2 (C23), 91.0 (C6), 80.4 (C28), 76.1 (C7), 63.6 (C17), 56.1 (C27), 50.7 (C8), 38.6 (C19), 34.3 (C9),
0
3.8 (C4), 32.8 and 32.7 (C29 and C29 ), 32.5 (C5), 30.6 (C12), 27.1 (3 C20), 26.1 (C11), 24.7 (C10),
0
+
+
4.0 (C30 and C30 ). HRMS (ESI): m/z calcd. for [C H NO ] 564.3320, found 564.3316 [M + H] .
34
46
6
◦
+)-(1S,2R,4S,6S)-17. Colorless oil. [α] = +188.6 (c = 0.09, EtOAc, 20 C). rac-17. Colorless oil.
D
(
Hydride reduction of 5,6-dihydro-4H-1,2-oxazine 17. Procedure 1: Enantiopure or racemic pivalate
(80 mg, 0.14 mmol) was dissolved in acetic acid (0.8 mL) and sodium cyanoborohydride (120 mg,
.9 mmol) was added to the solution upon intensive stirring. The reaction mixture was stirred under
1
1
7
argon for 30 min at rt, then diluted with EtOAc (3 mL) and transferred into a separating funnel
containing EtOAc (20 mL) and a sat. aq. NaHCO solution (20 mL). The aqueous layer was extracted
3
with EtOAc (20 mL). The combined organic layers were washed with sat. aq. NaHCO solution (20 mL)
3
and brine (40 mL), then dried over Na SO and concentrated under reduced pressure. The residue
2
4
was subjected to a column chromatography on silica gel (Hexane/EtOAc = 10/1
→
5/1 3/1) to yield
→

Molecules 2020, 25, 3613
9 of 13
0
9 mg (62%) of a mixture of 1,2-oxazines 18 and 18 (d.r. 3: 1). Also, 26 mg (33%) of unreacted pivalate
4
1
7 was isolated from the column chromatography.
Procedure 2: Enantiopure or racemic pivalate 17 (190 mg, 0.34 mmol) was dissolved in acetic acid
(
1.8 mL) and sodium cyanoborohydride (250 mg, 3.97 mmol) was added to the solution upon intensive
stirring. The reaction mixture was stirred under argon at rt for 1.7 h, then diluted with EtOAc (3 mL)
and transferred into a separating funnel containing EtOAc (20 mL) and a sat. aq. NaHCO solution
3
(20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were
washed with sat. aq. NaHCO solution (20 mL) and brine (40 mL), then dried over Na SO and
3
2
4
concentrated under reduced pressure. The residue was subjected to a column chromatography on
silica gel (Hexane/EtOAc = 10/1
→
5/1
→
3/1) to yield 48 mg (25%) of the fast moving isomer 18 and
0
6
9 mg (36%) of the slow moving isomer 18 .
((3R,4S,6S)- and (3R*,4S*,6S*)-4-(3-(Cyclopentyloxy)-4-methoxyphenyl)-6-(((1S,2R)-2-phenylcyclohexyl)
oxy)-1,2-oxazinan-3-yl)methyl pivalate (18). Colorless oil (both enantiopure and racemic). R = 0.37
f
(
hexane/EtOAc = 3/1). 1H-NMR (300 MHz, COSY, HSQC, CDCl3)
δ
7.55–7.32 (m, 4H, H14, H15),
7
4
3
8
.29–7.21 (m, 1H, H16), 6.76 (d, J = 8.0 Hz, 1H, H23), 6.61 (dd, J = 8.0, 2.1 Hz, 1H, H22), 6.59 (br s, 1H, H26),
.99 (d, J = 3.0 Hz, 1H, H6), 4.79–4.68 (m, 1H, H28), 4.03 (br d, J = 10.7 Hz, 1H, Hax2), 3.80 (s, 3H, H27)
.78 (ddd, J = 10.0, 10.0, 3.9 Hz, 1H, Hax7), 3.51 (dd, J = 11.8, 2.8 Hz, 1H, H17 ), 3.22 (br ddd, J = 10.7, 9.8,
,
0
.5 Hz, 1H, Hax3), 3.08 (dd, J = 11.8, 8.5 Hz, 1H, H17”), 2.68 (ddd, J = 12.3, 10.3, 3.7 Hz, 1H, Hax8), 2.32
0
(
ddd, J = 11.9, 11.9, 4.5 Hz, 1H, Hax4), 2.21 (br d, J = 10.6 Hz, 1H, Hax12), 2.05–1.75 (m, 11H, H5, H9 , H10,
0
13
H29, H30 ), 1.70–1.54 (m, 3H, H9”, H30”), 1.48–1.25 (m, 3H, H11, Heq12), 1.12 (s, 9H, H20). C-NMR
(
75 MHz, HSQC, HMBC, DEPT135, CDCl3)
33.9 (C21), 128.8 and 128.0 (2 C14 and 2 C15), 126.9 (C16), 119.5 (C22), 114.2 (C26), 112.3 (C23)
δ
178.1 (C18), 149.1 and 147.8 (C24 and C25), 144.5 (C13)
,
,
,
1
9
3
3.5 (C6), 80.5 (C28), 77.7 (C7), 63.3 (C17), 60.1 (C3), 56.1 (C27), 50.7 (C8)
,
38.6 (C19)
,
37.2 (C4)
,
37.0 (C5)
0
3.3 (C9), 32.7 and 32.8 (C29 and C29 ), 31.3 (C12), 27.1 (3 C20)
,
26.0 (C11)
,
24.8 (C10), 24.0 (C30 and
0
+
+
C30 ). HRMS (ESI): m/z calcd. for [C H NO ] 566.3476, found 566.3474 [M + H] .
3
4
48
6
(
(3R,4S,6R)- and (3R*,4S*,6R*)-4-(3-(Cyclopentyloxy)-4-methoxyphenyl)-6-(((1S,2R)-2-phenylcyclohexyl)
0
0
oxy)-1,2-oxazinan-3-yl)methyl pivalate (18 ). Characterized in mixture with 18 (d.r. 18
oil (both enantiopure and racemic). R = 0.30 (hexane/EtOAc = 3/1). H-NMR (300 MHz, COSY, HSQC,
/
18 = 1: 4). Colorless
1
f
CDCl3)
δ
7.55–7.32 (m, 5H, H14, H15, H16), 6.79 (d, J = 8.2 Hz, 1H, H23), 6.60 (dd, J = 8.2, 2.2 Hz,
1
4
1
H, H22), 6.55 (d, J = 2.2 Hz, 1H, H26), 5.43 (d, J = 10.4 Hz, 1H, H2), 5.28 (d, J = 2.9 Hz, 1H, H6),
.73 (m, 1H, H28), 3.93 (ddd, J = 10.3, 10.2, 4.0 Hz, 1H, H7), 3.81 (s, 3H, H27), 3.59 (d, J = 12.9 Hz,
H, H17), 3.48 (ddd, J = 11.2, 10.4, 5.7 Hz, 1H, Hax3), 3.38 (dd, J = 12.9, 5.7 Hz, 1H, H17), 2.71 (ddd,
J = 10.6, 10.3, 3.3 Hz, 1H, Hax8), 2.63 (ddd, J = 12.5, 11.2, 4.0 Hz, 1H, Hax4), 2.24 (br d, J = 11.9 Hz,
0
0
1
1
H, Hax12), 2.06 (td, J = 13.3, 12.5, 2.9 Hz, 1H, Hax5), 1.99–1.76 (m, 10H, Heq5, H9 , H10, H29, H30 ),
.72–1.53 (m, 3H, H9”, H30”), 1.53–1.25 (m, 3H, H11, Heq12), 1.10 (s, 9H, H20). 13C-NMR (75 MHz,
HSQC, HMBC, DEPT135, CDCl3)
δ
177.4 (C18), 149.9 and 148.2 (C24 and C25), 143.7 (C13), 130.6 (C21),
1
7
3
29.6 (C16), 127.7 and 127.5 (2 C14 and 2 C15), 120.0 (C22), 113.7 (C26), 112.4 (C23), 95.2 (C6), 80.7 (C28),
8.5 (C7), 65.8 (C3), 61.3 (C17), 56.0 (C27), 50.5 (C8), 38.5 (C19), 36.7 (C4), 36.4 (C5), 33.1 (C9), 32.8 and
0
0
2.7 (C29 and C29 ), 30.7 (C12), 27.0 (3 C20), 25.8 (C11), 24.4 (C10), 24.0 (C30 and C30 ). HRMS (ESI):
+
+
m/z calcd. for [C H NO ] 566.3476, found 566.3476 [M + H] .
34
48
6
0
Hydrogenation of 1,2-oxazines 18 and 18 . A glass vial was charged with a solution of enantiopure
,2-oxazine 18 (48 mg, 0.086 mmol) and Boc O (58 mg, 0.264 mmol) in methanol (0.5 mL). A suspension
1
2
of Raney nickel (ca. 100 mg, prepared from 50% slurry in water) in methanol (ca. 0.5 mL) was
added, and the vial was placed in a steel autoclave, which was then flushed and filled with hydrogen
◦
to a pressure of ca. 40 bar and heated to 50 C. The hydrogenation was conducted for 2 h with
intensive stirring. Then, the autoclave was cooled to rt, slowly depressurized, and the catalyst was
removed using a magnet and washed with methanol. The solution was concentrated to dryness under
reduced pressure. The residue was subjected to a column chromatography on silica gel (hexane/EtOAc
=
20/1
→
10/1) to yield 31 mg (74%) of N-Boc pyrrolidine 19. The column was then washed with
hexane/EtOAc = 5/1 to recover (+)-trans-2-phenylcyclohexanol (12 mg, 77%).

Molecules 2020, 25, 3613
10 of 13
0
Application of the same procedure for the reduction of enantiopure 1,2-oxazine 18
69 mg, 0.13 mmol) afforded 36 mg (60%) of N-Boc pyrrolidine 19 and 15 mg (66%) of
+)-trans-2-phenylcyclohexanol.
(
(
Application of the same procedure for the reduction of a mixture of racemic 1,2-oxazines rac-18
0
and rac-18 (90 mg, 0.159 mmol, d.r. 1: 1.4) afforded 46 mg (61%) of racemic N-Boc pyrrolidine rac-19.
Tert-butyl (2R,3S)- and (2R*,3S*)-3-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-((pivaloyloxy)methyl)
1
pyrrolidine-1-carboxylate (19). R = 0.30 (hexane/EtOAc = 3/1). H-NMR (300 MHz, 320K, COSY,
f
HSQC, CDCl3)
δ
6.82 (d, J = 8.7 Hz, 1H, H15), 6.75–6.70 (m, 2H, H14 and H21), 4.76 (m, 1H, H18),
0
4
3
2
.41–4.26 (m, 1H, H9 ), 4.20 (br d, J = 9.9 Hz, 1H, H9”), 4.11–3.88 (br m, 1H, H2), 3.84 (s, 3H, H17),
.77–3.62 (br m, 1H, H5 ), 3.46–3.31 (m, 1H, H5”), 3.29–3.10 (br m, 1H, H3), 2.35–2.18 (m, 1H, H4 ),
.01–1.76 (m, 7H, H4 ’, H19, H20 ), 1.72–1.54 (m, 2H, H20”), 1.49 (s, 9H, H8), 1.21 (s, 9H, H12). C-NMR
178.2 (C10), 154.2 (C6), 148.9 and 147.9 (C16 and C22), 135.1 (C13)
19.2 (C14), 114.0 (C21), 112.3 (C15), 80.5 (C18), 80.0 (C7), 63.5 (br, C9), 63.1 (br, C2), 56.2 (C17), 47.2 (C3),
0
0
0
0
13
(
75 MHz, HSQC, DEPT135, CDCl3)
δ
,
1
4
0
0
6.3 (C5), 38.8 (C11), 32.8 (C19 and C19 ), 31.8 (C4), 28.5 (3 C8), 27.2 (3 C12), 24.0 (C20 and C20 ) (signals
+
are broadened due to the presence of N-Boc rotamers). HRMS (ESI): m/z calcd. for [C H NO ]
27
42
6
+
4
76.3007, found 476.3006 [M + H] .
−)-(2R,3S)-19. Colorless oil, [α] = −19.0 (c = 1, EtOAc, 24 C). rac-19. Colorless oil.
◦
(
D
Saponification of pivalate 19. Enantiopure or racemic pivalate 19 (67 mg, 0.14 mmol) was dissolved
in MeOH (2.8 mL) and a solution of KOH (237 mg, 4.2 mmol) in H O (1.4 mL) was added. The mixture
2
was stirred at room temperature for 24 h. Then, acetic acid (0.4 mL) was added and the reaction mixture
was stirred for 5 min. The resulting solution was concentrated in vacuum. To the residue, MeOH
(
2 mL) and Boc O (0.065 g, 0.28 mmol) were added and the resulting solution was stirred for 1 h. Then,
2
volatiles were removed in vacuum and the residue was subjected to a column chromatography on
silica gel (hexane/EtOAc = 5/1→3/1→1/1) to yield 46 mg (84%) of prolinol 20.
Tert-butyl (2R,3S)- and (2R*,3S*)-3-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-
1
1
-carboxylate (20). R = 0.21 (hexane/EtOAc = 1/1). H-NMR (300 MHz, COSY, HSQC, CDCl3)
δ
f
6
.81 (d, J = 7.6 Hz, 1H, H13), 6.76 (d, J = 7.6 Hz, 1H, H12), 6.74 (s, 1H, H16), 5.13–4.88 (br, 1H,
0
0
H10), 4.77 (m, 1H, H18), 3.97–3.85 (br m, 1H, H2), 3.83 (s, 3H, H17), 3.80–3.66 (br m, 2H, H9 , H5 ),
.63 (dd, J = 11.5, 6.8 Hz, 1H, H9”), 3.44–3.27 (br m, 1H, H5”), 2.89–2.79 (br m, 1H, H3), 2.22–2.07
3
0 0 0 0
13
(
(
br m, 1H, H4 ), 2.02–1.75 (m, 7H, H20 , H19, H4 ’), 1.67–1.57 (m, 2H, H20 ’), 1.51 (s, 9H, H8). C-NMR
75 MHz, HSQC, DEPT135, CDCl3)
δ
156.8 (C6), 149.2 and 147.9 (C14 and C15), 133.3 (C11), 119.7 (C12)
,
1
3
4
14.5 (C16), 112.3 (C13), 80.5 (C18), 80.4 (C7), 67.1 (C2), 66.1 (C9), 56.2 (C17), 47.4 (C3), 47.0 (C5), 32.9 and
0
0
+
2.8 (C-4, C19 and C19 ), 28.5 (3 C8), 24.0 (C20 and C20 ). HRMS (ESI): m/z calcd. for [C H NO Na]
22
33
5
+
14.2251, found 414.2247 [M + Na] .
◦
(
−)-(2R,3S)-20. Colorless oil, [α] = −9.3 (c = 1, EtOAc, 24 C). rac-20. Colorless oil.
D
Synthesis of (
−
)- and rac-CMPO. To a stirred solution of enantiopure or racemic prolinol 20 (45 mg,
◦
0.115 mmol) in DCM (0.9 mL) was added CF COOH (0.18 mL, 2.4 mmol) at 0–5 C. The cooling bath
3
was removed, and the solution was stirred for 1 h. Then, volatiles were removed under reduced
pressure and the residue was dried until constant weight. The resulting trifluoroacetate was dissolved
0
in DCM (0.85 mL), and Et N (0.08 mL, 0.58 mmol) and 1,1 -carbonyldiimidazole (47 mg, 0.29 mmol)
3
were added at rt. The solution was stirred for 18 h at rt, and then concentrated under reduced pressure.
The product was isolated by column chromatography on silica gel (hexane/EtOAc = 3/1) followed by
1
recrystallization from hexane
agreement with previously published data [24].
)-(7S,7aR)-CMPO. White solid. Mp = 134–137 C (lit.[24] 137–139 C). HPLC analysis: ee > 97%
\
diethyl ether (ca. 1: 1). Yield: 18 mg (49%). H NMR spectra were in
◦
◦
(
−
◦
(
RT 9.8 min; column CHIRALPAK IA-3 (15 cm); solvent Hexane/i-PrOH = 90:10; temperature 40 C;
◦
◦
] = 69.1 (c = 0.83, MeOH, 26 C).
flow rate 1 mL/min). [
α
] =
D
−
63.0 (c = 0.5, EtOAc, 25 C). lit.[24] [
α
−
D
◦
◦
rac-CMPO. White solid. Mp = 103–104 C (lit.[30] 99–101 C). HPLC analysis: (+)-(7R,7aS)-CMPO
(
RT 8.8 min) and (
−
)-(7S,7aR)-CMPO (RT 9.8 min); column CHIRALPAK IA-3 (15 cm); solvent
◦
Hexane/i-PrOH = 90:10; temperature 40 C; flow rate 1 mL/min.

Molecules 2020, 25, 3613
11 of 13
5
. Conclusions
In conclusion, we were able to solve the problem of site-selective C–H oxygenation of the
cyclic nitronate intermediate in the asymmetric synthesis of a potent PDE4 inhibitor CMPO by
using tandem acylation/(3,3)-sigmatropic rearrangement. In comparison with the previous synthesis,
this method afforded the required 3-oxymethyl-substituted 1,2-oxazine intermediate in a much higher
yield (76% vs. 27%). This key intermediate could be readily converted into the target (
by the reductive contraction of the 1,2-oxazine ring followed by deprotection and carbamylation
with Im CO. A rapid epimerization of the C-6 acetal moiety was observed upon the reduction of the
−
)-CMPO
2
5
,6-dihydro-4H-1,2-oxazine ring with NaBH CN in acetic acid. DFT calculations suggest that the
3
epimerization is favored by an unprecedented double anchimeric assistance from a remote acyloxy
group and the nitrogen atom of the 1,2-oxazine ring.
0
, 18, 18 , 19, 20
Supplementary Materials: The following are available online: NMR spectra for compounds 10
,
17
and CMPO, chiral phase HPLC chromatograms for rac-CMPO and (
−
)-CMPO, Cartesian coordinates, absolute
energies for all optimized geometries.
Author Contributions: E.V.P. carried out synthesis, separation, and purification of compounds; I.S.G. performed
DFT calculations; S.L.I. collaborated in the discussion and interpretation of the results, manuscript editing;
A.Y.S. supervised the whole research, including conceptualization, methodology, data curation and original draft
preparation. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Russian Science Foundation (grant 17-13-01411).
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
References
1.
2.
3.
4.
Denmark, S.E.; Thorarensen, A. Tandem [4 + 2]/[3 + 2] Cycloadditions of Nitroalkenes. Chem. Rev. 1996, 96,
37–166. [CrossRef] [PubMed]
Tabolin, A.A.; Sukhorukov, A.Y.; Ioffe, S.L.; Dilman, A.D. Recent Advances in the Synthesis and Chemistry of
Nitronates. Synthesis 2017, 49, 3255–3268. [CrossRef]
Mukaijo, Y.; Yokoyama, S.; Nishiwaki, N. Comparison of Substituting Ability of Nitronate versus Enolate for
Direct Substitution of a Nitro Group. Molecules 2020, 25, 2048. [CrossRef] [PubMed]
de Carvalho, L.L.; Burrow, R.A.; Pereira, V.L.P. Diastereoselective synthesis of nitroso acetals from
1
(S,E)-γ-aminated nitroalkenes via multicomponent [4 + 2]/[3 + 2] cycloadditions promoted by LiCl or
LiClO . Beilstein J. Org. Chem. 2013, 9, 838–845. [CrossRef] [PubMed]
4
5.
6.
7.
8.
9.
Kano, T.; Yamamoto, A.; Song, S.; Maruoka, K. Catalytic asymmetric syntheses of isoxazoline-N-oxides
under phase-transfer conditions. Chem. Commun. 2011, 47, 4358–4360. [CrossRef] [PubMed]
Koc, E.; Kwon, O. Total syntheses of heliotridane and pseudoheliotridane through nitrodiene–acrylate
6
π-electrocyclization/[3+2] cycloaddition. Tetrahedron 2017, 73, 4195–4200. [CrossRef]
Creech, G.S.; Kwon, O. Tandem 6 -Electrocyclization and Cycloaddition of Nitrodienes to Yield Multicyclic
π
Nitroso Acetals. J. Am. Chem. Soc. 2010, 132, 8876–8877. [CrossRef]
Zhu, C.-Y.; Deng, X.-M.; Sun, X.-L.; Zheng, J.-C.; Tang, Y. Highly enantioselective synthesis of isoxazoline
N-oxides. Chem. Commun. 2008, 6, 738–740. [CrossRef]
Streitferdt, V.; Haindl, M.H.; Hioe, J.; Morana, F.; Renzi, P.; von Rekowski, F.; Zimmermann, A.; Nardi, M.;
Zeitler, K.; Gschwind, R.M. Unprecedented Mechanism of an Organocatalytic Route to Conjugated Enynes
with a Junction to Cyclic Nitronates. Eur. J. Org. Chem. 2019, 2019, 328–337. [CrossRef]
1
0. Jiang, H.; Elsner, P.; Jensen, K.L.; Falcicchio, A.; Marcos, V.; Jørgensen, K.A. Achieving Molecular Complexity
by Organocatalytic One-Pot Strategies—A Fast Entry for Synthesis of Sphingoids, Amino Sugars, and
Polyhydroxylated α-Amino Acids. Angew. Chem. Int. Ed. 2009, 48, 6844–6848. [CrossRef]
1. Baiazitov, R.Y.; Denmark, S.E. Tandem [4 + 2]/[3 + 2] Cycloadditions. In Methods and Applications of
Cycloaddition Reactions in Organic Syntheses; Nishiwaki, N., Ed.; John Wiley & Sons: Hoboken, NJ, USA, 2014;
pp. 471–550.
1

Molecules 2020, 25, 3613
12 of 13
1
2. Denmark, S.E.; Martinborough, E.A. Enantioselective Total Syntheses of (+)-Castanospermine,
+)-6-Epicastanospermine, (+)-Australine, and (+)-3-Epiaustraline. J. Am. Chem. Soc. 1999, 121, 3046–3056.
CrossRef]
(
[
1
1
3. Denmark, S.E.; Thorarensen, A.; Middleton, D.S. Tandem [4 + 2]/[3 + 2] Cycloadditions of Nitroalkenes. 9.
Synthesis of (−)-Rosmarinecine. J. Am. Chem. Soc. 1996, 118, 8266–8277. [CrossRef]
4. Denmark, S.E.; Baiazitov, R.Y.; Nguyen, S.T. Tandem double intramolecular [4 + 2]/[3 + 2] cycloadditions
of nitroalkenes: Construction of the pentacyclic core structure of daphnilactone B. Tetrahedron 2009, 65,
6
535–6548. [CrossRef] [PubMed]
1
1
1
1
5. Denmark, S.E.; Montgomery, J.I.; Kramps, L.A. Synthesis, X-ray Crystallography, and Computational
Analysis of 1-Azafenestranes. J. Am. Chem. Soc. 2006, 128, 11620–11630. [CrossRef]
6. Denmark, S.E.; Montgomery, J.I. Synthesis of cis,cis,cis,cis-[5.5.5.4]-1-Azafenestrane with Discovery of an
Unexpected Dyotropic Rearrangement. Angew. Chem. Int. Ed. 2005, 44, 3732–3736. [CrossRef]
7. For a review see: Sukhorukov, A.Y. C-H Reactivity of the
α-Position in Nitrones and Nitronates.
Adv. Synth. Catal. 2020, 362, 724–754. [CrossRef]
8. Tishkov, A.A.; Lesiv, A.V.; Khomutova, Y.A.; Strelenko, Y.A.; Nesterov, I.D.; Antipin, M.Y.; Ioffe, S.L.;
Denmark, S.E. 2-Silyloxy-1,2-oxazines, a New Type of Acetals of Conjugated Nitroso Alkenes. J. Org. Chem.
2
003, 68, 9477–9480. [CrossRef]
9. Sukhorukov, A.Y.; Kapatsyna, M.A.; Yi, T.L.T.; Park, H.R.; Naumovich, Y.A.; Zhmurov, P.A.; Khomutova, Y.A.;
Ioffe, S.L.; Tartakovsky, V.A. A General Metal-Assisted Synthesis of -Halo Oxime Ethers from Nitronates
1
2
2
2
2
2
2
α
and Nitro Compounds. Eur. J. Org. Chem. 2014, 2014, 8148–8159. [CrossRef]
0. Naumovich, Y.A.; Buckland, V.E.; Sen’ko, D.A.; Nelyubina, Y.V.; Khoroshutina, Y.A.; Sukhorukov, A.Y.;
Ioffe, S.L. Metal-assisted addition of a nitrate anion to bis(oxy)enamines. A general approach to the synthesis
of α-nitroxy-oxime derivatives from nitronates. Org. Biomol. Chem. 2016, 14, 3963–3974. [CrossRef]
1. Tabolin, A.A.; Lesiv, A.V.; Khomutova, Y.A.; Nelyubina, Y.V.; Ioffe, S.L. Rearrangement of
3
3
-alkylidene-2-siloxy-tetrahydro-1,2-oxazines (ASENA). A new approach toward the synthesis of
-α-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines. Tetrahedron 2009, 65, 4578–4592. [CrossRef]
2. Naumovich, Y.A.; Golovanov, I.S.; Sukhorukov, A.Y.; Ioffe, S.L. Addition of HO-Acids to
N,N-Bis(oxy)enamines: Mechanism, Scope and Application to the Synthesis of Pharmaceuticals. Eur. J. Org.
Chem. 2017, 2017, 6209–6227. [CrossRef]
3. Zhmurov, P.A.; Khoroshutina, Y.A.; Novikov, R.A.; Golovanov, I.S.; Sukhorukov, A.Y.; Ioffe, S.L. Divergent
Reactivity of In Situ Generated Metal Azides: Reaction with N,N-Bis(oxy)enamines as a Case Study.
Chem. Eur. J. 2017, 23, 4570–4578. [CrossRef] [PubMed]
4. Zhmurov, P.A.; Sukhorukov, A.Y.; Chupakhin, V.I.; Khomutova, Y.V.; Ioffe, S.L.; Tartakovsky, V.A. Synthesis
of PDE IV inhibitors. First asymmetric synthesis of two of GlaxoSmithKline’s highly potent Rolipram
analogues. Org. Biomol. Chem. 2013, 11, 8082–8091. [CrossRef] [PubMed]
5. Sukhorukov, A.Y.; Boyko, Y.D.; Ioffe, S.L.; Khomutova, Y.A.; Nelyubina, Y.V.; Tartakovsky, V.A. Synthesis
of PDE IVb Inhibitors. 1. Asymmetric Synthesis and Stereochemical Assignment of (+)- and
(
7
−
)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one. J. Org. Chem. 2011, 76,
893–7900. [CrossRef] [PubMed]
2
6. Kokuev, A.O.; Antonova, Y.A.; Dorokhov, V.S.; Golovanov, I.S.; Nelyubina, Y.V.; Tabolin, A.A.;
Sukhorukov, A.Y.; Ioffe, S.L. Acylation of Nitronates: [3,3]-Sigmatropic Rearrangement of in Situ Generated
N-Acyloxy,N-oxyenamines. J. Org. Chem. 2018, 83, 11057–11066. [CrossRef]
2
7. Brackeen, M.F.; Stafford, J.A.; Cowan, D.J.; Brown, P.J.; Domanico, P.L.; Feldman, P.L.; Rose, D.;
Strickland, A.B.; Veal, J.M.; Verghese, M. Design and Synthesis of Conformationally Constrained Analogs
of 4-(3-Butoxy-4-methoxybenzyl)imidazolidin-2-one (Ro 20-1724) as Potent Inhibitors of cAMP-Specific
Phosphodiesterase. J. Med. Chem. 1995, 38, 4848–4854. [CrossRef]
2
8. Jackson, E.K.; Carcillo, J.A. Treatment of Sepsis-Induced Acute Renal Failure. U.S. Patent 5849774, 15
December 1998.
2
9. Mulhall, A.M.; Droege, C.A.; Ernst, N.E.; Panos, R.J.; Zafar, M.A. Phosphodiesterase 4 inhibitors for the
treatment of chronic obstructive pulmonary disease: A review of current and developing drugs. Exp. Opin.
Investig. Drugs 2015, 24, 1597–1611. [CrossRef]

Molecules 2020, 25, 3613
13 of 13
3
0. Zhmurov, P.A.; Tabolin, A.A.; Sukhorukov, A.Y.; Lesiv, A.V.; Klenov, M.S.; Khomutova, Y.A.; Ioffe, S.L.;
Tartakovsky, V.A. Synthesis of phosphodiesterase IVb inhibitors 2. Stereoselective synthesis of
hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one and tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one derivatives.
Russ. Chem. Bull. 2011, 60, 2390–2395. [CrossRef]
3
3
3
1. Yasuo, T.; Norihiko, Y.; Hiroko, M.; Toshihide, K.; Masahiro, A.; Yutaka, M. Synthesis and a Novel
Fragmentation of 6-Alkoxy-5,6-dihydro-4H-1,2-oxazine 2-Oxide. Bull. Chem. Soc. Jpn. 1988, 61, 461–465.
2. Sukhorukov, A.Y.; Ioffe, S.L. Chemistry of Six-Membered Cyclic Oxime Ethers. Application in the Synthesis
of Bioactive Compounds. Chem. Rev. 2011, 111, 5004–5041. [CrossRef]
3. Zimmer, R.; Arnold, T.; Homann, K.; Reissig, H.-U. An Efficient and Simple Synthesis of
3
,4,5,6-Tetrahydro-2H-1,2-oxazines by Sodium Cyanoborohydride Reduction of 5,6-Dihydro-4H-1,2-oxazines.
Synthesis 1994, 1994, 1050–1056. [CrossRef]
3
4. Demchenko, A.V.; Rousson, E.; Boons, G.-J. Stereoselective 1,2-cis-galactosylation assisted by remote
neighboring group participation and solvent effects. Tetrahedron Lett. 1999, 40, 6523–6526. [CrossRef]
3
5. Ma, Y.; Lian, G.; Li, Y.; Yu, B. Identification of 3,6-di-O-acetyl-1,2,4-O-orthoacetyl-
direct evidence for the 4-O-acyl group participation in glycosylation. Chem. Commun. 2011, 47, 7515–7517.
CrossRef] [PubMed]
α-d-glucopyranose as a
[
3
3
6. Beaver, M.G.; Billings, S.B.; Woerpel, K.A. C-Glycosylation Reactions of Sulfur-Substituted Glycosyl Donors:
Evidence against the Role of Neighboring-Group Participation. J. Am. Chem. Soc. 2008, 130, 2082–2086.
[CrossRef] [PubMed]
7. Stalford, S.A.; Kilner, C.A.; Leach, A.G.; Turnbull, W.B. Neighbouring group participation vs. addition to
oxacarbenium ions: Studies on the synthesis of mycobacterial oligosaccharides. Org. Biomol. Chem. 2009, 7,
4
842–4852. [CrossRef] [PubMed]
3
3
8. Yang, B.; Yang, W.; Ramadan, S.; Huang, X. Pre-Activation-Based Stereoselective Glycosylations. Eur. J.
Org. Chem. 2018, 2018, 1075–1096. [CrossRef]
9. Crich, D.; Hu, T.; Cai, F. Does Neighboring Group Participation by Non-Vicinal Esters Play a Role in
Glycosylation Reactions? Effective Probes for the Detection of Bridging Intermediates. J. Org. Chem. 2008
3, 8942–8953. [CrossRef]
0. Komarova, B.S.; Tsvetkov, Y.E.; Nifantiev, N.E. Design of
Remote Anchimeric Assistance. Chem. Rec. 2016, 16, 488–506. [CrossRef]
,
7
4
α-Selective Glycopyranosyl Donors Relying on
Sample Availability: Samples of racemic and enantiopure PDE4 inhibitor CMPO are available from the authors.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
CC BY) license (http://creativecommons.org/licenses/by/4.0/).
(