Asymmetric synthesis of an aminomethyl morpholine via double allylic substitution

Article abstract of DOI:10.1016/j.tetlet.2005.05.038

The development of an asymmetric route to an aminomethyl morpholine intermediate via palladium-catalysed allylic substitution is described.

Full text of DOI:10.1016/j.tetlet.2005.05.038

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4773–4775
Asymmetric synthesis of an aminomethyl morpholine via
double allylic substitution
Mark. C. Wilkinson*
Chemical Development Division, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 18 March 2005; revised 3 May 2005; accepted 11 May 2005
Available online 31 May 2005
Abstract—The development of an asymmetric route to an aminomethyl morpholine intermediate via palladium-catalysed allylic
substitution is described.
Ó 2005 Elsevier Ltd. All rights reserved.
Recently we disclosed a series of amido and urea ap-
pended morpholine skeletons as potent antagonists of
CCR3.1 These have potential therapeutic applications
to asthma and rhinitis, and urea 1 is representative of
this series (Scheme 1).
.
OAc
2.5 mol% Pd2dba3 CHCl3
HO
HN
O
N
5 mol% (R)-BINAP
+
THF, 40 °C
Ph
4
72%, 61% e.e.
OAc
3
Ph
5
The chiral (dichloro)benzyl aminomethylmorpholine 2
was the key intermediate in the preparation of this series
of compounds. Previously, a Mitsunobu diol cyclisation
had been utilised to prepare the morpholine core,2 but as
we sought methods for scale-up, alternative routes were
examined. We became interested in the work by Hayashi
et al. preparing asymmetric vinyl morpholines via palla-
dium-catalysed allylic substitution (Scheme 2).3 This ini-
tial report was followed by work from Achiwa and
Yamazaki (83% ee),4 Ito et al. (81% ee)5 and notably
Nakano et al.,6 who achieved the highest ee recorded
of 94%, with a P,N-xylofuranose-based ligand (prepared
in 3-steps).
Scheme 2.
In looking to apply this chemistry to an industrial prob-
lem, aims for our work would be to increase the ee,
lower the metal loading, and find a ligand that was
readily accessible on a commercial scale.
The anticipated extension of the literature chemistry for
benzylethanolamine to dichlorobenzyl ethanolamine
was fortunately trivial. Good conversion was obtained
with racemic BINAP which gave us markers for chiral
HPLC development (Scheme 3).
We then undertook a ligand screening exercise, as shown
in Table 1. We were able to repeat the literature ee val-
ues with (S)-BINAP, and achieve slight improvements
with (S)-tol-BINAP. However, we became aware of
the commercial availability of the phenyl ꢀTrostꢁ ligand
O
NH2
HN
NH
O
N
O
N
H2N
Cl
Cl
Cl
Cl
O
HO
HN
2.5 mol% Pd2dba3
5 mol% rac-BINAP
OAc
O
N
+
THF, 66 °C
50%
1
2
Cl
Cl
Cl
Cl
Scheme 1.
OAc
Keywords: Asymmetric synthesis; Palladium; Allylic substitution.
*
3
6
7
Tel.: +44 1438 762189; fax: +44 1438 764869; e-mail:
mark.c.wilkinson@gsk.com
Scheme 3.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.038

4774
Mark. C. Wilkinson / Tetrahedron Letters 46 (2005) 4773–4775
Table 1. Ligand screening for tandem allylic substitution
Entry
Methoda
Ligand
Mol% ligand [Pd 2.5 mol%]
eec
% Conversion to 7
1
Ab
Ab
A
A
A
A
B
BINAP
tol-BINAP
BIPHEP
5
65
70
65
30
36
—
—
77
89
0
47
78
31
58
30
<2
<2
24
88
77
<5
<5
<15
67
16
30
88
37
56
79
2
5
3
5
4
Monophos, 13
P,N-oxazoline, 10
t-Bu-BOX
t-Bu-BOX
BIPHEP
5
5
5
6
5
7
5
8
B
5
9
B
Ph Trost, 12
Quinap
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
10
11
12
13
14
15
16
17
18
19
20
B
B
Ph-PyBOX
MOP
—
—
—
0
B
B
Chiraphos
DIOP
B
B
DUPHOS
BPE
0
B
ꢀlowꢁ
0
B
Walphos, 8
Mandyphos, 9
Mandyphos, 11
Monophos, 14
B
20
0
B
B
30
a Method A—charge ligand, then THF, then Pd2dba3ÆCHCl3, then NEt3. Stir 1 h, then charge 6, then 3, at room temp. Method B—charge THF,
degas (vacuum), charge ligand, charge Pd2dba3ÆCHCl3, then NEt3, degas, charge 3, stir 15 min, charge 6, at room temp.7
b Entry 1 reaction at 50 °C, entry 2 reaction at 40 °C.
c Determined on Chiralcel OJ column, heptane/IPA eluent.
12 (Scheme 4), which was well precedented for AAA
(Asymmetric Allylic Alkylation) reactions.7 Screening
this ligand gave us excellent yields and ee (entry 9).
The ꢀTrostꢁ charging regime was then used for the
remainder of our screening experiments.
yield to 80% at 90% ee on a 10 g (45 mmol) input, using
only 1 mol% of catalyst (Scheme 5).
To apply this enantioselective morpholine synthesis to
the preparation of urea 1 we were required to transform
the vinyl moiety of 15 to the desired aminomethyl
group.
These conditions from Trostꢁs work had given us a ma-
jor lead. We also examined iridium catalysis but this was
a much slower reaction in refluxing THF.8 The naphthyl
analogue of the ꢀTrostꢁ ligand was not superior,7 neither
were toluene nor DCM as reaction solvents. We did
establish that slow addition of ethanolamine 6 was mini-
mised impurities arising from attack of two benzylic
amines on the allylic acetate, and favoured the desired
intramolecular cyclisation. We utilised a statistical ꢀde-
sign of experimentsꢁ approach to identify rapidly the
important factors for improving this reaction. Both con-
version and ee benefited from an increase in tempera-
ture, so reactions were now run at 50 °C (consistent
with an equilibration in the enantiodetermining step).7
These improvements enabled an increase in the isolated
This was achieved via dihydroxylation, followed by oxi-
dative cleavage (one pot protocols gave significant
OAc
1 mol% Pd2dba3
3 mol% 12
O
THF, 50 °C
N
then 6 over 50 min
Cl
Cl
OAc
80%, 90% e.e.
3
15
Scheme 5.
Ph2P
Ph
NMe2
PPh2
Ph
Me2N
Cx2P
N
O
Fe
O
O
PCx2
Fe
P
NR2
PCx2
8
9
10
Ph
NMe2
13 R = Me2
14 R =
Ph
Me2N
Ph2P
O
O
N
H
Ph2P
N
H
Fe
PPh2
PPh2
11
12
Scheme 4.

Mark. C. Wilkinson / Tetrahedron Letters 46 (2005) 4773–4775
4775
OH
OH
NH2
N
O
N
i) NaIO4
THF/H2O
O
N
O
O
HO
OsO4, NMO
LiAlH4
N
N
ii) NH2OH
THF
59%
THF/Et2O
52%
acetone/H2O
83%
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
15 90% e.e.
16
17
2 88% e.e.
i) NaIO4
THF/H2O
ii) NaBH4
NH2
OH
Phth
N
O
N
HNMe2
(40% aq)
O
N
O
PhthNH, TPP
N
DIAD, THF
54% (16 to 20)
97%
Cl
Cl
Cl
Cl
Cl
Cl
19
20 93% e.e.
2
Scheme 6.
decomposition on this substrate). The oxime 17 was
then produced from an intermediate formyl morpholine,
and finally reduced to give the desired aminomethyl
morpholine 2 with retention of stereochemistry (Scheme
6).
for analytical support, and thanks also to all other mem-
bers of Analytical Sciences and Synthetic Chemistry
who assisted. Professor Barry Trost (Stanford) is also
acknowledged for useful discussions.
Alternatively, the unisolated formyl morpholine could
be reduced to the hydroxymethylmorpholine 19. Subse-
quent Mitsunobu reaction using phthalimide as the
nucleophile gave phthalimido morpholine 20, which
was an intermediate in our existing route. An apparent
slight increase in ee was recorded, perhaps in the crystal-
lisation of highly crystalline 20. Subsequent deprotec-
tion using methylamine was effected to give 2 in
excellent yield, and we have demonstrated complete
retention of chirality through this deprotection many
times on up to 40 kg scale.
References and notes
1. Ancliff, R. A.; Cook, C. M.; Eldred, C. D.; Gore, P. M.;
Harrison, L. A.; Hayes, M. A.; Hodgson, S. T.; Judd, D. B.;
Keeling, S. E.; Lewell, X. Q.; Mills, G.; Robertson, G. M.;
Swanson, S.; Walker, A. J.; Wilkinson, M. PCT Int. Appl.
WO 2003082861 (CAN 139:307777), 2003.
2. Hayes, M. A.; Mills, G.; Swanson, S.; Walker, A. J.;
Wilkinson, M. PCT Int. Appl. WO 2003082835 (CAN
139:307774), 2003.
3. Hayashi, T.; Uozumi, Y.; Tanahashi, A. J. Org. Chem.
1993, 58, 6826–6832.
4. Achiwa, K.; Yamazaki, A. Tetrahedron: Asymmetry 1995,
6, 1021–1024.
5. Ito, K.; Imahayashi, Y.; Kuroda, T.; Shuuichiro, E.;
Saito, B.; Katsuki, T. Tetrahedron Lett. 2004, 45, 7277–
7281.
In summary, we have demonstrated a catalytic asym-
metric route to the key aminomethyl morpholine core
of CCR3 antagonist 1 giving up to 35% yield from
dichlorobenzyl ethanolamine.
6. Nakano, H.; Yokoyama, J.; Fujita, R.; Hongo, H. Tetra-
hedron Lett. 2002, 43, 7761–7764.
7. (a) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1–14; (b)
Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96,
395–422.
Acknowledgements
Simon Watson, Lorna Graham, Marco Smith and Ju-
dith Carreira specifically are gratefully acknowledged
8. Hartwig, J. F.; Lopez, F.; Ohmura, T. J. Am. Chem. Soc.
2003, 125, 3426–3427.