2
Tetrahedron Letters
The morpholine ring is used extensively in drug discovery
O
O
research and is present in numerous drugs approved by the FDA.1
While N-substituted morpholines are often used as a hydrophilic
handle to improve the physico-chemical properties of a ligand,
carbon-substituted morpholines also display activity2 and have
found applications as antidepressants,3 appetite suppressants such
as Phendimetrazine4 or anti-emetics such as Aprepitant5 (Figure
1). Finafloxacin, which possesses a morpholine ring fused onto a
pyrrolidine ring, is a fluoroquinolinone antibiotic indicated in the
treatment of acute otitis externa (swimmer’s ear).6
O
O
N
O
Br
O
3
O
KOH (aq)
NEt3, CH2Cl2
95%
THF, EtOH, RT
100%
HO
1
2
O2N
OH
O
O
O
O
H2, Pd(OH)2
KOtBu
O
O
O
N
O
tBuOH, THF, 0 °C
EtOH
99%
N
Br
O
85%
O
N
H
4
5
6
O
Scheme 2. Synthesis of trans-disubstituted morpholine 6.
R1
H
R1
C2
O
H
C2
C3
Phendimetrazine
Aprepitant
Finafloxacin
O
R2
O
R2
N
N
H
O
H
C3
O
O
Figure 1. Representative bioactive morpholines.
We became interested in the [3-(hydroxymethyl)morpholin-2-
yl]methanol scaffold (D, Scheme 1)7,8 in an attempt to modulate
the pharmacokinetic properties of a morpholine-based ligand. An
orthogonally protected morpholine was required to allow
subsequent sequential functionalization of the 2 hydroxyl groups,
while a stereoselective approach had to be designed that would
allow access to all diasteroisomers. Herein, we disclose the
results of our strategy for the development of a base-catalysed
cascade reaction for the synthesis of chiral morpholines. The
bespoke synthesis relies on the pool of readily available chiral
epoxide starting materials, or where necessary, the
stereochemistry is readily installed and assigned unambiguously
from the well-known Sharpless asymmetric epoxidation of allylic
alcohols.9
Figure 2. Inversion of configuration at C3 and X-Ray crystal structure of
compound 6.
In such an approach the nitrogen atom and one of the hydroxyl
groups are tied up together as an oxazolidinone,11,12,13 and the free
aminoalcohol could be revealed in a subsequent step, while the
other methanol functionality, protected as benzyl ether, can be
independently deprotected at any subsequent stage.
As
a first example, a straight-forward hydrolysis of
commercially available 4-nitrobenzoic ester 1 gave the primary
alcohol 2 with the chiral epoxide already in place and of known
stereochemistry (Scheme 2). 2-Bromoethyl isocyanate 3 is a very
useful synthon in organic synthesis in that it has two reactive
electrophilic centres that can be sequentially engaged. Carbamate
formation afforded the required cyclisation precursor 4 in
excellent yield. Subsequently, treatment of 4 with 2 equivalents
of KOtBu at RT in tBuOH/THF very rapidly effected the cascade
sequence to deliver 5 in 85% yield with no intermediate detected.
The benzyl protecting group could be removed using
hydrogenation conditions to give the free alcohol 6. X-Ray
crystallography of alcohol 6 (Figure 2) confirmed not only the
validity of the synthetic design of our approach but also the
relative stereochemistry of the 2 contiguous stereocentres: with
the stereochemistry at C2 being dictated by that of the
commercial epoxide, stereochemistry at C3 arises from a
regiospecific 5-exo-tet cyclisation and opening of the epoxide
with inversion of configuration.
Single-pot cascade reactions are an efficient way to generate
molecular complexity in a concise fashion.10 The key stage of our
synthesis is the unprecedented one-pot 2-step synthesis of
morpholine C by formation of the O-C bond via SN2
displacement of the bromide with the alkoxide [intermediate B]
resulting from regio- and stereoselective epoxide opening using
the nitrogen atom of the carbamate A, and an appropriate base
(Scheme 1).
A
B
We then turned our attention to the cis-disubstituted
morpholine isomers. The corresponding chiral epoxide 7 was
made in 3 steps according to literature precedent via 1-pot
oxidation-Wittig olefination, followed by ester reduction and
Sharpless asymmetric epoxidation, starting from 2-
benzyloxyethanol.14 Carbamate formation proceeded well to give
8 in 73% yield and set the stage for our key morpholine
formation cyclisation step (Scheme 3). Using our standard
conditions (KOtBu, tBuOH, THF, RT), cyclisation occurred to
give the desired product 9 in 51% yield. A non-quantified by-
product of this reaction is the alcohol 7 resulting from cleavage
of the carbamate. It is noteworthy that reaction time took much
longer for this set of diastereoisomers (typically overnight) and
following the reaction by LCMS suggested the oxazolidinone
intermediate could be isolated.
C3
C2
C
D
Scheme 1. One-pot synthesis of morpholines from epoxyurethanes.
Marlin, Frederic J.
