Synthesis of optically active α-aminoalkyl α′-halomethyl ketone: A cross-claisen condensation approach

Article abstract of DOI:10.1021/ol017163s

(Equation presented) A simple and versatile method was developed for the synthesis of α-aminoalkyl α′-halomethyl ketone derivatives, which are useful intermediates of protease inhibitors. It involves selective halogenation of the α-position on a β-ketoester, which is prepared by cross-Claisen condensation using N-protected amino acid ester. The title compound is obtained in high yield after decarboxylation of the α-halo-β-ketoester.

Full text of DOI:10.1021/ol017163s

ORGANIC
LETTERS
2002
Vol. 4, No. 3
447-449
Synthesis of Optically Active
r-Aminoalkyl r′-Halomethyl Ketone: A
Cross-Claisen Condensation Approach
Yutaka Honda, Satoshi Katayama, Mitsuhiko Kojima, Takayuki Suzuki, and
Kunisuke Izawa*
AminoScience Laboratories, Ajinomoto Co. Inc., Suzuki-cho, Kawasaki-ku,
Kawasaki-shi 210-8681, Japan
kunisuke_izawa@ajinomoto.com
Received December 3, 2001
ABSTRACT
A simple and versatile method was developed for the synthesis of r-aminoalkyl r′-halomethyl ketone derivatives, which are useful intermediates
of protease inhibitors. It involves selective halogenation of the r-position on a â-ketoester, which is prepared by cross-Claisen condensation
using N-protected amino acid ester. The title compound is obtained in high yield after decarboxylation of the r-halo-â-ketoester.
Optically active R-aminoalkyl R′-halomethyl ketone deriva-
tives are usually synthesized from the corresponding amino
acids through multistep transformation. While conversion
involving diazomethyl ketone and subsequent acidolysis with
HX has been the classic approach in this area,1 direct
chloromethylation to N-protected amino acid ester has also
been investigated to overcome the safety issue of using
diazomethane.2 Since R-aminoalkyl R′-halomethyl ketone can
be readily converted into the amino epoxide, which is a key
intermediate for several HIV protease inhibitors,3 the use of
phenylalanine as a starting material has been extensively
studied with regard to industrially applicable synthesis.
Recently, a method for synthesizing N-protected amino
epoxide from the corresponding amino acids via â-ketoester
was reported.4 As the authors noted in their article, a similar
synthetic approach had been previously reported by us in
the patent literature.5 Although they successfully extended
our approach to other amino acids, their report prompted us
to disclose our full results for comparison with their method.
In addition, an elegant method (for R-aminoalkyl R′-
halomethyl ketones) involving the condensation of L-phen-
(1) (a) Getman, D. P.; DeCrescenzo, G. A.; Heintz, R. M.; Reed, K. L.;
Talley, J. J.; Bryant, M. L.; Clare, M.; Houseman, K. A.; Marr, J.; Mueller,
R. A.; Vazques, M. L.; Shieh, H.-S.; Stallings, W. C.; Stegeman. R. A. J.
Med. Chem. 1993, 36, 288. (b) Raddatz, P.; Jonczyk, A.; Minck, K.-O.;
Schmitges, C. J.; Sombroek, J. J. Med. Chem. 1991, 34, 3267. (c) Albeck,
A.; Persky, R. Tetrahedron 1994, 50, 6333. (d) Heinsoo, A.; Raidaru, G.;
Linask, K.; Jarv, J.; Zetterstrom, M.; Langel, U. Tetrahedron: Asymmetry
1995, 6, 2245. (e) Handa, B. K.; Machin, P. J.; Martin, J. A.; Redshaw, S.;
Thomas, G. J.; F. Eur. Pat. Appl. EP346847, 1989.
(2) (a) Barluenga, J.; Baragana, B.; Alonso, A.; Concellon, J. M. J. Chem.
Soc., Chem. Commun. 1994, 969. (b) Chen, P.; Cheng, P. T. W.; Spergel,
S. H.; Zahler, R.; Wang, X.; Thottathil, J.; Barrish, J. C.; Polniaszek, R. P.
Tetrahedron Lett. 1997, 38, 3175. (c) Onishi, T.; Hirose, N.; Nakano. T.;
Nakazawa, M.; Izawa, K. Tetrahedron Lett. 2001, 42, 5883. (d) Onishi, T.;
Nakano, T.; Hirose, N.; Nakazawa, M.; Izawa, K. Tetrahedron Lett. 2001,
42, 6337.
(3) (a) Parkes, K. E. B.; Bushnell, D. J.; Crackett, P. H.; Dunsdon, S. J.;
Freeman, A. C.; Gunn, M. P.; Hopkins, A.; Lambert, R. W.; Martin, J. A.;
Merrett, J. H.; Redshaw, S.; Spurden, W. C.; Thomas, G. J. J. Org. Chem.
1994, 59, 3656. (b) Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61,
3635. (c) Ng, J. S.; Przybyla, C. A.; Liu, C.; Yen, C.; Muellner, F. W.;
Weyker, C. L. Tetrahedron. 1995, 51, 6397.
(4) Hoffman, R. V.; Weiner, W. S.; Maslouh, N. J. Org. Chem. 2001,
66, 5790.
(5) (a) Honda, Y.; Katayama, S.; Izawa, K. Eur. Pat. Appl. 1097919,
2001. (b) Honda, Y.; Katayama, S.; Izawa, K.; Nakazawa, M.; Suzuki, T.;
Kanno, N. U.S. Pat. 5,767,316, 1998. (c) Honda, Y.; Katayama, S.; Izawa,
K.; Nakazawa, M.; Suzuki, T.; Kanno, N. U.S. Pat. 5,902,887, 1999.
10.1021/ol017163s CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/05/2002

ylalanine derivatives with magnesium enolate of chloroacetic
acid followed by one-pot decarboxylation during workup was
reported in the course of our study.6
Scheme 2a
Our synthetic approach to R-aminoalkyl R′-halomethyl
ketones consists of three steps, namely, (1) conversion of
the N-protected amino acid ester to â-ketoester, (2) mono-
halogenation of the R-methylene, and (3) hydrolysis of the
ester and decarboxylation to give the desired halomethyl
ketones (Scheme 1). Our objective was to establish an
a (a) t-BuOAc (4.0 equiv), LDA (3.5 equiv), THF, -45 to -50
°C; (b) H+ (97% from 1).
derivative. Furthermore, we did not detect a tertiary alcohol
formed by further attack of the enolate. The details of this
method will be reported soon.
Scheme 1
Effective halogenation of the â-ketoester 2 is another
important issue in this process (Scheme 3). Chloromethyl
Scheme 3
industrially applicable process that would not require a
hazardous reaction or chromatographic purification.
Claisen condensation is a well-known method for the
general synthesis of â-ketoesters. However, there have been
very few reports on the application of cross-condensation
between different esters,7 and successful results were ex-
ceptionally obtained in the reaction using hydroxyl ester.8
A nucleophilic reaction of ester enolate to acid imidazolide
has been widely used as a common method for synthesizing
â-ketoester,9 but it can be rather expensive to use imidazolide
or active ester in an industrial setting. Therefore, we
considered that cross-Claisen condensation between two
stable and readily available esters, i.e., N-protected amino
acid alkyl ester and alkyl acetate, might be worth investigat-
ing. Thus, N-carbobenzyloxy L-phenylalanine methyl ester
1 was reacted with excess lithium enolate prepared from tert-
butyl acetate and lithium diisopropylamide in tetrahydrofuran
at -50 °C (Scheme 2); the reaction gave the corresponding
â-ketoester 2 quantitatively without racemization.10 To the
best of our knowledge, this is the first successful cross-
Claisen condensation with an alkyl ester of an R-amino acid
ketone is equivalent to bromomethyl ketone as a precursor
of amino epoxide, since it has been reported that reduction
with sodium borohydride proceeded with the same trend of
selectivity.11 The selectivity of this reduction could be
influenced mainly by the reaction conditions, such as
temperature or solvent, and less by the halogen at the
R-position. Since the chloro ketone is more stable than the
bromo derivative, chlorination seemed to be a good choice
for halogenation. Therefore, the optimal conditions for
chlorination were investigated. (Table 1) As noted by
Table 1. Results of Halogenation at the R-Position of
â-Ketoester 2 (Reaction (a))
yield
product
reagent
conditions
(%)a
3a
3a
3b
3b
3b
NCS (1.0 equiv)
SO2Cl2 (1.2 equiv)
NBS (1.0 equiv)
NBS (1.0 equiv)/DMAP CH2Cl2, 25 °C, 2.0 h
Br2 (1.0 equiv)/CaCO3
(1.0 equiv)
CHCl3, 25 °C, 3.5 h
CH2Cl2, 15 °C, 1.0 h
CH2Cl2, 25 °C, 2.0 h
43
95
40
56
93
(6) Nishiyama, A.; Sugawa, T.; Manabe, H.; Inoue, K.; Yoshida, N. U.
S. Pat. 5,929,284, 1999
(7) Ohta, S.; Shimabayashi, A.; Hayakawa, S.; Sumino, M.; Okamoto,
M. Synthesis 1985, 45.
(8) (a) Trotter, N. S.; Takahashi, S.; Nakata, T. Org. Lett. 1999, 1, 957.
(b) Spino, C.; Mayes, N.; Desfosses, H. Tetrahedron. Lett. 1996, 37, 6503.
(c) Nakata, T.; Komatsu, T.; Nagasawa, K. Chem. Pharm. Bull. 1994, 42,
2403. (d) Shao, L.; Seki, T.; Kawano, H.; Saburi, M. Tetrahedron. Lett.
1991, 32, 7699. (e) Deschenaux, P. F.; Kallimopoulos, T.; Stoeckli-Evans,
H.; Jacot-Guillarmod, A. HelV. Chim. Acta 1989, 72, 731. (f) Shao, L.;
Kawano, H.; Saburi, M.; Uchida, Y. Tetrahedron 1993, 49, 1997. (g) Patel,
D. V.; Schmidt, R. J.; Gordon, E. M. J. Org. Chem. 1992, 57, 7143. (h)
Cardani, S.; Scolastico, C.; Villa, R. Tetrahedron 1990, 46, 7283. (i)
Jendralla, H.; Baader, E.; Bartmann, W.; Bech, G.; Bergmann, A.; Granzer,
E.; v. Kerekjarto, B.; Kesseler, K.; Krause, R.; Schubert, W.; Wess, G. J.
Med. Chem. 1990, 33, 61.
(9) (a) Hoffman, R. V.; Tao, J. Tetrahedron 1997, 53, 7119. (b) Tao, J.;
Hoffman, R. V. J. Org. Chem. 1997, 62, 6240. (c) Jouin, P.; Dufour, M.
N.; Maugras, I.; Pantaloni, A.; Castro, B. Tetrahedron Lett. 1988, 29, 2661.
(d) Ino, A.; Hasegawa, Y.; Murabayashi, A. Tetrahedron Lett. 1998, 39,
3509.
CH2Cl2, -10 °C, 2.0 h
a Reaction yield determined by HPLC.
Hoffman et al., chlorination with N-chlorosuccinimide gave
disappointing results. On the other hand, sulfuryl chloride,
which is an effective reagent for chlorination at the R-position
to a carbonyl group,12 induced a selective reaction without
dichlorination, and R-chloro-â-ketoester 3a was produced
in 95% yield.13 The pure material could be isolated by
recrystallization from toluene. Bromination was also studied
448
Org. Lett., Vol. 4, No. 3, 2002

for comparison. Bromine induced a rapid reaction at low
temperature, and 3b was produced in 93% yield. Although
N-bromosuccinimide worked more efficiently in the presence
of an additive such as DMAP, the results were not promising.
In the bromination studies, the results varied and were
sometimes difficult to reproduce. This problem may have
been due to the instability of 3b.
The R-halo-â-ketoesters 3a and 3b were converted into
halomethyl ketones by acidic hydrolysis and subsequent
decarboxylation (Table 2). Even though most of the reactions
took place smoothly, the yields after isolation via TLC were
rather low. On the other hand, 4a, which was obtained
quantitatively by reacting 3a in formic acid, could be purified
by recrystallization from 2-propanol with a satisfactory
Table 2. Results of Hydrolysis and Decarboxylation of 3a and
3b (Reaction (b))
yield
reactant product
reagent
HCO2H
4 M HCl (30 equiv) 25 °C, 15 h
in AcOEt
TFA (30 equiv)
in AcOEt
HCO2H
conditions
(%)a
3a
3a
4a
4a
80 °C, 20 min 60a, 74b
30a
42a
53a
3b
4b
60 °C, 17 h
3b
4b
25 °C, 15 h
a Isolated yield purified on preparative TLCa with an eluent of n-hexane:
AcOEt ) 4:1, or purified by recrystallization from 2-propanolb.
yield.14 These halomethyl ketones might readily decompose
on silica gel. We concluded that hydrolysis and decarboxy-
lation proceed in formic acid and the pure product can be
isolated by recrystallization. Thus, we obtained R-N-car-
bobenzyloxyaminobenzyl-R′-chloromethyl ketone in an over-
all yield of 65% from Cbz-L-phenylalanine methyl ester. We
also converted 4a into the corresponding Cbz-protected
amino epoxide in 56% yield as a single stereoisomer.
In conclusion, a practical synthesis of R-aminoalkyl R′-
halomethyl ketone derivatives via a â-ketoester was achieved.
It involves efficient cross-Claisen condensation using amino
acid derivatives and halogenation of the â-ketoester.
(10) Typical procedure: A solution of tert-butyl acetate (4.0 equiv vs
1) in THF was added dropwise to a mixture of dry THF and LDA (3.5
equiv in THF) with stirring at -45 °C. After stirring at -45 °C for 60 min,
to the mixture at a temperature under -50 °C was added dropwise a solution
of 1 in THF. The resulting mixture was stirred at -50 °C for 60 min and
was then poured into 1 M HCl and extracted with toluene, washed with
5% NaHCO3, and concentrated under reduced pressure to afford a crude
product, which was purified by column chromatography to give 2 (96.6%
1
from 1) as a colorless oil. H NMR (300 MHz, CDCl3) δ ) 1.44 (s, 9H),
2.99 (dd, 1H, J ) 7.1, 14.1 Hz), 3.17 (dd, 1H, J ) 6.1, 14.1 Hz), 3.38 (m,
2H), 4.68 (bq, 1H, J ) approximately 7 Hz), 5.07 (s, 2H), 5.38 (bd, 1H, J
) 7.9 Hz), 7.12-7.35 (m, 10H); 13C NMR (75 MHz, CDCl3) δ ) 28.0,
37.1, 48.2, 60.7, 67.0, 82.4, 127.1, 128.1, 128.2, 128.5, 128.7, 129.2, 135.8,
137.9, 165.8, 182.0, 201.7; mass (FAB) 398 (MH+).
(11) (a) Albeck, A.; Persky, R. Tetrahedron 1994, 50, 6333. (b) Chen,
P.; Cheng, P. T. W.; Spergel, S. H.; Barrish, J. C.; Thottathil, J. K.; Zahler,
R. P.; Richard, P.; Wang, X. U. S. Pat. 5,481,011, 1996. (c) Rotella, D. P.
Tetrahedron Lett. 1995, 36, 5453.
OL017163S
(12) De Kimpe, N.; De Cock, W.; Schamp, N. Synthesis 1987, 188.
(13) Typical procedure: Sulfuryl chloride (1.2 equiv) was added
dropwise to a solution of 2 in dichloromethane in an ice bath with stirring
at a temperature under 10 °C. After a reaction with stirring at 15 °C for 60
min, the resulting mixture was concentrated at 25-30 °C under reduced
pressure to give crude 3a as a pale yellowish crystal (95% determined by
HPLC). The crude material was recrystallized from toluene to give a pure
crystal (major isomer): 1H NMR (300 MHz, CDCl3) δ ) 1.44 (s, 9H),
2.99 (dd, 1H, J ) 7.5, 14.1 Hz), 3.20 (dd, 1H, J ) 6.1, 14.1 Hz), 4.85 (s,
1H), 4.97 (bq, 1H, J ) 8.4 Hz), 5.06 (s, 2H), 5.25 (bd, 1H, J ) 8.4 Hz),
7.14-7.35 (m, 10H); 13C NMR (75 MHz, CDCl3) δ ) 27.5, 37.7, 59.5,
60.0, 67.2, 85.0, 127.3, 128.1, 128.3, 128.5, 128.9, 129.2, 135.3, 136.0,
155.6, 163.1, 197.4; mass (FAB) 432 (MH+), 454 (MNa+).
(14) Typical procedure: 3a was added to 90% formic acid at 25 °C
and the suspended mixture was heated in an oil bath at 80 °C with stirring
for 20 min. The resulting mixture was cooled to 25 °C and concentrated
under reduced pressure at 30-35 °C. The residual crude material was
recrystallized from 2-propanol to afford 4a (70.3%): 1H NMR (300 MHz,
CDCl3) δ ) 3.00 (dd, 1H, J ) 7.0, 13.9 Hz), 3.09 (dd, 1H, J ) 6.9, 13.9
Hz), 3.97 (d, 1H, J ) 16.2 Hz), 4.14 (d, 1H, J ) 16.2 Hz), 4.75 (bq, 1H,
J ) approximately 7 Hz), 5.06 (s, 2H), 5.38 (bd, 1H, J ) 7.6 Hz), 7.11-
7.38 (m, 10H); 13C NMR (75 MHz, CDCl3) δ ) 37.6, 47.3, 58.7, 67.2,
127.4, 128.1, 128.3, 128.5, 128.9, 129.0, 135.2, 135.9, 155.7, 200.8; mass
(ESI) 332.2 (MH+).
Org. Lett., Vol. 4, No. 3, 2002
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