Practical synthesis of α-aminoalkyl-α′-chloromethylketone derivatives. Part 1: Chloromethylation of N-protected 3-oxazolidin-5-ones

Article abstract of DOI:10.1016/S0040-4039(01)01114-5

Reaction of N-protected 3-oxazolidin-5-ones with in situ-generated chloromethyllithium afforded N-protected 5-chloromethyl-5-hydroxy-3-oxazolidines without racemization. They were easily hydrolyzed to give α-aminoalkyl-α′-chloromethylketone derivatives, which are useful intermediates for several protease inhibitors.

Full text of DOI:10.1016/S0040-4039(01)01114-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5883–5885
Practical synthesis of a-aminoalkyl-a%-chloromethylketone
derivatives. Part 1: Chloromethylation of N-protected
3-oxazolidin-5-ones
Tomoyuki Onishi, Naoko Hirose, Takashi Nakano, Masakazu Nakazawa and Kunisuke Izawa*
AminoScience Laboratories, Ajinomoto Co. Inc., 1-1 Suzuki-cho, Kawasaki 210-8681, Japan
Received 18 May 2001; revised 21 June 2001; accepted 25 June 2001
Abstract—Reaction of N-protected 3-oxazolidin-5-ones with in situ-generated chloromethyllithium afforded N-protected 5-
chloromethyl-5-hydroxy-3-oxazolidines without racemization. They were easily hydrolyzed to give a-aminoalkyl-a%-
chloromethylketone derivatives, which are useful intermediates for several protease inhibitors. © 2001 Elsevier Science Ltd. All
rights reserved.
reported that chloromethylation of Moc-Phe-OMe (3)
gave chloromethylketone 4 in only modest yield (35–
51%), while an improved process involving in situ pro-
tection of the carbamate group in 3 with trimethylsilyl
chloride prior to the reaction with chloromethyllithium
gave 4 in 76% yield after aqueous workup (Scheme 2).10
However, to obtain unprotected a-aminoalkyl-a%-
chloromethylketone, this procedure has a limitation due
to lack of method to deprotect the Moc group while
maintaining the chloromethylketone moiety. We
attempted chloromethylation of Boc-Phe-OMe and
Boc(TMS)-Phe-OMe, but did not realize good results.
This prompted us to investigate the chloromethylation
of 3-oxazolidin-5-one derivatives and successive depro-
tection.
a-Aminoalkyl-a%-chloromethylketone derivatives serve
as irreversible inhibitors of serine protease1–3 and are
useful precursors to the hydroxyethyl isostere subunits
found in many inhibitors of renin4 and HIV protease.5
For instance, chloromethylketone 1 can be easily con-
verted to epoxide 2, which is the key intermediate for
various enzyme inhibitors (Scheme 1).6 The need for
practical syntheses of a-aminoalkyl-a%-chloromethylke-
tone derivatives has become of crucial importance, and
considerable effort has been directed towards the devel-
opment of efficient processes.6–11 We report here a
novel practical method for the synthesis of a-
aminoalkyl-a%-chloromethylketone derivatives.
We have focused on the reaction of chloromethyl-
lithium12,13 with N-protected amino acid esters, since
such a carbenoid species can be conveniently generated
in situ from BrCH2Cl and n-BuLi, which are not
unreasonably expensive. Although the chloromethyl-
First, chloromethylation of N-Boc-protected 3-oxazo-
lidin-5-one 5, which can be prepared by reacting Boc-
Phe-OH and paraformaldehyde in the presence of acid
catalyst,14 was performed to obtain N-Boc-protected
ation of N,N-dibenzyl-L-phenylalanine ester has been
5-chloromethyl-5-hydroxy-3-oxazolidine
6
quantita-
described,8,9 no method has been reported for depro-
tecting the dibenzyl group while keeping the
chloromethylketone moiety intact. The Roche group
tively (Scheme 3).15 Compound 6 was easily hydrolyzed
with hydrochloric acid to give unprotected a-
aminoalkyl-a%-chloromethylketone 716 in 64% isolated
yield without racemization.17 This is contributed by the
weak basicity of the chloromethyl-lithium which is
O
O
BocHN
Ph
1) Reduction
BocHN
Ph
Cl
1) TMSCl, nBuLi
O
O
2) Epoxide formation
2) BrCH2Cl, nBuLi
Cl
MocHN
Ph
MocHN
Ph
OMe
3) H+
3 steps, 76%
1
2
3
4
Scheme 1.
Moc; Methoxycarbonyloxy group
* Corresponding
author.
Fax:
+81-44-211-7610;
e-mail:
Scheme 2.
kunisuke izawa@ajinomoto.com
–
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01114-5

5884
T. Onishi et al. / Tetrahedron Letters 42 (2001) 5883–5885
Cl
O
O
O
6 mol/l HCl aq.
BrCH2Cl (1.3 eq.)
nBuLi (1.3 eq.)
BocN
Ph
HClH2N
Ph
Cl
BocN
Ph
O
OH
THF rt
Reaction yield; 77%
Isolated yield; 64%
THF, -78°C
quant.
5
6
+
7
99.2% e.e.
1) NaBH4 / MeOH
2) H+
OH
OH
HClH2 N
Ph
Cl
HClH2N
Cl
Ph
8a (51%)
8b (35%)
Scheme 3.
immediately generated in situ from BrCH2Cl and n-
BuLi. NaBH4 reduction of 6 and successive deprotec-
tion was also tested and gave chlorohydrin 818 in good
yield (86%), but with no significant diastereo-
selectivity.19
Acknowledgements
We thank to Mr. Takayuki Suzuki for his helpful
discussion.
In the example above, both the N,O-acetal and Boc
groups were simultaneously deprotected by acid treat-
ment to give unprotected a-aminoalkyl-a%-chloro-
methylketone. To obtain N-protected a-aminoalkyl-a%-
chloromethylketone, chloromethylation of N-Cbz-pro-
tected 3-oxazolidin-5-one 9, which can be prepared by
References
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reacting the sodium salt of
L-Phe and p-anisaldehyde
followed by Cbz-protection,20 was examined (Scheme
4). The reaction proceeded nicely to give the desired
N-protected a-aminoalkyl-a%-chloromethylketone 1015
directly in 62% yield without the need for deprotec-
tion.21
In conclusion, practical syntheses of a-aminoalkyl-a%-
chloromethylketone derivatives using the chloromethyl-
ation of N-protected 3-oxazolidin-5-one were achieved.
This methodology is particularly useful for the synthe-
sis of N-Cbz-protected a-aminoalkyl-a%-chloromethyl-
ketone since it can be prepared efficiently from amino
acid in only three steps.
MeO
MeO
10. Goehring, W.; Gokhale, S.; Hilpert, H.; Roessler, F.;
Schlageter, M.; Vogt, P. Chimia 1996, 50, 532.
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Yoshida, N. US Patent 5929284, 1999.
12. Matteson, D. S. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: New
York, 1995; Vol. 2, pp. 1154–1156.
13. Koebrich, G.; Fischer, R. H. Tetrahedron 1968, 24, 4343.
14. Walter, M. W.; Adlington, R. M.; Baldwin, J. E.;
Chuhan, J.; Schofield, C. J. Tetrahedron Lett. 1995, 36,
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BrCH2Cl (1.3 eq.)
Cl
OLi
O
O
nBuLi (1.3 eq.)
CbzN
CbzN
Ph
O
THF, -78°C
Ph
9
O
Work up
CbzHN
Ph
Cl
15. A solution of 3-oxazolidin-5-one
5
and bromo-
10
62%, >98% e.e.
chloromethane (1.3 equiv.) in anhydrous THF was cooled
to −78°C and n-butyllithium (1.3 equiv.) in hexane was
added dropwise. After stirring for 1 h at −78°C, 10%
Scheme 4.

T. Onishi et al. / Tetrahedron Letters 42 (2001) 5883–5885
5885
KHSO4 aq. was added. The product was extracted and
19. 5-Chloromethyl-5-hydroxy-3-oxazolidine 6 was treated
with NaBH4 (2 equiv.) in MeOH at 0°C for 1 h. An
excess of 6 mol/l HCl was then added and the mixture
was stirred at 50°C for 1 h. Yield and diastereoselectivity
were determined by HPLC using an Inertsil ODS-2
column.
purified by silica gel chromatography to give 6 as a
1
colorless oil. H NMR (CDCl3) l 1.48 (s, 9H), 3.02 (dd,
J=10.1, 13.2 Hz, 1H), 3.24–3.34 (m, 3H), 3.80 (d, J=
11.5 Hz, 1H), 3.93 (dd, J=4.5, 10.0 Hz, 1H), 4.87 (d,
J=4.7 Hz, 1H), 5.17 (bs, 1H), 7.18–7.33 (m, 5H); FAB
MASS m/z 328 (MH+).
20. Walter, M. W.; Adlington, R. M.; Baldwin, J. E.;
Schofield, C. J. J. Org. Chem. 1998, 63, 5179.
16. Fittkau, S. J. Prakt. Chem. 1973, 315, 1037.
17. A solution of 5-chloromethyl-5-hydroxy-3-oxazolidine 6
in THF was treated with an excess of 6 mol/l HCl at
50°C for 1 h. After concentration, the resultant slurry
was washed with MeOH–MTBE to give 7 as a white
solid. Reaction yield was determined by HPLC using an
Inertsil ODS-2 column. Enantiomer purity was deter-
mined by HPLC using a Crownpak CR(+) column.
21. A solution of the 3-oxazolidin-5-one 9 and bromo-
chloromethane (1.3 equiv.) in anhydrous THF was
cooled to −78°C and n-butyllithium (1.3 equiv.) in hex-
ane was added dropwise. After stirring for 30 min at
−78°C, 5% KHSO4 aq. was added. The product was
extracted and purified by silica gel chromatography to
give 10 as a white solid. Enantiomer purity was deter-
mined by HPLC using a Chiralcel OD-H column. 1H
NMR (CDCl3) l 3.00 (dd, J=7.0, 13.9 Hz, 1H), 3.09
(dd, J=6.9, 13.9 Hz), 3.97 (d, J=16.2 Hz), 4.14 (d,
J=16.2 Hz), 4.75 (bq, J=7.0 Hz, 1H), 5.06 (s, 2H), 5.38
(bd, J=7.6 Hz, 1H), 7.12–7.35 (m, 10H); ESI MASS m/z
332 (MH+).
[h]2D5=+30.2 (c=0.5, H2O); H NMR (DMSO-d6) l 3.04
1
(dd, J=7.1, 15.2 Hz, 1H), 3.22 (dd, J=7.1, 15.2 Hz,
1H), 4.54 (t, J=7.1 Hz, 1H), 4.58 (d, J=17.3 Hz, 1H),
4.70 (d, J=17.3 Hz, 1H), 7.28–7.41 (m. 5H), 8.37 (bs,
3H); ESI MASS m/z 198 (MH+).
18. Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61,
3635.
.