An enantioselective formal synthesis of the proteasome inhibitor (+)-lactacystin

Article abstract of DOI:10.1016/S0040-4039(02)01459-4

An enantioselective formal synthesis of the proteasome inhibitor (+)-lactacystin has been achieved using an alkylidene carbene 1,5-CH insertion reaction as a key step. The key cyclisation precursor was synthesised in high diastereomeric excess using a combination of known procedures, with the two key asymmetric centres being introduced via a Sharpless asymmetric epoxidation reaction. KHMDS induced 1,5-CH insertion produced a 3-pyrroline product, which was oxidised to the corresponding 3-pyrrolin-2-one using (1) TPAP/NMO; (2) NaClO₂; (3) NaBH₄. The formal synthesis was then completed with a few standard functional group interconversions.

Full text of DOI:10.1016/S0040-4039(02)01459-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6609–6611
An enantioselective formal synthesis of the proteasome inhibitor
(+)-lactacystin
Martin P. Green,a Jeremy C. Prodgerb and Christopher J. Hayesa,*
aThe School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Received 30 May 2002; accepted 12 July 2002
Abstract—An enantioselective formal synthesis of the proteasome inhibitor (+)-lactacystin has been achieved using an alkylidene
carbene 1,5-CH insertion reaction as a key step. The key cyclisation precursor was synthesised in high diastereomeric excess using
a combination of known procedures, with the two key asymmetric centres being introduced via a Sharpless asymmetric
epoxidation reaction. KHMDS induced 1,5-CH insertion produced a 3-pyrroline product, which was oxidised to the correspond-
ing 3-pyrrolin-2-one using (1) TPAP/NMO; (2) NaClO2; (3) NaBH4. The formal synthesis was then completed with a few standard
functional group interconversions. © 2002 Published by Elsevier Science Ltd.
(+)-Lactacystin (1) was isolated from the fermentation
broth of streptomyces sp. OM-6519 and first attracted
interest due to its ability to inhibit cell proliferation and
induce neurite outgrowth in the mouse neuroblastoma
cell line Neuro 2A.1 It was subsequently shown that the
20S proteasome was the cellular target of lactacystin,2
and since this discovery 1 has been used as a tool to
study proteasome function. The interesting biological
activity and intriguing chemical structure of 1 soon
stimulated interest from the synthetic organic chemistry
community. Corey and Reichard published the first
total synthesis of 1 in 19923 and their approach used
Seebach-type oxazolidine chemistry to construct the
key a,a-dialkyl-a-amino acid moiety. During the fol-
lowing year, Smith et al. published their total synthesis
of 1.4 Similarly, their route used Seebach-type chem-
istry to synthesise the a,a-dialkyl-a-amino acid moiety.
In 1994, Baldwin et al. successfully completed another
synthesis of 1 using a diastereoselective Mukaiyama-
type aldol reaction as a key step.5 Since these early
reports, a number of alternative syntheses of 1 have
been published,6 and with the exception of Chida’s and
Kang’s approaches,7 diastereoselective aldol-type reac-
tions have been employed to construct the quaternary
centre (Scheme 1).
struction of nitrogen-bearing stereocentres, and we
have shown that alkylidene carbene 1,5-CH insertion
reactions can be used for this purpose.8 As part of this
work, we recently reported our studies on the construc-
tion of 3-pyrrolines9 and we now wish to show how this
methodology can be used to complete an enantioselec-
tive formal synthesis of 1.10
OH
OH
OH
S
OH
OH
O
O
NHAc
CO2H
N
H
N
H
O
O
(+)-lactacystin 1
steps
OH
O
N
OTBS
N
H
O
OTBS
Ph
Baldwin's
3
Intermediate 2
1,5-CH insertion
OTBS
H
OTBS
KHMDS
OTBS
OTBS
HN
N
H
Over the last few years, we have been interested in the
development of methods for the enantioselective con-
4
5
Br
* Corresponding author. Tel.: +44-(0)115-951-3045; fax: +44-(0)115-
951-3564; e-mail: chris.hayes@nottingham.ac.uk
Scheme 1. Retrosynthetic analysis of (+)-lactacystin
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01459-4

6610
M. P. Green et al. / Tetrahedron Letters 43 (2002) 6609–6611
During their total synthesis of 1, Baldwin et al. showed
that the 3-pyrrolin-2-one 2 could be used as a key
synthetic intermediate. In contrast to the route chosen
by Baldwin et al., we felt that 2 could be accessed from
a suitably functionalised 3-pyrroline 3 via a few func-
tional group interconversions. Further disconnection of
3, via the alkylidene carbene 5, revealed the 1-bromo-1-
alkene 4 as a potential acyclic precursor.
Having established a reliable route to the key cyclisa-
tion precursor 4, we were now ready to examine the key
1,5-CH insertion reaction. Pleasingly, treatment of 4
with KHMDS (2 equiv.) in Et2O17 resulted in the
formation of the desired 3-pyrroline 3 as the major new
1
product (49%)9,18 (Scheme 3). Analysis of both the H
and 13C NMR spectra of this material confirmed that
only one diastereoisomer of the product had been
formed, thus showing that the 1,5-CH insertion reac-
tion had proceeded in a highly stereoselective manner.
In order to complete a synthesis of Baldwin’s intermedi-
ate 2, the last significant synthetic challenge was oxida-
In order to examine the key 1,5-CH insertion reaction,
we first had to develop an efficient synthesis of the
amine 4 (Scheme 2). Hatakeyama et al. had previously
reported the enantioselective synthesis of the oxazoline
8 and we felt that this would be an excellent precursor
to 4. Thus, the E-allylic alcohol 711 was synthesised
from isobutyraldehyde 6 with excellent stereochemical
integrity, and Sharpless asymmetric epoxidation of 7
next afforded the corresponding epoxide in high enan-
tiomeric excess (>95% ee).12 Formation of the
trichloroacetimidate 913 and Lewis acid-mediated ring
closure then afforded the oxazoline 8.14 In our hands,
the isomeric 5-membered 8 and 6-membered 10 hetero-
cycles were obtained in a 5:1 ratio during this cyclisa-
tion, but the major isomer 8 was readily separated from
10 by column chromatography and could be isolated in
70% yield as a single diastereoisomer.
tion of the 3-pyrroline
3-pyrrolin-2-one 14.
3 to the corresponding
According to our previously developed procedure, 319
was oxidised with TPAP/NMO to afford the cyclic
imine 13 (85%) and further oxidation with sodium
chlorite then afforded the N-chlorolactam 15. Due to
the instability of this material to column chromatogra-
phy, the N-chlorolactam was treated with sodium boro-
hydride and the desired 3-pyrrolin-2-one 14 could be
isolated in 73% yield for the two steps. Exposure of 14
to 1 equiv. of TBAF resulted in selective deprotection
of the primary TBS ether to afford the alcohol 16, and
aminal formation under standard conditions20 then
afforded the bicyclic lactam 17 as a single diastereoiso-
mer. TBAF-mediated deprotection of 17 produced the
desired secondary alcohol 2, whose data matched that
reported by Baldwin et al., thus completing a formal
synthesis of (+)-lactacystin 1. Studies directed at com-
pleting a new, shorter total synthesis of 1 from the
3-pyrroline intermediate 3 are currently underway, and
the results of this study will be published in due course.
Protection of the secondary hydroxyl in 8 was achieved
in near quantitative yield by exposure to TBSOTf, Et3N
in CH2Cl2, and acid-mediated hydrolysis then afforded
the amino alcohol 11 in excellent yield. Selective protec-
tion of the primary hydroxyl, and caesium hydroxide-
mediated mono-alkylation15 of the primary amine with
12 (2.3:1, E:Z)16 finally produced the desired 1,5-CH
insertion precursor 4 as a 2.3:1 mixture of E:Z isomers.
O
a, b
a
b
OH
4
3
H
OTBS
OTBS
N
13
7
6
c, d
c
OH
O
e
O
d
O
OTBS
OTBS
N
OTBS
OTBS
O
O
N
N
H
HN
CCl3
9
CCl3
Cl
15
8
f, g
14
OTBS
OH
e
OH
NH2
11
N
O
f
g
OTBS
O
2
h, i
Br
Br
OTBS
N
CCl
10
3
O
N
H
12
O
Ph
HO
4
17
16
Scheme 2. Reagents and conditions: (a) (EtO)2P(O)-
CH2CO2Et, NaH, THF, 0°C (97%); (b) DIBAL-H, THF,
Scheme 3. Reagents and conditions: (a) KHMDS (0.5 M in
PhMe, 2 equiv.), Et2O (49%); (b) TPAP, NMO, MeCN
(85%); (c) NaClO2, NaH2PO4, tBuOH/H2O; (d) NaBH4,
MeOH (73%, two steps); (e) TBAF, THF (87%); (f)
PhCH(OMe)2, TsOH, PhMe, D (67%); (g) TBAF, THF
(66%).
t
−78°C (62%); (c) Ti(iPrO)4, (+)-DET, BuOOH (in PhMe),
DCM, −20°C (94%); (d) Cl3CCN, DBU, DCM, 0°C (90%);
(e) Et2AlCl, DCM, −10°C (70% 8); (f) TBSOTf, Et3N, DCM,
0°C (98%); (g) HCl (2 M), THF, rt (97%); (h) TBSOTf, Et3N,
DCM, 0°C (73%); (i) CsOH·H2O, 12, DMF (72%).

M. P. Green et al. / Tetrahedron Letters 43 (2002) 6609–6611
6611
Acknowledgements
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The Authors thank the EPSRC (GR/M74696) and
GlaxoSmithKline for generous financial support.
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