Short and versatile route to a key intermediate for lactacystin synthesis.

Article abstract of DOI:10.1021/ol027387q

[reaction: see text] A key intermediate 14 for the synthesis of lactacystin 1 has been constructed in four steps and 33% overall yield. The key steps involve cyclization of a suitably functionalized glutamic acid derivative and concomitant alkylation of the resulting beta,beta-diketoester system, C-acylation of the cyclic alpha-amidoketone 9, and decarboxylbenzylation of 12. Alkylation of a related beta,beta-diketoester 5 was additionally achieved with several electrophiles.

Full text of DOI:10.1021/ol027387q

ORGANIC
LETTERS
2003
Vol. 5, No. 3
353-355
Short and Versatile Route to a Key
Intermediate for Lactacystin Synthesis
Philip C. Bulman Page,* A. Sazali Hamzah,1 David C. Leach, Steven M. Allin,
David M. Andrews,2 and Gerasimos A. Rassias
Department of Chemistry, Loughborough UniVersity, Loughborough,
Leicestershire LE11 3TU, England
pcbpage@lboro.ac.uk
Received December 2, 2002
ABSTRACT
A key intermediate 14 for the synthesis of lactacystin 1 has been constructed in four steps and 33% overall yield. The key steps involve
cyclization of a suitably functionalized glutamic acid derivative and concomitant alkylation of the resulting â,â-diketoester system, C-acylation
of the cyclic r-amidoketone 9, and decarboxylbenzylation of 12. Alkylation of a related â,â-diketoester 5 was additionally achieved with
several electrophiles.
In 1991, Omura reported the isolation of (+)-lactacystin 1,
a novel amino acid metabolite from a Streptomyces species.3
The compound inhibits cell growth and also induces neurite
outgrowth in the murine neuroblastoma cell line (Neuro 2a),
prompting study of the usefulness of the compound in
treating neurologically related diseases such as Alzheimer’s.4
The specific target of lactacystin is the 20S proteasome,5
part of the 28 protein complex responsible for the normal
turnover of cellular proteins, the removal of damaged
proteins, and control of cell growth and metabolism.6 Due
to its unique ability to inhibit the activity of the 20S
proteasome, the compound is in great demand in many
laboratories today, and several synthetic approaches to the
the R-substituted pyroglutamic acid 2. Corey has shown that
this may be coupled with (R)-N-acetylcysteine without
hydroxy group protection in one step (Scheme 1).7
Scheme 1
7
compound have been reported and reviewed.8 This paper
reports the synthesis of a key intermediate 14 for lactacystin
synthesis in just four steps without any column chromatog-
raphy.
Retrosynthesis of lactacystin by disconnection at the thiol
ester linkage leads to the principal synthetic target molecule,
Our synthetic approach to 2 began with condensation
between N-benzyl glycine ethyl ester and benzyl malonyl
chloride to give the amide 3 in 83% yield (Scheme 2).9
Similar reaction with ethyl malonyl chloride gave the
corresponding amide 4 in 91% yield. Dieckmann cyclization
of diester 4 with sodium/methanol under reflux gave methyl
N-benzylpyrrolidin-2,4-dione 3-carboxylate 5 in 88% yield.
(1) Department of Chemistry, MARA University of Technology, 40450
Shah Alam, Selangor, Malaysia.
(2) Glaxo SmithKline, Gunnels Wood Road, Stevenage, Hertfordshire.
(3) Omura, S.; Fujimoto, T.; Otogurro, K.; Matsuzaki, K.; Moriguchi,
R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113.
(4) Hefti, F.; Weinen, W. J. Ann. Neurol. 1986, 20, 275. Dohty, P.;
Dickson, J. G.; Flanigan, T. P.; Walsh, F. S. J. Neurochem. 1985, 44, 1259.
(5) Bogyo, M.; Wang, E. W. Curr. Top. Microbiol. Immunol. 2002, 268,
185. Lee, D. H.; Goldberg, A. L. Trends Cell Biol. 1998, 8, 397.
(6) Fenteany, G.; Schreiber, S. L. J. Biol. Chem. 1998, 273, 8545.
Fenteany, G.; Standaert, R. F.; Lane, W. S.; Choi, S.; Corey, E. J.; Schreiber,
S. L. Science 1995, 268, 726. Craiu, A.; Gaczynska, M.; Akopian, T.;
Gramm, C. F.; Fenteany, G.; Goldberg, A. L.; Rock, K. L. J. Biol. Chem.
1997, 272, 13437. Fenteany, G.; Standaert, R. F.; Reichard, G. A.; Corey,
E. J.; Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3358.
10.1021/ol027387q CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/15/2003

Initial attempts using sodium/benzyl alcohol for the cycliza-
tion of 3 gave only a low yield of the pyrrolidin-2,4-dione
3-carboxylate 6 (14%), but treatment of 3 with sodium
hydride in benzene furnished 6 in 63% yield.
Scheme 3
Scheme 2
Alkylation of such â,â-diketoester systems appears to be
very uncommon in the literature. To investigate the efficiency
of the reaction, we have carried out the alkylation of this
system using several different electrophiles, using 5 as the
substrate, to give 10 as products (Scheme 4, Table).
Introduction of the required methyl group into 3-positions
of 5 and 6 proved to be extremely troublesome, as the
compounds are poorly soluble in common organic solvents.
Standard methods such as NaH/MeI, K2CO3/MeI, and
tBuOK/BuOH/MeI failed to give any of the desired methy-
lated products. Fedorynski has reported the alkylation of
malonates and related materials in good yield using potas-
sium or sodium carbonates in the presence of tetraalkylam-
monium salts or crown ethers at elevated temperatures,10 but
use of this system in acetonitrile was also unsuccessful in
our hands; the major product of treatment of methyl
pyrrolidin-2,4-dione 3-carboxylate 7 with potassium carbon-
ate and tetrabutylammonium bromide in acetonitrile under
reflux was 3,3-dimethylpyrrolidin-2,4-dione 8, presumably
formed through decarboxymethylation of the ester group.11
We had previously observed similar decarboxylation of 8
upon simple heating in acetonitrile. Fortunately, we were
able to overcome this problem by treatment of 6, 5, and 7
with tetrabutylammonium fluoride/MeI in THF solution to
give 9 (70%), 10 (R ) Me, 77%), and 11 (82%), respectively,
in very good yields (e.g., Scheme 3).
Scheme 4
We subsequently discovered that treatment of 3 with
tetrabutylammonium fluoride in ether at room-temperature
induces cyclization and enolate formation to give the enolate
of 6, which may be treated with iodomethane in THF to lead
directly from 3 to 9 in 53% yield (Scheme 5).
(7) Corey, E. J.; Li, W.-D. Z.; Nagamitsu, T.; Fenteany, G. Tetrahedron
1999, 55, 3305. Corey, E. J.; Reichard, G. A.; Li, W.-D. Z. J. Am. Chem.
Soc. 1998, 120, 2330. Corey, E. J.; Li, W.-D. Z.; Nagamitsu, T. Angew.
Chem., Int. Ed. 1998, 37, 1676. Corey, E. J.; Li, W.-D. Z. Tetrahedron
Lett. 1998, 39, 7475. Corey, E. J.; Reichard, G. A. J. Am. Chem. Soc. 1992,
114, 10677. Chida, N.; Takeoka, J.; Ando, K.; Tsutsumi, N.; Ogawa, S.
Tetrahedron 1997, 53, 16287. Chida, N.; Takeoka, J.; Tsutsumi, N.; Ogawa,
S. J. Chem. Soc., Chem. Commun. 1995, 793. Nagamitsu, T.; Sunazuka,
T.; Tanaka, H.; Omura, S.; Sprengeler, P. A.; Smith, A. B. J. Am. Chem.
Soc. 1996, 118, 3584. Sunazuka, T.; Nagamitsu, T.; Matsuzaki, K.; Tanaka,
H.; Omura, S.; Smith, A. B. J. Am. Chem. Soc. 1993, 115, 5302. Uno, H.;
Baldwin, J. E.; Russell, A. T. J. Am. Chem. Soc. 1994, 116, 2139. Kang, S.
H.; Jun, H.-S. J. Chem. Soc., Chem. Commun. 1998, 1929. Kang, S. H.;
Jun, H.-S.; Youn, J.-H. Synlett 1998, 1045. Iwama, S.; Gao, W.-G.; Shinada,
T.; Ohfune, Y. Synlett 2000, 1631. Panek, J. S.; Masse, C. E. Angew. Chem.,
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(8) Masse, C. E.; Morgan, A. J.; Adams, J.; Panek, J. S. Eur. J. Org.
Chem. 2000, 2513. Corey, E. J.; Li, W.-D. Chem. Pharm. Bull. 1999, 47,
1.
(9) Heinicke, G. W.; Morella, A. M.; Orban, J.; Prager, R. H.; Ward, A.
D. Aust. J. Chem. 1985, 38, 1847.
(10) Fedorynski, M.; Wojciechowski, K.; Matacz, Z.; Makosza, M. J.
Org. Chem. 1978, 43, 4682.
(11) Lowe, G.; Yeung, H. W. J. Chem. Soc., Perkin Trans. 1 1973, 2907.
Scheme 5
Having successfully prepared the methylated compound
9, the next step required the introduction of a methyl ester
function adjacent to the nitrogen atom by acylation at the
carbon of the corresponding enol or enolate. This carboxy-
methylation reaction also proved to be problematic because
the compound undergoes O-acylation in most reaction
systems (for example, with ethyl chloroformate using LDA,
354
Org. Lett., Vol. 5, No. 3, 2003

9 to give 12 as a 5:1 mixture of diastereoisomers, with no
competing O-acylation (Scheme 6).12 C-Acylation of 10 (R
) Me) takes place under similar conditions to give 13 in
76% yield as a 2:1 diastereoisomeric mixture.
Scheme 6
Removal of the ester benzyl group of 12 by hydrogenolysis
and concomitant decarboxylation was achieved in 20 min at
room temperature with Pd(OH)2/THF to give 14 in 95% yield
(Scheme 6). Further studies toward the elaboration of 13 and
14 for a total synthesis of lactacystin are currently under
investigation in our laboratories.
Acknowledgment. This investigation has enjoyed the
support of MARA University of Technology, Charnwood
Molecular, Ltd., and the EPSRC.
OL027387Q
NaH, KOt-Bu, or LiOt-Bu as a base). By using Mander’s
reagent, however, we were able to carry out C-acylation of
(12) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
Org. Lett., Vol. 5, No. 3, 2003
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