Practical synthesis of threo-(1S, 2S)- and erythro-(1R, 2S)-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) from L-serine

Article abstract of DOI:10.1055/s-1998-3132

Both L-threo and D-erytho-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) were synthesized stereoselectively from L-serine.

Full text of DOI:10.1055/s-1998-3132

April 1998
SYNLETT
389
Practical Synthesis of threo-(1S, 2S)- and erythro-(1R, 2S)-1-Phenyl-2-palmitoylamino-3-morpholino-1-
propanol (PPMP) from L-Serine
Atsushi Nishida, Hiroshi Sorimachi, Mie Iwaida, Miyako Matsumizu, Tomohiko Kawate, and Masako Nakagawa*
Faculty of Pharmaceutical Sciences, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
Fax 81-43-290-3021; nakagawa@p.chiba-u.ac.jp
Received 13 January 1998
Abstract: Both L-threo and D-erythro-1-phenyl-2-palmitoylamino-3-
morpholino-1-propanol (PPMP) were synthesized stereoselectively
from L-serine.
1-Phenyl-2-acylamino-3-morpholino-1-propanol (1 and 2) was
developed as an inhibitor of sphingolipid synthesis by Radin and
1
Inokuchi, and is expected to be a useful compound for treating tumors.
Very recently, 1 was reported to be effective in inhibiting the growth of
2
malaria parasite by inhibiting sphingomyelinase. Although some
structure-activity relationships of 1 and 2, with regard to the inhibition
of sphingolipid synthesis, have been reported, the effect of the stereo
3
centers on this activity is still unclear. We are interested in further
modification of these compounds and decided to develop a practical
route for the synthesis of this type of compound in a stereo-defined
manner.
Scheme 1
As a chiral starting material, we chose Garner aldehyde (4), since both
enantiomers of the aldehyde are readily available from D- and L-serine
4
by simple four-step procedures, and because the stereoselective
5
addition of alkyl and aryl metals to 4 has been reported previously.
Therefore, we examined the nucleophilic addition of phenyl metal
reagents to 4 in the absence and presence of metal salts. However, we
6
could not achieve a high level of selectivity (syn:anti=1:<4, Table 1),
and separation of the isomers 3 by column chromatography was
from petroleum ether. Therefore, both diastereomers of 3 were
difficult.
synthesized in a highly selective manner.
Next, we turned our attention to the stereoselective reduction of ketone
Both syn- and anti-3 were converted to 1 as follows (Scheme 2). First,
5, which was obtained in 94% yield from the mixture of syn- and anti-3
we synthesized triflate 6 from anti-3 to examine the introduction of a
morpholino group. However, the desired product was not observed
when 6 was heated in morpholine, due to the bulkiness of the
palmitoylamino group.
7
by Dess-Martin oxidation.
Reduction of ketone 5 by Red-Al and borohydride reagents gave syn-3
as a major diastereomer (Table 2). Among these reagents, NaBH and
nBu NBH gave syn-3 with relatively high selectivity (syn/anti= ~11/
4
4
4
Anti-3 was converted to 7 in 74% yield by deprotection-protection
procedures (3 steps). Desilylation of 7 followed by standard mesylation
gave 8 in quantitative yield. When 8 was heated at 50°C in morpholine
for 3.5 h, the desired product 9 was isolated in 60% yield as a colorless
crystal.
1). Reduction with K- and L-Selectride proceeded at a lower
temperature, and the highest syn selectivity (syn/anti=23/1) was
8
observed in reduction using K-Selectride. In contrast to the above
results, high anti selectivity (syn/anti=1/40) was observed when ketone
8
5 was reduced by DIBAH in THF at 0 °C in quantitative yield.
Optically pure syn- and anti-3 were obtained by simple recrystallization

390
LETTERS
SYNLETT
(2) Lauer, S. A.; Ghori, N.; Halder, K. Proc. Natl. Acad. Sci. USA,
1995, 92, 9181-9185.
(3) Carson, K. G.; Ganem, B. Tetrahedron Lett. 1994, 35, 2659-2662.
(4) a) Garner, P.; Ramakanth, R. J. Org. Chem. 1986, 51, 2609-2612;
b) Garner, P. Tetrahedron Lett. 1984, 25, 5855-5858.
(5) a) Shimizu, M.; Wakioka, I.; Fujisawa, T. Tetrahedron Lett. 1997,
38, 6027-6030; b) Kumar, J. S. R.; Dotta, A. Tetrahedron Lett.
1997, 38, 473-476; c) Williams, L.; Zhang, Z.; Shao, F.; Carroll,
P. J.; Joullié, M. M. Tetrahedron, 1996, 52, 11673-11694; d) Wee,
A. G. H.; Tang F. Tetrahedron Lett. 1996, 37, 6677-6680;
e) Coleman, R. S.; Carpenter, A. J. Tetrahedron Lett. 1992, 33,
1697-1700; f) Beaulieu, P. L. Tetrahedron Lett. 1991, 32, 1031-
1034; g) Herold, P. Helv. Chim. Acta 1988, 71, 354-362;
h) Radunz, H.-E.; Devant, R. M.; Eiermann, V. Liebigs Ann.
Chem. 1988, 1103-1105.
(6) The diastereomer ratios were determined by HPLC analysis using
a chiral column (Daicel Chiralcel-OD, i-PrOH-n-hexane, 1:9), and
no racemization of 4 was observed under these arylation
Scheme 2
1
conditions. However, the H-NMR technique was superior for
determining the diastereomer ratio, as shown in Table 2. The
stereochemistry of anti-3 was determined as reported elsewhere
(ref. 5h). The structure of syn-3 was confirmed by X-ray
crystallographic analysis.
Deprotection followed by acylation using palmitoyl chloride of 9
afforded 1a (8 steps, 30% from anti-3a). Using the same procedure,
9
syn-3 was converted to 1bþ(L-threo-PPMP) by way of 10 (8 steps, 51%,
9,10
Scheme 3).
(7) Stereoselective reduction of structurally related ketones;
a) Murakami, M.; Iwama, S.; Fujii, S.; Ikeda, K.; Katsumura. S.
Bioorg. Med. Chem. Lett. 1997, 7, 1725-1728; b) Doi, Y.;
Ishibashi, M.; Kobayashi, J. Tetrahedron, 1996, 52, 4573-4580;
and also ref. 5b.
(8) The selectivity was reproducible when the reaction was carried
out using 1 g of 5.
Scheme 3
(9) Selected physical and spectral data for 1a and 1b.
25
1a: mp 104-106 °C (CHCl -Et O). [α]
IR (KBr) ν 3321, 1641 cm . H-NMR (400 MHz, CDCl , at 55
-26.5 (c 1.1, CHCl ).
3
3
2
D
-1
1
3
In conclusion, we developed a stereoselective and practical route for the
synthesis of both 1a and 1b (L-threo and D-erythro-PPMP) from L-
serine. This synthetic route enables the synthesis of many analogs of 1,
including their enantiomers, which have interesting biological and
chemical properties.
°C) δ 7.35-7.22 (m, 5H), 5.77 (d, 1H, J=5.8 Hz), 4.84 (d, 1H,
J=4.6 Hz), 4.25 (dt, 1H, J=11.4 and 6.6 Hz), 3.66 (t, 4H, J=4.6
Hz), 2.58-2.42 (m, 6H), 2.16-2.04 (m, 2H), 1.53 (t, 2H, J=6.6 Hz),
13
1.26 (broad s, 25H), 0.88 (t, 3H, J=6.8 Hz). C-NMR (100 MHz,
CDCl , at 55 °C) δ 173.82 (CO), 141.60, 128.24, 127.65, 126.46,
3
76.90 (C1), 66.83 (-OCH CH N-), 59.11 (C3), 54.08
2
2
Acknowledgment
(-OCH CH N-), 51.95 (C2), 36.68, 31.88, 29.64, 29.42, 29.29,
2
2
We thank Professor K. Yamaguchi, Dr. H. Seki, and Miss R. Hara at the
Analytical Center of Chiba University for X-ray crystallographic
analysis, for measuring mass spectra and for conducting elemental
analyses. This research was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and Culture.
29.18, 25.65, 22.61, 13.96.
1b: mp 70-70.5 °C (pet. ether). [α]
IR (KBr) ν 3438, 3338, 1631 cm . H-NMR (400 MHz, CDCl ,
at 55 °C) δ 7.30-7.19 (m, 5H), 5.76 (d, 1H, J=7.0 Hz), 4.90 (d,
1H, J=3.9 Hz), 4.24-4.18 (m, 1H), 3.65 (t, 4H, J=4.7 Hz), 2.57-
2.40 (m, 6H), 2.03 (t, 2H, J=7.6 Hz), 1.49-1.42 (m, 2H), 1.22
25
-7.0 (c 0.89, CHCl ).
3
D
-1
1
3
13
(broad s, 24H), 1.18 (broad, 1H), 0.83 (t, 3H, J=6.9 Hz). C-
References and Notes
NMR (100 MHz, CDCl , at 55 °C) δ 173.61 (CO), 141.20,
3
(1) a) Inokuchi, J.-i.; Mizutani, A.; Jimbo, M.; Usuki, S.; Yamagishi,
K.; Mochizuki, H.; Muramoto, K.; Kobayashi, K.; Kuroda, Y.;
Iwasaki, K.; Ohgami, Y.; Fujiwara, M. Biochem. Biophys. Res.
Commun. 1997, 237, 595-600; b) Inokuchi, J.-i.; Radin, N. S.
J. Lipid Res. 1987, 28, 565-571; c) Abe, A.; Radin, S. N.; Shaman,
J. A.; Wotring, L. L.; Zipkin, R. E.; Sivakumar, R.; Ruggiere, J.
M.; Carson, K. G.; Ganem. B. J. Lipid Res. 1995, 36, 611-621,
and references cited therein.
128.35, 127.62, 126.09, 75.34 (C1), 66.98 (-OCH CH N-), 59.90
2
2
(C3), 54.46 (-OCH CH N-), 51.60 (C2), 36.78, 31.90, 29.65,
2
2
29.43, 29.30, 29.16, 25.65, 22.63, 13.98.
(10) Racemic 1 (PPMP) and 2 (PDMP) are commercially available.
Preparations of optically active 1 and 2 by separation of the four
stereo isomers, which were obtained from non-stereoselective
synthesis, were reported (ref. 1b and 1c).