A straightforward synthesis of enantiopure 2,6-disubstituted morpholines by a regioselective O-protection/activation protocol

Article abstract of DOI:10.1055/s-2008-1078054

Enantiopure 2,6-disubstituted morpholines have been synthesized through the ring opening of chiral, nonracemic oxiranes with nitrogen nucleophiles, under solid-liquid phase-transfer catalysis (SL-PTC) conditions. The β-hydroxytosyl amides resulting from the ring opening of a first epoxide with TsNH₂ was used as nucleophile, after protection of the hydroxyl group, in the reaction with a second oxirane. The morpholine skeleton has been generated through standard functional group chemistry, followed by cyclization of the intermediate β-hydroxy-β′-tosyloxy-tosylamides carried out under SL-PTC conditions. N-Tosyl morpholines produced can be employed as building blocks in the synthesis of pharmaceuticals and as chiral tools. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078054

LETTER
2451
A Straightforward Synthesis of Enantiopure 2,6-Disubstituted Morpholines by
a Regioselective O-Protection/Activation Protocol
S
ynthesis of Enantiopu
i
re 2,6-
c
D
isubstitut
h
e
es le Penso,*a Vittoria Lupi,*b,1 Domenico Albanese,b Francesca Foschi,b Dario Landini,b Aaron Tagliabueb
a
CNR, Institute of Molecular Science and Technologies (ISTM), Via Golgi 19, 20133 Milano, Italy
Dipartimento di Chimica Organica e Industriale dell’Università, Via Venezian 21, 20133 Milano, Italy
Fax +39(02)50314159; E-mail: michele.penso@istm.cnr.it
b
Received 6 June 2008
R2
R1
OH
Abstract: Enantiopure 2,6-disubstituted morpholines have been
synthesized through the ring opening of chiral, nonracemic oxiranes
with nitrogen nucleophiles, under solid-liquid phase-transfer catal-
ysis (SL-PTC) conditions. The b-hydroxytosyl amides resulting
from the ring opening of a first epoxide with TsNH2 was used as nu-
cleophile, after protection of the hydroxyl group, in the reaction
with a second oxirane. The morpholine skeleton has been generated
through standard functional group chemistry, followed by cycliza-
tion of the intermediate b-hydroxy-b¢-tosyloxy-tosylamides carried
out under SL-PTC conditions. N-Tosyl morpholines produced can
be employed as building blocks in the synthesis of pharmaceuticals
and as chiral tools.
i
i
NHTs
+
+
TsNH2
R1
O
O
1
2
3
2
H
R2
R2
R1
H
H
OTf
H
H
ii
TsN
TsN
TsN
R2
ONa+
OH
+
ONa+
R1
R1
H
OTf
5b
OH
4
5a
H
H
R1
R1
TsN
NTs
R2
R2
+
O
O
H
H
6a
6b
Key words: morpholines, regioselectivity, phase-transfer catalysis,
epoxides, ring opening
Scheme 1 Synthesis of racemic morpholines 6.12 Reagents and con-
ditions: (i) TEBA (cat.), K2CO3 (cat.), dioxane, 90 °C; 3a (83%), 3b
(92%), 3c (93%), 3d (97%); (ii) NaH, Tf2O, CH2Cl2, 0–25 °C. (•) Ste-
reogenic C atom that undergoes inversion during the ring closure.
Many C-substituted morpholines of natural origin show a
broad range of powerful biological activity.2 Their inher-
ent value is also demonstrated by the various morpholine
derivatives synthesized for pharmacological use as antitu-
mors,3 antidepressants,4 antioxidants,5 antiparasitic,6 and
more,7 in antisense chemistry,8 and in agrochemicals.9
Furthermore, enantiopure C-functionalized morpholines
are used in asymmetric synthesis as chiral tools,10 but their
application is limited by the restricted access to the stereo-
selective preparation of this kind of molecules.
O
R2
O
O
OH
i
ii
2
NHTs
NHTs
+
R1
R1
O
3
7
OTHP
OH
R2
OTHP
OTs
R2
iii
v
iv
Ts
N
Ts
N
R1
R1
8
9
While few general synthetic methods and several asym-
metric syntheses of specific compounds are reported in lit-
erature,2,11 novel efficient protocols for the preparation of
enantiopure C-substituted morpholines could lead to the
discovery of new drugs and chiral auxiliaries.
Ts
N
OH
OTs
R2
Ts
N
R1
R1
O
R2
10
11
In a preceding paper,12 we described the synthesis of sym-
metric (R1 = R2) and nonsymmetric (R1π R2) 2,6-disubsti-
tuted morpholines 6, through regioselective nucleophilic
ring opening of oxiranes 2 with tosylamide (1), under sol-
id-liquid phase-transfer catalysis (SL-PTC) conditions
(Scheme 1). The ring closure of the resulting tosylamido
diols 4 was realized in one pot, through a nonregioselec-
tive mono-O-triflation of the corresponding O,O¢-dian-
ions, followed by an intramolecular SN2 attack of the
monoanionic species 5 formed in situ. As a result, under
the reaction conditions adopted, the produced morpho-
lines 6 were racemic, even when nonracemic epoxides
Scheme 2 Reagents and conditions: (i) PPTS, CH2Cl2, 25 °C, 6 h;
7a (89%), 7b (85%), 7c (87%), 7d (96%); (ii) TBAB (cat.), M2CO3
(cat.), dioxane (see Table 1); (iii) TsCl, base, solvent (see Table 1);
(iv) PPTS, 95% EtOH, 55 °C, 20 h; 10a (88%), 10b (86%), 10c
(93%), 10d (87%), 10e (90%); (v) NaH, solvent or under SL-PTC
conditions (see Table 2).
were used in the synthetic sequence, as shown in
Scheme 1.
It is evident that the differentiation of the hydroxyl groups
of the tosylamido diol 4 is the solution for the overall ste-
reocontrol of the procedure and, therefore, we decided to
O-protect the tosylamido alcohols 3 (Scheme 2, step i),
prior to the second ring-opening reaction (step ii).
SYNLETT 2008, No. 16, pp 2451–2454
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.09.2008
DOI: 10.1055/s-2008-1078054; Art ID: G20308ST
© Georg Thieme Verlag Stuttgart · New York

2452
M. Penso et al.
LETTER
BnO
BnO
PhO
S
Table 1 Preparation of O-THP-O-tosyltosylamides 9
Step iia Step iiib
R
R
S
C6H13
Ph
Et
Et
O
O
O
S
R
O
O
O
2a
2b
2c
2e
2d
2f
Sub- Epoxide Time Product Yield Time Product
Yield
(%)c
strate
(h)
25
20
20
20
24
(%)c
(h)
X
X
X
X
S
Ts
NH
Ts
Ts
Ts
R
R
S
NH
NH
BnO
NH
7a
2b
2f
8a
8b
8c
8d
8e
94
5
9a
9b
9c
9d
9e
87d
94
87
95
90
C6H13
Ph
3,7a
3,7b
3,7c
3,7d
7a
88e
97
6
X
R
Ts
Y
S
X
Ts
N
Y
R
S
N
OPh
7b
2d
2f
6
Et
C6H13
Et
8a–10a
8b–10b
7c
93e
95
6
X
S
Ts
N
Y
X
Ts
N
Y
R
S
S
OBn
OPh
7d
2e
7
C6H13
Ph
a Reaction conditions: 7 (2 mmol), epoxide 2 (1 mmol), TBAB (0.1
mmol), K2CO3 (0.1 mmol), dioxane (1 mL), 90 °C.
b Reaction conditions: 8b–e (1 mmol), TsCl (1.5 mmol), Et3N (1.5
mmol), DMAP (1.5 mmol), CH2Cl2 (1.5 mL), 0–25 °C.
c Isolated yields.
8c–10c
8d–10d
3
7
8
9
10
X
Ts
N
Y
X
OH OTHP OTHP OTHP OH
R
S
BnO
OBn
Y
OH
OTs OTs
d Reaction conditions: 8a (1 mmol), TsCl (1.5 mmol), NaH (1.5
mmol), THF (5 mL), 0 °C.
8e–10e
Figure 1
e The ring-opening reaction was conducted with Cs2CO3 (0.1 mmol).
Ts
N
Ts
N
Ts
N
The O-monoprotected intermediates 8 were then O¢-tosy-
lated to 9 (step iii), which were deprotected (step iv) and
cyclized to the final morpholines 11 (step v).
Et
O
11a
C6H13 Et
O
11b
CH2OPh C6H13
O
11c
CH2OBn
R
R
R
R
R
S
Optically pure oxiranes 2a–d (Figure 1) were ring opened
with TsNH2 under SL-PTC conditions, by the procedure
reported previously,12 and the resulting tosylamido alco-
hols 3a–d were transformed into the corresponding O-tet-
rahydropyranyl derivatives 7a–d, isolated as mixtures of
diastereoisomers (Scheme 2, step i), which by SL-PTC re-
action with the second epoxide 2a–f gave the mono-O-
THP tosylamido diols 8a–e (Table 1, step ii). Both ring-
opening steps required catalytic amounts of a PT agent
and of an anhydrous alkaline metal carbonate, as a base.
In particular, the couple TEBA–K2CO3 was more active in
the first ring opening, whereas TBAB–Cs2CO3 was pre-
ferred in step ii.
Ts
N
Ts
N
Ph
O
11d
CH2OPh
BnOCH2
O
11e
CH2OBn
S
R
R
S
Figure 2
Table 2 Cyclization of Hydroxy-O-tosyltosylamides 10 to Enan-
tiopure Morpholines 11a
Substrate
10a
Time (h)
Morpholine
11a
Yield (%)b,c
25
20
72
3
91
90
86
88
85
The O-THP-O¢-tosyl derivatives 9 (Table 1, step iii) were
prepared from 8 by reaction with TsCl, following typical
procedures, i.e. in the presence of an organic soluble basic
system, such as Et3N–DMAP, or by generating the corre-
sponding oxyanion with sodium hydride. The O-tetrahy-
dropyranyl group was easily removed from 9 by mild acid
hydrolysis in aqueous ethanol (Scheme 2, step iv). The
N,O-ditosyl alcohols 10a–e were diastereomeric pure
10b
11b
10cd
10d
11c
11d
10e
60
11e
a Reaction conditions: 10a,b,d,e (1 mmol), Cs2CO3 (2.5 mmol),
TEBA (0.1 mmol), MeCN (10 mL), 25 °C.
b Isolated yields.
1
compounds, as confirmed by H NMR analysis. Finally,
c A 99% ee was determined by chiral HPLC analysis.
d Reaction conditions: 10c (1 mmol), NaH (1.5 mmol), THF (1 mL),
40 °C.
alcohols 10 were cyclized to enantiopure morpholines 11
(Figure 2 and Table 2),13 both under SL-PTC conditions
and under anhydrous anaerobic conditions. In the case of
optically active morpholine 11e, bearing symmetric side
arms, the enantiomeric oxiranes 2d and 2e were used in
the sequential ring-opening reactions. On the contrary, the
use of the same oxirane in both steps would produce the
achiral meso morpholine.
transfer catalysis in both the epoxide ring opening and the
morpholines formation steps, allowed mild reaction con-
ditions and the isolation of the products in good yields
(e.g. 55% overall yield of 11d, from starting epoxide 2c)
and without loss of the original stereochemical informa-
tion.
In conclusion, we have sketched out a general protocol to
prepare symmetric and nonsymmetric, enantiopure mor-
pholines from nonracemic oxiranes. The use of phase-
Synlett 2008, No. 16, 2451–2454 © Thieme Stuttgart · New York

LETTER
Synthesis of Enantiopure 2,6-Disubstituted Morpholines
2453
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Acknowledgment
This research was carried out within the framework of the National
Project ‘Nuovi metodi catalitici stereoselettivi e sintesi stereoselet-
tiva di molecole funzionali’ and is supported by the MIUR (Rome)
and the CNR (Italy).
References and Notes
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(13) Synthesis of (2R,6R)-2-Phenoxymethyl-6-phenyl-4-
(toluene-4-sulfonyl)morpholine (11d); Typical
Cyclization (Step v): In a screw cap vial, a heterogeneous
mixture of 10d (0.60 g, 1 mmol) and TEBA (23 mg, 0.1
mmol) solution in anhyd MeCN (10 mL), and anhyd Cs2CO3
(0.83 g, 2.5 mmol), was magnetically stirred at 25 °C for 3
h. Then the crude was diluted with CH2Cl2 (10 mL), and
filtered through a celite pad. The solvent was evaporated
under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (230–400 mesh,
EtOAc–hexane, 1:4) to give 11d (373 mg, 88%) as a white
solid; mp 146–148 °C; ee >99%; HPLC: 4.6/250 mm
CHIRALPAK-AD column, 25 °C, i-PrOH–hexane (75:25),
flow 0.8 mL/min; tR = 11.9 min; [a]D20 –31.1 (c = 1.0,
CHCl3). IR (Nujol): 1598, 1587, 1493, 1345, 1236, 1167,
1131, 1122, 1065, 1051, 968, 813, 776, 757, 682 cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.63 (d, 2 H, J = 8.2 Hz), 7.25–
7.44 (m, 9 H), 6.97 (t, 1 H, J = 7.3 Hz), 6.91 (d, 2 H, J = 8.2
Hz), 4.73 (dd, 1 H, J = 10.4, 2.6 Hz), 4.09–4.21 (m, 2 H),
3.96–3.99 (m, 2 H), 3.83 (dd, 1 H, J = 11.5, 1.9 Hz), 2.43 (s,
3 H), 2.33 (t, 1 H, J = 11.0 Hz), 2.23 (t, 1 H, J = 11.0 Hz).
13C NMR–APT (75 MHz, CDCl3): d = 158.86 (CArO),
144.46 (CArMe), 138.82 (CAr), 132.69 (CArS), 130.51,
129.97, 128.98, 128.67, 128.29, 126.54, 121.71, 115.17 (14
CHAr), 78.01 (OCHPh), 74.40 (OCH), 68.78 (CH2OPh),
52.17 (CH2N), 48.21 (CH2N), 22.00 (Me). Anal. Calcd for
C24H25NO4S: C, 68.06; H, 5.95; N, 3.31. Found: C, 68.10; H,
5.99; N, 3.26.
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(b) Blagg, J.; Allerton, C. M. N.; Batchelor, D. V. J.; Baxter,
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Bioconjugate Chem. 2005, 16, 383. (b) Nelson, M. H.;
Stein, D. A.; Kroeker, A. D.; Hatlevig, S. A.; Iversen, P. L.;
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(c) Summerton, J.; Weller, D. Antisense Nucleic Acid Drug
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J. D.; Iversen, P. L.; Geller, B. L. Antimicrob. Agents
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Crop Protection Council: Alton, 1983, 265, 550.
(b) Bowers, W. S.; Ebing, W.; Fukuto, T. R.; Martin, D.
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(10) (a) Licandro, E.; Maiorana, S.; Papagni, A.; Pryce, M.;
Zanotti-Gerosa, A.; Riva, SA. Tetrahedron: Asymmetry
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Maiorana, S.; Papagni, A.; Zanotti-Gerosa, A. J.
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Physical, Spectroscopic and Analytical Data of
Intermediate Compounds (Steps i–iv) in the Synthesis of
Morpholine (11d):
3c: white solid; mp 105–106 °C (lit.14 107–108 °C); [a]D
20
–70.5 (c = 1.0, CHCl3). IR (Nujol): 3401, 3149, 1918, 1662,
1598, 1318, 1148, 1098, 1088, 1065 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.72 (d, 2 H, J = 8.3 Hz), 7.23–7.34 (m, 8
H), 4.99–5.01 (m, 1 H), 3.05 (dd, 1 H, J = 8.6, 3.6 Hz), 3.01
(dd, 1 H, J = 8.5, 4.6 Hz), 2.42 (s, 3 H), 2.31 (d, 1 H, J = 3.5
Hz). Anal. Calcd for C15H17NO3S: C, 61.83; H, 5.88; N,
4.81. Found: C, 61.91; H, 5.92; N, 4.78.
7c (Diastereomeric mixture): wax. IR (Nujol): 3291, 2925,
2854, 1599, 1495, 1377, 1162, 1121, 1094, 1074, 1022, 982
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.73 (d, 2 H, J = 8.4
Hz), 7.16–7.32 (m, 7 H), 5.32 (dd, 1 H, J = 8.1, 3.1 Hz),
4.63–4.71 (m, 1 H), 4.33–4.37 (m, 1 H), 3.90–4.10 (m, 1 H),
3.47–3.51 (m, 1 H), 3.18–3.31 (m, 1 H), 2.99–3.12 (m, 1 H),
2.42 (s, 3 H), 1.48–1.81 (m, 6 H). Anal. Calcd for
C20H25NO4S: C, 63.97; H, 6.71; N, 3.73. Found: C, 63.90; H,
6.65; N, 3.68.
8d (Diastereomeric mixture): wax. IR (Nujol): 3431, 3062,
3030, 1599, 1496, 1245, 1157, 1076, 1027, 978, 815, 757,
702, 659 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.73 (d, 2
H, J = 8.4 Hz), 7.25–7.37 (m, 9 H), 6.94 (t, 1 H, J = 7.5 Hz),
Synlett 2008, No. 16, 2451–2454 © Thieme Stuttgart · New York

2454
M. Penso et al.
LETTER
6.90 (d, 2 H, J = 8.4 Hz), 5.28 (dd, 1 H, J = 9.6, 2.4 Hz), 4.48
(br s, 1 H), 4.35 (dd, 2 H, J = 6.9, 2.4), 4.13 (dd, 1 H, J = 9.6,
5.4 Hz), 3.99–4.08 (m, 1 H), 3.94 (dd, 1 H, J = 9.6, 6.0 Hz),
3.42–3.58 (m, 3 H), 3.10–3.18 (m, 2 H), 2.39 (s, 3 H), 1.48–
1.81 (m, 6 H). 13C NMR–APT (75 MHz, CDCl3; major
diastereoisomer): d = 159.1 (CArO), 144.0 (CArMe), 139.7
(CAr), 136.0 (CArS), 130.1, 129.8, 129.1, 128.6, 128.1, 127.1,
121.3, 119.9 (14 × CHAr), 98.6 (OCHOTHP), 78.9 (OCHPh),
69.9 (CH2OPh), 67.9 (CHOH), 65.2 (CH2OTHP), 57.2
(CH2N), 55.2 (CH2N), 31.4, 25.4, 21.3 [3 × CH2 (THP)], 21.9
(Me). 13C NMR–APT (75 MHz, CDCl3; minor
diastereoisomer, visible signals): d = 130.3, 130.0, 128.5,
126.4, 121.7, 115.0 (CHAr), 73.6 (OCHPh), 69.3 (CHOH),
64.2 (CH2OTHP), 59.0 (CH2N), 54.1 (CH2N), 31.3, 20.7
(CH2OTHP). Anal. Calcd for C29H35NO6S: C, 66.26; H, 6.71;
N, 2.66. Found: C, 66.30; H, 6.67; N, 2.60.
9d (Diastereomeric mixture): wax. IR (Nujol): 3440, 2926,
2853, 1598, 1495, 1303, 1246, 1156, 1120, 1090, 908, 813
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.78 (d, 2 H, J = 8.3
Hz), 7.72 (d, 2 H, J = 8.2 Hz), 7.21–7.31 (m, 11 H), 6.93 (t,
1 H, J = 7.3 Hz), 6.66 (d, 2 H, J = 8.1 Hz), 5.00 (dd, 1 H, J =
8.5, 4.7 Hz), 4.82–4.87 (m, 1 H), 4.30–4.33 (m, 1 H), 4.07
(dd, 1 H, J = 11.0, 3.5 Hz), 3.99 (dd, 1 H, J = 11.0, 5.8 Hz),
3.65–3.73 (m, 2 H), 3.60 (dd, 1 H, J = 15.2, 6.0 Hz), 3.42 (dd,
1 H, J = 15.0, 8.6 Hz), 3.25–3.32 (m, 1 H), 3.17 (dd, 1 H,
J = 15.0, 4.7 Hz), 2.42 (s, 3 H), 2.41 (s, 3 H), 1.25–1.56 (m,
6 H). 13C NMR–APT (75 MHz, CDCl3; major
129.3, 128.5, 128.2, 128.1, 127.6, 127.1, 121.0, 114.3 (18 ×
CHAr), 95.8 (OCHOTHP), 78.9 (OCHPh), 76.0 (CHOTs),
66.7 (CH2OPh), 62.6 (CH2OTHP), 55.8 (CH2N), 50.0
(CH2N), 30.5, 25.2, 19.6 [3 × CH2 (THP)], 21.6, 21.5 (2 × Me).
13C NMR–APT (75 MHz, CDCl3; minor diastereoisomer,
visible signals): d = 129.9, 126.6, 125.9, 121.3 (CHAr), 78.4
(OCHPh), 72.5 (CHOTs), 58.8 (CH2OTHP), 55.5 (CH2N),
51.1 (CH2N), 29.6, 19.1 [CH2 (THP)]. Anal. Calcd for
C36H41NO8S2: C, 63.60; H, 6.08; N, 2.06. Found: C, 63.54;
H, 6.03; N, 2.10.
10d: wax; [a]D20 –12.0 (c = 1.0, CHCl3). IR (Nujol): 3504,
2924, 1733, 1598, 1243, 1159, 1090, 1045, 917 cm–1. 1H
NMR (300 MHz, CDCl3) : d = 7.81 (d, 2 H, J = 8.3 Hz), 7.69
(d, 2 H, J = 8.3 Hz), 7.20–7.31 (m, 11 H), 6.94 (t, 1 H, J =
7.3 Hz), 6.69 (d, 2 H, J = 8.1 Hz), 5.01–5.06 (m, 1 H), 4.96
(dd, 1 H, J = 9.3, 3.2 Hz), 4.07–4.18 (m, 2 H), 3.63–3.70 (dd,
1 H, J = 15.3, 6.7 Hz), 3.46–3.53 (dd, 1 H, J = 12.2, 6.2 Hz),
3.26–3.34 (dd, 1 H, J = 14.7, 9.3 Hz), 3.08–3.14 (dd, 1 H,
J = 14.7, 3.3 Hz), 2.81 (br s, 1 H), 2.41 (s, 6 H). 13C NMR–
APT (75 MHz, CDCl3): d = 157.7 (CArO), 145.0, 144.1 (2 ×
CArMe), 141.0 (CArCHOH), 134.5, 133.0 (2 × CArS), 129.9,
129.7, 129.3, 128.5, 128.1, 127.9, 127.5, 125.8, 121.3, 114.4
(18 × CHAr), 78.4 (OCHPh), 72.4 (CHOTs), 66.5 (CH2OPh),
58.8 (CH2N), 51.1 (CH2N), 21.6, 21.5 (2 × Me). Anal. Calcd
for C31H33NO7S2: C, 62.50; H, 5.58; N, 2.35. Found: C,
62.44; H, 5.53; N, 2.39.
(14) Sharpless, K. B.; Chong, A. O.; Oshima, K. J. Org. Chem.
1976, 41, 177.
diastereoisomer): d = 157.9 (CArO), 144.8, 143.7 (2 ×
CArMe), 139.0 (CAr), 135.7, 133.4 (2 × CArS), 129.7, 129.6,
Synlett 2008, No. 16, 2451–2454 © Thieme Stuttgart · New York