A short preparation of an advanced intermediate for lactacystin synthesis: The complete carbon skeleton of clasto-lactacystin dihydroxyacid

Article abstract of DOI:10.1055/s-2003-39290

An advanced intermediate 22 for lactacystin synthesis, containing the full carbon skeleton of the pyrrolidinone component, has been achieved in four steps from a protected glycine ester.

Full text of DOI:10.1055/s-2003-39290

LETTER
1025
A Short Preparation of an Advanced Intermediate for Lactacystin Synthesis:
The Complete Carbon Skeleton of Clasto-Lactacystin Dihydroxyacid
T
he Complete
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C
arbonSkel
i
e
ton of
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Clasto
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ystin
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ihydroxyac
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id . Bulman Page,* David C. Leach, Colin M. Hayman, A. Sazali Hamzah,1 Steven M. Allin, Vickie McKee
Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
Fax +44(1509)223926; E-mail: p.c.b.page@lboro.ac.uk
Received 26 March 2003
pared by condensation of a protected glycine ester 7 with
Abstract: An advanced intermediate 22 for lactacystin synthesis,
containing the full carbon skeleton of the pyrrolidinone component,
has been achieved in four steps from a protected glycine ester.
activated malonate 8. We anticipated that a blocking
group X would be required at position C-3 of 5 to avoid
problems during the subsequent aldol or other enolate re-
actions, and an ester moiety was chosen for this purpose
as this would aid pyrrolidinone formation and would be
potentially removable by subsequent decarboxylation
(Scheme 1).
Key words: lactacystin, clasto-lactacystin, Dieckmann, acylation
(+)-Lactacystin (1) is a microbial metabolite isolated by
Omura from the culture broth of a Streptomyces species.2
It inhibits cell growth and induces neurite outgrowth in
the murine neuroblastoma cell line (Neuro 2a), and this
property has prompted study of the utility of the com-
pound in treating neurologically-related diseases, includ-
ing Alzheimer’s.3 (+)-Lactacystin is a uniquely selective
and powerful inhibitor of the 20S proteasome,4 which is
part of a 28-protein complex that is involved in control-
ling cell growth and metabolism, and which is responsible
for the normal turnover of cellular proteins and the remov-
al of damaged proteins.5 As a result, lactacystin is in de-
mand in many laboratories; a number of synthetic
approaches to the compound have been reported,6,7 and
the synthetic work has been reviewed.8 The b-lactone 2,
known as clasto-lactacystin b-lactone (omuralide), into
which lactacystin is converted in vivo prior to hydrolysis
to clasto-lactacystin dihydroxyacid, is the active mole-
cule, and also inhibits the 20S proteasome (Figure 1).
Scheme 1
Figure 1
After some experimentation, benzyl groups were chosen
for the protecting groups of 7 and 8. Benzyl malonyl
chloride (11) was generated by careful partial hydrolysis
of commercial dibenzyl malonate (9) followed by treat-
ment with oxalyl chloride. N-Benzyl glycine ethyl ester
(13) is commercial but expensive, but can be easily pre-
pared from a condensation of ethyl bromoacetate (12)
and benzylamine.10 The precursor 14 to the Dieckmann
cyclization (Scheme 2) was prepared by condensation of
benzyl malonyl chloride 11 with N-benzyl glycine ethyl
ester (13) in 95% yield.
Our approach to the synthesis of lactacystin involves a
new route to the advanced intermediate 3,9 from which the
natural product can be obtained in two steps by a docu-
mented procedure.6 We first envisaged an aldol condensa-
tion of 4 to form the C-5 quaternary centre of 3; reduction
of the b-keto ester 5 would provide the b-hydroxyester 4.
The pyrrolidinone ring would be formed by a Dieckmann
cyclization of the diester 6, which would in turn be pre-
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,1025,1027,ftx,en;D07003ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1026
P. C. B. Page et al.
LETTER
Scheme 4
We were unable to achieve the envisaged aldol condensa-
tion with 18 to form the C-5 quaternary centre. Using
isobutyraldehyde under various conditions including
Mukaiyama’s protocol failed in our hands.12 Having suc-
cessfully C-alkylated 16 with methyl cyanoformate, we
attempted acylation with isobutyryl cyanide,13 but no re-
action was observed. Attempted acylations using Katritz-
ky’s benzotriazole procedure also gave no reaction.14
Acylation of 18 with isobutyryl chloride, however, gave
rise exclusively to 19 through O-acylation, in 68% yield.
Attempted hydrogenolysis and decarboxylation of the
benzyl ester of 19 over palladium with concomitant hy-
drogenation of the enol ether double bond gave only 20,
in which the enol ether is still intact but the benzyl ester
had been removed, in 98% yield (Scheme 5).
Scheme 2
The Dieckmann cyclization proved problematic under
standard conditions, but was found to be successful using
TBAF, producing the tetrabutylammonium salt 15. This
compound can be treated in situ with methyl iodide to pro-
duce 16 in 73% yield from 14, together with the regioiso-
mer 17 as an easily separable 3.5:1 mixture (Scheme 3). It
is pleasing to note that this is the first stage where purifi-
cation by column chromatography is required.
Scheme 5
O-Acylation is therefore feasible. Similar introduction of
an allyl substituent could give either O-alkylation or C-
alkylated compound 21.
Scheme 3
Addition of the C-5 ester functionality was achieved using
Mander’s protocol: generation of the enolate from 16 us-
ing LHMDS in THF in the presence of DMPU was fol-
lowed by addition of methyl cyanoformate to give 18 in
70% yield (Scheme 4).11 This short sequence provides the
pyrrolidinone ring, the C-5 ester unit, and the C-3 methyl
group along with a blocking group at the same position in
the form of a benzyl ester labile towards hydrogenolysis
and decarboxylation.
Scheme 6
Synlett 2003, No. 7, 1025–1027 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
The Complete Carbon Skeleton of Clasto-Lactacystin Dihydroxyacid
1027
(6) (a) Corey, E. J.; Li, W.-D. Z.; Nagamitsu, T.; Fenteany, G.
Tetrahedron 1999, 55, 3305. (b) Corey, E. J.; Reichard, G.
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Int. Ed. 1998, 37, 1676. (d) Corey, E. J.; Li, W.-D. Z.
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Tsutsumi, N.; Ogawa, S. J. Chem. Soc., Chem. Commun.
1995, 793. (c) Nagamitsu, T.; Sunazuka, T.; Tanaka, H.;
Omura, S.; Sprengeler, P. A.; Smith, A. B. J. Am. Chem. Soc.
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Matsuzaki, K.; Tanaka, H.; Omura, S.; Smith, A. B. J. Am.
Chem. Soc. 1993, 115, 5302. (e) Uno, H.; Baldwin, J. E.;
Russell, A. T. J. Am. Chem. Soc. 1994, 116, 2139. (f)Kang,
S. H.; Jun, H.-S. Chem. Commun. 1998, 1929. (g) Kang, S.
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38, 1093.
Testing the reaction by deprotonation with sodium hy-
dride in DMF at room temperature followed by addition
of allyl bromide gave exclusively C-allylated compound
21 in 44% yield. To our delight, repeating the reaction
with methallyl bromide gave the analogous compound 22
in 75% yield (Scheme 6),15 the structure of which was
confirmed by single crystal X-ray diffraction.16 A com-
pound containing all of the carbon atoms present in the
carbon skeleton of clasto-lactacystin dihydroxyacid, suit-
ably functionalized for further elaboration, has thus been
constructed in only four steps from glycine ester. We have
further shown that hydrogenolysis of 22 gives rise as ex-
pected to decarboxylation in situ, with concomitant reduc-
tion of the double bond, to give 23 in 90% yield
(Scheme 7).
(8) (a) Masse, C. E.; Morgan, A. J.; Adams, J.; Panek, J. S. Eur.
J. Org. Chem. 2000, 2513. (b) Corey, E. J.; Li, W.-D. Chem.
Pharm. Bull. 1999, 47, 1.
(9) Page, P. C. B.; Hamzah, A. S.; Leach, D. C.; Allin, S. M.;
Andrews, D. M.; Rassias, G. A. Org. Lett. 2003, 353.
(10) Kruijtzer, J. A. W.; Hofmeyer, L. J. F.; Heerma, W.;
Versluis, C.; Liskamp, R. M. J. Chem.–Eur. J. 1998, 4, 1570.
(11) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
(12) Mukaiyama, T.; Bonno, K.; Naraska, K. J. Am. Chem. Soc.
1974, 96, 7503.
Scheme 7
Acknowledgment
(13) Howard, A. S.; Meerholz, C. A.; Michael, J. P. Tetrahedron
Lett. 1979, 20, 1339.
This investigation has enjoyed the support of the EPSRC and
Charnwood Molecular Ltd.
(14) Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000, 65, 3679.
(15) Analytical data of compound 22: Colorless powder, 1:1
mixture of diastereoisomers, mp 109 °C. (Found: C,
69.26%; H, 5.98%; N, 3.10%. C26H27NO6 requires C,
69.47%; H, 6.05%; N, 3.12%). IR(nujol): nmax = 1778, 1748,
1698 cm–1. [Found (M+): 449.18307. C26H27NO6 requires
449.18384]. MS: m/z (%) = 449 (2) [M+], 394 (8), 314 (3),
91 (100), 65 (3). 1H NMR (400 MHz, CDCl3): d = 1.48 (3 H,
s), 1.59 (3 H, s), 1.69 (3 H, s, major), 1.72 (3 H, s, minor),
2.67 (3 H, s, major), 2.77–2.96 (4 H, m, major + minor), 3.11
(3 H, s, minor), 4.03 (1 H, d, J = 15.2 Hz, major), 4.18 (1 H,
d, J = 15.2 Hz, minor), 4.51 (1 H, bs, minor), 4.56–4.57 (1
H, m, minor), 4.67 (1 H, br s, major), 4.97–4.98 (1 H, m,
major), 5.06 (1 H, d, J = 12.4 Hz, minor), 5.14 (1 H, d,
J = 12.4 Hz, major), 5.12–5.25 (1 H, m, minor), 5.12–5.25 (1
H, m, minor), 5.24 (1 H, d, J = 12.4 Hz, major), 5.36 (1 H,
d, J = 15.2 Hz, major), 7.17–7.35. 13C NMR ( 100 MHz,
CDCl3): d = 17.35 (major), 19.19 (minor), 23.73 (minor),
24.45 (major), 36.92 (major), 37.81 (minor), 44.47, 44.55,
52.19, 52.84 (OCH3, minor), 57.59, 57.97, 68.11, 68.28,
76.11, 75.85, 118.21(minor), 118.78(major), 127.68,
127.94, 128.26, 128.29, 128.31, 128.48, 128.51, 128.53,
128.58, 128.63, 128.75, 129.08, 134.82, 135.15, 135.39,
137.83, 138.15, 164.84, 165.09, 166.72, 167.15, 170.62,
170.89, 199.95, 200.22.
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the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK, fax: +44(1223)336033,
deposit@ccdc.cam.ac.uk, quoting the deposition number
CCDC 206650.
Synlett 2003, No. 7, 1025–1027 ISSN 1234-567-89 © Thieme Stuttgart · New York