New synthetic route to access (±) salinosporamide A via an oxazolone-mediated ene-type reaction

Article abstract of DOI:10.1016/j.tetlet.2008.10.154

We report herein a racemic key intermediate in the synthesis of salinosporamide A via a tert-alkyl amino hydroxy carboxylic ester produced in an ene-type reaction of an oxazolone with an enol ether.

Full text of DOI:10.1016/j.tetlet.2008.10.154

Tetrahedron Letters 50 (2009) 295–297
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New synthetic route to access ( ) salinosporamide A via an oxazolone-mediated
ene-type reaction
*
Robert A. Mosey, Jetze J. Tepe
Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein a racemic key intermediate in the synthesis of salinosporamide A via a tert-alkyl amino
hydroxy carboxylic ester produced in an ene-type reaction of an oxazolone with an enol ether.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 27 October 2008
Accepted 30 October 2008
Available online 11 November 2008
Cultivation and characterization of salinosporamide A (1, Fig. 1)
by Fenical et al. in 20031 have led to many syntheses of the natural
product and structurally related analogues.2–16 The natural prod-
uct, as well as some analogues, has been shown to inhibit the
26S proteasome, which is an emerging area in anticancer ther-
apy.17–19 The structure of salinosporamide A comprises a bicylic
core, composed of a pyrrolidinone and a b-lactone, which is critical
for its biological activity1,20 and is similar to the biologically active
terrestrial microbial product omuralide (2).21 Many of the struc-
tural features necessary for activity of compounds in this class
have been identified through structure-activity relationships, nat-
ural product analogues (e.g., 3 and 4, Fig. 1), and X-ray crystallog-
raphy.12,22 Even though many elegant syntheses2–16 have been
reported of this intriguing class of proteasome inhibitors, its poten-
tial clinical relevance warrants the development of new ap-
proaches that may provide access to additional candidates.
Recently, we reported the diastereoselective synthesis of tert-
alkyl amino hydroxy carboxylic esters by means of a sequential
ene-type reaction of oxazolones with enol ethers followed by hy-
dride reduction (Fig. 2).23,24 This new reaction allowed the con-
struction of compounds with high diversity depending on the
nature of the oxazolone and enol ether used.25
The functionalities surrounding the quaternary stereocenter
formed in this reaction are also represented at the C4 center in sal-
inosporamide A (Fig. 1). To the best of our knowledge, this center
has never been constructed via an oxazolone intermediate and
may be a useful means to incorporate a wide range of diversities
into the pyrrolidinone skeleton. The total synthesis of salinospora-
mide A by Corey and co-workers involves the construction of piv-
otal intermediate 5, which undergoes cyclization via a Baylis–
Hillman-aldol reaction to give the core pyrrolidinone scaffold.16
This key intermediate could be readily accessed using our chemis-
try after a few functional group modifications. Due to the skeletal
diversity afforded by the use of various enol ethers in the afore-
mentioned ene-type reaction, this could potentially serve as a
H
R1
O
H
O
N
O
H
N
OH
O
O
O
N
R5
R4
OH
O
R1
O
R2
O
R3O
O
R2
R5
Me
N
O
Cl
ene-type
reaction
1: Salinosporamide A
2: omuralide
R3O
R1
R4
NaBH4
OH
H
O
H
N
O
N
OH
OH
O
OH
O
N
R2
O
O
Me
3
Me
Cl
4
O
R5
R2
R4
R1
N
H
Figure 1. Natural proteasome inhibitors and their synthetic analogues.
OR3
* Corresponding author. Tel.: +1 517 355 9715; fax: +1 517 353 1322.
E-mail address: tepe@chemistry.msu.edu (J. J. Tepe).
Figure 2. Intermolecular ene-type reaction utilizing oxazolones and enol ethers
followed by reduction.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.154

296
R. A. Mosey, J. J. Tepe / Tetrahedron Letters 50 (2009) 295–297
hydroxy carboxylic ester 6 as a 3:1 mixture of diastereomers in
MeO
CO2Me
OBn
H
O
88% yield (Scheme 2).23 The synthesis of 5 was continued using
only the major diastereomer as indicated in Scheme 3. However,
it should be noted that both diastereomers could be used to com-
plete the racemic synthesis of salinosporamide A due to the
destruction of the second stereocenter during the oxidation of
alcohol 11 (or 12) (Scheme 3).
PMB
N
H
N
O
O
O
OH
O
O
N
O
R1
5: R1=Me
CO2Me
R1
R1
RO
Cl
The synthesis of 5 continued with the reduction of the amide
functionality present in the tert-alkyl amino hydroxy carboxylic es-
ter 6. This reduction was performed smoothly via dehydrative
cyclization under basic conditions with MsCl followed by oxazoline
reduction with sodium cyanoborohydride in acetic acid to afford
amino alcohol 8 (Scheme 3). This transformation accomplished
two goals in our synthesis: (1) the reduction of a stable amide in
the presence of an ester, a feat we found to be unsuccessful under
a variety of attempted conditions and (2) the protection of the
amine as a PMB amine. The resultant primary alcohol was pro-
tected under basic conditions with benzyl bromide to give benzyl
ether 9, and acylation of the secondary amine with acrylyl chloride
under Corey’s conditions16 gave amide 10 in 94% yield. Deprotec-
tion of the tert-butyl ether in 10 under acidic conditions proved
to be problematic.
The reaction was often messy and low yielding, as treatment
with TFA or aqueous phosphoric acid gave 25% and 27% yields,
respectively, of alcohol 11 as a single diastereomer. Finally, oxida-
tion of the free alcohol was performed using the reported proce-
dure to cleanly afford racemic ketone 5, the spectroscopic data of
which matched with those of the known compound. The disap-
pointing yields obtained from the deprotection of the tert-butyl
ether prompted investigation into its removal in an earlier stage
of the synthesis.
Scheme 1. Strategy for the synthesis of 5 and analogues of 1.
strategy for the synthesis of C3 analogues of 1 (Scheme 1). We
sought Corey’s intermediate 5,16 then, as our target to demonstrate
the utility of quaternary centers produced via oxazolones in the
synthesis of natural products.
The starting material for our synthesis of 5 was obtained
through our ene-type reaction/reduction protocol to yield amino
MeO
MeO
OtBu
O
O
O
O
N
(PhO)2PO2H (10%)
benzene, rt
N
CO2Me
Me
CO2Me
tBuO
NaBH4
OH
O
CO2Me
Me
N
Access to 5 involved modification of alcohol 12 in the original
synthesis, which could be accessed in our synthesis as well. Depro-
tection of the tert-butyl ether in compound 9 could be performed
by treatment with aqueous phosphoric acid26 to afford secondary
alcohol 12 in near quantitative yield, thereby granting access to de-
sired compound 5.
OtBu
H
MeO
6 (major
diastereomer)
Scheme 2. Synthesis of 6 via an oxazolone-mediated ene-type reaction.
OH
MeO
O
CO2Me
Me
PMB
HN
N
H
NaCNBH3, AcOH
rt, 40 h
CO2Me
O
CO2Me
OH
MsCl, TEA
DCE, reflux, 4 h
OtBu
MeO
N
92%
73%
tBuO
Me
tBuO
Me
6
8
7
BnBr, NaH
DMF, rt,
0.25 h
96%
O
PMB
N
PMB
N
PMB
CO2Me
CO2Me
OBn
H3PO4(aq)
O
CO2Me
OBn
O
Cl
iPr2NEt, 0 oC, 4.5 h
94%
tBuO
CH2Cl2
HN
OBn
rt, 20 h
27%
HO
Me
Me
tBuO
Me
11
10
9
H3PO4(aq)
CH2Cl2
as described in
ref. 16
rt, 6 h
98%
PMB
CO2Me
OBn
PMB
HN
O
N
CO2Me
OBn
as described in
ref. 16
O
Me
HO
Me
5
12
Scheme 3. Synthesis of Corey’s intermediate 5.

R. A. Mosey, J. J. Tepe / Tetrahedron Letters 50 (2009) 295–297
297
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In conclusion, we report a short racemic synthesis of an inter-
mediate used in the synthesis of salinosporamide A starting from
a tert-alkyl amino hydroxy carboxylic ester produced via an ene-
type reaction.
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Acknowledgments
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We gratefully acknowledge the financial support provided by
American Cancer Society (RSG CDD-106972) and Michigan State
University. Additional thanks goes to Mr. Rahman Saleem from
Michigan State University for high resolution mass spectrometry.
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Supplementary data
Experimental procedures, IR, 1H, and 13C NMR data for all new
compounds. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.10.154.
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