Conversion of α-amino acids into bioactive o-aminoalkyl resorcylates and related dihydroxyisoindolinones

Article abstract of DOI:10.1021/jo2009356

The synthesis of biologically active o-aminoalkyl resorcylates and related dihydroxyisoindolinones from functionalized α-amino acids without the use of phenolic protection is described. The key aminoalkyl-diketo-dioxinone intermediates were prepared utilizing a crossed Claisen condensation reaction in the presence of diethylzinc. The aromatic unit was constructed via late stage cyclization and aromatization, and subsequent modification provided the novel resorcylates which showed activity against a selection of receptors and kinases, including 5-HT and CDK.

Full text of DOI:10.1021/jo2009356

ARTICLE
pubs.acs.org/joc
Conversion of r-Amino Acids into Bioactive o-Aminoalkyl
Resorcylates and Related Dihydroxyisoindolinones
Bhavesh H. Patel,† Andrew M. Mason,‡ Hetal Patel,† R. Charles Coombes,† Simak Ali,†
and Anthony G. M. Barrett*,†
†Departments of Chemistry and Cancer Medicine, Imperial College, London SW7 2AZ, England
‡GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, Herts SG1 2NY, England
S Supporting Information
b
ABSTRACT: The synthesis of biologically active o-aminoalkyl
resorcylates and related dihydroxyisoindolinones from function-
alized R-amino acids without the use of phenolic protection is
described. The key aminoalkyl-diketo-dioxinone intermediates
were prepared utilizing a crossed Claisen condensation reaction
in the presence of diethylzinc. The aromatic unit was constructed
via late stage cyclization and aromatization, and subsequent
modification provided the novel resorcylates which showed activ-
ity against a selection of receptors and kinases, including 5-HT
and CDK.
’ INTRODUCTION
The resorcylic acid lactone (RAL) family of natural products
consists of a diverse variety of biologically active compounds
bearing the resorcylate unit 1 (Figure 1).1 Within this family are
the 14-membered resorcylic macrolides (S)-zearalenone (2), an
estrogen agonist,2 radicicol (3), a HSP-90 inhibitor (20 nM),3
aigialomycin D (4), a CDK (cyclin-dependent kinase) 1 and 5
inhibitor (6 μM)4 and antimalarial (18 μM),5 and LL-Z1640À2
(5), a TAK-1 kinase inhibitor (8.1 nM).6
Small differences in macrocyclic ring functionality have re-
sulted in diverse biological effects, and in consequence of this, we
sought to synthesize additional classes of resorcylates from
readily available building blocks, as novel, potentially active
drug-like templates. Having recently published the biomimetic
Figure 1. Resorcylate unit and related natural products.
syntheses of several macrocyclic resorcylate natural products by
late stage aromatization reactions from triketo-ester precursors,7
we sought to employ this methodology,8 to generate resorcylate
amino acid derivatives as potentially novel pharmacophoric
classes. Herein, we report the conversion of simple R-amino
acids into resorcylates bearing o-1-aminoalkyl residues both as
potential biologically active hit structures and as templates for the
synthesis of new classes of potential pharmaceuticals.
We considered that the amino acid-derived resorcylates 6
(Scheme 1) with variable functionality (R1, R2, R3) at C-6, should
be available from the C-acylation of the dianion derived from
dioxinone 9, with the Weinreb amides 8, and aromatization of the
resultant diketo-dioxinones 7. In turn, amides 8 should be
available from amino acid derivatives 10. Clearly such precursor
acids 10 would include derivatives of the common R-amino acids
of either antipodal series.
’ RESULTS AND DISCUSSION
The N-Boc protected R-amino acids 11aÀf, and freshly
prepared (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-car-
boxylic acid (11g)9 and (()-cis-5-(ethoxycarbonyl)-1-benzyl-
pyrrolidine-2-carboxylic acid (11h)10 (both in two steps from
commercially available precursors), were subjected to amide
Received: May 12, 2011
Published: June 06, 2011
r
2011 American Chemical Society
6209
dx.doi.org/10.1021/jo2009356 J. Org. Chem. 2011, 76, 6209–6217
|

The Journal of Organic Chemistry
ARTICLE
Scheme 1. Retrosynthesis of o-Aminoalkyl-Functionalized
Resorcylates
Scheme 3. Synthesis of Functionalized r-Sulfonamido
Weinreb Amides via Key Coupling Intermediate 13
Scheme 2. Synthesis of r-Amino Acid-Related Weinreb
Amides
Scheme 4. Synthesis of Functionalized Imidazole Derivatives
Scheme 5. Improved Synthesis of Keto-dioxinone 9
coupling with N,O-dimethylhydroxylammonium chloride under
mild conditions using carbonyl diimidazole (CDI),11 to give the
sarcosine 12a, glycine 12b, L-alanine 12c, L-proline 12d, L-valine
12e, L-leucine 12f, (S)-1-(tert-butyldimethylsilyl) β-lactam 12g,
and cis-2,5-substituted pyrrolidine 12h-derived Weinreb amides
in 65À86% yield (Scheme 2).12
Alternative resorcylate precursors containing an aromatic or
heteroaromatic sulfonamide unit were also synthesized from
Weinreb amide 13 (Scheme 3). Carbamate 12a was N-Boc
deprotected under acidic conditions to give hydrochloride salt
13 in 96% yield. Subsequent reaction with the appropriate arene
or heteroarene sulfonyl chloride 14aÀd using triethylamine as
base gave the Weinreb amide sulfonamides with phenyl- 15a,
2-pyridyl- 15b, 3,5-dimethyl-4-isoxazolyl- 15c, and 1,3-dimethyl-
5-chloro-4-pyrazoyl- 15d substituents in 80À86% yield (Scheme 3).
For the more elaborately functionalized amino acids pre-
viously mentioned (11eÀj, Scheme 2), an alternative process
was employed because of the somewhat low reactivity of the
Weinreb amides in subsequent C-acylation reactions, relative to
N-acyl imidazoles (Scheme 4). N-Protected-amino acids 11eÀj
were allowed to react with carbonyl diimidazole at 0 °C,13 to
directly provide the corresponding acyl imidazoles 16aÀf in
65À91% yield (Scheme 4).14
An improved synthesis of key intermediate keto-dioxinone 9
has been developed. Dioxinone 17 was allowed to react with an
excess of lithium hexamethyldisilazide followed by diethylzinc
at À20 °C. Subsequent reaction with N-acetylimidazole 18
at À10 °C gave 9 in 67À70% yield (Scheme 5). The use of
diethylzinc was employed to minimize further reaction of 9 via
proton transfer with the lithium enolate of 17. This leads to the
formation of the double acylated byproduct 19 which was a major
limitation of the previous syntheses of this key building block.7b,15
Consequently, this procedure was much preferred for large scale
synthesis, giving rise to no significant byproduct.16
A generalized route for the Claisen condensationÀ
cyclizationÀaromatizationÀring-opening sequence is shown in
Scheme 6. The dilithium enolate of keto-dioxinone 9, which was
generated using lithium diisopropylamide, was consecutively
allowed to react with diethylzinc17 and the Weinreb amides
12aÀd, 15aÀd, or acyl imidazoles 16aÀf at À30 or À78 °C
6210
dx.doi.org/10.1021/jo2009356 |J. Org. Chem. 2011, 76, 6209–6217

The Journal of Organic Chemistry
ARTICLE
respectively, to give the functionalized diketo-dioxinones 20aÀn
(Scheme 6).18 Reaction of the valine-derived Weinreb amide 12e
failed to give the desired diketo-dioxinone in sufficient yield
(<5% conversion to 21e), presumably due to the added steric
bulk close to the reactive sites. Furthermore, an extension of the
isopropyl group by one carbon atom (leucine-derived amide 12f)
resulted in a 60% conversion to diketo-dioxinone 20f, signifying
that steric congestion was still an issue. In both cases, the more
reactive imidazole derivatives 16a,b gave complete conversion.19
Subsequent cyclization and aromatization of crude diketo-
dioxinones 20aÀn using triethylamine20 gave the corresponding
isopropylidene-protected resorcylates 21aÀn in 32À72% yield
over the two steps.21 Without the use of diethylzinc in the crossed
Claisen coupling step, the overall two-step yields decreased
significantly to 0À25%. Presumably higher yielding C-acylation
was due to the reduced basicity of the zinc dienolates relative to
the lithium systems.
Scheme 6. Synthesis of Novel Amino Resorcylates 22aÀj
Transesterification with ring-opening of several dioxinone-
resorcylates using methanol at 60 °C in the presence of cesium
carbonate (Scheme 6)22 gave the aminoalkyl resorcylates or
dihydroxyisoindolinones 22aÀj in 82À94% yield, all the struc-
tures of which are shown in Figure 2.
The synthesis of N-alkyl dihydroxyisoindolinones such as 24
(Scheme 7, alkyl = Me) has not been reported in the literature;
however, related structures are known.23 Herein we report the
use of this methodology to form isoindolinone 24 without the
use of phenolic protection (Scheme 7), which could be applied
to obtain specific isoindolinones dependent upon the precursor
R-amino acid.
Methanolysis of resorcylate precursor 21a in the presence of
cesium carbonate gave resorcylate 22a, which was subjected
directly to acidic N-Boc deprotection to give hydrochloride salt
23,24 followed by base-mediated lactamization,25 to give func-
tionalized isoindolinone 24 in 86% over the three steps.
Figure 2. Structures of the R-amino acid-related resorcylate derivatives synthesized.
6211
dx.doi.org/10.1021/jo2009356 |J. Org. Chem. 2011, 76, 6209–6217

The Journal of Organic Chemistry
ARTICLE
Scheme 7. Facile Synthesis of Dihydroxyisoindolinone 24
(Table 2, entries 5 and 6) showed micromolar inhibition
of GSK3B.
In summary, we have shown the synthesis of a new series of
o-aminoalkyl resorcylate derivatives and isoindolinones of novel
structural classes. This efficient synthesis produced compounds
displaying promising biological activities, at least toward CDKs 2
and 7, R1 nAChR, and 5-HT receptors. We have highlighted that
this methodology is amenable to the inclusion of diverse func-
tional groups and can potentially lead to many varied resorcylate
compounds. Further studies will be reported in due course.
’ EXPERIMENTAL SECTION
General Methods. All reactions were carried out in oven-dried
glassware under N2, using commercially supplied solvents and reagents
unless otherwise stated. THF, CH2Cl2, Et3N, and MeOH were redis-
tilled from Na-Ph2CO, CaH2, CaH2, and Mg turningsÀI2, respectively.
Hexanes refers to BDH AnalaR petroleum spirit 40À60 °C. Column
chromatography was carried out on silica gel, using flash techniques
(eluants are given in parentheses). Analytical thin layer chromatography
was performed on precoated silica gel F254 aluminum plates with
visualization under UV light or by staining using either acidic vanillin,
anisaldehyde, or ninhydrin spray reagents. Melting points were obtained
using a melting point apparatus and are uncorrected. Infrared data were
carried out neat unless otherwise stated. Indicative features of each
spectrum are given with adsorptions reported in wavenumbers (cmÀ1).
1H NMR spectra were recorded at 400 MHz with chemical shifts (δ)
quoted in parts per million (ppm) and coupling constants (J) recorded
in hertz (Hz). 13C NMR spectra were recorded at 100 MHz with
chemical shifts (δ) quoted in ppm.
General Procedure for the Synthesis of Weinreb Amides
12aÀh. Carbonyl diimidazole (0.72 g, 4.4 mmol) was added to the
N-protected amino acid 11aÀh (4.0 mmol) in CH2Cl2 (8 mL) at room
temperature. After 1.5 h, N,O-dimethylhydroxylammonium chloride
(0.43 g, 4.4 mmol) was added, and, after 16 h, the mixture was diluted
with EtOAc (25 mL), washed consecutively with 1 M aqueous HCl
(20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL),
dried (MgSO4), and rotary evaporated to give the desired Weinreb amide
12aÀh, which was used in the next step without further purification.
tert-Butyl 2-(Methoxy(methyl)amino)-2-oxoethyl(methyl) Carba-
mate (12a). 78%; colorless oil; Rf 0.35 (hexanes:EtOAc 1:1); 1H
NMR (CDCl3, 400 MHz) δ 4.15 (s, 1.2H, rotamer 1), 4.07 (s, 0.8H,
rotamer 2), 3.71À3.69 (2s, 3H, rotamer 1 and 2), 3.19À3.18 (2s, 3H,
rotamer 1 and 2), 2.93À2.92 (2s, 3H, rotamer 1 and 2), 1.47 (s, 5.4H,
rotamer 1), 1.43 (s, 3.6H, rotamer 2).
Table 1. CDK2 and CDK7 Cellular Inhibition by Resorcy-
lates 22a,b,dÀj
entry resorcylate GI50a (μM) CDK2 IC50a (μM) CDK7 IC50a (μM)
1
2
3
4
5
6
7
8
9
22a
22b
22d
22e
22f
22g
22h
22i
48.6
49.0
0.64
0.61
>1.00
0.45
0.34
0.37
0.58
0.44
0.52
0.68
0.28
>1.00
0.39
0.43
1.29
0.41
0.35
1.44
>100
83.7
20.3
58.3
53.0
75.9
22j
2.71
a GI50: concentration that inhibits 50% of cell growth; IC50: concentra-
tion that inhibits 50% of enzyme activity.
A selection of the novel amino resorcylates (22a,b,dÀj, Figure 2)
were initially screened in MCF7 breast cancer cell lines against
the cyclin dependent kinases CDK2 and CDK7 to evaluate their
biological activities. We hoped to see CDK inhibition due to the
previously observed activities of several resorcylate macrolactone
natural products and related analogues toward CDK,4,26 and
other kinases.27 Table 1 shows the inhibition data of the reso-
rcylates tested.
Micromolar activity was recorded for all nine examples
screened. Significant selectivity for CDK2 over CDK7 was shown
for compounds 22g (Table 1, entry 6) and 22j (Table 1, entry 9),
with the latter inhibiting cell growth the most.
Following on from these promising activities against CDK, we
further screened resorcylates 22a,b,gÀj (Figure 2) in a series of
biological assays to determine any significant bioactivity due to
the varied activities displayed by known resorcylate macro-
lactones.1 These assays included inhibition of alpha 1 nicotinic
acetylcholine receptor (R1 nAChR), 5-hydroxytryptamine (5-HT)
receptors, and glycogen synthase kinase 3 beta (GSK3B). The
data are shown in Table 2.
tert-Butyl 2-(Methoxy(methyl)amino)-2-oxoethyl Carbamate (12b).
1
84%; white solid; Rf 0.30 (hexanes:EtOAc 1:1); H NMR (CDCl3, 400
MHz) δ 5.37À4.96 (br m, 1H), 4.08 (d, J = 4.0 Hz, 2H), 3.71 (s, 3H), 3.20
(s, 3H), 1.45 (s, 9H).
(S)-tert-Butyl 1-(Methoxy(methyl)amino)-1-oxopropan-2-yl Carba-
mate (12c). 81%; white solid, Rf 0.28 (hexanes:EtOAc 1:1); 1H NMR
(CDCl3, 400 MHz) δ 5.53À4.90 (br m, 1H), 4.79À4.43 (br m, 1H),
3.76 (s, 3H), 3.20 (s, 3H), 1.43 (s, 9H), 1.30 (d, J = 6.8 Hz, 3H).
(S)-tert-Butyl 2-(Methoxy(methyl)carbamoyl)pyrrolidine-1-carbox-
1
ylate (12d). 76%; pale yellow oil; Rf 0.40 (hexanes:EtOAc 1:1); H
NMR (CDCl3, 400 MHz) δ 4.69 (br m, 0.47H, rotamer 1), 4.59 (br m,
0.53H, rotamer 2), 3.77 (s, 1.4H, rotamer 1), 3.71 (s, 1.6H, rotamer 2),
3.61À3.36 (br m, 2H, rotamer 1 and 2), 3.19 (s, 3H, rotamer 1 and 2),
2.26À2.10 (br m, 1H, rotamer 1 and 2), 2.03À1.78 (br m, 3H, rotamer 1
and 2), 1.45 (s, 4.2H, rotamer 1), 1.40 (s, 4.8H, rotamer 2).
All six resorcylates tested displayed micromolar activity against
R1 nAChR and some micromolar activity toward 5-HT recep-
tors. Furthermore, two of the sulfonamide-alkyl resorcylates 22i,j
(S)-tert-Butyl 1-(Methoxy(methyl)amino)-3-methyl-1-oxobutan-2-
yl Carbamate (12e). 86%; colorless oil; Rf 0.32 (hexanes:EtOAc 1:1);
1H NMR (CDCl3, 400 MHz) δ 5.12 (br d, J = 8.4 Hz, 1H), 4.57 (br m,
6212
dx.doi.org/10.1021/jo2009356 |J. Org. Chem. 2011, 76, 6209–6217

The Journal of Organic Chemistry
ARTICLE
Table 2. IC50 Values for Resorcylates 22a,b,dÀj against 5-HT2A, 5-HT2C, 5-HT3, R1 nAChR, and GSK3B
entry
resorcylate
5-HT2Aa IC50 (μM)
5-HT2Ca IC50 (μM)
5-HT3a IC50 (μM)
R1 nAChRa IC50 (μM)
GSK3Bb IC50 (μM)
1
2
3
4
5
6
22a
22b
22g
22h
22i
na
20.0
na
5.01
na
3.16
31.6
3.98
12.6
3.16
3.98
na
25.1
7.94
20.0
na
na
12.6
na
3.98
na
na
na
7.94
na
na
7.94
7.94
22j
31.6
na
a Human antagonist. b Human inhibitor; na: no activity <100 μM.
1H), 3.77 (s, 3H), 3.21 (s, 3H), 2.02À1.94 (br m, 1H), 1.43 (s, 9H), 0.95
(d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H).
(S)-tert-Butyl 1-(Methoxy(methyl)amino)-4-methyl-1-oxopentan-
N-Methoxy-N-methyl-2-(N-methylpyridine-2-sulfonamido)acetamide
(15b). 85%; off-white solid; Rf 0.20 (hexanes:EtOAc 1:1); mp 88À90 °C
(Et2O:hexanes 1:1); IR 2941, 1669, 1577, 1424, 1337, 1176, 1113 cmÀ1
;
2-yl Carbamate (12f). 80%; colorless gum, Rf 0.60 (hexanes:EtOAc
1H NMR (CDCl3, 400 MHz) δ 8.70À8.69 (m, 1H), 7.96À7.87 (m, 2H),
7.49À7.46 (m, 1H), 4.35 (s, 2H), 3.73 (s, 3H), 3.14 (s, 3H), 3.05 (s, 3H);
13C NMR (CDCl3, 400 MHz) δ 168.7, 156.9, 149.6, 137.9, 126.5, 122.4,
61.4, 51.1, 36.4, 32.2; HRMS (ESI) calcd C10H15N3O4S: [M + H]+
274.0862; found [M + H]+ 274.0857. Anal. Calcd for C10H15N3O4S: C,
43.95; H, 5.53; N, 15.37; S, 11.73. Found: C, 44.05; H, 5.60; N, 15.29;
S, 11.67.
1
1:1); H NMR (CDCl3, 400 MHz) δ 5.17 (br d, J = 9.2 Hz, 0.8H,
rotamer 1), 4.98 (br d, J = 9.2 Hz, 0.2H, rotamer 2), 4.69 (br m, 0.8H,
rotamer 1), 4.30 (br m, 0.2H, rotamer 2), 3.77 (brs, 3H, rotamer 1 and 2),
3.17 (s, 3H, rotamer 1 and 2), 1.76À1.62 (br m, 1.6H, rotamer 1),
1.57À1.47 (br m, 0.4H, rotamer 2), 1.41À1.40 (br m, 9H + 1H, rotamer
1 and 2), 0.93 (d, J = 6.4 Hz, 3H, rotamer 1 and 2), 0.90 (d, J = 6.8 Hz,
3H, rotamer 1 and 2).
(S)-1-(tert-Butyldimethylsilyl)-N-methoxy-N-methyl-4-oxoazetidine-2-
carboxamide (12g). 70%; white gum; Rf 0.10 (hexanes:EtOAc 1:1); 1H
NMR (CDCl3, 400 MHz) δ 4.45 (br dd, J = 5.6, 2.8 Hz, 1H), 3.71 (s, 3H),
3.31 (dd, J = 14.8, 6.0 Hz, 1H, 3.21 (s, 3H), 2.98 (dd, J = 15.2, 3.2 Hz, 1H),
0.98 (s, 9H), 0.32 (s, 3H), 0.11 (s, 3H); HRMS (ESI) calcd C12H24N2O3Si:-
[M + H]+ 273.1634; found [M + H]+ 273.1627.
(()-cis-Ethyl 5-(Methoxy(methyl)carbamoyl)-1-benzylpyrrolidine-
2-carboxylate (12h). 65%; pale yellow gum; Rf 0.15 (hexanes:EtOAc
1:1); 1H NMR (CDCl3, 400 MHz) δ 7.36À7.20 (m, 5H), 4.04 (q, J =
7.0 Hz, 2H), 3.94À3.84 (br m, 2H), 3.74 (br m, 1H), 3.54 (s, 3H), 3.41
(br m, 1H), 3.12 (br s, 3H), 2.22À1.93 (br m, 4H), 1.20 (t, J = 7.0 Hz,
3H); HRMS (ESI) calcd C17H24N2O4: [M + H]+ 321.1814; found [M +
H]+ 321.1809.
N-Methoxy-N-methyl-2-(N,3,5-trimethylisoxazole-4-sulfonamido)-
acetamide (15c). 83%; white gum; Rf 0.16 (hexanes:EtOAc 1:1); IR
1
2940, 1677, 1591, 1407, 1338, 1176, 1115, 988, 938 cmÀ1; H NMR
(CDCl3, 400 MHz) δ 4.24 (s, 2H), 3.71 (s, 3H), 3.15 (s, 3H), 2.96
(s, 3H), 2.63 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3, 400 MHz) δ
173.2, 168.6, 157.9, 115.7, 61.5, 50.0, 35.4, 32.4, 12.8, 11.1; HRMS (ESI)
calcd C10H17N3O5S: [M + H]+ 292.0967; found [M + H]+ 292.0950.
2-(5-Chloro-N,1,3-trimethyl-1H-pyrazole-4-sulfonamido)-N-meth-
oxy-N-methylacetamide (15d). 80%; white gum; Rf 0.20 (hexanes:
EtOAc 1:1); IR 2939, 1679, 1502, 1437, 1364, 1340, 1175, 1122, 989,
938 cmÀ1; 1H NMR (CDCl3, 400 MHz) δ 4.23 (s, 2H), 3.81 (s, 3H),
3.72 (s, 3H), 3.15 (s, 3H), 2.97 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3,
400 MHz) δ 168.9, 148.9, 129.5, 115.0, 61.5, 50.4, 36.6, 35.6, 32.4, 14.0;
HRMS (ESI) calcd C10H17ClN4O4S: [M + H]+ 325.0706; found [M +
H]+ 325.0721.
General Procedure for the Synthesis of Imidazoles 16aÀf.
N-Protected amino acid 11eÀj (2.0 mmol) in THF (4 mL) was cooled
to 0 °C, and carbonyl diimidazole (0.36 g, 2.2 mmol) was added
portionwise over 5 min. After 2 h, the mixture was diluted with Et2O
(25 mL), and H2O (10 mL) was added carefully. The organic layer was
washed with H2O (2 Â 10 mL) and brine (10 mL), dried (MgSO4), and
rotary evaporated to give the desired product 16aÀf, which was used in
the next step without further purification.
N-Methoxy-N-methyl-2-(methylamino)acetamide Hydrochloride
(13). Amide 12a (5.0 g, 21.5 mmol) was dissolved in HCl in dioxane
(4.0 M; 30 mL) at room temperature. After 6 h, rotary evaporation gave
the desired hydrochloride salt 13 (3.48 g, 96%) as a white solid: Rf 0.08
(hexanes:EtOAc 1:1); mp 156À158 °C (Et2O:MeOH 2:1); IR 3007,
2966, 2752, 2690, 2414, 1668, 1467, 1383, 954 cmÀ1 1H NMR
;
(DMSO-d6, 400 MHz) δ 8.95 (br s, 2H), 4.05 (s, 2H), 3.72 (s, 3H),
3.16 (s, 3H), 2.58 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 165.9,
61.4, 47.6, 32.5, 31.7; HRMS (ESI) calcd C5H13ClN2O2: [M À Cl]+
133.0977; found [M À Cl]+ 133.0968.
(S)-tert-Butyl 1-(1H-Imidazol-1-yl)-3-methyl-1-oxobutan-2-yl Car-
1
General Procedure for the Synthesis of Weinreb Amides
15aÀd. Hydrochloride 13 (0.42 g, 2.5 mmol) in CH2Cl2 (15 mL) was
cooled to 0 °C, and Et3N (0.70 mL, 5.0 mmol) was added with stirring.
After 10 min, RSO2Cl (2.5 mmol) in CH2Cl2 (3 mL) was added slowly
and the mixture allowed to warm up to room temperature. After 16 h,
H2O (25 mL) was added and the product extracted with EtOAc (2 Â
25 mL). The combined organic extracts were washed with 1 M aqueous
HCl (30 mL) and brine (30 mL), dried (MgSO4), and rotary evaporated
to give the desired sulfonamides 15aÀd.
bamate (16a). 91%; white gum; Rf 0.12 (hexanes:EtOAc 1:1); H
NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 5.27
(br d, J = 8.8 Hz, 1H), 4.78 (br dd, J = 9.2, 5.6 Hz, 1H), 2.21À2.12 (br m,
1H), 1.43 (s, 9H), 1.03 (br d, J = 6.4 Hz, 3H), 0.94 (br d, J = 6.8 Hz, 3H).
(S)-tert-Butyl 1-(1H-Imidazol-1-yl)-4-methyl-1-oxopentan-2-yl Car-
bamate (16b). 86%; off-white gum; Rf 0.15 (hexanes:EtOAc 1:1); 1H
NMR (CDCl3, 400 MHz) δ 8.28 (s, 1H), 7.52 (s, 1H), 7.13 (s, 1H), 5.12
(br d, J = 8.8 Hz, 1H), 5.01À4.91 (br m, 1H), 1.84À1.74 (br m, 1H),
1.66À1.59 (br m, 2H), 1.43 (s, 9H), 1.03 (br d, J = 6.8 Hz, 3H), 0.95 (br
d, J = 6.8 Hz, 3H).
(S)-tert-Butyl 3-(Benzyloxy)-1-(1H-imidazol-1-yl)-1-oxopropan-2-yl
Carbamate (16c). 82%; white gum, Rf 0.10 (hexanes:EtOAc 1:1); 1H
NMR (CDCl3, 400 MHz) δ 8.23 (s, 1H), 7.50 (s, 1H), 7.33À7.27
(m, 3H), 7.18À7.16 (m, 2H), 7.10 (s, 1H), 5.47 (br d, J = 8.4 Hz, 1H),
5.10À5.06 (br m, 1H), 4.54À4.46 (m, 2H), 3.83À3.73 (br m, 2H), 1.44
(s, 9H).
N-Methoxy-N-methyl-2-(N-methylphenylsulfonamido)acetamide (15a).
86%; pale yellow solid; Rf 0.24 (hexanes:EtOAc 1:1); mp 73À75 °C (Et2O:
hexanes 1:1); IR 2973, 2938, 1664, 1448, 1331, 1162, 1152 cmÀ1; 1H NMR
(CDCl3, 400 MHz) δ7.86À7.84 (m, 2H), 7.60À7.50 (m, 3H), 4.17 (s, 2H),
3.73 (s, 3H), 3.15 (s, 3H), 2.90 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
168.7, 138.3, 132.6, 128.9 (2C), 127.4 (2C), 61.5, 50.2, 35.8, 32.3; HRMS
(ESI) calcd C11H16N2O4S: [M + H]+ 273.0909; found [M + H]+ 273.0914.
Anal. Calcd for C11H16N2O4S: C, 48.52; H, 5.92; N, 10.29; S, 11.77. Found: C,
48.49; H, 6.00; N, 10.23; S, 11.68.
(S)-tert-Butyl 1-(1H-Imidazol-1-yl)-1-oxo-3-phenylpropan-2-yl Car-
1
bamate (16d). 78%; white gum; Rf 0.20 (hexanes:EtOAc 1:1); H
6213
dx.doi.org/10.1021/jo2009356 |J. Org. Chem. 2011, 76, 6209–6217

The Journal of Organic Chemistry
ARTICLE
NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.44 (s, 1H), 7.31À7.24
(m, 3H), 7.12À7.11 (m, 2H), 7.06 (s, 1H), 5.24À5.09 (br m, 2H), 3.21
(dd, J = 13.6, 6.0 Hz, 1H), 3.08 (dd, J = 13.6, 6.4 Hz, 1H), 1.44 (s, 9H).
(S)-1-(tert-Butyldimethylsilyl)-4-(1H-imidazole-1-carbo-
rotamer 2); 13C NMR (acetone-d6, 100 MHz) δ 165.8, 161.3, 161.1,
157.2, 147.9, 147.6, 110.4, 110.2, 106.7, 105.1, 103.4, 80.7, 80.6, 53.2,
52.5, 36.4, 36.1, 29.6 (3C, rotamer 1), 29.4 (3C, rotamer 2), 26.6 (2C)
(contains rotamers); HRMS (ESI) calcd C17H23NO6: [M + Na]+
360.1423; found [M + Na]+ 360.1414. Anal. Calcd for C17H23NO6:
C, 60.52; H, 6.87; N, 4.15. Found: C, 60.58; H, 6.75; N, 4.07.
tert-Butyl (7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-
5-yl)methyl Carbamate (21b). 68%; off-white solid; Rf 0.56 (hexanes:
EtOAc 1:1); mp 185À189 °C (Et2O:EtOAc 10:1); IR 3454, 3184, 2982,
1714, 1666, 1617, 1504, 1451, 1287, 1270, 1250, 1164, 1138 cmÀ1; 1H
NMR (acetone-d6, 400 MHz) δ 9.66 (s, 1H), 6.71 (d, J = 2.0 Hz, 1H),
6.36À6.33 (m, 1H + 1H), 4.56 (d, J = 6.4 Hz, 2H), 1.66 (s, 6H), 1.42 (s,
9H); 13C NMR (acetone-d6, 100 MHz) δ 165.7, 161.7, 161.0, 157.6,
148.4, 112.7, 106.8, 105.0, 103.6, 80.0, 44.7, 29.6 (3C), 26.6 (2C);
HRMS (ESI) calcd C16H21NO6: [M + Na]+ 346.1267; found [M +
Na]+ 346.1265. Anal. Calcd: C, 59.43; H, 6.55; N, 4.33. Found: C, 59.49;
H, 6.43; N, 4.24.
nyl)azetidin-2-one (16e). 65%; white gum; Rf 0.10 (hexanes:EtOAc
1:1); 1H NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 7.45 (s, 1H), 7.17
(s, 1H), 4.67 (br dd, J = 6.4, 3.2 Hz, 1H), 3.61 (dd, J = 15.2, 6.4 Hz, 1H),
3.17 (dd, J = 15.2, 3.2 Hz, 1H), 1.00 (s, 9H), 0.34 (s, 3H), 0.13 (s, 3H).
(()-cis-Ethyl 5-(1H-Imidazole-1-carbonyl)-1-benzylpyrrolidine-2-
carboxylate (16f). 79%; off-white gum; Rf 0.16 (hexanes:EtOAc 1:1);
1H NMR (CDCl3, 400 MHz) δ 8.83 (s, 1H), 7.81 (s, 1H), 7.19À7.13
(m, 5H), 6.99 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.93À3.86 (m, 1H), 3.90
(d, J = 12.8 Hz, 1H), 3.72 (d, J = 12.8 Hz, 1H), 3.57À3.53 (m, 1H),
2.38À2.12 (m, 4H), 1.28 (t, J = 7.2 Hz, 3H).
2,2-Dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (9). Dioxinone
17 (50 g, 352 mmol) in THF (150 mL) was added dropwise to lithium
hexamethyldisilazide in THF (1.0M; 500 mL, 500 mmol) and THF
(330 mL) at À20 °C, and after 45 min, diethylzinc in hexanes (1.0M;
500 mL, 500 mmol) was added over 2 h. After a further 30 min, the
reaction mixture was allowed to warm up to À10 °C and N-acetylimi-
dazole (55 g, 500 mmol) was added portionwise over 15 min. After 3.5 h,
H2O:THF (1:9; 150 mL) was added dropwise, followed by 2 M aqueous
HCl (250 mL) and EtOAc (500 mL). The pH was adjusted to pH 1À2
using aqueous HCl (25%; 265 mL), and the layers were separated. The
aqueous layer was extracted with EtOAc (250 mL), and the combined
organic extracts wer washed with brine (500 mL), dried (MgSO4),
rotary evaporated, and chromatographed (heptane:EtOAc 3:2) to give 9
(40À42 g, 67À70%) as pale yellow crystals: Rf 0.40 (hexanes:EtOAc
1:1); mp 48À51 °C (hexanes:Et2O 2:1); IR 1726, 1636, 1374, 1275,
1206, 1013 cmÀ1; 1H NMR (CDCl3, 400 MHz) δ 5.29 (s, 1H), 3.31 (s,
2H), 2.19 (s, 3H), 1.66 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 200.8,
164.3, 160.5, 107.0, 96.5, 47.7, 30.0, 24.8; HRMS (CI) calcd C9H12O4:
[M + H]+ 185.0814; found: [M + H]+ 185.0812. Anal. Calcd for
C9H12O4: C, 58.69; H, 6.57; found: C, 58.75; H, 6.62.
General Procedure for the C-AcylationÀCyclizationÀ
Aromatization Sequence. n-BuLi in hexanes (1.6 M; 1.35 mL,
2.16 mmol) was added dropwise with stirring to iso-Pr2NH (0.31 mL,
2.16 mmol) in THF (10 mL) at À78 °C. After 20 min, keto-dioxinone 9
(0.19 g, 1.03 mmol) in THF (1.5 mL) was added dropwise with stirring
at À78 °C. After 40 min, Et2Zn in hexanes (1.0 M; 2.16 mL, 2.16 mmol)
was added slowly, and after a further 20 min, the mixture was allowed to
warm up to À30 °C.28 The Weinreb amide (0.52 mmol) in THF
(1.5 mL) was added and the mixture stirred for 3 h. The reaction was
quenched with saturated aqueous NH4Cl (15 mL) and 1 M aqueous
HCl (5 mL), and the aqueous layer was acidified to pH 1À2 using 1 M
aqueous HCl. The product was extracted twice with EtOAc (50 mL,
25 mL), the combined organic extracts were dried (MgSO4) and rotary
evaporated to give the crude acylation product 20aÀn, which was
dissolved in CH2Cl2 (15 mL), Et3N (2 mL) was added, and the mixture
was stirred at room temperature. After 16 h, saturated aqueous NH4Cl
(40 mL) and EtOAc (80 mL) were added, and the aqueous layer was
acidified to pH 1À2 using 1 M aqueous HCl. The layers were separated,
and the aqueous layer was further extracted with EtOAc (40 mL). The
combined organic extracts were dried (MgSO4), rotary evaporated, and
chromatographed (hexanes:EtOAc 5:1 to 1:1) to give the isopropyli-
dene-protected resorcylate 21a-n.
(S)-tert-Butyl 1-(7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-
5-yl)ethyl Carbamate (21c). 57%; yellow solid; Rf 0.52 (hexanes:EtOAc
1:1); mp 166À170 °C (Et2O:EtOAc 4:1); IR 3346, 2932, 1716, 1696,
1612, 1586, 1336, 1270, 1246, 1165, 1112 cmÀ1; 1H NMR (acetone-d6,
400 MHz) δ 9.57 (s, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.59 (br d, J = 6.4 Hz,
1H), 6.33 (d, J = 2.4 Hz, 1H), 5.70 (br m, 1H), 1.68 (s, 3H), 1.65 (s, 3H),
1.40À1.23 (br m, 9H + 3H); 13C NMR (acetone-d6, 100 MHz) δ 165.7,
165.6, 161.2, 160.8, 156.6, 155.4, 110.5, 110.5, 106.4, 105.0, 103.4, 79.7,
29.6 (3C), 27.0, 26.2, 23.6 (contains rotamers); HRMS (ESI) calcd
C17H23NO6: [M + Na]+ 360.1423; found [M + Na]+ 360.1422. Anal.
Calcd for C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C, 60.62; H,
6.76; N, 4.22.
(S)-tert-Butyl 2-(7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-
5-yl)pyrrolidine-1-carboxylate (21d). 47%; pale yellow solid; Rf 0.68
(hexanes:EtOAc 1:1); mp 197À200 °C (Et2O:EtOAc 5:1); IR 3161,
2975, 1719, 1661, 1612, 1430, 1365, 1304, 1160, 1136 cmÀ1; 1H NMR
(acetone-d6, 400 MHz) δ 9.47 (s, 1H, rotamer 1 and 2), 6.50 (br s, 1H,
rotamer 1 and 2), 6.33À6.32 (br m, 1H, rotamer 1 and 2), 5.77 (br d, J =
8.0 Hz, 0.35 H, rotamer 1), 5.68 (br d, J = 10.4 Hz, 0.65 H, rotamer 2),
3.63À3.47 (m, 2H, rotamer 1 and 2), 2.51À2.33 (br m, 1H, rotamer 1
and 2), 1.86À1.78 (m, 2H, rotamer 1 and 2), 1.70 (s, 3.2H, rotamer 2),
1.64 (s, 2.8H, rotamer 1), 1.43 (s, 3.2H, rotamer 2), 1.21 (s, 5.8H,
rotamer 1); 13C NMR (acetone-d6, 100 MHz) δ 165.5, 161.1, 161.0,
155.5, 154.5, 154.5, 153.8, 110.1, 110.0, 106.5, 104.5, 103.3, 80.0, 60.6,
49.3, 49.0, 36.5, 35.7, 29.7 (3C, rotamer 1), 29.5 (3C, rotamer 2), 27.5,
26.9, 26.5, 25.8, 24.7, 24.1 (contains rotamers); HRMS (ESI) calcd
C19H25NO6: [M + H]+ 364.1761; found [M + H]+ 364.1766. Anal.
Calcd for C19H25NO6: C, 62.80; H, 6.93; N, 3.85. Found: C, 62.89; H,
6.85; N, 3.82.
(S)-tert-Butyl 1-(7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-
5-yl)-2-methylpropyl Carbamate (21e). 56%; white solid; Rf 0.62
(hexanes:EtOAc 1:1); mp 161À163 °C (Et2O:EtOAc 10:1); IR 3237,
2971, 1711, 1615, 1587, 1391, 1368, 1290, 1169 cmÀ1 1H NMR
;
(acetone-d6, 400 MHz) δ 9.36 (br s, 1H), 6.73 (d, J = 2.0 Hz, 1H),
6.37 (d, J = 2.0 Hz, 1H), 6.34 (br m, 1H), 5.34 (br m, 1H), 2.12 (br m,
1H), 1.68 (s, 3H), 1.66 (s, 3H), 1.37 (br s, 9H), 0.96 (d, J = 5.2 Hz, 3H),
0.87 (d, J = 5.6 Hz, 3H); 13C NMR (acetone-d6, 100 MHz) δ 165.5,
161.9, 161.2, 157.4, 152.4, 113.9, 106.5, 106.0, 104.0, 79.8, 60.1, 34.4,
29.8 (3C), 27.2, 26.3, 21.6, 19.8; HRMS (ESI) calcd C19H27NO6: [M +
H]+ 366.1917; found [M + H]+ 366.1907.
tert-Butyl (7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-
5-yl)methyl(methyl) Carbamate (21a). 72%; pale yellow solid; Rf
0.62 (hexanes:EtOAc 1:1); mp 139À143 °C (Et2O:EtOAc 10:1); IR
3260, 2984, 1718, 1670, 1617, 1449, 1269, 1250, 1167, 1145 cmÀ1; 1H
NMR (acetone-d6, 400 MHz) δ 9.61 (br s, 1H, rotamer 1 and 2),
6.47À6.44 (br m, 1H, rotamer 1 and 2), 6.35 (br s, 1H, rotamer 1 and 2),
4.82À4.79 (2br s, 2H, rotamer 1 and 2), 2.91 (s, 3H, rotamer 1 and 2),
1.66 (s, 6H, rotamer 1 and 2), 1.48 (s, 4.15H, rotamer 1), 1.36 (s, 4.85H,
(S)-tert-Butyl 1-(7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-
5-yl)-3-methylbutyl Carbamate (21f). 51%; pale yellow solid; Rf 0.62
(hexanes:EtOAc 1:1); mp 121À123 °C (Et2O:EtOAc 10:1); IR 3223,
2958, 2871, 1691, 1613, 1585, 1287, 1269, 1166 cmÀ1 1H NMR
;
(acetone-d6, 400 MHz) δ 9.32 (br s, 1H), 6.79 (d, J = 1.6 Hz, 1H),
6.37 (br m, 1H), 6.34 (d, J = 2.0 Hz, 1H), 5.69 (br m, 1H), 1.85À1.77
(br m, 1H), 1.67 (2s, 6H, rotamer 1 and 2), 1.64À1.57 (br m, 1H),
6214
dx.doi.org/10.1021/jo2009356 |J. Org. Chem. 2011, 76, 6209–6217

The Journal of Organic Chemistry
ARTICLE
1.54À1.46 (br m, 1H), 1.37 (br s, 9H), 1.01 (br d, J = 5.2 Hz, 3H), 0.92
(br d, J = 5.6 Hz, 3H); 13C NMR (acetone-d6, 100 MHz) δ 165.7, 161.1,
157.1, 112.0, 106.5, 105.4, 103.7, 79.8, 52.9, 47.1, 27.4 (3C, rotamer 1),
27.2 (3C, rotamer 2), 26.4 (2C), 24.8 (2C), 22.8 (contains rotamers);
HRMS (ESI) calcd C20H29NO6: [M + H]+ 380.2073; found [M + H]+
380.2059.
400 MHz) δ9.71 (br s, 1H), 6.86 (d, J= 2.4 Hz, 1H), 6.40 (d, J= 2.4 Hz, 1H),
4.79 (s, 2H), 2.89 (s, 3H), 2.70 (s, 3H), 2.43 (s, 3H), 1.66 (s, 6H); 13C NMR
(acetone-d6, 100MHz) δ173.7, 164.1, 159.6, 159.3, 157.5, 143.6, 114.7, 109.7,
105.1, 103.4, 102.1, 51.8, 34.9, 24.8 (2C), 12.1, 10.6; HRMS (ESI) calcd
C17H20N2O7S: [M + H]+ 397.1069; found [M + H]+ 397.1072. Anal. Calcd
for C17H20N2O7S: C, 51.51; H, 5.09; N, 7.07; S, 8.09. Found: 51.58; H, 5.11;
N, 7.00; S, 8.00.
5-Chloro-N-((7-hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-
yl)methyl)-N,1,3-trimethyl-1H-pyrazole-4-sulfonamide (21l). 59%; white
solid; Rf 0.25 (hexanes:EtOAc 1:1); mp 196À199 °C(Et2O:EtOAc 3:1); IR
3397, 2927, 1720, 1698, 1614, 1584, 1338, 1287, 1165, 1123 cmÀ1;1HNMR
(acetone-d6, 400 MHz) δ 9.67 (br s, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.39
(d, J = 2.4 Hz, 1H), 4.77 (s, 2H), 3.86 (s, 3H), 2.84 (s, 3H), 2.40 (s, 3H),
1.66 (s, 6H); 13C NMR (acetone-d6, 100 MHz) δ 165.9, 161.4, 161.1, 150.0,
146.0, 130.9, 115.8, 111.7, 106.9, 105.3, 103.8, 53.8, 38.1, 36.9, 26.6 (2C),
15.3; HRMS (ESI) calcd C17H20ClN3O6S:[M+H]+ 430.0840; found [M +
H]+ 430.0825. Anal. Calcd for C17H20ClN3O6S: C, 47.50; H, 4.69; N, 9.77;
S, 7.46. Found: C, 47.61; H, 4.77; N, 9.73; S, 7.41.
(S)-1-(tert-Butyldimethylsilyl)-4-(7-hydroxy-2,2-dimethyl-4-oxo-4H-
benzo[d][1,3]dioxin-5-yl)azetidin-2-one (21m). 36%; off-white solid;
Rf 0.48 (hexanes:EtOAc 1:1); mp 142À144 °C (Et2O:EtOAc 3:1); IR
3070, 2931, 1703, 1611, 1451, 1295, 1270, 1207, 1170, 1041, 838,
822 cmÀ1; 1H NMR (acetone-d6, 400 MHz) δ 9.71 (br s, 1H), 6.94 (d,
J = 2.4 Hz, 1H), 6.40 (d, J = 2.4 Hz, 1H), 5.68À5.66 (dd, J = 6.0, 2.8 Hz,
1H), 3.62À3.56 (dd, J = 15.2, 6.0 Hz, 1H), 2.66À2.62 (dd, J = 15.2, 2.8
Hz, 1H), 1.69 (s, 3H), 1.66 (s, 3H), 0.98 (s, 9H), 0.31 (s, 3H), À0.02 (s,
3H); 13C NMR (acetone-d6, 100 MHz) δ 174.1, 165.9, 161.1, 160.9,
151.6, 110.2, 106.8, 105.3, 104.3, 50.4, 50.2, 27.8 (3C), 27.5, 25.7, 20.5,
À4.01, À4.91; HRMS (ESI) calcd C19H27NO5Si: [M + H]+ 378.1737;
found [M + H]+ 378.1732. Anal. Calcd for C19H27NO5Si: C, 60.45; H,
7.21; N, 3.71. Found: C, 60.51; H, 7.08; N, 3.61.
(()-cis-Ethyl 5-(7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-
5-yl)-1-benzylpyrrolidine-2-carboxylate (21n). 32%; pale yellow gum; Rf
0.50 (hexanes:EtOAc 1:1); IR 2927, 1698, 1452, 1416, 1243, 1075,
1028 cmÀ1; 1H NMR (CDCl3, 400 MHz) δ 9.66 (s, 1H), 7.64 (d, J = 2.4
Hz, 1H), 7.34À7.13 (m, 5H), 6.27 (d, J= 2.4 Hz, 1H), 4.91 (t, J= 7.2 Hz, 1H),
4.02À3.93 (m, 2H), 3.81 (d, J = 13.2 Hz, 1H), 3.69 (d, J = 13.2 Hz, 1H), 3.52
(dd, J= 8.0, 6.4 Hz, 1H), 2.46À2.38 (m, 1H), 2.15À2.09 (m, 1H), 1.90À1.82
(m, 1H), 1.66 (s, 3H), 1.60 (s, 3H), 1.62À1.51 (m, 1H), 1.15 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 176.2, 163.0, 160.2, 158.8, 138.0, 129.6
(2C), 127.9 (3C), 127.1, 110.8, 104.8, 103.6, 101.9, 66.1, 65.1, 60.8, 58.7, 34.0,
30.3, 29.6, 26.3, 24.8, 14.0; HRMS (ESI) calcd C24H27NO6: [M + H]+
426.1917; found [M + H]+ 426.1927.
(S)-tert-Butyl 2-(Benzyloxy)-1-(7-hydroxy-2,2-dimethyl-4-oxo-4H-
benzo[d][1,3]dioxin-5-yl)ethyl Carbamate (21g). 54%; white solid;
Rf 0.48 (hexanes:EtOAc 1:1); mp 133À136 °C (Et2O:EtOAc 10:1); IR
3300, 2980, 2932, 1719, 1691, 1615, 1588, 1292, 1168 cmÀ1; 1H NMR
(acetone-d6, 400 MHz) δ 9.38 (br s, 1H), 7.44À7.42 (br m, 2H),
7.31À7.28 (m, 4H), 7.27À7.22 (m, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.37
(d, J = 1.6 Hz, 1H), 6.28 (br s, 1H), 5.99 (br m, 1H), 4.61 (d, J = 9.6 Hz,
1H), 4.49 (d, J = 9.6 Hz, 1H), 3.77 (br dd, J = 8.0, 3.6 Hz, 1H), 3.61 (br
dd, J = 8.0, 5.2 Hz, 1H), 1.66 (2s, 6H, rotamer 1 and 2), 1.38 (br s, 9H);
13C NMR (acetone-d6, 100 MHz) δ 165.6, 161.5, 161.0, 157.1, 140.8,
130.1 (2C), 129.5 (2C), 129.2, 112.8, 106.7, 105.6, 104.1, 80.3, 80.1,
80.1, 79.8, 74.5, 74.3, 54.0, 53.9, 29.7 (3C), 27.1 (2C, rotamer 1), 26.5
(2C, rotamer 2) (contains rotamers); HRMS (ESI) calcd C24H29NO7:
[M + H]+ 444.2022; found [M + H]+ 444.2021. Anal. Calcd for
C24H29NO7: C, 65.00; H, 6.59; N, 3.16. Found: C, 65.13; H, 6.52;
N, 3.04.
(S)-tert-Butyl 1-(7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-
5-yl)-2-phenylethyl Carbamate (21h). 52%; pale yellow solid; Rf 0.60
(hexanes:EtOAc 1:1); mp 95À98 °C (Et2O:EtOAc 10:1); IR 3258,
2925, 1681, 1613, 1585, 1497, 1366, 1290, 1268, 1164 cmÀ1; 1H NMR
(acetone-d6, 400 MHz) δ 9.59 (br s, 1H), 7.44À7.42 (br m, 2H),
7.30À7.26 (br m, 2H), 7.20À7.17 (br m, 1H), 6.87 (br s, 1H), 6.54 (br
d, J = 5.2 Hz, 1H), 6.38 (br s, 1H), 6.09À6.01 (br m, 1H), 3.12 (br dd, J =
14.0, 3.2 Hz, 1H), 2.77 (br m, 1H), 1.68 (s, 6H), 1.27 (s, 9H); 13C NMR
(acetone-d6, 100 MHz) δ 164.7, 160.5, 160.5, 159.9, 155.9, 140.0, 130.1
(2C), 128.9 (2C), 127.0, 125.8, 110.3, 105.6, 104.1, 102.7, 78.7, 54.5,
54.2, 42.9, 28.5 (3C), 25.9 (2C, rotamer 1), 25.4 (2C, rotamer 2)
(contains rotamers); HRMS (ESI) calcd C23H27NO6: [M + Na]+
436.1736; found [M + Na]+ 436.1737. Anal. Calcd for C23H27NO6:
C, 66.81; H, 6.58; N, 3.39. Found: C, 66.86; H, 6.61; N, 3.50.
N-((7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl)methyl)-
N-methylbenzene-sulfonamide (21i). 64%; white solid; Rf 0.60 (hexanes:
EtOAc 1:1); mp 214À217 °C (Et2O:EtOAc 3:1); IR 3378, 2927, 1701,
1615, 1586, 1337, 1291, 1263, 1160 cmÀ1; 1H NMR (acetone-d6, 400
MHz) δ 9.68 (br s, 1H), 7.91À7.89 (m, 2H), 7.76À7.66 (m, 3H), 6.95
(d, J = 2.0 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 4.67 (s, 2H), 2.80 (s, 3H),
1.65 (s, 6H); 13C NMR (acetone-d6, 100 MHz) δ 165.9, 161.4, 161.0,
146.0, 140.1, 134.7, 131.3 (2C), 129.1 (2C), 112.0, 106.9, 105.4, 103.9,
53.8, 37.3, 26.6 (2C); HRMS (ESI) calcd C18H19NO6S: [M + H]+
378.1012; found [M + H]+ 378.1013. Anal. Calcd for C18H19NO6S: C,
57.28; H, 5.07; N, 3.71; S, 8.50. Found: C, 57.29; H, 5.00; N, 3.80;
S, 8.43.
General Procedure for the Cesium Carbonate-Mediated
Ring-Opening. Dioxinone-resorcylates 21aÀd,f,g,iÀl (0.20 mmol)
and Cs2CO3 (130 mg, 0.40 mmol) were suspended in MeOH (3 mL)
and heated in a sealed tube at 60 °C. After 18 h, the solvent was
evaporated and the mixture partitioned between 1 M aqueous HCl
(15 mL) and EtOAc (25 mL). The layers were separated, and the
organic layer was washed with brine (20 mL), dried (MgSO4), rotary
evaporated, and chromatographed (hexanes:EtOAc 2:1 to 1:1) to give
the resorcylate esters or isoindolinones 22aÀj.
N-((7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl)methyl)-
N-methylpyridine-2-sulfonamide (21j). 62%; white solid; Rf 0.30 (hexanes:
EtOAc:acetone 2:1:1); mp 210À212 °C (Et2O:EtOAc 3:1); IR 3368, 2936,
1701, 1615, 1587, 1331, 1290, 1264, 1169, 1151 cmÀ1; 1H NMR (acetone-d6,
400 MHz) δ 9.71 (br s, 1H), 8.79À8.78 (m, 1H), 8.15À8.11 (m, 1H),
8.01À7.99 (m, 1H), 7.71À7.68 (m, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.38(d, J=
2.0 Hz, 1H), 4.89 (s, 2H), 2.95 (s, 3H), 1.66 (s, 6H); 13C NMR (acetone-d6,
100 MHz) δ164.0, 159.5, 159.2, 157.4, 150.2, 144.4, 138.4, 127.0, 122.6, 109.9,
105.0, 103.5, 102.0, 52.9, 36.2, 24.8 (2C); HRMS (ESI) calcd C17H18N2O6S:
[M + H]+ 379.0965; found [M + H]+ 379.0970. Anal. Calcd for
C17H18N2O6S: C, 53.96; H, 4.79; N, 7.40; S, 8.47. Found: C, 54.02 H, 4.83;
N, 7.37; S, 8.40.
Methyl 2-((tert-Butoxycarbonyl(methyl)amino)methyl)-4,6-dihy-
droxybenzoate (22a). 89%; pale yellow solid; Rf 0.52 (hexanes:EtOAc
1:1); mp 149À152 °C (Et2O:EtOAc 5:1); IR 3207, 2956, 1649, 1624,
1450, 1435, 1403, 1256, 1151, 1102 cmÀ1; 1H NMR (acetone-d6, 400
MHz) δ 11.58 (s, 1H, rotamer 1 and 2), 9.27 (br s, 1H, rotamer 1 and 2),
6.32 (s, 1H, rotamer 1 and 2), 6.23 (br m, 1H, rotamer 1 and 2), 4.68 (s,
2H, rotamer 1 and 2), 3.94 (s, 3H, rotamer 1 and 2), 2.86 (s, 3H, rotamer
1 and 2), 1.48 (s, 4.85H, rotamer 1), 1.36 (s, 4.15H, rotamer 2); 13C
NMR (acetone-d6, 100 MHz) δ 172.4, 172.3, 166.5, 166.3, 163.8, 156.3,
144.9, 144.5, 107.3, 106.7, 104.2, 104.0, 102.1, 79.6, 53.2, 52.8, 52.4, 35.1,
35.0, 29.8 (3C) (contains rotamers); HRMS (ESI) calcd C15H21NO6:
[M + Na]+ 334.1267; found [M + Na]+ 334.1264. Anal. Calcd for
N-((7-Hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl)methyl)-
N,3,5-trimethylisoxazole-4-sulfonamide (21k). 54%; Rf white solid; 0.45
(hexanes:EtOAc 1:1); mp 202À205 °C (Et2O:EtOAc 3:1); IR 3332, 2924,
1702, 1616, 1588, 1336, 1290, 1263, 1175, 1113 cmÀ1; 1H NMR (acetone-d6,
6215
dx.doi.org/10.1021/jo2009356 |J. Org. Chem. 2011, 76, 6209–6217

The Journal of Organic Chemistry
ARTICLE
C15H21NO6: C, 57.87; H, 6.80; N, 4.50. Found: C, 57.75; H, 6.76;
N, 4.44.
tert-Butyl 5,7-Dihydroxy-1-oxoisoindoline-2-carboxylate (22b).
Methyl 2,4-Dihydroxy-6-((N-methylpyridine-2-sulfonamido)meth-
yl)benzoate (22h). 94%; white solid; Rf 0.30 (hexanes:EtOAc 1:1);
mp 184À186 °C (Et2O:EtOAc 2:1); IR 3106, 2957, 1649, 1624, 1587,
1351, 1332, 1256, 1166, 1113 cmÀ1; 1H NMR (acetone-d6, 400 MHz) δ
11.45 (s, 1H), 9.36 (s, 1H), 8.82À8.81 (m, 1H), 8.17À8.13 (m, 1H),
8.02À8.00 (m, 1H), 7.73À7.70 (m, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.33
(d, J = 2.4 Hz, 1H), 4.76 (s, 2H), 3.90 (s, 3H), 2.85 (s, 3H); 13C NMR
(acetone-d6, 100 MHz) δ 171.2, 165.3, 163.0, 157.3, 150.2, 142.0, 138.4,
127.0, 122.7, 108.1, 103.5, 101.9, 54.6, 51.6, 35.8; HRMS (ESI) calcd
C15H16N2O6S: [M + H]+ 353.0808; found [M + H]+ 353.0805. Anal.
Calcd for C15H16N2O6S: C, 51.13; H, 4.58; N, 7.95; S, 9.10. Found: C,
51.09; H, 4.47; N, 7.86; S, 8.97.
Methyl 2,4-Dihydroxy-6-((N,3,5-trimethylisoxazole-4-sulfonami-
do)methyl)benzoate (22i). 90%; white solid; Rf 0.28 (hexanes:EtOAc
1:1); mp 218À221 °C (Et2O:EtOAc 3:1); IR 3197, 2924, 2856, 1655,
1625, 1588, 1409, 1329, 1257, 1168, 1112 cmÀ1; 1H NMR (acetone-d6,
400 MHz) δ 11.43 (s, 1H), 9.37 (s, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.34
(d, J = 2.8 Hz, 1H), 4.69 (s, 2H), 3.94 (s, 3H), 2.79 (s, 3H), 2.70 (s, 3H),
2.44 (s, 3H); 13C NMR (acetone-d6, 100 MHz) δ 175.5, 173.0, 167.3,
164.8, 159.4, 143.2, 116.5, 109.9, 105.4, 103.9, 55.2, 53.6, 36.3, 14.0,
12.5; HRMS (ESI) calcd C15H18N2O7S: [M + H]+ 371.0914; found
[M + H]+ 371.0901. Anal. Calcd: C, 48.64; H, 4.90; N, 7.56; S, 8.66.
Found: C, 48.59; H, 4.86; N, 7.48; S, 8.57.
Methyl 2-((5-Chloro-N,1,3-trimethyl-1H-pyrazole-4-sulfonamido)-
methyl)-4,6-dihydroxybenzoate (22j). 90%; white solid; Rf 0.25
(hexanes:EtOAc 1:1); mp 126À130 °C (Et2O:EtOAc 3:1); IR 3169,
2924, 1654, 1621, 1589, 1433, 1326, 1253, 1163, 1114 cmÀ1; 1H NMR
(acetone-d6, 400 MHz) δ 11.45 (s, 1H), 9.36 (s, 1H), 6.67 (d, J = 2.8 Hz,
1H), 6.33 (d, J = 2.4 Hz, 1H), 4.63 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H),
2.74 (s, 3H), 2.41 (s, 3H); 13C NMR (acetone-d6, 100 MHz) δ 173.1,
167.3, 164.8, 150.0, 143.6, 130.9, 115.5, 109.8, 105.3, 103.7, 55.4, 53.6,
38.1, 36.6, 15.3; HRMS (ESI) calcd C15H18ClN3O6S: [M + H]+
404.0684; found [M + H]+ 404.0671. Anal. Calcd for C15H18ClN3O6S:
C, 44.61; H, 4.49; N, 10.41; S, 7.94. Found: C, 44.67; H, 4.56; N, 10.36;
S, 7.86.
5,7-Dihydroxy-2-methylisoindolin-1-one (24). Resorcylate 21a
(0.10 g, 0.30 mmol) and Cs2CO3 (0.20 g, 0.60 mmol) were suspended
in MeOH (3 mL) and heated at 60 °C. After 18 h, the solvent was
evaporated and the mixture partitioned between 1 M aqueous HCl
(10 mL) and EtOAc (20 mL). The layers were separated, and the
organic layer was washed with brine (15 mL), dried (MgSO4), and
rotary evaporated to give crude 22a, which was dissolved in MeOH
(3 mL). To the stirred solution was added HCl in Et2O (1.0 M; 10 mL,
10 mmol) at room temperature. After 14 h, the solvent was rotary
evaporated, the crude intermediate salt 23 dissolved in MeOH (10 mL),
Et3N (1 mL) added, and the resultant mixture stirred at room
temperature. After 3 h, the solvent was evaporated and the mixture
partitioned between 1 M aqueous HCl (20 mL) and EtOAc (20 mL).
The layers were separated, the aqueous layer was extracted further with
EtOAc (20 mL), and the combined organic extracts were washed with
brine (25 mL), dried (MgSO4), rotary evaporated, and chromato-
graphed (hexanes:EtOAc 1:1 to 0:1) to give isoindolinone 24 (45.5
mg, 86%) as a pale yellow solid: Rf 0.13 (hexanes:EtOAc 1:1); mp
151À153 °C (Et2O:EtOAc 3:1); IR 3078, 1680, 1649, 1624, 1593, 1396,
1327, 1260, 1239, 1147, 1045 cmÀ1; 1H NMR (DMSO-d6,29 400 MHz)
δ 9.67 (br s, 1H + 1H), 6.35 (d, J = 1.6 Hz, 1H), 6.20 (d, J = 1.6 Hz, 1H),
4.25 (s, 2H), 2.93 (s, 3H); 13C NMR (acetone-d6, 100 MHz) δ 171.5,
164.6, 158.4, 146.0, 111.5, 103.8, 102.6, 54.0, 29.5; HRMS (ESI) calcd
C9H9NO3: [M + H]+ 180.0661; found [M + H]+ 180.0661.
82%; off-white solid; Rf 0.48 (hexanes:EtOAc 1:1); mp 102À105 °C
(Et2O:EtOAc 5:1); IR 3364, 2927, 1754, 1632, 1347, 1295, 1152 cmÀ1
;
1H NMR (acetone-d6, 400 MHz) δ 9.44 (s, 1H), 8.65 (s, 1H), 6.54 (d,
J = 0.8 Hz, 1H), 6.32 (d, J = 1.2 Hz, 1H), 4.69 (s, 2H), 1.55 (s, 9H); 13C
NMR (acetone-d6, 100 MHz) δ 169.7, 166.7, 160.2, 151.6, 145.8, 110.4,
104.0, 103.3, 83.6, 51.3, 29.3 (3C); HRMS (ESI) calcd C13H15NO5:
[M + MeCN + Na]+ 329.1113; found [M + MeCN + Na]+ 329.1122.
(S)-tert-Butyl 4,6-Dihydroxy-1-methyl-3-oxoisoindoline-2-carboxy-
late (22c). 85%; white solid; Rf 0.50 (hexanes:EtOAc 1:1); mp
115À116 °C (Et2O:EtOAc 5:1); IR 3366, 2980, 1751, 1631, 1477,
1334, 1227, 1152 cmÀ1; 1H NMR (acetone-d6, 400 MHz) δ 9.41 (br s,
1H), 8.68 (br s, 1H), 6.52 (d, J = 0.8 Hz, 1H), 6.31 (d, J = 1.6 Hz, 1H),
4.99 (q, J = 2.4 Hz, 1H), 1.57À1.56 (m, 9H + 3H); 13C NMR (acetone-
d6, 100 MHz) δ 169.5, 166.8, 160.2, 151.7, 151.5, 108.9, 103.3, 83.7,
58.7, 29.3 (3C), 21.6; HRMS (ESI) calcd C14H17NO5: [M + MeCN +
Na]+ 343.1270; found [M + MeCN + Na]+ 343.1260.
(S)-tert-Butyl 4,6-Dihydroxy-1-isopropyl-3-oxoisoindoline-2-carboxylate
(22d). 85%; off-white solid; Rf 0.56 (hexanes:EtOAc 1:1); mp 149À
152 °C (Et2O:EtOAc 4:1); IR 3351, 2974, 1747, 1626, 1350, 1310,
1284, 1228, 1135 cmÀ1; 1H NMR (acetone-d6, 400 MHz) δ 9.92À8.54
(br m, 1H + 1H), 6.51 (br s, 1H), 6.34 (d, J = 1.6 Hz, 1H), 4.97 (d, J = 2.8
Hz, 1H), 2.64 (m, 1H), 1.55 (s, 9H), 1.15 (d, J = 7.2 Hz, 3H), 0.54 (d, J =
6.8 Hz, 3H); 13C NMR (acetone-d6, 100 MHz) δ 170.1, 166.2, 160.3,
151.6, 147.8, 110.3, 104.8, 103.4, 83.9, 67.2, 32.0, 29.3 (3C), 20.0, 16.4;
HRMS (ESI) calcd C16H21NO5: [M + MeCN + Na]+ 371.1583; found
[M + MeCN + Na]+ 371.1562. Anal. Calcd for C16H21NO5: C, 62.53;
H, 6.89; N, 4.56. Found: C, 62.65; H, 6.75; N, 4.52.
(S)-tert-Butyl 4,6-Dihydroxy-1-isobutyl-3-oxoisoindoline-2-carbox-
ylate (22e). 86%; white solid; Rf 0.58 (hexanes:EtOAc 1:1); mp
97À100 °C (Et2O:EtOAc 4:1); IR 3332, 2964, 2690, 1742, 1668,
1
1628, 1469, 1383, 1142, 1117, 953 cmÀ1; H NMR (acetone-d6, 400
MHz) δ 9.79À8.49 (br m, 1H + 1H), 6.52 (br s, 1H), 6.33 (d, J = 1.6 Hz,
1H), 5.06 (d, J = 3.6 Hz, 1H), 1.98À1.86 (m, 2H), 1.72À1.61 (m, 1H),
1.56 (s, 9H), 0.90 (d, J = 5.2 Hz, 3H), 0.88 (d, J = 4.8 Hz, 3H); 13C NMR
(acetone-d6, 100 MHz) δ 169.9, 166.6, 160.4, 151.4, 150.5, 109.6, 103.9,
83.8, 61.6, 43.5, 29.3 (3C), 25.7, 25.2, 24.2; HRMS (ESI) calcd
C17H23NO5: [M + MeCN + Na]+ 385.1739; found [M + MeCN +
Na]+ 385.1719. Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36.
Found: C, 63.67; H, 7.13; N, 4.30.
(S)-tert-Butyl 1-(Benzyloxymethyl)-4,6-dihydroxy-3-oxoisoindoline-
2-carboxylate (22f). 88%; pale pink solid; Rf 0.62 (hexanes:EtOAc 1:1);
mp 70À72 °C (Et2O:EtOAc 10:1); IR 3312, 1751, 1682, 1615, 1365,
1335, 1287, 1146 cmÀ1; 1H NMR (CDCl3, 400 MHz) δ 8.51 (s, 1H),
7.35 (m, 3H), 7.23 (m, 2H), 6.49 (s, 1H),6.34 (s, 1H), 6.06 (br s, 1H),
5.01 (dd, J = 6.4, 2.8 Hz, 1H), 4.50 (m, 2H), 4.01 (dd, J = 9.2, 3.2 Hz,
1H), 3.72 (dd, J = 9.2, 2.4 Hz, 1H), 1.54 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 168.9, 163.2, 158.4, 149.7, 146.3, 137.5, 128.5 (2C), 127.8
(2C), 127. 7, 108.6, 102.6, 102.4, 83.6, 69.7, 60.2, 28.1 (3C); HRMS
(ESI) calcd C21H23NO6: [M + Na]+ 408.1423; found [M + Na]+
408.1409.
Methyl2,4-Dihydroxy-6-((N-methylphenylsulfonamido)methyl)benzoate
(22g). 91%; white solid; Rf 0.36 (hexanes:EtOAc 1:1); mp: 134À137 °C
(Et2O:EtOAc 2:1); IR 3390, 2625, 1654, 1620, 1591, 1436, 1325, 1257, 1194,
1141, 1085 cmÀ1; 1H NMR (CDCl3, 400 MHz) δ 11.54 (s, 1H), 7.88À7.85
(m, 2H), 7.67À7.57 (m, 3H), 6.65 (d, J = 2.4 Hz, 1H), 6.61 (br s, 1H), 6.39
(d, J = 2.8 Hz, 1H), 4.46 (s, 2H), 3.88 (s, 3H), 2.69 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ171.0, 165.5, 161.6, 140.8, 137.1, 132.9, 129.2 (2C),
127.4 (2C), 108.5, 104.1, 102.8, 54.0, 52.1, 35.6; HRMS (ESI) calcd
C16H17NO6S: [M + H]+ 352.0856; found [M + H]+ 352.0863. Anal. Calcd
for C16H17NO6S: C, 54.69; H, 4.88; N, 3.99; S, 9.13. Found: C, 54.57; H, 4.67;
N, 3.92; S, 9.07.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra corresponding to all reported compounds and further
6216
dx.doi.org/10.1021/jo2009356 |J. Org. Chem. 2011, 76, 6209–6217

The Journal of Organic Chemistry
ARTICLE
information related to the biological assay methods. This material
is available free of charge via the Internet at http://pubs.acs.org.
(21) The lower yields obtained for compounds 21m and 21n were
most likely due to side reactions occurring in the C-acylation step with
the β-lactam ring and the pyrrolidine ester, respectively.
(22) Compounds 21d and 21h were not transesterified because
several other examples of naturally occurring amino acids had been
carried out successfully; compounds 21m and 21n were not transester-
ified because of the unfortunate lower yields in the preceding steps.
(23) (a) Hoarau, C.; Couture, A.; Deniau, E.; Grandclaudon, P.
Synthesis 2000, 5, 655.(b) Wagenen B. V.; Ukkiramapandian R.; Clayton
J.; Egle I.; Empfield J. R.; Isaac M.; Ma F.; Slassi A.; Steelman G.;
Urbanek R.; Walsh S. US Patent 7,868,008, 2009.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: agm.barrett@imperial.ac.uk.
’ ACKNOWLEDGMENT
We thank GlaxoSmithKline for the generous endowment
(to A.G.M.B.), the Engineering and Physical Sciences Research
Council (EPSRC) Pharma Synthesis Programme and GlaxoS-
mithKline for grant support (to B.H.P.), and P. R. Haycock and
R. N. Sheppard (Imperial College) for high-resolution NMR
spectroscopy.
(24) An alternative route was attempted via N-Boc deprotection of
21a and subsequent intramolecular ring opening to give 24; however,
high temperature (135 °C) was required and the yield was lower (67%).
(25) Both Et3N or NaOMe in MeOH can be used for this
lactamization.
(26) Schirmer, A.; Kennedy, J.; Murli, S.; Reid, R.; Santi, D. V. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 4234.
(27) Moulin, E.; Barluenga, S.; Totzke, F.; Winssinger, N. Chem.—
Eur. J. 2006, 12, 8819.
’ REFERENCES
(28) For the imidazole derivatives, the reaction mixture was held at
À78 °C, the imidazole (0.52 mmol) in THF (1.5 mL) was added, and
the reaction mixture was stirred for 2 h.
(1) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 1, 22.
(2) Miksicek, R. J. J. Steroid Biochem. Mol. Biol. 1994, 49, 153.
(3) (a) Schulte, T. W.; Akinaga, S.; Soga, S.; Sullivan, W.; Stensgard,
B.; Toft, D.; Neckers, L. M. Cell Stress Chaperones 1998, 3, 100. (b)
Sharma, S. V.; Agatsuma, T.; Nakano, H. Oncogene 1998, 16, 2639.
(4) Barluenga, S.; Dakas, P.-Y.; Meijer, L.; Winssinger, N. Angew.
Chem., Int. Ed. 2006, 45, 3951.
(29) 1H NMR was initially recorded in acetone-d6; however, the OH
protons were not observed and therefore the spectrum was recorded in
DMSO-d6.
(5) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree,
P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
(6) Ninomiya-Tsuji, J.; Kajino, T.; Ono, K.; Ohtomo, T.; Matsumo-
to, M.; Shiina, M.; Mihara, M.; Tsuchiya, M.; Matsumoto, K. J. Biol.
Chem. 2003, 278, 18485.
(7) (a) Navarro, I.; Basset, J.-F.; Hebbe, S.; Major, S. M.; Werner, T.;
Howsham, C.; Brackow, J.; Barrett, A. G. M. J. Am. Chem. Soc. 2008,
130, 10293. (b) Calo, F.; Richardson, J.; Barrett, A. G. M. Org. Lett. 2009,
11, 4910.
(8) Harris, T. M.; Harris, C. M. Tetrahedron 1977, 33, 2159.
(9) Baldwin, J. E.; Adlington, R. M.; Gollins, D. W.; Schofield, C. J.
Tetrahedron 1990, 46, 4733.
(10) Wang, P.-A.; Xu, Z.-S.; Chen, C.-F.; Gao, X.-G.; Sun, X.-L.;
Zhang, S.-Y. Chirality 2007, 19, 581.
(11) Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. Org. Lett.
2002, 4, 2665.
(12) The known Weinreb amides were authenticated by compar-
isons of their 1H NMR spectra with reported data and used immediately
in the following step: (a) Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-
Pett, M.; Xu, J. Tetrahedron 2002, 58, 1719. (b) Sibi, M. P.; Stessman,
C. C.; Schultz, J. A.; Christensen, J. W.; Lu, J.; Marvin, M. Synth.
Commun. 1995, 25, 1255.
(13) Anderson, J. C.; Ford, J. G.; Whiting, M. Org. Biomol. Chem.
2005, 3, 3734.
(14) Because of their instability and unsuccessful purification by
silica gel column chromatography, the structures of the imidazole
derivatives were immediately verified using 1H NMR spectroscopy,
and the compounds were used directly in the following step.
(15) Navarro, I.; P€overlein, C.; Schlingmann, G.; Barrett, A. G. M.
J. Org. Chem. 2009, 74, 8139.
(16) Patel, B. H.; Mason, A. M.; Barrett, A. G. M. Org. Synth. 2011,
manuscript submitted.
(17) Morita, Y.; Masaaki, S.; Noyori, R. J. Org. Chem. 1989, 54, 1785.
(18) Other electrophiles such as the acyl chloride, acyl benzotriazole,
and activated ester were attempted for C-acylation; however, further
improvements in yield were not observed.
(19) Conversions determined from 1H NMR spectra of crude
product.
(20) (a) Basset, J.-F.; Leslie, C.; Hamprecht, D.; White, A. J. P.;
Barrett, A. G. M. Tetrahedron Lett. 2010, 51, 783. (b) Patel, B. H.; Heath,
S. F .A.; Mason, A. M.; Barrett, A. G. M. Tetrahedron Lett. 2011, 52, 2258.
6217
dx.doi.org/10.1021/jo2009356 |J. Org. Chem. 2011, 76, 6209–6217