An Approach to 3-Oxa-7-azabicyclo[33.0]octanes - Bicyclic Morpholine Surrogates

Article abstract of DOI:10.1055/s-0036-1588785

An approach to 3-oxa-7-azabicyclo[3.3.0]octanes, bicyclic morpholine analogues, is reported, which relies on [3+2] cycloaddition of maleic anhydrides or furan-2(5 H)-ones and an in situ generated azomethine ylide. The utility of the method was demonstrated on a multigram scale.

Full text of DOI:10.1055/s-0036-1588785

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
paper
A
en
Y. M. Sokolenko et al.
Paper
Synthesis
An Approach to 3-Oxa-7-azabicyclo[3.3.0]octanes – Bicyclic
Morpholine Surrogates
Yevhenii M. Sokolenkoa,b
Eugeniy N. Ostapchuka,b
Artem Artemenkob
Oleksandr O. Grygorenko*a
a Taras Shevchenko National University of Kyiv, Volodymyrska
Street 60, Kyiv 01601, Ukraine
b Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103,
Ukraine
gregor@univ.kiev.ua
Received: 02.02.2017
Accepted after revision: 21.03.2017
Published online: 13.04.2017
weight hydrophilic building blocks for medicinal chemistry
that fully comply with requirements of lead-oriented syn-
thesis.8 In particular, 3-oxa-7-azabicyclo[3.3.0]octane (1)
can be considered as a bicyclic non-flattened morpholine
surrogate, with the distance between the heteroatoms
slightly increased (Figure 1). Such surrogates can be useful
for bioisosteric replacements during compound optimiza-
tion in drug discovery to fine-tune binding with potential
biological targets, to reduce off-target activity, or to im-
prove DMPK properties. Derivatives of 1 were found among
effective inhibitors of very late antigen-4 (VLA-4) 2;9 pros-
taglandin E2 synthase 1 (PGES-1) 3,10 glycogen synthase ki-
nase 3β (GSK-3β) 4,11 leukotriene A4 hydrolase (LTA4H) 5,12
antagonists of CC chemokine receptors (CCR2) 6,13 or anti-
bacterial agents 7 (Figure 1).14
DOI: 10.1055/s-0036-1588785; Art ID: ss-2017-t0066-op
Abstract An approach to 3-oxa-7-azabicyclo[3.3.0]octanes, bicyclic
morpholine analogues, is reported, which relies on [3+2] cycloaddition
of maleic anhydrides or furan-2(5H)-ones and an in situ generated
azomethine ylide. The utility of the method was demonstrated on a
multigram scale.
Key words cycloaddition, bicyclic compounds, morpholine ana-
logues, conformational restriction, pyrrolidines, oxygen heterocycles
Morpholine is one of the most recognized saturated het-
erocyclic secondary amines; its derivatives are widely used
in drug discovery, agricultural chemistry, and many other
areas.1–4 In particular, more than 30 approved drugs5 and
several hundreds of natural products6 contain the morpho-
line moiety. Bicyclic conformationally restricted morpho-
line analogues7 are promising sp3-rich low-molecular-
Although the use of building block 1 or its C-substituted
derivatives was documented in several medicinal chemis-
try papers and patents,9–15 their synthesis remained virtu-
ally unpublished in the open literature. In 1975, Achini and
F
F
NH
F
F
H
O
O
NH
O
HN
O Cl
F
Cl
O
N
O
N
N
N
N
H
NH
Cl
O
OH
H
H
H
H
H2N
O
N
N
N
N
O
NH
O
O
3
2
O
O
H
PGES-1 inhibitor
VLA-4 inhibitor
H
OH
7
1
H
antibacterial
O
N
S
O
N
H
N
N
H
O
N
N
N
H
H
N
HN
N
N
H
N
O
H
N
O
O
O
N
H
4
5
6
LTA4H inhibitor
CCR2 antagonist
GSK-3β inhibitor
Figure 1 3-Oxa-7-azabicyclo[3.3.0]octane (1) and its biologically active derivatives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
Y. M. Sokolenko et al.
Paper
Synthesis
Oppolzer reported base-promoted cyclization of epoxides
7, leading to the formation of bicyclic iminolactones 8 (to-
gether with minor amounts of their acyclic precursors 9),
which in turn were transformed into derivatives 10 via hy-
drolysis, reduction, tosylation, and cyclization (Scheme 1).16
Recently, titanocene(III)-catalyzed intramolecular radical
arylation of epoxide 11 was reported, giving a mixture of
products 12 and 13.17 Syntheses of oxaza- and oxadi-
aza[3.3.3]propellanes via cyclization of the corresponding
3-aza- and 3,7-diazabicyclo[3.3]octane derivatives were
also reported.18–20
ducts 17a–d were obtained in 88–97% yields. Analogously,
adduct 17e was prepared in 70% yield from 4-phenylfuran-
2(5H)-one (15e), although in this case, the reaction was
slower and required elevated temperature (reflux in
CH2Cl2). Reduction of compounds 17 with LiAlH4 in THF
gave diols 18, which were isolated in 74–85% yields. To re-
form the bicyclic 3-oxa-7-azabicyclo[3.3.0]octane system,
reaction of 18 with MsCl/t-BuOK was used, leading to the
formation of N-benzylamines 19 (56–70%). Finally, catalytic
debenzylation of 19 gave the target 3-oxa-7-azabicyc-
lo[3.3.0]octanes 20 (isolated as hydrochlorides) in 90–97%
yields. Notably, up to 40–60 g of the target compounds
20·HCl were obtained using the described method. The re-
action sequence was also effective for the preparation of
[3.3.3]propellane derivatives (e.g. 20d), starting from an ap-
propriate fused bicyclic anhydride 15d.
O
R2
O
HN
O
H
H
R1
KNH2
HCl
R1
N
N
R1
O
N
R2
R2
CN
7
8
R1 = Me, Bn
70–72%
OH
AlH3
Table 1 Synthesis of 3-Oxa-7-azabicyclo[3.3.0]octanes via [3+2] Cy-
cloaddition of Ylide 14 and Substrates 15a
R2 = Ph, 3-MeOC6H4
H
NC
TsCl
R1
R1
N
R1
N
OH
N
O
O
R1
NMM
O
R1
R2
80–84%
R2
R1
R2
R2
R2
CH2Cl2
LiAlH4
HO
HO
9
10
O
Bn N+
+
O
NBn
NBn
20–40 °C
2–3 h
THF
rt, 1 h
_
O
R2
17
14
X
X
OH
18
15
TFA
Bn
(cp)2TiCl2, Mn
Cl–
Ph
+
Ph
N
O
N Ph
N
THF
t-BuOK
MsCl
rt, 1 h, then
reflux, 2 h
MeO
N
TMS
HO
11
12 (47%)
13 (28%)
R1
R1
16
1. HCl, THF–dioxane
N
H+
+
O
NH2
Cl–
O
NBn
2. H2, Pd/C, MeOH
rt, 12 h
Scheme 1 Syntheses of 3-oxa-7-azabicyclo[3.3.0]octanes reported in
the literature (relative configurations are shown)
R2
20.HCl
R2
19
Entry
Substrate
X
R1
R2
Yield (%)
17 18
All these methods commence from the starting materi-
als that are not readily available, and their key steps lead to
the formation of mixtures of products; therefore, they are
not amendable for scalable preparation of the target com-
pounds. In this work, we report an approach to the multi-
gram-scale synthesis of 3-oxa-7-azabicyclo[3.3.0]octane
derivatives, which relies on [3+2] cycloaddition of azo-
methine ylide 14 and maleic anhydrides 15a–d, followed by
recyclization of the adducts 17 thus obtained. In addition, a
modification of the method for the preparation of aryl-sub-
stituted 3-oxa-7-azabicyclo[3.3.0]octanes is also described,
involving [3+2] cycloaddition of 14 with furan-2(5H)-one
15e. To the best of our knowledge, [3+2] cycloaddition of 14
with substrates of the type 15 has not been documented in
the literature, although it was reported for maleic acid es-
ters.21
19
56
20
97
1
2
3
4
5
15a
15b
15c
15d
15e
O
O
O
O
H2
H
H
89
74
79
78
74
85
Me
Me
H
92
97
88
70
56
63
59
70
95
96
90
93
Me
(CH2)4
Ph
H
a Relative configurations are shown in the scheme.
As seen in the synthetic scheme, all the compounds 20
had cis relative configuration. To confirm this, we have per-
formed NOE experiments with non-symmetric 3-oxa-7-
azabicyclo[3.3.0]octane derivative 20b·HCl (R1 = H, R2 = Me)
(Figure 2). Significant NOEs were observed at either the 1-
CH3 group or the 5-CH proton when they were irradiated
and vice versa. The values of these NOEs were comparable
to the effects found for other protons in a cis position to the
group irradiated, which supports the cis configuration of
the compound.
We found that standard conditions for the in situ gener-
ation of ylide 14 [from N-(methoxymethyl)-N-[(trimethyl-
silyl)methyl]benzylamine (16) upon the action of TFA in
CH2Cl221,22] are very effective for cycloaddition with maleic
anhydrides 15a–d (Table 1). The corresponding cycload-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
Y. M. Sokolenko et al.
Paper
Synthesis
cis-5-Benzyl-3a-methyltetrahydro-1H-furo[3,4-c]pyrrole-
1,3(3aH)-dione (17b)
0.7%
H
H
rel
3.3%
H
H
3.5%
H
CH3
H
H
rel
H
CH3
+
Brownish oil; yield: 202 g (92%); used in the next step without char-
acterization.
1H NMR (DMSO-d6, 400 MHz): δ = 1.39 (s, 3 H), 2.17 (br d, J = 9.5 Hz, 1
H), 2.50–2.57 (m, 1 H), 3.14 (br d, J = 9.5 Hz, 1 H), 3.23 (br d, J = 9.5 Hz,
1 H), 3.29 (d, J = 7.0 Hz, 1 H), 3.55 (s, 2 H), 7.18–7.34 (m, 5 H).
2.5%
O
NH2
+
O
NH2
Cl–
3.8%
H
H
1.8%
H
0.5%
Cl–
H
H
H
0.5%
H
H
1.9%
H
H
0.7%
Figure 2 Significant NOE effects observed in 1H NMR spectra of
20b·HCl with irradiation of the 1-CH3 group (left) and the 5-CH proton
(right)
cis-5-Benzyl-3a,6a-dimethyltetrahydro-1H-furo[3,4-c]pyrrole-
1,3(3aH)-dione (17c)
Yellowish oil; yield: 200 g (97%); used in the next step without char-
acterization.
1H NMR (DMSO-d6, 400 MHz): δ = 1.24 (s, 6 H), 2.24 (br d, J = 9.0 Hz, 2
H), 3.24 (br d, J = 9.0 Hz, 2 H), 3.52 (s, 2 H), 7.21–7.31 (m, 5 H).
In conclusion, [3+2] cycloaddition of maleic anhy-
drides/furan-2(5H)-ones and the azomethine ylide generat-
ed
from
N-(methoxymethyl)-N-[(trimethylsilyl)meth-
yl]benzylamine is an efficient method for the multigram
preparation of 3-oxa-7-azabicyclo[3.3.0]octane derivatives.
Bicyclic adducts 17 obtained in this reaction can be effec-
tively transformed to 1,6-disubstituted (or less substituted)
3-oxa-7-azabicyclo[3.3.0]octanes, bicyclic morpholine sur-
rogates that are promising building blocks for medicinal
chemistry, via reductive cyclic anhydride cleavage and sub-
sequent reconstruction of the tetrahydrofuran ring. Com-
pounds 17 are also potential key intermediates in the
preparation of other hetero-substituted bicyclo[3.3.0]oc-
tanes.
2-Benzylhexahydro-1H-3a,7a-(methanooxymethano)isoindole-
8,10-dione (17d)
Yellowish oil; yield: 165 g (88%); used in the next step without char-
acterization.
1H NMR (DMSO-d6, 400 MHz): δ = 1.55–1.71 (m, 6 H), 1.88–1.98 (m, 2
H), 2.40 (br d, J = 10.0 Hz, 2 H), 3.24 (br d, J = 10.0 Hz, 2 H), 3.57 (s, 2
H), 7.18–7.33 (m, 5 H).
cis-5-Benzyl-3a-phenylhexahydro-1H-furo[3,4-c]pyrrol-1-one
(17e)
The [3+2] cycloaddition was performed at reflux for 2 h. The crude
product was purified by column chromatography (MeOH–CHCl3 1:8);
brownish oil; yield: 128 g (70%); Rf = 0.62 (MeOH–CHCl3 1:8).
Solvents were purified according to standard procedures.23 N-(Meth-
oxymethyl)-N-[(trimethylsilyl)methyl]benzylamine (16)22d and 4-
phenylfuran-2(5H)-one (15e)24 were prepared using the procedures
reported in the literature. All the starting materials were purchased
from Acros, Merck, Fluka, and UORSY. Analytical TLC was performed
using Polychrom SI F254 plates. Column chromatography was per-
formed using Kieselgel Merck 60 (230–400 mesh) as the stationary
phase. 1H and 13C NMR spectra were recorded on a Bruker 170 Avance
500 spectrometer (at 500 MHz for 1H and 125 MHz for 13C) or Varian
Unity Plus 400 spectrometer (at 400.4 MHz for 1H, 100.7 MHz for 13C)
with respect to TMS (1H, 13C) as an internal standard. Mass spectra
were recorded on an Agilent 1100 LCMSD SL instrument (chemical
ionization; APCI) and Agilent 5890 Series II 5972 GCMS instrument
(EI).
1H NMR (500 MHz, CDCl3): δ = 2.62 (d, J = 9.3 Hz, 1 H), 2.73 (t, J = 8.8
Hz, 1 H), 3.26 (d, J = 9.3 Hz, 1 H), 3.30 (d, J = 8.0 Hz, 1 H), 3.44 (d, J = 9.3
Hz, 1 H), 3.57 (d, J = 13.2 Hz, 1 H), 3.79 (d, J = 13.2 Hz, 1 H), 4.45 (d, J =
8.5 Hz, 1 H), 4.50 (d, J = 8.5 Hz, 1 H), 7.17 (d, J = 7.7 Hz, 2 H), 7.26–7.40
(m, 8 H).
13C NMR (125 MHz, CDCl3): δ = 50.4, 53.6, 58.1, 58.8, 65.9, 80.6, 125.4,
127.29, 127.3, 128.5, 129.1, 138.2, 143.8, 179.4.
MS (CI): m/z = 294 ([M + H]+).
Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.87;
H, 6.38; N, 4.65.
(1-Benzylpyrrolidine-3,4-diyl)dimethanols 18a–e; General Proce-
dure
To a solution of 17 (0.909 mol) in THF (300 mL) was added to a sus-
pension of LiAlH4 (69 g, 1.82 mol) in THF (1200 mL) dropwise at 25 °C,
and the resulting mixture was stirred at rt for 1 h. The reaction was
quenched by careful addition of H2O (100 mL), 10% aq KOH (200 mL),
and more H2O (100 mL). The precipitate was filtered, washed with
THF, and the combined filtrates were evaporated under reduced pres-
sure to give diol 18.
5-Benzyltetrahydro-1H-furo[3,4-c]pyrrole-1,3(3aH)-diones 17a–d
and 5-Benzylhexahydro-1H-furo[3,4-c]pyrrol-1-one 17e; General
Procedure
To a solution of 15 (1.02 mol) in CH2Cl2 (700 mL), N-(methoxymeth-
yl)-N-[(trimethylsilyl)methyl]benzylamine (16, 244 g, 1.03 mol) was
added. To the resulting mixture, a solution of TFA (11.6 g, 0.102 mol)
in CH2Cl2 (20 mL) was added dropwise at 25 °C under an inert atmo-
sphere. The mixture was stirred for 3 h, washed with H2O (400 mL)
and brine (400 mL), dried (Na2SO4), and evaporated under reduced
pressure to give adduct 17, which was used in the next step without
purification.
cis-(1-Benzylpyrrolidine-3,4-diyl)dimethanol (18a)
White solid; yield: 150 g (74%); mp 73–74 °C.
1H NMR (DMSO-d6, 400 MHz): δ = 2.06–2.13 (m, 2 H), 2.24–2.33 (m, 2
H), 2.67–2.74 (m, 2 H), 3.32 (dd, J = 10.5, 6.5 Hz, 2 H), 3.50 (s, 2 H),
3.53 (dd, J = 10.5, 6.5 Hz, 2 H), 4.17 (br s, 2 H), 7.18–7.33 (m, 5 H).
cis-5-Benzyltetrahydro-1H-furo[3,4-c]pyrrole-1,3(3aH)-dione
(17a)
13C NMR (DMSO-d6, 101 MHz): δ = 41.5, 57.4, 59.8, 60.5, 127.1, 128.5,
128.8, 139.9.
MS (CI): m/z = 222 ([M + H]+).
Slightly reddish oil; yield: 210 g (89%); used in the next step without
characterization.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
Y. M. Sokolenko et al.
Paper
Synthesis
Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.85;
H, 8.38; N, 6.43.
The mixture was stirred at rt for 1 h, then refluxed for 2 h and cooled
to rt. The solvent was evaporated in vacuo, the residue was diluted
with H2O (500 mL) and extracted with t-BuOMe (3 × 300 mL). The
combined organic extracts were washed with H2O and evaporated
under reduced pressure to give the crude product which was purified
by vacuum distillation (0.2 Torr) to give the product 19.
cis-(1-Benzyl-3-methylpyrrolidine-3,4-diyl)dimethanol (18b)
Yellowish oil; yield: 154 g (79%).
1H NMR (DMSO-d6, 400 MHz): δ = 1.04 (s, 3 H), 1.85–1.99 (m, 1 H),
2.21–2.35 (m, 2 H), 2.42 (d, J = 9.0 Hz, 1 H), 2.74 (t, J = 8.5 Hz, 1 H),
3.28–3.41 (m, 3 H), 3.44–3.63 (m, 3 H), 4.60 (br s, 2 H), 7.16–7.35 (m,
5 H).
13C NMR (DMSO-d6, 101 MHz): δ = 24.9, 44.0, 49.8, 57.8, 59.9, 60.6,
64.7, 65.5, 127.2, 128.7, 128.9, 140.0.
cis-5-Benzylhexahydro-1H-furo[3,4-c]pyrrole (19a)
Yellowish oil; yield: 78.3 g (56%); bp 80 °C/0.2 Torr.
1H NMR (CDCl3, 400 MHz): δ = 2.28–2.38 (m, 2 H), 2.62–2.72 (m, 2 H),
273–2.84 (m, 2 H), 3.54–3.62 (m, 4 H), 3.75–3.85 (m, 2 H), 7.19–7.34
(m, 5 H).
13C NMR CDCl3, 101 MHz): δ = 43.5, 59.0, 59.4, 73.5, 127.1, 128.5,
128.9, 139.5.
MS (CI): m/z = 236 ([M + H]+).
Anal. Calcd for C14H21NO2: C, 71.46; H, 8.99; N, 5.95. Found: C, 71.7; H,
9.27; N, 6.02.
MS (CI): m/z = 204 ([M + H]+).
Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 77.15;
H, 8.28; N, 7.00.
cis-(1-Benzyl-3,4-dimethylpyrrolidine-3,4-diyl)dimethanol (18c)
Colorless oil; yield: 150 g (78%).
1H NMR (DMSO-d6, 400 MHz): δ = 0.96 (s, 6 H), 2.35 (br d, J = 9.3 Hz, 2
H), 2.66 (br d, J = 9.3 Hz, 2 H), 3.33 (br d, J = 10.3 Hz, 2 H), 3.46 (br d, J =
10.3 Hz, 2 H), 3.55 (s, 2 H), 4.75 (br s, 2 H), 7.17–7.34 (m, 5 H).
13C NMR (DMSO-d6, 101 MHz): δ = 20.3, 46.2, 60.1, 64, 66.2, 127.1,
128.67, 128.72, 140.1.
cis-5-Benzyl-3a-methylhexahydro-1H-furo[3,4-c]pyrrole (19b)
Colorless liquid; yield: 80.1 g (56%); bp 88–89 °C/0.2 Torr.
1H NMR (CDCl3, 400 MHz): δ = 1.10–1.22 (s, 3 H), 2.12– 2.30 (m, 2 H),
2.34–2.45 (m, 1 H), 2.50 (d, J = 8.8 Hz, 1 H), 2.59–2.71 (m, 1 H), 3.45
(d, J = 8.5 Hz, 1 H), 3.50–3.59 (m, 3 H), 3.64 (d, J = 8.5 Hz, 1 H), 3.94 (t,
J = 8.0 Hz, 1 H), 7.17–7.35 (m, 5 H).
MS (CI): m/z = 250 ([M + H]+).
Anal. Calcd for C15H23NO2: C, 72.25; H, 9.3; N, 5.62. Found: C, 72.29; H,
9.54; N, 5.47.
13C NMR (CDCl3, 101 MHz): δ = 24.2, 50.94, 51.07, 59.34, 59.37, 65.3,
74.5, 79.9, 127.1, 128.5, 128.8, 139.6.
MS (CI): m/z = 218 ([M + H]+).
cis-(2-Benzyloctahydro-1H-isoindole-3a,7a-diyl)dimethanol (18d)
Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.50;
H, 8.77; N, 6.29.
Colorless oil; yield: 118 g (74%).
1H NMR (DMSO-d6, 400 MHz): δ = 1.35–1.45 (m, 6 H), 1.48–1.57 (m, 2
H), 2.80 (br d, J = 9.3 Hz, 2 H), 2.90 (br d, J = 9.3 Hz, 2 H), 3.34–3.42 (m,
4 H), 3.91 (s, 2 H), 5.91 (br s, 2 H), 7.25–7.44 (m, 5 H).
13C NMR (DMSO-d6, 101 MHz): δ = 20.2, 27.2, 45.4, 59.0, 60.1, 62.8,
126.8, 127.8, 128.4, 137.0.
cis-5-Benzyl-3a,6a-dimethylhexahydro-1H-furo[3,4-c]pyrrole
(19c)
Colorless liquid; yield: 87.0 g (63%); bp 96–97 °C/0.2 Torr.
1H NMR (CDCl3, 400 MHz): δ = 1.01 (s, 6 H), 2.20 (br d, J = 9.0 Hz, 2 H),
2.64 (br d, J = 9.0 Hz, 2 H), 3.47–3.55 (m, 4 H), 3.75 (br d, J = 8.5 Hz, 2
H), 7.21–7.35 (m, 5 H).
MS (CI): m/z = 276 ([M + H]+).
Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: C, 73.8; H,
9.11; N, 5.47.
13C NMR (CDCl3, 101 MHz): δ = 19.6, 50.9, 59.4, 66.9, 81.7, 127.1,
128.4, 128.7, 139.8.
MS (CI): m/z = 232 ([M + H]+).
cis-(1-Benzyl-3-phenylpyrrolidine-3,4-diyl)dimethanol (18e)
LiAlH4 (1 mol) was used for 17e (1 mol); yellowish solid; yield: 111 g
(85%); mp 131–132 °C.
Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 78.07;
H, 8.75; N, 6.25.
1H NMR (500 MHz, DMSO-d6): δ = 2.45–2.54 (m, 2 H), 2.72–2.82 (m, 1
H), 2.88 (d, J = 9.3 Hz, 1 H), 2.99 (d, J = 9.3 Hz, 1 H), 3.5–3.61 (m, 2 H),
3.62–3.74 (m, 3 H), 3.77–3.85 (m, 1 H), 4.64 (br s, 1 H), 4.88 (br s, 1 H),
7.14–7.20 (m, 1 H), 7.26–7.31 (m, 3 H), 7.32–7.37 (m, 4 H), 7.38–7.43
(m, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 50.6, 52.4, 58.6, 60.1, 61.3, 64.7,
66.0, 126.0, 127.7, 127.4, 128.2, 128.7, 128.9, 139.6, 147.9.
cis-2-Benzylhexahydro-1H-3a,7a-(methanooxymethano)isoin-
dole (19d)
Colorless liquid; yield: 65 g (59%); bp 126–128 °C/0.2 Torr.
1H NMR (CDCl3, 400 MHz): δ = 1.42–1.64 (m, 8 H), 2.56 (br d, J = 9.3
Hz, 2 H), 2.65 (br d, J = 9.3 Hz, 2 H), 3.62–3.74 (m, 6 H), 7.18–7.37 (m,
5 H).
13C NMR (CDCl3, 101 MHz): δ = 17.9, 28.1, 50.8, 59.4, 63.2, 79.2, 127.3,
128.5, 128.9, 139.0.
MS (CI): m/z = 298 ([M + H]+).
Anal. Calcd for C19H23NO2: C, 76.74; H, 7.80; N, 4.71. Found: C, 76.47;
H, 7.95; N, 4.91.
MS (CI): m/z = 258 ([M + H]+).
Anal. Calcd for C17H23NO: C, 79.33; H, 9.01; N, 5.44. Found: C, 79.11;
H, 8.68; N, 5.28.
5-Benzylhexahydro-1H-furo[3,4-c]pyrroles 19a–e; General Proce-
dure
To a solution of diol 18 (0.678 mol) in THF (1000 mL), t-BuOK (152 g,
1.36 mol) was added, the mixture was stirred 15 min, and MsCl (88 g,
0.678 mol) and additional t-BuOK (76 g, 0.678 mol) were added at rt.
cis-5-Benzyl-3a-phenylhexahydro-1H-furo[3,4-c]pyrrole (19e)
Colorless oil; yield: 74.0 g (70%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
Y. M. Sokolenko et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 2.56–2.71 (m, 3 H), 2.84–2.96 (m, 2
H), 3.67–3.69 (m, 3 H), 3.75–3.87 (m, 2 H), 4.12 (t, J = 8.5 Hz, 1 H),
7.10–7.38 (m, 10 H).
1H NMR (DMSO-d6, 400 MHz): δ = 1.32–1.45 (m, 4 H), 1.45–1.56 (m, 2
H), 1.57–1.68 (m, 2 H), 3.09–3.2 (m, 4 H), 3.66 (br d, J = 9.0 Hz, 2 H),
3.76 (br d, J = 9.0 Hz, 2 H), 9.83 (br s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 50.3, 59.1, 59.5, 60.0, 64.6, 75.2,
80.0, 126.46, 126.53, 127.3, 128.70, 128.72, 128.75, 139.5, 147.1.
MS (CI): m/z = 280 ([M + H]+).
13C NMR (DMSO-d6, 101 MHz): δ = 19.4, 26.1, 49.3, 50.7, 74.0.
MS (CI): m/z = 168 ([M + H]+).
Anal. Calcd for C10H18ClNO: C, 58.96; H, 8.91; N, 6.88; Cl, 17.4. Found:
C, 59.19; H, 9.25; N, 6.68; Cl, 17.55.
Anal. Calcd for C19H21NO: C, 81.68; H, 7.58; N, 5.01. Found: C, 81.93;
H, 7.69; N, 5.39.
cis-3a-Phenylhexahydro-1H-furo[3,4-c]pyrrole (20e·HCl)
Hexahydro-1H-furo[3,4-c]pyrrole Hydrochlorides 20a–e·HCl; Gen-
eral Procedure
White solid; yield: 55.8 g (93%); mp 239–241 °C.
1H NMR (400 MHz, DMSO-d6): δ = 3.19–3.32 (m, 2 H), 3.39–3.46 (m, 1
H), 3.47–3.55 (m, 1 H), 3.58–3.3.69 (m, 2 H), 3.80–3.92 (m, 1 H), 3.95–
4.05 (m, 1 H), 4.16 (d, J = 9.0 Hz, 1 H), 7.24–7.32 (m, 1 H), 7.33–7.43
(m, 4 H), 9.74 (br s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 48.5, 51.1, 55.2, 59.4, 74.3, 79.3,
126.8, 127.5, 129.2, 143.1.
Compound 19 was dissolved in THF (200 mL), and 10% HCl in dioxane
(280 mL) was added. The mixture was evaporated under reduced
pressure to give 19·HCl, which was dissolved in MeOH (500 mL). This
solution was added to 10% Pd/C (19.8 g, 0.0187 mol), and the result-
ing mixture was stirred under H2 atmosphere at rt for 12 h. The cata-
lyst was filtered off, and the filtrate was evaporated in vacuo to give
the target compound 20·HCl.
MS (CI): m/z = 190 ([M + H]+).
Anal. Calcd for C12H16ClNO: C, 63.85; H, 7.14; N, 6.21; Cl, 15.71.
Found: C, 63.47; H, 7.53; N, 6.03; Cl, 15.82.
cis-Hexahydro-1H-furo[3,4-c]pyrrole Hydrochloride (20a·HCl)
Yellowish solid; yield: 54.6 g (97%); mp 76–77 °C.
1H NMR (DMSO-d6, 400 MHz): δ = 2.83–2.92 (m, 2 H), 2.93–3.01 (m, 2
H), 3.33–3.41 (m, 2 H), 3.55–3.63 (m, 2 H), 3.64–3.71 (m, 2 H), 9.42 (br
s, 2 H).
13C NMR (DMSO-d6, 101 MHz): δ = 41.5, 48.4, 70.9.
MS (CI): m/z = 114 ([M + H]+).
Acknowledgment
The authors thank Mr. Vitaliy Polovinko for 2D NMR and NOE experi-
ments, and Prof., Dr. Sci. Andrey A. Tolmachev for support.
Anal. Calcd for C6H12ClNO: C, 48.17; H, 8.08; N, 9.36; Cl, 23.7. Found:
C, 47.87; H, 8.07; N, 8.97; Cl, 23.35.
Supporting Information
Supporting information for this article is available online at
cis-3a-Methylhexahydro-1H-furo[3,4-c]pyrrole Hydrochloride
(20b·HCl)
https://doi.org/10.1055/s-0036-1588785.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Colorless oil; yield: 51.7 g (95%).
References
1H NMR (DMSO-d6, 400 MHz): δ = 1.23 (s, 3 H), 2.87–2.95 (m, 1 H),
3.00–3.09 (m, 2 H), 3.28 (br d, J = 9.3 Hz, 1 H), 3.34–3.38 (m, 1 H),
3.40–3.50 (m, 1 H), 3.64–3.70 (m, 1 H), 3.71–3.76 (m, 1 H), 3.80 (br d,
J = 9.3 Hz, 1 H), 9.44 (br s, 1 H), 9.72 (br s, 1 H).
13C NMR (DMSO-d6, 101 MHz): δ = 21.1, 48.5, 48.9, 49.9, 53.9, 71.4,
76.8.
(1) Pal’chikov, V. A. Russ. J. Org. Chem. 2013, 49, 787.
(2) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.;
Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641.
(3) Vo, C.-V. T.; Bode, J. W. J. Org. Chem. 2014, 79, 2809.
(4) Al-Ghorbani, M.; Bushra Begum, A.; Zabiulla Mamatha, S. V.;
MS (CI): m/z = 128 ([M + H]+).
Khanum, S. A. J. Chem. Pharm. Res. 2015,
http://www.jocpr.com/.
7 (5), 281;
Anal. Calcd for C7H14ClNO: C, 51.38; H, 8.62; N, 8.56; Cl, 21.66. Found:
C, 51.68; H, 8.61; N, 8.77; Cl, 21.76.
(5) Wishart, D. S.; Knox, C.; Guo, A. C.; Shrivastava, S.; Hassanali, M.;
Stothard, P.; Chang, Z.; Woolsey, J. Nucleic Acids Res. 2006, 34,
D668.
(6) Gu, J.; Gui, Y.; Chen, L.; Yuan, G.; Lu, H.-Z.; Xu, X. PLoS ONE 2013,
8, e62839.
(7) For selected recent works on synthesis of bicyclic morpholine
analogues, see: (a) Zaytsev, A. V.; Pickles, J. E.; Harnor, S. J.;
Henderson, A. P.; Alyasiri, M.; Waddell, P. G.; Cano, C.; Griffin, R.
J.; Golding, B. T. RSC Adv. 2016, 6, 53955. (b) Geoghegan, K.;
Bode, J. W. Org. Lett. 2015, 17, 1934. (c) Dugar, S.; Sharma, A.;
Kuila, B.; Mahajan, D.; Dwivedi, S.; Tripathi, V. Synthesis 2015,
47, 712. (d) Zhang, D.-F.; Li, P.; Lin, Z.-Y.; Huang, H.-H. Chin.
Chem. Lett. 2014, 25, 479. (e) Siau, W.-Y.; Bode, J. W. J. Am. Chem.
Soc. 2014, 136, 17726. (f) Walker, D. P.; Eklov, B. M.; Bedore, M.
W. Synthesis 2012, 44, 2859. (g) Brice, H.; Gill, D. M.; Goldie, L.;
Keegan, P. S.; Kerr, W. J.; Svensson, P. H. Chem. Commun. 2012,
48, 4836.
cis-3a,6a-Dimethylhexahydro-1H-furo[3,4-c]pyrrole Hydrochlo-
ride (20c·HCl)
White solid; yield: 62.4 g (96%); mp 192–193 °C.
1H NMR (DMSO-d6, 400 MHz): δ = 1.04 (s, 6 H), 3.04 (br d, J = 12.5 Hz,
2 H), 3.16 (br d, J = 12.5 Hz, 2 H), 3.30 (br d, J = 9 Hz, 2 H), 3.87 (br d, J =
9 Hz, 2 H), 9.32 (br s, 1 H), 9.82 (br s, 1 H).
13C NMR (DMSO-d6, 101 MHz): δ = 16.6, 49.9, 54.8, 77.6.
MS (CI): m/z = 142 ([M + H]+).
Anal. Calcd for C8H16ClNO: C, 54.08; H, 9.08; N, 7.88; Cl, 19.95. Found:
C, 53.88; H, 9.33; N, 7.74; Cl, 20.27.
cis-Hexahydro-1H-3a,7a-(methanooxymethano)isoindole Hydro-
chloride (20d·HCl)
(8) Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem. Int. Ed.
2012, 51, 1114.
Slightly yellowish solid; yield: 43.3 g (90%); mp 227–228 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
Y. M. Sokolenko et al.
Paper
Synthesis
(9) Machinaga, N.; Iimura, S.; Yoneda, Y.; Chiba, J.; Muro, F.; Hoh,
H.; Nakayama, A. EP 1961750, 2008.
(20) Dave, P. R.; Forohar, F.; Axenrod, T.; Das, K. K.; Qi, L.; Watnick, C.;
Yazdekhasti, H. J. Org. Chem. 1996, 61, 8897.
(10) Priepke, H.; Doods, H.; Heim-Riether, A.; Kuelzer, R.; Pfau, R.;
Rudolf, K.; Stenkamp, D. WO 2012076673, 2012.
(11) Turner, S. C.; Bakker, M. H. M.; Hornberger, W. WO
2009/130317, 2009.
(12) Bacani, G.; Chrovian, C. C.; Eccles, W.; Fourie, A. M.; Gomez, L.;
Grice, C. A.; Kearney, A. M.; Landry-Bayle, A. M.; Lee-Dutra, A.;
Santillan, A.; Tanis, V. M.; Wiener, J. J. M. WO 2010/132599,
2010.
(13) Ebel, H.; Frattini, S.; Giovannini, R.; Scheuerer, S. WO
2012171863, 2012.
(14) Ma, Z.; Chu, D. T. W.; Cooper, C. S.; Li, Q.; Fung, A. K. L.; Wang, S.;
Shen, L. L.; Flamm, R. K.; Nilius, A. M.; Alder, J. D.; Meulbroek, J.
A.; Or, Y. S. J. Med. Chem. 1999, 42, 4202.
(15) Henderson, J. L.; Kormos, B. L.; Hayward, M. M.; Coffman, K. J.;
Jasti, J.; Kurumbail, R. G.; Wager, T. T.; Verhoest, P. R.; Noell, G.
S.; Chen, Y.; Needle, E.; Berger, Z.; Steyn, S. J.; Houle, C.; Hirst,
W. D.; Galatsis, P. J. Med. Chem. 2015, 58, 419.
(16) Achini, R.; Oppolzer, W. Tetrahedron Lett. 1975, 16, 369.
(17) Gansäuer, A.; Von Laufenberg, D.; Kube, C.; Dahmen, T.;
Michelmann, A.; Behlendorf, M.; Sure, R.; Seddiqzai, M.;
Grimme, S.; Sadasivam, D. V.; Fianu, G. D.; Flowers, R. A. Chem.
Eur. J. 2015, 21, 280.
(18) Altman, J.; Cohen, E.; Maymon, T.; Petersen, J. B.; Reshef, N.;
Ginsburg, D. Tetrahedron 1969, 25, 5115.
(19) Weinberg, O.; Knowles, P.; Ginsburg, D. Helv. Chim. Acta 1985,
68, 610.
(21) (a) McAlpine, I.; Tran-Dubé, M.; Wang, F.; Scales, S.; Matthews,
J.; Collins, M. R.; Nair, S. K.; Nguyen, M.; Bian, J.; Alsina, L. M.;
Sun, J.; Zhong, J.; Warmus, J. S.; O’Neill, B. T. J. Org. Chem. 2015,
80, 7266. (b) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem.
Pharm. Bull. 1985, 33, 2762. (c) Padwa, A.; Dent, W. J. Org. Chem.
1987, 52, 235. (d) Srihari, P.; Yaragorla, S. R.; Basu, D.;
Chandrasekhar, S. Synthesis 2006, 2646.
(22) (a) Golz, C.; Strohmann, C.; Kumar, K. Chem. Eur. J. 2016, 22,
18373. (b) Yarmolchuk, V. S.; Mukan, I. L.; Grygorenko, O. O.;
Tolmachev, A. A.; Shishkina, S. V.; Shishkin, O. V.; Komarov, I. V.
J. Org. Chem. 2011, 76, 7010. (c) Pandiancherri, S.; Ryana, S. J.;
Lupton, D. W. Org. Biomol. Chem. 2012, 10, 7903. (d) Sankar, U.;
Kumar, C. V. S.; Subramanian, V.; Balasubramanian, K. K.;
Mahalakshimi, S. J. Org. Chem. 2016, 81, 2340. (e) Cai, C.; Kang,
F.-A.; Beauchamp, D. A.; Sui, Z.; Russell, R. K.; Teleh, C. A. Tetra-
hedron: Asymmetry 2013, 24, 651. (f) Mandal, M.; Wu, Y.;
Misiaszek, J.; Li, G.; Buevich, A.; Caldwell, J. P.; Liu, X.; Mazzola,
R. D.; Orth, P.; Strickland, C.; Voigt, J.; Wang, H.; Zhu, Z.; Chen,
X.; Grzelak, M.; Hyde, L. A.; Kuvelkar, R.; Leach, P. T.; Terracina,
G.; Zhang, L.; Zhang, Q.; Michener, M. S.; Smith, B.; Cox, K.;
Grotz, D.; Favreau, L.; Mitra, K.; Kazakevich, I.; McKittrick, B. A.;
Greenlee, W.; Kennedy, M. E.; Parker, E. M.; Cumming, J. N.;
Stamford, A. W. J. Med. Chem. 2016, 59, 3231.
(23) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chem-
icals; Elsevier: Oxford, 2003, 1–609.
(24) Damodara, K.; Kimb, J.-K.; Jun, J.-G. Tetrahedron Lett. 2017, 58,
50.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F