Asymmetric formal synthesis of (+)-lactacystin

Article abstract of DOI:10.1002/ejoc.201402700

A formal synthesis of (+)-lactacystin was achieved from commercially available isobutyraldehyde and ethyl acrylate. A Baylis-Hillman reaction, an intermolecular nucleophilic displacement under Mitsunobu conditions, a Sharpless asymmetric epoxidation, a palladium(0)-catalyzed syn-selective ring opening of an epoxide by treatment with an azide, a one-pot azide reductive lactamization, and a ruthenium-catayzed oxidation were employed as the key steps. A formal synthesis of (+)-lactacystin was achieved from readily available isobutyraldehyde and ethyl acrylate by using a Baylis-Hillman reaction, an intermolecular nucleophilic displacement under Mitsunobu conditions, a Sharpless asymmetric epoxidation, a palladium-catalyzed syn-selective ring opening of an epoxide, an azide reductive lactamization, and a ruthenium-catalyzed oxidation as the key steps.

Full text of DOI:10.1002/ejoc.201402700

Job/Unit: O42700
/KAP1
Date: 13-08-14 18:32:02
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201402700
Asymmetric Formal Synthesis of (+)-Lactacystin
[
a]
[a,b]
[a]
Chirumarry Sridhar, Bodduri V. D. Vijaykumar,
Laghuvarapu Radhika,
[
b]
[a]
Dong-Soo Shin,* and Srivari Chandrasekhar*
Keywords: Natural products / Lactams / Asymmetric synthesis / Epoxidation / Chiral resolution / Palladium
A formal synthesis of (+)-lactacystin was achieved from com-
mercially available isobutyraldehyde and ethyl acrylate. A
Baylis–Hillman reaction, an intermolecular nucleophilic dis-
metric epoxidation, a palladium(0)-catalyzed syn-selective
ring opening of an epoxide by treatment with an azide, a
one-pot azide reductive lactamization, and a ruthenium-
placement under Mitsunobu conditions, a Sharpless asym- catayzed oxidation were employed as the key steps.
Introduction
The (20S) proteasomes play an important role in the pro-
teolytic degradation of damaged or misfolded cellular pro-
teins of living cells and in the turnover of proteins to con-
[
1]
trol cell growth, cell division, regulation, and metabolism.
The proteasome inhibitors can effect the accumulation of
proteasome substrates, which include cyclins and transcrip-
tion factors, as well as induce cell-cycle arrest with apop-
totic program activation, and thus are effective anticancer
drugs. Targeting the ubiquitin-proteasome pathway in
protein degradation is an essential tool to develop mecha-
Figure 1. Structures of lactacystin (1) and clasto-lactacystin β-lact-
one (2).
[
2]
The stereoselective construction of the nitrogen-substi-
tuted quaternary carbon atom was the most challenging
task amongst all divergent synthetic strategies that were em-
ployed of the asymmetric and chiral approaches for the syn-
theses of lactacystin (1). Some notable strategies to install
the amine-containing quaternary carbon stereocenter of 1
nism-based drugs for many diseases such as neurodegener-
ative disorders, malignancies, and tumorigenesis.[3] Lacta-
cystin (1), a structurally new microbial natural product (see
Figure 1), inhibits cell cycle progression that is mediated by
proteasomes and induces neurite outgrowth in a murine
[
8c,8i,8k,8x]
neuroblastoma cell line.[4] Lactacystin was isolated from a
include an aldol condensation,
an Overman rear-
[
8e,8af]
Brown’s asymmetric crotylation,[8o] a cata-
rangement,
lytic Michael addition of a β-silyl unsaturated imide,
Streptomyces strain and characterized by Omura et al. in
[8s]
[
5]
a
1
991. After its first isolation, lactacystin attracted much
[
8u]
[8w]
Strecker reaction,
an Ugi reaction,
dition of trimethylsilyl cyanide to an acyliminium ion,
and the use of some chiral building blocks.
a selective ad-
attention in protein biochemistry and cell biology, and it
[8y]
thus became a potential drug candidate for the treatment
[
8z]
of asthma, arthritis, heart attacks, and strokes.[6] β-Lactone
In recent
[
8ab,8ae]
years, Hayes et al.
reported two syntheses of 1 that
2
is another acylating derivative of lactacystin and similarly
[
7]
use an alkylidene carbene 1,5-CH insertion and a diastereo-
selective enolate acylation to construct the chiral amine,
deactivates the (20S) proteasome at a much faster rate.
Because of the high demand and scarcity of natural lacta-
cystin, tremendous work has been done with regard to its
laboratory synthesis, and a great number of total and for-
[
8ad]
whereas Gu and Silverman
exploited a Dieckmann con-
densation approach. Herein, we have employed a successful
[
9a]
[8]
method previously performed by our group to introduce
an azide moiety, which can then be converted into the re-
quired amine at the quaternary carbon atom.
mal syntheses have been achieved since the Corey et al.
[
8a]
report in 1992.
[
[
a] Division of Natural Products Chemistry, Indian Institute of
Chemical Technology,
Results and Discussion
Hyderabad 500007, India
E-mail: srivaric@iict.res.in
b] Department of Chemistry, Changwon National University,
Our group has been engaged in the total synthesis of al-
kaloids that contain various nitrogen heterocycles such as
pyrrolidines, piperidines, and indolizidines. In continua-
tion of our efforts towards the synthesis of the pyrrolidine
9
, Sarim-dong, Changwon, GN 641-773, S. Korea
E-mail: dsshin@changwon.ac.kr
[
9]
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402700.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42700
/KAP1
Date: 13-08-14 18:32:02
Pages: 7
D.-S. Shin, S. Chandrasekhar et al.
FULL PAPER
class of bioactive natural products, we embarked on the ploying a Sharpless asymmetric epoxidation under standard
asymmetric synthesis of (+)-lactacystin, another fascinating conditions that included (+)-diethyl tartrate [(+)-DET],
target. As described earlier, it is evident that the asymmetric tert-butylhydroperoxide (TBHP), and Ti(OiPr) to give chi-
4
construction of the nitrogen-substituted quaternary ste- ral epoxy alcohol 12 in 95% yield and with Ͼ96%ee (Chiral
[
14,15]
reocenter is our foremost priority. With this intention, we Pak OD-H, 250ϫ4.6 mm, 5 µm).
relied on the Sharpless asymmetric epoxidation of an atom-
economic Baylis–Hillman derivative as a key tool for the
chirality induction and then a palladium-catalyzed stereo-
specific quaternary azide substitution. The retrosynthetic
strategy to synthesize (+)-lactacystin (1) is summarized be-
low (see Scheme 1). (+)-Lactacystin (1) can be obtained
from the known key pyroglutamic ester 3,[
8u]
which is
formed from a one-pot reductive cyclization of azido deriv-
ative 4 by using a hydrogenation reaction in presence of
palladium on activated charcoal. This crucial azide 4 can
be synthesized by employing a tetrakis(triphenylphosphine)
palladium(0)-catalyzed syn-selective ring opening of the ep-
oxide of α,β-unsaturated γ,δ-epoxy ester 5 by treatment
with an azide through Miyashita’s approach (with double
inversion of epoxide).[
10]
Ester 5 can be obtained by a
Sharpless asymmetric epoxidation of alcohol 6, which in
turn can be synthesized through a Baylis–Hillman reaction Scheme 2. Synthesis of Sharpless epoxide 12.
from commercially available isobutyraldehyde 7 and ethyl
cinnamate 8.
The oxidation of epoxy alcohol 12 by treatment with 2-
iodoxybenzoic acid (IBX) in ethyl acetate (EtOAc) afforded
an aldehyde, which was subjected to a two-carbon homolo-
gation by using a Wittig reaction with a stable ylide [i.e.,
(ethoxycarbonylmethylene)triphenylphosphorane] in benz-
ene to furnish the (E)-α,β-unsaturated γ,δ-epoxy ester 5
1
[
9
separable isomers; (E)/(Z) = 95:5 by H NMR analysis] in
1
0% yield (see Scheme 3). The H NMR spectrum of the
major isomer 5 showed two doublets at δ = 7.05 ppm (J =
5.6 Hz, 1 H) and δ = 6.09 ppm (J = 15.6 Hz, 1 H) for the
1
olefin protons, which support the (E) geometry of the
double bond. The stage was now ready for the deliberate
stereo- and regioselective epoxide ring-opening reaction. In
this regard, epoxy ester 5 was treated with TMSN , accord-
3
[
10]
ing to the procedure of Miyashita,
in the presence of a
catalytic amount of tetrakis(triphenylphosphine)palla-
Scheme 1. Retrosynthetic analysis of (+)-lactacystin (Boc = tert-
butoxycarbonyl, TMS = trimethylsilyl).
dium(0) in THF to afford quaternary azide 4 with a dr of
[
15]
1
00% (by LC–MS analysis ).
First, isobutyraldehyde 7 was treated with ethyl acrylate
8
in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO)
in the solvent polyethylene glycol (PEG) to yield Baylis–
Hillman adduct 9 in 70% yield (see Scheme 2).[ Adduct
11]
9
was then subjected to an intermolecular nucleophilic dis-
placement reaction with benzoic acid by using Mistunobu
conditions with diisopropyl azodicarboxylate (DIAD) and
Ph P in tetrahydrofuran (THF) to achieve a benzoate,
3
which was treated with K CO in MeOH to afford primary
2
3
[
12]
allylic alcohol 6. The treatment of primary alcohol 6 with
NaH, BnBr, and a catalytic amount of tetra-n-butylammo-
nium iodide (TBAI) in N,N-dimethylformamide (DMF) af-
forded benzylic ether 10 in 81% yield.[ The classical re-
duction of unsaturated ester 10 was achieved by using diiso-
butylaluminum hydride (DIBAL) in CH Cl to afford pri-
13]
Scheme 3. Synthesis of 4,5-syn-disubstituted azide 4.
2
2
mary allyl alcohol 11 in 96% yield. The next task to intro-
The desired azide group was regioselectively substituted
duce chirality into allylic alcohol 11 was achieved by em- at the epoxide of (E)-α,β-unsaturated γ,δ-epoxy ester 5 with
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42700
/KAP1
Date: 13-08-14 18:32:02
Pages: 7
Asymmetric Formal Synthesis of (+)-Lactacystin
retention of configuration by taking advantage of the for- Conclusions
mation of a (π-allyl)Pd complex with the neighboring olefin
We have successfully achieved the formal synthesis of
+)-lactacystin by starting from commercially available iso-
moiety followed by a double inversion (see Scheme 3). Thus,
we were able to isolate the single diastereomer 4,5-syn-
disubstituted azide 4, unlike the reported syn-azido
(
butyraldehyde and ethyl acrylate. A palladium(0)-catalyzed
syn-selective ring opening of an epoxide by treatment with
an azide was employed to install the amino-substituted qua-
ternary carbon stereocenter. The other key steps involved
a Baylis–Hillman reaction, an inversion under Mitsunobu
conditions, a Sharpless asymmetric epoxidation, a one-pot
reductive lactamization, and a ruthenium-mediated oxi-
dation. We strongly believe that this synthetic study pro-
vides a new strategy for the stereospecific syntheses of po-
tential proteasome inhibitors, (+)-lactacystin, and its ana-
logues, which include clasto-lactacystin β-lactone.
[
9a,10]
1
alcohol.
The H NMR spectrum of compound 4
showed two doublets at δ = 6.94 ppm (J = 15.8 Hz, 1 H)
and δ = 6.10 ppm (J = 15.8 Hz, 1 H) for the olefin protons
and a singlet at δ = –0.05 ppm (9 H) for the TMS protons.
–
1
The IR absorption at ν˜ = 2115 cm clearly indicates the
installation of the azide group.
4,5-syn-Disubstituted azide 4 was then subjected to a hy-
drogenation by using Pd/C and H gas (1 atm) in MeOH in
2
the presence of Na CO and a catalytic amount of ammo-
2
3
nium acetate to facilitate the one-pot reductive lactam-
ization, which occurred through the reduction of the azide
and double bond followed by cyclization to give lactam 13
in 78% yield (see Scheme 4). During the hydrogenation, the
Experimental Section
TMS ether was also cleaved to provide the corresponding General Methods: FTIR spectra were recorded as KBr thin films
alcohol. The IR spectra showed a band at ν˜ = 1684 cm–1 or neat. For low-resolution (MS) and high-resolution mass spec-
(
C=O ), which confirmed the formation of the γ-butyrol- trometry (HRMS), the m/z (mass/charge) ratios are reported as val-
str
ues in atomic mass units. All reagents and solvents were reagent
actam. The alcohol moiety of lactam 13 was then treated
with acetic anhydride in pyridine as the solvent and a cata-
lytic amount of 4-(dimethylamino)pyridine (DMAP) to af-
ford acetate 14 in 96% yield. Further treatment of acetate
grade and used without further purification, unless otherwise speci-
fied. The technical grade ethyl acetate and petroleum ether for
column chromatography were distilled prior to use. Column
chromatography was performed with silica gel (60–120 mesh) that
was packed into a glass column. All reactions were performed un-
der nitrogen by using flame- or oven-dried glassware and magnetic
stirring. IR spectra were recorded with a Thermo Nicolet Nexus
1
4 with triethylamine and (Boc) O in CH Cl afforded 15
2 2 2
in 97% yield. The benzylic ether moiety of 15 was cleaved
by hydrogenation in the presence of a catalytic amount of
–
1
1
Pd/C in MeOH to give primary alcohol 16 in 91% yield. 670 spectrometer and are reported in wavenumbers (cm ).
Primary alcohol 16 was subjected to an oxidation in the NMR spectra were recorded at 300, 400, and 500 MHz and
H
C
1
3
presence of catalytic RuCl and NaIO in H O/CCl /MeCN NMR spectra at 75 and 125 MHz with Avance-300, Inova-400 and
3
4
2
4
3
Avance-500 spectrometers in CDCl solution unless otherwise men-
(
2:1:1) as the solvent mixture to give Boc-protected pyro-
[16]
tioned. High-resolution mass spectra (HRMS) (ESI+) were ob-
tained with either a TOF or a double focusing spectrometer Or-
bitrap Exactive (Thermo Scientific, Germany).
glutamic acid derivative 17 in 79% yield. Finally, acid 17
was esterified by using ethanol, 1-ethyl-3-[3-(dimeth-
ylamino)propyl]carbodiimide hydrochloride (EDC·HCl),
and DMAP to provide ethyl ester 3 in 57% yield to realize
the formal synthesis of (+)-lactacystin. All analytical data
Ethyl 3-Hydroxy-4-methyl-2-methylenepentanoate (9): Isobutyral-
dehyde (7, 15 g, 0.2 mol), ethyl acrylate (8, 33.9 g, 0.3 mol) and
DABCO (20 mol-%) were added to polyethylene glycol 400 at room
temperature. The reaction reached completion within 4 h, and the
product was isolated by extraction with diethyl ether (5ϫ 50 mL).
Evaporation of the solvent gave a residue, which was purified by
column chromatography (60–120 silica gel; EtOAc/hexane, 1:5) to
afford alcohol 9 (25 g, 70% yield) as a colorless liquid. IR (neat):
1
13
(
H NMR, C NMR, and MS) of 3 were in accordance
[8u]
with those reported.
–
1 1
ν˜ max = 3501, 2965, 1714, 1265, 1027 cm . H NMR (300 MHz,
CDCl ): δ = 6.25 (d, J = 1.5 Hz, 1 H), 5.75–5.77 (m, 1 H), 4.22 (q,
J = 6.7, 14.3 Hz, 2 H), 4.11 (d, J = 6.7 Hz, 1 H), 3.24 (br. s, 1 H),
3
1
0
1
.91 (m, 1 H), 1.31 (t, J = 6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H),
1
3
.88 (d, J = 6.7 Hz, 3 H) ppm. C NMR (75 MHz, CDCl
66.5, 141.5, 125.5, 77.1, 60.5, 32.5, 19.3, 17.3, 13.9 ppm. HRMS:
[M + Na]+ 195.0992; found 195.0980.
3
): δ =
9 16 3
calcd. for C H O
Methyl (E)-2-(Hydroxymethyl)-4-methylpent-2-enoate (6): To a
solution of allylic alcohol 9 (10 g, 0.06 mol) in THF (70 mL) were
add PPh
The clear solution was cooled to 0 °C, and DIAD (18.6 mL,
.09 mmol) was added over a period of 10 min. The reaction mix-
3
(24 g, 0.09 mmol) and benzoic acid (11.5 g, 0.09 mmol).
0
ture was stirred at 0 °C until TLC analysis showed consumption of
the starting material (15 min). The solution was diluted with diethyl
ether (100 mL) and H
The organic layer was washed with H
NaOH (1.0 n solution, 2ϫ 100 mL). The aqueous layer was ex-
2
O (10 mL), and the layers were separated.
2
O (100 mL) and aqueous
Scheme 4. Formal synthesis of (+)-lactacystin (Py = pyridine).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42700
/KAP1
Date: 13-08-14 18:32:02
Pages: 7
D.-S. Shin, S. Chandrasekhar et al.
(200 mL) at –20 °C were added Ti(OiPr)
4
FULL PAPER
tracted with diethyl ether (2ϫ 50 mL). The combined organic lay-
ers were washed with saturated aqueous NaHCO (60 mL) and sat-
urated aqueous NaCl (60 mL), dried with MgSO , and then con-
centrated. The residue was triturated with a 5% ether/hexane solu-
tion, and the mixture was filtered to eliminate Ph PO. The volatiles
were evaporated under reduced pressure, and the residue was puri-
fied by column chromatography (5% EtOAc/hexane) to give the
benzoate. This was dissolved in MeOH (50 mL), and the resulting
15 g) and dry CH
2
Cl
2
3
(2.0 mL, 7.2 mmol) and (+)-d-diethyl tartrate (1.8 mL, 9.0 mmol),
and the mixture was stirred for 30 min. To this reaction mixture
were added allyl alcohol 11 (8.0 g, 36 mmol) over a period of
30 min followed by TBHP (4 m solution in toluene, 36 mL,
145 mmol), and the stirring was continued until the reaction
reached completion (8 h). The mixture was warmed to 0 °C and
then filtered through Celite. The filtrate was quenched with water
(8 mL) and 15% aqueous NaOH solution (3.6 mL), and the re-
sulting mixture was stirred vigorously for 1 h. The biphasic solution
4
3
2 3
solution was cooled to 0 °C. K CO (29 g, 0.21 mol) was added,
and the mixture was stirred for 30 min. Upon completion of the
reaction, the mixture was concentrated to remove the MeOH. The
mixture was diluted with water (80 mL), and the solution was ex-
was separated, and the aqueous layer was extracted with CH
(2ϫ 50 mL). The combined organic extracts were dried with anhy-
SO and concentrated under vacuum. The crude product
2 2
Cl
tracted with diethyl ether (2ϫ 75 mL). The organic layer was dried drous Na
with Na SO and concentrated to give a residue, which was purified
by column chromatography (20% EtOAc/hexane) to afford alcohol
2
4
2
4
was purified by column chromatography to afford the pure epoxide
12 (8.1 g, 95% yield) as a colorless oil with Ͼ96%ee (Chiral Pak
OD-H, 250ϫ4.6 mm, 5 µm, 4% isopropyl alcohol (IPA) in hexane,
6
2
6
1
(7.5 g, 87% yield) as a yellowish liquid. IR (neat): ν˜ max = 3500,
–1
1
–1
25
961, 2928, 1715, 1269 cm . H NMR (300 MHz, CDCl
.69 (d, J = 9.8 Hz, 1 H), 4.34 (s, 2 H), 3.78 (s, 3 H), 2.72–2.84 (m,
H), 1.05 (d, J = 6.7 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl
): CDCl
3
): δ =
1 mLmin ). [α]
2963, 2870, 1453, 1095, 1029, 740, 698 cm . H NMR (300 MHz,
): δ = 7.22–7.38 (m, 5 H), 4.45–4.62 (dd, J = 12.0, 35.5 Hz,
D
= –18 (c = 3.7, MeOH). IR (neat): ν˜ max = 3453,
–
1 1
3
3
δ = 183.4, 152.2, 128.8, 57.4, 51.8, 29.7, 22.4 ppm. HRMS: calcd. 2 H), 3.72–3.88 (m, 2 H), 3.64 (q, J = 10.5, 21.1 Hz, 2 H), 2.73 (d,
+
for C
9
H
16
O
3
[M + H] 159.1016; found 159.1021.
J = 9.0 Hz, 1 H), 2.49 (br. s, 1 H), 1.41–1.58 (m, 1 H), 1.06 (d, J
1
3
=
(
6
6.79 Hz, 3 H), 0.95 (d, J = 6.7 Hz, 3 H) ppm. C NMR
75 MHz, CDCl ): δ = 137.5, 128.2, 127.6, 127.5, 73.4, 68.5, 66.0,
3.3, 62.3, 27.2, 20.1, 18.6 ppm. HRMS: calcd. for C14 [M +
Methyl (E)-2-(Benzyloxymethyl)-4-methylpent-2-enoate (10): NaH
60% in mineral oil, 2.4 g, 61.1 mmol) was added in a small portion
over 15 min to a solution of alcohol 6 (8.0 g, 50.5 mmol), BnBr
8.1 mL, 71.3 mmol), and Bu
150 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min and
ambient temperature for 30 min and was then quenched with
MeOH (35 mL). The mixture was partitioned between Et
3
(
20 3
H O
+
Na] 259.1305; found 259.1329.
(
(
4
NI (1.8 g, 5.09 mmol) in DMF
Ethyl (E)-3-[(2R,3S)-2-(Benzyloxymethyl)-3-isopropyloxiran-2-yl]-
acrylate (5): To a stirred solution of epoxy alcohol 12 (8.0 g,
33 mmol) in EtOAc (80 mL) was added IBX (28.4 g, 101 mmol) at
2
O
room temperature. The resulting suspension was vigorously stirred
at reflux for 2 h. The reaction mixture was then warmed to room
temperature and filtered through a pad of Celite. The residue was
washed with EtOAc (3ϫ 15 mL), and the combined filtrates were
concentrated to afford the crude product, which was used directly
in the Wittig olefination. To the stirred solution of the crude epoxy
aldehyde in benzene (70 mL) was added (ethoxycarbonylmethylene)
triphenylphosphorane (17.6 g, 50.8 mmol) at room temperature un-
(
Et
H
200 mL) and H
2
O (200 mL). The aqueous layer was extracted with
O (3ϫ 50 mL). The combined organic layers were washed with
O (100 mL) and brine (75 mL), dried with MgSO , and concen-
trated in vacuo to afford an orange oil. Column chromatography
2–5% EtOAc/hexanes) of the residue gave benzyl ether 10 (10.2 g,
2
2
4
(
8
1
7
1% yield) as a colorless oil. IR (neat): ν˜ max = 2962, 2871, 1718,
237, 1089, 740, 698 cm . H NMR (300 MHz, CDCl
.38 (m, 5 H), 6.78 (dd, J = 10.0 Hz, 1 H), 4.55 (s, 2 H), 4.25 (s, 2
–1 1
3
): δ = 7.21–
2
der N , and the mixture was stirred for 30 min. Upon complete
H), 3.76 (s, 3 H), 2.65–2.80 (m, 1 H), 1.05 (d, J = 7.1 Hz, 6 H)
ppm. 1 C NMR (75 MHz, CDCl
3
conversion of the epoxy aldehyde, the benzene was removed in
vacuo, and the crude product was purified by chromatography on
silica gel (5% EtOAc/petroleum ether) to afford (E)-α,β-unsatu-
3
): δ = 154.7, 138.3, 128.4, 128.2,
28.0, 127.7, 127.5, 72.4, 63.5, 51.8, 28.0, 22.2 ppm. HRMS: calcd.
1
+
22 3
for C16H O [M + Na] 271.1305; found 271.1315.
2
5
rated γ,δ-epoxy ester 5 [9.2 g, 90% yield; (E)/(Z) = 95:5]. [α]
D
=
(
1
Z)-2-(Benzyloxymethyl)-4-methylpent-2-en-1-ol (11): Compound
0 (10.0 g, 38.1 mmol) was dissolved in CH Cl (65 mL) under ni-
+
18 (c = 4.5, MeOH). IR (neat): ν˜ max = 3425, 2965, 2934, 2871,
–1 1
2
2
1
719, 1655, 1307, 1165, 1096, 738, 699 cm . H NMR (300 MHz,
CDCl ): δ = 7.23–7.39 (m, 5 H), 7.05 (d, J = 15.6 Hz, 1 H), 6.09
d, J = 15.6 Hz, 1 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.49 (d, J =
trogen, and the resulting mixture was cooled to –15 °C. To this
solution was slowly added DIBAL-H (28% in hexanes, 54 mL,
7
for 2 h. The mixture was quenched with saturated aqueous sodium
potassium tartrate (200 mL) at 0 °C, and the layers were separated.
The aqueous layer was extracted with CH
combined organic layers were washed with brine (75 mL) and dried
with anhydrous Na SO . The solvent was removed in vacuo. The
crude product was purified by silica gel chromatography (petroleum
ether/EtOAc, 90:10) to give primary alcohol 11 (8.5 g, 96% yield)
as a colorless liquid. IR (neat): ν˜ max = 3409, 2958, 2927, 2868, 1454,
1
7
3
(
6.3 mmol). The reaction mixture was stirred at room temperature
1
1
1
0
1
2
1.9 Hz, 1 H), 4.20 (q, J = 7.1, 14.3 Hz, 3 H), 3.76 (d, J = 10.7 Hz,
H), 3.63 (d, J = 10.6 Hz, 1 H), 2.54 (d, J = 9.4 Hz, 1 H), 1.44–
.59 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.08 (d, J = 6.6 Hz, 3 H),
2
Cl
2
(2ϫ 60 mL). The
13
3
.97 (d, J = 6.7 Hz, 3 H) ppm. C NMR (75 MHz, CDCl ): δ =
66.1, 146.3, 137.5, 128.3, 127.7, 121.6, 73.3, 72.0, 69.3, 60.9, 60.4,
7.9, 20.1, 18.7, 14.2 ppm. HRMS: calcd. for C18 [M +
2
4
24 4
H O
+
Na] 327.1567; found 327.1555.
Ethyl (4R,5S,E)-4-Azido-4-(benzyloxymethyl)-6-methyl-5-(trimeth-
ylsilyloxy)hept-2-enoate (4): To a stirred solution of (E)-α,β-unsatu-
rated γ,δ-epoxy ester 5 (4.5 g, 14.8 mmol) in THF (60 mL) were
–1 1
070, 1026, 735, 698 cm . H NMR (300 MHz, CDCl
.39 (m, 5 H), 5.45 (d, J = 9.8 Hz, 1 H), 4.51 (s, 2 H), 4.16 (s, 2
3
): δ = 7.22–
added TMSN
1.48 mmol) under N
perature for 12 h. Then, 10% citric acid in methanol (15 mL) was
added, and the mixture was stirred at 0 °C for 1 h. Solid NaHCO
12 g) was added, and the resulting mixture was stirred for 15 min
3
3 4
(3.9 mL, 29.6 mmol) and Pd(PPh ) (230 mg,
H), 4.12 (s, 2 H), 2.48–2.60 (m, 1 H), 2.32 (br. s, 1 H), 0.96 (d, J =
6
1
.7 Hz, 6 H) ppm. 1 C NMR (75 MHz, CDCl
3
2
, and the mixture was stirred at room tem-
3
): δ = 140.1, 139.1,
32.6, 128.4, 127.7, 114.7, 74.9, 72.4, 66.9, 26.8, 23.1 ppm. HRMS:
+
3
calcd. for C14
20 2
H O [M + H] 221.1536; found 221.1245.
(
[
(2R,3S)-2-(Benzyloxymethyl)-3-isopropyloxiran-2-yl]methanol (12):
and was then filtered. The methanol was completely removed in
vacuo at 30 °C, and the residue was purified by silica gel
chromatography (12% EtOAc/petroleum ether) to yield azide 4
To a freshly flame-dried double-necked round-bottomed flask that
was equipped with activated molecular sieves (4 Å, approximately
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42700
/KAP1
Date: 13-08-14 18:32:02
Pages: 7
Asymmetric Formal Synthesis of (+)-Lactacystin
4.9 g, 80% yield) as a colorless liquid. [α]2
5
= –2.5 (c = 1.2,
(
D
3
CDCl ): δ = 7.14–7.30 (m, 5 H), 5.35 (d, J = 3.7 Hz, 1 H), 4.40 (s,
MeOH). IR (neat): ν˜ max = 3724, 2923, 2852, 2115, 1720, 1219, 2 H), 3.94 (d, J = 9.0 Hz, 1 H), 3.21 (d, J = 9.0 Hz, 1 H), 2.50–
–
1 1
7
7
1
2
72 cm . H NMR (300 MHz, CDCl
.19–7.24 (m, 3 H), 6.78 (d, J = 15.8 Hz, 1 H), 5.94 (d, J = 15.8 Hz, H), 1.43 (s, 9 H), 0.84 (dd, J = 3.0, 6.7 Hz, 6 H) ppm. C NMR
H), 4.37 (dd, J = 12.0, 19.6 Hz, 2 H), 4.10 (q, J = 6.7, 14.3 Hz, (75 MHz, CDCl ): δ = 176.0, 170.4, 149.9, 137.7, 128.4, 127.7,
H), 3.79 (d, J = 2.2 Hz, 1 H), 3.58 (d, J = 9.8 Hz, 1 H), 3.24 (d, 127.4, 76.2, 73.6, 73.4, 68.7, 30.9, 28.5, 28.0, 22.8, 21.3, 20.8,
[M + Na]+ 442.2200;
3
): δ = 7.34–7.39 (m, 2 H), 2.68 (m, 1 H), 2.18–2.41 (m, 2 H), 1.99 (s, 3 H), 1.83–1.96 (m, 2
1
3
3
J = 9.8 Hz, 1 H), 1.67–1.80 (m, 1 H), 1.29 (t, J = 6.7, 14.3, 20.3 Hz, 17.6 ppm. HRMS: calcd. for C23H33NO
6
3
9
1
1
4
H), 0.79 (d, J = 7.5 Hz, 3 H), 0.64 (d, J = 6.7 Hz, 3 H), –0.05 (s,
found 442.2195.
H) ppm. 13C NMR (75 MHz, CDCl
): δ = 144.9, 144.5, 130.1,
3
tert-Butyl (R)-2-[(S)-1-Acetoxy-2-methylpropyl]-2-(hydroxymethyl)-
5-oxopyrrolidine-1-carboxylate (16): To the stirred solution of acetyl
compound 15 (0.5 g, 30.69 mmol) in MeOH (10 mL) was added
28.8, 127.9, 122.5, 118.2, 77.9, 73.6, 73.0, 70.0, 60.5, 29.3, 22.4,
Si [M + Na]+
33 3 4
H N O
6.9, 14.2, 0.5 ppm. HRMS: calcd. for C21
42.2133; found 442.2136.
1
0% Pd/C (45 mg), and the reaction mixture was stirred at room
temperature for 6 h under H . The reaction progress was monitored
by TLC, which showed consumption of the starting material after
3
(760 mg, 6 h. The reaction mixture was then filtered through a pad of Celite,
(
R)-5-(Benzyloxymethyl)-5-[(S)-1-hydroxy-2-methylpropyl]pyrrol-
idin-2-one (13): To the stirred solution of azide 4 (1 g, 2.3 mmol) in
EtOH (15 mL) were added 10% Pd/C (80 mg), Na CO
.1 mmol), and ammonium acetate (18 mg, 0.23 mmol), and the
2
2
7
and the solid was washed with EtOAc. The combined filtrates were
concentrated under reduced pressure to remove the solvent. The
residue was purified by silica gel (100–200 mesh) column
chromatography (15% EtOAc/petroleum ether) to afford the de-
benzylated primary alcohol 16 (0.35 g, 91%) as a white sticky solid.
mixture was stirred under hydrogen (balloon) at room temperature
for 8 h. The reaction mixture was then filtered through Celite, and
the filtrate was concentrated in vacuo to remove the solvents. The
crude product was purified by chromatography on silica gel (12%
2
5
acetone/petroleum ether) to afford bicyclic lactam 13 (510 mg, 78%
[α]
D
= –1.6 (c = 1.6, MeOH). IR (neat): ν˜ max = 3348, 2973, 1775,
yield) as a light yellow liquid. [α]2
5
= –4.3 (c = 1.2, MeOH). IR
1743, 1233, 1025 cm . H NMR (400 MHz, CDCl ): δ = 5.39 (d,
–1 1
D
3
(
neat): ν˜ max = 3379, 2958, 2923, 2872, 1684, 1100, 1028, 738, J = 4.4 Hz, 1 H), 4.07 (d, J = 11.7 Hz, 1 H), 3.47 (d, J = 11.7 Hz,
–1 1
6
98 cm . H NMR (300 MHz, CDCl
.65 (br. s, 1 H), 4.39 (s, 2 H), 3.55 (d, J = 9.0 Hz, 1 H), 3.36 (d, J
9.0 Hz, 1 H), 3.16 (d, J = 6.0 Hz, 1 H), 2.15–2.39 (m, 2 H), 1.56–
.89 (m, 3 H), 0.85 (d, J = 6.7 Hz, 6 H) ppm. 13C NMR (75 MHz,
CDCl ): δ = 177.5, 137.1, 128.4, 127.9, 127.6, 81.8, 74.5, 73.7, 65.1,
0.2, 30.1, 27.9, 21.5, 18.2 ppm. HRMS: calcd. for C16 [M
3
): δ = 7.13–7.29 (m, 5 H), 1 H), 2.57–2.67 (m, 1 H), 2.41–2.52 (m, 1 H), 2.28–2.37 (m, 1 H),
6
=
1
2.10 (s, 3 H), 1.90–2.0 (m, 2 H), 1.70 (br. s, 1 H), 1.56 (s, 9 H), 0.94
1
3
(dd, J = 6.6, 10.3 Hz, 6 H) ppm. C NMR (75 MHz, CDCl
3
): δ =
175.5, 170.4, 150.7, 84.1, 75.8, 69.9, 66.9, 30.8, 28.5, 28.0, 22.3,
+
3
21.5, 20.8, 17.9 ppm. HRMS: calcd. for C16
352.1731; found 352.1736.
6
H27NO [M + Na]
3
+
H23NO
3
+
Na] 300.1570; found 300.1567.
(
S)-2-[(S)-1-Acetoxy-2-methylpropyl]-1-(tert-butoxycarbonyl)-5-oxo-
(
S)-1-[(R)-2-(Benzyloxymethyl)-5-oxopyrrolidin-2-yl]-2-methyl- pyrrolidine-2-carboxylic Acid (17): To a solution of 16 (0.2 g,
propyl Acetate (14): In a clean, dry round-bottomed flask, acetic
anhydride (1.4 mL, 14.4 mmol) and 4-(dimethylamino)pyridine
0.6 mmol) in CH
added NaIO (520 mg, 2.40 mmol). The reaction mixture was
stirred vigorously for 5 min, and then RuCl (3 mg, 0.02 mmol) was
3 4 2
CN/CCl /H O (0.5 mL/0.5 mL/0.75 mL) was
4
(17 mg, 0.14 mmol) were added to 13 (0.40 g, 1.4 mmol) in pyridine
3
(
5 mL) at room temperature. The mixture was stirred for 2 h and
added. The resulting brown solution was stirred at room temp. for
3 h, whereupon it turned bright orange in color. The reaction was
quenched by the addition of 2-propanol (1 mL), and the resulting
4
then poured into saturated aqueous NH Cl (5 mL). After 2 h, the
products were extracted with EtOAc (2ϫ 15 mL). The combined
organic phases were washed with brine (30 mL), dried with
black mixture was diluted with Et
stirred for 30 min and then filtered through a pad of Celite, which
was washed with Et O (2ϫ 10 mL) and CH Cl (2ϫ 10 mL). The
combined filtrates were dried with MgSO and concentrated in
IR (neat): ν˜ max = 3472, 2976, 2924, 1725, 1701, 1231, 1143, vacuo to yield the crude acid 3, which was purified by flash column
2
O (4 mL). The mixture was
2 4
Na SO , and concentrated. The residue was purified by flash col-
umn chromatography (EtOAc/hexane, 2:1) to afford acetate 14
2
2
2
2
5
(
0.442 g, 96% yield) as a colorless oil. [α]
D
= –1.7 (c = 1.0, MeOH).
4
–1 1
7
44 cm . H NMR (300 MHz, CDCl
3
): δ = 7.20–7.31 (m, 5 H), chromatography (EtOAc/hexane, 1:1) to afford pure 17 (160 mg,
2
5
6.53 (br. s, 1 H), 4.90 (d, J = 5.2 Hz, 1 H), 4.44 (s, 2 H), 3.35 (s, 2 79% yield) as a colorless, viscous liquid. [α]
D
= +1.3 (c = 0.57,
H), 2.23–2.35 (m, 2 H), 2.01 (s, 3 H), 1.87–1.97 (m, 3 H), 0.90 (d, MeOH). IR (neat): ν˜ max = 3444, 2923, 2853, 1722, 1462, 1371,
J = 6.7 Hz, 3 H), 0.82 (d, J = 6.7 Hz, 3 H) ppm. 1 C NMR
3
–1 1
3
1234, 1151, 1031 cm . H NMR (300 MHz, CDCl ): δ = 11.05,
(
75 MHz, CDCl ): δ = 178.1, 170.4, 128.4, 127.7, 127.6, 127.5, 78.9,
3
4.93 (d, J = 4.5 Hz, 1 H), 2.97–3.71 (m, 1 H), 2.61–2.84 (m, 3 H),
7
3.6, 73.4, 64.5, 29.9, 28.6, 27.1, 21.6, 20.7, 17.9 ppm. HRMS 2.26–2.19 (m, 1 H), 2.16 (s, 3 H), 1.49 (s, 9 H), 1.01 (d, J = 6.7 Hz,
+
13
(ESI): calcd. for C18
H25NO
4
[M + H] 320.1856; found 320.1851.
3
3 H), 0.94 (d, J = 6.7 Hz, 3 H) ppm. C NMR (75 MHz, CDCl ):
δ = 181.1, 173.9, 170.1, 159.2, 91.0, 82.4, 67.7, 33.4, 29.6, 29.4,
7.9, 20.6, 19.1 ppm. HRMS (ESI): calcd. for C16 [M +
Na] 366.1523; found 366.1534.
tert-Butyl (R)-2-[(S)-1-Acetoxy-2-methylpropyl]-2-(benzyloxy-
methyl)-5-oxopyrrolidine-1-carboxylate (15): To a stirred solution of
triethylamine (1.8 mL, 13 mmol), di-tert-butyl dicarbonate (1.1 g,
2
H25NO
7
+
5
.2 mmol), and 4-(dimethylamino)pyridine (0.19 g, 1.5 mmol) in 1-tert-Butyl 2-Ethyl (2S)-2-[(1S)-1-(Acetyloxy)-2-methylpropyl]-5-
CH
temperature. After stirring for 11 h, the reaction mixture was
poured into saturated aqueous NH Cl (10 mL). The solution was
extracted with CH Cl (2ϫ 10 mL). The combined organic phases
were washed with brine (10 mL), dried with Na SO , and concen-
trated. The residue was purified by flash column chromatography
2
Cl
2
(10 mL) was added acetate 14 (0.43 g, 1.3 mmol) at room
oxopyrrolidine-1,2-dicarboxylate (3): To a solution of carboxylic
acid 2 (0.15 g, 0.43 mmol), ethanol (0.25 mL, 4.3 mmol), and
DMAP (54 mg, 0.43 mmol) in dichloromethane (DCM, 10 mL)
was added EDC portionwise (0.1 g, 0.65 mmol), and the resulting
mixture was stirred at room temp. for 4 h. The reaction mixture
was diluted with DCM (20 mL), and the mixture was washed with
4
2
2
2
4
(
EtOAc/hexane, 1:1) to afford 15 (547 mg, 97% yield) as a colorless
HCl (0.5 m solution, 2ϫ 15 mL), saturated NaHCO
and brine (20 mL). The organic layer was separated, dried with
MgSO , filtered, and concentrated in vacuo. The residue was puri-
3
(2ϫ 15 mL),
25
oil. [α]
1
D
= +6.4 (c = 1.7, MeOH). IR (neat): ν˜ max = 2969, 2927,
–1 1
786, 1734, 1706, 1232, 1146, 1108, 744 cm . H NMR (300 MHz,
4
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42700
/KAP1
Date: 13-08-14 18:32:02
Pages: 7
D.-S. Shin, S. Chandrasekhar et al.
FULL PAPER
fied by flash column chromatography (EtOAc/hexane, 1:1) to af-
E. J. Corey, W. D. Li, T. Nagamitsu, Angew. Chem. Int. Ed.
1998, 37, 1676–1679; Angew. Chem. 1998, 110, 1784; i) E. J.
Corey, W. D. Li, G. A. Reichard, J. Am. Chem. Soc. 1998, 120,
ford 3 (92 g, 57% yield) as a colorless oil. [α]2
5
D
= –33.1 (c = 1,
–1 1
CHCl
500 MHz, CDCl
H), 2.70–2.62 (m, 1 H), 2.54–2.45 (m, 2 H), 2.10 (s, 3 H), 2.06–1.84
m, 2 H), 1.51 (br. s, 9 H), 1.22 (t, J = 8.0 Hz, 3 H), 0.93 (d, J =
.9 Hz, 3 H), 0.85 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl ): δ = 175.5, 172.0, 169.8, 151.0, 84.1, 75.1, 69.0, 61.7, 30.6,
9.4, 28.3, 23.1, 21.6, 21.2, 17.1, 13.9 ppm. HRMS (ESI): calcd. for
[M + H]+ 372.2017; found 372.2014.
3
). IR (neat): ν˜ max = 2927, 1748, 1545, 1093 cm . H NMR
2
1
3
330–2336; j) S. H. Kang, S. Jun, J. H. Youn, Synlett 1998,
045; k) J. S. Panek, C. E. Masse, Angew. Chem. Int. Ed. 1999,
8, 1093–1095; Angew. Chem. 1999, 111, 1161; l) S. Iwama,
(
3
): δ = 5.78 (d, J = 2.9 Hz, 1 H), 4.20–4.11 (m, 2
(
6
W. G. Gao, T. Shinada, Y. Ohfune, Synlett 2000, 1631–1633;
m) M. P. Green, J. C. Prodger, C. J. Hayes, Tetrahedron Lett.
2002, 43, 6609–6611; n) C. J. Brennan, G. Pattenden, G. Re-
scourio, Tetrahedron Lett. 2003, 44, 8757–8760; o) H. Ooi, N.
Ishibashi, Y. Iwabuchi, J. Ishihara, S. Hatekeyama, J. Org.
Chem. 2004, 69, 7765–7768; p) T. J. Donohoe, H. O. Sintim, L.
Sisangia, J. D. Harling, Angew. Chem. Int. Ed. 2004, 43, 2293–
2296; Angew. Chem. 2004, 116, 2343; q) T. J. Donohoe, H. O.
Sintim, L. Sisangia, K. W. Ace, P. M. Guyo, A. Cowley, J. D.
Harling, Chem. Eur. J. 2005, 11, 4227–4238; r) D. J. Wardrop,
E. G. Bowen, Chem. Commun. 2005, 5106–5108; s) E. P.
Balskus, E. N. Jacobsen, J. Am. Chem. Soc. 2006, 128, 6810–
3
2
18 7
C H29NO
Supporting Information (see footnote on the first page of this arti-
1
13
cle): H and C NMR spectra of all new compounds.
Acknowledgments
6
812; t) C. J. Hayes, A. E. Sherlock, M. D. Selby, Org. Biomol.
C. S., B. V. D. V., and L. R. are grateful to the Council of Scientific
and Industrial Research (CSIR), New Delhi, India for research fel-
lowships. This work was also cosupported by grants from the Min-
istry of Environment (KME, 412-111-008), the National Research
Foundation (NRF-2009-0094063), and the Ministry of Knowledge
Economy, S. Korea (MKE, R0000495).
Chem. 2006, 4, 193–195; u) N. Fukuda, K. Sasaki, T. V. R. S.
Sastry, M. Kanai, M. Shibasaki, J. Org. Chem. 2006, 71, 1220–
1225; v) M. Shibasaki, M. Kanai, N. Fukuda, Chem. Asian J.
2007, 2, 20–38; w) C. B. Gilley, M. J. Buller, Y. Kobayashi, Org.
Lett. 2007, 9, 3631–3634; x) C. H. Yoon, D. L. Flanigan, K. S.
Yoo, K. W. Jung, Eur. J. Org. Chem. 2007, 37–39; y) J.-C. Le-
geay, N. Langlois, J. Org. Chem. 2007, 72, 10108–10113; z) H.
Miyaoka, M. Yamanishi, A. Hoshino, H. Mitome, E. Kawash-
ima, Chem. Pharm. Bull. 2008, 56, 738–741; aa) G. Pattenden,
G. Rescourio, Org. Biomol. Chem. 2008, 6, 3428–3438; ab) C. J.
Hayes, A. E. Sherlock, M. P. Green, C. Wilson, A. J. Blake,
M. D. Selby, J. C. Prodger, J. Org. Chem. 2008, 73, 2041–2051;
ac) A. Hameed, A. J. Blake, C. J. Hayes, Synlett 2010, 535–538;
ad) W. Gu, R. B. Silverman, J. Org. Chem. 2011, 76, 8287–
8293; ae) D. K. Mycock, P. A. Glossop, W. Lewis, C. J. Hayes,
Tetrahedron Lett. 2013, 54, 55–57; af) J. Gonda, D. Malinak,
M. Kovacova, M. Martinkova, Tetrahedron Lett. 2013, 54,
6768–6771.
[
1] a) K. L. Rock, C. Gramm, L. Rothstein, K. Clark, R. Stein,
L. Dick, D. Hwang, A. L. Goldberg, Cell 1994, 78, 761–771;
b) G. Fenteany, R. F. Standaert, W. S. Lane, S. Choi, E. J. Co-
rey, S. L. Schreiber, Science 1995, 268, 726–731; c) A. Ciechan-
over, Angew. Chem. Int. Ed. 2005, 44, 5944–5967; Angew.
Chem. 2005, 117, 6095.
[
[
[
[
2] L. J. Crawford, B. Walker, A. E. Irvine, J. Cell Commun. Signal.
2011, 5, 101–110.
3] Y. Tu, C. Chen, J. Pan, J. Xu, Z.-G. Zhou, C.-Y. Wang, Int. J.
Clin. Exp. Pathol. 2012, 5, 726–738.
4] G. Fenteany, S. L. Schreiber, J. Biol. Chem. 1998, 273, 8545–
[9] a) S. Chandrasekhar, B. B. Parida, Ch. Rambabu, J. Org.
Chem. 2008, 73, 7826–7828; b) S. Chandrasekhar, B. V. D. Vi-
jaykumar, T. V. Pratap, Tetrahedron: Asymmetry 2008, 19, 746–
750; c) S. Chandrasekhar, B. B. Parida, Ch. Rambabu, Tetra-
hedron Lett. 2009, 50, 3294–3295; d) S. Chandrasekhar,
R. V. N. S. Murali, Ch. Rajireddy, Tetrahedron Lett. 2009, 50,
5686–5688; e) P. Mallesham, B. V. D. Vijaykumar, D. S. Shin,
S. Chandrasekhar, Tetrahedron Lett. 2011, 52, 6145–6147; f)
B. V. D. Vijaykumar, P. Mallesham, S. Chandrasekhar, Eur. J.
Org. Chem. 2012, 988–994; g) N. K. Reddy, S. Chandrasekhar,
J. Org. Chem. 2013, 78, 3355–3360.
[10] M. Miyashita, T. Mizutani, G. Tadano, Y. Iwata, M. Miyaz-
awa, K. Tanino, Angew. Chem. Int. Ed. 2005, 44, 5094–5097;
Angew. Chem. 2005, 117, 5224.
[11] S. Chandrasekhar, C. Narsimhulu, B. Saritha, S. S. Sultana,
Tetrahedron Lett. 2004, 45, 5865–5867.
[12] A. B. Charette, B. Cote, S. Monroc, S. Prescott, J. Org. Chem.
1995, 60, 6888–6894.
[13] B. R. Bear, J. S. Parnes, K. J. Shea, Org. Lett. 2003, 5, 1613–
1616.
[14] a) T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102,
5974–5976; b) T. Ichige, Y. Okano, N. Kanoh, M. Nakata, J.
Org. Chem. 2009, 74, 230–243.
8548.
5] a) S. Omura, T. Fujimoto, K. Otoguro, K. Matsuzaki, R. Mori-
guchi, H. Tanaka, Y. Sasaki, J. Antibiot. 1991, 44, 113–116; b)
S. Omura, K. Matsuzaki, T. Fujimoto, K. Kosuge, T. Furuya,
S. Fujita, A. Nakagawa, J. Antibiot. 1991, 44, 117–118.
[
6] a) E. M. Conner, S. Brand, J. M. Davis, F. S. Laroux, V. J. Pal-
ombella, J. W. Fuseler, D. Y. Kang, R. E. Wolf, M. B. Grisham,
J. Pharmacol. Exp. Ther. 1997, 282, 1615–1622; b) F. Soucy,
L. Grenier, M. L. Behnke, A. T. Destree, T. A. McCormack, J.
Adams, L. Plamondon, J. Am. Chem. Soc. 1999, 121, 9967–
9976.
[
7] a) E. J. Corey, G. A. Reichard, R. Kania, Tetrahedron Lett.
1
993, 34, 6977–6980; b) L. R. Dick, A. A. Cruikshank, L.
Greiner, F. D. Melandri, S. L. Nunes, V. J. Palombella, L. A.
Parent, L. Plamondon, R. L. Stein, J. Biol. Chem. 1997, 272,
1
82–188.
[
8] a) E. J. Corey, G. A. Reichard, J. Am. Chem. Soc. 1992, 114,
10677–10678; b) E. J. Corey, G. A. Reichard, R. Kania, Tetra-
hedron Lett. 1993, 34, 6977–6980; c) T. Sunazuka, T. Nagam-
itsu, K. Matsuzaki, H. Tanaka, S. Omura, A. B. Smith, J. Am.
Chem. Soc. 1993, 115, 5302; d) H. Uno, J. E. Baldwin, A. T.
Russell, J. Am. Chem. Soc. 1994, 116, 2139–2140; e) N. Chida,
J. Takeoka, N. Tsutsumi, S. Ogawa, J. Chem. Soc., Chem. Com-
mun. 1995, 793–794; f) T. Nagamitsu, T. Sunazuka, H. Tanaka,
S. Omura, P. A. Sprengeler, A. B. Smith, J. Am. Chem. Soc.
[15] See Supporting Information.
[16] C. H. Yoon, D. L. Flanigan, K. S. Yoo, K. W. Jung, Eur. J. Org.
Chem. 2007, 37–39.
1
996, 118, 3584–3590; g) N. Chida, J. Takeoka, K. Ando, N.
Received: June 6, 2014
Published Online: ᭿
Tsutsumi, S. Ogawa, Tetrahedron 1997, 53, 16287–16298; h)
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42700
/KAP1
Date: 13-08-14 18:32:02
Pages: 7
Asymmetric Formal Synthesis of (+)-Lactacystin
Natural Product Synthesis
A formal synthesis of (+)-lactacystin was
achieved from readily available isobutyral-
dehyde and ethyl acrylate by using a
Baylis–Hillman reaction, an intermolecular
nucleophilic displacement under Mitsu-
nobu conditions, a Sharpless asymmetric
epoxidation, a palladium-catalyzed syn-
selective ring opening of an epoxide, an
azide reductive lactamization, and a ru-
thenium-catalyzed oxidation as the key
steps.
Ch. Sridhar, B. V. D. Vijaykumar,
L. Radhika, D.-S. Shin,*
S. Chandrasekhar* ............................ 1–7
Asymmetric Formal Synthesis of (+)-
Lactacystin
Keywords: Natural products / Lactams /
Asymmetric synthesis / Epoxidation / Chi-
ral resolution / Palladium
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7