Asymmetric Synthesis of Merck's Potent hNK1Antagonist and Its Stereoisomers via Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine N-Oxides

Article abstract of DOI:10.1021/acs.joc.0c01322

An asymmetric total synthesis of Merck's hNK1 antagonist and three of its stereoisomers was accomplished in 10 steps. The synthesis involves a stereoselective assembly of 1,2-oxazine N-oxide by the [4 + 2]-cycloaddition, site-selective C-H oxygenation usi

Full text of DOI:10.1021/acs.joc.0c01322

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Featured Article
Asymmetric Synthesis of Merck’s Potent hNK1
Antagonist and Its Stereoisomers via Tandem
Acylation/[3,3]-Rearrangement of 1,2-Oxazine-N-oxides
Valentin Dorokhov, Yulia Nelyubina, Sema Ioffe, and Alexey Yu. Sukhorukov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01322 • Publication Date (Web): 11 Aug 2020
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Asymmetric Synthesis of Merck’s Potent hNK1 Antagonist and Its Stereoisomers via
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Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine-N-oxides
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Valentin S. Dorokhov,a Yulia V. Nelyubina,b Sema L. Ioffea and Alexey Yu. Sukhorukova,c,*
a N. D. Zelinsky Institute of Organic Chemistry, 119991, Leninsky prospect, 47, Moscow, Russia
b A. N. Nesmeyanov Institute of Organoelement Compounds, 119991, Vavilov str. 28, Moscow,
Russia
c Plekhanov Russian University of Economics, 117997, Stremyanny per. 36, Moscow, Russia
* sukhorukov@ioc.ac.ru
F
tandem
acylation/[3,3]-
rearrangement
10 steps
F3C
F3C
stereoselective assembly
of trisubstituted pyrrolidine
H
O
carbomoylation
O
N
4 individual stereoisomers
synthesized
etherification
with imidate
O
1,2-oxazine ring
contraction
stereochemistry confirmed
by X-Ray
Merck's potent hNK1 antagonist
Abstract: An asymmetric total synthesis of Merck’s hNK1 antagonist and three of its
stereoisomers was accomplished in 10 steps. The synthesis involves a stereoselective assembly
of 1,2-oxazine-N-oxide by the [4+2]-cycloaddition, site-selective CH oxygenation using a
novel tandem acylation/[3,3]-rearrangement process and the reductive 1,2-oxazine ring
contraction into a pyrrolidine ring as key stages. Using this strategy, the fused pyrrolidine
subunit was constructed with exceptionally high regio- and stereoselectivities. The approach
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described here can be used to access enantiopure 3,4-disubstituted prolinols, which are
frequently found in pharmaceutically relevant molecules and organocatalysts.
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Introduction and background
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Neurokinins are peptides that modulate a wide variety of processes in human physiology
through the neurokinin G-protein-coupled receptors (GPCRs) involved in numerous pathological
processes.1 Human neurokinin 1 (hNK1) receptor antagonists have gained considerable interest
as inhibitors of emesis associated with cancer chemotherapy.2 Aprepitant (Emend®) developed
by Merck was the first selective hNK1 antagonist used as a treatment for chemotherapy-induced
and postoperative nausea and vomiting.3 Later, other structurally related hNK1 antagonists such
as Fosaprepitant (Ivemend®),3c,4 Rolapitant (Varubi®)5 and Netupitant (Akynzeo®)6 with
improved performance were approved by FDA for the use as antiemetic drugs. Further research
revealed the potential of hNK1 antagonists for treatment of various CNS disorders owing to their
ability to penetrate the blood-brain barrier.7
O
R
N
O
HN
HN
HN
CF3
O
F3C
N
N
O
O
CF3
CF3
F
Rolapitant
Aprepitant (R = H)
Fosaprepitant (R = P(O)(OH)2)
F
11
10
CF3
N
F3C
9
13
12
N
N
O
8
17
H
14
7
O
7a
1
F3C
N
15
6
16
2 O
5
F3C
N
3
18
4
O
1
Merck12a2-2 ( )
Netupitant
Figure 1. Aprepitant and its analogs
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In the course of Merck’s studies aimed at finding efficient analogs of Aprepitant,8 a fused
pyrrolooxazolidinone Merck12-a2-2 (1) was identified as a lead compound among a series of
bicyclic aryl-substituted pyrrolidine derivatives (Figure 1).8a However, the synthesis of this
molecule developed by Merck gave rise to low regio- and diastereoselectivities of reactions used
to assemble the 3,4-disubstituted prolinol motif.8a
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Among sixteen possible stereoisomers of compound 1 only the one, which is shown in Figure
1, was prepared by Merck.8a Given the spatial structure of antagonist 1 with a large Fsp3 index
(four stereogenic centers, two saturated heterocycles), one can expect that the binding of its
stereoisomers to hNK1 receptor may differ. Molecular docking of compound 1 or its C-12 epimer
1’ using the recently reported9 crystallographic structure of hNK1 receptor demonstrate that aryl
rings serve as anchoring groups, while the spatial orientation of the C-13 methyl is different
(Figure 2, A).10 Same picture is observed for enantiomers of 1 and 1’ (Figure 2, B). This is in
line with a known fact that the hNK1 binding activity of Aprepitant analogs depends on the
absolute configuration of the bis(trifluoromethyl)phenylethoxy unit.8a
(A)
(B)
Figure 2. Molecular docking of 1 and its stereoisomers into the binding site of hNK1 receptor
(PDB: 6HLO): view on the C-13 methyl group. (A) Superimposition of stereoisomers
(6R,7S,7aR,12R)-1 (magenta) and (6R,7S,7aR,12S)-1’ (sand). (B) Superimposition of
stereoisomers (6S,7R,7aS,12S)-1 (blue) and (6S,7R,7aS,12R)-1’ (orange)'
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The stereochemistry of hNK1 antagonist 1 postulated in Merck’s paper8a seems to be
ambiguous, since no confirmation of the absolute configuration of the stereocenter C-12 was
provided.11 Hence, the compound synthesized and studied by Merck could be the C-12 epimer of
1 (compound 1’), which is expected to be less potent. Moreover, no spectroscopic
characterization data for compound 1 was given.8a This leaves the question of stereochemistry of
compound 1 and structure-activity relationship for its stereoisomers to be clarified. For the
reasons outlined above, a convenient asymmetric synthesis of Merck12-a2-2 1, which allows for
the preparation of its stereoisomers and establishment of their absolute stereochemistry, is
needed.
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In continuation of our studies towards total synthesis of bioactive pyrrolidine derivatives,12
we describe herein an asymmetric synthesis and full characterization of individual Merck12-a2-2
(1), its C-12 epimer (1’) and their enantiomers. The strategy disclosed in this paper provides a
general stereoselective access to polysubstituted prolinols, which are frequently found in
pharmaceutically relevant molecules.
Results and Discussion
The synthesis of Merck12-a2-2 (1) is challenging due to the presence of a fused pyrrolidine
skeleton possessing three contiguous stereogenic centers with a pre-defined configuration. The
construction of a sec-sec ether connection between C-6 and C-12 atoms is also difficult since
bis(trifluoromethyl)phenylethyl halides and sulfonates exhibit very poor reactivity in SN
reactions.13
The synthetic strategy towards compound 1 used by Merck is depicted in Scheme 1.8a
According to this strategy, the final stage was the construction of the oxazolidinone ring by
carbomoylation of prolinol intermediate I-1. The sec-sec ether unit was formed from the
corresponding benzoyl ester I-2 by Tebbe reaction and subsequent hydrogenation of the double
C,C-bond, which was not stereoselective. The introduction of aryl group in the pyrrolidine ring
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(I-3) was accomplished by the addition of 4-fluorophenyl magnesium bromide to the epoxide I-
4. However, the epoxide ring opening was not regioselective and produced 3- and 4-aryl
substituted pyrrolidines in nearly equal amounts. The epoxide I-4 was prepared by non-
stereoselective epoxidation of (R)-3,4-dehydroprolinol I-5 (d.r. 2 : 1), which was obtained from
the racemic 3,4-dehydroproline I-6 using an enzymatic resolution process and subsequent
DIBAL reduction of the ester group. Thus, this 13-steps synthesis of hNK1 antagonist 1 suffered
from low regio- and stereoselectivity in the construction of the trisubstituted pyrrolidine ring. For
none of these intermediates (as well as for the final compound) the X-Ray analysis was
performed to confirm the stereochemistry.
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Scheme 1. Merck’s strategy to hNK1 antagonist 1
F
F
F3C
F3C
H
12 O
7
O
7a
6
carbomoylation
OH
F3C
NH
I-1
O
F3C
N
- Tebbe reaction
O
- non-stereoselective
hydrogenation
1
Merck12a2-2 ( )
F
F
F3C
non-regioselective
epoxide opening
O
HO
O
OTBDMS
N
OH
F3C
N
Boc
benzoylation
Boc
I-3
I-2
enzymatic
resolution
DIBAL
reduction
non-stereoselective
epoxide opening
CO2Me
NH
O
OH
Boc
N
OTBDMS
Boc
I-4
N
I-6
I-5
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In our synthesis of Merck12-a2-2 (1), a completely different strategy to construct the
trisubstituted pyrrolidine motif was undertaken in order to ensure complete regio- and
stereocontrol. Moreover, in contrast to Merck’s synthesis we planned to introduce
bis(trifluoromethyl)phenylethyl group at the last stage of the synthesis by using acid-mediated SN
reactions between bis(trifluoromethyl)phenylethyl imidates I-7 and secondary alcohol I-8
(Scheme 2).
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According to our strategy, the enantiopure 3-aryl-substituted prolinol I-9 could be accessed
by the reductive contraction of the 1,2-oxazine ring having an alkoxy-group at the C-6 position
(Scheme 2, vide infra).14 To synthesize the required 1,2-oxazine I-10, we planned to use the
spontaneous [3,3]-sigmatropic rearrangement of N-acyloxy,N-oxyenamines of type I-11, which
could be generated in situ by the acylation of 1,2-oxazine-N-oxide I-12. This straightforward and
very mild CH-oxygenation of non-aromatic N-oxides was recently developed by us,15 and here
we intended to test its application in asymmetric total synthesis for the first time. The
corresponding 1,2-oxazine-N-oxide I-12 could be assembled by an inverse electron demand
[4+2]-cycloaddition of a simple nitroalkene I-14 and a dienophile I-13 bearing a chiral auxiliary
group. Given the known high exo-selectivity in this type of cycloaddition reactions,16 we
anticipated to establish the required 4,5-trans-disposition of the aryl and the acyloxy-group in the
1,2-oxazine ring. Moreover, [4+2] reactions of nitroalkenes with l-(acyloxy)-2-alkoxyethenes of
type I-13 proceed in a regioselective fashion affording 1,2-oxazine-N-oxides with the acyloxy-
group at the C-5 position as reported by Denmark et al.16
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Scheme 2. Proposed strategy to Merck12-a2-2 (1)
4
5
F
F
CF3
6
7
8
9
F3C
F3C
F3C
12
H
H
7
7
HO
O
7a
O
7a
6
6
O
O
10
11
12
13
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N
N
N
benzylation
X3C
R
carbomoylation
O
O
I-8
I-7
1
Merck12a2-2 ( )
F
F
[3,3]-
rearrangement
stereoselective
reduction
AlkC(O)O
G*O
O
HO
NH
N
OH
O
O
R'
I-10
reductive
amination
I-9
F
F
AlkC(O)O
G*O
4
AlkC(O)O
G*O
5
O
N
N
O
O
O
O
R'
[4+2]-cycloaddition
acylation
I-12
I-11
F
AlkC(O)O
G*O
G* - chiral auxiliary group
N
O
O
I-13
I-14
We started with the preparation of the dienophile I-13 bearing a chiral alkoxy-group (Scheme
3). Based on the previous studies,12a,17 Whitesell’s auxiliary (trans-2-phenylcyclohexyl ether)
was chosen as G* group, because it is known to induce high levels of stereocontrol in [4+2]-
cycloaddition reactions. Commercially available (+)- and ()-trans-2-phenylcyclohexanols 2
were transformed into allyl ethers 3, which were then subjected to ozonolysis to afford the
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corresponding aldehydes 4. At this stage, the procedure for the reductive cleavage of trioxolane 5
was found to be crucial. With Zn/AcOH, only 34 % yield of aldehyde 4 was obtained along with
27 % of unexpected formate 6, which likely results from the peroxide rearrangement in
trioxolane 5. Interestingly, in the reduction with SMe2, formate was also generated, yet in a
smaller amount. Fortunately, when PPh3 was used as a reducing agent, only the desired aldehyde
4 was obtained in 70 % yield. Acylation of aldehydes 4 with propionic anhydride in the presence
of K2CO3/KOH afforded alkenes 7 almost solely as Z-isomers.
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Scheme 3. Steps (1)  (3): synthesis of dienophiles 7
Br
O3, -78 oC
O
OH
Ph
CH2Cl2
NaH, THF
then PPh3
81 %
reflux
Ph
99 %
3
3
(+)- , (-)-
2
2
(+)- , (-)-
3
rac-
2
rac-
O
(EtCO)2O
O
Et
KOH, K2CO3
PhCH3
O
O
O
reflux
Ph
Ph
84 %
4
4
(+)- , (-)-
7
7
(+)- , (-)-
4
rac-
7
rac-
O
O
O
O
O
O
Ph
O
6
Ph
PPh3, 0 %
SMe2, 16 %
Zn/AcOH, 27 %
5
With two enantiomeric dienophiles (+)-7 and ()-7 in hand, their [4+2]-cycloaddition with
nitroalkene to give nitronates 9 was investigated (Scheme 4). Denmark et al reported,18 that l-
acyloxy-2-((2-phenylcyclohexyl)oxy)ethenes of type 7 show poor -facial stereoselectivity in
MAPh-promoted [4+2]-cycloaddition with nitroalkenes. In our case, however, the SnCl4-
promoted reaction turned to be highly stereoselective and afforded only two of four possible
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stereoisomers of the 1,2-oxazine-N-oxide 9 in 10 : 1 ratio. The major isomer could be easily
separated by column chromatography. NMR studies revealed that the major isomer has 4,5-
trans-stereochemistry and originates from the exo-approach of dienophile 7 to nitroalkenes 9.
Thus, exceptionally high exo- and -facial selectivity were observed in the formation of nitronate
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9 from dienophile 7. Using this method, both enantiomers (+)-9 and ()-9 were prepared on up to
three grams scale with ee > 99 % and d.r. 30 : 1 (chiral HPLC) after column chromatography.
Scheme 4. Steps (4)  (5): assembly 1,2-oxazine-N-oxaides 9 and their functionalization
F
F
O
SnCl4, -94 °C
O
4
CH2Cl2
O
3
5
6
O
N
+
O
O
O
N
d.r. = 15 : 1
O
O
O
Ph
7
Ph
8
8
1
2
major isomer, 89 %
7
7
(+)-(1S,2R)-
(-)-(1R,2S)-
9
(+)-(4S,5R,6S,7S,8R)-
9
(-)-(4R,5S,6R,7R,8S)-
7
rac-
9
rac- (X-Ray)
F
F
PivCl, Et3N
MeCN
O
4
O
O
3
5
6
O
-30 to 0 oC
[3,3]
tBu
O
N
O
N
O
O
O
tBu
O
O
O
96 %
Ph
7
Ph
8
10
11
(+)-(4S,5R,6S,7S,8R)-
11
(-)-(4R,5S,6R,7R,8S)-
11
rac-
Although two stereogenic centers of the target molecule were now set, their absolute
stereochemistry could not be determined from NMR data. We were not able to obtain crystals for
the X-Ray analysis from the enantiopure samples of N-oxide 9. Fortunately, we succeeded in
getting X-Ray data for the racemic N-oxide rac-9, which was specially prepared from the
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racemic trans-2-phenylcyclohexanol rac-2 using the same synthetic sequence. Given the known
configuration of the chiral auxiliary, the absolute stereochemistry of enantiomeric 1,2-oxazine-
N-oxides (+)-9 and ()-9 could be unambiguously deduced from the relative configuration of
stereocenters in rac-9 determined by X-Ray.
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Each of enantiomeric 1,2-oxazine-N-oxides (+)-9 and ()-9 was subjected to acylation with
pivaloyl chloride/Et3N under conditions reported by us previously (Scheme 4).14 We were
pleased to find, that the desired 3-pivaloyloxymethyl-1,2-oxazines (+)-11 and ()-11 originating
from the [3,3]-rearrangement of transient N-acyloxyenamines 10 were obtained in 96 % yield
under very mild conditions and without any epimerization of the sensitive acetal moiety at C-6.
Importantly, this protocol proved to be highly site-selective, since oxygenation of the endo-
cyclic C-4 carbon was not observed.
On the next stage, reductive ring contraction of 1,2-oxazine to the pyrrolidine ring had to be
performed according to our synthetic plan. However, direct catalytic hydrogenation of the oxime
unit in 1,2-oxazines is known to be non-chemoselective and non-stereoselective attributed to the
formation of highly reactive C=NH imines as intermediates.19 For this reason, hydride reduction
of the C=N bond with NaBH3CN in acetic acid was initially performed (Scheme 5). Fortunately,
the reduction of 11 was stereospecific and afforded solely the required 3,4-trans-isomer of fully
saturated 1,2-oxazine 12. The trans-disposition of hydrogens H-3 and H-4 was deduced from the
1,2-diaxial spin-spin coupling constant (JH-3/H-4 = 10.3 Hz) and the presence of 1,3-diaxial
interaction between hydrogens H-3 and H-5 in the 2D NOESY spectra. Thus, the last stereogenic
center of the bicyclic moiety of target Merck12-a2-2 was correctly installed at this stage. This
stereochemical result is in line with the axial addition of the hydride to the most stable twist-like
conformation of protonated 1,2-oxazine 11 leading to the chair-like conformation of product 12.
It is noteworthy, that we observed small amounts of the C-6 epimer 12’, which, however, could
be used in the next step equally to the major isomer 12.
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Scheme 5. Step (6): hydride reduction of the oxime C=N bond in 1,2-oxazines 11
4
5
F
6
7
8
9
OG*
O
NaBH3CN
AcOH
OPiv
H
H
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11
12
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O
N
N
O
O
O
Ar
H
rt, 1.5 h
O
Ph
[BH3CN]-
H
O
Ar - 4-F-C6H4-
G* - 2-Ph-cyclohexyl
11
11
(+)-(4S,5R,6S,7S,8R)-
(-)-(4R,5S,6R,7R,8S)-
11
rac-
- CH2OPiv
F
F
O
O
O
4
4
OPiv
OPiv
5
6
3
5
6
3
O
NH
O
NH
O
O
O
Ph
Ph
73 %
14 %
12'
12
(+)-(4S,5R,6S,7S,8R)-
12
C-6-epimer (
)
(-)-(4R,5S,6R,7R,8S)-
12
rac-
Hydrogenation of 1,2-oxazines (+)-12 and ()-12 over Raney nickel led to the formation of
the protected prolinol derivatives, which were formed via tandem hydrogenolysis of the NO
bond, fragmentation of the hemiacetal moiety in 13 to give 14 and subsequent intramolecular
reductive amination in the intermediate 14 (Scheme 6).14 At this stage, the chiral auxiliary
alcohol 2 could be recovered (91 %) for further reuse. At least 1 g quantity of protected prolinols
(+)-15 and ()-15 could be prepared according to this method. Thus, we succeeded in preparing
the key unit of target Merck12-a2-2 (pyrrolidine ring with three contiguous stereogenic centers)
in a regio- and stereoselective manner on gram scale.
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Scheme 6. Step (7): reductive contraction of 1,2-oxazine ring in 12
4
5
F
F
6
7
8
9
45 - 50 bar H2
Ra-Ni, MeOH
O
Boc2O
O
O
4
OPiv
5
6
3
OPiv
10
11
12
13
14
15
16
17
18
19
20
21
22
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45
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51
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56
57
58
59
60
45 - 50 oC
68 %
NH2
OH
O
NH
O
O
O
Ph
Ph
7
8
12
13
(+)-(4S,5R,6S,7S,8R)-
12
(-)-(4R,5S,6R,7R,8S)-
12
rac-
F
F
H2, Ra-Ni
Boc2O
O
O
O
OPiv
O
OPiv
NH2
N
O
Boc
OH
Ph
14
15
(+)-(2R,3S,4R)-
15
(-)-(2S,3R,4S)-
15
rac-
2
, 91 %
Next, the construction of oxazolidinone ring to complete the fused bicyclic framework of
Merck12-a2-2 was performed. To do so, careful saponification of ester groups in 15 with 1 M
KOH in aqueous methanol to give Boc-protected diols 16 was initially carried out (Scheme 7,
route 1). Diols 16 were treated with TFA to remove Boc-group, and the resulting deprotected
prolinols were reacted without isolation with triphosgene and Et3N to give the desired saturated
pyrrolooxazolidinones (+)-17 and ()-17 in an acceptable yield.
Alternatively, the synthesis of fused pyrrolidines 17 from prolinols 15 could be accomplished
using an inverted sequence of deprotection operations as demonstrated on the racemic substrate
(Scheme 7, route 2). Boc-group was removed with TFA to give salt rac-18 followed by
hydrolysis of esters with KOH and acidification to give hydrochloride rac-19. However,
separation of highly polar hydrochloride rac-19 from residual inorganic salts and carboxylic
acids was problematic, while the presence of impurities dramatically decreased the yield in the
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subsequent reaction with triphosgene. Nevertheless, treatment of purified hydrochloride rac-19
with triphosgene and Et3N afforded the desired pyrrolooxazolidinone rac-17 in an acceptable
yield.
8
9
At this point, the relative configuration of stereocenters in pyrrolidine 18 and
pyrrolooxazolidinone 17 was secured by 2D NMR including COSY, HSQC, HMBC and
NOESY (see Experimental section and Supporting information). In the 2D NOESY spectra of
product 17, characteristic correlations between the aryl ring and hydrogens H-7a and H-6 were
observed, which confirm the proposed stereochemistry of the bicyclic motif (Scheme 7). Similar
correlations were found in the 2D NOESY spectra of pyrrolidine 18.
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13
14
15
16
17
18
19
20
21
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Scheme 7. Steps (8) – (9): construction of fused pyrrolidine subunit of Merck12-a2-2
route 1:
F
F
F
NOE
NOE
KOH
H
H
H
H
1. TFA, CH2Cl2, 0°C
MeOH-H2O
O
HO
7
O
7a
6
OPiv
OH
HO
N
N
N
O
78 %
2. triphosgene
Et3N, MeCN, 0 oC
Boc
Boc
O
16
15
(+)-(2R,3S,4R)-
16
60 %
(+)-(2R,3S,4R)-
15
17
(+)-(2R,3S,4R)-
17
(-)-(2S,3R,4S)-
16
(-)-(2S,3R,4S)-
15
(-)-(2S,3R,4S)-
rac-
rac-
17
rac-
F
F
route 2:
NOE
NOE
H
H
H
H
triphosgene,
Et3N, MeCN
KOH
MeOH-H2O
TFA
CH2Cl2
HO
17
rac-
4
2
O
OH
15
rac-
0 °C
NH2
NH2
OPiv
CF3COO
18
then
4 HCl/dioxane
0 °C
O
Cl
55 %
86 %
18
(from rac-
)
rac-
19
rac-
To complete the synthesis of target hNK1 antagonist 1, bis(trifluoromethyl)phenylethyl ether
moiety had to be installed at the free hydroxyl group in the bicyclic intermediate 17. Following
the report by Kuethe et al,13 we attempted to use bis(trifluoromethyl)phenylethanol
trichloroimidate 20 as an electrophile for the construction of the sec-sec ether unit under
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catalysis with strong protic acids. Model reaction of the racemic secondary alcohol rac-17 with
the imidate (R)-20 in the presence of HBF4Et2O did give the desired ether 1 as a mixture of two
diastereomers with a combined yield of only 15 % (Scheme 8). Variation of solvent,
temperature, the nature and the amount of protic acid did not result in any significant increase of
the yield (see Supporting information for details). Fortunately, we found that the use of a
stoichiometric amount of TMSOTf instead of a protic acid resulted in the formation of the
desired ether in a better yield (34 %) as a 1.4 : 1 mixture of C-12 epimers along with some
amount of TMS-ether of the initial pyrrolooxazolidinone 17. Same stereochemical result was
observed with the enantiomeric imidate (S)-20. Chiral HPLC analysis revealed that both epimers
were racemates demonstrating that the etherification reaction proceeds through an SN1-like
mechanism.
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Scheme 8. Benzylation of rac-17 with trichloroimidates 20
18CF3
NH
CCl3
F3C
16
17
O
F
15
14
F
11
F3C
13
12
10
CF3
8
O
9
20
20
(R)- or (S)-
7
6
5
H
HO
7a
N 4
1
conditions
N
O
2
3
O
O
O
17
rac-
1
1'
rac- + rac-
1
1'
)
Yield (d.r. rac- /rac-
Conditions
HBF4•Et2O (0.15 eq.), DCM/cyclohexane, 0 oC, 24 h
TMSOTf (1.25 eq.), CH2Cl2, 0 oC, 24 h
15 % (1 : 1)
34 % (1.4 : 1)
From recent total synthesis of some complex carbohydrates,20 we learned that 2,2,2-trifluoro-N-
phenylacetimidates are highly efficient electrophiles in the formation of glycosidic linkages.21 To
test this approach for the construction of sec-sec bis(trifluoromethyl)phenylethyl ether motif, a
new 2,2,2-trifluoro-N-phenylacetimidate (R)-21 was prepared and tested in the TMSOTf-
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promoted reaction with alcohols 17 (Scheme 9). The desired sec-sec ether was obtained in 67 %
yield as a nearly stoichiometric mixture of C-12 epimers. The isomers could be easily separated
by column chromatography on silica gel (slow moving isomer rac-1 and fast moving rac-1’).
Application of this procedure separately to (+)-17 and ()-17 delivered target Merck12-a2-2 (1)
and three of its stereoisomers individually. The enantiomeric purity of all obtained samples was
> 96 % ee as determined by chiral HPLC analysis.
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Scheme 9. Step (10): Introduction of bis(trifluoromethyl)phenylethyl group into
pyrrolooxazolidinones (+)-17 and ()-17
CF3
CF3
F
F
F
F3C
F3C
12
12
NPh
CF3
O
O
TMSOTf, CH2Cl2
MS AW-300
F3C
6
7
7a
6
7
7a
H
H
7
HO
O
7a
6
0 oC to rt
N
N
N
O
O
O
67 %
CF3
O
O
O
d.r. = 1 : 1
slow moving diastereomer fast moving diastereomer
1'
1 Merck12-a2-2
)
(6R,7S,7aR,12
S)-
(6R,7S,7aR,12R)-
(
17
(6R,7S,7aR)-
21
(R)-
21
(R)-
(R)-
17
17
(6S,7R,7aS)-
1
1'
(6S,7R,7aS,12S)-
(6S,7R,7aS,12R)-
21
rac-
1
rac-
1' (X-Ray)
rac-
Although the absolute stereochemistry of the bicyclic scaffold was determined on the
previous stages of the synthesis, the stereochemistry of the newly formed C-12 stereocenter was
not known and could not be determined from the 2D NOESY NMR data. Compound 1 and its
stereoisomers were obtained as viscous oils and attempts to crystallize them failed. We were
fortunate to get single crystals of the racemate of the fast moving isomer, which turned out to be
a diastereomer of Merck12-a2-2 (rac-1’). Thus, the relative and absolute configuration of all four
obtained stereoisomers was unambiguously deduced from this X-Ray.
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Conclusion
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8
9
In conclusion, we accomplished the asymmetric synthesis of a potent hNK1 antagonist Merck12-
a2-2 (1) using selective CH-oxygenation of 1,2-oxazine-N-oxides via a tandem acylation/[3,3]-
sigmatropic rearrangement process. The synthesis involved 10 steps in the longest sequence and
afforded target product in ca. 5 % overall yield. Although we were not able to install the C-12
center stereoselectively, our strategy allows the assembly of the pyrrolooxazolidinone subunit of
target molecule in a regio- and stereoselective manner. Using the developed strategy, we succeed
in the synthesis of three stereoisomers of Merck12-a2-2, for which SAR studies will be
performed in near future. The absolute stereochemistry of these stereoisomers was
unambiguously determined by X-Ray analysis of intermediates and the final product.
We believe that the straightforward strategy described here is general and can be used to access
enantiopure 3,4-disubstituted prolinols, which are frequently found in pharmaceutically relevant
molecules and organocatalysts.
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Experimental section
All reactions were carried out in oven-dried (150°C) glassware. The NMR spectra were recorded
at room temperature with residual solvents peaks as an internal reference. The 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 HRMS were measured on electrospray ionization (ESI)
instrument with a time-of-flight (TOF) detector. Peaks in the FT-IR spectra data are reported in
cm–1 with the following relative intensities: s (strong), m (medium), w (weak), br (broad), sh
(shoulder). Concentrations c in optical rotation angles are given in g/100 mL. [α]D values are
given in 10-1 deg cm2 g-1. Column chromatography was performed using Kieselgel 40-60 μm
60A. Analytical thin-layer chromatography was performed on silica gel plates with QF 254.
Visualization was accomplished with UV light and solution of anisaldehyde/H2SO4 in ethanol.
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Chiral HPLC analysis was performed on a chromatograph with a UV-VIS photodiode array
detector. The ozone/oxygen mixture was generated from dry oxygen (dried by Drierite column)
using a laboratory-made ozone generator (ozone output 8-12 mmol/h)
8
9
In most experiments, very similar yields in (+), (–) and racemic series were obtained if not
otherwise stated. In Schemes and procedures, the best yields among three series are given.
Docking was performed using AutoDock Vina software22 with using default parameters and the
degree of exhaustiveness set to 16. For the docking the crystallographic structure of hNK1
receptor with Aprepitant (PDB: 6HLO9a) was used. The receptor structure was prepared
according to classical AutoDock scenario: ligand and water molecules were removed, polar
hydrogens, Gasteiger-Huckel charges were added to protein (pdbqt input files of ligands were
prepared using AutoDock Tools 1.5.6). The receptor model was verified by successful redocking
of Aprepitant. 3D structures of ligands were generated using ChemBio3D Ultra 13.0 (MM2 force
field for geometry optimization). Gasteiger charges and all the active torsions were added to the
structures of ligands using AutoDock Tools 1.5.6 software. AutoGrid implemented in AutoDock
Tools 1.5.6 was used for defining the active site. The grid (60 Å × 60 Å × 60 Å points) was
centered on the co-crystallized ligand present in the complex. Top scored poses according to
predicted free energy of binding were selected for further comparison and analysis of protein-
ligand interactions (see Supporting information for details). Visualization of ligands in the
binding site of hNK1 receptor was done using Pymol v. 2.1.1.
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Steps (1)  (3): synthesis of chiral and racemic dienophile 7
O
8
11
7
9
O
10
6
3
8
8
6
3
6
3
1
2
O
1 O
O
1
5
4
9
5
4
O
5
4
7
7
2
2
9
12
10
11
10
12
15
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Synthesis of (2-(allyloxy)cyclohexyl)benzene (3). Sodium hydride (510 mg, 12.73 mmol, w. ca.
60 % in mineral oil) was suspended in dry THF (20 mL) and the mixture was cooled to 0 °C. The
solution of enantiopure or racemic trans-2-phenyl-1-cyclohexanol 2 (2.00 g, 11.35 mmol) in dry
THF (20 mL) was added and the reaction mixture was stirred for 30 min at rt. Allyl bromide (1.1
mL, 12.48 mmol) was added and the reaction mixture was refluxed (silicone oil bath) under
argon for 3.5 h. Then, additional portions of allyl bromide (0.55 mL, 6.24 mmol) and NaH (250
mg, 6.24 mmol, w. ca. 60 % in mineral oil) were added and the mixture was refluxed for another
5 h. The reaction mixture was cooled to rt, sat. aq. NH4Cl solution (40 mL) was added, and the
mixture was transferred into a separating funnel with sat. aq. NH4Cl solution (60 mL) and MTBE
(60 mL). The aqueous layer was extracted with MTBE (2×60 mL), and then the combined
organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was subjected to a column chromatography on silica gel
(Hexane → Hexane/EtOAc = 20/1 → 10/1) to yield 2.42 g (99 %) of alkene 3. Rf = 0.61
(Hexane/EtOAc = 3/1). 1H NMR (300 MHz, COSY, HSQC, CDCl3) δ 7.42 – 7.16 (m, 5H, H11,
H12 and H13), 5.63 (ddt, J = 19.1, 9.7, 5.5 Hz, 1H, H8), 5.07 – 5.00 (m, 1H, H9’), 5.00 – 4.94
(m, 1H, H9’’), 3.84 (ddt, J = 12.9, 5.7, 1.5 Hz, 1H, H7’), 3.63 (ddt, J = 12.9, 5.6, 1.6 Hz, 1H,
H7’’), 3.40 (td, J = 10.0, 4.5 Hz, 1H, H1), 2.60 (ddd, J = 12.3, 10.1, 3.7 Hz, 1H, H2), 2.29 – 2.17
(m, 1H, H6’), 2.00 – 1.85 (m, 2H, H3’ and H5’), 1.85 – 1.70 (m, 1H, H4’), 1.66 – 1.48 (m, 1H,
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13
H3’’), 1.48 – 1.25 (m, 3H, H4’’, H5’’ and H6’’). C{1H} NMR (75 MHz, DEPT135, HSQC,
CDCl3) δ 144.9 (C10), 135.6 (C8), 128.2 and 127.9 (C11 and C12), 126.1 (C13), 116.1 (C9),
81.7 (C1), 70.3 (C7), 51.4 (C2), 34.0 (C3), 32.7 (C6), 26.1 (C4), 25.2 (C5). HRMS (ESI): m/z
calcd. for [C15H21O]+ 217.1587, found 217.1596 [M+H]+.
(+)-(1R,2S)-3 (obtained from (+)-2): colorless oil, [α]D = +66 (с = 1, EtOAc, 24 C).
(−)-(1S,2R)-3 (obtained from (−)-2): colorless oil, [α]D = −64 (c = 1, EtOAc, 24 C).
rac-3 (obtained from rac-2): colorless oil.
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Synthesis of 2-((2-phenylcyclohexyl)oxy)acetaldehyde (4). Allyl ether 3 (2.42 g, 11.2 mmol)
was dissolved in dry DCM (40 mL) in a Schlenk flask, and the solution was cooled to −78 °C.
The ozone was bubbled through the solution until it turned light blue (ca. 2 h). Then, oxygen was
bubbled through the solution until the blue colour disappeared (ca. 20 min). The flask was filled
with argon, and triphenylphosphine (4.4 g, 16.8 mmol) was added. The mixture was stirred for
20 min, being allowed to warm up to −40 °C, and then kept in a freezer for 16 h. The volatile
components were then evaporated under reduced pressure, and the residue was subjected to a
column chromatography on silica gel (eluent: Hexane/EtOAc = 20/1 → 10/1 → 5/1 → 3/1) to
yield 1.97 g (81 %) of aldehyde 4. Rf = 0.54 (Hexane/EtOAc = 3/1). 1H NMR (300 MHz, COSY,
HSQC, HMBC, CDCl3) δ 9.29 (dd, J = 1.3, 1.1 Hz, 1H, H8), 7.37 – 7.20 (m, 5H, H9, H10, H11,
H12), 3.81 (dd, J = 17.7, 1.1 Hz, 1H, H7’), 3.65 (dd, J = 17.7, 1.3 Hz, 1H, H7’’), 3.39 (td, J =
10.0, 4.6 Hz, 1H, H1), 2.63 (ddd, J = 12.4, 10.0, 3.7 Hz, 1H, H2), 2.29 – 2.13 (m, 1H, H6’), 2.00
– 1.85 (m, 2H, H3’ and H5’), 1.85 – 1.73 (m, 1H, H4’), 1.65 – 1.49 (m, 1H, H3’’), 1.48 – 1.26
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13
(m, 3H, H4’’, H5’’ and H6’’). C{1H} NMR (75 MHz, DEPT135, HSQC, HMBC, CDCl3) δ
202.6 (C8), 144.2 (C9), 128.5 and 127.8 (C10 and C11), 126.6 (C12), 84.3 (C1), 75.2 (C7), 51.3
(C2), 33.7 (C3), 32.6 (C6), 25.9 (C4), 25.1 (C5). HRMS (ESI): m/z calcd. for [C14H18O2Na]+
241.1199, found 241.1203 [M+Na]+.
(+)-(1S,2R)-4 (obtained from (+)-3): colorless oil, [α]D = +60 (c = 1, EtOAc, 24 C).
(−)-(1R,2S)-4 (obtained from (−)-3): colorless oil, [α]D = −59 (c = 1, EtOAc, 24 C).
rac-4 (obtained from rac-3): colorless oil.
Synthesis of racemic 2-phenylcyclohexyl)oxy)methyl formate (6). Racemic allyl ether rac-2
(2.21 g, 10.2 mmol) was dissolved in dry DCM (35 mL) in a Schlenk flask, and the solution was
cooled to −78 °C. The ozone was bubbled through the solution until it turned light blue. Then, air
was bubbled through the solution until the blue colour disappeared. Zinc powder (1.0 g, 15.3
mmol) was added followed by 50 % aqueous AcOH (33.8 mL). The suspension was allowed to
warm to 0 °C, stirred for 30 minutes at 0 °C and then stirred for 2 h at rt. The reaction mixture
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was diluted with DCM (100 mL) and washed with water (40 mL), sat. aq. NaHCO3 solution (2 
20 ml), and brine (20 mL). The aqueous layers were back-extracted with DCM (40 mL). The
combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The
residue was subjected to a column chromatography on silica gel (eluent: Hexane/EtOAc = 20/1
→ 10/1 → 5/1) to give 0.64 g (27 %) of formate rac-6 (fast moving fraction) and 0.76 g (34 %)
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of aldehyde rac-4 (slow-moving fraction). Rf = 0.68 (Hexane/EtOAc = 3/1). Oil. H NMR (300
MHz, CDCl3) δ 7.74 (s, 1H), 7.41 – 7.16 (m, 5H), 5.07 (d, J = 6.4 Hz, 1H), 4.90 (d, J = 6.4 Hz,
1H), 3.67 (ddd, J = 10.1, 10.1, 4.6 Hz, 1H), 2.56 (ddd, J = 10.9, 9.9, 3.5 Hz, 1H), 2.28 – 2.07 (m,
13
1H), 2.02 – 1.22 (m, 7H). C{1H} NMR (75 MHz, CDCl3) δ 160.3 (CH), 143.6 (C), 128.1 (2
CH), 127.8 (2 CH), 126.3 (CH), 87.6 (CH2), 83.2 (CH), 50.7 (CH), 33.2 (CH2), 33.1 (CH2), 25.6
(CH2), 24.8 (CH2). FT-IR (thin layer): 3029 (w), 2932 (s), 2859 (m), 1730 (s), 1602 (w), 1493
(m), 1450 (m), 1372 (w), 1163 (s), 1132 (s), 1080 (s), 967 (m, sh), 870 (s), 757 (m), 701 (m), 521
(m). HRMS (ESI): m/z calcd. for [C14H18O3K]+ 273.0888, found 273.0889 [M+K]+.
Synthesis of (Z)-2-((2-phenylcyclohexyl)oxy)vinyl propionate (7). To a stirred solution of
enantiopure or racemic aldehyde 4 (1.36 g, 6.23 mmol) in toluene (9 mL) were added propionic
anhydride (8.0 mL, 62.3 mmol), KOH (37 mg, 0.66 mmol), and K2CO3 (4.30 g, 31.2 mmol). The
mixture was refluxed (silicon oil bath) under argon for 6 h and then cooled to rt. Diethyl ether
(40 mL) and sat. aq. Na2CO3 solution (60 mL) were added to the reaction mixture, and it was
intensively stirred for 3 h. Then, the mixture was poured into a separating funnel containing
diethyl ether (100 mL) and sat. aq. Na2CO3 solution (100 mL). The aqueous layer was washed
with diethyl ether (2×50 mL), combined organic layers were washed with water (2×150 mL) and
brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was
subjected to a column chromatography on silica gel (Hexane/EtOAc = 20/1 → 10/1) to yield
1.43 g (84 %) of alkene 7. Rf = 0.70 (Hexane/EtOAc = 3/1). 1H NMR (300 MHz, COSY, HSQC,
CDCl3) δ 7.35 – 7.17 (m, 5H, H13, H14, H15), 6.24 (d, J = 3.7 Hz, 1H, H8), 5.38 (d, J = 3.7 Hz,
1H, H7), 3.73 (td, J = 10.3, 4.4 Hz, 1H, H1), 2.73 (ddd, J = 12.3, 10.3, 3.8 Hz, 1H, H2), 2.39 (q,
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J = 7.6 Hz, 2H, H10), 2.30 – 2.13 (m, 1H, H6’), 2.01 – 1.85 (m, 2H, H3’ and H5’), 1.85 – 1.71
(m, 1H, H4’), 1.68 – 1.47 (m, 2H, H3’’ and H6’’), 1.47 – 1.28 (m, 2H, H4’’ and H5’’), 1.15 (t, J
6
7
13
= 7.6 Hz, 3H, H11). C{1H} NMR (75 MHz, HSQC, DEPT135, CDCl3) δ 171.3 (C9), 143.4
8
9
(C12), 132.2 (C7), 128.3 and 127.8 (C13 and C14), 126.5 (C15), 117.2 (C8), 85.6 (C1), 50.4
(C2), 33.7 (C3), 32.8 (C6), 27.3 (C10), 25.8 (C4), 25.0 (C5), 9.0 (C11). HRMS (ESI): m/z calcd.
for [C17H23O3]+ 275.1642, found 275.1643 [M+H]+.
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(+)-(1S,2R)-7 (obtained from (+)-4): colorless oil.
(−)-(1R,2S)-7 (obtained from (−)-4): colorless oil, [α]D = −123 (c = 1, EtOAc, 25 C).
rac-7 (obtained from rac-4): colorless oil.
Steps (4)  (6)): synthesis and functionalization of 1,2-oxazine-N-oxide 9
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(E)-1-Fluoro-4-(2-nitroprop-1-en-1-yl)benzene (8). To
a
stirred solution of 4-
fluorobenzaldehyde (2.59 mL, 24.2 mmol) and nitroethane (2.61 mL, 36.3 mmol) in toluene (25
mL) was added n-butylamine (0.25 mL, 2.5 mmol). The mixture was refluxed with a Dean-Stark
trap for ca. 6 h. The resulting dark-colored solution was kept in the fridge overnight and the
resulting nitroalkene 8 was filtered off (1.77 g). Mother liquors were concentrated in vacuum and
the residue was crystallized from methanol to give additionally 0.49 g of nitroalkene 8. Overall
yield: 2.26 g (52 %). Yellow solid. m.p. = 60 ‒ 62 °C (MeOH). Rf = 0.71 (Hexane/EtOAc = 3/1).
Lit.23 64 °C. NMR spectra are in agreement with literature data.23
4-(4-Fluorophenyl)-3-methyl-6-((2-phenylcyclohexyl)oxy)-5-(propionyloxy)-5,6-dihydro-
4H-1,2-oxazine 2-oxide (9). Nitroalkene 8 (1.00 g, 5.52 mmol) was dissolved in dry DCM (30
mL) in a Schlenk flask under argon atmosphere, then CaH2 (ca. 100 mg) was added and the
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mixture was cooled to −94 °C (dry ice/acetone). Tin tetrachloride (720 μL, 6.16 mmol) was
added and the mixture was stirred for 10 min. Then, a solution of enantiopure or racemic alkene
7 (1.85 g, 6.73 mmol) in dry DCM (15 mL) was added dropwise with intensive stirring. The
reaction mixture was stirred at −94 °C for 2 h, then transferred into a separating funnel
containing EtOAc (150 mL) and sat. aqueous Na2CO3 solution (150 mL). The aqueous layer was
extracted with EtOAc (2×100 mL). The combined organic layers were washed with water
(3×100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure. The residue was subjected to a column chromatography on silica gel
(Hexane/EtOAc = 10/1 → 5/1 → 3/1) to give 1.95 g (78 %) of nitronate 9 as a main fraction (d.r.
ca. 30 : 1 by HPLC). The minor fraction contained 0.51 g (20 %) of a 5 : 1 mixture of nitronate 9
and its diastereomer 9’ with an opposite configuration of stereocenters in the 1,2-oxazine ring.
Second column chromatography of the mixed fraction afforded additional 0.29 g (11 %) of a
pure major diastereomer 9. In case of the racemic nitronate synthesis, column chromatography
was not required, and the residue from the aqueous work-up was crystallized from diethyl ether
to yield 59 % of nitronate 9 (2.72 g from 1.84 g of nitroalkene 8) after a single recrystallization.
Rf = 0.19 (Hexane/EtOAc = 3/1). 1H NMR (300 MHz, COSY, HSQC, HMBC, CDCl3) δ 7.35 –
7.21 (m, 4H, H14 and H15), 7.18 – 7.10 (m, 1H, H16), 7.05 – 6.91 (m, 4H, H21 and H22), 5.64
(d, J = 3.0 Hz, 1H, H6eq), 4.87 (dd, J = 10.2, 3.0 Hz, 1H, H5ax), 4.14 (td, J = 10.5, 4.1 Hz, 1H,
H7ax), 3.31 (dq, J = 10.2, 1.7 Hz, 1H, H4ax), 2.63 (ddd, J = 12.3, 10.5, 3.6 Hz, 1H, H8ax), 2.19 (q,
J = 7.6 Hz, 2H, H18), 2.33 – 2.05 (m, 1H, H12’), 1.94 – 1.82 (m, 2H, H9’ and H11’), 1.81 – 1.68
(m, 1H, H10’), 1.66 – 1.46 (m, 1H, H9’’), 1.46 – 1.21 (m, 3H, H10’’, H11’’ and H12’’), 1.19 (d,
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J = 1.7 Hz, 3H, H24), 1.00 (t, J = 7.6 Hz, 3H, H19). C{1H} NMR (75 MHz, HSQC, HMBC,
DEPT135, CDCl3) δ 173.4 (C17), 162.5 (d, J = 247.2 Hz, C23), 143.9 (C13), 132.8 (d, J = 3.3
Hz, C20), 130.2 (d, J = 8.3 Hz, C21), 128.4 and 127.7 (C14 and C15), 126.2 (C16), 120.1 (C3),
116.1 (d, J = 21.7 Hz, C22), 94.0 (C6), 77.3 (C7), 70.4 (C5), 50.7 (C8), 44.4 (C4), 34.1 (C9),
30.2 (C12), 27.3 (C18), 26.0 (C10), 24.5 (C11), 16.9 (C24), 9.1 (C19). 19F NMR (282 MHz,
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CDCl3) δ -114.5 (m). HRMS (ESI): m/z calcd. for [C26H31FNO5]+ 456.2181, found 456.2185
[M+H]+. Elemental analysis: calcd. C, 68.55; H, 6.64; N, 3.07; found C, 68.32; H, 6.68; N, 3.16
(rac-9).
8
9
(+)-(4S,5R,6S,7S,8R)-9 (obtained from (+)-(1S,2R)-7): yellowish foam, [α]D = +304 (c = 1,
EtOAc, 24 C). HPLC analysis: ee > 99.5 % (RT 16.7 min; column CHIRALPAK IA-3 (15 cm);
solvent Hexane/i-PrOH = 90 : 10; temperature 40°C; flow rate 1 mL/min).
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(−)-(4R,5S,6R,7R,8S)-9 (obtained from (−)-(1R,2S)-7): yellowish foam, [α]D = −304 (c = 1,
EtOAc, 23 °C). HPLC analysis: ee > 99.5 % (RT 9.2 min; column CHIRALPAK IA-3 (15 cm);
solvent Hexane/i-PrOH = 90 : 10; temperature 40 °C; flow rate 1 mL/min).
rac-9 (obtained from rac-7): white crystals, m.p. = 116.5 ‒ 118.0 °C (Et2O). Sample for single
crystal X-Ray analysis was obtained by crystallization from diethyl ether. CCDC 1987344
contains the supplementary crystallographic information for rac-9.
Characteristic NMR data of minor diastereomer rel-(4S,5R,6S,7R,8S)-9’ (in mixture with major
1
isomer 9). H NMR (300 MHz, CDCl3, characteristic signals) δ 4.99 (d, J = 3.0 Hz, 1H), 4.74
(dd, J = 9.8, 3.0 Hz, 1H), 4.00 (td, J = 10.3, 4.6 Hz, 1H), 3.73 (dd, J = 9.9, 1.7 Hz, 1H), 0.87 (t, J
= 7.5 Hz, 3H).
(4-(4-Fluorophenyl)-6-((2-phenylcyclohexyl)oxy)-5-(propionyloxy)-5,6-dihydro-4H-1,2-
oxazin-3-yl)methyl pivalate (11). Enantiopure or racemic nitronate 9 (3.68 g, 8.08 mmol) was
dissolved in dry acetonitrile (18 mL) in a Schlenk flask under argon atmosphere, then NEt3 (2.3
mL, 16.52 mmol) was added. The reaction mixture was cooled to −30 °C and pivaloyl chloride
(1.5 mL, 12.2 mmol) was added. The reaction mixture was stirred at ca. −30 °C for 1 h, then kept
in a fridge (ca. 0 °C) for 20 h. The mixture was transferred into a separating funnel containing
MTBE (200 mL) and 0.25 M aq. NaHSO4 solution (100 mL). The aqueous layer was extracted
with MTBE (2×100 mL), then the combined organic layers were washed with brine (100 mL),
dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The residue
was subjected to a column chromatography on silica gel (Hexane/EtOAc = 10/1) to yield 4.18 g
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(96 %) of pivalate 11. Rf = 0.71 (Hexane/EtOAc = 3/1). H NMR (300 MHz, COSY, HSQC,
HMBC, CDCl3) δ 7.34 – 7.14 (m, 5H, H14, H15 and H16), 7.12 – 6.91 (m, 4H, H21 and H22),
5.43 (d, J = 2.9 Hz, 1H, H6eq), 4.97 (dd, J = 10.8, 2.9 Hz, 1H, H5ax), 4.07 – 3.91 (m, 1H, H7),
3.99 (d, J = 4.7 Hz, 2H, H24), 3.34 (d, J = 10.8 Hz, 1H, H4ax), 2.64 (ddd, J = 12.3, 10.6, 3.7 Hz,
1H, H8ax), 2.21 (qd, J = 7.7, 5.5 Hz, 2H, H18), 2.31 – 2.13 (m, 1H, H12’), 2.00 – 1.85 (m, 2H,
H9’ and H11’), 1.85 – 1.74 (m, 1H, H10’), 1.67 – 1.45 (m, 1H, H9’’), 1.45 – 1.20 (m, 3H, H10’’,
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H11’’ and H12’’), 1.10 (s, 9H, H27), 1.02 (t, J = 7.7 Hz, 3H, H19). C{1H} NMR (75 MHz,
HSQC, HMBC, DEPT135, CDCl3) δ 177.4 (C25), 173.5 (C17), 162.4 (d, J = 247.4 Hz, C23),
154.3 (C3), 144.0 (C13), 131.5 (d, J = 3.4 Hz, C20), 130.6 (d, J = 8.1 Hz, C21), 128.2 and 127.9
(C14 and C15), 126.2 (C16), 116.0 (d, J = 21.6 Hz, C22), 91.0 (C6), 78.0 (C7), 70.8 (C5), 63.0
(C24), 50.4 (C8), 40.7 (C4), 38.7 (C26), 34.3 (C9), 31.0 (C12), 27.4 (C18), 27.2 (C27), 26.1
(C10), 24.8 (C11), 9.2 (C19). 19F NMR (282 MHz, CDCl3) δ -114.8 (m). HRMS (ESI): m/z
calcd. for [C31H39FNO6]+ 540.2756, found 540.2755 [M+H]+.
(+)-(4S,5R,6S,7S,8R)-11 (obtained from (+)-9): yellowish oil, [α]D = +280 (с = 1, EtOAc, 24 C).
(−)-(4R,5S,6R,7R,8S)-11 (obtained from (−)-9): yellowish oil, [α]D = −288 (с = 1, EtOAc, 23 C).
rac-11 (obtained from rac-9): yellowish oil.
(4-(4-Fluorophenyl)-6-((2-phenylcyclohexyl)oxy)-5-(propionyloxy)-1,2-oxazinan-3-
yl)methyl pivalate (12). To an intensively stirred solution of enantiopure or racemic 5,6-
dihydro-4H-1,2-oxazine 11 (1.31 g, 2.43 mmol) in acetic acid (10 mL) was added sodium
cyanoborohydride (0.92 g, 14.64 mmol) under argon. The reaction mixture was stirred at rt for
1.5 h, then sat. aq. NaHCO3 solution (150 mL) and EtOAc (50 mL) were carefully added, and
the mixture was poured into a separating funnel containing EtOAc (50 mL). The aqueous layer
was extracted with EtOAc (2×50 mL), the combined organic layers were washed with sat. aq.
NaHCO3 solution (2×100 mL), water (100 mL) and brine (200 mL), dried over Na2SO4 and
concentrated under reduced pressure to dryness. The residue was subjected to a column
chromatography on silica gel (Hexane/EtOAc = 5/1 → 3/1) to yield 1.14 g (87 %) of oxazine 12
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in a mixture with C-6 epimer (d.r. 12/12’ = 5 : 1). Pure fraction of 12 was obtained by second
column chromatography. In case of the racemic synthesis, column chromatography was not
required, and the residue after aqueous work-up was crystallized from methanol to yield 77 % of
1,2-oxazine rac-12 (contained no epimer). Rf = 0.30 (Hexane/EtOAc = 3/1). 1H NMR (300 MHz,
COSY, HSQC, HMBC, NOESY, CDCl3) δ 7.40 – 7.33 (m, 4H, H14 and H15), 7.26 – 7.15 (m,
1H, H16), 7.07 (m, 2H, H21), 6.94 (m, 2H, H22), 5.07 (d, J = 3.5 Hz, 1H, H6eq), 4.94 (dd, J =
11.5, 3.5 Hz, 1H, H5ax), 4.13 (d, J = 12.8 Hz, 1H, NH), 3.74 (td, J = 10.3, 4.2 Hz, 1H, H7ax), 3.48
(dd, J = 11.7, 2.7 Hz, 1H, H24’), 3.31 (dddd, J = 12.8, 10.3, 7.2, 2.7 Hz, 1H, H3ax), 3.19 (dd, J =
11.7, 7.2 Hz, 1H, H24’’), 2.70 (ddd, J = 12.6, 10.3, 3.9 Hz, 1H, H8ax), 2.61 (dd, J = 11.5, 10.3
Hz, 1H, H4ax), 2.08 (q, J = 7.7 Hz, 2H, H18), 2.07 – 1.90 (m, 2H, H9’ and H12’), 1.90 – 1.72 (m,
2H, H10’ and H11’), 1.69 – 1.47 (m, 1H, H9’’), 1.33 (m, 3H, H10’’, H11’’ and H12’’), 1.10 (s,
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9H, H27), 0.91 (t, J = 7.6 Hz, 3H, H19). C{1H} NMR (75 MHz, HSQC, HMBC, DEPT135,
CDCl3) δ 178.0 (C25), 173.7 (C17), 162.1 (d, J = 245.8 Hz, C23), 144.3 (C13), 133.0 (d, J = 3.1
Hz, C20), 129.5 (d, J = 7.2 Hz, C21), 129.0 (C14 or C15), 127.9 (C14 or C15), 127.1 (C16),
115.7 (d, J = 21.4 Hz, C22), 93.6 (C6), 79.7 (C7), 72.4 (C5), 62.8 (C24), 60.5 (C3), 50.7 (C8),
42.6 (C4), 38.7 (C26), 33.8 (C9), 31.7 (C12), 27.4 (C18), 27.2 (C27), 26.0 (C10), 24.8 (C11), 9.1
(C19). 19F NMR (282 MHz, CDCl3) δ -115.9 (m). Characteristic 2D NOESY correlations:
H3ax/H5ax. HRMS (ESI): m/z calcd. for [C31H41FNO6]+ 542.2912, found 542.2906 [M+H]+.
(+)-(3R,4S,5R,6S,7S,8R)-12 (obtained from (+)-11): white foam, [α]D = +210 (с = 1, EtOAc, 23
C).
(−)-(3S,4R,5S,6R,7R,8S)-12 (obtained from (−)-11): white foam, [α]D = −200 (с = 1, EtOAc, 25
C).
rac-12 (obtained from rac-11): white crystals, m.p. = 135.5 − 136.5 °C (CH3OH).
1
Characteristic NMR data of C-6 epimer 12’ (in a mixed fraction with 12, 12/12’ = 3 : 1). H
NMR (300 MHz, CDCl3) δ 5.79 (br d, J = 10.7 Hz, 1H), 5.46 (d, J = 3.5 Hz, 1H), 5.02 (dd, J =
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11.6, 3.5 Hz, 1H), 4.01 (ddd, J = 10.4, 10.4, 4.1 Hz, 1H), 3.74 (d, J = 13.3 Hz, 1H), 3.66 (br ddd,
J = 11.8, 10.7, 4.0 Hz, 1H), 3.48 (d, J = 13.3, 4.4 Hz, 1H), 2.97 (dd, J = 11.8, 11.6 Hz, 1H).
Steps (7)  (9): synthesis of pyrrolooxazolidinones 17
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Tert-butyl
3-(4-fluorophenyl)-2-((pivaloyloxy)methyl)-4-(propionyloxy)pyrrolidine-1-
carboxylate (15). A solution of enantiopure or racemic 1,2-oxazine 12 (0.40 g, 0.738 mmol) and
Boc2O (490 mg, 2.25 mmol) in methanol (1.5 mL) was placed in a glass vial. A suspension of
Raney nickel (ca. 100 mg) in methanol (ca. 1 mL) was added. The reaction vial was placed in a
steel autoclave, that was then flushed and filled with hydrogen to a pressure of 45 bar and heated
to 45 − 50 °C. The hydrogenation was conducted for 2 h with intensive stirring. Then, the
autoclave was cooled to rt and evacuated, the catalyst was removed using a magnet and washed
with methanol several times. 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 0.226 g (68 %) of N-Boc pyrrolidine 15. The column was then washed with
Hexane/EtOAc = 5/1 to collect the recovered trans-2-phenylcyclohexanol (0.118 g, 91 %). Rf =
1
0.76 (Hexane/EtOAc = 3/1). H NMR (300 MHz, COSY, HSQC, 320 K, CDCl3) δ 7.22 – 7.11
(m, 2H, H7), 7.07 – 6.92 (m, 2H, H8), 5.18 – 4.95 (m, 1H, H4), 4.44 – 4.17 (m, 2H, H10), 4.15 –
3.87 (m, 2H, H2 and H5’), 3.46 – 3.23 (m, 2H, H3 and H5’’), 2.33 (q, J = 7.5 Hz, 2H, H15), 1.49
(s, 9H, H19), 1.15 (s, 9H, H13), 1.11 (t, J = 7.6 Hz, 3H, H16). 13C{1H} NMR (75 MHz, HSQC,
320 K, CDCl3) δ 178.1 (C11), 173.9 (C14), 162.3 (d, J = 246.4 Hz, C9), 154.1 (C17), 135.2
(C6), 129.0 (d, J = 8.1 Hz, C7), 116.0 (d, J = 21.4 Hz, C8), 80.8 (C18), 77.4 (C4), 63.5 (C10),
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61.3 (C2), 51.4 (C3), 50.9 (C5), 39.0 (C12), 28.6 (C19), 27.7 (C15), 27.3 (C13), 9.0 (C16). F
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NMR (282 MHz, CDCl3) δ -115.8 (m), -115.9 (m). Signal of fluorine appears as two singlets due
to the presence of N-Boc rotamers. HRMS (ESI): m/z calcd. for [C24H35FNO6]+ 452.2443, found
452.2431 [M+H]+.
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(+)-(2R,3S,4R)-15 (obtained from (+)-12): colorless oil , [α]D24 = +0.3 (c = 1, EtOAc, 24 C).
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(−)-(2S,3R,4S)-15 (obtained from (−)-12): colorless oil, [α]D24 = −0.3 (c = 1, EtOAc, 28 C).
rac-15 (obtained from rac-12): colorless oil.
Tert-butyl 3-(4-fluorophenyl)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (16).
Enantiopure or racemic pyrrolidine 15 (151 mg, 0.334 mmol) was treated with 1M solution of
potassium hydroxide in methanol/water = 1 : 1 mixture (6.7 mL, 6.7 mmol). The reaction
mixture was stirred at rt for 24 h, then the solvent was evaporated under reduced pressure and the
residue was subjected to a column chromatography on silica gel (Hexane/EtOAc = 1/1 →
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EtOAc) to yield 81 mg (78 %) of diol 16. Rf = 0.61 (EtOAc). H NMR (300 MHz, COSY,
HSQC, CDCl3) δ 7.17 – 7.11 (m, 2H, H7), 7.05 – 6.97 (m, 2H, H8), 4.09 (dd, J = 6.1, 4.6 Hz,
1H, H4), 4.04 – 3.91 (m, 2H, H10), 3.85 (dd, J = 11.8, 6.1 Hz, 1H, H5’), 3.79 (s, 2H, both OH),
3.66 (dd, J = 11.4, 4.2 Hz, 1H, H2), 3.34 (dd, J = 11.8, 4.6 Hz, 1H, H5’’), 3.07 (br s, 1H, H3),
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1.48 (s, 9H, H13). C{1H} NMR (75 MHz, COSY, HSQC, CDCl3) δ 162.1 (d, J = 245.0 Hz,
C9), 156.1 (C11), 135.4 (C6), 129.1 (C7), 116.0 (d, J = 21.3 Hz, C8), 80.9 (C12), 75.7 (C4), 65.4
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(C10), 64.9 (C2), 55.3 (C3), 54.0 (C5), 28.6 (C13). F NMR (282 MHz, CDCl3) δ -116.2 (m).
HRMS (ESI): m/z calcd. for [C16H23FNO4]+ 312.1606, found 312.1606 [M+H]+.
(+)-(2R,3S,4R)-16 (obtained from (+)-15): colorless oil, [α]D = +17 (c = 1, EtOAc, 25 C).
(−)-(2S,3R,4S)-16 (obtained from (−)-15): colorless oil, [α]D = −21 (c = 1, EtOAc, 27 C).
rac-16 (obtained from rac-15): colorless oil.
Rel-(2R,3S,4R)-3-(4-fluorophenyl)-2-((pivaloyloxy)methyl)-4-(propionyloxy)pyrrolidin-1-
ium trifluoroacetate (rac-18). To a stirred solution of rac-15 (280 mg, 0.62 mmol) in DCM (4.2
mL) was added CF3COOH (0.96 mL, 12.6 mmol) at 0 C. The mixture was stirred at this
temperature for 2 h, and then concentrated under reduced pressure. The residue was treated with
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diethyl ether to give 251 mg (86 %) of the trifluoroacetate salt rac-18 as white solid. m.p. =
145.5 − 152.0 °C (Et2O). 1H NMR (300 MHz, COSY, HSQC, HMBC, NOESY, CDCl3) δ 11.0 −
9.5 (br, 2H, NH), 7.27 (m, 2H, H7), 7.12 (m, 2H, H8), 5.25 (dd, J = 11.1, 6.8 Hz, 1H, H4), 4.36
(d, J = 4.7 Hz, 2H, H10), 3.97 (dt, J = 9.6, 4.7 Hz, 1H, H2), 3.86 (dd, J = 12.8, 6.8 Hz, 1H, H5’),
3.45 (m, 2H, H3 and H5’’), 2.35 (q, J = 7.5 Hz, 2H, H15), 1.18 (s, 9H, H13), 1.11 (t, J = 7.5 Hz,
3H, H16). 13C{1H} NMR (75 MHz, HSQC, HMBC, DEPT135, CDCl3) δ 178.2 (C11), 173.9
(C14), 167.6 (CF3COO), 162.6 (q, J = 75 Hz, CF3COO), 162.8 (d, J = 248 Hz, C9), 131.0 (C6),
129.4 (d, J = 8.2 Hz, C7), 116.6 (d, J = 21.7 Hz, C8), 77.1 (C4), 62.5 (C2), 61.3 (C10), 51.0
(C3), 49.2 (C5), 38.9 (C12), 27.1 (C15), 26.9 (C13), 8.8 (C16). 19F NMR (282 MHz, CDCl3) δ -
76.4 (s), -113.8 (m). Characteristic 2D NOESY correlations: H4/H7, H7/H2. HRMS (ESI): m/z
calcd. for [C19H27FNO4]+ 352.1919, found 352.1917 [M-CF3COO]+.
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7-(4-Fluorophenyl)-6-hydroxytetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (17). Method 1:
Enantiopure or racemic diol 16 (29.5 mg, 0.095 mmol) was dissolved in DCM (0.95 mL), and
the solution was cooled to 0 °C. Trifluoroacetic acid (0.15 mL, 1.96 mmol) was added, and the
mixture was stirred for 30 min under argon atmosphere, then the volatile components were
removed under reduced pressure. The residue was dried in vacuum until constant weight and
then dissolved in dry acetonitrile (0.60 mL). The resulting solution was cooled to 0 − 5 C, then
a solution of triphosgene (14 mg, 0.047 mmol) in dry acetonitrile (0.35 mL) and triethylamine
(0.070 mL, 0.50 mmol) were added. The reaction mixture was stirred at 0 °C for 1 h, and the
volatile components were removed under reduced pressure. The residue was subjected to a
chromatography on preparative TLC-plate (eluent: EtOAc) to yield 13.5 mg (60 %) of target
pyrrolooxazolone 17.
Method 2: Racemic trifluoroacetate rac-18 (750 mg, 1.61 mmol) was treated with 32 mL of 1M
solution of KOH in MeOH/H2O (1 : 1). The mixture was stirred for 9 h at rt and then kept
overnight without stirring. The resulting solution was cooled to 0 − 5 C and 4 M solution of
HCl in dioxane (32 mL) was added. After 20 min of stirring, volatiles were removed under
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reduced pressure. Acetonitrile (5 mL) was added and the mixture was concentrated again. The
residue was dried in vacuum and triturated with pentane (2  20 mL) to remove carboxylic acids.
The remaining solid was dried in vacuum and treated with MeCN (2  15 mL) and then MeOH
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(2  15 mL). The insoluble material (inorganic salts) was filtered off, and the combined organic
extracts were concentrated under reduced pressure. The residual solid (crude hydrochloride salt
rac-19) was dried in vacuum and then dissolved in dry MeCN (6 mL). The solution was cooled
to 0 − 5 C and a solution of triphosgene (240 mg, 0.81 mmol) in MeCN (5 ml) was added
followed by Et3N (1.12 ml, 8.05 mmol). The mixture was stirred at this temperature for 20
minutes and then allowed to warm to rt. After stirring for 2.5 h at rt, the mixture was
concentrated under reduced pressure and the residue was subjected to a column chromatography
on silica gel (Hexane/EtOAc = 5/1→1/1→ EtOAc) to yield 208 mg (55 % based on rac-18) of
target pyrrolooxazolone rac-17.24
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Rf = 0.67 (EtOAc/methanol = 10/1). H NMR (300 MHz, COSY, HSQC, HMBC, NOESY,
CDCl3) δ 7.23 – 7.14 (m, 2H, H9), 7.09 – 6.97 (m, 2H, H10), 4.52 – 4.40 (m, 1H, H6), 4.46 (dd,
J = 9.0, 8.4 Hz, 1H, H1’), 4.23 (dd, J = 9.0, 3.7 Hz, 1H, H1’’), 4.04 (ddd, J = 9.0, 8.4, 3.7 Hz,
1H, H7a), 3.60 (d, J = 5.7 Hz, 2H, H5), 3.56 (br, 1H, OH), 3.00 (dd, J = 9.0, 6.8 Hz, 1H, H7).
13C{1H} NMR (75 MHz, HSQC, HMBC, DEPT135, CDCl3) δ 162.3 (d, J = 246.6 Hz, C11),
162.2 (C3), 133.2 (d, J = 3.1 Hz, C8), 129.3 (d, J = 8.0 Hz, C9), 116.1 (d, J = 21.3 Hz, C10),
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79.9 (C6), 67.6 (C1), 64.0 (C7a), 57.7 (C7), 53.7 (C5). F NMR (282 MHz, CDCl3) δ -115.4
(m). Characteristic 2D NOESY correlations: H7a/H9, H6/H9. HRMS (ESI): m/z calcd. for
[C12H13FNO3]+ 238.0874, found 238.0874 [M+H]+.
(+)-(6R,7S,7aR)-17 (obtained from (+)-16): white crystals, m.p. = 165.0 − 166.5 °C (Et2O), [α]D
= +12 (с = 0.5, EtOH 96 %, 24 °C). HPLC analysis: ee > 99.5 % (RT 6.7 min; column
CHIRALPAK IA-3 (15 cm); solvent Hexane/i-PrOH = 80 : 20; temperature 40 °C; flow rate 1
ml/min).
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