Synthesis of reboxetine intermediate and carnitine acetyltransferase inhibitor via NBS-induced electrophilic multicomponent reaction

Article abstract of DOI:10.1021/jo500609a

N-Bromosuccinimide-induced electrophilic multicomponent reaction has been applied to the synthesis of Reboxetine intermediate, a highly potent selective norepinephrine reuptake inhibitor. By simply changing the olefinic partner, the synthesis of a carniti

Full text of DOI:10.1021/jo500609a

Article
pubs.acs.org/joc
Synthesis of Reboxetine Intermediate and Carnitine
Acetyltransferase Inhibitor via NBS-Induced Electrophilic
Multicomponent Reaction
Jing Zhou and Ying-Yeung Yeung*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
S
* Supporting Information
ABSTRACT: N-Bromosuccinimide-induced electrophilic
multicomponent reaction has been applied to the synthesis
of Reboxetine intermediate, a highly potent selective
norepinephrine reuptake inhibitor. By simply changing the
olefinic partner, the synthesis of a carnitine acetyltransferase
inhibitor, which contains a 2,6,6-trisubstituted morpholine
system, can be accomplished.
Comparing to other substituted morpholines (e.g., 3-subsituted
morpholines) that can readily be constructed by using amino
acid building blocks,7 enantioselective syntheses of 2-
substituted morpholine systems are less reported.8 In one of
our focuses on the electrophilic MCRs using epoxide as the
nucleophilic partner, epichlorohydrin was found to be effective,
which gave rise to the corresponding morpholine with a
chloride handle (Scheme 1).3e We reasoned that this kind of
functionalized scaffold is very useful as an advanced
intermediate for pharmaceutically important morpholines.
INTRODUCTION
■
The importance in ensuring the economic competitiveness of
pharmaceutical industry while reducing the impact on environ-
ment has emerged in recent years.1 Multicomponent reaction
(MCR), in which three or more reactants are combined in a
single chemical operation, is one of the ideal solutions for
sustainable manufacture.2 Recently, we have developed a
number of electrophilic MCRs using N-bromosuccinimide
(NBS) as the initiator.3 Herein we are pleased to report the
application of electrophilic MCR in the synthesis of bioactive 2-
substituted morpholines Reboxetine (1) (a norepinephrine
reuptake inhibitor, marketed as an antidepressant by Pfizer)
and 2 (a potent carnitine acetyltransferase inhibitor) (Scheme
1).4,5
RESULTS AND DISCUSSION
■
Racemic Reboxetine (1) is marketed currently. However,
recently it was found that the pure enantiomer (+)-(S,S)-
Reboxetine (1) is significantly more active, and a number of
biologically studies are underway.9 As a result, an efficient and
enantioselective entry toward the synthesis of enantiopure
Reboxetine (1) is highly desirable.10
Morpholines with substitutions at the α-oxygen positions (2-
substituted or 2,6-disubstituted morpholines) are a class of
molecules that possess interesting biological activities.6
Toward the formal synthesis of Reboxetine (1), we simply
need to react ethylene with epichlorohydrin, NBS, and NsNH2
at −30 °C for 16 h. Morpholine 3 with a methylene chloride
handle at the 2-position could be achieved in 66% yield
(Scheme 2). The structure of 3 was confirmed by an X-ray
crystallographic study. Substitution of the chloride in 3 with
acetate followed by hydrolysis allowed for the introduction of
an oxygen functionality, providing morpholine 4. Subsequently,
conventional protecting group manipulation accomplished
hydroxyl morpholine 5, which is a key intermediate in the
synthesis of Reboxetine (1).10g By using appropriate hands of
epichlorohydrin, one can access both enantiomers of
Reboxetine (1) efficiently.
Scheme 1. NBS-Induced MCR in the Synthesis of 2-
Substituted Morpholines
Other than the synthesis of 1, we also found that this type of
electrophilic MCR can be applied to the total synthesis of the
Received: March 20, 2014
Published: April 17, 2014
© 2014 American Chemical Society
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Article
give N-methyl morpholine 9. Subsequent treatment of 9 with
sodium cyanide in DMSO at 100 °C accomplished 10. The
cyanide group in 10 is a precursor for the introduction of
carboxylate group at the later stage.
Scheme 2. Formal Synthesis of Reboxetine (1)
Global desilylation of 10 gave diol 11 in excellent yield
(Scheme 4). The structure of 11 was confirmed by an X-ray
Scheme 4. Attempts to Synthesize 12
carnitine acetyltransferase inhibitor 2. Toward the enantiose-
lective synthesis of 2, we first reacted the olefinic partner with
enantiopure (S)-epichlorohydrin, NBS, and NsNH2 to
construct the morpholine core. After screening some olefins,
it was found that 6 was suitable, which gave rise to 7 in 72%
yield (6:1 regioselectivity) (Scheme 3). The unreacted (S)-
crystallographic study. Attempt to differentiate the two
hydroxyl groups by transforming 11 into lactone 12 via Pinner
reaction was not successful; carboxylic acid 13 was isolated in
85% yield when heating 11 in 6 N HCl for 12 h. Further trials
to dehydrate 13 aiming to synthesize lactone 12 using various
reagents were also fruitless. We suspected that the rigidity of
the seven-membered ring lactone might disfavor the cyclization
process.11
Scheme 3. NBS-Induced MCR in the Synthesis of 2-
Substituted Morpholines
After extensive experimentations, it was found that treatment
of 11 with 1.0 equiv of n-BuLi followed by 1.0 equiv of p-TsCl
gave tosylate 14 (R = p-Ts) in 81% yield with the desired
isomer 14a as the major product (14a:14b = 9:1, R = p-Ts)
(Scheme 5). Interestingly, when MsCl was used in the same
reaction, isomer 14b (R = Ms) was obtained as the major
product (14a:14b = 1:4, R = Ms). We speculate that the n-butyl
lithium might first coordinate to the nitrogen in 11 to give
complex A. Because of the close proximity of the n-BuLi and
the axial methylene OH, the deprotonation might proceed to
give lithium alkoxide B.5a,12 The relatively smaller size MsCl
might be able to react with the axial alkoxide in B to yield 14b.
On the other hand, the reaction between B and the bulkier p-
TsCl might be disfavored. Instead, B could isomerize to C,
which contains an equatorial OLi, and then react with p-TsCl
to yield 14a. At this point, the two hydroxyl groups were
differentiated, which is important for the subsequent
functionalization.
After silylation of the hydroxyl group in 14a, the OTs group
in 15 was removed by heating it with sodium boronhydride in
DMSO at 100 °C (Scheme 6). Treating 16 with MeI gave
quaternary ammonium salt 17 in 91% yield. Finally, subjecting
17 in 6 N HCl at reflux transformed the cyanide into a
carboxylic acid. The silyl protection was also removed under
the same conditions. Workup of the reaction mixture with
aqueous base accomplished the desired carnitine acetyltransfer-
ase inhibitor 2 in 72% yield.
epichlorohydrin was recovered by a simple distillation. Attempt
to scale up the reaction (using 2 g of olefin 6) returned with
comparable reaction yield of 65%. Subsequent treatment of 7
with base under reflux furnished the multifunctionalized
morpholine 8 in 83% yield.
Next, we attempted to substitute the chloride with cyanide.
However, it was found that chloride 8 was inert toward the
substitution. The N-nosyl group in 8 was then removed to give
the corresponding free amine, which was then methylated to
In summary, we have successfully applied the NBS-induced
electrophilic MCR in the formal synthesis of the antidepressant
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integration). Data for 1H NMR spectra are referenced to the centerline
of CDCl3 δ 7.26) as the internal standard. Data for 13C NMR spectra
are referenced to the centerline of CDCl3 (δ 77.0). High resolution
mass spectra were obtained on spectrometer in ESI or EI mode using a
TOF mass analyzer.
Scheme 5. Selective Tosylation of 11
Formal Synthesis of Reboxetine (1) Intermediate. 2-
Chloromethyl-4-nosylmorpholine (3). Nosylamide (202 mg, 1.0
mmol) and NBS (214 mg, 1.2 mmol) were dissolved in
epichlorohydrin (2 mL) at −30 °C. With the protection of N2,
ethylene gas was then bubbled into the solution for 2 h. After stirring
at the same temperature for 24 h, the reaction was quenched by
saturated sodium sulfite solution (1 mL). The mixture was then
extracted with EtOAc (5 mL × 3). The combined organic extracts
were washed with brine (1 mL), dried with Na2SO4, filtered, and
concentrated under reduced pressure. The crude bromoether product
was used in the next step without further purification.
To the crude bromoether product was added CH3CN (10 mL) and
K2CO3 (276 mg, 2.0 mmol) at 25 °C. The resultant mixture was then
stirred for 16 h. Upon completion, the reaction was quenched by
adding water (3 mL). The mixture was extracted with EtOAc (5 mL ×
3). The combined organic extracts were washed with water (2 mL)
and brine (2 mL), dried with Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(Hexane:EtOAc = 5:1) to give compound morpholine 3 (211 mg, 66%
for 2 steps) as solid: mp 132−135 °C; 1H NMR (500 MHz, CDCl3) δ
8.42 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 4.05−3.93 (m, 1H),
3.87−3.77 (m, 2H), 3.73 (td, J = 11.5, 2.7 Hz, 1H), 3.67−3.58 (m,
1H), 3.55 (dd, J = 11.7, 4.7 Hz, 1H), 3.46 (dd, J = 11.7, 5.9 Hz, 1H),
2.53 (td, J = 11.5, 3.4 Hz, 1H), 2.34 (t, J = 11.1 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 150.5, 141.4, 128.9, 124.5, 74.4, 66.0, 48.0, 45.2,
43.6; IR (KBr) 3108, 2992, 1528, 1352, 1177, 1107 cm−1; HRMS (EI)
calcd for C11H13ClN2O5S [M]+ 320.0234, found 320.0226.
Scheme 6. Enantioselective Synthesis of 2
2-Hydroxymethyl-4-nosylmorpholine (4). To a solution of
morpholine 3 (160 mg, 0.5 mmol) in DMF (5 mL) was added
potassium acetate (490 mg, 5 mmol) at 25 °C. Under the protection of
N2, the reaction mixture was stirred at 90 °C for 16 h. Upon
completion, the reaction was quenched by adding water (2 mL). The
mixture was extracted with EtOAc (5 mL × 3). The combined organic
extracts were washed with water (2 mL) and brine (2 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (Hexane:EtOAc = 3:1)
to give 2-Acetoxymethyl-4-nosylmorpholine (139 mg, 81%) as a light-
yellow solid: mp 95−97 °C; 1H NMR (500 MHz, CDCl3) δ 8.42 (d, J
= 8.7 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 4.06 (qd, J = 11.8, 5.2 Hz,
2H), 3.98 (dd, J = 11.8, 1.9 Hz, 1H), 3.82−3.77 (m, 1H), 3.75−3.66
(m, 2H), 3.61 (d, J = 11.4 Hz, 1H), 2.51 (td, J = 11.5, 3.4 Hz, 1H),
2.26 (t, J = 10.9 Hz, 1H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 170.5, 150.4, 141.4, 128.9, 124.5, 73.0, 65.9, 64.0, 47.3, 45.3, 20.7; IR
(KBr) 3111, 2980, 1749, 1542, 1351, 1248, 1167 cm−1; HRMS (EI)
calcd for C13H16N2O7S [M]+:344.0678, found 344.0690.
2-Acetoxymethyl-4-nosylmorpholine (172 mg, 0.5 mmol) was
dissolved in CH3OH/H2O (5 mL, 1:1 v/v) and K2CO3 (207 mg,
1.5 mmol) was added at 25 °C. The reaction mixture was stirred at the
same temperature for 16 h. The mixture was then extracted with
EtOAc (5 mL × 3). The combined organic extracts were washed with
water (2 mL) and brine (2 mL), dried with Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (Hexane:EtOAc = 1:1) to give 4 (140 mg, 93%)
as a light-yellow powder: mp 173−174 °C; 1H NMR (500 MHz,
MeOD) δ 8.47 (d, J = 8.9 Hz, 2H), 8.03 (d, J = 8.9 Hz, 2H), 3.94
(ddd, J = 11.5, 3.2, 1.3 Hz, 1H), 3.72−3.67 (m, 1H), 3.64 (td, J = 11.5,
2.7 Hz, 1H), 3.61−3.46 (m, 4H), 2.47 (td, J = 11.5, 3.4 Hz, 1H), 2.26
(dd, J = 11.5, 10.0 Hz, 1H); 13C NMR (125 MHz, MeOD) δ 152.0,
142.6, 130.4, 125.6, 77.1, 67.0, 63.6, 46.9; IR (KBr) 3450, 3114, 2921,
1530, 1350, 1176 cm−1 HRMS (EI) calcd for C11H14N2O6S
[M]+:302.0573, found 302.0575.
drug Reboxetine (1) intermediate. In addition, the enantiose-
lective synthesis of carnitine acetyltransferase inhibitor 2,6,6-
trisubsituted morpholine 2 was accomplished by using (S)-
epichlorohydrin as the nucleophilic partner. This approach not
only provides an efficient approach toward biologically relevant
2-subsituted morpholine systems, but also offers flexibility in
making drug analogues for further biological studies.
EXPERIMENTAL SECTION
■
Materials and Methods. All reactions that required anhydrous
conditions were carried by standard procedures under nitrogen
atmosphere. Commercially available reagents and solvents were used
without further treatment. Tetrahydrofuran (THF) was freshly
distilled prior to use from sodium/benzophenone ketyl under N2.
CH2Cl2 was freshly distilled from CaH2. Thin-layer chromatography
(TLC) was performed using precoated silica gel foils, and compounds
were visualized with a spray of 5% (w/v) dodecamolybdophosphoric
acid in ethanol and subsequent heating. Chromotographic purification
1
was performed on silica gel (0.040−0.063 mm). H and 13C NMR
2-Hydroxymethyl-4-bocmorpholine (5). A mixture of compound 4
(121 mg, 0.4 mmol), lithium hydroxide monohydrate (84 mg, 2.0
mmol) and 1-propanethiol (18 μL, 2.0 mmol) was stirred at 25 °C in
CH3CN (4 mL) for 8 h. After the reaction was complete, the solvent
spectra were either recorded on spectrometer operating at 300 MHz
for proton and 75 MHz for carbon nuclei or 500 MHz for proton and
125 MHz for carbon nuclei. Data for 1H NMR spectra are reported as
follows: chemical shift δ ppm (multiplicity, coupling constant (Hz),
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was evaporated. The mixture was used in the next step without further
purification.
dried with Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (Hexane:EtOAc =
20:1) to give morpholine 8 (760 mg, 83%) as a semisolid: mp 116.1−
118.3 °C; [α]D26 +6.7 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ
8.40 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 4.04 (m, 1H), 3.86
(d, J = 11.1 Hz, 1H), 3.80 (dd, J = 10.5, 15.2 Hz, 2H), 3.67(m, 2H),
3.49 (dd, J = 4.4, 11.4 Hz, 1H), 3.33 (m, 2H), 2.25 (d, J = 11.7 Hz,
1H), 2.12(t, J = 10.8 Hz, 1H), 0.91 (s, 9H), 0.84 (s, 9H), 0.09 (s, 3H),
0.08 (s, 3H), 0.01 (s, 3H), −0.01 (s, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 150.5, 141.5, 128.9, 124.4, 76.7, 68.8, 64.9, 58.5, 48.1, 47.0,
44.0, 25.79, 25.77, 18.20, 18.18, −5.41, −5.45, −5.49, −5.54 ppm; IR
(KBr) 2957, 2858, 1528, 1356, 1172, 1102, 835 cm−1; HRMS (EI)
calcd for C21H36ClN2O7SSi2 [M − t-Bu]+ 551.1470, found 551.1466.
(+)-(6S)-2,2-Bis((tert-butyldimethylsilyloxy)methyl)-6-chloro-
methyl-4-methylmorpholine (9). A mixture of compound 8 (1.0 g,
1.6 mmol), lithium hydroxide monohydrate (344 mg, 8.2 mmol) and
1-propanethiol (742 μL, 8.2 mmol) was stirred at 25 °C in CH3CN
(15 mL) for 6 h. The reaction was then quenched with water (5 mL),
extracted with EtOAc (20 mL × 3). The combined organic extracts
were washed with water (5 mL) and brine (5 mL), dried with Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (Hexane:EtOAc = 5:1) to give 2,2-
Bis((tert-butyldimethylsilyloxy)methyl)-6-chloromethylmorpholine
(590 mg, 85%) as a clear oil: [α]D +3.1 (c 1.0, CHCl3); H NMR
(500 MHz, CDCl3) δ 3.97 (m, 1H), 3.93 (d, J = 10.4 Hz, 1H), 3.79 (d,
J = 10.4 Hz, 1H), 3.55 (d, J = 9.8 Hz, 1H), 3.43 (dd, J = 5.1, 11.1 Hz,
1H), 3.33 (m, 2H), 3.07 (dd, J = 2.1, 12.2 Hz, 1H), 2.98 (d, J = 13.0
Hz, 1H), 2.60 (d, J = 13.0 Hz, 1H), 2.47 (t, J = 11.5 Hz, 1H), 0.90 (s,
9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.03 (s, 6H) ppm; 13C NMR (125
MHz, CDCl3) δ 75.4, 70.4, 66.1, 61.6, 48.9, 48.1, 45.3, 25.9, 25.8,
18.21, 18.18, −5.43, −5.46, −5.50, −5.52 ppm; IR (neat) 3319, 2956,
2858, 1472, 1257, 1216, 1105, 759 cm−1; HRMS (ESI) calcd for
C19H43ClNO3Si2 [M + H]+ 424.2465, found 424.2466.
The mixture was dissolved in CH2Cl2/H2O (8 mL, 1:1 v/v). NaOH
(32 mg, 0.8 mmol) and Boc2O (174 mg, 0.8 mmol) were added
subsequently. The resultant mixture was stirred at 25 °C for 4 h. The
mixture was then extracted with EtOAc (10 mL × 3). The combined
organic extracts were washed with water (2 mL) and brine (2 mL),
dried with Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (Hexane:EtOAc =
1
1:1) to afford morpholine 5 (70 mg, 80%): H NMR (500 MHz,
CDCl3) δ 3.88−3.86 (m, 3H), 3.69−3.44 (m, 4H), 2.90 (bs, 1H), 2.72
(bs, 1H), 2.34 (t, J = 5.4 Hz, 1H), 1.44 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 154.8, 80.2, 75.8, 66.4, 63.5, 28.4; MS (EI) 217 m/z. (The
physical data are in full accordance with the literature 10g.)
Enantioselective Total Synthesis of 2. 3-tert-Butyldimethylsi-
lyoxy-2-(tert-butyldimethylsilyoxy)methylpropene (6). To a stirred
solution of dihydroxyacetone dimer (2.0 g, 11.1 mmol) and imidazole
(4.0 g, 58.8 mmol) in DMF (16 mL) was added tert-butyldimthylsilyl
chloride (8.8 g, 58.4 mmol) portion-wise at 0 °C. After stirring at 25
°C for 6 h, the reaction was quenched by water (10 mL). The mixture
was then extracted with EtOAc (20 mL × 3). The combined organic
extracts were washed with brine (10 mL), dried with Na2SO4, and
filtered. After filtration through a short plug of silica, ketone S2 was
used in the next step without further purification: 1H NMR (500 MHz,
CDCl3) δ 4.41 (s, 4H), 0.92 (s, 18H), 0.09 (s, 12H) ppm; 13C NMR
(125 MHz, CDCl3) δ 208.5, 67.9, 25.8, 18.3, −5.6 ppm.
To a stirred solution of methyltriphenylphosphonium bromide
(10.0 g, 28.1 mmol) in THF (300 mL), NaHMDS (2.0 M in THF,
26.2 mmol, 13.1 mL) was added dropwise at 0 °C. After stirring at the
same temperature for 30 min, ketone S2 obtained from the previous
step was then added dropwise. The mixture was further stirred for 4 h
at 25 °C, after which water (30 mL) was added to quench the reaction.
The mixture was extracted with EtOAc (50 mL × 3). The combined
organic extracts were washed with brine (30 mL), dried with Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by passing through a short plug of silica eluted with
Hexane:EtOAc (50:1) to give the desired product 6 (6.4 g, 91% for
two steps) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 5.08 (t, J
= 1.3 Hz, 2H), 4.16 (t, J = 1.3 Hz, 4H), 0.91 (s, 18H), 0.07 (s, 12H)
ppm; 13C NMR (125 MHz, CDCl3) δ 148.0, 109.0, 63.9, 25.9, 18.4,
−5.4 ppm.
26
1
To a solution of 2,2-Bis((tert-butyldimethylsilyloxy)methyl)-6-
chloromethylmorpholine (850 mg, 2.0 mmol) in 1,2-dichloroethane
(20 mL) was added formaldehyde (37% aqueous solution, 0.17 mL,
2.2 mmol) and NaBH(OAc)3 (466 mg, 2.2 mmol) at 25 °C. After
stirring at the same temperature for 16 h, the mixture was extracted
with CH2Cl2 (10 mL × 3). The combined organic extracts were
washed with water (5 mL) and brine (5 mL), dried with Na2SO4,
filtered, and concentrated under reduce pressure. The residue was
purified by flash chromatography (Hexane:EtOAc = 6:1) to give
( − ) - ( 2 S ) - N - N o s y l a t e - 2 - [ 1 - b r o m o - 2 , 2 - b i s ( ( t e r t -
butyldimethylsilyoxy)methyl)ethan-2-yloxy]-3-chloropropan-1-
amine (7). Into the mixture of nosylamide (505 mg, 2.5 mmol), NBS
(534 mg, 3 mmol) and (S)-epichlorohydrin (5 mL) was added olefin 6
(948 mg, 3 mmol) at −30 °C. After stirring at the same temperature
for 16 h, the reaction was quenched by saturated sodium sulfite
solution (5 mL). After recovery of the excessive (S)-epichlorohydrin
by distillation, the mixture was extracted with EtOAc (5 mL × 3). The
combined organic extracts were washed with brine (5 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (Hexane:EtOAc = 10:1)
26
morpholine 9 (762 mg, 87%) as a clear oil: [α]D +7.0 (c 1.0,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 3.96 (m, 1H), 3.92 (d, J =
10.4 Hz, 1H), 3.72 (m, 2H), 3.49 (dd, J = 4.9, 11.0 Hz, 1H), 3.34 (m,
2H), 2.88 (d, J = 10.8 Hz, 1H), 2.70 (d, J = 11.6 Hz, 1H), 2.22 (s, 3H),
1.79 (d, J = 11.6 Hz, 1H), 1.71 (t, J = 10.8 Hz, 1H), 0.89 (s, 9H), 0.88
(s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 6H) ppm; 13C NMR (125
MHz, CDCl3) δ 76.9, 69.7, 65.4, 59.2, 58.2, 57.3, 46.6, 45.1, 25.9,
18.27, 18.24, −5.39, −5.42 ppm; IR (neat) 3020, 2956, 2857, 1216,
758 cm−1; HRMS (ESI) calcd for C20H45ClNO3Si2 [M + H]+
438.2621, found 438.2621.
26
to give 7 (1.3 g, 72%) as a semisolid: mp 84−88 °C; [α]D −7.7 (c
1.0, CHCl3, 99% ee); 1H NMR (500 MHz, CDCl3) δ 8.36 (d, J = 8.8
Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H), 5.42 (t, J = 6.0 Hz, 1H), 4.20 (m,
1H), 3.73−3.32 (m, 9H), 3.21(m, 1H), 0.89 (s, 9H) 0.88(s, 9H),
0.09(s, 3H), 0.08(s, 3H), 0.07(s, 3H), 0.06(s, 3H) ppm; 13C NMR
(125 MHz, CDCl3) δ 150.1, 145.8, 128.4, 124.4, 80.3, 71.6, 63.4, 63.1,
45.0, 43.3, 34.4, 25.8, 25.8, 18.2, 18.1, −5.6, −5.6 ppm; IR (KBr) 3287,
2956, 2858, 1528, 1346, 1169, 1091, 838 cm−1; HRMS (ESI) calcd for
C25H46BrClN2NaO7SSi2 [M + Na]+ 711.1328, found 711.1346. The
enantiopurity of 4 was determined by HPLC analysis: Daicel Chiralpak
IA, i-PrOH/hexane =5/95, 0.5 mL/min, 254 nm; t = 19.369 (major), t
= 22.082 (minor).
(+)-(6S)-2,2-Bis((tert-butyldimethylsilyloxy)methyl)-6-chloro-
methyl-4-nosylmorpholine (8). The CH3CN (15 mL) solution of
compound 7 (1.0 g, 1.5 mmol) and K2CO3 (414 mg, 3.0 mmol) was
heated under reflux for 6 h. After cooling to room temperature, the
mixture was extracted with EtOAc (10 mL × 3). The combined
organic extracts were washed with water (5 mL) and brine (5 mL),
(−)-(6R)-2,2-Bis((tert-butyldimethylsilyloxy)methyl)-6-cyano-
methyl-4-methylmorpholine (10). A mixture of compound 9 (1.0 g,
2.3 mmol) and NaCN (336 mg, 6.9 mmol) was stirred in DMSO (10
mL) at 110 °C for 24 h. The mixture was then extracted with EtOAc
(5 mL × 5). The combined organic extracts were washed with water
(2 mL) and brine (2 mL), dried with Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (Hexane:EtOAc = 5:1) to give the starting
material compound 9 (635 mg, 64%) and cyanide 10 (296 mg, 30%,
brsm 83%) as a clear oil: [α]D −1.9 (c 1.0, CHCl3); H NMR (500
MHz, CDCl3) δ 4.01 (m, 1H), 3.90 (d, J = 10.3 Hz, 1H), 3.72 (d, J =
10.3 Hz, 1H), 3.68 (d, J = 9.7 Hz, 1H), 3.34 (d, J = 9.7 Hz, 1H), 2.79
(d, J = 10.8 Hz, 1H), 2.70 (d, J = 11.7 Hz, 1H), 2.46 (m, 2H), 2.22 (s,
3H), 1.79 (m, 2H), 0.89 (s, 9H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s,
3H), 0.04 (s, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 116.8, 65.6,
65.2, 59.2, 59.0, 56.8, 46.4, 25.86, 25.84, 22.5, 18.25, 18.21, −5.42,
−5.45 ppm; IR (neat) 2953, 2857, 2247, 1468, 1255, 1104, 838, 777
26
1
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Article
cm−1; HRMS (ESI) calcd for C21H45N2O3Si2 [M + H]+ 429.2961,
found 429.2963.
concentrated under reduced pressure. The residue was purified by
flash chromatography (Hexane:EtOAc = 6:1) to give the morpholine
25
1
(−)-(6R)-2,2-Bis(hydroxymethyl)-6-cyanomethyl-4-methylmor-
pholine (11). Cyanide 10 (900 mg, 2.1 mmol) was added into 1 N
HCl aqueous solution (10 mL) and stirred at 25 °C for 10 h. After the
reaction was completed, the solution was neutralized by saturated
NaHCO3 solution to pH 7. The aqueous solution was concentrated
under reduced pressure. The residue was purified by flash
chromatography (CH2Cl2:CH3OH = 10:1) to give the diol 11 (395
16 (55 mg, 43%) as a colorless oil: [α]D + 11.4 (c 1.0, CHCl3); H
NMR (500 MHz, CDCl3) δ 3.99 (m, 1H), 3.89 (d, J = 9.3 Hz, 1H),
3.51 (d, J = 9.3 Hz, 1H), 2.77 (m, 2H), 2.48 (dd, J = 5.7, 16.7 Hz, 1H),
2.43 (dd, J = 6.3, 16.7 Hz, 1H), 2.22 (s, 3H), 1.77 (t, J = 10.8 Hz, 1H),
1.68 (d, J = 11.7 Hz, 1H), 1.13 (s, 3H), 0.89 (s, 9H), 0.05 (s, 6H)
ppm; 13C NMR (126 MHz, CDCl3) δ 116.9, 75.3, 66.0, 63.6, 59.6,
59.0, 46.1, 25.8, 23.6, 22.8, 18.2, −5.4, −5.5 ppm; IR (neat) 2932,
2856, 2360, 1462, 1255, 1100, 853, 777 cm−1; HRMS (ESI) calcd for
C15H31N2O2Si [M + 1]+ 299.2149, found 299.2152.
23
mg, 94%) as a white solid: mp 105−107 °C; [α]D −12.2 (c 1.0,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 4.41 (m, 1H), 3.94 (d, J =
11.7 Hz, 1H), 3.84 (d, J = 11.7 Hz, 1H), 3.52 (d, J = 11.6 Hz, 1H),
3.45 (d, J = 11.6 Hz, 1H), 2.83 (m, 1H), 2.80 (d, J = 11.7 Hz, 1H),
2.59 (dd, J = 5.8, 16.8 Hz, 1H), 2.50 (dd, J = 5.3, 16.8 Hz, 1H), 2.29
(s, 3H), 2.21 (d, J = 11.7 Hz, 1H), 1.96 (t, J = 10.9 Hz, 1H) ppm; 13C
NMR (125 MHz, CDCl3) δ 116.4, 76.0, 66.7, 66.3, 66.0, 58.4, 56.6,
46.0, 22.8 ppm; IR (KBr) 2951, 2857, 2252, 1469, 1249, 1102, 844
cm−1; HRMS (ESI) calcd for C9H16N2NaO3 [M + Na]+ 223.1053,
found 223.1063.
(+)-(2S,6R)-2-((tert-Butyldimethylsilyloxy)methyl)-6-(cyanometh-
yl)-2,4,4-trimethylmorpholin-4-ium iodide (17). Morpholine 16 (40
mg, 0.13 mmol) was dissolved in anhydrous Et2O (5 mL) and MeI
(185 mg, 1.3 mmol) was then added. The mixture was stirred at 25 °C
for 2 d. The precipitate (54 mg, 91%) formed was then filtered, and
washed with anhydrous Et2O to give iodide salt 17 as a white solid: mp
193−195 °C; [α]D + 13.6 (c 1.0, CH3OH); H NMR (500 MHz,
CD3OD) δ 4.65 (m, 1H), 4.13 (d, J = 11.0 Hz, 1H), 3.80 (dd, J = 1.8,
13.5 Hz, 1H), 3.64 (d, J = 12.8 Hz, 1H), 3.60 (d, J = 10.9 Hz, 1H),
3.35 (s, 3H), 3.34 (s, 3H), 3.25 (m, 1H), 3.18 (d, J = 13.5 Hz, 1H),
2.88 (dd, J = 4.6, 17.1 Hz, 1H), 2.78 (dd, J = 6.5, 17.1 Hz, 1H), 1.34
(s, 3H), 0.96 (s, 9H), 0.16 (s, 6H) ppm; 13C NMR (125 MHz,
CD3OD) δ 117.1, 75.4, 65.7, 63.4, 63.4, 59.5, 51.5, 27.3, 27.2, 26.3,
22.3, 19.0, −5.3, −5.5 ppm; IR (KBr) 2928, 2850, 2253, 1470, 1257,
1098, 849, 777 cm−1; HRMS (ESI) calcd for C16H33N2O2Si [M − I]+
313.2306, found 313.2316.
25
1
(−)-(2S,6R)-2-Hydroxymethyl-2-tosyloxymethyl-6-cyanomethyl-
4-methylmorpholine (14a). To a solution of diol 11 (400 mg, 2.0
mmol) in THF (10 mL) was added n-BuLi (1.6 M in hexane, 1.3 mL,
2 mmol) dropwise at −78 °C. After stirring the solution at the same
temperature for 30 min, a solution of TsCl (382 mg, 2 mmol) in THF
(2 mL) was added dropwise. The reaction was further stirred at −78
°C for 16 h. The temperature was then raised to 0 °C and water (3
mL) was added to quench the reaction. The mixture was then
extracted with EtOAc (5 mL × 3). The combined organic extracts
were washed with water (2 mL) and brine (2 mL), dried with Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by flash chromatography (CH2Cl2:CH3OH = 10:1, 14a Rf
= 0.30, 14b Rf = 0.35) to give tosylate 14a (517 mg, 73%) as a
semisolid: mp 99−101 °C; [α]D23 −2.8 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H),
4.25 (m, 1H), 3.99 (d, J = 12.0 Hz, 1H), 3.91 (d, J = 10.0 Hz, 1H),
3.82 (d, J = 10.0 Hz, 1H), 3.71 (d, J = 12.0 Hz, 1H), 2.81 (m, 2H),
2.45 (m, 5H), 2.25 (s, 3H), 2.01 (d, J = 11.7 Hz, 1H), 1.88 (t, J = 10.9
Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 145.2, 132.3, 130.0,
128.0, 116.3, 74.9, 71.0, 66.6, 63.0, 58.3, 56.7, 46.0, 22.5, 21.6 ppm; IR
(KBr) 2947, 2828, 2247, 1598, 1465, 1355, 1172, 1073, 849 cm−1;
HRMS (ESI) calcd for C16H22N2NaO5S [M + Na]+ 377.1142, found
377.1150.
(+)-(2S,6R)-6-(Hydroxymethyl)-4,4,6-trimethylmorpholin-4-ium-
2-yl)acetate (2). Compound 17 (50 mg, 0.11 mmol) in 6 N HCl (4
mL) was refluxed for 4 h. 5% aqueous NaOH was added to neutralize
the mixture to pH 7. The product was purified following the same
23
procedure reported. Compound 2 was obtained (18 mg, 72%): [α]D
1
+21.2 (c 0.05, CH3OH); H NMR (500 MHz, CD3OD) δ 4.55 (m,
1H), 3.85 (d, J = 11.9 Hz, 1H), 3.78 (dd, J = 1.8, 13.4 Hz, 1H), 3.68
(d, J = 11.8 Hz, 1H), 3.58 (ddd, J = 1.8, 1.9, 12.6 Hz, 1H), 3.33 (s,
3H), 3.27 (s, 3H), 3.13 (dd, J = 11.9, 13.6 Hz, 1H), 3.10 (d, J = 13.6
Hz, 1H), 2.45 (dd, J = 6.9, 15.5 Hz, 1H), 2.33 (dd, J = 6.1, 15.5 Hz,
1H), 1.27 (s, 3H) ppm; 13C NMR (125 MHz, CD3OD) δ 177.2, 74.7,
65.0, 64.9, 63.8, 59.4, 51.4, 42.1, 26.8 ppm; HRMS (ESI) calcd for
C10H20NO4 [M + 1]+ 218.1387, found 218.1386. (The physical data
are in full accordance with the literature 5a.)
ASSOCIATED CONTENT
* Supporting Information
CIF files of 3 and 11, and NMR spectra. This material is
(+)-(2S,6R)-2-tert-Butyldimethylsilyloxymethyl-2-tosyloxymethyl-
6-cyanomethyl-4-methylmorpholine (15). To a stirred solution of
tosylate 14a (350 mg, 1 mmol) and imidazole (204 mg, 3 mmol) in
DMF (2 mL) was added tert-butyldimthylsilyl chloride (225 mg, 1.5
mmol) at 0 °C. After stirring at 25 °C for 8 h, the reaction was
quenched by adding water (1 mL). The mixture was then extracted
with EtOAc (5 mL × 3). The combined organic extracts were washed
with brine (2 mL), dried with Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography (Hexane:EtOAc = 5:1) to give morpholine 15 (430
■
S
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chmyyy@nus.edu.sg.
■
Notes
23
1
mg, 92%) as a clear oil: [α]D + 3.2 (c 1.0, CHCl3); H NMR (500
MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 2H), 7.33 (J = 8.2 Hz, 2H), 3.99
(d, J = 9.7 Hz, 1H), 3.94 (m, 1H), 3.87 (d, J = 9.7 Hz, 1H), 3.80 (d, J
= 10.2 Hz, 1H), 3.73 (d, J = 10.2 Hz, 1H), 2.73 (d, J = 10.8 Hz, 1H),
2.69 (d, J = 11.6 Hz, 1H), 2.43 (s, 3H), 2.37 (m, 2H), 2.21 (s, 3H),
1.84 (d, J = 11.6 Hz, 1H), 1.78 (t, J = 10.8 Hz, 1H), 0.82 (s, 9H), 0.01
(s, 3H), 0.00 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 144.8,
132.7, 129.8, 128.0, 116.4, 75.7, 71.2, 66.1, 59.4, 58.5, 55.0, 46.1, 25.7,
22.3, 21.6, 18.0, −5.6, −5.7 ppm; IR (KBr) 2951, 2856, 2253, 1599,
1465, 1363, 1178, 1098, 839 cm−1; HRMS (ESI) calcd for
C22H36N2NaO5SSi [M + Na]+ 491.2006, found 491.2021.
(+)-(2S,6R)-2-(−6-((tert-Butyldimethylsilyloxy)methyl)-4,6-dime-
thylmorpholin-2-yl)acetonitrile (16). A mixture of morpholine 15
(200 mg, 0.43 mmol) and NaBH4 (82 mg, 2.15 mmol) in DMSO (5
mL) was heated at 100 °C for 8 h. The reaction was then cooled to 25
°C and quenched by adding water (1 mL). The resultant mixture was
extracted with EtOAc (5 mL × 4). The combined organic extracts
were washed with brine (2 mL), dried with Na2SO4, filtered, and
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank GSK-EDB (Grant No. 143-000-564-592), ASTAR-
Public Sector Funding (Grant No. 143-000-536-305), and
NEA-ETRP (Grant No. 143-000-547-490) for financial
support. J. Zhou would like to thank National University of
Singapore for sponsoring his PhD scholarship.
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