Catalytic, asymmetric Mannich-type reactions of N-acylimino esters for direct formation of N-acylated amino acid derivatives. Efficient synthesis of a novel inhibitor of ceramide trafficking, HPA-12.

Article abstract of DOI:10.1021/ol017062u

[reaction: see text] Catalytic, enantioselective Mannich-type reactions of N-acylimino esters for direct formation of N-acylated amino acid derivatives are described. A chiral copper catalyst prepared from Cu(OTf)(2) and a chiral diamine ligand is used. A

Full text of DOI:10.1021/ol017062u

ORGANIC
LETTERS
2
002
Vol. 4, No. 1
43-145
Catalytic, Asymmetric Mannich-Type
Reactions of N-Acylimino Esters for
Direct Formation of N-Acylated Amino
Acid Derivatives. Efficient Synthesis of
a Novel Inhibitor of Ceramide
1
Trafficking, HPA-12
Sh u¯ Kobayashi,* Ryosuke Matsubara, and Hidetoshi Kitagawa
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, CREST,
Japan Science and Technology Corporation (JST), Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received November 16, 2001
ABSTRACT
Catalytic, enantioselective Mannich-type reactions of N-acylimino esters for direct formation of N-acylated amino acid derivatives are described.
A chiral copper catalyst prepared from Cu(OTf) and a chiral diamine ligand is used. A novel inhibitor of ceramide trafficking, HPA-12, is
efficiently synthesized using this reaction.
2
Many biologically important, chiral N-acylated amino acid
derivatives are observed in Nature.1 In particular, our
laboratories have focused on (1R,3R)-N-(3-hydroxy-1-hy-
droxymethyl-3-phenylpropyl)dodecanamide (HPA-12, 1) (Fig-
ure 1), a new inhibitor of ceramide trafficking from
endoplasmic reticulum to the site of sphingomyelin (SM)
synthesis. HPA-12 is the first compound of a specific
inhibitor for SM synthesis in mammalian cells and is
expected as a drug that inhibits intracellular trafficking of
2
sphingolipids.
For the synthesis of these compounds, catalytic enantio-
3
selective Mannich-type reactions of R-imino esters with
(
1) For example: (a) Helms, G. L.; Moore, R. E.; Niemczura, W. P.;
Patterson, G. M. L.; Tomer, K. B.; Gross, M. L. J. Org. Chem. 1988, 53,
298. (b) Matsunaga, S.; Fusetani, N.; Hashimoto, K.; W a¨ lchli, M. J. Am.
1
Chem. Soc. 1989, 111, 2582. (c) Humphrey, J. M.; Chamberlin, A. R. Chem.
ReV. 1997, 97, 2243. (d) von D o¨ hren, H.; Keller, U.; Vater, J.; Zocher, R.
Chem. ReV. 1997, 97, 2675. (e) Dickson, R. C. Annu. ReV. Biochem. 1998,
6
7, 27. (f) Kolter, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38, 1532.
(
2) Yasuda, S.; Kitagawa, H.; Ueno, M.; Ishitani, H.; Fukasawa, M.;
Nishijima, M.; Kobayashi, S.; Hanada, K. J. Biol. Chem. 2001, 276, 43994-
4002.
Figure 1. A novel inhibitor of ceramide trafficking, HPA-12.
4
1
0.1021/ol017062u CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/13/2001

1
4
enolates would provide an efficient method. We have recently
developed zirconium-catalyzed enantioselective Mannich-
type reactions, and other groups have also reported metal-
min. The yield was dramatically improved, and the desired
adduct was obtained in 92% yield with 94% ee.
4
Several examples of the Mannich-type reactions are shown
in Table 2. N-Acetylimino ester 2b also reacted smoothly to
afford the desired adduct in high yield with excellent ee.
For N-benzoylimino ester 2c, the use of Cu(OTf)
only gave a low ee (58% yield, 14% ee). In this substrate,
high ee’s were obtained when CuClO ‚4CH CN-(S)-xylyl-
BINAP was used as the catalyst (Table 2, entries 6-9). As
for enolate components, silyl enol ethers derived from
ketones, an ester, and a thioester worked well. Moreover, it
is noted that an alkyl vinyl ether also reacted smoothly to
afford the corresponding N-acylated amino acid derivatives
in high yields with excellent ee’s. In the reaction of the alkyl
catalyzed asymmetric Mannich-type reactions of R-imino
5
esters. In these reactions, however, the N-protected groups
6
of the products have to be removed and then acylated. More
2
-ligand 3e
conveniently, N-acylimino esters would react with enolates
to afford N-acylated amino acid derivatives directly. How-
ever, the starting materials, N-acylimino esters, are known
to be unstable in several cases, and their use in organic
synthesis has been limited. In this Letter, we report the first
enantioselective Mannich-type reactions of N-acylimino
esters using a chiral copper catalyst. Efficient synthesis of
HPA-12 using this reaction is also described.
4
3
We have quite recently developed a convenient preparation
method of N-acylimino esters using a polymer-supported
(3) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
7
(4) (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997,
amine. According to this method, N-acylimino ester 2a was
1
1
19, 7153. (b) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc.
998, 120, 431. (c) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem.
Soc. 2000, 122, 8180. (d) Kobayashi, S.; Ishitani, H.; Yamashita, Y.; Ueno,
M.; Shimizu, H. Tetrahedron 2001, 57, 861.
8
prepared from the corresponding R-chloroglycine derivative,
and the Mannich-type reaction with the silyl enol ether
derived from acetophenone was examined using a chiral
catalyst. After screening various metals and chiral ligands,
(5) (a) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998,
120, 2474. (b) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem.
Soc. 1998, 120, 4548. (c) Ferraris, D.; Young, B.; Cox, C.; Drury, W. J.,
III.; Dudding, T.; Lectka, T. J. Org. Chem. 1998, 63, 6090. (d) Fujii, A.;
Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450. (e) Ferraris,
D.; Dudding, T.; Young, B.; Drury, W. J., III; Lectka, T. J. Org. Chem.
999, 64, 2168. (f) Ferraris, D.; Young, B.; Dudding, T.; Drury, W. J., III.;
Lectka, T. Tetrahedron 1999, 55, 8869. (g) Juhl, K.; Gathergood, N.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995.
it was revealed that a chiral copper catalyst prepared from
9
Cu(OTf)
2
and chiral ligand 3e was effective. The effects of
chiral ligands and reaction conditions are summarized in
1
Table 1. When CuClO ‚4CH
4
3
CN10 was combined with (S)-
(
6) Quite recently, we have completed the first asymmetric synthesis of
HPA-12. See ref 16.
7) Kobayashi, S.; Kitagawa, H.; Matsubara, R. J. Comb. Chem. 2001,
, 401.
8) N-Acyl-R-chloroglycine ethyl esters were readily prepared from
(
Table 1. Effect of Chiral Ligands and Reaction Conditions
3
(
N-acyl-R-hydroxyglycine ethyl esters by treatment with SOCl2. For the
preparation of N-acyl-R-hydroxyglycine ethyl esters, see: Schmitt, M.;
Bourguignon, J.; Barlin, G. B.; Davies, L. P. Aust. J. Chem. 1997, 50, 719.
See also: Kober, R.; Steglich, W. Liebigs Ann. Chem. 1983, 599.
(9) (a) Mimoun, H.; Laumer, J. Y. S.; Giannini, L.; Scopelliti, R.; Floriani,
C. J. Am. Chem. Soc. 1999, 121, 6158. (b) Cavallo, L.; Cucciolito, M. E.;
Martino, A. D.; Giordano, F.; Orabona, I.; Vitagliano, A. Chem. Eur. J.
2
000, 6, 1127, and references therein.
10) For the preparation of CuClO4‚4CH3CN, see: Kubas, G. J. Inorganic
Synthesis; Shriver, D. F., Ed.; Plenum: New York, 1979; Vol. XIX, p 90.
11) Provided from Takasago Chemical Co. Ltd. For the preparation of
(
(
xylyl-BINAP, see: Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.;
Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa,
S.; Takaya, H. J. Org. Chem. 1994, 59, 3064. The use of xylyl-BINAP,
see, for example: Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa,
M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1998, 120, 13529.
(
12) For the use of the Cu-BINAP system in enantioselective reactions
of R-imino esters, see: (a) Drury, W. J., III; Ferraris, D.; Cox, C.; Young,
B.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 11006. (b) Yao, S.; Johannsen,
M.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 1998, 37, 3121.
(c) Yao, S.; Fang, X.; Jørgensen, K. A. Chem. Commun. 1998, 2547. (d)
Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 1999, 64, 4844. (e) Juhl, K.; Hazell, R. G.; Jørgensen,
K. A. J. Chem. Soc., Perkin Trans. 1 1999, 2293. (f) Johannsen, M. Chem.
Commun. 1999, 2233. (g) Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2000, 39, 4114. (h) Yao, S.; Saaby, S.; Hazell,
R. G.; Jørgensen, K. A. Chem. Eur. J. 2000, 6, 2435. (i) Knudsen, K. R.;
Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem.
Soc. 2001, 123, 5843. (j) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992. Cf. (k) Kr u¨ ger,
J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837.
a
S)-(-)-Bis[bis(3,5-dimethylphenyl)phosphino]-1,1′-binaphthyl. b 0 °C.
1-13
(
xylyl-BINAP1
and used as a catalyst, a low enantiomeric
excess (ee) was obtained. On the other hand, in the presence
of Cu(OTf) and ligand 3e (10 mol %), 2a and the silyl enol
2
(13) For other chiral Cu-catalyzed reactions, see, for example: (a) Evans,
ether were added successively to afford the desired adduct
in 80% ee, but in low yield. In this case, formation of a
dimer of 2a was observed, presumably due to contamination
by water. We carefully performed the reaction under
anhydrous conditions, and the silyl enol ether was added to
the catalyst first and then 2a was slowly charged over 20
D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am.
Chem. Soc. 2000, 122, 7936-7943. (b) Johnson, J. S.; Evans, D. A. Acc.
Chem. Res. 2000, 33, 325. (c) Bromidge, S.; Wilson, P. C.; Whiting, A.
Tetrahedron Lett. 1998, 39, 8905. (d) Jnoff, E.; Ghosez, L. J. Am. Chem.
Soc. 1999, 121, 2617. (e) Audrain, H.; Jørgensen, K. A. J. Am. Chem. Soc.
2000, 122, 11543. (f) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J.
Am. Chem. Soc. 2000, 122, 12517.
(14) Experimental details are shown in Supporting Information.
144
Org. Lett., Vol. 4, No. 1, 2002

Table 2. Catalytic Asymmetric Mannich-Type Reactions
no.
R1
R2
R3
R4
cat.a
temp (°C)
product
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
9
a
C11H23 (2a )
C11H23 (2a )
C11H23 (2a )
C11H23 (2a )
CH3 (2b)
Ph (2c)
Ph (2c)
Ph (2c)
Ph (2c)
Ph
SiMe3
SiMe3
SiMe3
Me
SiMe3
SiMe3
SiMe3
SiMe3
Me
H
H
H
H
H
H
Me
H
H
A
A
A
A
A
B
B
B
B
0
0
0
0
0
5a
5b
5c
5a
5d
5e
5f
92
97
88
85
85
79
81
76
77
94
92
93
90
94
97
96
90
95
MeOPh
ClPh
Ph
Ph
Ph
MeO
EtS
Ph
-78
-78
-78
-78
5g
5e
A: Cu(OTf)2 + 3e. B: CuClO4‚4CH3CN + (S)-xylyl-BINAP. b For determination of absolute configurations, see Supporting Information.
vinyl ether, the initial adduct was vinyl ether 4, which was
converted to the corresponding amino acid derivative 5 under
acidic conditions. A possible mechanism for the formation
of 4 is [4 + 2]-cycloaddition of 2a and the alkyl vinyl ether
followed by proton transfer (Scheme 1).15 In the reactions
acylated for the preparation of the N-acylated amino acid
derivative, and total efficiency was moderate (total yield
6.0%, six steps). The Mannich-type adduct (5a) was treated
1
7
with K-Selectride at -78 °C for 2 h and then LiBEt
3
H at
rt for further 2 h (one-pot) to afford HPA-12 in high yield
(Scheme 2). It should be noted that HPA-12 has been
Scheme 1
Scheme 2
synthesized from 2a in three steps (two-pot) and that the
total yield was 68.6%. According to this efficient synthetic
pathway, the preparation of many other HPA-12 analogues
is feasible.
of silyl enol ethers, similar intermediates that were less stable
than 4 were observed in the reaction pots. In this mechanism,
it is noteworthy that chiral induction by the chiral catalyst
occurred at the initial [4 + 2]-cycloaddition stage.
In summary, the first asymmetric Mannich-type reactions
of N-acylimino esters with enolates have been achieved using
18
a novel chiral copper catalyst. As enolate components, silyl
Finally, synthesis of HPA-12 was performed using the
present asymmetric Mannich-type reaction. We have quite
recently performed the first asymmetric synthesis of HPA-
enol ethers as well as a vinyl ether reacted smoothly. This
is the first example of using a vinyl ether in catalytic
asymmetric Mannich-type reactions. Moreover, a new type
of reaction mechanism of the catalytic asymmetric Mannich-
type reactions has been proposed. Catalytic enantioselective
synthesis of a novel inhibitor of ceramide trafficking, HPA-
19
1
2 using a chiral zirconium-catalyzed enantioselective Man-
16
nich reaction as a key step. In this synthesis, however, the
N-protected group of the product was removed and then
1
2, has been attained in three steps (two-pot) using this novel
(
15) Similar reaction pathways were reported. (a)Weinreb, S. M.; Scola,
asymmetric reaction.
P. A. Chem. ReV. 1989, 89, 1525-1534. (b)Gizecki, P.; Dhal, R.; Toupet,
L.; Dujardin, G. Org. Lett. 2000, 2, 585-588. See also the following: (c)
Kitajima, H.; Katsuki, T. Synlett 1997, 568. (d)Evans, D. A.; Scheidt, K.
A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Japan Society
of the Promotion of Science.
(
16) Ueno, M.; Kitagawa, H.; Ishitani, H.; Yasuda, S.; Nishijima, K.;
Hanada, K.; Kobayashi, S. Tetrahedron Lett. 2001, 42, 7863.
17) Pilli, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin Trans.
1990, 1213-1214.
18) Catalytic enantioselective addition of N-(alkoxycarbonyl)-R-imino
esters to aromatic compounds was recently reported. See ref 12g.
19) For the utility of vinyl ethers, see, for example: Carreira, E. M.;
(
Supporting Information Available: Experimental details
and characterization of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
(
(
Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649.
OL017062U
Org. Lett., Vol. 4, No. 1, 2002
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