Synthesis of kurasoin B using phase-transfer-catalyzed acylimidazole alkylation

Article abstract of DOI:10.1055/s-0028-1087809

The hydroxy ketone natural product kurasoin B is synthesized using a phase-transfer-catalyzed alkylation reaction with benzyloxyacetyl imidazole. A biscinchonidinium dimethylnaphthalene catalyst allowed for high yield and near complete selectivity (99% ee

Full text of DOI:10.1055/s-0028-1087809

CLUSTER
653
Synthesis of Kurasoin B Using Phase-Transfer-Catalyzed Acylimidazole
Alkylation
Synthesis of
Kurasoin
iB chael A. Christiansen, Aaron W. Butler, Amanda R. Hill, Merritt B. Andrus*
Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, UT 84602, USA
Fax +1(801)4220153; E-mail: mbandrus@chem.byu.edu
Received 25 August 2008
ality in 24% overall yield.6 We now report a PTC route to
kurasoin B (2), the indole-containing PFTase inhibitor,
using the newly developed 2-acylimidazole substrate.7
Abstract: The hydroxy ketone natural product kurasoin B is syn-
thesized using a phase-transfer-catalyzed alkylation reaction with
benzyloxyacetyl imidazole. A biscinchonidinium dimethylnaphtha-
lene catalyst allowed for high yield and near complete selectivity
(99% ee) for the S-product using 3-methylbromoindole as the elec-
trophile.
A significant drawback to the original aryl ketone sub-
strate was a reliance on an oxidative Baeyer–Villiger-type
oxidation to access the generally applicable ester products
following PTC alkylation. 2-Acylimidazoles were devel-
oped as an alternative for PTC alkylation possessing an a-
hydrogen sufficiently acidic for low-temperature reactivi-
ty. In addition, the products can be conveniently trans-
formed for direct applications. Alkylations with various
electrophiles were shown to occur in high yields and se-
lectivity (>90%ee).7 The PTC products were readily con-
verted into the methyl ester without epimerization via the
N-methyl imidazolium intermediate formed using methyl
triflate and sodium methoxide for nucleophilic displace-
ment.8
Key words: alkylations, asymmetric catalysis, asymmetric synthe-
sis, natural products, total synthesis
The hydroxy ketones kurasoin A (1) and B (2) are protein
farnesyltransferase (PFTase) inhibitors isolated from the
fungus, Paecilomyces sp. (Scheme 1).1 These compounds
have potential as novel cancer drug leads in that the aro-
matic positions can be easily modified around the central
core structure.2 A Sharpless asymmetric epoxidation
asymmetric route from 4-hydroxyphenyl-2-ethanol (5%
overall yield) to kurasoin A (1) was used to establish the
stereochemistry.3 A racemic route to 1, using a benzyl
Grignard–Weinreb amide addition, was also reported.4
We previously developed an asymmetric phase-transfer
catalytic (PTC) alkylation method for the synthesis of a-
hydroxy esters using aryl ketone glycolate substrates. This
PTC reaction was employed in a route to the known dia-
betes drug (–)-ragaglitazar.5 An efficient, seven-step syn-
thesis of kurasoin A was also developed using this
reaction as the key step to install the S-hydroxy function-
The precursor to the target benzyl ketone is the Weinreb
amide 3 (Scheme 1), which is generated from the PTC
product, S-acylimidazole 4. The N-tert-Boc-protected 3-
bromomethyl electrophile 5 is employed as the PTC cou-
pling partner with benzyloxyacyl imidazole 6 using a cin-
chonidinium (CD) catalyst at low temperature.
Catalysts employed in this study included dihydro-N-2,3,4-
trifluorobenzyl cinchonidinium bromide 7 (Figure 1) and
the dimeric N,N-2,7-dimethylnaphthyl dibromide 8
O
O
OH
OH
HO
HN
(1)
(2)
kurasoin A
kurasoin B
Me
O
O
N
Me
N
OMe
2
N
OBn
OH
N
HN
3
t-Boc
4
O
Me
N
Br
BnO
+
N
6
5
N
t-Boc
Scheme 1
SYNLETT 2009, No. 4, pp 0653–0657
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087809; Art ID: Y00808ST
© Georg Thieme Verlag Stuttgart · New York

654
M. A. Christiansen et al.
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(HCD, hydrocinchonidinium). These catalysts have been significant amount of monodebenzylated methyl ether A
shown to be highly efficient for solid–liquid PTC alkyla- resulted along with 10. Lowered PTC selectivity was ob-
tions with the O’Donnell diphenylbenzophenone imine served when this mixture is converted into catalyst. The
glycine substrate for the synthesis of amino acids.9 These complex NMR spectra of cinchona-based compounds can
catalysts were also found to be superior for asymmetric lead to difficulties with purity assessment. Mass spec-
arylketone alkylation and for acylimidazole glycolates as trometry has proven useful with detection of non-N-ben-
previously reported.7
zylated 10 and debenzylated monomethyl-naphthylated A
impurities in this case. By verifying the absence of impu-
rities with dry solvents and sufficient reaction times, high
catalyst efficiency has been ensured. The appearance of
intermediate 11 is also useful. If it is obtained as light-
pink crystals, not red or purple in color, the resultant cat-
alyst 8 will be optimal. Allylation of 11, with allyl bro-
mide and 50% KOH (15 min), gave the light-orange
catalyst 8. This compound, obtained now by recrystalliza-
tion, is free of impurities. If impure 11 is used, 8 and var-
ious allylated ammonium impurities are detected by MS
and catalyst function is compromised.
Br–
N+
F
O
F
N
HCD
HCD
F
7
N+
2 Br–
HCD
O
The imidazole 6 was made by the previous route in three
steps from bromoacetic acid 12 (Scheme 3).7 Treatment
with benzyl alcohol, NaH, and tetra-n-butylammonium
iodide (TBAI) gave benzyloxy acetic acid. The acid chlo-
ride was formed with oxalyl chloride and DMF, and mor-
pholine was added to give 13 in 98% combined yield. N-
Methylimidazole was metalated with n-butyllithium and
added to generate 6 (86%) as a white solid.
N
8
Figure 1
The PTC catalysts, developed by Park and Jew,9e,f as with
all cinchona-based catalysts, are made from inexpensive
materials in pseudo-enantiomeric form, from cinchoni-
dine (CD) or cinchonine (CN). We have modified the
original route to reliably obtain the CD dimer 8 in high pu-
rity (Scheme 2). Dibromide 9, obtained from 2,7-dimethyl-
naphthalene using NBS and benzoyl peroxide (PhH,
reflux 8 h, 92%), was reacted with dihydro-CD 10
(120 °C, 2 h). After cooling, methanol and diethyl ether
were added, and the resulting pink compound 11 was fil-
tered, rinsing with diethyl ether.9f If this product is rinsed
with methanol, as described in the original procedure, a
Acylimidazole PTC reactions were performed previously
with a naphthylmethyl-protected substrate (91% ee).7 The
1) BnOH, NaH,
TBAI
2) (COCl)2,
DMF, morpholine
Me
O
N
Li
O
BnO
Br
N
N
OH
6
O
98%
13
12
86%
Scheme 3
Br
Br
N
EtOH⋅DMF⋅CHCl3
120 °C, 2 h
+
OH
MeOH, filter
74%
9
N
10
HCD
HCD
N+
2 Br–
Br
HCD
8
OH
50% KOH
96%
N
11
MeO
HCD
A
impurity:
Scheme 2
Synlett 2009, No. 4, 653–657 © Thieme Stuttgart · New York

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Synthesis of Kurasoin B
655
benzyloxy 6 was explored with catalysts 7 and 8 using using BCl3, using conditions of De Clercq,12 and the
benzyl bromide (5 equiv) and CsOH·H2O under liquid– Weinreb amide was formed in high yield. It was previous-
solid conditions at –40 °C (Scheme 4). Product 14 was ly found in the kurasoin A synthesis that amide formation
obtained in high yield and good selectivities (86%, 74% was problematic with a-benzyl ethers6 and that benzyl
ee, chiral HPLC) using either 7 or 8. Originally, kurasoin Grignard addition was most efficient using an a-TES (tri-
B was pursued using the naphthylmethyl acylimidazole; ethylsilyl) ether.13 Following this precedent, the TES
however, due to deprotection problems, this protecting ether was formed and the Grignard addition in this case
group was abandoned. Fortunately, the benzyl-protected was found to be efficient. The TBAF removal of the TES
substrate 6 proved to be highly efficient with indole 5.
group gave the target natural product, (+)-kurasoin B as a
yellow crystalline solid identical in all respects to the re-
ported material.1 The final steps did not promote racem-
ization or enolization of the sensitive a-hydroxy ketone
functionality.6,14 The nine-step route is direct, and effi-
cient (34% overall) and allows for modifications of both
the electrophile and the Grignard addition to readily ac-
cess analogues. The key PTC step is very efficient install-
ing a major portion of the functionality along with the
S-hydroxy stereocenter using only two equivalents of the
3-methylbromoindole electrophile.
catalyst 7 or 8 (10 mol%)
BnBr (5 equiv)
Me
O
Me
O
CsOH⋅H2O (4 equiv)
CH2Cl2, –40 °C
N
BnO
N
Ph
14
N
OBn
N
86% 74% ee (7)
75% 82% ee (8)
6
Scheme 4
A modification of Coelho’s route was followed to gener-
ate bromomethyl indole 5 (Scheme 5).10 The tert-Boc-
protected 3-formyl 15 was obtained as reported and re-
duced with NaBH4 to give the 3-methyl alcohol. Phospho-
rous tribromide,11 now applied to this substrate, proved
more reliable than the original procedure with CBr4 and
P3Ph, giving 5 in high yield (92%). The key PTC reaction
was performed with CD-dimer 8 (10 mol%) and two
equivalents of the new electrophile 5 relative to 6 to gen-
erate the product 4 in near quantitative yield and selectiv-
ity (98%, 99% ee). Racemic 4 was also made using TBAI
as catalyst and compared by chiral HPLC.
2,7-Bis(hydrocinchonidinium-N-methyl)naphthalene Dibro-
mide (11)
2,7-Bis(bromomethyl)naphthalene (9, 1.5 g, 4.77 mmol, 1 equiv)
and hydrocinchonidine (10, 2.88 g, 9.73 mmol, 2.04 equiv) were
dissolved in dry EtOH (7.2 mL, 0.662 M), DMF (8.6 mL, 0.552 M),
and CHCl3 (2.9 mL, 1.655 M) and heated to reflux (100–120 °C)
with stirring for 2 h. The reaction was monitored for the consump-
tion of 2,7-bis(bromomethyl)naphthalene by TLC (Rf = 0.345, 5%
EtOAc–hexanes). The mixture was cooled to r.t. and diluted with
MeOH (29 mL, 0.1655 M) and Et2O (87 mL, 0.055 M), and the sus-
pension was stirred for 1 h. The crude, light-pink precipitate was fil-
tered (25–50 micron cup) and rinsed with Et2O (3 × 25 mL).
Product was transferred by spatula and isolated as a pink solid (3.18
g, 74% yield).
The acylimidazole functionality was easily removed with
MeOTf and MeOH with added DBU to give ester 16
(Scheme 5). The N-Boc group was also removed under
these conditions. The benzyl ether was then removed
Analytical Data
1H NMR (500 MHz, DMSO-d6): d = 9.00 (d, J = 2.3 Hz, 2 H), 8.33
(d, J = 4.0 Hz, 2 H), 8.22 (d, J = 4.0 Hz, 2 H), 8.14 (d, J = 4.0 Hz, 2
H), 7.92 (d, J = 4.2 Hz, 2 H), 7.88–7.84 (m, 4 H), 7.75 (t, J = 7.5 Hz,
2 H), 6.78 (d, J = 2.0 Hz, 2 H), 6.63 (s, 2 H), 5.31 (d, J = 6.5 Hz, 2
H), 5.12 (d, J = 6.0 Hz, 2 H), 4.36 (br s, 2 H), 3.98 (t, J = 8.0 Hz, 2
H), 3.53 (m, 2 H), 2.18–2.08 (m, 4 H), 1.98 (br s, 2 H), 1.77–1.72
(m, 4 H), 1.41–1.39 (m, 2 H), 1.28–1.61 (m, 4 H), 0.72 (t, J = 7.0
Hz, 4 H); large extraneous peaks: d = 3.36 (H2O in DMSO-d6), 2.50
(DMSO-Hx in DMSO-d6). HRMS: calcd for C50H58N4O22+: 746.46;
found: 746.4554 for [M+]; also calcd for [C50H58N4O2]2+/2: 373.23;
found 374.2353 for [M + 2 H]2+/2.
O
1) NaBH4
88%
2) PBr3
92%
6, CD-dimer 8 (10 mol%)
CsOH⋅H2O, CH2Cl2
–40 °C, 28 h
Br
H
N
N
t-Boc
5
t-Boc
15
Me
O
O
MeOTf,
MeOH
DBU
N
OMe
OBn
N
OBn
N
N
16
86%
4
t-Boc
H
98%, 99% ee
tert-Butyl 3-(Bromomethyl)-1H-indole-1-carboxylate (5)
Phosphorus tribromide (0.683 mL, 7.27 mmol, 0.4 equiv) was dis-
solved in Et2O (11.4 mL, 1.6 M) in a dried flask (A) with a stir bar.
This solution was cooled under N2 to –40 °C. In a separate flask
with a spin vane (B), tert-butyl 3-(hydroxymethyl)-1H-indole-1-
carboxylate (4.5 g, 18.197 mmol, 1.0 equiv) was dissolved in Et2O
(11.4 mL, 1.6 M) and cooled under N2 to –40 °C. The contents of
flask B were transferred dropwise, via syringe, to flask A. Flask B
was then rinsed with Et2O (2 × 11.4 mL) at r.t., with each rinse be-
ing transferred into flask B, bringing the total Et2O volume to 45.6
mL. The reaction suspension was warmed to –10 °C and became a
yellow-pink solution. It was stirred at –10 °C for 25 h, and the reac-
tion was quenched with ice water (100 mL) and Et2O (150 mL). The
layers were separated and extracted with Et2O (3 × 75 mL). The
combined organic layers were washed with brine (50 mL), dried
O
1) BCl3, –78 °C, 90%
2) AlMe3, NH(OMe)Me
Me
N
OMe
OH
HN
92%
3
O
1) TESCl, imidazole
70%
2) BnMgCl 99%
3) TBAF 87%
OH
HN
[a]D +45°
kurasoin B (2)
Scheme 5
Synlett 2009, No. 4, 653–657 © Thieme Stuttgart · New York

656
M. A. Christiansen et al.
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over MgSO4, filtered, concentrated by rotary evaporation and vacu-
um for 1 h to give 5.15 g (92% yield) of the product as a pea-green,
crystalline solid, which was used without further purification. TLC:
Rf = 0.82 (20% EtOAc–hexanes).
J = 4.0 Hz, 1 H), 7.33–7.18 (m, 7 H), 7.14 (t, J = 7.5 Hz, 1 H), 7.00
(s, 1 H), 4.60 (dd, J1 = 58.0 Hz, J2 = 11.5 Hz, 2 H), 4.32 (dd, J1 = 1.0
Hz, J2 = 5.0 Hz, 1 H), 3.72 (s, 3 H), 3.35–3.26 (m, 2 H). 13C NMR
(125 MHz, CDCl3): d = 173.4, 137.7, 136.3, 128.6, 128.5, 128.2,
127.7, 123.7, 122.1, 119.5, 119.0, 111.5, 110.7, 79.0, 72.8, 52.2,
29.3. HRMS: calcd for [C19H20NO3]+: 310.36; found: 310.1434 [M
+ H]+. Chiral HPLC (DAICEL Chiralpack AD-H column): 10%
EtOH–hexane, 0.75 mL/min, 23 °C, l = 254 nm; tR (S, major) =
16.99 min; tR (R, minor) = 21.69 min; er = 94.1:5.9). [a]D24 +34.68
(c 2.508, CHCl3).
Analytical Data
1H NMR (500 MHz, CDCl3): d = 8.15 (br s, 1 H), 7.70 (q, J = 3.5
Hz, 2 H), 7.39–7.31 (m, 2 H), 4.70 (s, 2 H), 1.68 (s, 9 H). 13C NMR
(125 MHz, CDCl3): d = 149.6, 135.9, 128.9, 125.3, 125.2, 123.1,
119.6, 117.4, 115.7, 84.4, 28.4, 24.8. Note: this compound should
be stored at –20 °C under nitrogen and used within 2–3 weeks.
(S)-4-(1H-Indol-3-yl)-1-phenyl-3-(triethylsilyloxy)butan-2-one
(S)-3-(1H-Indol-3-yl)-N-methoxy-N-methyl-2-(triethylsilyloxy)-
propanamide (91 mg, 0.357 mmol, 1 equiv) was dissolved in THF
(4.25 mL, 0.059 M) in a dry flask with a stir bar. This solution was
then cooled, while stirring under N2, to 0 °C. A solution of benzyl-
magnesium chloride (2.0 M in THF, 0.628 mL, 1.255 mmol, 5.0
equiv) was then added slowly over 5 min, and the mixture was
warmed to r.t. It was then stirred for 5 h, until the starting material
had been consumed. The reaction was diluted with H2O (7 mL) and
CH2Cl2 (20 mL) and was transferred to a separatory funnel. The lay-
ers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated by rotary evaporation. The crude
material was purified by column chromatography (15% EtOAc–
hexanes). The product was isolated to afford 98 mg (99%) of the tar-
get compound as a clear, colorless oil. TLC: Rf = 0.43 (20%
EtOAc–hexanes). 1H NMR (500 MHz, CDCl3): d = 8.00 (br s, 1 H),
7.60 (d, J = 3.75 Hz, 1 H), 7.35 (d, J = 4.25, 1 H), 7.26–7.18 (m, 4
H), 7.12 (t, J = 7.5 Hz, 1 H), 6.99 (br s, 1 H), 6.94 (d, J = 3.5 Hz, 2
H), 4.49 (t, J = 5.5 Hz, 1 H), 3.68 (dd, J1 = 16.5 Hz, J2 = 16.5 Hz, 2
H), 3.13 (d, J = 2.8 Hz, 2 H), 0.90 (t, J = 8.0 Hz, 9 H), 0.52 (q,
J = 4.0 Hz, 6 H). 13C NMR (125 MHz, CDCl3): d = 210.7, 136.0,
134.0, 129.7, 128.3, 127.7, 126.6, 123.2, 122.0, 119.5, 119.2, 111.0,
110.8, 78.6, 44.9, 31.4, 6.7, 4.7. HRMS: calcd for [C24H31NO2Si]:
394.21; found: 394.2197 [M + H]+. [a]D24 –13.79 (c 0.29, CHCl3).
(S)-tert-Butyl 3-[2-(Benzyloxy)-3-(1-methyl-1H-imidazol-2-yl)-
3-oxopropyl]-1H-indole-1-carboxylate (4)
To a dry flask with a stir bar were added 2-(benzyloxy)-1-(1-meth-
yl-1H-imidazol-2-yl)ethanone (6, 0.5 g, 2.17 mmol, 1 equiv), 2,7-
bis[O(9)-allylhydrocinchonidinium-N-methyl]naphthalene dibro-
mide (8, 0.214 g, 0.217 mmol, 0.1 equiv), and tert-butyl 3-(bro-
momethyl)-1H-indole-1-carboxylate (5, 1.35 g, 4.34 mmol, 2
equiv). These were dissolved, while stirring under N2, in CH2Cl2
(21.7 mL, 0.1 M) that had been prechilled to –40 °C prior to addi-
tion, and the entire solution was placed in a cold bath at –40 °C un-
der N2. After 10 min, CsOH·H2O (1.46 g, 8.68 mmol, 4 equiv) was
added in one portion, and the suspension was stirred at –40 °C for
28 h. Once the starting material had been consumed the reaction was
diluted with H2O (20 mL) and Et2O (50 mL) and was transferred to
a separatory funnel. The layers were mixed and then separated; the
organic layer was washed with a sat. aq NaCl soln (20 mL), and was
then dried over MgSO4. The mixture was filtered, concentrated, and
the crude product was purified by column chromatography (30%
EtOAc–hexanes) to afford 0.977 g (98%) of the desired compound
as an off-white solid. TLC: Rf = 0.56 (30% EtOAc–hexanes).
Analytical Data
1H NMR (500 MHz, CDCl3): d = 8.14 (br s, 1 H), 7.55 (d, J = 3.8
Hz, 1 H), 7.50 (s, 1 H), 7.29 (t, J = 9.5 Hz, 2 H), 7.22–7.17 (m, 6 H),
7.06 (s, 1 H), 5.52 (dd, J = 2.0 Hz, 1 H), 4.55 (dd, J1 = 53.2 Hz,
J2 = 11.5 Hz, 2 H), 3.91 (s, 3 H), 3.28 (dq, J1 = 42.0 Hz, J2 = 7.0 Hz,
2 H), 1.67 (s, 9 H). 13C NMR (125 MHz, CDCl3): d = 191.14, 149.9,
142.2, 138.1, 131.0, 129.8, 128.4, 128.1, 127.8, 127.4, 124.8, 124.3,
122.5, 119.6, 116.5, 115.2, 83.5, 80.1, 72.7, 36.2, 29.3, 28.5.
HRMS: calcd for C27H29N3O4: 459.22; found: 459.2153 [M+].
Chiral HPLC (DAICEL Chiralpack AD-H column): 10% EtOH–
hexane, 0.75 mL/min, 23 °C, l = 254 nm, tR (S, major) = 9.99 min;
Kurasoin B (2)
(S)-4-(1H-indol-3-yl)-1-phenyl-3-(triethylsilyloxy)butan-2-one (86
mg, 0.2187 mmol, 1 equiv) was dissolved in THF (1.57 mL, 0.042
M) in a dry flask with a stir bar. This solution was then cooled, while
stirring under N2, to 0 °C. A solution of TBAF (1.0 M in THF, 0.235
mL, 0.23424 mmol, 1.071 equiv) was then added, and the reaction
was stirred at 0 °C for 1 h. The reaction was diluted with a saturated
solution of aqueous NH4Cl (10 mL) and CH2Cl2 (30 mL). The lay-
ers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated by rota-evaporator. The crude
material was purified by column chromatography (30% EtOAc–
hexanes). The final product was isolated to afford 53 mg (87%) of
the target compound as a yellow, crystalline solid. TLC: Rf = 0.38
(30% EtOAc–hexanes). 1H NMR (500 MHz, CD3OD): d = 7.54 (d,
J = 3.8 Hz, 1 H), 7.35 (d, J = 4.0 Hz, 1 H), 7.23–7.18 (m, 3 H),
7.12–7.09 (m, 2 H), 7.01 (t, J = 7.0 Hz, 2 H), 6.96 (d, J = 3.8 Hz, 2
H), 4.52 (t, J = 5.5 Hz, 1 H), 3.70 (q, J = 7.3 Hz, 2 H), 3.16 (dq,
J1 = 12.8 Hz, J2 = 6.5 Hz, 2 H), 3.01 (t, J = 8.0 Hz, 1 H). 13C NMR
(125 MHz, CD3OD): d = 211.3, 136.6, 134.0, 129.4, 127.9, 127.4,
126.3, 123.3, 121.0, 118.4, 118.2, 110.8, 109.5, 76.4, 45.4, 29.7.
HRMS: calcd for [C18H17NO2]: 280.13; found: 280.1332 [M + H]+.
[a]D24 +45 (c 0.83, CHCl3).
24
tR (R, minor) = 93.10 min; er >99:<1); [a]D +16.75 (c 5.55,
CHCl3).
(S)-Methyl 2-(Benzyloxy)-3-(1H-indol-3-yl)propanoate (16)
To a dried flask was added (S)-tert-butyl 3-[2-(benzyloxy)-3-(1-me-
thyl-1H-imidazol-2-yl)-3-oxopropyl]-1H-indole-1-carboxylate (4,
2.19 g, 4.769 mmol, 1 equiv), powdered 4 Å MS (0.475 g), and
MeCN (28 mL, 0.17 M). These were stirred vigorously at r.t. for 5
min. Methyl triflate (2.7 mL, 23.84 mmol, 5.0 equiv) was added,
and the mixture was stirred at r.t. for 2 h. Dry MeOH (28 mL, 0.17
M) was then added, followed by DBU (1.78 mL, 11.92 mmol, 2.5
equiv), and the mixture was stirred for 6 h. The reaction was
quenched by H2O (30 mL) and CH2Cl2 (75 mL) and was transferred
to a separatory funnel. The layers were mixed and then separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried over MgSO4, filtered, and con-
centrated by rotary evaporation. TLC showed that two products
were formed: the desired product (Rf = 0.69 in 30% EtOAc–hex-
anes) and deprotected starting material (Rf = 0.33 in 30% EtOAc–
hexanes). The crude residue was purified by column chromatogra-
phy (20% EtOAc–hexanes) to afford 1.27 g (86%) of the target
compound as a yellow oil. TLC: Rf = 0.69 (30% EtOAc–hexanes).
1H NMR (500 MHz, CDCl3): d = 8.305 (d, J = 4.5 Hz, 1 H), 7.62 (d,
Acknowledgment
We are grateful for support provided by the Research Corporation
Research in the form of an Opportunity Award, and the Brigham
Young University Cancer Research Center.
Synlett 2009, No. 4, 653–657 © Thieme Stuttgart · New York

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References
Synthesis of Kurasoin B
657
(9) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353. (b) Corey, E. J.; Xu, F.; Noe, M. C.
J. Am. Chem. Soc. 1997, 119, 12414. (c) Lygo, B.;
Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.
(d) Ooi, T.; Kameda, K.; Maruoka, K. J. Am. Chem. Soc.
1999, 121, 6519. (e) Jew, S.; Yoo, M.; Jeong, B.; Park, I. Y.;
Park, H. Org. Lett. 2002, 4, 4245. (f) Park, H.; Jeong, B.;
Yoo, M.; Lee, J.; Park, M.; Lee, Y.; Kim, M.; Jew, S. Angew.
Chem. Int. Ed. 2002, 41, 3036. (g) O’Donnell, M. J.;
Delgado, F.; Hostettler, C.; Schwesinger, R. Tetrahedron
Lett. 1998, 39, 8775.
(10) Oliveira, D. J.; Coelho, F. Synth. Commun. 2000, 30, 2143.
(11) Binns, M. R.; Haynes, R. K.; Lambert, D. E.; Schober, P. A.;
Turner, S. G. Aust. J. Chem. 1987, 40, 281.
(12) Rai-Mali, S.; Svedrui, D.; Gazivoda, T.; Marunovi, A.;
Hergold-Brundi, A.; Nagl, A.; Balzarini, J.; De Clercq, E.;
Mintas, M. J. Med. Chem. 2000, 43, 4806.
(13) (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.;
Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 10879.
(b) Hulme, A. N.; Montgomery, C. H. Tetrahedron Lett.
2003, 44, 7649. (c) Okitsu, O.; Suzuki, R.; Kobayashi, S.
J. Org. Chem. 2001, 66, 809. (d) Dineen, T. A.; Roush,
W. R. Org. Lett. 2005, 7, 1355. (e) Rivkin, A.; Biswas, K.;
Chou, T.-C.; Danishefsky, S. J. Org. Lett. 2002, 4, 4081.
(14) (a) Creary, X.; Geiger, C. C. J. Am. Chem. Soc. 1982, 104,
4151. (b) Hartman, M.; Christian, R.; Zbiral, E. Liebigs Ann.
Chem. 1990, 83. (c) Ivonin, S. P.; Lapandin, A. V. Synth.
Commun. 2004, 34, 3727.
(1) Uchida, R.; Shiomi, K.; Inokoshi, J.; Masuma, R.;
Kawakubo, T.; Tanaka, H.; Iwai, Y.; Omura, S. J. Antibiot.
1996, 49, 932.
(2) (a) Kohl, N. E.; Wilson, F. R.; Mosser, S. D.; Giuliani, E.;
DeSolms, S. J. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 9141.
(b) Kohl, N. E.; Omer, C. A.; Conner, M. W.; Anthony,
N. J.; Davide, J. P. Nat. Med. 1995, 1, 792.
(3) (a) Sunazuka, T.; Hirose, T.; Zhi-Ming, T.; Uchida, R.;
Shiomi, K.; Harigaya, Y.; Omura, S. J. Antibiotics 1997, 50,
453. (b) Hirose, T.; Sunazuka, T.; Zhi-Ming, T.; Handa, M.;
Uchida, R.; Shiomi, K.; Harigaya, Y.; Omura, S.
Heterocycles 2000, 53, 777.
(4) Uchida, R.; Shiomi, K.; Sunazuka, T.; Inokoshi, J.;
Nishizawa, A.; Hirose, T.; Tanaka, H.; Iwai, Y.; Omura, S.
J. Antibiotics 1996, 49, 886.
(5) (a) Andrus, M. B.; Hicken, E. J.; Stephens, J. S. Org. Lett.
2004, 6, 2289. (b) Andrus, M. B.; Hicken, E. J.; Stephens,
J. C.; Bedke, D. K. J. Org. Chem. 2005, 70, 9470.
(6) Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K.
J. Org. Chem. 2006, 71, 8651.
(7) Andrus, M. B.; Christiansen, M. A.; Hicken, E. J.; Gainer,
M. J.; Bedke, K. D.; Harper, K. C.; Mikkelson, S. R.;
Dodson, D. D.; Harris, D. V. Org. Lett. 2007, 8, 4865.
(8) (a) Evans, D. A.; Song, H.-J.; Fandrick, K. R. Org. Lett.
2006, 8, 3351. (b) Evans, D. A.; Fandrick, K. R.; Song,
H.-J. J. Am. Chem. Soc. 2005, 127, 8942. (c) Miyashita, A.;
Suzuki, Y.; Nagasaki, I.; Ishiguro, C.; Iwamoto, K.-I.;
Higashino, T. Chem. Pharm. Bull. 1997, 45, 1254.
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