T. D. Nelson et al. / Tetrahedron Letters 45 (2004) 8917–8920
8919
O
N
OH
O
O
N
OH
O
Ph
O
N
OH
O
Me
R
OMe
or
OEt
OH
OR'
MeO
MeO
OH
O
MeO
MeO
O
O
Ph
Ph
Me
Ph
Ph
13
14
15
10
22% (dr 3:2)
73% (dr 3:2)
80% (dr 6:1)
11, R=Me, R'=Me
12, R=H, R'=Et
Scheme 8.
1.
O
OH
O
NH
Bn
NaH or
n-BuLi
N
Bn
NBEA. In addition, an initial N,O-acetal adduct crystal-
lizes from solution if the reaction is performed at room
temperature.2 After heating for 18h, the THF was dis-
tilled,11 and lactol 1a was crystallized from water (72%
isolated). A mechanistic discussion of this transform-
ation has been reported.2
2. HCl
65-70%
1a
Scheme 6.
While this route met our objective of using starting
materials that had the correct oxidation state, we envi-
sioned that a more straightforward entry to this sub-
strate could be achieved. Disconnection of lactol 1a at
both the amide bond and acetal linkage provided N-benz-
ylethanolamine (NBEA) and glyoxylicaidc as the
potential starting materials (Scheme 7). A direct conden-
sation between NBEA (1equiv) and crystalline glyoxylic
acid hydrate (1equiv) in THF resulted in 30% yield of
1a. Performing the reaction in aqueous glyoxylic acid
(50wt%) resulted in a 38% HPLC assay yield of prod-
uct. The reaction profiles were clean but the progress
of the reaction stalled. An additional equivalent of gly-
oxylic acid (50wt%) was added at four intervals, which
allowed the reaction to ultimately achieve 87% yield
(Table 1).
A brief investigation into the scope of this condensation
was performed. Attempts to condense unprotected ami-
no alcohols (ethanolamine and phenyl glycinol) failed to
produce the desired lactam lactols.
Increasing the size of the N-substituent (a-methylbenzyl
ethanolamine) resulted in a low yield of lactol 13 (22%)
(Scheme 8). However, there did not appear to be an
effect from the substitution on the ethanol backbone.
Both N-benzyl phenyl glycinol and N-benzyl-1-phenyl-
ethanolamine provided good yields of the desired lactols
14 and 15 (73% and 80%, respectively).
In summary, we have described simple, practical and
high yielding protocols for the synthesis of 2-hydroxy-
morpholin-3-ones and morpholine-2,3-diones. The
general method for the synthesis of numerous 2-hydr-
oxymorpholin-3-ones was by the mono-reduction of
the corresponding morpholine-2,3-diones. However,
the preferred method for the synthesis of desired
N-benzyl morpholinone 1a, which was used in the
synthesis of aprepitant, was by the condensation of
N-benzylethanolamine and glyoxylicacid.
NMR studies have shown that aqueous glyoxylicacid is
primarily in the form of monomerichydrate (69–88%)
with dimerichemiacetals (3–12%) and higher oligomers
(<5%).9 Regardless, of the acetal content, we viewed the
reaction as being thermodynamically driven by the
formation of the amide.10 Hence, the exact composition
of glyoxylicaicd was irrelevant, as long as under the
acidic aqueous conditions an equilibrium pathway with
the NBEA could occur. Exogenous acid sources and
alcohol additives showed no rate or yield enhancement.
Thus, the optimized conditions for the formation of lac-
tol 1a were to slowly add neat NBEA to a preheated
solution of THF and 50wt% glyoxylicacid (2.2:1; v/v).
Prewarming the glyoxylicacid to a point below reflux
drove off dissolved CO2 that could potential react with
References and notes
1. For a recent review of aprepitant, see: (a) Dando, T. M.;
Perry, C. M. Drugs 2004, 64, 777; (b) Hale, J. J.; Mills, S.
G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski,
S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.;
Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N.
J. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.;
MacIntyre, D. E. J. Med. Chem. 1998, 41, 4607.
2. Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T.
D.; Candelario, A.; Huffman, M. A.; Zhao, M. M.; Li, J.;
Craig, B.; Song, Z. J.; Tschaen, D. M.; Hansen, K.;
Devine, P. N.; Pye, P. J.; Rossen, K.; Dormer, P. G.;
Reamer, R. A.; Welch, C. J.; Mathre, D. J.; Tsou, N. N.;
McNamara, J. M.; Reider, P. J. J. Am. Chem. Soc. 2003,
125, 2129.
3. Hansen, K. B.; Chilenski, J. R.; Desmond, R.; Devine, P.
N.; Grabowski, E. J. J.; Heid, R.; Kubryk, M.; Mathre, D.
J.; Varsolona, R. Tetrahedron: Asymmetry 2003, 14, 3581.
4. For a recent review on the biological relevance and
synthesis of C-substituted morpholine derivatives, see:
Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van
Delft, F. L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis
2004, 22, 641.
OH
O
OH
O
HO
HO
OH
O
THF, 65°C,18h
75%
+
NH
Bn
N
Bn
aqueous
(50 wt%)
1a
Scheme 7.
Table 1. Effect of glyoxylic acid charge
Glyoxylic acid (equiv)
Concentration (g/L)
Yielda (%)
1
2
3
4
76
110
138
131
38
61
84
87
a Based on no solvent loss during reaction.