Development of a scalable synthetic route towards a 2,2,6-trisubstituted chiral morpholine via stereoselective hydroalkoxylation

Article abstract of DOI:10.1016/j.tetlet.2018.03.042

A scalable synthetic route towards a chiral 2,2,6-trisubstituted chiral morpholine, which is a known opioid antagonist, was developed. The synthetic route involves incorporating an aryl group via Suzuki-Miyaura coupling and stereoselective hydroalkoxylati

Full text of DOI:10.1016/j.tetlet.2018.03.042

Accepted Manuscript
Development of a Scalable Synthetic Route Towards a 2, 2, 6-Trisubstituted
Chiral Morpholine via Stereoselective Hydroalkoxylation
Chan Woo Huh, Bruce M. Bechle, Joseph S. Warmus
PII:
S0040-4039(18)30356-3
https://doi.org/10.1016/j.tetlet.2018.03.042
TETL 49811
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 January 2018
1 March 2018
15 March 2018
Please cite this article as: Huh, C.W., Bechle, B.M., Warmus, J.S., Development of a Scalable Synthetic Route
Towards a 2, 2, 6-Trisubstituted Chiral Morpholine via Stereoselective Hydroalkoxylation, Tetrahedron Letters
(2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.042
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Development of a Scalable Synthetic Route
Towards a 2, 2, 6-Trisubstituted Chiral
Morpholine via Stereoselective
Hydroalkoxylation
Leave this area blank for abstract info.
Chan Woo Huh,* Bruce M. Bechle, and Joseph S. Warmus

1
Tetrahedron Letters
journal homepage: www.els evier.com
Development of a Scalable Synthetic Route Towards a 2, 2, 6-Trisubstituted Chiral
Morpholine via Stereoselective Hydroalkoxylation
Chan Woo Huh,* Bruce M. Bechle, and Joseph S. Warmus
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
A scalable synthetic route towards a chiral 2, 2, 6-trisubstituted chiral morpholine, which is a
known opioid antagonist, was developed. The synthetic route involves incorporating an aryl
group via Suzuki-Miyaura coupling and stereoselective hydroalkoxylation catalyzed by
trifluoromethanesulfonic acid. Late stage incorporation of both the aryl and N-alkyl groups make
this route suitable for further SAR studies on this molecule.
Received in revised form
Accepted
Available online
.
Keywords:
Multi-substituted morpholine
µ-opioid receptor antagonist
Stereoselective hydroalkoxylation
Scalable synthesis
Introduction
During our search for a µ-opioid receptor antagonist as a
potential analgesic, we discovered trisubstituted morpholine
C-Substituted chiral morpholines are an sp3-rich structural
motif commonly found in pharmacologically active molecules.1
Significant attention has been paid to morpholine because of its
ability to participate in a donor-acceptor interaction through its
oxygen atom and the decreased basicity of the nitrogen atom
which can have a beneficial impact on ADME and safety
properties.1a,2 Representative examples of pharmaceutical agents
compound 1a, which had previously been prepared by Wyeth
pharmaceuticals (Fig. 2). Closely analogous compounds
including 1b have been reported as opiate antagonists.3 When we
initiated the synthesis of 1b for further biological studies, we
focused on two aspects. First, we intended to efficiently
resynthesize 1b with reasonable stereoselectivity and scalability.
Second, and more importantly, we intended to develop a route
that allows late stage incorporation of C2-aryl and N-alkyl
groups, which are two important vectors for further SAR studies.
which incorporate
(antidepressant), aprepitant (antiemetic), finafloxacin (antibiotic),
and fenpropimorph (fungicide) are highlighted in Figure 1.
a
substituted morpholine: reboxetine
Figure 2. Trisubstituted morpholines with µ-opioid antagonistic activity
In seeking to identify a synthetic route to resynthesize 1a,
several literature examples of di-substituted morpholines (e.g.
2,6-, 2,5-, 3,5-) indicated that they have been synthesized by
using one of two approaches: combination of two chiral
fragments (Scheme 1A)4 or diastereoselective cyclization with a
pre-existing chiral center (Scheme 1B).5a-f,2,5g,6 Due to the
complexity of the molecule, a diastereoselective cyclization to
form 1a was preferred. However, there are only few examples
regarding the synthesis of challenging tri-substituted chiral
Figure 1. C-substituted chiral morpholine drugs
*Corresponding author. E-mail address: chan.w.huh@pfizer.com (C. W. Huh)
morpholines with
a
quaternary center as in 1a via
diastereoselective cyclization.5a,5b,6

2
Tetrahedron
Next, we tested the possibility of Shi epoxidation on the known
compound 9.8 The resulting epoxide 10 can be converted to
amines via desilylation and epoxide opening, which was
previously developed by Shi and co-workers.9 Although the
chiral epoxide 10 could be synthesized with high yield and
enantioselectivity (99% clean crude, ee>98%), the epoxidation
conditions required high loading of expensive D-epoxone
catalyst. Literature conditions required 0.65 equivalents of D-
epoxone. However, in our hands, up to 1.5 equivalents of the
catalyst was required to ensure complete reaction. Due to the
problems described, these two approaches were eventually
discarded.
Scheme 1. Strategies for constructing morpholine derivatives with multiple
chiral centers
Results and Discussion
Kozlowski and co-workers previously reported the synthesis
of a closely related compound 1b, which provided us initial
access to 1a (Scheme 2).5a The synthesis begins with the early
stage introduction of the quaternary stereogenic center-bearing
chiral amino-alcohol 5. This was achieved by the stereoselective
addition of diethyl zinc to α-ketoester 2, catalyzed by a titanium
complex with a non-commercial salen ligand 3. The resulting
chiral quaternary alcohol 4 was obtained with a modest
enantioselectivity of 80% ee, and the major enantiomer separated
by chiral HPLC. A two-step functional group conversion of 4 to
5, followed by acylation with 2-chlorobutanoyl chloride, and then
KOH-promoted etherification provided morpholine 6 as a 1:1
mixture of diastereomers, which were again separated by HPLC
to isolate the desired (2S,6R)-6.
Although Kozlowski’s method provided the desired tri-
substituted morpholine 1a, we sought to improve upon several
limitations. The modest enantioselectivity in the generation of
chiral alcohol 4, use of a non-commercial salen ligand, scalability
concerns regarding the use of pyrophoric diethyl zinc under
cryogenic conditions, and the lack of diastereoselectivity during
introduction of the second stereocenter to form 6 were major
issues. In addition, difficulties in the diversification of both the
aryl group and N-alkyl group due to their early incorporation in
the sequence (9 and 7 steps, respectively, from the final analogs)
reduce the utility of this route in further SAR studies.
Alternatively, we attempted to generate chiral aminoalcohol 5
utilizing chiral auxiliary methods (Scheme 3)7 Substrate 7 was
prepared as described in the literature.7 Grignard addition to
chiral ketone 7 at low temperature proceeded smoothly.
However, chiral aldehyde 8 was isolated in only 24% yield after
acidic hydrolysis of the auxiliary, along with the formation of
numerous unidentified side-products.
Scheme 3. Alternative approaches to chiral aminoalcohol 5
During our search for an alternative method of ring
construction, a boron trifluoride-mediated hydroalkoxylation
emerged as a potential solution to obtain our tri-substituted
morpholine target (Scheme 4).6 The reported examples indicated
alcohol 11 could be cyclized to form tri-substituted morpholine
12 as a single diastereomer. However, it was unclear if this
methodology could be extended to highly hindered, tri-
substituted internal olefins such as 13 with reasonable reactivity
and diastereoselectivity.
To
test
the
feasibility of
this
stereoselective
hydroalkoxylation, and more importantly to utilize it as SAR-
amenable and scalable route for further biological studies, a
synthetic route to access olefin 17 was needed (Scheme 5).
Therefore, chiral N-tosylaminoalcohol 15 was synthesized by
opening the chiral epoxide (S)-(-)-butylene oxide with
Scheme 2. Reproduction of Kozlowski and co-workers route5a

3
resulting in the formation of 22 in 49% yield with 3.3:1 dr,
which is still reasonable for the formation of a highly crowded
quaternary stereogenic center (Entry 2). The reaction was
attempted at a higher temperature (60 °C) using DCE as a solvent
for 6 h. The desired morpholine product 22 was formed in 62%
isolated yield as a mixture of diastereomers with 2.2:1 dr (Entry
3). In an attempt to further optimize yield and
diastereoselectivity, several Brønsted acids as well as a gold
catalyst were screened.12 Trifluoromethanesulfonic acid13
emerged as the best option for scale-up, promoting the reaction
with only catalytic acid (10 mol%) at 60 °C with 76% isolated
yield and 2.0:1 dr (Entry 5). These conditions allowed for a
scaled-up synthesis with a short reaction time, high yield, and use
of catalytic trifluoromethanesulfonic acid, eliminating the use of
the more toxic BF3·OEt2.14
Scheme 4. Hydroalkoxylation and its application to a multi-substituted
morpholine
N-tosylamide following the known procedure using TEBAC
B(OH)2
Me
I
(benzyltriethylammonium chloride) as
a
phase transfer
catalyst.4f,10 This was treated with 2-bromoallylbromide under
basic conditions to form N-(2-bromoallyl)-N-tosylamide 16. The
resulting vinyl bromide 16 and 3-methoxyphenylboronic acid
were coupled under typical Pd(PPh3)4 catalyzed Suzuki-Miyaura
conditions. The resulting 2-aryl-allylamide 17 was treated with
boron trifluoride diethyl etherate (1.2 equiv.) at room temperature
for 5 h, following Saikia and co-workers protocol.6 The cyclized
product 18 was obtained in 84% yield as a mixture of
diastereomers (dr = 4.6:1). 1D NOE experiments confirmed the
relative stereochemistry of the major product. The success of this
route provided us the ability to replace the aryl group and N-alkyl
group at relatively late stages of the synthesis for further SAR
studies.
Br
Et
OH
Et
OH
19
OMe
N
Ts
Me
Pd(PPh3)4 (3 mol%)
Na2CO3
NH
Ts
K2CO3, DMF
rt, 18h, 93%
I
dioxane/water (9:1)
100 °C, 18 h, 83%
15
20
Et
OH
Et
O
see Table 1
OMe
Et
N
Ts
Me
N
Ts
OMe
21
Scheme 6. Hydroalkoxylation of the tri-substituted internal olefin
22
Table 1. Screening conditions for hydroalkoxylation
Entry
Catalyst (equiv.)
BF3·OEt2 (1.2)
BF3·OEt2 (1.2)
BF3·OEt2 (1.2)
TfOH (1.2)
Conditions
Yielda
0%
drb
1
2
3
4
5
6
7
8
CH2Cl2, rt, 5 h
N/A
CH2Cl2, 40 °C, 24 h
CH2Cl2, 60 °C, 24 h
CH2Cl2, rt, 1 h
49%
62%
65%
76%
65%
58%
59%
3.3:1
2.2:1
2.0:1
1.9:1
2.0:1
1.9:1
1.5:1
Scheme 5. Synthesis of the substrate by Suzuki-Miyaura coupling and
subsequent hydroalkoxylation.
TfOH (0.1)
CH2Cl2, 60 °C, 1 h
CH2Cl2, 60 °C, 1 h
CH2Cl2, 60 °C, 21 h
toluene, 80 °C, 24 h
With confidence in the reproducibility of this methodology
with reasonable stereoselectivity, it was extended to the tri-
substituted internal olefin substrate 21 (Scheme 6). (Z)-1-Bromo-
2-iodobut-2-ene (19) was easily synthesized from crotonaldehyde
following a known three-step sequence in high yield and purity
without the need for purification.11 N-Tosylaminoalcohol 15 was
combined with 19 under basic conditions to afford vinyl iodide
20 in 93% yield without the necessity for column purification.
This was then coupled with 3-methoxyphenylboronic acid under
the same Suzuki-Miyaura coupling conditions to obtain 21 in
83% yield.
H2SO4 (1.2)
p-TsOH (1.2)
Ph3PAuCl/AgOTf
a Isolated yield after column chromatography. b Determined by integration of peaks from the
methoxy group, 2.39 ppm (major) vs 2.46 ppm (minor) by 1H NMR (600 MHz, CDCl3).
For a more efficient synthesis, unprotected phenol substrate 23
was used in the multi-gram synthesis (Scheme 7). Fortunately, a
free hydroxyl group was tolerated with comparable selectivity
and yield. The resulting diastereomeric mixture of 24 was
purified by HPLC to afford the desired major isomer (2R,6S)-24
in 54% overall yield along with 23% of the minor isomer
(2S,6S)-24. Finally, the tosyl protecting group of (2R,6S)-24 was
With the internal olefin substrate 21 in hand, the
hydroalkoxylation reaction was attempted (Table 1). The initial
attempt at room temperature with boron trifluoride resulted in no
reaction (Entry 1). Even at reflux, the reaction was slow,

4
Tetrahedron
removed using sodium bis(2-methoxyethoxy)aluminum hydride
(Red-Al) to form 25 in 70% yield (5.3 g). A small amount of 25
was converted to N-methylmorpholine 1a to confirm the identity
by comparison to previously synthesized 1a (Scheme 2). Our
route is better suited for scale-up, avoiding the use of cryogenic
conditions or hazardous reagents. Moreover, from a medicinal
chemistry perspective, late stage incorporation of C2-aryl groups
and N-alkyl groups allow for efficient and rapid SAR studies.
With this route, only three steps were required to complete the
synthesis after introducing the C2-aryl group, and N-alkylation is
the last step. These are significantly less than those from the
previously reported synthetic route, which requires 9 (C2-aryl)
and 7 (N-alkyl) steps after those diversifications were introduced.
Scheme 7. Scale-up synthesis of 1a by TfOH-catalyzed hydroxyalkoxylation
Supplementary Date
1
Copies of H/13C/1D-NOE NMR spectra of the products and
the characterization conditions of LCMS, HRMS, and HPLC can
be found at https:// Single crystal X-ray structure of ent-1a,
obtained from the reproduction of Kozlowski and co-workers
route (Scheme 2) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
1583526 CCDC. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.Uk).
Conclusion
We have developed an improved, scalable synthesis of a
2,2,6-trisubstituted chiral morpholine scaffold, containing a
chiral quaternary stereogenic center using a diastereoselective
cyclization from readily available chiral starting materials.
Adaptation of a boron trifluoride mediated hydroalkoxylative
cyclization originally developed by Saikia and co-workers
provided the desired relative stereoselectivity needed to construct
the highly challenging quaternary stereogenic center. However,
stoichiometric amounts of BF3·OEt2 were required to promote
cyclization of the hindered tri-substituted internal olefinic
substrate. Reaction optimization demonstrated catalytic
trifluoromethanesulfonic acid can provide nearly identical
results. Our route negates the need for phenol protection,
eliminates toxic reagents, cryogenic conditions, and has clean
reaction profiles. Not only does our improved route allow for
safe scale up, it also allows for later stage incorporation of C2
aryl groups and N-substituents in support of driving efficient
SAR optimization studies.
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N
H

5
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6
Tetrahedron
Scalable synthesis of less common morpholines
containing multi-substituents next to oxygen
Reasonably diastereoselectivity in forming a highly
crowded quaternary stereocenter
Suitable for further SAR studies with later stage
key substituent incorporations