Formal synthesis of salinosporamide a starting from D-glucose

Article abstract of DOI:10.1055/s-0029-1216927

A formal synthesis of salinosporamide A is described. The tertiary alcohol function in salinosporamide A was stereoselectively generated via the substrate control by the reaction of a cyclic ketone derived from D-glucose with Me3Al, and subsequent Overman rearrangement of an allylic trichloroacetimidate effectively constructed the tetrasubstituted carbon with nitrogen. Formation of g-lactam, followed by the introduction of a cyclohexenyl unit furnished the Corey's intermediate of salinosporamide A. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216927

PAPER
2983
Formal Synthesis of Salinosporamide A Starting from D-Glucose
F
ormal Synthes
a
is of Salino
k
sporamide
A
ayuki Momose, Yuji Kaiya, Jun-ichi Hasegawa, Takaaki Sato, Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Fax +81(45)5661551; E-mail: chida@applc.keio.ac.jp
Received 19 July 2009
Our previous total syntheses of lactacystin7a,b (3), (+)-
Abstract: A formal synthesis of salinosporamide A is described.
myriocin7c,e (4), and (–)-sphingofungin E7d,e (5) starting
The tertiary alcohol function in salinosporamide A was stereoselec-
from aldohexoses revealed that the methodology involv-
tively generated via the substrate control by the reaction of a cyclic
ing Overman rearrangement8 on sugar scaffolds, followed
ketone derived from D-glucose with Me3Al, and subsequent Over-
man rearrangement of an allylic trichloroacetimidate effectively by further manipulation by use of the residual functional
constructed the tetrasubstituted carbon with nitrogen. Formation of
groups in sugars, is effective for the chiral synthesis of
g-lactam, followed by the introduction of a cyclohexenyl unit fur-
natural products possessing complex a-substituted a-ami-
nished the Corey’s intermediate of salinosporamide A.
no acid structures.7 These successful results led us to
apply a similar methodology to the synthesis of
salinosporamide A starting from carbohydrates. Our ret-
Key words: stereoselective synthesis, carbohydrates, chiral pool,
rearrangements, pericyclic reactions
rosynthetic analysis, taking into account previous suc-
cessful total syntheses by Corey,6a,c Pattenden,6d,i and
Hayakeyama,6j suggested that the Corey’s intermediate
66a would be a suitable target molecule (Scheme 1). Com-
pound 6 was expected to be prepared by the reaction of al-
dehyde 7 with cyclohex-2-enylzinc reagent following the
Corey’s procedure.6a The formation of the g-lactam skel-
eton in 7 was planned by conversion of hemiacetal 8 to
hemiaminal, followed by oxidation. The tetrasubstituted
carbon with nitrogen in 8 was envisioned to be generated
by Overman rearrangement of allylic trichloroacetimidate
9.9 The compound 9, in turn, was planned to be synthe-
sized from the known furanose derivative 1110 via diol 10.
The stereoselective construction of the tertiary alcohol
function in 10 would also be an important task.
Salinosporamide A (1, Figure 1), isolated by Fenical and
co-workers in 2003 from the marine bacterium Salinospo-
ra tropica,1 is a highly potent inhibitor of the 20S protea-
some, and recently expected to be a promising anticancer
therapeutic agent.2 The structure of salinosporamide A, a
highly functionalized g-lactam bearing a tetrasubstituted
carbon with nitrogen (a-substituted a-amino acid struc-
ture), is structurally related to omuralide (2) and
lactacystin3 (3), which are also known as potent useful co-
valent inhibitors of proteasome function. The important
biological activities4 as well as intriguing structures of
these natural products have naturally received consider-
able attention from the synthetic community, and a num-
ber of synthetic studies and total syntheses have been
reported to date.5,6 In this paper, we disclose a formal syn-
thesis of salinosporamide A starting from D-glucose.
H
Cbz
H
N
CHO
CO2Me
OTMS
OH
N
O
O
H
CO2Me
1
OH
H
N
H
N
H
N
OH
O
OH
O
OH
S
BnO
O
O
O
HO
Corey's intermediate 6
7
O
O
O
CO2H
OH
AcHN
CCl3
Cl
HO
O
salinosporamide A (1) omuralide (2)
lactacystin (3)
PMBO
O
HN
O
NHCbz
OH
R
H2N
HOH2C
HO2C
OH
OTMS
BnO
BnO
9
8
OH
O
R = H: myriocin (4)
R = OH: sphingofungin E (5)
O
O
H
PMBO
O
Figure 1 Structures of representative natural products possessing a-
substituted a-amino acid structures
O
diacetone-D-
glucose
O
OH
O
OH
10
SYNTHESIS 2009, No. 17, pp 2983–2991
Advanced online publication: 07.08.2009
x
x.
x
x
.
2
0
0
9
BnO
HO
11
DOI: 10.1055/s-0029-1216927; Art ID: C03109SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis of salinosporamide A

2984
T. Momose et al.
PAPER
Protection of a primary alcohol in the known compound the axial oxygen and the imino nitrogen would also render
11, that was prepared from diacetone-D-glucose in 4 step the TS-b less favorable. On the other hand, the TS-a that
reactions,10 afforded 12 in 90% yield (Scheme 2). The generates 23, has the similar gauche interactions between
exocyclic acetonide was selectively cleaved to give diol an equatorial methyl group at C-4 and the imino nitrogen,
13 in 93% yield, whose primary hydroxy group was con- however, does not suffer repulsive electronic interactions
verted into a TBS ether, and the secondary one was pro- between the OTMS group and the nitrogen.
tected as a p-toluenesulfonyl ester to give 15 in 80% yield
from 13. Hydrolysis of the remaining acetonide group,
O
O
followed by glycol cleavage afforded pyranose derivative
16, which was then transformed into PMB b-glycoside via
an a-trichloroacetimidate intermediate.11 Removal of the
O-formyl group provided the properly protected PMB
pyranoside 17 in 79% overall yield from 15. Oxidation of
17 with DMSO–Ac2O12 afforded ketone 18 (90% yield),
which was then reacted with Me3Al in toluene at –40 to
–5 °C to give tertiary alcohol 19 as the sole product in
88% yield. The substrate control, namely, the presence of
bulky neighboring substituents (alkyl side chain and OTs
groups) to the ketone carbonyl would be responsible for
the observed high stereoselectivity. The structure of com-
H
O
H
O
known
4 steps
O
O
3a
5
6
b
3
O
O
(ref. 10)
6a
HO
O
O
1
diacetone-D-
glucose
RO
a
11: R = H
12: R = Bn
OR2
H
R1O
O
HO
O
3a
5
6
3
e
f,g
O
6a
BnO
OTs
O
1
OCHO
BnO
1
pound 19 was confirmed by H NMR analyses; the ob-
13: R1 = R2 = H
14: R1 = TBS, R2 = H
15: R1 = TBS, R2 = Ts
16
c
served large coupling constants (J2ax,3 and J5,6) revealed
that 19 has a chair conformation and the substituents on C-
3, C-5 and C-6 are all in the equatorial positions, and the
observed NOEs between C-4 methyl and H-3, and those
between C-4 methyl and H-5 clearly assigned the stereo-
chemistry of the tertiary alcohol at C-4 as S. The tosyl
group in 19 was then deprotected by the action of Mg in
MeOH13 to give 10 in 81% yield. Oxidation of the second-
ary alcohol afforded ketone 20 (73% yield), whose
Horner–Wadsworth–Emmons reaction, followed by sily-
lation of a tertiary alcohol function provided E-alkene 21
as a single isomer in 84% yield. The E-geometry of the
double bond in 21 was confirmed by the observed NOEs
between a vinyl proton and C-4 methyl, as well as methyl
groups in OTMS. Reduction of the ester function in 21
with DIBAL-H smoothly gave primary alcohol 22 in 97%
yield, which was converted into trichloroacetimidate 9 by
the action of trichloroacetonitrile and DBU (97% yield)
(Scheme 3). When imidate 9 was heated in tert-butylben-
d
PMBO
O
PMBO
O
2
2
3
6
6
5
h
i
5
3
4
4
BnO
OTs
BnO
OTs
O
OH
17
18
PMBO
O
2
BnO
Me
OH
6
H
6
H
2
5
3
5
4
OPMB
BnO
OR
3
TsO
O
OH
H
H
J5,6 = 8.4 Hz
J2ax,3 = 9.9 Hz
19: R = Ts
10: R = H
j
: NOE
selected NMR data of 19
k
PMBO
O
PMBO
O
2
l,m
4
CO2Et
5
BnO
O
BnO
14
zene at 150 °C in the presence of Na2CO3 in a sealed
OH
OTMS
tube for 2 days, the crucial Overman rearrangement suc-
cessfully took place to provide rearranged products, 23
and epi-23 in 69% and 16% isolated yields from 22, re-
spectively. The structure of the major rearranged product
23 was confirmed by NOE experiments as shown in
Scheme 3; especially the observed NOEs between a vinyl
proton and H-2, and those between NH and C-4 methyl
clearly revealed that the newly formed tetrasubstituted
carbon in 23 has an S-configuration. The steric and elec-
tronic factors might account for the observed stereoselec-
tivity (23/epi-23 = 4.3:1). There would be two plausible
chair-like transition models in the Overman
rearrangement8a of 9, TS-a and TS-b, where the tetrahy-
dropyran rings adopt the stable chair conformation
(Figure 2). In TS-b, which gives rise to epi-23, an axially
oriented OTMS group at C-4 would hinder the attack of
the imino nitrogen from the upper side, and the electro-
static repulsion (and/or dipole-dipole interaction) between
20
21
Scheme 2 Synthesis of intermediate E-alkene 21. Reagents and
conditions: (a) BnBr, NaH, DMF, 90%; (b) AcOH–H2O (4:1), 50 °C,
93%; (c) TBSCl, Et3N, DMAP, CH2Cl2, 96%; (d) TsCl, Et3N, DMAP,
CH2Cl2, 83%; (e) aq 6 M HCl, THF, then NaIO4, aq THF, 96%; (f)
Cl3CCN, DBU, CH2Cl2, then PMBOH, TMSOTf, CH2Cl2; (g)
K2CO3, MeOH, 82% from 15; (h) Ac2O, DMSO, 50 °C, 90%; (i)
Me3Al, toluene, –40 to –5 °C, 88%; (j) Mg, MeOH, 81%; (k) SO3·py,
DMSO, Et3N, 73%; (l) (EtO)2P(O)CH2CO2Et, NaH, THF, 96%; (m)
TMSOTf, py, CH2Cl2, 87%.
CCl3
OTMS
OTMS
H
PMBO
PMBO
O
4
O
4
N
5
5
BnOCH2CH2
BnOCH2CH2
O
O
H3C
H3C
N
H
CCl3
TS-a
TS-b
Figure 2 Transition models of Overman rearrangement of 9
Synthesis 2009, No. 17, 2983–2991 © Thieme Stuttgart · New York

PAPER
Formal Synthesis of Salinosporamide A
2985
COCCl3
PMBO
O
HO
O
a
c
b
N
21
9
HO
b
NHCOCCl3
a
CH2OH
PMBO
BnO
23
CH2OH
OH
X
BnO
OTMS
22
OTMS
BnO
24
25
BnO
PMBO
O
O
2
6
5
NHCOCCl3
NHCOCCl3
3
4
PMBO
O
+
2
6
a,b
c
NHCbz
5
3
8
OTMS
23
OTMS
epi-23
4
or d
BnO
OTMS
26
BnO
BnO
OTMS
H
5 H
6
H
Cbz
N
Cbz
OPMB
Me
2
O
HO
N
2
H
O
H
e
f,g
5
CH2OH
OH
CHO
OH
HN
4
COCCl3
: NOE
3
J5,6 = 11.4 Hz
BnO
BnO
Scheme 3 Formation of 23 and epi-23 from 21. Reagents and con-
ditions: (a) DIBAL-H, toluene, –50 °C, 97%; (b) Cl3CCN, DBU,
CH2Cl2, 97%; (c) Na2CO3, tert-butylbenzene, 150 °C, in a sealed
tube, 2 d, 85% from 22 (23: 69%, epi-23: 16%).
27
28
Cbz
Cbz
N
CHO
N
2
3
O
O
i
j
5
CO2Me
OR
CO2Me
4
With rearranged product 23 in hand, we turned our atten-
tion to conversion of 23 to Corey’s intermediate 6
(Scheme 4). Treatment of 23 with DDQ smoothly afford-
ed hemiacetal 24, however, attempted conversion of 24 to
hemiaminal 25 by the treatment with TBAF or TFA
proved unsuccessful. This result led us to exchange the
protecting group of the nitrogen. The trichloroacetyl
group in 23 was removed by the action of DIBAL-H7d,e
and the resulting amine was protected with CbzCl to give
26 (ca. 100% yield for 2 steps). Removal of the PMB
group in 26 with DDQ, and subsequent treatment with
TBAF afforded 8, which spontaneously turned into 5-
membered hemiaminal 27 under the reaction conditions
(67% yield from 26). Alternatively, 27 was also obtained
in 96% yield in one step by the treatment of 26 with aque-
ous TFA in CH2Cl2 at 0 °C. Jones oxidation of hemiami-
nal 27 afforded g-lactam aldehyde 28 in 67% crude yield.
It is interesting to note that aldehyde 28 did not undergo
further oxidation to carboxylic acid under the conditions
of Jones oxidation; the severe steric hindrance around the
aldehyde carbonyl group would inhibit the formation of a
bulky chromate ester. Fortunately, aldehyde 28 could be
oxidized by NaClO2, and the product was esterified to
OTMS
BnO
BnO
7
29: R = H
h
30: R = TMS
H
H
Cbz
H
N
OH
k
2
OH
CO2Me
N
O
O
5
CO2Me
4
3
OH
OTMS
HO
6
BnO
31
(Corey's intermediate)
known
3 steps
(refs. 6a, 6i, 6j)
salinospramide A (1)
Scheme 4 Synthesis of Corey’s intermediate 6. Reagents and con-
ditions: (a) DDQ, aq CH2Cl2; (b) TBAF, THF; (c) DIBAL-H, toluene,
–78 °C, then CbzCl, EtOAc, 0.5 M aq NaOH, 100%; (d) TFA–H2O
(4:1), CH2Cl2, 0 °C, 96%; (e) Jones reagent, aq acetone, 0 °C; (f)
NaClO2, NaH2PO4, 2-methylbut-2-ene, aq t-BuOH; (g) MeI, K2CO3,
DMF, 44% from 26; (h) TMSOTf, py, CH2Cl2, 98%; (i) OsO4, NaIO4,
py, 1,4-dioxane, 60 °C, 62%; (j) cyclohex-2-eneylzinc chloride, THF,
provide methyl ester 29 in 44% overall yield from 26. Pro- –78 °C, 90%; (k) BCl3, CH2Cl2, 0 °C, then MeOH, 78%.
tection of a tertiary alcohol in 29 afforded 30 in 98% yield.
Oxidative cleavage of the vinyl function in 30 with OsO4
Corey,6a Pattenden,6i and Hatakeyama,6j the synthesis of 1
and NaIO415 gave aldehyde 7 in 62% yield. Reaction of 7
in the formal sense has been accomplished.
with cyclohex-2-enylzinc chloride as described by the
Corey group6a gave 31 as the sole product in 90% yield.
Finally, deprotection of Cbz, Bn, and TMS groups in 31
by treatment with BCl3 furnished Corey’s intermediate 6
in 78% yield. The spectral (1H and 13C NMR) data as well
as the [a]D value of the synthetic specimen showed a good
accord with those reported by Hatakeyama.6j Since the
three-steps conversion of compound 6 into salinospor-
amide A (1) has already been described by the groups of
In summary, the stereoselective formal synthesis of sali-
nosporamide A (1) starting from D-glucose has been ac-
complished. This work proved that the methodology
involving Overman rearrangement of allylic alcohols de-
rived from carbohydrates, followed by further manipula-
tion by use of the residual functional groups in
carbohydrates, is quite effective for the chiral synthesis of
natural products possessing complex a-substituted a-ami-
no acid structures with multi functionalities.
Synthesis 2009, No. 17, 2983–2991 © Thieme Stuttgart · New York

2986
T. Momose et al.
PAPER
The melting points were determined on a Mitamura-riken micro hot
stage and are uncorrected. H NMR spectra were measured with a
(d, J = 12.0 Hz, 1 H, PhCH2), 4.50 (d, J = 12.0 Hz, 1 H, PhCH2),
3.88 (dd, J = 10.1, 4.9 Hz, 1 H, H-5), 3.72–3.68 (m, 2 H, HOCH2
and HOCH), 3.66–3.61 (m, 2 H, HOCH2 and BnOCH2), 3.54–3.59
(m, 1 H, BnOCH2), 2.10–2.04 (m, 1 H, H-6), 1.92–1.95 (m, 2 H,
BnOCH2CH2), 1.48 (s, 3 H, CCH3), 1.29 (s, 3 H, CCH3).
13C NMR (125 MHz, CDCl3): d = 138.0, 128.4, 127.8, 127.7, 111.7,
104.6, 82.6, 81.6, 73.2, 73.0, 68.6, 63.7, 44.1, 26.7, 26.3, 25.2.
1
JEOL ECA-500 (500 MHz) or a Varian MVX-300 (300 MHz) spec-
trometers, with TMS as the internal standard for solutions in CDCl3
at r.t., unless otherwise noted. Chemical shifts are reported as d val-
ues in ppm. 13C NMR spectra were taken on a JEOL ECA-500 (125
MHz) or a Varian MVX-300 (75 MHz) spectrometers, in CDCl3 at
r.t., unless otherwise noted. Chemical shifts are reported as d values
in ppm. Mass spectra (EI and FAB) were measured by a JEOL GC-
Mate spectrometer, and those of ESI were measured by a JMS-
T100LC spectrometer. Optical rotations were measured with a
JASCO DIP-370 instrument with 1 dm tube and values of [a]D are
recorded in units of 10–1 deg·cm2·g–1. IR spectra were taken with a
JASCO FT/IR-200 spectrometer. Organic extracts were dried over
anhyd Na2SO4 and concentrated below 40 °C under reduced pres-
sure. Benzene, toluene, and DMF were distilled from CaH2. MeOH
was distilled from CaSO4 (Drierite®). AcOH was distilled from
Ac2O and KMnO4. EtOH (95%, dried over 3Å molecular sieves),
Et2O (anhyd), THF (anhyd, stabilizer free), and CH2Cl2 (anhyd)
were purchased from Kanto Chemical Co., Inc., Japan. For column
chromatography, Merck silica gel 60 (230–400 mesh) was used, un-
less otherwise noted. For TLC analysis, Merck precoated TLC
plates (silica gel 60 F254 on glass plates, 0.25 mm) were used.
HRMS-ESI: m/z [M + Na+] calcd for C18H26O6 + Na: 361.1627;
found: 361.1632.
(R)-1-{(3aR,5S,6R,6aR)-6-[2-(Benzyloxy)ethyl]}-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-tert-butyldimethyl-
silyloxyethanol (14)
To a solution of alcohol 13 (2.11 g, 6.24 mmol) in CH2Cl2 (40 mL)
at 0 °C were added Et3N (1.3 mL, 9.33 mmol), TBSCl (1.13 g, 7.48
mmol), and DMAP (76 mg, 0.624 mmol), and the mixture was
stirred at r.t. for 16 h. The mixture was washed successively with aq
0.2 M HCl (40 mL) and brine (40 mL). The organic layer was dried
and concentrated. The residue was purified by silica gel column
chromatography (EtOAc–hexane, 1:6 → 1:4) to give 14 (2.72 g,
96%) as a colorless syrup; [a]D27 +42.1 (c 2.55, CHCl3).
IR (neat): 3500, 2960, 2940, 2860, 1460, 1370 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.26 (m, 5 H, C6H5), 5.72 (d,
J = 3.9 Hz, 1 H, H-3a), 4.60 (dd, J = 3.9, 3.9 Hz, 1 H, H-6a), 4.56
(d, J = 12.0 Hz, 1 H, PhCH2), 4.51 (d, J = 12.0 Hz, 1 H, PhCH2),
3.82–3.76 (m, 2 H, H-5 and TBSOCH2), 3.67–3.60 (m, 4 H,
TBSOCH2, HOCH and BnOCH2), 2.62 (d, J = 4.2 Hz, 1 H, OH),
2.17–2.09 (m, 2 H, H-6 and BnOCH2CH2), 1.91 (m, 1 H,
BnOCH2CH2), 1.49 (s, 3 H, CCH3), 1.30 (s, 3 H, CCH3), 0.90 (s, 9
H, t-C4H9), 0.07 (s, 6 H, SiCH3).
13C NMR (125 MHz, CDCl3): d = 138.5, 128.3, 127.6, 127.4, 111.5,
104.8, 81.6, 81.0, 74.0, 72.6, 68.7, 64.5, 44.9, 26.8, 26.4, 25.8, 25.3,
18.2, –5.40, –5.43.
HRMS-EI: m/z [M+] calcd for C24H40O6Si: 452.2594; found:
452.2594.
(3aR,5S,6R,6aR)-6-[2-(Benzyloxy)ethyl]-2,2-dimethyl-5-[(R)-
2,2-dimethyl-1,3-dioxolan-4-yl]tetrahydrofuro[2,3-d][1,3]diox-
ole (12)
To a solution of alcohol 11 (17.3 g, 60.0 mmol) and BnBr (8.6 mL,
72.0 mmol) in DMF (170 mL) was added NaH (1.73 g, 72.0 mmol)
in DMF (30 mL) at 0 °C. After stirring for 10 min at 0 °C, the reac-
tion mixture was further stirred at r.t. for 1.5 h. The mixture was
quenched with EtOH (30 mL) at 0 °C and diluted with H2O (800
mL). The products were extracted with EtOAc (2 ꢀ 250 mL). The
combined organic layers were washed with brine (500 mL), dried,
and concentrated to give a residue, which was purified by silica gel
column chromatography (EtOAc–hexane, 1:5 → 1:3) to afford 12
(20.4 g, 90%) as a colorless syrup; [a]D25 +48.0 (c 2.85, CHCl3).
IR (neat): 2985, 2940, 2880, 1460, 1380, 1370 cm–1.
(R)-1-{(3aR,5S,6R,6aR)-6-[2-(Benzyloxy)ethyl]}-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-tert-butyldimethyl-
silyloxyethyl 4-Methylbenzenesulfonate (15)
1H NMR (300 MHz, CDCl3): d = 7.36–7.26 (m, 5 H, C6H5), 5.73 (d,
J = 4.0 Hz, 1 H, H-3a), 4.59 (dd, J = 4.0, 4.0 Hz, 1 H, H-6a), 4.56
(d, J = 12.3 Hz, 1 H, PhCH2), 4.50 (d, J = 12.3 Hz, 1 H, PhCH2),
4.07 (dd, J = 8.0, 6.3 Hz, 1 H, Me2COCH2), 4.02 (m, 1 H,
Me2COCH), 3.92 (dd, J = 8.0, 5.5 Hz, 1 H, Me2COCH2), 3.79 (dd,
J = 9.7, 6.6 Hz, 1 H, H-5), 3.64–3.60 (m, 2 H, BnOCH2), 2.13–1.98
(m, 2 H, H-6 and BnOCH2CH2), 1.88 (m, 1 H, BnOCH2CH2), 1.50
(s, 3 H, CCH3), 1.41 (s, 3 H, CCH3), 1.34 (s, 3 H, CCH3), 1.30 (s, 3
H, CCH3).
13C NMR (125 MHz, CDCl3): d = 138.5, 128.3, 127.6, 127.5, 111.7,
109.5, 105.0, 81.9, 81.5, 77.7, 72.7, 68.5, 67.4, 45.4, 26.8, 26.5,
26.4, 25.3, 25.1.
HRMS-ESI: m/z [M + Na+] calcd for C21H30O6 + Na: 401.1940;
found: 401.1933.
To a solution of alcohol 14 (3.82 g, 8.44 mmol) in pyridine (40 mL)
at r.t. were added TsCl (3.22 g, 16.9 mmol) and DMAP (103 mg,
0.844 mmol), and the mixture was stirred at 60 °C for 30 h. The
mixture was concentrated to give a residue, which was purified by
silica gel column chromatography (EtOAc–hexane, 1:6 → 1:3) to
25
give 15 (4.27 g, 83%) as a colorless syrup; [a]D +32.0 (c 0.92,
CHCl3).
IR (neat): 2960, 2940, 2860, 1460, 1370 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.4 Hz, 2 H, C6H5),
7.36–7.27 (m, 7H, C6H5), 5.48 (d, J = 3.3 Hz, 1 H, H-3a), 4.64 (ddd,
J = 5.7, 5.7, 3.3 Hz, 1 H, TsOCH), 4.56–4.47 (m, 3 H, H-6a and
PhCH2), 4.06 (dd, J = 10.5, 3.3 Hz, 1 H, H-5), 3.77 (d, J = 5.7 Hz,
2 H, TBSOCH2), 3.60–3.55 (m, 2 H, BnOCH2), 2.42 (s, 3 H,
PhCH3), 2.19 (m, 1 H, BnOCH2CH2), 1.87–1.80 (m, 2 H, H-6 and
BnOCH2CH2), 1.40 (s, 3 H, CCH3), 1.26 (s, 3 H, CCH3), 0.83 (s, 9
H, t-C4H9), 0.07 (s, 6 H, SiCH3).
(R)-1-{(3aR,5S,6R,6aR)-6-[2-(Benzyloxy)ethyl]}-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethane-1,2-diol (13)
A solution of 12 (20.4 g, 53.9 mmol) in AcOH (200 mL) and H2O
(50 mL) was stirred at 50 °C for 1 h. The reaction mixture was con-
centrated to give a residue, which was purified by silica gel column
chromatography (EtOAc–hexane, 1:1 → 1:0) to give 13 (16.9 g,
93%) as a colorless syrup; [a]D25 +51.8 (c 2.35, CHCl3).
13C NMR (75 MHz, CDCl3): d = 144.6, 138.7, 134.6, 129.8, 128.5,
128.1, 127.7, 127.6, 111.9, 104.9, 82.5, 81.5, 80.1, 72.9, 68.5, 61.4,
42.7, 27.0, 26.7, 25.9, 25.5, 21.7, 18.3, –5.4, –5.5.
HRMS-ESI: m/z [M + Na+] calcd for C31H46O8SSi + Na: 629.2580;
IR (neat): 3440, 2980, 2940, 2860, 1455, 1375 cm–1.
found: 629.2570.
1H NMR (300 MHz, CDCl3): d = 7.36–7.25 (m, 5 H, C6H5), 5.73 (d,
J = 4.0 Hz, 1 H, H-3a), 4.57 (dd, J = 4.0, 4.0 Hz, 1 H, H-6a), 4.54
Synthesis 2009, No. 17, 2983–2991 © Thieme Stuttgart · New York

PAPER
Formal Synthesis of Salinosporamide A
2987
(3R,4S,5R,6R)-5-[2-(Benzyloxy)ethyl]-4-hydroxy-6-(4-meth-
oxybenzyloxy)tetrahydro-2H-pyran-3-ol 4-Methylbenzene-
sulfonate (17)
4.34 (m, 5 H, H-2, H-6 and PhCH2), 3.80 (s, 3 H, OCH3), 3.61 (dd,
J = 11.7, 8.4 Hz, 1 H, H-2), 3.52–3.38 (m, 2 H, BnOCH2), 2.75
(ddd, J = 7.2, 7.2, 4.8 Hz, 1 H, H-5), 2.44 (s, 3 H, PhCH3), 2.05 (m,
1 H, BnOCH2CH2), 1.76 (m, 1 H, BnOCH2CH2).
To a solution of 15 (4.20 g, 6.92 mmol) in 1,4-dioxane (40 mL) at
r.t. was added aq 6 M HCl (40 mL), and the mixture was stirred for
3 h. After the addition of aq 5 M NaOH (40 mL) at 0 °C, the mixture
was extracted with EtOAc (2 ꢀ 40 mL). The combined organic lay-
ers were washed with brine (40 mL), dried, and concentrated to give
the crude triol as a pale yellow syrup. To a solution of the crude tirol
in THF–H2O (1:1, 60 mL) at r.t. was added a solution of NaIO4
(4.44 g, 20.8 mmol) in H2O (30 mL), and the mixture was stirred for
2 h. The mixture was diluted with EtOAc (50 mL), and washed suc-
cessively with H2O (40 mL) and brine (60 mL). The organic layer
was dried and concentrated to give a residue, which was roughly pu-
rified by silica gel column chromatography (EtOAc–hexane, 1:2 →
1:1) to give crude 16 (2.98 g, 96%) as a colorless syrup. To a solu-
tion of crude 16 (2.98 g, 6.62 mmol) in CH2Cl2 (56 mL) at 0 °C were
added Cl3CCN (1.99 mL, 19.8 mmol) and DBU (0.10 mL 0.67
mmol) and the mixture was stirred for 30 min at 0 °C. The mixture
was diluted with toluene (40 mL) and roughly purified by filtration
through a pad of silica gel (EtOAc–hexane, 1:3, 0.5% Et3N) to give
the intermediate imidate as a colorless syrup (3.47 g, 88%). To a so-
lution of the crude imidate (3.47 g, 5.83 mmol) in CH2Cl2 (62 mL)
at 0 °C were added 4-methoxybenzyl alcohol (0.80 mL, 6.43 mmol)
and a solution of TMSOTf (21 mL, 0.11 mmol) in CH2Cl2 (7 mL),
and the mixture was stirred for 1.5 h at 0 °C. The mixture was
quenched with Et3N (33 mL, 0.23 mmol), and then washed succes-
sively with H2O (50 mL) and brine (50 mL). The organic layer was
dried and concentrated to give a colorless residue. This residue was
dissolved in MeOH (40 mL), and to this solution was added K2CO3
(403 mg, 2.92 mmol) at r.t. After 30 min, the mixture was concen-
trated and then diluted with EtOAc (70 mL). The mixture was
washed successively with H2O (50 mL) and brine (50 mL). The or-
ganic layer was dried and concentrated to give a residue, which was
purified by silica gel column chromatography (EtOAc–hexane, 1:6
13C NMR (75 MHz, CDCl3): d = 198.5, 159.5, 145.3, 138.2, 132.9,
129.9, 129.8, 128.6, 128.3, 128.0, 127.6, 127.5, 113.9, 102.6, 77.4,
72.6, 70.3, 67.3, 63.8, 55.2, 52.6, 24.4, 21.7.
HRMS-FAB: m/z [M + Na+] calcd for C29H32O8S + Na: 563.1716;
found: 563.1713.
(3R,4S,5R,6R)-5-[2-(Benzyloxy)ethyl]-4-hydroxy-6-(4-meth-
oxybenzyloxy)-4-methyltetrahydro-2H-pyran-3-ol 4-Methyl-
benzenesulfonate (19)
To a solution of ketone 18 (2.38 g, 4.40 mmol) in toluene (40 mL)
was added Me3Al (2 M in toluene, 6.6 mL, 13.2 mmol) at –40 °C
over 5 min. The mixture was warmed to –5 °C and further stirred at
–5 °C for 1 h. The reaction was quenched with aq 1 M HCl (15 mL)
at –5 °C and diluted with EtOAc (40 mL). The EtOAc layer was
washed successively with aq 1 M HCl (40 mL), aq sat. NaHCO3 (40
mL), and brine (40 mL). The organic layer was dried and concen-
trated to give a residue, which was purified by silica gel column
chromatography (EtOAc–hexane, 1:5 → 1:2) to give 19 (2.13 g,
88%) as a pale yellow oil; [a]D27 –34.3 (c 0.95, CHCl3).
IR (neat): 3450, 2940, 2880, 1515, 1360, 1250, 1180 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.81 (d, J = 8.1 Hz, 2 H, C6H5),
7.36–7.25 (m, 7 H, C6H5), 7.17 (d, J = 8.7 Hz, 2 H, C6H5), 6.84 (d,
J = 8.7 Hz, 2 H, C6H5), 4.70 (d, J = 11.4 Hz, 1 H, PhCH2), 4.56 (d,
J = 8.4 Hz, 1 H, H-6), 4.41 (s, 2 H, PhCH2), 4.36 (d, J = 11.4 Hz, 1
H, PhCH2), 4.30 (dd, J = 9.9, 5.7 Hz 1 H, H-3), 3.79 (s, 3 H, OCH3),
3.78 (dd, J = 10.8, 9.9 Hz, 1 H, H-2), 3.70 (dd, J = 10.8, 5.7 Hz, 1
H, H-2), 3.43–3.37 (m, 2 H, BnOCH2), 2.93 (s, 1 H, OH), 2.45 (s, 3
H, PhCH3), 1.93 (m, 1 H, BnOCH2CH2), 1.68 (m, 1 H,
BnOCH2CH2), 1.57 (m, 1 H, H-5), 1.13 (s, 3 H, CCH3).
13C NMR (75 MHz, CDCl3): d = 159.3, 145.2, 138.0, 133.4, 129.9,
129.6, 129.4, 128.3, 127.9, 127.6, 113.8, 100.3, 80.4, 72.8, 72.0,
70.4, 68.4, 61.7, 55.2, 47.1, 25.2, 23.8, 21.6.
HRMS-ESI: m/z [M + Na+] calcd for C30H36O8S + Na: 579.2029;
found: 579.2020.
27
→ 1:3) to give 17 (2.95 g, 79% from 15) as a colorless syrup; [a]D
–28.5 (c 0.6, CHCl3).
IR (neat): 3460, 2920, 2880, 1730, 1520, 1380 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.1 Hz, 2 H, C6H5),
7.38–7.26 (m, 7 H, C6H5), 7.20 (d, J = 8.7 Hz, 2 H, C6H5), 6.84 (d,
J = 8.7 Hz, 2 H, C6H5), 4.68 (d, J = 11.4 Hz, 1 H, PhCH2), 4.59 (d,
J = 6.6 Hz, 1 H, H-6), 4.50 (m, 1 H, H-3), 4.45 (s, 2 H, PhCH2), 4.38
(d, J = 11.4 Hz, 1 H, PhCH2), 4.16 (m, 1 H, H-4), 3.82 (dd, J = 11.7,
8.7 Hz, 1 H, H-2), 3.79 (s, 3 H, OCH3), 3.65 (dd, J = 11.7, 4.5 Hz,
1 H, H-2), 3.54–3.42 (m, 2 H, BnOCH2), 3.00 (d, J = 3.9 Hz, 1 H,
OH), 2.43 (s, 3H, PhCH3), 1.86–1.78 (m, 3 H, H-5 and
BnOCH2CH2).
13C NMR (75 MHz, CDCl3): d = 159.3, 145.1, 137.8, 133.4, 130.0,
129.6, 129.4, 128.4, 127.8, 113.8, 99.9, 77.3, 73.0, 70.2, 68.0, 67.1,
60.8, 55.2, 43.2, 26.6, 21.6.
HRMS-ESI: m/z [M + Na+] calcd for C29H34O8S + Na: 565.1872;
found: 565.1871.
(3R,4S,5R,6R)-5-[2-(Benzyloxy)ethyl]-6-(4-methoxybenzyloxy)-
4-methyltetrahydro-2H-pyran-3,4-diol (10)
To a solution of alcohol 19 (4.70 g, 8.44 mmol) in MeOH (60 mL)
at r.t. was added Mg (2.1 g, 86 mmol), and the mixture was stirred
for 2.5 h. The reaction was quenched with aq 1 M HCl (150 mL) at
0 °C and then diluted with EtOAc (100 mL). The organic layer was
washed successively with aq 1 M HCl (100 mL), aq 0.5 M NaOH
(150 mL), and brine (150 mL). The organic layer was dried and con-
centrated to give a residue, which was purified by silica gel column
chromatography (EtOAc–hexane, 1:2 → 2:1) to give 10 (2.76 g,
81%) as a pale yellow syrup; [a]D25 –78.7 (c 1.1, CHCl3).
IR (neat): 3430, 2940, 2870, 1615, 1515, 1455, 1360, 1250 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.17 (m, 7 H, C6H5), 6.84 (d,
J = 8.7 Hz, 2 H, C6H5), 4.75 (d, J = 11.4 Hz, 1 H, PhCH2), 4.60 (d,
J = 8.7 Hz, 1 H, H-6), 4.43 (s, 2 H, PhCH2), 4.39 (d, J = 11.4 Hz, 1
H, PhCH2), 4.18 (s, 1 H, OH), 3.87 (dd, J = 10.5, 4.8 Hz, 1 H, H-3),
3.80 (s, 3 H, OCH3), 3.54 (dd, J = 10.5, 10.5 Hz, 1 H, H-2), 3.49–
3.31 (m, 3 H, H-2 and BnOCH2), 2.17 (br s, 1 H, OH), 2.05–1.83
(m, 2 H, BnOCH2CH2), 1.66 (m, 1 H, H-5), 1.29 (s, 3 H, CCH3).
(3R,5R,6R)-5-[2-(Benzyloxy)ethyl]-6-(4-methoxybenzyloxy)-4-
oxotetrahydro-2H-pyran-3-ol 4-Methylbenzenesulfonate (18)
A solution of alcohol 17 (4.22 g, 7.78 mmol) in DMSO (40 mL) and
Ac2O (16 mL) was stirred for 1.5 h at 50 °C. The reaction mixture
was diluted with EtOAc (150 mL), and washed successively with
H2O (150 mL) and brine (150 mL). The organic layer was dried and
concentrated to give a residue, which was purified by silica gel col-
umn chromatography (EtOAc–hexane, 1:6 → 1:3) to give 18 (3.80
g, 90%) as a pale yellow syrup; [a]D27 –23.6 (c 1.06, CHCl3).
13C NMR (75 MHz, CDCl3): d = 159.3, 137.4, 129.8, 128.4, 127.7,
113.8, 99.5, 73.1, 71.7, 71.4, 70.0, 67.6, 65.1, 55.2, 47.1, 25.0, 24.0.
HRMS-ESI: m/z [M + Na+] calcd for C23H30O6 + Na: 425.1940;
found: 425.1936.
1H NMR (300 MHz, CDCl3): d = 7.84 (d, J = 8.1 Hz, 2 H, C6H5),
7.36–7.20 (m, 9 H, C6H5), 6.85 (d, J = 8.7 Hz, 2 H, C6H5), 4.93 (dd,
J = 8.1, 6.6 Hz, 1 H, H-3), 4.75 (d, J = 5.7 Hz, 1 H, PhCH2), 4.49–
Synthesis 2009, No. 17, 2983–2991 © Thieme Stuttgart · New York

2988
T. Momose et al.
PAPER
(4S,5R,6R)-5-[2-(Benzyloxy)ethyl]-4-hydroxy-6-(4-methoxy-
benzyloxy)-4-methyldihydro-2H-pyran-3(4H)-one (20)
(E)-2-{(4S,5R,6S)-5-[2-(Benzyloxy)ethyl]}-6-(4-methoxybenzyl-
oxy)-4-methyl-4-trimethylsilyloxydihydro-2H-pyran-3(4H)-
ylidene)ethanol (22)
To a solution of alcohol 10 (2.71 g, 6.73 mmol) in DMSO (30 mL)
at r.t. were added Et3N (7.5 mL, 54 mmol) and SO3·py (5.36 g, 33.7
mmol), and the mixture was stirred for 1.5 h. The mixture was di-
luted with EtOAc (120 mL), and washed successively with H2O
(100 mL) and brine (100 mL). The organic layer was dried and con-
centrated to give a residue, which was purified by silica gel column
chromatography (EtOAc–hexane, 1:4 → 1:2) to give 20 (1.96 g,
73%) as a pale yellow oil; [a]D26 –88.0 (c 1.1, CHCl3).
To a solution of ester 21 (711 mg, 1.31 mmol) in toluene (14 mL)
under argon was added DIBAL-H (0.99 M in toluene, 3.31 mL, 3.28
mmol) at –50 °C and the mixture was stirred at this temperature for
30 min. The reaction was quenched with aq 1 M HCl (10 mL) at
–50 °C and then diluted with EtOAc (20 mL). The organic layer was
washed successively with aq 1 M HCl (15 mL), aq 1 M NaOH (20
mL), and brine (20 mL). The organic layer was dried and concen-
trated to give a residue, which was purified by silica gel column
chromatography (EtOAc–hexane, 1:2 → 2:1) to give 22 (634 mg,
97%) as a colorless oil; [a]D25 –12.3 (c 2.88, CHCl3).
IR (neat): 3480, 2940, 2870, 1730, 1615, 1515, 1460, 1250 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.25–7.35 (m, 7 H, C6H5), 6.88 (d,
J = 8.6 Hz, 2 H, C6H5), 4.90 (d, J = 3.2 Hz, 1 H, H-6), 4.71 (d,
J = 11.5 Hz, 1 H, PhCH2), 4.47 (d, J = 11.5 Hz, 1 H, PhCH2), 4.45
(d, J = 12.0 Hz, 1 H, PhCH2), 4.31 (d, J = 12.0 Hz, 1 H, PhCH2),
4.36 (d, J = 16.0 Hz, 1 H, H-2), 4.01 (d, J = 16.0 Hz, 1 H, H-2), 3.81
(s, 3 H, OCH3), 3.63 (s, 1 H, OH), 3.53–3.44 (m, 2 H, m, BnOCH2),
2.31 (dt, J = 3.2, 7.7 Hz, 1 H, H-5), 2.00–1.94 (m, 1 H,
BnOCH2CH2), 1.71–1.64 (m, 1 H, BnOCH2CH2), 1.53 (s, 3 H,
CCH3).
13C NMR (75 MHz, CDCl3): d = 209.3, 159.4, 138.1, 129.5, 129.2,
128.4, 127.7, 127.6, 113.9, 100.7, 75.3, 72.9, 69.8, 68.3, 65.5, 55.2,
49.3, 27.5, 26.1.
HRMS-ESI: m/z [M + Na+] calcd for C23H28O6 + Na: 423.1784;
found: 423.1788.
IR (neat): 3440, 2950, 2860, 1615, 1515, 1250 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.23 (m, 7 H, C6H5), 6.85 (d,
J = 8.4 Hz, 2 H, C6H5), 5.75 (t, J = 6.6 Hz, 1 H, C=CH), 4.75 (d,
J = 11.1 Hz, 1 H, PhCH2), 4.71 (d, J = 5.1 Hz, 1 H, H-6), 4.44 (s, 2
H, PhCH2), 4.43 (d, J = 11.1 Hz, 1 H, PhCH2), 4.37 (d, J = 12.9 Hz,
1 H, H-2), 4.29–4.15 (m, 3 H, 2-H and HOCH2), 3.79 (s, 3 H,
OCH3), 3.55 (m, 1 H, BnOCH2), 3.44 (m, 1 H, BnOCH2), 1.96 (m,
1 H, BnOCH2CH2), 1.61–1.43 (m, 2 H, H-5 and BnOCH2CH2), 1.51
(s, 3 H, CCH3), 0.07 [s, 9 H, Si(CH3)3].
13C NMR (75 MHz, CDCl3): d = 159.1, 140.9, 138.7, 130.1, 129.3,
128.3, 127.5, 127.4, 122.9, 113.7, 101.9, 75.6, 72.7, 70.1, 70.0,
59.2, 58.6, 55.2, 49.9, 27.1, 25.6, 2.2.
HRMS-ESI: m/z [M + Na+] calcd for C28H40O6Si + Na: 523.2492;
Ethyl (E)- 2-{(4S,5R,6S)-5-[2-(Benzyloxy)ethyl]}-6-(4-methoxy-
benzyloxy)-4-methyl-4-trimethylsilyloxydihydro-2H-pyran-
3(4H)-ylidene)acetate (21)
found: 523.2490.
Overman Rearrangement of 9
To a solution of triethyl phosphonoacetate (0.390 mL, 1.97 mmol)
in THF (5 mL) at 0 °C was added NaH (47.0 mg, 1.96 mmol) and
the mixture was stirred for 10 min. A solution of ketone 20 (392 mg,
0.979 mmol) in THF (2 ꢀ 3 mL) was added to the reaction mixture
at 0 °C, and the resulting mixture was warmed to r.t. After stirring
for 2 h at r.t., the mixture was diluted with EtOAc (120 mL), and
washed successively with aq 0.5 M HCl (60 mL) and brine (60 mL).
The organic layer was dried and concentrated to give a residue,
which was purified by silica gel column chromatography (EtOAc–
hexane, 1:5 → 1:2) to give the intermediate alkene (440 mg, 96%)
as a pale yellow syrup. To a solution of the alkene (440 mg, 0.933
mmol) in CH2Cl2 (9 mL) were added pyridine (0.45 mL, 5.6 mmol)
and TMSOTf (0.51 mL, 2.6 mmol) at 0 °C, and the mixture was
stirred at 0 °C for 40 min. The mixture was washed successively
with aq 0.5 M HCl (20 mL), aq sat. NaHCO3 (20 mL) and brine (20
mL). The organic layer was dried and concentrated to give a resi-
due, which was purified by silica gel column chromatography
(EtOAc–hexane, 1:8 → 1:5) to give 21 (442 mg, 84% from 20) as a
colorless syrup; [a]D26 –47.1 (c 0.86, CHCl3).
To a solution of alcohol 22 (634 mg, 1.27 mmol) in CH2Cl2 (10 mL)
were added trichloroacetonitrile (0.254 mL, 2.53 mmol) and DBU
(0.019 mL, 0.13 mmol) at 0 °C. After stirring at 0 °C for 30 min, the
mixture was diluted with toluene (10 mL) and roughly purified by
filtration through a pad of silica gel (EtOAc–hexane, 1:4) to give
crude imidate 9 as a colorless oil (791 mg, 97%). A solution of
crude 9 (791 mg, 1.23 mmol) and Na2CO3 (204 mg, 1.92 mmol) in
degassed tert-butylbenzene (41 mL) was heated in a sealed tube at
150 °C for 48 h. After cooling, the insoluble material was removed
by filtration and the filtrate was concentrated to give a residue,
which was purified by silica gel column chromatography (EtOAc–
hexane, 1:10 → 1:8) to give first, the rearranged product 23 (560
mg, 69% from 22) as a colorless syrup. Further elution afforded epi-
23 (130 mg, 16% from 22) as a colorless syrup.
23
Rf = 0.50 (EtOAc–hexane, 1:5); [a]D25 +7.5 (c 2.4, CHCl3).
IR (neat): 2960, 2860, 1730, 1615, 1515, 1250 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.20 (m, 8 H, C6H5 and NH),
6.86 (d, J = 8.7 Hz, 2 H, C6H5), 6.24 (dd, J = 18.0, 11.1 Hz, 1 H,
CH=CH2), 5.38 (d, J = 11.1 Hz, 1 H, CH=CH2), 5.18 (d, J = 18.0
Hz, 1 H, CH=CH2), 4.80 (d, J = 11.7 Hz, 1 H, PhCH2), 4.46 (d, 1 H,
J = 11.7 Hz, PhCH2), 4.45 (d, 1 H, J = 11.4 Hz, H-6), 4.44 (s, 2 H,
PhCH2), 4.02 (d, J = 11.7 Hz, 1 H, H-2), 3.92 (d, J = 11.7 Hz, 1 H,
H-2), 3.80 (s, 3 H, OCH3), 3.63 (m, 1 H, BnOCH2), 3.49 (m, 1 H,
BnOCH2), 1.76 (m, 1 H, BnOCH2CH2), 1.67–1.53 (m, 2 H, H-5 and
BnOCH2CH2), 1.35 (s, 3 H, CCH3), 0.11 [s, 9 H, Si(CH3)3].
13C NMR (75 MHz, CDCl3): d = 159.4, 159.3, 138.7, 132.2, 129.6,
128.3, 127.4, 127.3, 117.7, 113.8, 102.7, 93.6, 80.9, 72.8, 70.5,
70.2, 66.7, 62.4, 55.3, 44.2, 26.8, 21.7, 2.8.
HRMS-ESI: m/z [M + K+] calcd for C30H40NO6SiCl3 + K:
682.1328; found: 682.1322.
IR (neat): 2950, 2860, 1715, 1515, 1250 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.24 (m, 7 H, C6H5), 6.86 (d,
J = 8.7 Hz, 2 H, C6H5), 6.01 (s, 1 H, C=CH), 5.04 (d, J = 14.7 Hz, 1
H, H-2), 4.77 (d, J = 3.6 Hz, 1 H, H-6), 4.72 (d, J = 11.4 Hz, 1 H,
PhCH2), 4.65 (d, J = 14.7 Hz, 1 H, H-2), 4.44 (s, 2 H, PhCH2), 4.41
(d, J = 11.4 Hz, 1 H, PhCH2), 4.17 (q, J = 7.2 Hz, 2 H, OCH2CH3),
3.79 (s, 3 H, OCH3), 3.55–3.41 (m, 2 H, BnOCH2), 2.00 (m, 1 H,
BnOCH2CH2), 1.84 (m, 1 H, H-5), 1.61 (s, 3 H, CCH3), 1.54 (m, 1
H, BnOCH2CH2), 1.30 (t, J = 7.2 Hz, 3 H, OCH2CH3), 0.13 [s, 9 H,
Si(CH3)3].
13C NMR (75 MHz, CDCl3): d = 166.4, 159.2, 158.8, 138.7, 130.1,
129.4, 128.3, 127.5, 127.4, 114.1, 113.8, 100.7, 75.6, 72.8, 69.6,
69.2, 60.1, 59.1, 55.3, 49.5, 28.1, 27.5, 14.3, 2.3.
HRMS-ESI: m/z [M + Na+] calcd for C30H42O7Si + Na: 565.2598;
found: 565.2599.
epi-23
Rf = 0.40 (EtOAc–hexane, 1:5); [a]D25 –65.8 (c 2.4, CHCl3).
Synthesis 2009, No. 17, 2983–2991 © Thieme Stuttgart · New York

PAPER
Formal Synthesis of Salinosporamide A
2989
IR (neat): 3380, 2960, 2860, 1730, 1615, 1495, 1250 cm–1.
reagent (1.29 mL, 3.45 mmol) at 0 °C, and the mixture was stirred
at this temperature for 2.5 h. The mixture was quenched with i-
PrOH (0.5 mL) and then diluted with EtOAc (20 mL). The mixture
was washed successively with H2O (20 mL) and brine (20 mL). The
organic layer was dried and concentrated to give a residue, which
was roughly purified by silica gel column chromatography
(EtOAc–hexane, 1:2) to give crude 28 as a pale yellow solid. To a
solution of crude 28 in t-BuOH–H2O (3:1, 3 mL) at r.t. were added
NaH2PO4 (93 mg, 0.78 mmol), 2-methylbut-2-ene (0.16 mL, 1.6
mmol) and NaClO2 (70 mg, 0.78 mmol). After stirring for 12 h, the
reaction was diluted with EtOAc (15 mL). The mixture was washed
successively with aq 5% Na2S2O3 (15 mL) and brine (15 mL). The
organic layer was dried and concentrated to give the intermediate
carboxylic acid. To a solution of the crude carboxylic acid in DMF
(2 mL) at r.t. were added K2CO3 (64 mg, 0.47 mmol) and MeI (30
mL, 0.47 mmol). After stirring for 1.5 h, the mixture was diluted
with EtOAc (20 mL) and washed successively with H2O (20 mL)
and brine (20 mL). The organic layer was dried and concentrated to
give a residue, which was purified by silica gel column chromatog-
raphy (EtOAc–hexane, 1:2) to give 29 (48 mg, 44% from 26) as a
colorless syrup; [a]D27 –9.9 (c 0.73, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.51 (br s, 1 H, NH), 7.33–7.22
(m, 7 H, C6H5), 6.86 (d, J = 8.7 Hz, 2 H, C6H5), 5.70 (dd, J = 17.7,
11.1 Hz, 1 H, CH=CH2), 5.32 (d, J = 11.1 Hz, 1 H, CH=CH2), 5.23
(d, J = 17.7 Hz, 1 H, CH=CH2), 4.85 (d, J = 1.8 Hz, 1 H, H-6), 4.66
(d, J = 11.7 Hz, 1 H, PhCH2), 4.66 (d, J = 11.7 Hz, 1 H, H-2), 4.45
(d, J = 6.9 Hz, 1 H, PhCH2), 4.42 (d, J = 6.9 Hz, 1 H, PhCH2), 4.38
(d, J = 11.7 Hz, 1 H, PhCH2), 3.89 (d, J = 11.7 Hz, 1 H, H-2), 3.80
(s, 3 H, OCH3), 3.46 (m, 1 H, BnOCH2), 3.40 (m, 1 H, BnOCH2),
2.11–2.05 (m, 1 H, BnOCH2CH2), 1.90 (m, 1 H, H-5), 1.78–1.72
(m, 1 H, BnOCH2CH2), 1.53 (s, 3 H, CCH3), 0.15 [s, 9 H, Si(CH3)3].
13C NMR (125 MHz, CDCl3): d = 159.6, 159.1, 138.4, 133.2, 129.8,
129.2, 128.3, 127.5, 127.4, 117.0, 113.8, 99.6, 93.7, 76.4, 72.8,
69.3, 69.2, 62.5, 58.7, 55.2, 47.2, 28.3, 25.9, 2.3.
HRMS-ESI: m/z [M + K+] calcd for C30H40NO6SiCl3 + K:
682.1328; found: 682.1319.
Benzyl(3S,4S,5R,6R)-5-[2-(Benzyloxy)ethyl]-6-(4-methoxyben-
zyloxy)-4-methyl-4-trimethylsilyoxy-3-vinyltetrahydro-2H-py-
ran-3-yl-carbamate (26)
IR (neat): 3480, 2930, 1790, 1730, 1280 cm–1.
To a solution of 23 (177 mg, 0.274 mmol) in toluene (3 mL) under
argon was added DIBAL-H (0.99 M in toluene, 0.420 mL, 0.412
mmol) at –78 °C and the mixture was stirred at this temperature for
30 min. The reaction was quenched with aq 1 M HCl (1 mL) at
–78 °C and then diluted with EtOAc (10 mL). The mixture was
washed successively with aq 1 M NaOH (10 mL) and brine (10
mL). The organic layer was dried and concentrated to give the crude
amine. To a solution of the crude amine in EtOAc (2 mL) and aq 0.5
M NaOH (2 mL) was added CbzCl (78 mL, 0.55 mmol) at 0 °C and
the mixture was stirred for 3 h at r.t. The reaction was diluted with
EtOAc (10 mL), and washed successively with H2O (10 mL) and
brine (10 mL). The organic layer was dried and concentrated to give
a residue, which was purified by silica gel column chromatography
(EtOAc–hexane, 1:8 → 1:4) to give 26 (174 mg, ca. 100%) as a col-
orless syrup; [a]D24 +13.5 (c 0.97, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.36–7.26 (m, 10 H, C6H5), 6.46
(dd, J = 17.7, 10.8 Hz, 1 H, CH=CH2), 5.29 (d, J = 12.6 Hz, 1 H,
PhCH2), 5.27 (d, J = 10.8 Hz, 1 H, CH=CH2), 5.21 (d, J = 12.6 Hz,
1 H, PhCH2), 5.01 (d, J = 17.7 Hz, 1 H, CH=CH2), 4.53 (d, J = 11.7
Hz, 1 H, PhCH2), 4.46 (d, J = 11.7 Hz, 1 H, PhCH2), 3.95 (br s, 1 H,
OH), 3.81 (m, 1 H, BnOCH2), 3.66 (m, 1 H, BnOCH2), 2.70 (dd,
J = 6.6, 5.1 Hz, 1 H, H-4), 2.09–2.01 (m, 2 H, BnOCH2CH2), 1.37
(s, 3 H, CCH3).
13C NMR (75 MHz, CDCl3): d = 173.3, 168.3, 151.0, 137.4, 135.2,
133.3, 129.5, 128.5, 128.4, 128.3, 128.1, 127.9, 114.7, 77.8, 73.2,
68.6, 68.2, 67.0, 52.5, 47.8, 23.6, 21.7.
HRMS-ESI: m/z [M + Na+] calcd for C26H29NO7 + Na: 490.1842;
found: 490.1855.
IR (neat): 2960, 2860, 1740, 1510, 1250 cm–1.
1-Benzyl 2-Methyl (2R,3S,4R)-4-[2-(Benzyloxy)ethyl]-3-meth-
yl-5-oxo-3-trimethylsilyloxy-2-vinylpyrrolidine-1,2-dicarboxy-
late (30)
1H NMR (300 MHz, CDCl3): d = 7.36–7.20 (m, 12 H, C6H5), 6.85
(d, J = 8.4 Hz, 2 H, C6H5), 6.12 (dd, J = 18.0, 11.7 Hz, 1 H,
CH=CH2), 5.32 (d, J = 11.7 Hz, 1 H, CH=CH2), 5.20 (s, 1 H, NH),
5.14 (d, J = 18.0 Hz, 1 H, CH=CH2), 5.06 (d, J = 12.3 Hz, 1 H,
PhCH2), 5.00 (d, J = 12.3 Hz, 1 H, PhCH2), 4.80 (d, J = 11.4 Hz, 1
H, PhCH2), 4.47–4.42 (m, 4 H, H-6 and PhCH2), 4.02 (d, J = 11.7
Hz, 1 H, H-2), 3.93 (d, J = 11.7 Hz, 1 H, H-2), 3.79 (s, 3 H, OCH3),
3.64 (ddd, J = 8.7, 8.7, 4.5 Hz, 1 H, BnOCH2), 3.45 (ddd, J = 8.7,
8.7, 8.7 Hz, 1 H, BnOCH2), 1.72 (m, 1 H, BnOCH2CH2), 1.60 (m, 1
H, H-5), 1.37 (m, 1 H, BnOCH2CH2), 1.27 (s, 3 H, CCH3), 0.10 [s,
9 H, Si(CH3)3].
13C NMR (75 MHz, CDCl3): d = 159.3, 154.3, 138.7, 136.6, 134.3,
129.6, 128.4, 128.3, 128.1, 128.0, 127.5, 127.4, 117.1, 113.8, 102.7,
80.7, 72.8, 70.6, 70.4, 66.6, 66.4, 61.0, 55.3, 43.9, 26.8, 21.2, 2.8.
HRMS-ESI: m/z [M + Na+] calcd for C36H47NO7Si + Na: 656.3020;
found: 656.3002.
To a solution of alcohol 29 (9.4 mg, 0.020 mmol) in CH2Cl2 (1 mL)
were added pyridine (10 mL, 0.12 mmol) and TMSOTf (11 mL,
0.055 mmol) at 0 °C. After stirring for 30 min, the mixture was di-
luted with CH2Cl2 (10 mL). The mixture was washed successively
with aq 0.5 M HCl (10 mL) and brine (20 mL). The organic layer
was dried and concentrated to give a residue, which was purified by
silica gel column chromatography (EtOAc–hexane, 1:5 → 1:2) to
give 30 (10.6 mg, 98%) as a colorless syrup; [a]D25 +41.7 (c 0.88,
CHCl3).
IR (neat): 2960, 1800, 1770, 1730, 1290 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39–7.26 (m, 10 H, C6H5), 6.44
(dd, J = 17.4, 10.5 Hz, 1 H, CH=CH2), 5.28 (d, J = 12.3 Hz, 1 H,
PhCH2), 5.27 (d, J = 10.5 Hz, 1 H, CH=CH2), 5.18 (d, J = 12.3 Hz,
1 H, PhCH2), 4.99 (d, J = 17.4 Hz, 1 H, CH=CH2), 4.50 (s, 2 H,
PhCH2), 3.74 (dd, J = 7.2, 4.8 Hz, 2 H, BnOCH2), 3.53 (s, 3 H,
CO2CH3), 2.60 (dd, J = 8.4, 3.6 Hz, 1 H, H-4), 1.96 (m, 1 H,
BnOCH2CH2), 1.66 (m, 1 H, BnOCH2CH2), 1.47 (s, 3 H, CCH3),
0.07 [s, 9 H, Si(CH3)3].
13C NMR (75 MHz, CDCl3): d = 174.0, 168.5, 151.1, 138.4, 135.3,
133.3, 128.4, 128.3, 128.2, 128.0, 127.6, 127.5, 114.8, 82.6, 78.2,
72.9, 68.0, 67.8, 52.3, 47.6, 24.5, 20.8, 2.5.
HRMS-FAB: m/z [M + H+] calcd for C29H38NO7Si: 540.2418;
found: 540.2406.
1-Benzyl 2-Methyl (2R,3S,4R)-4-[2-(Benzyloxy)ethyl]-3-hy-
droxy-3-methyl-5-oxo-2-vinylpyrrolidine-1,2-dicarboxylate
(29)
To a solution of 26 (146 mg, 0.230 mmol) in CH2Cl2 (4 mL) were
added TFA (1.6 mL) and H2O (0.4 mL) at 0 °C, and the mixture was
stirred at this temperature for 2.5 h. The mixture was diluted with
CH2Cl2 (20 mL) and washed successively with aq 1 M NaOH (20
mL) and brine (20 mL). The organic layer was dried and concentrat-
ed to give crude 27 (98 mg, 96%). To a solution of crude aminal 27
(98 mg, 0.22 mmol) in acetone–H2O (4:1, 4 mL) was added Jones
Synthesis 2009, No. 17, 2983–2991 © Thieme Stuttgart · New York

2990
T. Momose et al.
PAPER
1-Benzyl 2-Methyl (2S,3S,4R)-4-[2-(Benzyloxy)ethyl]-2-formyl-
3-methyl-5-oxo-3-trimethylsilyloxypyrrolidine-1,2-dicarboxy-
late (7)
at 0 °C. After the addition of MeOH (0.5 mL) at 0 °C, the mixture
was concentrated to give a residue, which was purified by silica gel
column chromatography (EtOAc–MeOH, 1:0 → 20:1) to afford 6
(12.1 mg, 78%) as an amorphous solid; [a]D24 –54.4 (c 0.60, CHCl3)
{Lit.6j [a]D26 –50.0 (c 1.56, CHCl3)}.
To a solution of 30 (22 mg, 0.041 mmol) in t-BuOH–H2O (1:1, 2
mL) at r.t. were added OsO4 (0.25 M in t-BuOH, 0.16 mL, 0.040
mmol), NaIO4 (87 mg, 0.41 mmol), and pyridine (33 mL, 0.41
mmol). After stirring at 50 °C for 38 h, the mixture was diluted with
EtOAc (10 mL) and washed successively with H2O (10 mL) and
brine (20 mL). The organic layer was dried and concentrated to give
a residue, which was purified by silica gel column chromatography
(EtOAc–hexane, 1:5 → 1:3) to give 7 (13.7 mg, 62%) as a colorless
oil; [a]D25 +62.7 (c 0.85, CHCl3).
IR (neat): 3300, 2930, 2860, 1725, 1690, 1680, 1435, 1380, 1280
cm–1.
1H NMR (500 MHz, CDCl3): d = 8.40 (br s, 1 H, NH), 6.10 (m, 1 H,
HC=CH), 5.75 (m, 1 H, HC=CH), 5.19 (br s, 1 H, OH), 4.14 (br d,
J = 8.0 Hz, 1 H, HOCH), 4.10 (br s, 1 H, OH), 3.84 (s, 3 H, OCH3),
3.82 (dt, J = 4.9, 10.6 Hz, 1 H, HOCH2), 3.74 (dt, J = 4.0, 10.6 Hz,
1 H, HOCH2), 2.83 (dd, J = 2.6, 10.3 Hz, 1 H, H-4), 2.21 (m, 1H,
CH2CH=CHCH), 2.01 (br s, 1 H, OH), 1.98–1.93 (m, 3 H,
CHCH=CHCH2 and HOCH2CH2), 1.83–1.71 (m, 3 H, HOCH2CH2
and CH2 of cyclohexene), 1.64–1.58 (m, 2 H, CH2 of cyclohexene),
1.56 (s, 3 H, CCH3).
13C NMR (125 MHz, CDCl3): d = 180.6, 172.7, 135.3, 123.3, 81.7,
79.9, 75.3, 62.2, 52.9, 51.6, 38.6, 28.7, 26.2, 24.8, 20.3, 19.8.
HRMS-FAB: m/z [M + H+] cacld for C16H26NO6: 328.1760; found:
328.1750.
IR (neat): 2960, 2860, 1800, 1770, 1730, 1380, 1310 cm–1.
1H NMR (300 MHz, CDCl3): d = 10.10 (s, 1 H, CHO), 7.38–7.26
(m, 10 H, C6H5), 5.29 (d, J = 12.3 Hz, 1 H, PhCH2), 5.17 (br d,
J = 12.3 Hz, 1 H, PhCH2), 4.53 (d, J = 11.7 Hz, 1 H, PhCH2), 4.46
(d, J = 11.7 Hz, 1 H, PhCH2), 3.73–3.67 (m, 2 H, BnOCH2), 3.65 (s,
3 H, CO2CH3), 2.61 (dd, J = 8.4, 3.9 Hz, 1 H, H-4), 1.95 (m, 1 H,
BnOCH2CH2), 1.68 (m, 1 H, BnOCH2CH2), 1.53 (s, 3 H, CCH3),
0.10 [s, 9 H, Si(CH3)3].
13C NMR (75 MHz, CDCl3): d = 195.9, 172.9, 166.9, 138.3, 134.9,
128.6, 128.4, 128.0, 127.7, 127.6, 81.5, 81.1, 73.1, 68.7, 67.6, 52.6,
49.3, 24.6, 21.3, 2.5.
References
HRMS-ESI: m/z [M + H+] calcd for C28H36NO8Si:542.2210; found:
542.2211.
(1) (a) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman,
C. A.; Jensen, P. R.; Fenical, W. Angew. Chem. Int. Ed.
2003, 42, 355. (b) Fenical, W.; Jensen, P. R.; Palladino, M.
A.; Lam, K. S.; Lloyd, G. K.; Potts, B. C. Bioorg. Med.
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Moriguchi, R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44,
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Corey, E. J.; Schreiber, S. L. Science 1995, 268, 726.
(b) Chauhan, D.; Catley, L.; Li, G.; Podar, K.; Hideshima,
T.; Velankar, M.; Mitsiades, C.; Mitsiades, N.; Yasui, H.;
Letai, A.; Ovaa, H.; Berkers, C.; Nicholson, B.; Chao, T.-H.;
Neuteboom, S. T. C.; Richardson, P.; Palladino, M. A.;
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1-Benzyl 2-Methyl (2R,3S,4R)-4-[2-(Benzyloxy)ethyl]-2-{(S)-
[(S)-cyclohex-2-enyl)](hydroxyl)methyl}-3-methyl-5-oxo-3-tri-
methylsilyloxypyrrolidine-1,2-dicarboxylate (31)
To a solution of tri-n-butyl(cyclohex-2-enyl)stannane (131.6 mg,
0.355 mmol) in THF (3 mL) at –78 °C was added n-BuLi (1.59 M
in hexane, 0.22 mL, 0.350 mmol). After stirring at –78 °C for 20
min, to this mixture was added ZnCl2 (0.5 M in THF, 0.71 mL,
0.355 mmol) and the mixture was further stirred at –78 °C for 20
min. To the resulting solution of the cyclohex-2-enylzinc chloride
at –78 °C was added a solution of aldehyde 30 (31.0 mg, 0.0572
mmol) in THF (1.2 mL) via cannula and the mixture was stirred at
this temperature for 1 h. The mixture was quenched with H2O (0.5
mL) and diluted with EtOAc (20 mL). The mixture was washed suc-
cessively with aq sat. NH4Cl (10 mL) and brine (10 mL). The organ-
ic layer was dried and concentrated to give a residue, which was
purified by silica gel column chromatography (EtOAc–hexane, 1:5
→ 1:3) to give 31 (32.0 mg, 90%) as a colorless syrup; [a]D24 –11.0
(c 0.73, CHCl3).
IR (neat): 3200, 2960, 2860, 1750, 1705, 1460, 1380, 1250 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.32–7.25 (m, 10 H, C6H5), 6.01
(s, 1 H, OH), 5.65 (m, 1 H, CH=CH), 5.46 (m, 1 H, CH=CH), 5.12
(d, J = 3.8 Hz, 1 H, HOCH), 5.09 (d, J = 12.0 Hz, 1 H, PhCH2), 4.96
(d, J = 12.0 Hz, 1 H, PhCH2), 4.48 (s, 2 H, PhCH2), 3.76 (s, 3 H,
OCH3), 3.76–3.66 (m, 2 H, BnOCH2), 2.68 (dd, J = 9.0, 3.6 Hz, 1
H, H-4), 2.28 (m, 1 H, CH2CH=CHCH), 1.90–1.84 (m, 3 H,
(5) For comprehensive reviews on syntheses of lactacystin and
omuralide, see: (a) Corey, E. J.; Li, W.-Z. D. Chem. Pharm.
Bull. 1999, 47, 1. (b) Masse, C. E.; Morgan, A. J.; Adams,
J.; Panek, J. S. Eur. J. Org. Chem. 2000, 2513.
BnOCH2CH2 and CHCH=CHCH2), 1.71–1.40 (m,
5
H,
BnOCH2CH2 and CH2 of cyclohexene), 1.45 (s, 3 H, CCH3), 0.07
[s, 9 H, Si(CH3)3].
13C NMR (75 MHz, CDCl3): d = 177.7, 169.2, 154.4, 138.8, 135.2,
130.0, 128.5, 128.3, 128.0, 127.5, 127.4, 124.8, 86.6, 80.0, 76.3,
72.9, 69.8, 68.5, 52.4, 48.5, 38.2, 27.5, 25.2, 24.5, 21.3, 20.6, 2.7.
HRMS-ESI: m/z [M + H+] calcd for C34H46NO8Si:624.2993; found:
624.3006.
(c) Shibasaki, M.; Kanai, M.; Fukuda, N. Chem. Asian J.
2007, 2, 20.
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To a solution of 31 (29.5 mg, 0.0472 mmol) in CH2Cl2 (3 mL) was
added BCl3 (1 M in heptane, 0.19 mL, 0.19 mmol) at –20 °C. The
reaction mixture was warmed to 0 °C and further stirred for 30 min
Synthesis 2009, No. 17, 2983–2991 © Thieme Stuttgart · New York

PAPER
Retailleau, P.; Langlois, N. Tetrahedron Lett. 2007, 48, 381.
Formal Synthesis of Salinosporamide A
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Synthesis 2009, No. 17, 2983–2991 © Thieme Stuttgart · New York