Synthesis of (±)-8-oxa-3-azabicyclo[32.1]octan-2-thione and (±)-2-oxa-5-azabicyclo[2.2.1]heptan-6-thione: Potential synthons for the preparation of novel heteroaryl-annulated bicyclic morpholines

Article abstract of DOI:10.1055/s-0030-1258464

The bridged bicyclic morpholinethiones (±)-8-oxa-3-azabicyclo[3.2.1] octane-2-thione and (±)-2-oxa-5-azabicyclo[2.2.1]heptane-6-thione have been prepared in five and eight steps, respectively. Both compounds were derived from a respective requisite cis-di

Full text of DOI:10.1055/s-0030-1258464

PAPER
1113
Synthesis of ( )-8-Oxa-3-azabicyclo[3.2.1]octan-2-thione and ( )-2-Oxa-5-
azabicyclo[2.2.1]heptan-6-thione: Potential Synthons for the Preparation of
Novel Heteroaryl-Annulated Bicyclic Morpholines
Preparation of
Bic
a
yclic
M
or
p
n
S
ynth
ions el P. Walker,* Donn G. Wishka, Paul Beagley, Gemma Turner, Nicola Solesbury
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA
Fax +1(860)6860013; E-mail: daniel.p.walker@pfizer.com
Received 13 December 2010
O
N
Abstract: The bridged bicyclic morpholinethiones ( )-8-oxa-3-
N
F
CO2H
azabicyclo[3.2.1]octane-2-thione
and
( )-2-oxa-5-azabicyc-
O
O
lo[2.2.1]heptane-6-thione have been prepared in five and eight
steps, respectively. Both compounds were derived from a respective
requisite cis-disubstituted tetrahydrofuran, which was stereoselec-
tively prepared via hydrogenation of the corresponding disubstitut-
ed furan derivatives.
N
H
N
H
N
HN
CN
S
H
CO2Na
O
finafloxacin
BLI-489
Key words: stereoselective synthesis, heterocycles, bicyclic com-
pounds, furans, hydrogenation
H
N
H
N
N
HN
AGN 193080
Morpholines are utilized extensively in drug discovery re-
search. Numerous drugs possessing a directly linked mor-
pholine have been approved by the FDA and other
regulatory agencies; a snapshot of recently marketed
drugs is shown in Figure 1, including linezolid (Zyvox®),1
gifitinib (Iressa®),2 and reboxetine.3
O
Figure 2 Clinical (BLI-489 and finafloxacin) and preclinical (AGN
193080) candidates possessing a fused morpholine ring
In addition, a number of reports detailing analogues incor-
porating a bridged bicyclic morpholine (e.g., 1 and 2,
Figure 3) have been reported in the medicinal chemistry
literature.7 In some instances, the bicyclic analogue
showed enhanced biological activity compared to the cor-
responding morpholine analogue.7c–e
F
O
N
O
Cl
NH
N
O
N
O
N
F
N
O
MeO
NH
linezolid
gifitinib
O
R
R
N
N
O
O
2
1
O
NH
O
O
OEt
S
N
H
7
reboxetine
Figure 3 Bridged bicyclic morpholine templates 1 and 2 utilized in
medicinal chemistry research programs, and structure of compound 7
Figure 1 Drugs possessing a directly linked morpholine ring
Analogues incorporating a fused morpholine ring have
also shown potential for treating various human diseases;
some recent preclinical and clinical candidates are shown
in Figure 2, including BLI-489,4 finafloxacin,5 and AGN
193080.6
Given the promising biological profiles of analogues pos-
sessing a fused morpholine ring and the emerging poten-
tial of bridged bicyclic morpholine analogues, we became
interested in preparing bridged bicyclic morpholines that
were fused to an additional heteroaryl ring (e.g., 3 and 4,
Figure 4). The logical precursors to structures 3 and 4
would be thiolactams 5 and 6, respectively. In general,
thioamides and thiolactams are useful synthons for the
preparation of a variety of fused heterocycles;8 many of
these heteroaryl-annulated analogues have shown inter-
esting biological properties.9 For instance, thiolactam 7
SYNTHESIS 2011, No. 7, pp 1113–1119
x
x
.
x
x
.2
0
1
1
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1258464; Art ID: M53110SS
© Georg Thieme Verlag Stuttgart · New York

1114
D. P. Walker et al.
PAPER
H
(Figure 3) is the precursor to the imidazo[2,1-c][1,4]ox-
azine skeleton contained in BLI-489.4a Hence, we have
targeted the novel thiolactams 5 and 6 as synthons for the
preparation of heteroaryl-annulated bicyclic morpholine
analogues. While the bicyclo[3.2.1]octane skeleton in 5
restricts the morpholine ring in a pseudo-chair conforma-
tion, the bicyclo[2.2.1]heptane skeleton in 6 restricts the
morpholine ring in a boat conformation. We detail below
a racemic synthesis of the novel thiolactams 5 and 6.
N
Boc
CO2Me
CO2Me
O
O
NH2
11
13
Figure 5 Structure of compounds 11 and 13
given that 10–15% of the trans-product is produced in the
hydrogenation of similar 2,5-disubstituted furans.11
Bicyclic lactam 10 was realized in 93% yield via cleavage
of the Boc group with hydrogen chloride, followed by
subsequent heating in the presence of sodium acetate
(Scheme 1). Subjection of the lactam in 10 to Lawesson’s
reagent furnished in 93% yield the desired thiolactam 5.
O
O
R
N
NH
from
Z
N
S
Y
3
5
Our next synthetic target was thiolactam 6. Toward this
end, we envisioned a synthetic route wherein the known
bicyclic lactam 1412a would be transformed into thiolac-
tam 6 via reductive removal of the tosyl moiety followed
by thiolactam formation (Scheme 2). However, the pub-
lished synthesis of 14 is lengthy, requiring 13 linear steps
from commercially available material, and it is nonstereo-
selective (Scheme 3).12 Hence, we sought to develop a
more efficient and stereoselective synthesis of lactam 14.
N
NH
S
Z
R
from
O
O
Y
N
4
6
Figure 4 Novel heteroaryl-annulated bicyclic morpholine ana-
logues 3 and 4 [Y = CH, CR, or N; Z = CH, CR, C(O), or N; R = H,
alkyl, acyl, or aryl (see: refs 8 and 9)] and new synthetic targets 5 and
6
The synthesis of bicyclic thiolactam 5 commenced from
commercially available chloride 8 (Scheme 1). Azide 9
was prepared in a single step in near quantitative yield us-
ing a modification of the known procedure by Moore and
Partain.10 In that same study, the authors reported a direct
conversion (H2, 5% Rh/C, MeOH, 50 psi, 96 h, 70%) of
azide 9 into bicyclic lactam 10. Unfortunately, we were
unable to repeat this procedure. In our hands, the major
product, based on the crude 1H NMR spectrum (500 MHz)
and LCMS, was amine 11 (Figure 5). Presumably, the cat-
alyst was being poisoned by the amine, preventing further
hydrogenation from taking place. We reasoned that in situ
protection of the amino group would resolve this issue. In-
deed, hydrogenation of azide 9 in the presence of di-tert-
butyl dicarbonate gave rise (85%) to tetrahydrofuran 12.
Under these conditions, none of the corresponding trans-
product 13 (Figure 5) could be detected based on the
(1) removal of
tosyl group
Ts
N
6
O
(2) thiolactam
formation
O
14
Scheme 2 Original synthetic plan for preparing bicyclic thiolactam
6
NH2
O
3 steps
3 steps
3 steps
EtO2C
Br
HO
N3
O
CO2Et
O
HO
3 steps
CO2Me
CO2H
15 (cis/trans ~ 1:1)
O
O
1
crude H NMR spectrum. This was somewhat surprising
b
c, d
CO2Me
CO2Me
O
H
O
85%
92%
N
Ac2O
reflux
X
HN
Ts
Boc
12
8 X = Cl
9 X = N3
14
a
CO2H
O
Scheme 3 Allen and Tran’s synthesis of bicyclic lactam 14 utilizing
Matsumoto’s tetrahydrofuran 15
O
NH
Z
Our synthetic route to prepare lactam 14 is outlined in
Scheme 4. The route is similar to the preparation of tet-
rahydrofuran 12 (vide supra) in that hydrogenation of an
10 Z = O
5 Z = S
e
Scheme 1 Reagents and conditions: (a) Bu4NN3 (1.05 equiv), 2- appropriately substituted furan ring was utilized to stereo-
MeTHF, r.t., 1.5 h, 98%; (b) H2, 5% Rh/C (cat.), (Boc)2O (1.5 equiv),
MeOH, 50 psi, r.t., 36 h; (c) aq 4 M HCl in 1,4-dioxane (4.0
equiv), CH2Cl2, r.t.; (d) NaOAc (1.5 equiv), butan-2-ol, 100 °C, 3 h;
prepared in three steps from commercial 3-furaldehyde
(e) Lawesson’s reagent, toluene, 90 °C, 1.5 h, 93%.
selectively generate a cis-disubstituted tetrahydrofuran.
Toward this end, hydrogenation of the known furan 16,13
Synthesis 2011, No. 7, 1113–1119 © Thieme Stuttgart · New York

PAPER
Preparation of Bicyclic Morpholine Synthons
1115
via remote functionalization,14 gave rise (86%) to tetrahy- case, refluxing amino ester 18 (prepared according to
1
drofuran 17. Inspection of the crude H NMR spectrum Scheme 4) in mesitylene (bp 163–165 °C/760 Torr) was
(500 MHz) showed a single stereoisomer. Subsequent 2D also unsuccessful. For both amino acid 22 and amino ester
NMR studies confirmed that the amine and carboxylic 18 no lactamization occurred at temperatures up to
acid groups were cis to one another (data not shown). 150 °C. At temperatures >150 °C, significant decomposi-
Cleavage of the Boc group in 17 generated amino ester 18, tion ensued. Fortunately, cyclization of amino acid 22 was
which upon exposure to tosyl chloride afforded sulfona- effected in refluxing acetonitrile in the presence of DCC,20
mide 19. Saponification of the ester led to carboxylic acid affording a 67% yield of the previously unknown bicyclic
20, which set the stage for the lactamization reaction. Sub- lactam 21. With lactam 21 finally in hand, treatment with
jection of 20 to acetic anhydride in the presence of sodium Lawesson’s reagent furnished the desired thiolactam 6 in
acetate15 gave rise to lactam 14. The use of sodium acetate good yield.
to facilitate the lactamization is noteworthy as it reduced
the reaction time by 46 hours and improved the yield from
42% to 98% compared to acetic anhydride alone.12a Un-
fortunately, attempts to convert N-tosyl lactam 14 into
lactam 21 met with no success. For instance, treatment of
14 with either sodium naphthalide in dimethoxyethane16
or sodium in liquid ammonia17 did result in efficient re-
moval of the tosyl moiety; however, the product subse-
quently underwent significant decomposition under the
reaction conditions. As a result, only trace amounts of the
H2N⋅HCl
c
a, b
17
CO2H
97%
67%
O
22
NH
Z
O
1
desired lactam could be detected in the crude H NMR
spectrum.
21 Z = O
6 Z = S
d
Scheme 5 Reagents and conditions: (a) LiOH·H2O (7.0 equiv),
THF–MeOH–H2O (6:3:1), r.t., 1 h; (b) aq 3 M HCl, 70 °C, 1 h;
(c) DCC (1.0 equiv), pyridine (3.0 equiv), MeCN, reflux, 1 h;
(d) Lawesson’s reagent, toluene, 90 °C, 1 h, 74%.
H
N
HN Boc
Boc
a
b
CO2Me
CO2Me
86%
92%
O
O
17
16
In summary, we have prepared in racemic form two dif-
ferent, conformationally restricted morpholinethiones 5
and 6, which should serve as useful synthons for the prep-
aration of heteroaryl-annulated bicyclic morpholine ana-
logues. Both bicyclic compounds 5 and 6 were derived
from a respective key cis-disubstituted tetrahydrofuran,
which, in turn, was prepared with high stereoselectivity
via hydrogenation of an appropriately substituted furan. In
addition, our novel synthesis of ( )-2-oxa-5-azabicyc-
lo[2.2.1]heptan-6-one (21) represents a significant im-
provement over the previously reported route to prepare
the 2-oxa-5-azabicyclo[2.2.1]heptan-6-one ring system.
H
N
⋅HCl
H2N
Ts
c
e
CO2R
CO2Me
89%
98%
O
O
18
19 R = Me
d
20 R = H
f or g
X
Ts
NH
N
O
O
O
O
21
14
Scheme 4 Reagents and conditions: (a) 5% Rh/C, MeOH, 50 psi,
r.t., 36 h; (b) aq 4 M HCl in 1,4-dioxane (4.0 equiv), CH2Cl2, r.t., 1 h;
(c) TsCl (1.0 equiv), Et3N (2.0 equiv), CH2Cl2, 24 h; (d) LiOH·H2O
(7.0 equiv), THF–MeOH–H2O (6:3:1), r.t., 1 h; (e) Ac2O, NaOAc (10
equiv), reflux, 2 h; (f) Na, naphthalene, DME, –78 °C, 30 min; (g) Li,
NH3, –78 °C, 30 min.
1H and 13C NMR spectra were collected on either a Varian Inova
500 with a 5 mm 4NG probe at 25 °C or a Varian Inova 400 with a
5 mm DBG probe at 25 °C. Chemical shifts are reported in parts per
million (d) relative to TMS (0.0). IR spectra were recorded on a
Thermo-Nicolet Avatar 370 IR spectrometer. High-resolution mass
spectra (HRMS) were acquired on an Agilent 1200 LCMS TOF
spectrometer with UV detection. Combustion analyses were per-
formed by QTI Intertek, Whitehouse, N.J. Melting points were re-
corded on a Thomas Hoover melting point apparatus and are
uncorrected. Reactions were monitored by TLC using Analtech sil-
ica gel GF 250 micron plates. The plates were visualized either by
UV inspection or by staining with an ammonium molybdate/ceric
sulfate mixture. Flash chromatography was performed on a Biotage
unit or glass column using EMD silica gel (230–400 mesh). All re-
agents were purchased from the Aldrich Chemical Co. and used
without further purification. All solvents were HPLC grade unless
otherwise stated. Anhyd solvents were purchased from EMD
Chemical Co. and used as supplied.
To circumvent the issues associated with removing the to-
syl moiety, we next attempted an intramolecular cycliza-
tion on the unprotected amino acid 22, which was
prepared in two steps from Boc-protected amino ester 17
(Scheme 5). However, heating a slurry of amino acid 22
in Dowtherm® A (bp 257 °C/760 Torr)18 led to significant
decomposition. Several reports on related carbocyclic
systems have shown that thermal cyclization on the corre-
sponding amino ester can be effected at lower tempera-
tures than the parent amino acid.19 Unfortunately, in our
Synthesis 2011, No. 7, 1113–1119 © Thieme Stuttgart · New York

1116
D. P. Walker et al.
PAPER
Methyl 5-(Azidomethyl)-2-furoate (9)
(70:10:20 → 40:40:20) afforded 10 as a white solid; yield: 2.74 g
(92%); mp 70–72 °C (Lit.10 mp 70–71 °C); Rf = 0.33 (EtOAc–
MeOH, 90:10).
The title compound was prepared according to the established
procedure10 with slight modification:
To a stirred solution of chloride 8 (10.0 g, 57.3 mmol) in 2-meth-
yltetrahydrofuran (230 mL) in a 500 mL one-necked round-bot-
tomed flask at r.t. was added Bu4NN3 (17.6 g, 60.1 mmol) in a single
portion. The mixture was stirred for 1.5 h at r.t. and then washed
with a 1:1 mixture of brine and 1 M aq HCl (2 × 100 mL). The or-
ganic layer was dried (MgSO4), filtered, and concentrated in vacuo
to afford 10.4 g of a pale yellow oil. The crude product was purified
by silica gel column chromatography (Biotage, 100 g SNAP car-
tridge). Elution with a heptane–EtOAc gradient (98:2 → 80:20) af-
forded azide 9 as a colorless oil; yield: 10.3 g (98%); Rf = 0.48
(hexanes–EtOAc, 80:20).
IR (film): 1660, 1491, 1345, 1024, 886 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.92 (br s, 1 H), 4.58 (m, 1 H),
4.38 (d, J = 6.84 Hz, 1 H), 3.65 (dd, J = 11.3, 4.10 Hz, 1 H), 2.97
(dd, J = 11.52, 3.12 Hz, 1 H), 2.22–2.00 (m, 3 H), 1.85 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 172.8, 76.91, 71.86, 47.83, 31.67,
27.75.
Anal. Calcd for C6H9NO2 (127.1): C, 56.49; H, 7.15; N, 10.98.
Found: C, 56.49; H, 7.17; N, 10.98.
( )-8-Oxa-3-azabicyclo[3.2.1]octan-2-thione (5)
To a stirred solution of lactam 10 (508 mg, 4.00 mmol) in toluene
(30 mL) was added Lawesson’s reagent (1.75 g, 4.20 mmol) and the
mixture was heated to 90 °C for 1.5 h. The mixture was cooled to
r.t. and the solvent was removed in vacuo to afford a yellow solid.
The solid was triturated with CH2Cl2 (5 mL) to remove insoluble
material. The filtrate containing the product was purified by silica
gel column chromatography (Biotage, 50 g SNAP cartridge). Elu-
tion with CH2Cl2–EtOAc gradient (100:0 → 80:20) afforded 5 as a
white solid; yield: 530 mg (93%); mp 117–118 °C; Rf = 0.28
(hexanes–EtOAc, 1:1).
IR (film): 2097, 1724, 1523, 1437, 1300, 1206, 1134, 1020, 761
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.15 (d, J = 3.5 Hz, 1 H), 6.46 (d,
J = 3.5 Hz, 1 H), 4.38 (s, 2 H), 3.90 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.8, 153.2, 144.8, 118.6, 110.9,
52.0, 46.9.
LRMS (ESI): m/z [M + H]+ calcd for C7H7N3O3: 182.1; found:
182.0.
Methyl ( )-cis-5-[(tert-Butoxycarbonylamino)methyl]tetrahy-
drofuran-2-carboxylate (12)
IR (film): 3227, 2945, 1533, 1337, 1160, 1121, 1064, 883 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.4 (br s, 1 H), 4.89 (d, J = 7.22
Hz, 1 H), 4.69 (m, 1 H), 3.73 (dd, J = 12.9, 4.49 Hz, 1 H), 3.06 (dd,
J = 12.9, 3.32 Hz, 1 H), 2.35–2.30 (m, 1 H), 2.27–2.15 (m, 2 H),
1.95–1.80 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 203.9, 82.19, 71.07, 50.48, 33.86,
28.11.
A mixture of azide 9 (5.0 g, 27.6 mmol), di-tert-butyl dicarbonate
(9.04 g, 41.4 mmol) and 5% Rh/C (Aldrich, 570 mg) in MeOH (190
mL) was placed in a 500 mL PARR shaker flask and hydrogenated
at 50 psi overnight. The catalyst was removed by filtration through
Celite. The filtrate was concentrated in vacuo to afford a pale oil.
The crude product was purified by silica gel column chromatogra-
phy (Biotage, 100 g SNAP cartridge). Elution with a heptane–
EtOAc gradient (88:12 → 25:75) afforded 12 as a colorless oil;
yield: 6.10 g (85%); Rf = 0.21 (hexanes–EtOAc, 80:20).
HRMS (ESI): m/z [M + H]+ calcd for C6H10NOS: 144.0484; found:
144.0479.
Anal. Calcd for C6H9NOS (143.2): C, 50.33; H, 6.34; N, 9.79.
Found: C, 50.39; H, 6.36; N, 9.76.
IR (film): 1738, 1709, 1512, 1365, 1250, 1213, 1166, 1093 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.52 (br s, 1 H), 4.49 (dd, J = 8.8,
4.1 Hz, 1 H), 4.24–4.15 (m, 1 H), 3.76 (s, 3 H), 3.43 (dt, J = 13.9,
4.2 Hz, 1 H), 3.31–3.22 (m, 1 H), 2.34–2.23 (m, 1 H), 2.14–2.06 (m,
1 H), 1.94 (dddd, J = 12.4, 8.1, 6.2, 4.1 Hz, 1 H), 1.79–1.67 (m, 1
H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 174.1, 156.3, 80.2, 78.9, 76.8,
52.1, 43.4, 30.7, 28.3, 27.0.
Methyl ( )-cis-4-(tert-Butoxycarbonylamino)tetrahydrofuran-
2-carboxylate (17)
A mixture of furan 1613 (800 mg, 3.32 mmol) and 5% Rh/C
(Aldrich, 80 mg) in MeOH (40 mL) was placed in a Parr bottle and
hydrogenated at 50 psi for 24 h at r.t. The mixture was filtered
through Celite and washed with MeOH (30 mL). Concentration of
the filtrate in vacuo afforded an oil. The crude product was passed
through a silica gel plug, eluting with hexanes–EtOAc (1:1) to af-
ford 17 as white solid; yield: 700 mg (86%); mp 53–54 °C; Rf = 0.51
(hexanes–EtOAc, 1:1).
HRMS (ESI): m/z [M + Na]+ C12H21NO5 + Na: 282.1318; found:
282.1304.
( )-8-Oxa-3-azabicyclo[3.2.1]octan-2-one (10)
IR (film): 3342, 2977, 1740, 1709, 1512, 1165, 1082 cm–1.
To a stirred solution of carbamate 12 (6.1 g, 23.5 mmol) in CH2Cl2
(20 mL) was added HCl (4.0 M soln in 1,4-dioxane; 24 mL, 96
mmol). The reaction mixture was stirred at r.t. for 4 h. The volatiles
were removed in vacuo to afford methyl ( )-cis-5-(aminometh-
yl)tetrahydrofuran-2-carboxylate hydrochloride as a viscous oil;
yield: 4.5 g (99%).
1H NMR (400 MHz, CD3OD): d = 4.61 (dd, 1 H, J = 8.8, 4.3 Hz),
4.37–4.30 (m, 1 H), 3.76 (s, 3 H), 3.21–3.15 (m, 1 H), 3.09–3.02 (m,
1 H), 2.45–2.34 (m, 1 H), 2.20–2.08 (m, 2 H), 1.80–1.70 (m, 1 H).
1H NMR (500 MHz, CDCl3): d = 5.15 (br s, 1 H), 4.48 (dd, J = 9.52,
4.15 Hz, 1 H), 4.33 (m, 1 H), 3.97 (dd, J = 9.27, 5.37 Hz, 1 H), 3.87
(br d, J = 8.06 Hz, 1 H), 3.76 (s, 3 H), 2.51 (ddd, J = 13.7, 9.51,
7.32 Hz, 1 H), 1.99 (dt, J = 13.1, 3.42 Hz, 1 H), 1.40 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 173.7, 155.2, 79.56, 75.93, 74.89,
52.32, 50.90, 36.95, 28.36.
HRMS (ESI): m/z [M + Na]+ calcd for C11H19NO5 + Na: 268.1161;
found: 268.1149.
A mixture of the above oil and anhyd NaOAc (2.89 g, 35 mmol) in
butan-2-ol (200 mL) was heated to 100 °C for 3 h. The mixture was
concentrated in vacuo to dryness. The remaining residue was tritu-
rated with CH2Cl2 (50 mL) to afford a precipitate. The precipitate
was filtered through Celite and washed with CH2Cl2 (20 mL). The
filtrate was concentrated in vacuo to a yellow oil. The crude product
was purified by silica gel column chromatography (Biotage, 50 g
SNAP cartridge). Elution with a CH2Cl2–EtOAc–MeOH gradient
Anal. Calcd for C11H19NO5 (245.3): C, 53.86; H, 7.81; N, 5.71.
Found: C, 53.89; H, 8.15; N, 5.72.
Methyl ( )-cis-4-Aminotetrahydrofuran-2-carboxylate Hydro-
chloride (18)
To a stirred solution of 17 (2.50 g, 10.2 mmol) in CH2Cl2 (15 mL)
was added HCl (4.0 M solution in 1,4-dioxane; 15 mL). The solu-
tion was stirred for 1 h. The solvent was removed in vacuo [Note:
Synthesis 2011, No. 7, 1113–1119 © Thieme Stuttgart · New York

PAPER
Preparation of Bicyclic Morpholine Synthons
1117
heating the reaction mixture to greater than 30 °C during concentra-
tion caused partial (ca. 10%) hydrolysis of the methyl ester]. The
crude product was triturated with EtOAc (20 mL) to give a precipi-
tate. The precipitate was filtered and dried in vacuo to afford 18 as
a white solid; yield: 1.86 g (92%); mp 150–152 °C.
IR (film): 1740, 1513, 1233, 1105, 1056, 666 cm–1.
1H NMR (500 MHz, D2O): d = 4.62 (dd, J = 9.03, 6.83 Hz, 1 H),
4.10–4.00 (m, 3 H), 3.79 (s, 3 H), 2.84 (m, 1 H), 2.19 (m, 1 H).
13C NMR (125 MHz, D2O): d = 173.8, 76.31, 71.25, 53.26, 50.67,
33.60.
HRMS (ESI): m/z [M + H]+ calcd for C6H12NO3: 146.0818; found:
( )-N-Tosyl-2-oxa-5-azabicyclo[2.2.1]heptan-6-one (14)
Carboxylic acid 20 (350 mg, 1.23 mmol) and NaOAc (1.01 g, 12.3
mmol), dissolved in Ac2O (11 mL), were heated to reflux for 30
min. The mixture was cooled to r.t., and the solvent was removed in
vacuo. The remaining residue was partitioned between H2O (10
mL) and EtOAc (40 mL), and the layers were separated. The aque-
ous layer was extracted with EtOAc (2 × 10 mL). The combined or-
ganics were washed with brine (5 mL), dried (MgSO4), filtered, and
concentrated in vacuo to afford 14 as an off-white solid; yield: 320
mg (98%); mp 125–127 °C (Lit.12a mp 127–128 °C); Rf = 0.35 (hex-
anes–EtOAc, 1:1).
IR (film): 1755, 1361, 1169, 1090, 675 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.93 (d, J = 8.54 Hz, 2 H), 7.35 (d,
J = 8.06 Hz, 2 H), 5.04 (s, 1 H), 4.49 (d, J = 1.95 Hz, 1 H), 3.85 (d,
J = 8.05 Hz, 1 H), 3.62 (d, J = 8.05 Hz, 1 H), 2.45 (s, 3 H), 2.10 (dd,
J = 10.7, 1.22 Hz, 1 H), 1.95 (dt, J = 10.9, 1.46 Hz, 1 H).
146.0813.
Anal. Calcd for C6H12ClNO3 (181.6): C, 39.68; H, 6.66; N, 7.71.
Found: C, 39.49; H, 6.73; N, 7.56.
13C NMR (100 MHz, CDCl3): d = 168.3, 145.5, 136.0, 129.9, 127.7,
79.94, 69.73, 61.13, 39.17, 21.68.
Methyl ( )-cis-4-(4-Methylphenylsulfonamido)tetrahydrofu-
ran-2-carboxylate (19)
To a stirred suspension of 18 (55 mg, 0.30 mmol) in CH2Cl2 (2.0
mL) at r.t. were added Et3N (93 mL, 0.67 mmol) and TsCl (60 mg,
0.32 mmol). The mixture was stirred at r.t. overnight. The mixture
was diluted with CH2Cl2 (3 mL) and aq 1.0 M HCl (4 mL). The lay-
ers were separated and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine (3
mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel. Elution
with CH2Cl2–EtOAc gradient (0:100 → 100:0) afforded 19 as a
white solid; yield: 80 mg (89%); mp 107–109 °C; Rf = 0.35 (hex-
anes–EtOAc, 1:1).
HRMS (ESI): m/z [M + Na]+ calcd for C12H13NO4S + Na: 290.0464;
found: 290.0450.
Anal. Calcd for C12H13NO4S (267.3): C, 53.93; H, 4.90; N, 5.24.
Found: C, 53.98; H, 4.82; N, 5.18.
( )-cis-4-Aminotetrahydrofuran-2-carboxylic Acid Hydrochlo-
ride (22)
To a stirred solution of ester 17 (1.60 g, 6.52 mmol) in THF–
MeOH–H2O (6:3:1; 60 mL) was added LiOH·H2O (1.92 g, 45.7
mmol) The mixture was stirred at r.t. for 2 h and concentrated in
vacuo to a volume of ca. 5 mL. The remaining residue was parti-
tioned between H2O (20 mL) and Et2O (20 mL), and the layers were
separated. The aqueous layer was extracted with Et2O (10 mL). The
combined ethereal layers were discarded. The aqueous layer was
acidified with concd HCl to pH 1. The aqueous layer was extracted
with EtOAc (2 × 25 mL). The combined organic layers were washed
with brine (5 mL), dried (MgSO4), filtered, and concentrated in vac-
uo to afford ( )-4-cis-(tert-butoxycarbonylamino)tetrahydrofuran-
2-carboxylic acid as a white solid; yield: 1.50 g (99%); mp 112–
114 °C; Rf = 0.24 (hexanes–EtOAc–AcOH, 90:9:1).
IR (film): 3250, 1736, 1438, 1218, 1157, 1089, 816, 663 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.75 (d, J = 8.30 Hz, 2 H), 7.32 (d,
J = 8.30 Hz, 2 H), 5.43 (br d, 9.52 Hz, 1 H), 4.44 (dd, J = 9.52, 3.17
Hz, 1 H), 4.08 (m, 1 H), 3.83 (dd, J = 9.76, 5.12 Hz, 1 H), 3.77 (m,
1 H), 3.76 (s, 3 H), 2.44 (s, 3 H), 2.34 (ddd, J = 14.2, 9.52, 7.32 Hz,
1 H), 1.91 (dt, J = 13.91, 2.44 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 173.7, 143.6, 137.7, 129.8, 127.0,
74.45, 53.69, 52.52, 36.61, 21.52.
HRMS (ESI): m/z [M + H]+ calcd for C13H18NO5S: 300.0906;
found: 300.0903.
IR (film): 1724, 1690, 1514, 1164, 1077 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.6 (br s, 1 H), 6.95 (br s, 1
H), 4.31 (dd, J = 8.19, 7.41 Hz, 1 H), 3.97 (m, 1 H), 3.85 (dd,
J = 8.20, 6.63 Hz, 1 H), 2.43 (dt, J = 12.9, 8.20 Hz, 1 H), 1.81 (dt,
J = 12.9, 7.03 Hz, 1 H), 1.38 (s, 9 H).
13C NMR (125 MHz, DMSO-d6): d = 173.7, 155.2, 77.94, 75.20,
71.94, 50.35, 35.18, 28.16.
Anal. Calcd for C13H17NO5S (299.3): C, 52.17; H, 5.73; N, 4.68.
Found: C, 52.42; H, 5.66; N, 4.57.
( )-cis-4-(4-Methylphenylsulfonamido)tetrahydrofuran-2-car-
boxylic Acid (20)
To a stirred solution of ester 19 (375 mg, 1.25 mmol) in THF–
MeOH–H2O (6:3:1; 12 mL) was added LiOH·H2O (368 mg, 8.77
mmol). The mixture was stirred at r.t. for 30 min and concentrated
in vacuo to a volume of ca. 2 mL. The remaining residue was diluted
with H2O (4 mL), and the pH was adjusted to 1 with concd HCl. The
mixture was extracted with EtOAc (2 × 20 mL). The organic layer
was washed with brine (4 mL), dried (MgSO4), filtered, and concen-
trated in vacuo to afford 20 as a white solid; yield: 358 mg (98%);
mp 124–126 °C (Lit.12a mp 122–125 °C).
HRMS (ESI): m/z [M + Na]+ calcd for C10H17NO5 +Na: 254.1005;
found: 254.0995.
Anal. Calcd for C10H17NO5 (231.2): C, 51.93; H, 7.41; N, 6.06.
Found: C, 51.94; H, 7.40; N, 5.98.
The above solid (1.50 g, 6.49 mmol), dissolved in aq 3 M HCl (30
mL) was heated to 70 °C for 2 h. The volatiles were removed in vac-
uo. The remaining residue was triturated with EtOAc (25 mL) to af-
ford a white precipitate. The precipitate was filtered and dried in
vacuo to afford 22 as a white solid with a H2O content of 8.7%, as
determined by Karl Fischer titration; yield: 1.05 g (97%); mp 98–
100 °C (loss of H2O).
IR (film): 1725, 1327, 1158, 1091, 666 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.61 (br s, 1 H), 7.85 (d,
J = 6.16 Hz, 1 H), 7.69 (d, J = 7.69 Hz, 2 H), 7.40 (d, J = 8.05 Hz,
2 H), 4.24 (t, J = 7.81 Hz, 1 H), 3.70 (dd, J = 8.29, 6.84 Hz, 1 H),
3.63 (m, 1 H), 3.44 (dd, J = 8.54, 7.08 Hz, 1 H), 2.39 (s, 3 H), 2.24
(dt, J = 12.7, 8.05 Hz, 1 H), 1.72 (dt, J = 12.7, 7.32 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 174.0, 143.5, 138.4, 130.4,
127.3, 75.69, 72.20, 53.06, 35.95, 21.64.
IR (film): 1728, 1203, 1100, 1051 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.90 (br s, 1 H), 8.25 (br s, 3
H), 4.35 (dd, J = 8.39, 7.61 Hz, 1 H), 3.90 (td, J = 8.20, 2.92 Hz, 1
H), 3.82–3.74 (m, 2 H), 2.59 (dt, J = 13.3, 8.20 Hz, 1 H), 1.95 (m, 1
H).
HRMS (ESI): m/z [M + Na]+ calcd for C12H15NO5S + Na: 308.0569;
found: 308.0555.
Synthesis 2011, No. 7, 1113–1119 © Thieme Stuttgart · New York

1118
D. P. Walker et al.
PAPER
Mansour, T. S. Patent Cooperation Treaty WO 2003/
093277, 2003; Chem. Abstr. 2003, 139, 381300. (b) Tabei,
K.; Feng, X.; Venkatesan, A. M.; Abe, T.; Hideki, U.;
Mansour, T. S.; Siegel, M. M. J. Med. Chem. 2004, 47,
3674. (c) Petersen, P. J.; Jones, C. H.; Venkatesan, A. M.;
Bradford, P. A. Antimicrob. Agents Chemother. 2009, 53,
1698.
13C NMR (125 MHz, DMSO-d6): d = 172.7, 75.74, 70.28, 49.45,
33.67.
HRMS (ESI): m/z [M + H]+ calcd for C5H10NO3: 132.0661; found:
132.0656.
Anal. Calcd for C5H10ClNO3·8.73%H2O: C, 53.09; H, 6.23; N,
12.39. Found: C, 53.56; H, 6.59; N, 12.37.
(5) Vasiliou, S.; Vicente, M.; Castaner, R. Drugs Future 2009,
34, 451.
(6) Munk, S. A.; Harcourt, D.; Ambrus, G.; Denys, L.;
Gluchowski, C.; Burke, J. A.; Kharlamb, A. B.; Manlapaz,
C. A.; Padillo, E. U.; Runde, E.; Williams, L.; Wheeler, L.
A.; Garst, M. E. J. Med. Chem. 1996, 39, 3533.
( )-2-Oxa-5-azabicyclo[2.2.1]heptan-6-one (21)
To a stirred suspension of 22 (550 mg, 3.28 mmol) in anhyd MeCN
(50 mL) was added pyridine (0.80 mL, 9.9 mmol). The mixture was
heated to reflux before DCC (677 mg, 3.28 mmol) was added in a
single portion. Heating at reflux was continued for 1 h. The mixture
was cooled to r.t. and the resulting precipitate was filtered through
a Büchner funnel. The filtrate was concentrated in vacuo to a clear
residue. The crude product was purified by flash chromatography
on silica gel. Elution with EtOAc–MeOH (95:5) afforded 21 as a
clear solid; yield: 250 mg (67%); mp 56–57 °C; Rf = 0.32 (EtOAc–
MeOH, 90:10).
(7) (a) Griffin, R. J.; Fontana, G.; Golding, B. T.; Guiard, S.;
Hardcastle, I. R.; Leahy, J. J. J.; Martin, N.; Richardson, C.;
Rigoreau, L.; Stockley, M.; Smith, G. C. M. J. Med. Chem.
2005, 48, 569. (b) Blizzard, T. B.; DiNinno, F.; Morgan, J.
D. II.; Chen, H. Y.; Wu, J. Y.; Gude, C.; Kim, S.; Chan, W.;
Birzin, E. T.; Yang, Y. T.; Pai, L.-Y.; Zhang, Z.; Hayes, E.
C.; DaSilva, C. A.; Tang, W.; Rohrer, S. P.; Schaeffer, J. M.;
Hammond, M. L. Bioorg. Med. Chem. Lett. 2004, 3861.
(c) Roecker, A. J.; Coleman, P. J.; Mercer, S. P.; Schreier, S.
D.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.;
Tao, W.; Diehl, R. E.; South, V. J.; Davide, J. P.; Kohl, N.
E.; Yan, Y.; Kuo, L. C.; Li, C.; Fernandez-Metzler, C.;
Mahan, E. A.; Prueksaritanont, T.; Hartman, G. D. Bioorg.
Med. Chem. Lett. 2007, 5677. (d) Venkatesan, A. M.; Chen,
Z.; Santos, O. D.; Dehnhardt, C.; Santos, E. D.; Ayral-
Kaloustian, S.; Mallon, R.; Hollander, I.; Feldberg, L.;
Lucas, J.; Yu, K.; Chaudhary, I.; Mansour, T. S. Bioorg.
Med. Chem. Lett. 2010, 5869. (e) Zask, A.; Kaplan, J.;
Verheijen, J. C.; Richard, D. J.; Curran, K.; Brooijmans, N.;
Bennett, E. M.; Toral-Barza, L.; Hollander, I.; Ayral-
Kaloustian, S.; Yu, K. J. Med. Chem. 2009, 52, 7942.
(8) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197.
(9) (a) Bromidge, S. M.; Arban, R.; Bertani, B.; Bison, S.;
Borriello, M.; Cavanni, P.; Dal Forno, G.; Di-Fabio, R.;
Donati, D.; Fontana, S.; Gianotti, M.; Gordon, L. J.; Granci,
E.; Leslie, C. P.; Moccia, L.; Pasquarello, A.; Sortori, I.;
Sava, A.; Watson, J. M.; Worby, A.; Zonzini, L.; Zucchelli,
V. J. Med. Chem. 2010, 53, 5827. (b) Thurkauf, A.; Chen,
X.; Zhang, S.; Gao, Y.; Kieltyka, A.; Wasley, J. W. F.;
Brodbeck, R.; Greenlee, W.; Ganguly, A.; Zhao, H. Bioorg.
Med. Chem. Lett. 2003, 2921. (c) Weber, M.; Jager, W.;
Erker, T. J. Heterocycl. Chem. 2003, 40, 851.
IR (film): 3253, 1699, 1253, 1053 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.09 (br s, 1 H), 4.47 (s, 1 H), 4.21
(s, 1 H), 3.94 (dd, J = 7.08, 0.98 Hz, 1 H), 3.59 (d, J = 7.08 Hz, 1
H), 2.04 (dd, J = 9.92, 1.86 Hz, 1 H), 1.87 (d, J = 10.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 175.1, 79.31, 70.42, 55.40, 40.83.
HRMS (ESI): m/z [M + H]+ calcd for C5H8NO2: 114.0555; found:
114.0548.
Anal. Calcd for C5H7NO2 (113.1): C, 53.09; H, 6.23; N, 12.39.
Found: C, 53.46; H, 6.59; N, 12.37.
( )-2-Oxa-5-azabicyclo[2.2.1]heptan-6-thione (6)
To a stirred solution of lactam 21 (130 mg, 1.15 mmol) in toluene
(12 mL) was added Lawesson’s reagent (465 mg, 1.15 mmol). The
mixture was heated to 90 °C for 1 h. The mixture was cooled to r.t.,
and the solvent was removed in vacuo. The crude product was puri-
fied by flash chromatography on silica gel. Elution with CH2Cl2–
EtOAc (4:1) afforded 6 as a white solid; yield: 110 mg (74%); mp
107–109 °C; Rf = 0.20 (hexanes–EtOAc, 1:1).
IR (film): 3229, 1465, 1239, 1105 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.15 (br s, 1 H), 4.74 (s, 1 H), 4.40
(s, 1 H), 4.00 (d, J = 7.32 Hz, 1 H), 3.66 (d, J = 7.32 Hz, 1 H), 2.10
(dd, J = 10.0, 2.19 Hz, 1 H), 2.00 (d, J = 10.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 203.2, 86.91, 70.13, 60.42, 42.61.
HRMS (ESI): m/z [M + H]+ calcd for C5H8NOS: 130.0327; found:
130.0318.
(10) Moore, J. A.; Partain, E. M. III J. Polym. Sci. Polym. Lett.
Ed. 1975, 13, 333.
(11) See: (a) Moore, J. A.; Kelly, J. E. Org. Prep. Proced. Int.
1972, 4, 289. (b) Moore, J. A.; Kelly, J. E. Org. Prep.
Proced. Int. 1974, 6, 255. (c) Bradshaw, J. S.; Baxter, S. L.;
Lamb, J. D.; Izatt, R. M.; Christensen, J. J. J. Am. Chem. Soc.
1981, 103, 1821.
(12) (a) Allen, R. D.; Tran, H. W. Aust. J. Chem. 1984, 34, 1123.
(b) Ichihara, A.; Yamanaka, T.; Matsumoto, T. Bull. Chem.
Soc. Jpn. 1965, 38, 1165. (c) Matsumoto, T.; Ichihara, A.
Bull. Chem. Soc. Jpn. 1960, 33, 1015.
(13) Wolter, F. E.; Schneider, K.; Davies, B. P.; Socher, E. R.;
Nicholson, G.; Seitz, O.; Sussmuth, R. D. Org. Lett. 2009,
11, 2804.
(14) Lee, G. C. M.; Holmes, J. M.; Harcourt, D. A.; Garst, M. E.
J. Org. Chem. 1992, 57, 3126.
(15) Bergmeier, S. C.; Cobas, A. A.; Rapoport, H. J. Org. Chem.
1993, 58, 2369.
(16) (a) Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K.
Tetrahedron Lett. 1985, 26, 657. (b) Ji, S.; Gortler, L. B.;
Waring, A.; Battisti, A.; Bank, S.; Closson, W. D. J. Am.
Chem. Soc. 1967, 89, 5311.
Anal. Calcd for C5H7NOS (129.1): C, 46.50; H, 5.46; N, 10.84.
Found: C, 46.47; H, 5.71; N, 10.47.
Acknowledgment
We thank Geeta Yalamanchi for analytical support.
References
(1) Brickner, S. J.; Barbachyn, M. R.; Hutchinson, D. K.;
Manninen, P. R. J. Med. Chem. 2008, 51, 1981.
(2) Barker, A. J.; Gibson, K. H.; Grundy, W.; Godfrey, A. A.;
Barlow, J. J.; Healy, M. P.; Woodburn, J. R.; Ashton, S. E.;
Curry, B. J.; Scarlett, L.; Henthorn, L.; Richards, L. Bioorg.
Med. Chem. Lett. 2001, 1911.
(3) Kasper, S.; El Giamal, N.; Hilger, E. Exp. Opin.
Pharmacother. 2000, 1, 771.
(4) (a) Abe, T.; Matsunaga, H.; Mihira, A.; Sato, C.;
Ushirogochi, H.; Sato, K.; Takasaki, T.; Venkatesan, A. M.;
Synthesis 2011, No. 7, 1113–1119 © Thieme Stuttgart · New York

PAPER
Preparation of Bicyclic Morpholine Synthons
1119
(17) Milne, H. B.; Peng, C.-H. J. Am. Chem. Soc. 1957, 79, 639.
(18) A related heterocycle, isoquinuclidinone, has been prepared
via thermal cyclization of cis-4-aminocyclohexane-
carboxylic acid in Dowtherm A, see: (a) Pearlman, W. M.
Org. Syn. 1969, 49, 75. (b) Chung, J. Y. L.; Ho, G.-J. Synth.
Commun. 2002, 32, 1985.
(19) See: (a) Werner, L. H.; Ricca, S. Jr. J. Am. Chem. Soc. 1958,
80, 2733. (b) Casabona, D.; Cativiela, C. Tetrahedron 2006,
62, 10000. (c) Gong, L.; Hogg, J. H.; Collier, J.; Wilhelm, R.
S.; Soderberg, C. Bioorg. Med. Chem. Lett. 2003, 3597.
(20) DCC has been used to effect lactamization on a related
carbocyclic system, see: Grunewald, G. L.; Sall, D. J.;
Monn, J. A. J. Med. Chem. 1988, 31, 433.
Synthesis 2011, No. 7, 1113–1119 © Thieme Stuttgart · New York