Total synthesis of (-)-salinosporamide A

Article abstract of DOI:10.1002/asia.201000602

A detailed description of our second-generation total synthesis of salinosporamideA is presented. Three contiguous stereocenters in the γ-lactam structure seen in the natural product were established by stereoselective functionalization of a D-arabinose scaffold, including an Overman rearrangement to generate a highly congested tetrasubstituted carbon center. One of the definitive reactions in the synthesis was a Lewis acid mediated skeletal rearrangement of a pyranose structure, which enabled the practical conversion of the carbohydrate scaffold to the γ-lactam structure embedded in salinosporamideA. The use of a benzyl ester as a protective group for a sterically hindered carboxylic acid led to a one-pot global deprotection at the end of the synthesis. Rearrange your chemistry! The total synthesis of anticancer natural product salinosporamideA has been achieved through a unique skeletal rearrangement (see scheme). This reaction enabled the construction of the densely functionalized γ-lactam structure found in salinosporamideA through practical methodologies including an Overman rearrangement on a D-arabinose scaffold. Copyright

Full text of DOI:10.1002/asia.201000602

DOI: 10.1002/asia.201000602
Total Synthesis of (ꢀ)-Salinosporamide A
Yuji Kaiya, Jun-ichi Hasegawa, Takayuki Momose, Takaaki Sato,* and Noritaka Chida*[a]
Abstract: A detailed description of our
second-generation total synthesis of
salinosporamide A is presented. Three
contiguous stereocenters in the g-
lactam structure seen in the natural
product were established by stereose-
lective functionalization of a d-arabi-
nose scaffold, including an Overman
rearrangement to generate a highly
congested
tetrasubstituted
carbon
nose structure, which enabled the prac-
tical conversion of the carbohydrate
scaffold to the g-lactam structure em-
bedded in salinosporamide A. The use
of a benzyl ester as a protective group
for a sterically hindered carboxylic acid
led to a one-pot global deprotection at
the end of the synthesis.
center. One of the definitive reactions
in the synthesis was a Lewis acid medi-
ated skeletal rearrangement of a pyra-
Keywords: carbohydrates · inhibi-
tors · natural products · rearrange-
ment · total synthesis
Introduction
Proteasomes play a central role in the degradation of most
intracellular proteins in eukaryotes and are involved in a va-
riety of cellular process, such as protein quality control, in-
flammation, signal transduction, cell differentiation, and
apoptosis.[1] Selective inhibitors for proteasomal activity
could, therefore, be an effective tool for the treatment of
human diseases, such as inflammation and cancer, as well as
for understanding the regulatory mechanism of protea-
somes.[1] After intensive studies to identify such a promising
proteasomal inhibitor, a g-lactam–b-lactone structure was
found to be one of the most potent structural motifs.[2] In
1991, Omura isolated lactacystin (2) from the culture broth
of Streptomyces sp. OM-6519 as a small molecule with neu-
rotrophic activities,[3] and then Schreiber and Corey revealed
that the 20S proteasome was its specific cellular target.[4]
Lactacystin (2) actually acts as a proinhibitor to generate
omuralide (3) (clasto-lactacystin b-lactone), which is a cell-
permeable and direct inhibitor of proteasomes.[5] Such im-
portant biologically active compounds inspired synthetic
chemists to achieve the total syntheses of 2, 3, and their ana-
logues.[6–10]
Recently, Fenical and co-workers reported that salinospor-
amide A (also known as marizomib or NPI-0052; 1) is a
potent and selective proteasome inhibitor isolated from a
bacterium of the new genus Salinospora tropica.[11] This b-
lactone natural product has been shown to possess in vitro
cytotoxicity against many cancer cell lines with IC50 values
at 10 nm or less and is currently in clinical trials for the
treatment of cancer. Structurally, salinosporamide A is more
complex than lactacystin (2) or omuralide (3) and possesses
a highly functionalized g-lactam–b-lactone scaffold contain-
ing two contiguous tetrasubstituted carbon centers (C3 and
C4, salinosporamide numbering). The more challenging ar-
[a] Y. Kaiya, J.-i. Hasegawa, Dr. T. Momose, Dr. T. Sato, Prof. N. Chida
Department of Applied Chemistry
Faculty of Science and Technology
Keio University, 3-14-1, Hiyoshi
Kohoku-ku, Yokohama 223-8522 (Japan)
Fax : (+81)45-566-1551
E-mail: takaakis@applc.keio.ac.jp
chida@applc.keio.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000602.
Chem. Asian J. 2011, 6, 209 – 219
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209

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chitecture of salinosporamide A (1) combined with its prom-
ising biological activity makes it an attractive synthetic
target. To date, nine completed total syntheses[12] and five
formal syntheses[13] have appeared including our first-gener-
ation formal synthesis,[13f] which features a stereoselective
Overman rearrangement[14] starting from d-glucose. In this
paper, we provide full details of our new approach, which
takes advantage of a carbohydrate scaffold to control stereo-
selective functionalizations, and can be considered as a
second-generation total synthesis of salinosporamide A (1).
cessful, this unique reaction would allow us to utilize the
pyranose scaffold, for which the stereoselectivity in various
transformations could be easily predicted. Considering its
similarity to hemiacetal 5, d-arabinose (8) was envisioned as
a readily available starting material, with three stereoselec-
tive functionalizations including an Overman rearrangement
(7!6) giving rise to hemiacetal 5. Although our previous
studies have shown that use of an Overman rearrangement
on a sugar scaffold is effective for the chiral total synthesis
of natural products with an a-substituted a-amino acid
structure,[15,16] the crucial skeletal rearrangement of 5 at
such a late stage was uncertain. Prediction of the behavior
of this equilibrium reaction might be possible, however, by
comparing the heats of formation between hemiacetal 5 and
hemiaminal 4 by using quantum calculations.
Results and Discussion
In designing an efficient synthetic route to salinosporami-
de A (1), the stereocontrolled construction of the three con-
tiguous carbon centers (C2, C3, and C4) on the g-lactam
core is crucial (Scheme 1). To achieve this goal, our central
Four simplified models (9a/b and 10a/b) corresponding to
hemiacetal 5 and hemiaminal 4 were subjected to a confor-
mational search by using MacroModel version 6.0[17] (MM2*
forcefield) to give a number of local minimized structures
(Scheme 2). Each local minimum was then further refined at
Scheme 2. Heats of formation of four model compounds for the skeletal
rearrangement.
Scheme 1. Synthetic plan for the total synthesis of salinosporamide A (1).
Cbz: carbobenzyloxy; TMS: trimethylsilyl.
the PM3 level (Spartan version 5.0.3).[18] The most stable
isomer was a-hemiaminal 10a, followed by b-hemiaminal
10b. Hemiacetals 9a and 9b were calculated to be more
than 2 kcalmolꢀ1 higher in energy than 10a and 10b, respec-
tively. This outcome was encouraging as 4 could be selec-
tively formed under thermodynamic conditions, and this
suggested the feasibility of our synthetic strategy
(Scheme 1).
strategy employed a conformationally well-defined pyranose
structure derived from d-arabinose (8). We postulated that
aminal 4 would be a promising intermediate in the total syn-
thesis. In turn, we hoped that aminal 4 could be formed
through skeletal rearrangement from hemiacetal 5. If suc-
The synthesis of salinosporamide A (1) commenced with
a Wittig reaction of the known ketone 11, which was pre-
pared from d-arabinose (8) in three steps (Scheme 3).[19] Ste-
reoselective hydrogenation of 12 with Raney-Ni then oc-
curred from the opposite side of the acetonide, and the re-
maining ester was reduced with LiBH4. Benzyl protection
followed by removal of the acetonide gave diol 14. The
large coupling constants (J1,2 =8.0, J4,5ax =10.0 Hz) of 14 cal-
Abstract in Japanese:
1
culated by H NMR spectroscopic analysis revealed that 14
had a chair conformation in which the C4-hydroxy group
was in the equatorial position and the C3-hydroxy group in
210
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Chem. Asian J. 2011, 6, 209 – 219

Total Synthesis of (ꢀ)-Salinosporamide A
Scheme 3. Synthesis of trichloroacetimidate 7. DBU: 1,8-diazabicycloACTHUNGTRENUN[NG 5.4.0]undec-7-ene; DIBAL: diisobutylaluminium hydride; DMAP: 4-dimethylami-
nopyridine; Py: pyridine; pTsCl: p-toluenesulfonyl chloride.
the axial position. This conformation enabled us to differen-
tiate the diol in the next reaction. Namely, treatment of diol
14 with pTsCl, DMAP, and pyridine in CH2Cl2 resulted in
regioselective monotosylation at C4. The subsequent oxida-
tion of the remaining C3 alcohol with Ac2O/DMSO provid-
ed ketone 15.[20] Treatment of 15 with trimethylaluminum in
toluene at ꢀ408C induced the equatorial attack of the
methyl group to give tertiary alcohol 16 as the sole prod-
uct.[21] This exclusive stereoselectivity was derived from the
two adjacent substituents of the ketone forcing the reagent
to approach from the a-side.[22] Cleavage of the tosyl group
with Mg in MeOH[23] followed by Swern oxidation[24] gave
ketone 17, which was converted to enoate 18 through the
Horner–Wadsworth–Emmons olefination reaction. To set up
the crucial Overman rearrangement, tertiary alcohol 18 was
protected as a TMS ether, and the resulting enoate 19 was
converted to key intermediate 7 in two steps involving
DIBAL reduction and formation of the trichloroimidate.
With a reliable route to trichloroimidate 7 in hand, we
turned our attention to the construction of the nitrogen-con-
taining tetrasubstituted carbon center by the Overman rear-
rangement (Table 1). Trichloroimidate 7 was dissolved in a
nonpolar solvent and heated in a sealed tube. Interestingly,
the choice of the solvent was critical. The use of o-xylene at
1408C resulted in complete decomposition with or without
Na2CO3 (Table 1, entries 1, 2).[16b,25] Fortunately, the reaction
in tert-butylbenzene at 1508C with Na2CO3 provided a 4:1
mixture of rearranged products 6 and 20 in 78% combined
yield, thus favoring the desired isomer 6 (entry 3).[26,27] Ad-
dition of Na2CO3 was also found to be a requirement;
severe decomposition was observed without Na2CO3
Table 1. Overman rearrangement of 7 and the plausible transition mod-
els.[a]
Entry
Solvent
Additive
T [8C]
Yield of
6:20
6+20 [%][b]
1
2
3
o-xylene
o-xylene
tBuPh
tBuPh
tBuPh
Na2CO3
none
Na2CO3
none
140
140
150
150
170
0
0
78
0
4.0:1
3.9:1
4
5[c]
Na2CO3
94
[a] Compound
7
(40 mmol), additive (5 mgmLꢀ1), solvent (0.03m).
[b] Combined yield of isolated products after purification by column
chromatography. [c] Compound 7 (532 mmol) was used.
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211

T. Sato, N. Chida et al.
FULL PAPERS
(entry 4). The best result was obtained at 1708C, and this
gave 6 and 20 in 94% yield (6/20 3.9:1, entry 5).
conspicuous effect on the results. While the reaction did not
proceed in aqueous toluene (entry 3), the use of aqueous
MeCN furnished cyclic carbamate 22 in 78% yield
(entry 4).[29]
We next sought to further increase the yield of the skele-
tal rearrangement (Scheme 4). In the course of the reaction,
As depicted in TS-a and TS-b, we sought to rationalize
the stereochemical outcome of the Overman rearrangement
based on the steric and electronic factors affecting two
chairlike transition models (Table 1).[14] In transition-state
TS-b, the access of the imino group from the b-face would
be suppressed by the steric hindrance created by the axially
ꢀ
oriented O TMS group at C3. In addition to the steric
factor, unfavorable dipole–dipole interactions between the
ꢀ
ꢀ
C OTMS bond at C3 and the forming C N bond at C4
might destabilize the transition state. On the other hand,
transition-state TS-a would have a smaller gauche interac-
tion with the equatorially oriented methyl group at C3, as
well as an antiparallel dipole–dipole interaction, which
might not generate the electrostatic repulsion seen in TS-b
and thus lead to 6 as the major product.
ꢀ
ꢀ
After having efficiently established the C2 C3 C4 stereo-
triad by utilizing the d-arabinose scaffold, the stage was now
set for the crucial skeletal rearrangement (Table 2). First,
Table 2. Skeletal rearrangement of hydropyrans 21 and 23.[a]
Scheme 4. Mechanistic pathway for the skeletal rearrangement of
methyl- and PMB-protected hydropyrans 21 and 25. DDQ: 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone; PMB: p-methoxybenzyl ether; TBAF: tet-
rabutylammonium fluoride.
Entry
Acid
TFA
Solvent
t
Yields [%][b]
4
22
23
21
1
2
3
4
CH2Cl2
CH2Cl2
toluene
MeCN
6 h
3 d
3 d
3 d
0
0
0
0
44
22
0
0
18
87
0
Sc
Sc(OTf)3
Sc(OTf)3
A
57
0
0
N
R
78
0
the cleavage of the TMS group (21!23) occurred first, fol-
lowed by the hydrolysis of the methyl acetal (23!24). Each
step was very slow, and hemiacetal 24 was never isolated.
That is, once both the TMS group and the methyl acetal
were hydrolyzed, the skeletal rearrangement took place in
CH2Cl2/H2O spontaneously, furnishing hemiaminal 4. Simi-
lar reactivity was also observed in the reaction of PMB-pro-
tected tetrahydropyran 25, which was prepared in our first-
generation synthesis.[13f] Interestingly, removal of the PMB
group in 25 with DDQ did not promote the skeletal rear-
rangement but gave hemiacetal 26. However, subsequent
cleavage of the TMS group with TBAF led to the quick re-
arrangement of 24. In both cases, it was clear that successful
rearrangement required the two hydroxy groups at C1 and
C3 to be free. Unfortunately, the TMS group and the methyl
[a] Compound 21 (35 mmol), acid (1.5 equiv), organic solvent/H2O (10:1;
0.02m), 408C. [b] Yields of isolated product after purification by column
chromatography. TFA: trifluoroacetic acid.
the trichloroacetyl group of 6 was replaced with the Cbz
group through DIBAL reduction[15b] followed by the Schot-
ten–Baumann reaction. The resulting tetrahydropyran 21
was exposed to a 10:1 mixture of an organic solvent and
water at 408C in the presence of various acids. Several
Brønsted acids (TFA, AcOH, HCl, pTsOH·H2O) did not
promote the reaction, but cleaved the TMS group without
touching the methyl acetal (Table 2, entry 1). Next, we
screened water-compatible Lewis acids. Gratifyingly, when
we used Sc
(OTf)3 in aqueous CH2Cl2, the rearrangement
acetal were robust in the hydrolysis of 21 with ScACTHUNGTERNNU(G OTf)3, and
a prolonged reaction time caused gradual decomposition. To
overcome this unfavorable reactivity, the TMS group of 21
was first removed with TBAF in quantitative yield
212
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Total Synthesis of (ꢀ)-Salinosporamide A
tection at the end of the synthesis, the proper choice of a
protecting group for the sterically hindered carboxylic acid
was critical. For example, a sterically small methyl ester,
which could be cleaved with [MeTeAlMe2]2, proved to be
one of the reliable protecting groups in previous total syn-
theses of salinosporamide A (1)[33] and was employed in our
first-generation synthesis.[13f] However, removal would re-
quire stepwise deprotection in this case. On the other hand,
a large tert-butyl ester, which would allow a single-step
global deprotection with a Lewis acid, was not formed at
this stage due to significant steric hindrance.[12b] After sever-
al protecting groups were screened, we ultimately adopted
the benzyl group, which was introduced to the acid of 28
with benzyl bromide and K2CO3 to give 29 in 66% yield
(2 steps from 27). Protection of the tertiary alcohol of 29 as
the TMS ether followed by one-pot oxidative cleavage of
the vinyl group with OsO4, pyridine, and NaIO4 furnished
aldehyde 31.[34] Addition of 2-cyclohexenylzinc chloride to
aldehyde 31 by Coreyꢁs method[12a] proceeded in high yield
with complete diastereoselectivity. Notably, careful exposure
of 32 to BCl3 in CH2Cl2 at 08C initiated one-pot global de-
protection. The Cbz group and two benzyl groups were
cleaved, followed by hydrolysis of the TMS group to afford
carboxylic acid 33. Finally, applying the b-lactonization–
chlorination sequence developed by Corey to 33 completed
the total synthesis of salinosporamide A (1) in 76% yield in
three steps from 32.[12a] The synthetic sample was found to
Scheme 5. Improved skeletal rearrangement.
(Scheme 5). As we expected, the reaction of the resulting al-
cohol 23 with ScACHTUNGTRENNUNG(OTf)3 in aqueous CH2Cl2 proceeded more
rapidly and provided hemiaminal 4 in 72% yield as an equi-
librium mixture. Subsequently, hemiaminal 4 was converted
to g-lactam 27 in 82% yield.[30]
To complete the total synthesis, the aldehyde 27 was oxi-
dized under Kraus–Pinnick conditions, thereby providing
acid 28 (Scheme 6).[31,32] Protection of the resulting acid 28
was then considered. To achieve an efficient global depro-
1
be indistinguishable from a natural source based on H and
13C NMR and IR spectroscopy, HRMS, and optical rotation.
Conclusions
In summary, the total synthesis of salinosporamide A (1) has
been accomplished in 2.6% overall yield by a sequence of
28 steps by starting from known ketone 11, which is derived
from d-arabinose. A definitive feature of the synthesis is the
skeletal rearrangement of 21 to hemiaminal 4, which ena-
bled the implementation of a practical strategy utilizing ste-
reoselective transformations on a carbohydrate scaffold for
preparation of the highly functionalized g-lactam structure
embedded in 1. This synthesis also demonstrated that a
strategy involving an Overman rearrangement of an allylic
alcohol prepared from a carbohydrate is a powerful tool for
the synthesis of complex natural products containing an a-
substituted a-amino acid moiety.
Experimental Section
Melting points were measured with a Mitamura-Riken microbot state.
1H NMR spectra were recorded at 500 MHz and 13C NMR spectra at
125 MHz with JEOL ECA-500 spectrometers. Chemical shifts are report-
ed in ppm with reference to solvent signals (1H NMR: CDCl3 (d=
7.26 ppm), C5D5N (d=7.19, 7.55, and 8.71 ppm); 13C NMR: CDCl3 (d=
77.16 ppm) C5D5N (d=123.5, 135.5, and 149.5 ppm) Mass spectra (EI)
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
Scheme 6. Total synthesis of salinosporamide A (1). BOPCl: bis(2-oxo-3-
oxazolidinyl)phosphinic chloride; TMSOTf: trimethylsilyl trifluorome-
thane sulfonate.
Chem. Asian J. 2011, 6, 209 – 219
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213

T. Sato, N. Chida et al.
FULL PAPERS
of [a]D are recorded in units of 10ꢀ1 degcm2 gꢀ1. IR spectra were taken
with a JASCO FT/IR-200 or BRUKER ALPHA FTIR spectrometer.
Benzene, toluene, DMSO, tBuPh, MeCN, o-xylene, and DMF were dis-
tilled from CaH2. MeOH was distilled from CaSO4 (DRIERITE). Pyri-
dine was distilled from sodium hydroxide. All distilled solvents, EtOH,
THF, and CH2Cl2 were dried over activated 3 ꢂ molecular sieves. pTsCl
was recrystallized from hexane. Other commercial reagents were used
without further purification. Flash column chromatography was per-
formed on silica gel (Silica Gel 60 N; 63–210 or 40–50 mesh, KANTO
CHEMICAL CO., Tokyo, Japan). TLC was performed on Merck 60 F254
precoated silica gel plates, which were visualized by exposure to UV
(254 nm) or stained by submersion in ethanolic phosphomolybdic acid so-
lution followed by heating on a hot plate.
1:1) to give primary alcohol 13 (18.4 g, 91%) as a colorless oil; [a]D20
=
ꢀ90.0 (c=0.49 in CHCl3); IR (film): n˜ =3442, 2933, 1453, 1373 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=4.51 (d, J=7.2 Hz, 1H), 4.35 (dd, J=
7.5, 2.3 Hz, 1H), 4.21 (ddd, J=7.5, 2.3, 1.7 Hz, 1H), 3.73–3.70 (m, 2H),
3.71 (dd, J=12.9, 2.3 Hz, 1H), 3.59 (dd, J=12.9, 1.7 Hz, 1H), 3.41 (s,
3H), 2.46 (brs, 1H), 1.86 (m, 3H), 1.47 (s, 3H), 1.32 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d=109.0 (C), 101.6 (CH), 74.0 (CH), 73.6
(CH), 62.3 (CH2), 60.2 (CH2), 55.3 (CH3), 36.8 (CH), 32.8 (CH2), 26.6
(CH3), 25.0 ppm (CH3); HRMS (ESI): m/z: calcd for C11H20O5Na+:
255.1208 [M+Na]+; found: 255.1203.
Diol 14: A mixture of NaH (63% in mineral oil, 5.21 g, 137 mmol),
which had been washed with hexane and DMF (25 mL) was transferred
to a solution of primary alcohol 13 (15.9 g, 68.5 mmol), BnBr (16 mL,
140 mmol), and DMF (250 mL) at 08C. This mixture was stirred for
10 min at 08C and was allowed to warm to room temperature. After stir-
ring for 5 h at room temperature, the mixture was quenched with EtOH
(30 mL) and H2O (500 mL) at 08C and extracted with EtOAc (2ꢃ
500 mL). The organic extracts were washed with brine (500 mL), dried
over Na2SO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/hexane 1:10) to
give the benzyl ether (19.8 g, 90%) as a colorless oil; [a]2D0 =ꢀ79.0 (c=
1.58 in CHCl3); IR (film): n˜ =3281, 2924, 2856, 1650, 1549, 1454, 1370,
Enoate 12: Ethyl(triphenylphosphoranylidene)acetate (52.8 g, 151 mmol)
was added to a solution of ketone 11 (24.2 g, 119 mmol) and toluene
(250 mL) at room temperature. The mixture was stirred at room temper-
ature for 3 h and was then concentrated. The residue was purified by
silica gel column chromatography (EtOAc/hexane 1:2) to give enoate 12
(27.7 g, 85%, two isomers, E/Z 2.4:1). For analytical samples, the diaste-
reomeric mixture was purified by HPLC (PEGASIL Silica 120–5, 250ꢃ
20 mm, EtOAc/hexane 1:5, 10 mLminꢀ1; E isomer: tR =14.3, Z isomer:
tR =17.6 min).
E isomer: Pale-yellow oil; [a]D20 =ꢀ145 (c=1.34 in CHCl3); IR (film): n˜ =
1310 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.34–7.26 (m, 5H), 4.55 (d,
;
3387, 2985, 2925, 1722, 1381 cmꢀ1 1H NMR (500 MHz, CDCl3): d=6.33
;
J=12.0 Hz, 1H), 4.48 (d, J=12.0 Hz, 1H), 4.41 (d. J=7.2 Hz, 1H), 4.34
(dd, J=7.2, 2.3 Hz, 1H), 4.14 (ddd, J=7.2, 2.6, 2.3 Hz, 1H), 3.72 (dd, J=
12.6, 2.6 Hz, 1H), 3.64–3.56 (m, 2H), 3.56 (dd, J=12.6, 2.3 Hz, 1H), 3.39
(s, 3H), 1.99–1.92 (m, 1H), 1.89–1.79 (m, 2H), 1.47 (s, 3H), 1.28 ppm (s,
3H); 13C NMR (125 MHz, CDCl3): d=138.6 (C), 128.4 (CH), 127.8
(CH), 127.7 (CH), 108.8 (C), 102.2 (CH), 73.4 (CH), 72.8 (CH2), 72.7
(CH), 67.7 (CH2), 62.4 (CH2), 55.6 (CH3), 37.0 (CH), 29.1 (CH2), 26.7
(CH3), 25.0 ppm (CH3); HRMS (ESI): m/z: calcd for C18H26O5Na+:
345.1678 [M+Na]+; found: 345.1678.
(d, J=1.7 Hz, 1H), 6.02 (d, J=7.5 Hz, 1H), 5.22 (d, J=1.7 Hz, 1H), 4.31
(ddd, J=7.5, 1.8, 0.9 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.66 (dd, J=12.9,
0.9 Hz, 1H), 3.61 (dd, J=12.9, 1.8 Hz, 1H), 3.46 (s, 3H), 1.52 (s, 3H),
1.39 (s, 3H), 1.28 ppm (t, J=7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d=165.5 (C), 147.8 (C), 124.2 (CH), 110.5 (C), 97.9 (CH), 75.2 (CH),
68.6 (CH), 63.1 (CH2), 60.8 (CH2), 55.6 (CH3), 26.4 (CH3), 25.3 (CH3),
14.3 ppm (CH3); HRMS (ESI): m/z: calcd for C13H20O6Na+: 295.1158
[M+Na]+; found: 295.1151.
Z isomer: Colorless oil; [a]D20 =ꢀ112 (c=0.61 in CHCl3); IR (film): n˜ =
The benzyl ether (7.51 g, 23.3 mmol) was dissolved in AcOH/H2O (4:1,
80 mL) at room temperature. This solution was maintained for 2 d at
room temperature and was then concentrated. The residue was purified
by silica gel column chromatography (EtOAc/hexane 1:1) to give diol 14
(5.07 g, 77%) as a colorless oil; [a]2D1 =ꢀ49.6 (c=1.06 in CHCl3); IR
2986, 2932, 1718, 1668 1448, 1383 cmꢀ1 1H NMR (500 MHz, CDCl3): d=
;
6.24 (s, 1H), 6.15 (d, J=2.0 Hz, 1H), 4.76 (dd, J=5.5, 2.0 Hz, 1H), 4.22
(dd, J=5.5, 2.6 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 4.09 (dd, J=13.2,
2.6 Hz, 1H), 3.97 (d, J=13.2 Hz, 1H), 3.46 (s, 3H), 1.50 (s, 3H), 1.38 (s,
3H), 1.28 ppm (t, J=7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=165.3
(C), 150.6 (C), 118.8 (CH), 109.8 (C), 95.4 (CH), 74.0 (CH), 71.7 (CH),
60.6 (CH2), 58.1 (CH2), 55.6 (CH3), 28.0 (CH3), 26.4 (CH3), 14.3 ppm
(CH3); LRMS (EI): m/z: 272 (14%) [M]+, 257 (26), 241 (10), 227 (16),
183 (49), 169 (51), 155 (43), 125 (22), 111 (64), 97 (20), 69 (100), 59 (36);
HRMS (EI): m/z: calcd for C13H20O6: 272.1260 [M]+; found: 272.1258.
(film): n˜ =3434, 2929, 2867, 1454, 1363 cmꢀ1
;
1H NMR (500 MHz,
CDCl3): d=7.37–7.30 (m, 5H), 4.53 (d, J=11.7 Hz, 1H), 4.49 (d, J=
11.7 Hz, 1H), 4.33 (d, J=8.0 Hz, 1H), 4.03 (dd, J=3.4, 2.6 Hz, 1H), 3.80
(dd, J=10.9, 4.9 Hz, 1H), 3.74 (ddd, J=10.0, 4.9, 3.4 Hz, 1H), 3.65 (ddd,
J=9.5, 6.2, 3.7 Hz, 1H), 3.56 (dd, J=10.9, 10.0 Hz, 2H), 3.52 (ddd, J=
9.5, 8.5, 3.4 Hz, 1H), 3.42 (s, 3H), 1.91–1.79 (m, 2H), 1.71 ppm (dddd,
J=11.6, 8.0, 2.6, 2.3 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=137.6 (C),
128.7 (CH), 128.1 (CH), 128.0 (CH), 102.5 (CH), 73.5 (CH2), 68.7 (CH),
68.5 (CH2), 67.6 (CH), 64.2 (CH2), 56.7 (CH3), 44.0 (CH), 26.9 ppm
(CH2); HRMS (ESI): m/z: calcd for C15H22O5Na+: 305.1365 [M+Na]+;
found: 305.1369.
Primary alcohol 13:
A round-bottomed flask containing alkene 12
(24.8 g, 91.1 mmol, two isomers, E/Z 2.4:1), Raney-Ni (W-1; ca. 25 cm3),
and ethanol (250 mL) was fitted with a septa and a balloon of hydrogen
gas. The reaction vessel was evacuated and backfilled with hydrogen (ꢃ
3). The reaction mixture was stirred at room temperature for 18 h and
then filtered through Celite. After concentration under reduced pressure,
the residue was purified by silica gel column chromatography (EtOAc/
hexane 1:10) to give the ester (23.9 g, 96%, two isomers, d.r.=13:1). Col-
orless oil; [a]2D0 =ꢀ95.1 (c=0.93 in CHCl3); IR (film): n˜ =3407, 2925,
Ketone 15: DMAP (106 mg, 0.87 mmol) was added to a solution of diol
14 (3.45 g, 12.2 mmol), pTsCl (3.3 g, 17.4 mmol), and pyridine (50 mL) at
room temperature. This solution was maintained for 24 h at room tem-
perature and was then quenched with HCl (1m, 100 mL). The mixture
was extracted with EtOAc (2ꢃ100 mL). The organic extracts were
washed with HCl (1m, 100 mL) and brine (100 mL), dried over Na2SO4,
and then concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (EtOAc/hexane 1:1) to give the p-
toluenesulfonyl ester (4.84 g, 91%). White crystals; m.p. 117–1198C;
[a]2D0 =ꢀ19.0 (c=1.50 in CHCl3); IR (film): n˜ =3674, 2972, 2902, 1363,
1736, 1382 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=4.45 (dd, J=7.5,
2.9 Hz, 1H), 4.42 (d, J=8.0 Hz, 1H), 4.21 (ddd, J=7.5, 2.6, 2.3 Hz, 1H),
4.14 (q, J=7.2 Hz, 2H), 3.76 (dd, J=12.6, 2.6 Hz, 1H), 3.59 (dd, J=12.6,
2.3 Hz, 1H), 3.37 (s, 3H), 2.58–2.56 (m, 2H), 2.16 (dddd, J=8.0, 8.0, 6.0,
2.9 Hz, 1H), 1.46 (s, 3H), 1.30 (s, 3H), 1.26 ppm (t, J=7.2 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=172.2 (C), 109.1 (C), 100.9 (CH), 73.2
(CH), 72.7 (CH), 62.6 (CH2), 60.7 (CH2), 55.8 (CH3), 37.3 (CH), 33.8
(CH2), 26.6 (CH3), 25.0 (CH3), 14.3 ppm (CH3); HRMS (ESI): m/z: calcd
for C13H22O6Na+: 297.1314 [M+Na]+; found: 297.1312.
1251 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.79 (d, J=8.3 Hz, 2H),
;
7.38–7.29 (m, 7H), 4.50 (d, J=11.8 Hz, 1H), 4.50 (m, 1H), 4.47 (d, J=
11.8 Hz, 1H), 4.41 (d, J=6.6 Hz, 1H), 4.16 (m, 1H), 3.80 (dd, J=11.3,
8.9 Hz, 1H), 3.63 (dd, J=11.3, 4.6 Hz, 1H), 3.56 (ddd, J=9.5, 6.6, 4.6 Hz,
1H), 3.47 (ddd, J=9.5, 7.6, 4.3 Hz, 1H), 3.37 (s, 3H), 2.95 (d, J=3.7 Hz,
1H), 2.43 (s, 3H), 1.89–1.78 ppm (m, 3H); 13C NMR (125 MHz, CDCl3):
d=145.3 (C), 138.0 (C), 133.5 (C), 130.1 (CH), 128.6 (CH), 128.0 (CH),
127.9 (CH), 127.9 (CH), 102.4 (CH), 77.4 (CH), 73.2 (CH2), 68.2 (CH2),
67.2 (CH), 60.8 (CH2), 56.6 (CH3), 43.4 (CH), 26.7 (CH2), 21.8 ppm
Lithium borohydride (2.28 g, 105 mmol) was added to a solution of the
above ester (23.9 g, 87.1 mmol) and THF (250 mL) at room temperature.
This mixture was stirred for 6 h at room temperature, quenched with sa-
turated aqueous NH4Cl (500 mL) at 08C, and then extracted with EtOAc
(2ꢃ500 mL). The organic extracts were washed with brine (500 mL),
dried over Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by silica gel column chromatography (EtOAc/hexane
214
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 209 – 219

Total Synthesis of (ꢀ)-Salinosporamide A
(CH3); HRMS (ESI): m/z: calcd for C22H28O7SNa+: 459.1453 [M+Na]+;
found: 459.1447.
tracted with EtOAc (2ꢃ60 mL). The organic extracts were washed with
brine (50 mL), dried over Na2SO4, and then concentrated under reduced
pressure. The residue was purified by silica gel column chromatography
(EtOAc/hexane 1:4 to 1:1) to give ketone 17 (1.24 g, 83%) as a yellow
oil; [a]2D1 =ꢀ87.2 (c=1.4 in CHCl3); IR (film): n˜ =3741, 2931, 2858, 1729,
Acetic anhydride (11 mL, 110 mmol) was added to a solution of the p-tol-
uenesulfonyl ester (4.84 g, 11.1 mmol) and DMSO (50 mL) at 508C. This
solution was maintained for 2 h at 508C and was then quenched with
H2O (200 mL). The mixture was extracted with EtOAc (2ꢃ100 mL). The
organic extracts were washed with and brine (100 mL), dried over
Na2SO4, and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/hexane 1:6) to
give ketone 15 (4.40 g, 91%) as a colorless oil; [a]2D2 =ꢀ36.9 (c=1.16 in
1
1454, 1367 cmꢀ1; H NMR (500 MHz, CDCl3): d=7.36–7.26 (m, 5H), 4.71
(d, J=3.2 Hz, 1H), 4.51 (d, J=11.7 Hz, 1H), 4.46 (d, J=11.7 Hz, 1H),
4.33 (d, J=16.0 Hz, 1H), 4.00 (d, J=16.0 Hz, 1H), 3.64 (s, 1H), 3.57–3.53
(m, 2H), 3.41 (s, 3H), 2.28 (ddd, J=7.8, 4.6, 3.2 Hz, 1H), 1.99 (dddd, J=
14.6, 6.0, 6.0, 4.6 Hz, 1H), 1.72–1.65 (m, 1H), 1.52 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=209.6 (C), 138.2 (C), 128.5 (CH), 127.9 (CH),
127.8 (CH), 103.2 (CH), 75.5 (C), 73.1 (CH2), 68.4 (CH2), 65.3 (CH2),
56.0 (CH3), 49.5 (CH), 27.7 (CH2), 26.4 ppm (CH3); HRMS (ESI): m/z:
calcd for C16H22O5Na+: 317.1365 [M+Na]+; found: 317.1357.
CHCl3); IR (film): n˜ =2930, 2860, 1740, 1598, 1453, 1367 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d=7.83 (d, J=8.3 Hz, 2H), 7.35–7.28 (m, 7H), 4.92
(ddd, J=8.3, 6.6, 0.5 Hz, 1H), 4.46 (d, J=12.0 Hz, 1H), 4.42 (d, J=
12.0 Hz, 1H), 4.36 (dd, J=11.7, 6.6 Hz, 1H), 4.33 (d, J=7.2 Hz, 1H),
3.62 (dd, J=11.7, 8.3 Hz, 1H), 3.53 (ddd, J=9.5, 6.3, 6.0 Hz, 1H), 3.46
(ddd, J=9.5, 7.2, 6.0 Hz, 1H), 3.45 (s, 3H), 2.71 (dddd, J=7.5, 7.2, 4.9,
0.5 Hz, 1H), 2.44 (s, 3H), 2.09 (dddd, J=14.1, 7.5, 6.3, 6.0 Hz, 1H),
1.79 ppm (dddd, J=14.1, 7.2, 6.0, 4.9 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=198.6 (C), 145.4 (C), 138.4 (C), 133.2 (C), 130.0 (CH), 128.5
(CH), 128.2 (CH), 127.8 (CH), 127.7 (CH), 105.4 (CH), 77.5 (CH), 72.9
(CH2), 67.5 (CH2), 63.9 (CH2), 56.8 (CH3), 52.9 (CH), 24.7 (CH2),
21.8 ppm (CH3); HRMS (ESI): m/z: calcd for C22H26O7SNa+: 457.1297
[M+Na]+; found: 457.1295.
Enoate 18: A mixture of NaH (63% in mineral oil, 92.8 mg, 2.44 mmol),
which had been washed with hexane and THF (3 mL) was transferred to
a solution of triethyl phosphonoacetate (730 mL, 3.7 mmol) and THF
(5 mL) at 08C. This mixture was stirred for 10 min at 08C and then a so-
lution of ketone 17 (359 mg, 1.22 mmol) and THF (4.0 mL) was added
dropwise to the mixture at 08C. This mixture was allowed to warm to
room temperature and was then stirred for 7 h. After this time, the mix-
ture was quenched with HCl (0.5m, 50 mL) and extracted with EtOAc
(2ꢃ100 mL). The organic extracts were washed with brine (50 mL), dried
over Na2SO4, and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (EtOAc/hexane 1:5) to
give enoate 18 (382 mg, 86%) as a colorless oil; [a]2D2 =ꢀ95.1 (c=0.85 in
CHCl3); IR (film): n˜ =3476, 2932, 2867, 1713, 1653, 1454, 1369,
Tertiary alcohol 16: Trimethylaluminum (2.0m in toluene, 19 mL,
38 mmol) was added to a solution of ketone 15 (4.25 g, 10.0 mmol) and
toluene (50 mL) at ꢀ408C. This solution was maintained for 4 h at
ꢀ408C, quenched with HCl (1m, 45 mL) at the same temperature, and
then extracted with EtOAc (2ꢃ150 mL). The organic extracts were
washed with brine (100 mL), dried over Na2SO4, and then concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane 1:5 to 1:4) to give tertiary alcohol 16
(3.18 g, 71%) as a yellow amorphous solid; [a]2D4 =ꢀ19.5 (c=0.62 in
1329 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.36–7.27 (m, 5H), 6.07 (dd,
;
J=1.7, 1.2 Hz, 1H), 5.15 (dd, J=15.9, 1.2 Hz, 1H), 4.59 (dd, J=15.9,
1.7 Hz, 1H), 4.52 (d, J=11.7 Hz, 1H), 4.52 (d, J=4.9 Hz, 1H), 4.48 (d,
J=11.7 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.59 (ddd, J=9.5, 5.4, 5.4 Hz,
1H), 3.56 (s, 1H), 3.48 (ddd, J=9.5, 8.3, 4.6 Hz, 1H), 3.37 (s, 3H), 1.97
(dddd, J=14.6, 8.3, 5.4, 4.6 Hz, 1H), 1.90 (ddd, J=5.4, 4.9, 4.6 Hz, 1H),
1.72 (dddd, J=14.6, 5.4, 5.4, 4.6 Hz, 1H), 1.49 (s, 3H), 1.27 ppm (t, J=
7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=166.5 (C), 160.1 (C), 137.8
(C), 128.6 (CH), 127.9 (CH), 127.9 (CH), 113.5 (CH), 103.7 (CH), 73.3
(CH2), 72.0 (C), 68.6 (CH2), 60.2 (CH2), 59.9 (CH2), 55.6 (CH3), 49.2
(CH), 28.5 (CH2), 28.2 (CH3), 14.4 ppm (CH3); HRMS (ESI): m/z: calcd
for C20H28O6Na+: 387.1776 [M+Na]+; found: 387.1784.
CHCl3); IR (film): n˜ =3532, 2932, 2872, 1598, 1454, 1366 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d=7.81 (d, J=8.3 Hz, 2H), 7.35–7.28 (m, 7H), 4.51
(d, J=12.0 Hz, 1H), 4.48 (d, J=12.0 Hz, 1H), 4.37 (d, J=8.3 Hz, 1H),
4.29 (dd, J=10.3, 5.2 Hz, 1H), 3.75 (dd, J=10.9, 10.3 Hz, 1H), 3.66 (dd,
J=10.9, 5.2 Hz, 1H), 3.54 (ddd, J=9.5, 7.3, 6.0 Hz, 1H), 3.46 (ddd, J=
9.5, 6.0, 6.0 Hz, 1H), 3.36 (s, 3H), 2.81 (s, 1H), 2.45 (s, 3H), 1.94 (dddd,
J=15.0, 6.0, 6.0, 4.3 Hz, 1H), 1.72 (dddd, J=15.0, 7.3, 6.0, 5.2 Hz, 1H),
1.50 (ddd, J=8.3, 5.2, 4.3 Hz, 1H), 1.14 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=145.4 (C), 138.1 (C), 133.5 (C), 130.1 (CH), 128.5
(CH), 128.1 (CH), 127.8 (CH), 127.8 (CH), 103.0 (CH), 80.6 (CH), 73.1
(CH2), 72.1 (C), 68.5 (CH2), 61.8 (CH2), 56.9 (CH3), 47.3 (CH), 25.3
(CH2), 24.0 (CH3), 21.8 ppm (CH3); HRMS (ESI): m/z: calcd for
C23H30O7SNa+: 473.1610 [M+Na]+; found: 473.1613.
Trimethylsilyl ether 19: TMSOTf (950 mL, 5.3 mmol) was added to a so-
lution of enoate 18 (382 mg, 1.05 mmol), pyridine (510 mL, 6.3 mmol),
and CH2Cl2 (8.0 mL) at 08C. This solution was maintained for 2 h at 08C
and was then quenched with HCl (0.5m, 20 mL). The mixture was ex-
tracted with CH2Cl2 (50 mL) and EtOAc (50 mL). The organic extracts
were washed with saturated aqueous NaHCO3 (20 mL) and brine
(20 mL), dried over Na2SO4, and then concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(EtOAc/hexane 1:6) to give trimethylsilyl ether 19 (419 mg, 92%) as a
colorless oil; [a]2D0 =ꢀ41.9 (c=1.48 in CHCl3); IR (film): n˜ =2957, 1716,
Ketone 17: Magnesium (510 mg, 21.0 mmol) was added to a solution of
tertiary alcohol 16 (945 mg, 2.09 mmol) and MeOH (10 mL) at room
temperature. This mixture was stirred for 2 h at room temperature and
then quenched with H2O (150 mL). The mixture was extracted with
EtOAc (2ꢃ100 mL). The organic extracts were washed with and brine
(100 mL), dried over Na2SO4, and then concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(EtOAc/hexane 1:1) to give the diol (586 mg, 94%) as a colorless oil;
[a]1D8 =ꢀ60.6 (c=1.45 in CHCl3); IR (film): n˜ =3440, 2969, 2932, 2870,
1654, 1455, 1370 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.35–7.25 (m,
;
5H), 6.00 (s, 1H), 5.02 (d, J=14.6 Hz, 1H), 4.60 (d, J=14.6 Hz, 1H),
4.55 (d, J=3.4 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.47 (d, J=12.0 Hz,
1H), 4.17 (q, J=7.2 Hz, 1H), 3.55–3.46 (m, 2H), 3.38 (s, 3H), 2.00 (dddd,
J=14.8, 7.5, 7.5, 3.4 Hz, 1H), 1.79 (ddd, J=9.2, 3.4, 3.4 Hz, 1H), 1.60 (s,
3H), 1.59–1.49 (m, 1H), 1.29 (t, J=7.2 Hz, 3H), 0.14 ppm (s, 9H);
13C NMR (125 MHz, CDCl3): d=166.5 (C), 158.9 (C), 138.7 (C), 128.4
(CH), 127.7 (CH), 127.6 (CH), 114.2 (CH), 102.8 (CH), 75.6 (C), 73.0
(CH2), 69.3 (CH2), 60.3 (CH2), 58.9 (CH2), 55.8 (CH3), 49.6 (CH), 28.2
(CH3), 27.5 (CH2), 14.4 (CH3), 2.5 ppm (CH3); HRMS (ESI): m/z: calcd
for C23H36O6SiNa+: 459.2179 [M+Na]+; found: 459.2179.
1369 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.38–7.29 (m, 5H), 4.57 (d,
;
J=11.7 Hz, 1H), 4.53 (d, J=11.7 Hz, 1H), 4.42 (d, J=8.3 Hz, 1H), 3.83
(dd, J=11.0, 5.2 Hz, 1H), 3.59–3.50 (m, 2H), 3.52 (dd, J=11.0, 10.0 Hz,
1H), 3.43 (dd, J=10.0, 5.2 Hz, 1H), 3.39 (s, 3H), 2.00 (dddd, J=15.2, 4.9,
4.9, 4.9 Hz, 1H), 1.94–1.87 (m, 1H), 1.58 (ddd, J=8.3, 4.9, 4.9 Hz, 1H),
1.29 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=137.5 (C), 128.6
(CH), 128.1 (CH), 128.0 (CH), 102.2 (CH), 73.3 (CH2), 71.8 (C), 71.6
(CH), 67.8 (CH2), 65.3 (CH2), 56.6 (CH3), 47.3 (CH), 25.1 (CH2),
24.1 ppm (CH3); HRMS (ESI): m/z: calcd for C16H24O5Na+: 319.1521
[M+Na]+; found: 319.1514.
Trichloroacetimidate 7: DIBAL (1.0m in toluene, 2.8 mL, 2.8 mmol) was
added dropwise to a solution of enoate 19 (353 mg, 809 mmol) and tolu-
ene (6 mL) at ꢀ788C. This solution was maintained for 30 min at ꢀ788C
and was then quenched with HCl (1m, 20 mL) at the same temperature
and extracted with EtOAc (2ꢃ20 mL). The organic extracts were washed
with 1m NaOH (20 mL) and brine (20 mL), dried over Na2SO4, and then
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (EtOAc/hexane 1:3 to 1:1) to give the allylic
Sulfur trioxide pyridine complex (3.36 g, 21.1 mmol) was added to a solu-
tion of the diol (1.25 g, 4.22 mmol), Et3N (4.7 mL, 34 mmol), and DMSO
(15 mL) at room temperature. This mixture was stirred for 4 h at room
temperature and then quenched with H2O (50 mL). The mixture was ex-
Chem. Asian J. 2011, 6, 209 – 219
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
215

T. Sato, N. Chida et al.
FULL PAPERS
alcohol (309 mg, 97%) as a colorless oil; [a]2D5 =9.9 (c=0.89 in CHCl3);
quenched with 1m HCl (5 mL). The mixture was extracted with EtOAc
(2ꢃ20 mL). The organic extracts were washed with 1m HCl (15 mL), 1m
NaOH (20 mL), and brine (20 mL), dried over Na2SO4, and then concen-
trated to give the crude amine.
IR (film): n˜ =3440, 2956, 2858, 1454, 1367 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=7.34–7.26 (m, 5H), 5.75 (dd, J=7.2, 6.9 Hz, 1H), 4.53–4.47
(m, 1H), 4.50 (s, 2H), 4.49 (d, J=5.7 Hz, 1H), 4.33 (d, J=12.9 Hz, 1H),
4.26 (dd, J=12.9, 6.9 Hz, 1H), 4.19 (dd, J=12.9, 7.2 Hz, 1H), 4.19 (d, J=
12.9 Hz, 1H), 3.57 (ddd, J=9.0, 5.7, 5.7 Hz, 1H), 3.50–3.44 (m, 1H), 3.41
(s, 3H), 1.96 (dddd, J=14.3, 7.2, 5.7, 3.2 Hz, 1H), 1.62–1.53 (m, 1H), 1.50
(s, 3H), 1.46 (ddd, J=6.9, 5.7, 3.2 Hz, 1H), 0.08 ppm (s, 9H); 13C NMR
(125 MHz, CDCl3): d=141.2 (C), 138.9 (C), 128.5 (CH), 127.7 (CH),
127.6 (CH), 123.0 (CH), 104.1 (CH), 75.7 (C), 73.0 (CH2), 70.2 (CH2),
59.3 (CH2), 58.8 (CH2), 56.3 (CH3), 50.2 (CH), 27.2 (CH2), 25.8 (CH3),
2.4 ppm (CH3); HRMS (ESI): m/z: calcd for C21H34O5SiNa+: 417.2073
[M+Na]+; found: 417.2068.
Benzyl chloroformate (79 mL, 550 mmol) was added to a mixture of the
crude amine, K2CO3 (115 mg, 829 mmol), and THF/H2O (1:1, 4.0 mL) at
08C. This mixture was stirred for 3 h at 08C and then quenched with
H2O (20 mL). The mixture was extracted with EtOAc (2ꢃ 20 mL). The
organic extracts were washed with brine (20 mL), dried over Na2SO4, and
then concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexane 1:10) to give 21
(135 mg, 93% for 2 steps) as a colorless oil; [a]2D2 =27.9 (c=0.88 in
CHCl3); IR (film): n˜ =3377, 2925, 2854, 1737, 1501, 1453, 1384 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=7.38–7.32 (m, 10H), 6.11 (dd, J=17.5,
11.2 Hz, 1H), 5.34 (d, J=11.2 Hz, 1H), 5.17 (s, 1H), 5.14 (d, J=17.5 Hz,
1H), 5.06 (d, J=12.2 Hz, 1H), 4.99 (d, J=12.2 Hz, 1H), 4.52 (d, J=
12.0 Hz, 1H), 4.49 (d, J=12.0 Hz, 1H), 4.26 (d, J=8.4 Hz, 1H), 4.03 (d,
J=11.5 Hz, 1H), 3.93 (d, J=11.5 Hz, 1H), 3.64 (ddd, J=8.9, 8.0, 4.9 Hz,
1H), 3.45 (s, 3H), 3.48–3.43 (m, 1H), 1.77 (dddd, J=14.0, 8.0, 8.0, 2.3 Hz,
1H), 1.55 (ddd, J=8.4, 6.4, 2.3 Hz, 1H), 1.48–1.40 (m, 1H), 1.28 (s, 3H),
0.15 ppm (s, 9H); 13C NMR (125 MHz, CDCl3): d=138.9 (C), 136.7 (C),
134.5 (CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 128.2 (CH), 127.7
(CH), 127.6 (CH), 127.2 (C), 117.4 (CH2), 105.4 (CH), 80.7 (C), 73.0
(CH2), 70.6 (CH2), 66.7 (CH2), 66.5 (CH2), 61.2 (C), 57.1 (CH3), 44.2
(CH), 27.0 (CH2), 21.4 (CH3), 3.08 ppm (CH3): HRMS (ESI): m/z: calcd
for C29H41NO6SiNa+: 550.2601 [M+Na]+; found: 550.2593.
Trichloroacetonitrile (97 mL, 970 mmol) was added to a solution of the al-
lylic alcohol (191 mg, 484 mmol) and CH2Cl2 (4.0 mL) at 08C. This solu-
tion was maintained for 1 h at 08C and was then filtered through a pad
of silica gel (EtOAc/hexane 1:4) to give crude trichloroacetimidate 7
(791 mg, 100%) as a colorless oil; [a]2D5 =7.1 (c=1.26 in CHCl3); IR
(film): n˜ =3344, 2957, 2857, 1664, 1454, 1371 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=8.31 (brs, 1H), 7.34–7.25 (m, 5H), 5.81 (dd, J=6.9, 6.9 Hz,
1H), 4.89 (dd, J=12.6, 6.9 Hz, 1H), 4.84 (dd, J=12.6, 6.9 Hz, 1H), 4.50
(d, J=5.7 Hz, 1H), 4.50 (s, 2H), 4.41 (d, J=12.9 Hz, 1H), 4.28 (d, J=
12.9 Hz, 1H), 3.58 (ddd, J=9.3, 9.3, 5.7 Hz, 1H), 3.50–3.45 (m, 1H), 3.42
(s, 3H), 1.97 (dddd, J=14.4, 9.3, 7.2, 3.2 Hz, 1H), 1.60–1.54 (m, 1H), 1.48
(ddd, J=6.4, 5.7, 3.2 Hz, 1H), 1.51 (s, 3H), 0.08 ppm (s, 9H); 13C NMR
(125 MHz, CDCl3): d=162.5 (C), 144.8 (C), 138.8 (C), 128.4 (CH), 127.7
(CH), 127.5 (CH), 117.1 (CH), 104.0 (CH), 91.5 (C), 75.7 (C), 72.9
(CH2), 70.1 (CH2), 64.9 (CH2), 59.5 (CH2), 56.3 (CH3), 50.0 (CH), 27.2
(CH2), 25.6 (CH3), 2.4 ppm (CH3); HRMS (ESI): m/z: calcd for
C23H3435Cl3NO5SiNa+: 560.1170 [M+Na]+; found: 560.1164.
Tertiary alcohol 23: TBAF (1.0m in THF, 410 mL, 410 mmol) was added
to a solution of 21 (108 mg, 204 mmol) and THF (2 mL) at 08C. This solu-
tion was maintained for 10 min at 08C and was then quenched with H2O
(20 mL). The mixture was extracted with EtOAc (2ꢃ20 mL). The organic
extracts were washed with brine (20 mL), dried over Na2SO4, and then
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (EtOAc/hexane 1:4) to give tertiary alcohol
23 (92.5 mg, 100%) as a colorless oil; [a]2D5 =9.94 (c=0.97 in CHCl3); IR
Trichloroacetamides
6 and 20: A stirring mixture of 7 (287 mg,
531 mmol), Na2CO3 (88.5 mg, 835 mmol), and tert-butylbenzene (18 mL)
was heated to 1708C in a sealed tube. This mixture was stirred for 24 h at
1708C. After cooling, the mixture was filtrated through a pad of silica gel
(EtOAc/hexane, 1:15). After concentration under reduced pressure, the
residue was purified by silica gel column chromatography (EtOAc/
hexane 1:15) to afford trichloroacetamides 6 (215 mg, 75%) and 20
(55 mg, 19%).
(film): n˜ =3351, 2927, 1730, 1506, 1455, 1385, 1242 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): d=7.36–7.28 (m, 10H), 6.22 (dd, J=18.0, 11.2 Hz,
1H), 5.36 (dd, J=11.2, 0.9 Hz, 1H), 5.18 (dd, J=18.0, 0.9 Hz, 1H), 5.15
(s, 1H), 5.08 (d, J=12.0 Hz, 1H), 5.00 (d, J=12.0 Hz, 1H), 4.55 (d, J=
12.0 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.46 (d, J=8.6 Hz, 1H), 4.07 (d,
J=11.7 Hz, 1H), 4.01 (d, J=11.7 Hz, 1H), 3.54 (ddd, J=9.6, 8.9, 4.9 Hz,
1H), 3.53 (s, 1H), 3.48 (ddd, J=9.6, 5.4, 5.4 Hz, 1H), 3.41 (s, 3H), 1.96
(dddd, J=15.8, 5.4, 5.4, 5.4 Hz, 1H), 1.83–1.78 (m, 2H), 1.24 ppm (s,
3H); 13C NMR (125 MHz, CDCl3): d=154.6 (C), 137.7 (C), 136.6 (C),
135.0 (CH), 128.7 (CH), 128.6 (CH), 128.4 (CH), 128.3 (CH), 128.0
(CH), 128.0 (CH), 117.4 (CH2), 103.0 (CH), 74.9 (C), 73.2 (CH2), 68.0
(CH2), 66.7 (CH2), 66.3 (CH2), 61.2 (C), 56.8 (CH3), 43.8 (CH), 25.3
(CH2), 22.7 ppm (CH3); HRMS (ESI): m/z: calcd for C26H33NO6Na+:
478.2206 [M+Na]+; found: 478.2201.
Trichloroacetamide 6: Colorless oil; [a]2D1 =13.8 (c=0.79 in CHCl3); IR
(film): n˜ =3386, 2924, 2854, 1736, 1511, 1384 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=7.34–7.27 (m, 5H), 7.18 (s, 1H), 6.26 (dd, J=18.0, 11.2 Hz,
1H), 5.38 (d, J=11.2 Hz, 1H), 5.18 (d, J=18.0 Hz, 1H), 4.49 (s, 2H),
4.29 (d, J=8.6 Hz, 1H), 4.03 (d, J=11.7 Hz, 1H), 3.90 (d, J=11.7 Hz,
1H), 3.65 (ddd, J=8.7, 8.7, 4.6 Hz, 1H), 3.50 (ddd, J=8.7, 8.7, 6.9 Hz,
1H), 3.46 (s, 3H), 1.82 (dddd, J=14.2, 8.7, 8.7, 2.3 Hz, 1H), 1.60 (ddd,
J=8.6, 6.9, 2.3 Hz, 1H), 1.44 (dddd, J=14.2, 6.9, 6.9, 4.6 Hz, 1H), 1.36 (s,
3H), 0.17 ppm (s, 9H); 13C NMR (125 MHz, CDCl3): d=159.6 (C), 138.8
(C), 132.4 (CH), 128.5 (CH), 127.6 (CH), 127.5 (CH), 118.0 (CH2), 105.4
(CH), 93.7 (C), 81.0 (C), 73.0 (CH2), 70.3 (CH2), 66.7 (CH2), 62.5 (C),
57.0 (CH3), 44.4 (CH), 27.0 (CH2), 21.9 (CH3), 3.0 ppm (CH3); HRMS
(ESI): m/z: calcd for C23H3435Cl3NO5SiNa+: 560.1170 [M+Na]+; found:
560.1167.
g-Lactam 27: ScandiumACTHNUTRGNEUGN(III) trifluoromethanesulfonate (151 mg,
305 mmol) was added to a solution of tertiary alcohol 23 (92.5 mg,
203 mmol) and CH2Cl2/H2O (10:1, 2.2 mL) at room temperature. This
mixture was stirred for 24 h at 408C and was then quenched with H2O
(20 mL). The mixture was extracted with CH2Cl2 (20 mL) and EtOAc
(20 mL). The organic extracts were washed with brine (20 mL), dried
over Na2SO4, and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (EtOAc/hexane 1:1) to
give hemiaminal 4 (64.8 mg, 72%).
Trichloroacetamide 20: Pale-yellow oil; [a]2D5 =ꢀ40.3 (c=1.57 in CHCl3);
IR (film): n˜ =3388, 2954, 1729, 1493, 1361 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=7.53 (s, 1H), 7.33–7.26 (m, 5H), 5.69 (dd, J=17.5, 10.9 Hz,
1H), 5.32 (d, J=10.9 Hz, 1H), 5.22 (d, J=17.5 Hz, 1H), 4.66 (d, J=
12.3 Hz, 1H), 4.66 (d, J=1.4 Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 4.47 (d,
J=12.3 Hz, 1H), 3.81 (d, J=12.3 Hz, 1H), 3.54–3.44 (m, 2H), 3.33 (s,
3H), 2.13–2.07 (m, 1H), 1.89–1.85 (m, 1H), 1.77 (dddd, J=13.6, 11.2, 5.4,
5.4 Hz, 1H), 1.51 (s, 3H), 0.16 ppm (s, 9H); 13C NMR (125 MHz,
CDCl3): d=159.8 (C), 138.6 (C), 133.3 (CH), 128.4 (CH), 127.6 (CH),
127.6 (CH), 117.1 (CH2), 102.0 (CH), 93.8 (C), 76.4 (C), 73.0 (CH2), 69.5
(CH2), 62.6 (C), 58.4 (CH2), 55.5 (CH3), 47.5 (CH), 28.4 (CH2), 26.0
Jones reagent (2.67m solution of CrO3 in aqueous sulfuric acid, 570 mL,
1.5 mmol) was added to
a solution of hemiaminal 4 (64.8 mg,
0.147 mmol) and acetone/H2O (4:1, 2.5 mL) at 08C. This solution was
maintained for 24 h at room temperature, quenched with iPrOH (5 mL)
at 08C, and then extracted with EtOAc (2ꢃ20 mL). The organic extracts
were washed with H2O (15 mL) and brine (20 mL), dried over Na2SO4,
and then concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (EtOAc/hexane 1:1) to give g-
lactam 27 (52.6 mg, 82%) as a pale-yellow oil; [a]2D5 =1.5 (c=0.95 in
(CH3),
2.4 ppm
(CH3);
HRMS
(ESI):
m/z:
calcd
for
C23H3435Cl3NO5SiNa+: 560.1170 [M+Na]+; found: 560.1168.
Benzyl carbamate 21: DIBAL (1.0m in toluene, 560 mL, 280 mmol) was
added dropwise to a solution of 6 (149 mg, 276 mmol) and toluene (4 mL)
at ꢀ788C. This mixture was stirred for 1 h at ꢀ788C and was then
CHCl3); IR (film): n˜ =3396, 2923, 1722, 1384 cmꢀ1
;
1H NMR (500 MHz,
CDCl3): d=9.42 (s, 1H), 7.39–7.24 (m, 10H), 6.40 (dd, J=17.4, 10.9, Hz,
216
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 209 – 219

Total Synthesis of (ꢀ)-Salinosporamide A
1H), 5.30 (d, J=12.6 Hz, 1H), 5.27 (d, J=12.6 Hz, 1H), 5.25 (d, J=
10.9 Hz, 1H), 4.99 (d, J=17.4 Hz, 1H), 4.54 (s, 1H), 4.51 (d, J=11.5 Hz,
1H), 4.47 (d, J=11.5 Hz, 1H), 3.78 (ddd, J=9.9, 9.9, 2.9 Hz, 1H), 3.62
(ddd, J=9.9, 6.2, 3.4 Hz, 1H), 2.70 (dd, J=6.3, 4.6 Hz, 1H), 2.13–2.00
(m, 2H), 1.31 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=197.5 (CH),
173.6 (C), 151.3 (C), 136.8 (C), 134.8 (C), 132.1 (CH), 128.74 (CH),
128.72 (CH), 128.67 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 115.0
(CH2), 80.1 (C), 76.5 (C), 73.5 (CH2), 68.8 (CH2), 66.8 (CH2), 49.4 (CH),
23.8 (CH2), 22.0 ppm (CH3); HRMS (ESI): m/z: calcd for
C25H27NO6Na+: 460.1736 [M+Na]+; found: 460.1730.
EtOAc (2ꢃ20 mL). The organic extracts were washed with brine
(20 mL), dried over Na2SO4, and then concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:8) to give aldehyde 31 (39.2 mg, 81%) as a colorless
oil; [a]2D4 =39.4 (c=1.20 in CHCl3); IR (film): n˜ =1804, 1769, 1722, 1385,
1309, 1255, 1224, 1100 cmꢀ1 1H NMR (500 MHz, CDCl3): d=10.12 (s,
;
1H), 7.35–7.24 (m, 15H), 5.24 (d, J=12.3 Hz, 1H), 5.09 (d, J=12.3 Hz,
1H), 5.13–4.90 (m, 2H), 4.53 (d, J=12.0 Hz, 1H), 4.46 (d, J=12.0 Hz,
1H), 3.74–3.67 (m, 2H), 2.61 (dd, J=8.3, 3.8 Hz, 1H), 1.96 (dddd, J=
14.5, 8.3, 5.2, 5.2 Hz, 1H), 1.68 (dddd, J=14.5, 8.3, 6.6, 3.7 Hz, 1H), 1.56
(s, 3H), 0.09 ppm (s, 9H); 13C NMR (125 MHz, CDCl3): d=196.1 (CH),
173.1 (C), 173.1 (C), 166.5 (C), 138.4 (C), 134.8 (C), 134.4 (C), 128.78
(CH), 128.76 (CH), 128.69 (CH), 128.52 (CH), 128.49 (CH), 128.44 (CH),
128.0 (CH), 127.84 (CH), 127.75 (CH), 81.7 (C), 81.3 (C), 73.2 (CH2),
68.9 (CH2), 68.1 (CH2), 67.7 (CH2), 49.4 (CH), 24.8 (CH2), 21.4 (CH3),
2.7 ppm (CH3); HRMS (ESI): m/z: calcd for C34H40NO8Si+: 618.2523
[M+H]+; found: 618.2526.
Benzyl ester 29: Sodium chlorite (55.0 mg, 608 mmol) was added to a mix-
ture of aldehyde 27 (53.0 mg, 121 mmol), NaH2PO4 (73.0 mg, 608 mmol),
2-methyl-2-butene (130 mL, 1.23 mmol), and tert-BuOH/H2O (3:1,
3.0 mL) at room temperature. The mixture was stirred for 12 h at room
temperature and was then quenched with H2O (20 mL). The mixture was
extracted with EtOAc (2ꢃ20 mL). The organic extracts were washed
with brine (20 mL), dried over Na2SO4, and then concentrated to give
crude carboxylic acid 28.
Secondary alcohol 32: n-Butyl lithium (1.6m in hexane, 410 mL,
640 mmol) was added to a solution of tri-n-butyl(cyclohex-2-enyl)stan-
nane (236 mg, 636 mmol) and THF (3.0 mL) at ꢀ788C. The resulting solu-
tion was maintained for 20 min at ꢀ788C, and then ZnCl2 (0.5m in THF,
710 mL, 640 mmol) was added at the same temperature. This mixture was
stirred for 20 min at ꢀ788C to give the 2-cyclohexenylzinc chloride. 2-Cy-
clohexenylzinc chloride was added to a solution of aldehyde 31 (39.2 mg,
63.7 mmol) and THF (1.2 mL) at ꢀ788C by cannula. The mixture was
stirred for 6 h at the same temperature, quenched with H2O (0.5 mL) at
ꢀ788C, and extracted with EtOAc (2ꢃ20 mL). The organic extracts were
washed with saturated aqueous NH4Cl (10 mL) and brine (10 mL), dried
over Na2SO4, and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (EtOAc/hexane 1:8 to
1:3) to give alcohol 32 (44.6 mg, 100%). Colorless oil; [a]2D2 =ꢀ12.8 (c=
Benzyl bromide (43 mL, 362 mmol) was added to a mixture of carboxylic
acid 28, K2CO3 (50 mg, 362 mmol), and DMF (1.0 mL) at room tempera-
ture. This mixture was stirred for 1 h at room temperature and was then
quenched with H2O (20 mL). The mixture was extracted with EtOAc (2ꢃ
20 mL). The organic extracts were washed with brine (20 mL), dried over
Na2SO4, and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/hexane 1:2) to
give benzyl ester 29 (43.4 mg, 66%) as a colorless oil; [a]2D4 =ꢀ7.9 (c=
1.00 in CHCl3); IR (film): n˜ =3471, 3380, 1790, 1732, 1455, 1383 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=7.38–7.22 (m, 15H), 6.46 (dd, J=17.5,
10.9 Hz, 1H), 5.26 (d, J=10.9 Hz, 1H,), 5.18 (d, J=12.3 Hz, 1H), 5.12 (d,
J=12.3 Hz, 1H), 5.08 (d, J=12.3 Hz, 1H), 5.05 (d, J=12.3 Hz, 1H), 5.01
(d, J=17.5 Hz, 1H), 4.50 (d, J=11.7 Hz, 1H), 4.44 (d, J=11.7 Hz, 1H),
3.88 (s, 1H), 3.77 (ddd, J=9.5, 7.7, 4.3 Hz, 1H), 3.64 (ddd, J=9.5, 6.6,
4.3 Hz, 1H), 2.70 (dd, J=6.4, 5.4 Hz, 1H), 2.10–1.99 (m, 2H), 1.36 ppm
(s, 3H); 13C NMR (125 MHz, CDCl3): d=173.5 (C), 167.7 (C), 151.1 (C),
137.5 (C), 135.3 (C), 135.2 (C), 133.2 (CH), 128.7 (CH), 128.7 (CH),
128.6 (CH), 128.6 (CH), 128.5 (CH), 128.33 (CH), 128.28 (CH), 128.1
(CH), 127.9 (CH), 115.0 (CH2), 78.1 (C), 77.2 (C), 73.2 (CH2), 68.3
(CH2), 67.8 (CH2), 67.1 (CH2), 48.0 (CH), 23.8 (CH2), 21.9 ppm (CH3);
HRMS (ESI): m/z: calcd for C32H33NO7Na+ [M+Na]+ 566.2155; found:
566.2149.
1
0.97 in CHCl3); IR (film): n˜ =3196, 1750, 1705, 1455, 1381 cmꢀ1; H NMR
(500 MHz, CDCl3): d=7.38–7.22 (m, 15H), 6.07 (s, 1H), 5.58 (dddd, J=
10.0, 3.4, 3.4, 3.4 Hz, 1H), 5.45 (d, J=10.0 Hz, 1H), 5.39–5.00 (m, 2H),
5.08 (d, J=3.1 Hz, 1H), 5.07 (d, J=12.3 Hz, 1H), 4.94 (d, J=12.3 Hz,
1H), 4.49 (d, J=12.3 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 3.75 (ddd, J=
9.3, 6.6, 4.6 Hz, 1H), 3.66 (ddd, J=9.3, 9.3, 6.0 Hz, 1H), 2.67 (dd, J=9.0,
3.7 Hz, 1H), 2.04 (m, 1H), 1.90 (dddd, J=13.9, 9.3, 6.0, 4.6 Hz, 1H),
1.80–1.75 (m, 2H), 1.65–1.59 (m, 1H), 1.54–1.45 (m, 1H), 1.46 (s, 3H),
1.39–1.25 (m, 2H), 1.15–1.05 (m, 1H), 0.07 ppm (s, 9H); 13C NMR
(125 MHz, CDCl3): d=177.9 (C), 168.6 (C), 154.5 (C), 138.9 (C), 135.3
(C), 134.5 (C), 130.1 (CH), 129.1 (CH), 129.0 (CH), 128.9 (CH), 128.60
(CH), 128.57 (CH), 128.4 (CH), 128.1 (CH), 127.7 (CH), 127.5 (CH),
124.9 (CH), 86.7 (C), 80.1 (CH), 76.6 (C), 73.0 (CH2), 69.9 (CH2), 68.6
(CH2), 67.9 (CH2), 48.6 (CH), 38.3 (CH), 27.9 (CH2), 25.3 (CH2), 24.6
(CH2), 21.5 (CH2), 20.7 (CH3), 2.9 ppm (CH3); HRMS (ESI): m/z: calcd
for C40H50NO8Si+: 700.3306 [M+H]+; found: 700.3303.
Trimethylsilyl ether 30: TMSOTf (81 mL, 450 mmol) was added to a solu-
tion of benzyl ester 29 (48.6 mg, 89.4 mmol), 2,6-lutidine (100 mL,
890 mmol), and DMF (1.0 mL) at room temperature. This solution was
maintained for 2 h at 608C and then quenched with saturated aqueous
NH4Cl (25 mL) at room temperature. The mixture was extracted with
EtOAc (2ꢃ20 mL). The organic extracts were washed with brine
(20 mL), dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (EtOAc/
hexane 1:4) to give trimethylsilyl ether 30 (47.0 mg, 85%) as a colorless
oil; [a]2D5 =30.5 (c=0.93 in CHCl3); IR (film): n˜ =1796, 1750, 1731,
Salinosporamide A (1): Boron trichloride (1.0m in heptane, 440 mL,
440 mmol) was added to a solution of 31 (38.7 mg, 55.3 mmol) and CH2Cl2
(3.0 mL) at 08C. After this solution had been maintained for 40 min at
08C, H2O (0.2 mL) was added to the solution at the same temperature.
This solution was stirred for 20 min at 08C and then concentrated. The
residue was dried by azeotropic distillation with EtOH to give the crude
carboxylic acid 33.
1
1382 cmꢀ1; H NMR (500 MHz, CDCl3): d=7.34–7.23 (m, 15H), 6.46 (dd,
J=17.5, 10.9 Hz, 1H), 5.26 (d, J=10.9 Hz, 1H), 5.13 (d, J=12.6 Hz, 1H),
5.07 (brd, J=12.6 Hz, 1H), 5.04 (d, J=12.6 Hz, 1H), 5.00 (d, J=17.5 Hz,
1H), 4.90 (d, J=12.6 Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 4.49 (d, J=
12.3 Hz, 1H), 3.76–3.73 (m, 2H), 2.60 (dd, J=8.5, 3.4 Hz, 1H), 1.98
(dddd, J=13.5, 8.5, 5.2, 5.2 Hz, 1H), 1.69 (dddd, J=13.5, 7.5, 7.5, 3.4 Hz,
1H), 1.50 (s, 3H), 0.08 ppm (s, 9H); 13C NMR (125 MHz, CDCl3): d=
174.2 (C), 174.2 (C), 151.1 (C), 138.6 (C), 135.2 (C), 134.9 (C), 133.4
(CH), 128.7 (CH), 128.53 (CH), 128.47 (CH), 128.45 (CH), 128.2 (CH),
128.2 (CH), 127.9 (CH), 127.73 (CH), 127.69 (CH), 115.2 (CH2), 82.9 (C),
78.5 (C), 73.0 (CH2), 68.0 (CH2), 67.9 (CH2), 67.7 (CH2), 47.7 (CH), 24.7
(CH2), 20.9 (CH3), 2.7 ppm (CH3); HRMS (ESI): m/z: calcd for
C35H42NO7Si+: 616.2731 [M+H]+; found: 616.2731.
BOPCl (42.2 mg, 168 mmol) was added to a solution of carboxylic acid
33, pyridine (0.2 mL), and CH2Cl2 (2.0 mL) at room temperature. This
mixture was stirred for 2 h at room temperature and then concentrated
to give the crude b-lactone.
Dichlorotriphenylphosphorane (184 mg, 552 mmol) was added to a solu-
tion of the crude b-lactone, MeCN (1 mL), and pyridine (1 mL) at room
temperature. This mixture was stirred for 3 h at room temperature and
then concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexane 1:4 to 1:1) to give sali-
nosporamide A (1) (13.2 mg, 76% for 3 steps) as white crystals; m.p.
167–1698C; [a]D21 =ꢀ75.6 (c=0.12 in MeOH) (lit.:[11a] [a]2D6 =ꢀ72.9 (c=
Aldehyde 31: Osmium tetroxide (0.25m in tBuOH, 310 mL, 80 mmol) was
added to a mixture of trimethylsilyl ether 30 (48.4 mg, 79.9 mmol), NaIO4
(168 mg, 780 mmol), pyridine (64 mL, 780 mmol), and tBuOH/H2O (1:1,
4.0 mL) at room temperature. This mixture was stirred for 18 h at 508C
and then quenched with H2O (20 mL). The mixture was extracted with
0.55 in MeOH); lit.:[12a] [a]D23 =ꢀ73.2 (c=0.49 in MeOH); lit.:[12b] [a]D23
=
ꢀ73.0 (c=0.40 in MeOH); lit.:[12g] [a]2D6 =ꢀ76.0 (c=0.48 in MeOH);
lit.:[12h] [a]2D2 =ꢀ75.8 (c=0.2 in MeOH); IR (film): n˜ =3367, 1824, 1700,
Chem. Asian J. 2011, 6, 209 – 219
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
217

T. Sato, N. Chida et al.
FULL PAPERS
1442, 1385, 1242 cmꢀ1
;
1H NMR (500 MHz, C5D5N): d=10.62 (s, 1H),
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6.41 (d, J=10.3 Hz, 1H), 5.91–5.86 (m, 1H), 4.25 (d, J=8.9 Hz, 1H),
4.16–4.10 (m, 1H), 4.05–3.98 (m, 1H), 3.18 (m, 1H), 2.89–2.81 (m, 1H),
2.53–2.44 (m, 1H), 2.36–2.27 (m, 2H), 2.07 (s, 3H), 1.99–1.88 (m, 2H),
1.74–1.66 (m, 2H), 1.41–1.33 ppm (m, 1H); 13C NMR (125 MHz, C5D5N):
d=176.4 (C), 169.0 (C), 128.6 (CH), 128.2 (CH), 85.9 (C), 79.9 (C), 70.5
(CH), 45.7 (CH), 42.8 (CH2), 38.8 (CH), 28.5 (CH2), 26.0 (CH2), 24.9
(CH2), 21.3 (CH2), 19.5 ppm (CH3); HRMS (ESI): m/z: calcd for
C15H2035ClNNaO4Na+: 336.0979 [M+Na]+; found: 336.0981.
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Acknowledgements
Support from a Grant-in-Aid for Scientific Research (B20350021) from
the Ministry of Education, Culture, Sports, Science and Technology,
Japan is gratefully acknowledged. We thank Prof. S. Hatakeyama in Na-
gasaki University for useful discussions.
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Total Synthesis of (ꢀ)-Salinosporamide A
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Received: August 24, 2010
Published online: November 5, 2010
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
219