Synthesis of the C1-C16 fragment of the ajudazols

Article abstract of DOI:10.1016/j.tet.2011.10.036

The synthesis of the C1-C16 framework of the ajudazols has been achieved taking advantage of a highly selective isobenzofuran oxidative rearrangement and a key Stille coupling to introduce the key C14-C15 bond.

Full text of DOI:10.1016/j.tet.2011.10.036

Tetrahedron 67 (2011) 9700e9707
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Synthesis of the C1eC16 fragment of the ajudazols
, ,
y
Ben A. Egan a, Michael Paradowski b, Lynne H. Thomas c, Rodolfo Marquez a
*
a WestChem, School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
b Pfizer Global R&D, Sandwich, Kent, CT13 9NJ, UK
c Department of Chemistry, University of Bath, BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2011
Received in revised form 26 September 2011
Accepted 10 October 2011
Available online 18 October 2011
The synthesis of the C1eC16 framework of the ajudazols has been achieved taking advantage of a highly
selective isobenzofuran oxidative rearrangement and a key Stille coupling to introduce the key C14eC15
bond.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ajudazol
Isobenzofuran
Oxidative rearrangement
1. Introduction
the bacterial mitochondrial electron transport at low nanomolar
concentrations (Fig. 1).3
Myxobacteria have been widely recognized as a rich source of
bioactive metabolites with significant biological activities. The
myxobacterial strain Chondromyces crocatus is particularly note-
worthy for having yielded extracts containing the chondramides
AeD and the crocacins AeC.1,2
Ajudazols A 1 and B 2 were isolated by Jansen and co-workers by
reverse phase chromatography from the acetone extracts of the wet
mass of C. crocatus.3 Structurally, the ajudazols showcase a number
of exquisite, and in some cases, unique features, such as a 4,8-
Biosynthetic studies by Muller have determined that the aju-
dazols are assembled by a hybrid polyketide synthase (PKS) non-
ribosomal peptide (NRPS) multienzyme, which efficiently puts
together the ajudazol framework in a linear fashion.4 Interestingly,
the key isochromanone ring formation is promoted by a novel
thioesterase domain rather than by an expected terminal cyclase.4
The exciting combination of unique structural features com-
bined with a promising therapeutic profile makes the ajudazols
highly attractive targets. Rizzacasa and Taylor have published ele-
gant approaches towards the total synthesis of the ajudazols;5,6
however, there have been no reported total syntheses of either
ajudazol A or B.
dihydroxy-7-methyl-isochroman-1-one,
a
3-methoxybutenoic
acid methyl amide as well as an internal oxazole and a Z,Z-diene
unit. Biologically, the ajudazols have been identified as inhibitors of
As part of our own efforts towards the synthesis of the ajudazols,
we envisioned the ajudazols as originating from the metal pro-
moted coupling of vinyl halide 3 to oxazole 4 via CeH activation of
the oxazole’s C2 position. Vinyl halide 3 could be formed from the
alkylation of bis-alkyne 5 and the condensation of the amine
functionality with methoxybutenoic acid 6. The key bis-alkyne 5 in
turn was envisioned as originating from the bis-acetylene unit 7
(Scheme 1).
27
OH
N
OMe
19
12
O
21
23
25
5
8
1
10
15
O
N
29
O
17
R1 R2
1 Ajudazol A
R1, R2 = CH2
2 Ajudazol B R1 = CH3, R2 = H
OH
O
The oxazole substituted isochroman-1-one unit 4 on the other
hand, was thought of as being obtained through the coupling of the
isobenzofuran anion 8 and aldehyde 9 followed by oxidative rear-
Fig. 1. Ajudazol A 1 and ajudazol B 2.
rangement of the resulting a-hydroxyisobenzofuran intermediate.
The isobenzofuran anion could be accessed readily through base
treatment of methyl acetal 10, whilst the oxazole containing alde-
hyde 9 was thought as having originated from oxazole ester 11.
* Corresponding author. Tel.: þ44 141 330 5953; fax: þ44 141 330 488; e-mail
address: rudi.marquez@glasgow.ac.uk (R. Marquez).
y
Ian Sword Reader of Organic Chemistry.
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doi:10.1016/j.tet.2011.10.036

B.A. Egan et al. / Tetrahedron 67 (2011) 9700e9707
9701
1) H2, Pd/C
2) DIBAL
N
OMe
O
N
O
N
O
N
CO2Et
MnO2
94%
Ph3P
O
N
3) TEMPO, BAIB
OH
HO
O
OHC
14
EtO2C
81%
14
12
13
Ajudazol A
R1 R2
R1, R2 = CH2
O
Ajudazol B
R1 = CH3, R2 = H
1)
2) mCPBA
OMe
Li
OH
O
3) TEMPO, BAIB
4) NaBH4, MeOH
C-Hactivation for ajudazol A
1
C-Hactivation and reduction for ajudazol B
2
MeLi
iPr2NH
MeLi
O
O
O
59%
iPr2NH
O
N
OH
H
17
16
N
OMe
15
X
O
O
O
O
N
OH
OH
O
4
3
N
OR
O
+
O
O
O
O
18b
2 : 3
O
HO
18a
O
NH
OMe
Scheme 3.
N
OHC
OR
OR
5
6
8
9
The syn/anti diastereomer 18b was then converted to the de-
sired anti/anti adduct 20 via Mitsunobu inversion of the C8 ster-
eocentre followed by mild hydrolysis of the resulting p-
nitrobenzoate ester 19 (Scheme 4).9 The relative stereochemistry of
the anti/anti isochromanone 20 was corroborated by X-ray crys-
tallography (Fig. 2).10
O
O
N
EtO2C
OMe
7
10
11
Scheme 1.
O
O
O
N
OH
p-NO2C6H4
O
O
2. Results and discussion
We have recently reported the oxidative rearrangement of
N
p-NO2C6H4CO2H
DIAD, PPh3
65%
O
O
a
-
hydroxy-isobenzofurans, which allows the efficient generation of
isochromanones quickly, efficiently, and with minimal purifica-
tion.7,8 The rearrangement can be directed to generate single regio-
isomers through the use of C4 or C7 substituents on the phthalan
starting unit (Scheme 2). Furthermore, we have also shown that it is
possible to couple isobenzofuran anions with highly functionalised
C2-unsubstituted oxazole containing aldehydes without any cross-
reactivity issues.
O
18b
19
O
N
OH
NaN3
CH3OH
77%
O
20
O
Scheme 4.
OMe
OR
OMe
O
O
R group
independent
OR
MeLi
MeLi
i
Pr2NH
OR
i
Pr2NH
O
MeLi
MeLi
i
i
Pr2NH
R group
Pr2NH
dependent
OR
OR
Fig. 2. Crystal structure of isochromanone 20.
O
O
Scheme 2.
Having the three diastereomeric isochromanones at hand, the
key C14eC15 bond formation by CeH activation of the oxazole C2
position was explored. Encouragingly, initial studies using the
oxazole model system 22 resulted in selective C2 CeH activation
under both palladium and copper mediated conditions to generate
the desired sp2esp2 coupled product 23 (Scheme 5).11
Unfortunately, to our disappointment, the reaction conditions
used to generate alkene 23 could not be applied successfully to any
of the oxazole containing isochromanones 18e20. Modification of
the CeH activation conditions proved fruitless with most of them
resulting in the complete degradation of the isochromanone units.
Faced with such a set-back, we referred to Taylor’s synthesis of
the ajudazol A’s eastern section 26 as an alternative model through
which C14eC15 bond formation could be achieved.6 In Taylor’s
approach, the key sp2esp2 bond was achieved cleanly and
Having demonstrated the feasibility of using substituted iso-
benzofurans to generate isochromanones, it was decided to focus
our efforts on the key oxazole CeH activation required to bring
together the western 4 and eastern 3 sections of the ajudazols. Our
initial model studies began with the known oxazole alcohol 12,
which was converted into the racemic homologated aldehyde 14
following our recently published procedure.8 Aldehyde 14 was then
coupled with the phthalan derived isobenzofuran anion 17. Oxi-
dative rearrangement, followed by oxidation of the lactol in-
termediate and selective ketone reduction yielded the desired
ajudazol western section framework as a separable mixture of syn/
syn and syn/anti diastereomers 18a and 18b (Scheme 3).

9702
B.A. Egan et al. / Tetrahedron 67 (2011) 9700e9707
N
O
a C-2 halogen substituted oxazole, could be coupled with a vinyl
N
O
TBDPSCl, imid
97%
stannane containing eastern section. The use of 2-chloro oxazoles
as Stille coupling partners has been recently described by Taylor as
a way of generating 2-alkenyl oxazoles quickly and efficiently.13
Unfortunately, as in the case of the stannanes, direct chlorina-
tion of the isochromanone units 18e20 could not be achieved using
a wide variety of reagents and conditions. However, using the bo-
rane complexation protocol, the TBS oxazole 27 was efficiently
chlorinated at the C-2 position in excellent yield and with complete
regio-selectivity to give chloride 31 (Scheme 8).12 TBS removal
then proceeded in near quantitative yield to provide the free al-
cohol 32, which upon TEMPO oxidation yielded the key aldehyde
precursor 33.
TBDPSO
HO
21
22
Br
N
O
TBDPSO
a 58%
b 62%
23
Reagents and Conditions: a) Pd(PPh3)4, BuOLi, Dioxane, 110 oC; b) CuI,
t
BuOLi, trans- N, N'- dimethylcyclohexane-1,2 diamine, Dioxane, 110 oC.
t
Scheme 5.
efficiently through the Stille coupling between vinyl iodide 24 and
2-(tributylstannyl)oxazole 25 (Scheme 6).
1. BH3, THF, R.T.
2. BuLi, -78 C
o
n
N
N
O
TBSO
TBSO
Cl
Cl
3. C2Cl6
O
O
-78 oC - R.T.
SnBu3
N
OMe
27
31
25
N
87%
I
O
PdCl2(PPh3)2, DMF
60%
N
OHC
N
O
24
HO
TBAF
95%
TEMPO,BAIB
Cl
95%
O
N
OMe
32
33
O
Scheme 8.
O
N
26
The chloro-aldehyde 33 was then coupled with phthalan 15 via
our isobenzofuran based reaction sequence to yield the desired
chloro-isochromanone unit as a 2:3 mixture of syn/syn and anti/syn
diastereomers 34a and 34b. Significantly, no de-halogenated side
products could be detected (Scheme 9).
Scheme 6.
Prompted by the starting material decomposition observed
during the attempted CeH activation of the isochromanone units,
the introduction of the stannyl group onto a simpler oxazole, which
could then be incorporated into the isochromanone core was ini-
tially attempted. Thus, the TBS silyl ether 27 was cleanly deproto-
nated and stannylated at the C2 position to yield the
tributylstannane 28 in good yield (Scheme 7). It must be noted that
pre-complexation of the oxazole with borane is essential for clean
deprotonation at C2 to take place. In the absence of borane, deg-
radation of the starting material through the well documented C-2
opening of oxazoles was the major product.12
1. MeLi, iPr2NH
2. 33
3. mCPBA
OMe
4. 2.5M Jones
5. NaBH4
O
53%
15
O
O
OH
OH
Cl
Cl
N
N
+
O
O
1. BH3, THF, R.T.
2 : 3
O
O
N
O
2. BuLi, -78 oC
34a
34b
n
N
TBSO
TBSO
SnBu3
Scheme 9.
3. Bu3SnCl
O
-78 oC - R.T.
28
27
69%
With the key chloro-isochromanone units 34a and 34b at hand,
the Stille coupling required to achieve the key C14eC15 bond for-
mation was explored (Scheme 10). Initial model studies using the
chlorooxazole intermediate 31 with vinyl stannane 35 as the cou-
pling partner suggested that the coupling was highly dependent on
the nature of the palladium ligands and the reaction temperature
(Table 1).14
N
N
HO
TBSO
SnBu3
O
O
29
30
Scheme 7.
Mg
Bu3SnCl
Unfortunately, all conditions attempted to remove the TBS
group resulted in concomitant destannylation. In a number of cases,
complete destannylation was observed before any desilylation had
taken place. The highly unstable nature of the stannyl group made
it clear that even if selective desilylation could have been achieved,
it is unlikely that the stannane 29 would have survived coupling
with the isobenzofuran anion and incorporation into the iso-
chromanone core unit.
Furthermore, model Stille couplings of stannane 28 with 2-
bromopropene failed to generate the expected alkenyl unit 30,
resulting instead in oxazole proto-destannylation. In any event, all
attempts to introduce the tributylstannyl moiety directly onto any
of the isochromanone units proved fruitless.
THF
Bu3Sn
Br
sonic bath
96%
35
N
N
SnBu3
Pd cat; DMF; heating
86%
TBSO
TBSO
Cl
O
O
31
30
Scheme 10.
The optimised conditions (entry 3) proved to be robust and
extremely reproducible, reliably affording the desired coupled
oxazole 30 in high yields. More importantly, the same conditions
were successfully used to couple both of the chloro-isochromanone
units 34a and 34b with the vinyl stannane 35 to generate the
Hence, it was then decided to explore the use of the reverse
Stille strategy in which the western section of ajudazol A, bearing

B.A. Egan et al. / Tetrahedron 67 (2011) 9700e9707
9703
absorptions (nmax) are reported in wavenumbers (cmꢂ1). Melting
points were recorded using a Bibby Stuart Scientific Melting Point
SMP1 and are uncorrected.
Table 1
Stille coupling optimisation conditions
Heat source Temp (ꢁC) Time (h) Catalyst
Yield
Proton magnetic resonance spectra (1H NMR) and carbon
magnetic resonance spectra (13C NMR) were, respectively, recorded
either at 400 MHz and 100 MHz using a Bruker DPX Avance400
instrument or at 500 MHz and 125 MHz using a Bruker AvanceIII
1
2
3
4
5
6
7
Conv
60
75
72
9
12
12
6
Pd(PPh3)2Cl2 (8%)
Pd(PPh3)2Cl2 (8%)
Pd(PPh3)2Cl2 (8%)
Pd(PPh3)4 (8%)
Pd(PPh3)4, TFP (20%)
Pd2(dba)3 (8%)
10 (25)
17 (47)
80
86
78 (87)
0
mwave
mwave
mwave
mwave
mwave
mwave
130
120
120
120
130
500 Instrument. Chemical shifts (d) are reported in parts per million
2
12
(ppm) and are referenced to the residual solvent peak. The order of
citation in parentheses is (1) number of equivalent nuclei (by in-
tegration), (2) multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, quint¼quintet, sext¼sextet, sept¼septet, m¼multiplet,
b¼broad, dm¼double multiplet), and (3) coupling constant (J)
quoted in Hertz to the nearest 0.1 Hz. High resolution mass spectra
were recorded on a JEOL JMS-700 spectrometer by electrospray and
chemical ionisation mass spectrometer operating at a resolution of
15,000 full widths at half height. Flash chromatography was per-
formed using silica gel (Fluorochem Scientific Silica Gel 60,
Pd(PPh3)2Cl2 (8%), CuI (20%) 70
N.B Stille reactions carried out in anhydrous, degassed DMF; TFP: trifuryl phosphine
(0.1 M) with 1.10 equiv of stannane 35.
Yields in parenthesis are based on recovered starting material.
desired alkenyl units 36 and 37 incorporating the C1eC16 frame-
work of ajudazol A in excellent yields (Scheme 11).
O
N
O
OH
OH
Cl
40e63 m) as the stationary phase. TLC was performed on alumin-
N
Bu3Sn
Pd(PPh3)2Cl2
70%
ium sheets pre-coated with silica (Merck Silica Gel 60 F254) or al-
uminium oxide (Merck Aluminium Oxide 60 F254 neutral) where
specified. The plates were visualised by the quenching of UV fluo-
rescence (lmax 254 nm) and/or by staining with either anisalde-
hyde, potassium permanganate, iodine or cerium ammonium
molybdate followed by heating.
O
O
O
O
34a
36
O
O
OH
OH
Cl
N
N
Bu3Sn
O
O
Pd(PPh3)2Cl2
83%
O
O
3.1.1. (ꢃ)-(3R,4R)-4-Hydroxy-3-((S)-1-(oxazol-4-yl)propan-2-yl)iso-
chroman-1-one, 18a and (ꢃ)-(3S,4S)-4-hydroxy-3-((S)-1-(oxazol-4-
34b
37
Scheme 11.
yl)propan-2-yl)isochroman-1-one, 18b. A
0
ꢁC solution of 1-
methoxy-1,3-dihydroisobenzofuran 15 (1.47 g, 9.8 mmol) in anhy-
drous THF (50 mL), was treated with diisopropylamine (137 L,
Furthermore, treatment of alkenyl oxazole 36 under standard
hydrogenation conditions cleanly and efficiently reduced the
methylene group into the corresponding methyl unit and thus
completing the C1eC16 framework of ajudazol B 38 in excellent
yield (Scheme 12).
m
0.9 mmol) and stirred for 10 min. Methyllithium solution (1.6 M in
diethyl ether, 12.9 mL, 20.5 mmol) was then added slowly, and the
solution was stirred at 0 ꢁC for 30 min. The reaction mixture was
cooled to ꢂ78 ꢁC, and 2-methyl-3-(oxazol-4-yl)propanal 14 (1.50 g,
10.8 mmol) was added dropwise. The resulting solution was then
stirred for a further 90 min at ꢂ78 ꢁC (until TLC analysis on alumina
plates showed reaction completion) before being warmed up and
quenched with water at 0 ꢁC. The mixture was extracted with
diethyl ether (3ꢄ100 mL) and the combined organic extracts were
washed with water (50 mL), saturated brine solution (50 mL), and
dried over sodium sulfate. The solvent was removed under reduced
O
O
OH
OH
H2, Pd/C
EtOH
98%
N
N
O
O
O
O
36
38
Scheme 12.
pressure at room temperature to afford the desired
a-hydrox-
yisobenzofuran intermediate, which was used in the next step
without further purification.
In conclusion, we have completed the C1eC16 frameworks of
both ajudazol A and ajudazol B taking advantage of a Stille coupling
and an a-hydroxyisobenzofuran oxidative rearrangement to gen-
The crude a-hydroxyisobenzofuran unit was dissolved in an-
hydrous DCM (50 mL) and cooled to 0 ꢁC. The resulting solution
was then treated with 3-chloroperoxybenzoic acid (77%, 2.41 g,
10.8 mmol) and the reaction was stirred at 0 ꢁC until completion
by TLC analysis on alumina plates (2 h). The reaction was
quenched with saturated sodium bicarbonate solution (40 mL),
extracted with dichloromethane (3ꢄ100 mL) and the combined
organic extracts were dried over sodium sulfate. The solvent was
then removed under reduced pressure at room temperature to
afford the crude ketoelactol as a yellow oil, which was taken on
as crude immediately to the next step without further
purification.
erate the key 4,8-dihydroxyisochroman-1-one and alkenyl oxazole
units, respectively. Furthermore, we have shown that the iso-
benzofuran anion methodology is compatible with sensitive alde-
hydes. Efforts in our group are focussed on the application of this
methodology to the total synthesis of the ajudazols.
3. Experimental
3.1. General
All reactions were performed in oven-dried glassware under an
inert argon atmosphere unless otherwise stated. Tetrahydrofuran
(THF), diethyl ether, dichloromethane (DCM), and toluene were
purified through a Pure Solv 400-5MD solvent purification system
(Innovative Technology, Inc). All reagents were used as received,
unless otherwise stated. Solvents were evaporated under reduced
pressure at ꢀ40 ꢁC.
The freshly prepared ketoelactol unit was dissolved in anhy-
drous DCM (60 mL) and sequentially treated with (diacetoxyiodo)
benzene (8.82 g, 27.4 mmol) and TEMPO (305 mg, 1.9 mmol) under
argon. The reaction mixture was stirred at room temperature
completion as indicated by TLC analysis (12 h). The reaction was
then diluted with DCM (100 mL) and washed with saturated so-
dium thiosulfate solution (2ꢄ30 mL), water (2ꢄ30 mL), and brine
(30 mL). The organic layer was dried over sodium sulfate and then
concentrated under reduced pressure. The crude residue was
IR spectra were recorded using a JASCO FT/IR410 Fourier
Transform spectrometer using a diamond gate. Only significant

9704
B.A. Egan et al. / Tetrahedron 67 (2011) 9700e9707
purified by flash column chromatography (silica gel, elution gra-
dient 0e10% diethyl ether/petroleum ether) to afford the desired
ketoelactone intermediate as a colourless oil.
HRMS found [M]þ 422.1119, C22H18N2O7 requires 422.1114; nmax
cmꢂ1 (film): 3115, 2970, 2936, 1722, 1607, 1528.
/
The ketoelactone intermediate was dissolved in anhydrous
methanol (50 mL) and treated with sodium borohydride (518 mg,
13.7 mmol). The resulting reaction mixture was then stirred at
ꢂ78 ꢁC until completion as indicated by TLC analysis (90 min). The
reaction mixture was then warmed to 0 ꢁC and quenched with
water (20 mL) and 10% aq citric acid (20 mL). The biphasic solution
was stirred at room temperature for 20 min before being extracted
with DCM (3ꢄ70 mL). The combined organic extracts were washed
with water (3ꢄ15 mL), saturated brine solution (15 mL), dried over
sodium sulfate, and concentrated under reduced pressure. The
crude residue was purified by flash column chromatography (silica
gel, elution gradient 0e50% diethyl ether in petroleum ether) to
give (ꢃ)-(3R,4R)-4-hydroxy-3-((S)-1-(oxazol-4-yl)propan-2-yl)iso-
chroman-1-one, 18a (749 mg, 28%) as a colourless crystalline solid.
Further elution afforded (ꢃ)-(3S,4S)-4-hydroxy-3-((S)-1-(oxazol-4-
yl)propan-2-yl)isochroman-1-one, 18b (1.12 g, 42%) as a colourless
crystalline solid.
3.1.5. (ꢃ)-(3S,4R)-4-Hydroxy-3-((S)-1-(oxazol-4-yl)propan-2-yl)iso-
chroman-1-one, 20. A solution of (ꢃ)-(3S,4R)-3-((S)-1-(oxazol-4-yl)
propan-2-yl)-1-oxoisochroman-4-yl 4-nitrobenzoate, 19 (117 mg,
0.3 mmol) in anhydrous methanol (2 mL) was treated with sodium
azide (72 mg, 1.1 mmol) and stirred under argon at 40 ꢁC for 24 h.
The reaction mixture was then cooled down to room temperature
and quenched by the addition of water (5 mL) before being
extracted with ethyl acetate (3ꢄ20 mL). The combined organics
were washed with water (5 mL) and saturated aqueous brine (5 mL)
before being dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to yield a crude product, which
was purified by flash column chromatography (silica gel, elution
gradient 0e75% ethyl acetate in hexanes) to afford the desired
product, (ꢃ)-(3S,4R)-4-hydroxy-3-((S)-1-(oxazol-4-yl)propan-2-yl)
isochroman-1-one, 20 (58 mg, 77%) as a white crystalline solid.
1H NMR (C6D6, 400 MHz)
d: 0.93 (3H, d, J¼7.1 Hz), 2.06 (1H, dd,
J¼15.6, 6.1 Hz), 2.37e2.46 (1H, m), 2.69 (1H, ddd, J¼15.6, 5.8,
1.4 Hz), 4.03 (1H, dd, J¼10.5, 2.2 Hz), 4.68 (1H, dd, J¼10.4, 4.9 Hz),
5.98 (1H, d, J¼5.9 Hz), 6.62 (1H, s), 6.91 (1H, s), 7.00 (1H, t, J¼7.6 Hz),
7.21 (1H, td, J¼7.6, 1.3 Hz), 7.83 (1H, d, J¼7.7 Hz), 8.21 (1H, dd, J¼7.7,
1.1 Hz); 13C NMR (CDCl3, 100 MHz) 18.2, 25.8, 32.3, 65.1, 86.0, 123.6,
124.6, 128.2, 130.1, 134.3, 135.3, 138.9, 143.4, 151.5, 165.3; m/z [EIþ
(þve)] 273 [M]þ (100%); HRMS found [M]þ 273.1003, C15H15O4N
requires 273.1001; nmax/cmꢂ1 (film): 3213, 2963, 2922, 2853, 1721,
1605, 1514, 1456; melting point: 158e160 ꢁC.
3.1.2. (ꢃ)-(3R,4R)-4-Hydroxy-3-((S)-1-(oxazol-4-yl)propan-2-yl)iso-
chroman-1-one, 18a. 1H NMR (CDCl3, 500 MHz)
d: 1.23 (3H, d,
J¼6.7 Hz), 2.56e2.64 (1H, m), 2.69 (1H, dd, J¼15.2, 5.5 Hz), 2.78 (1H,
ddd, J¼15.2, 5.4, 0.9 Hz), 4.23 (1H, dd, J¼9.2, 1.7 Hz), 5.02 (1H, s),
7.49e7.55 (3H, m), 7.65 (1H, td, J¼7.5, 1.4 Hz), 7.85 (1H, br s),
8.16e8.12 (1H, m); 13C NMR (CDCl3, 125 MHz)
d: 16.9, 28.5, 33.1,
65.0, 84.8, 124.6, 128.2, 129.8, 130.4, 134.4, 135.7, 137.7, 140.5, 151.4,
165.2; m/z [Clþ (þve), isobutene] 274 [MþH]þ (100%); HRMS found
[MþH]þ 274.1075, C15H16NO4 requires 274.1079; nmax/cmꢂ1 (film):
3377, 2932, 1713; melting point: 160e162 ꢁC.
3.1.6. (ꢃ)-4-(3-(tert-Butyldiphenylsilyloxy)-2-methylpropyl)oxazole,
22. (ꢃ)-2-Methyl-3-(oxazol-4-yl)propan-1-ol
21
(959
mg,
6.8 mmol) was dissolved in anhydrous DMF (14 mL) and then se-
quentially treated with imidazole (924 mg, 13.6 mmol) and tert-
butylchlorodiphenylsilane (2.12 mL, 8.2 mmol) and the resulting
homogeneous solution was stirred under argon at room tempera-
ture for 150 min. The reaction mixture was then diluted with
diethyl ether (300 mL) and washed with water (5ꢄ60 mL) followed
by saturated brine solution (50 mL) before being dried over sodium
sulfate. The solvent was evaporated under reduced pressure to af-
ford a crude product that was purified by flash column chroma-
tography (silica gel, elution gradient 0e10% diethyl ether in
petroleum ether) to afforded the desired (ꢃ)-4-(3-(tert-butyldi-
phenylsilyloxy)-2-methylpropyl)oxazole 22 (2.51 g, 97%) as a col-
ourless oil.
3.1.3. (ꢃ)-(3S,4S)-4-Hydroxy-3-((S)-1-(oxazol-4-yl)propan-2-yl)iso-
chroman-1-one, 18b. 1H NMR (CDCl3, 500 MHz)
d: 1.11 (3H, d,
J¼6.5 Hz), 2.59e2.68 (2H, m), 3.04 (1H, br d, J¼5.6 Hz), 3.14 (1H, d,
J¼14.0 Hz), 4.23 (1H, dd, J¼8.7, 1.3 Hz), 4.78 (1H, d, J¼6.3 Hz),
7.45e7.50 (2H, m), 7.53 (1H, td, J¼7.7, 1.3 Hz), 7.65 (1H, td, J¼7.3,
1.0 Hz), 7.72 (1H, s), 8.13 (1H, d, J¼7.7 Hz); 13C NMR (CDCl3,
125 MHz) d: 15.5, 28.2, 33.6, 65.6, 84.0, 124.5, 128.2, 130.1, 130.6,
134.5, 135.8, 138.2, 140.4, 150.9, 164.8; m/z [Clþ (þve), isobutene]
274 [MþH]þ (100%); HRMS found [MþH]þ 274.1082, C15H16NO4
requires 274.1079; nmax/cmꢂ1 (film): 3187, 2984, 2971, 1707; melt-
ing point: 196e198 ꢁC.
3.1.4. (ꢃ)-(3S,4R)-3-((S)-1-(Oxazol-4-yl)propan-2-yl)-1-
oxoisochroman-4-yl 4-nitrobenzoate, 19. A solution of (ꢃ)-(3S,4S)-
4-hydroxy-3-((S)-1-(oxazol-4-yl)propan-2-yl)isochroman-1-one,
18b (413 mg, 1.5 mmol) in anhydrous toluene (21 mL) was treated
with triphenylphosphine (991 mg, 3.7 mmol) and 4-nitrobenzoic
acid (480 mg, 3.8 mmol) and the resulting solution was cooled
down to 0 ꢁC. The solution was treated dropwise with diisopro-
1H NMR (CDCl3, 400 MHz)
d
: 0.95 (3H, d, J¼6.8 Hz), 1.06 (6H, s),
1.07 (3H, s), 2.05e2.13 (1H, m,), 2.38 (1H, dd, J¼14.6, 8.0 Hz), 2.75
(1H, dd, J¼14.5, 5.9 Hz), 3.53 (2H, d, J¼5.6 Hz), 7.30 (1H, s),
7.36e7.45 (6H, m), 7.66 (3H, m), 7.71e7.73 (1H, m), 7.79 (1H, s); 13C
NMR (CDCl3, 100 MHz) d: 16.7, 19.5, 26.7, 27.0, 29.7, 35.3, 68.2, 127.8,
129.8, 133.9, 134.8, 135.8, 139.1, 150.8; m/z [CIþ (þve), isobutane]
380 [MþH]þ (100%); HRMS found [MþH]þ 380.2050, C23H30NO2Si
requires 380.2046; nmax/cmꢂ1 (film): 2959, 2932, 2859, 1427.
pylazodicarboxylate (744 mL, 3.8 mmol) before being warmed up
and heated at reflux under argon for 16 h. The reaction mixture was
cooled to room temperature before the solvent was evaporated
under reduced pressure and the crude residue purified by flash
column chromatography (silica gel, elution gradient 0e15% ethyl
acetate in hexanes) to afford the desired nitrobenzoate ester 19
(415 mg, 65%) as a colourless oil.
3.1.7. (ꢃ)-4-(3-(tert-Butyldiphenylsilyloxy)-2-methylpropyl)-2-
(prop-1-en-2-yl)oxazole, 23. Method A: Pd catalyzed CeH activation.
A
mixture
methylpropyl)oxazole, 21 (80 mg, 0.2 mmol), tetrakis-
(triphenylphosphine)palladium (13 mg, 11 mol), lithium tert-
butoxide (34 mg, 0.4 mmol) and 2-bromopropene (38 L,
of
(ꢃ)-4-(3-(tert-butyldiphenylsilyloxy)-2-
m
1H NMR (CDCl3, 400 MHz)
d: 1.04 (3H, d, J¼6.9 Hz), 2.08e2.12
m
(1H, m), 2.63 (1H, dd, J¼14.7, 8.2 Hz), 2.94 (1H, dd, J¼14.6, 4.1 Hz),
4.71 (1H, dd, J¼8.9, 2.9 Hz), 6.35 (1H, d, J¼2.9 Hz), 7.49 (1H, s),
7.56e7.57 (1H, m), 7.60 (1H, td, J¼7.6, 1.4 Hz), 7.67 (1H, td, J¼7.5,
1.4 Hz), 7.79 (1H, s), 8.17e8.21 (3H, m), 8.25e8.28 (2H, d, J¼8.0 Hz);
0.4 mmol) in anhydrous 1,4-dioxane (0.6 mL) was stirred in a sealed
tube at 110 ꢁC for 24 h under an atmosphere of argon. The reaction
was then cooled down to room temperature before being quenched
with water (5 mL) and extracted with ethyl acetate (3ꢄ20 mL). The
resultant organics were washed with water (2ꢄ7 mL) and saturated
brine solution (10 mL) before being dried over sodium sulfate and
solvent evaporated to afford the crude product. Purification by flash
13C NMR (CDCl3, 100 MHz)
d: 16.2, 28.5, 35.0, 68.7, 84.3, 123.8, 128.7,
128.8, 128.9, 130.6, 130.9, 131.2, 132.2, 132.3, 134.2, 134.6, 136.0,
137.3, 151.0, 151.2, 163.1, 164.0; m/z [EIþ (þve)] 422 [M]þ (100%);

B.A. Egan et al. / Tetrahedron 67 (2011) 9700e9707
9705
column chromatography (silica gel elution gradient 0e0.5% ethyl
acetate in pentane) of the crude residue afforded the desired
product, (ꢃ)-4-(3-(tert-butyldiphenylsilyloxy)-2-methylpropyl)-2-
(prop-1-en-2-yl)oxazole 23 (51 mg, 58%) as a colourless oil. Further
elution with 5% ethyl acetate in pentane afforded the recovered
ꢂ78 ꢁC. n-Butyllithium (2.5 M in hexanes, 2.47 mL, 6.2 mmol) was
then added dropwise over 5 min and the resulting mixture was
allowed to stir at ꢂ78 ꢁC for a further 25 min before being quenched
with the dropwise addition of tributyltin chloride (1.68 mL,
5.9 mmol). The resulting mixture was stirred for 30 min at ꢂ78 ꢁC
before being warmed up to 0 ꢁC and quenched with water (4 mL).
The biphasic mixture was diluted with diethyl ether (25 mL), the
phases separated, and the organic fraction was sequentially washed
with water (3ꢄ5 mL) and brine (8 mL) before being dried over
sodium sulfate. The solvent was evaporated under reduced pres-
sure to afford a crude residue that was purified by flash column
chromatography (silica gel, elution gradient 0e2% diethyl ether in
petroleum ether) to afford (ꢃ)-4-(3-(tert-butyldimethyllsilyloxy)-
2-methylpropyl)-2-(tributylstannyl)oxazole, 28 (2.23 g, 69%) as
a colourless oil.
starting
material,
(ꢃ)-4-(3-(tert-butyldiphenylsilyloxy)-2-
methylpropyl)oxazole 22 (9 mg, 11%) as a colourless oil.
Method B: Cu catalyzed CeH activation. A suspension of (ꢃ)-4-(3-
(tert-butyldiphenylsilyloxy)-2-methylpropyl)oxazole 21 (80 mg,
0.2 mmol), trans-N,N0-dimethylcyclohexane-1,2-diamine (6 mg,
4
mmol), copper iodide (4 mg, 21
mmol), lithium tert-butoxide
(34 mg, 0.4 mmol) and 2-bromopropene (38
mL, 0.4 mmol) in an-
hydrous 1,4-dioxane (0.6 mL) was stirred in a sealed tube at 110 ꢁC
under an atmosphere of argon for 24 h. The reaction mixture was
then cooled down to room temperature before being quenched
with water (5 mL) and extracted with ethyl acetate (3ꢄ20 mL). The
combined organics were washed with water (2ꢄ7 mL) and satu-
rated brine solution (10 mL) before being dried over sodium sulfate
and the solvent evaporated under reduced pressure. Purification of
the crude residue by flash column chromatography (silica gel,
elution gradient with 0e1% ethyl acetate in pentane) afforded the
1H NMR (CDCl3, 500 MHz)
d
: ꢂ0.04 (6H, s), 0.88 (9H, s),
0.88e0.93 (9H, m), 0.94 (3H, d, J¼6.7 Hz), 1.26e1.35 (12H, m),
1.55e1.61 (6H, m), 2.07e2.12 (1H, m), 2.49 (1H, ddd, J¼15.4, 8.0,
0.9 Hz), 2.81 (1H, ddd, J¼15.4, 6.2, 1.0 Hz), 3.46e3.51 (2H, m), 7.58
(1H, s); 13C NMR (CDCl3,125 MHz)
d
: ꢂ5.3, ꢂ5.3,12.1,13.8,16.8,18.5,
26.1, 27.0, 27.2, 28.8, 34.1, 67.4, 137.4, 139.9, 177.5; m/z [CIþ (þve)]
desired
product,
(ꢃ)-4-(3-(tert-butyldiphenylsilyloxy)-2-
670 [MþH]þ (100%). HRMS found [MþH]þ 670.3105, C35H56NO2
-
methylpropyl)-2-(prop-1-en-2-yl)oxazole 23 (55 mg, 62%) as
a colourless oil. Further elution with 5% ethyl acetate in pentane
afforded the recovered starting material, (ꢃ)-4-(3-(tert-butyldi-
phenylsilyloxy)-2-methylpropyl)oxazole 22 (10 mg, 12%) as a col-
ourless oil.
Si118Sn requires 670.3102; nmax/cmꢂ1 (film): 2959, 2932, 2857.
3.1.10. (ꢃ)-4-(3-(tert-Butyldimethylsilyloxy)-2-methylpropyl)-2-
chlorooxazole, 31. A solution of (ꢃ)-4-(3-(tert-butyldimethylsily-
loxy)-2-methylpropyl)oxazole 27 (2.2 g, 8.4 mmol) in anhydrous
THF (40 mL) was treated with borane (1 M in THF, 8.86 mL,
8.9 mmol) and the resulting mixture was stirred under argon at
room temperature for 30 min. The solution was cooled down to
ꢂ78 ꢁC, and n-butyllithium (2.5 M in hexane) (5.54 mL, 8.9 mmol)
was added dropwise over 5 min. The reaction mixture was stirred
for 25 min at ꢂ78 ꢁC before being quenched with the dropwise
addition of a solution of hexachloroethane (3.99 g, 16.9 mmol) in
THF (15 mL). The reaction mixture was stirred for 60 min at ꢂ78 ꢁC
before being warmed up to 0 ꢁC and stirred for a further 2 h before
being quenched with water (50 mL). The mixture was diluted with
diethyl ether (100 mL) and the phases separated. The organic
fraction was sequentially washed with water (3ꢄ20 mL) and brine
(30 mL) before being dried over sodium sulfate. The solvent was
evaporated under reduced pressure to afford a crude residue, which
was purified by flash column chromatography (silica gel, elution
gradient 0e5% diethyl ether in petroleum ether) to afford (ꢃ)-4-(3-
(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-chlorooxazole, 31
(2.12 g, 87%) as a colourless oil.
1H NMR (CDCl3, 500 MHz)
d: 1.00 (3H, d, J¼6.7 Hz), 1.07 (9H, s),
2.05e2.12 (1H, m), 2.14e2.16 (3H, m), 2.39 (1H, ddd, J¼14.6, 7.8,
0.9 Hz), 2.71 (1H, ddd, J¼14.6, 6.3, 0.9 Hz), 3.54 (1H, dd, J¼9.9,
5.6 Hz), 3.59 (1H, dd, J¼9.9, 5.3 Hz), 5.32e5.33 (1H, m), 5.89e5.91
(1H, m), 7.20 (1H, br s), 7.36e7.44 (6H, m), 7.65e7.68 (4H, m); 13C
NMR (CDCl3, 125 MHz) d: 16.9, 19.3, 19.5, 27.0, 30.0, 35.2, 68.1, 117.6,
127.7, 129.7, 132.0, 134.0, 134.5, 135.7, 140.6, 162.3; m/z [FABþ (þve),
NOBA] 420 [MþH]þ (100%); HRMS found [MþH]þ 420.2354,
C26H34NO2Si requires 420.2359; nmax/cmꢂ1 (film): 2959, 2930,
2857, 1589, 1532, 1462, 1427.
3.1.8. (ꢃ)-4-(3-(tert-Butyldimethylsilyloxy)-2-methylpropyl)oxazole,
27. A solution of (ꢃ)-2-methyl-3-(oxazol-4-yl)propan-1-ol 21
(1.31 g, 9.3 mmol) in anhydrous DMF (15 mL) was treated with
imidazole (1.26 g, 18.5 mmol) and tert-butylchlorodimethylsilane
(1.66 g, 10.7 mmol) and the resulting homogeneous mixture was
stirred under argon at room temperature for 16 h. The reaction
mixture was then diluted with diethyl ether (300 mL) and washed
sequentially with water (5ꢄ60 mL) and brine (50 mL) before being
dried over sodium sulfate. The solvent was evaporated under vac-
uum to afford a crude residue that was purified by flash column
chromatography (silica gel, elution gradient 0e10% diethyl ether in
petroleum ether) to afford the desired product, (ꢃ)-4-(3-(tert-
butyldimethylsilyloxy)-2-methylpropyl)oxazole 27 (2.09 g, 88%) as
a colourless oil.
1H NMR (CDCl3, 500 MHz)
d: 0.02 (6H, s), 0.88 (9H, s), 0.89 (3H,
d, J¼6.5 Hz), 1.97e1.99 (1H, m), 2.25 (1H, ddd, J¼14.7, 8.2, 0.9 Hz),
2.63 (1H, ddd, J¼14.7, 5.8, 1.1 Hz), 3.42e3.47 (2H, m), 7.35 (1H, br t,
J¼1.1 Hz); 13C NMR (CDCl3, 125 MHz)
: ꢂ5.3, 16.5, 18.4, 26.0, 29.9,
d
35.0, 67.3, 137.2, 142.2, 146.4; m/z [CIþ (þve)] 290 [M(35Cl)þH]þ
(100%), 292 [M(37Cl)þH]þ (35%); HRMS found [MþH]þ 290.1350,
35
C13
H
ClNO2Si requires 290.1343; nmax/cmꢂ1 (film): 2957, 2930,
25
1H NMR (CDCl3, 500 MHz)
d: 0.03 (6H, s), 0.89 (9H, s), 0.90 (3H,
2886, 2857, 1520, 1472, 1464.
d, J¼6.8 Hz), 1.98e2.02 (1H, m), 2.32 (1H, dd, J¼14.6, 8.2 Hz), 2.68
(1H, ddd, J¼14.6, 5.8, 1.0 Hz), 3.43e3.49 (2H, m), 7.40 (1H, m), 7.81
3.1.11. (ꢃ)-3-(2-Chlorooxazol-4-yl)-2-methylpropan-1-ol, 32. A 0 ꢁC
solution of (ꢃ)-4-(3-(tert-butyldimethylsilyloxy)-2-methylpropyl)-
2-chlorooxazole, 31 (2.00 g, 6.90 mmol) in anhydrous THF (28 mL)
was treated with the dropwise addition of tetrabutylammonium
fluoride (1 M in THF, 10.4 mL, 10.4 mmol). After 30 min, the reaction
mixture was warmed up to room temperature and stirred for 16 h
before being quenched with water (20 mL) and extracted with
diethyl ether (3ꢄ50 mL). The combined organics were washed se-
quentially with water (3ꢄ10 mL) and brine (20 mL) before being
dried over sodium sulfate. The solvent was evaporated under re-
duced pressure to give a crude product that was purified by flash
column chromatography (silica gel, elution gradient 0e50% diethyl
(1H, s); 13C NMR (CDCl3, 125 MHz)
d
: ꢂ5.3, ꢂ5.2, 16.6, 18.5, 26.1,
29.6, 35.3, 67.5, 135.0, 139.3, 150.8; m/z [CIþ (þve), isobutane] 256
[MþH]þ (100%). HRMS found [MþH]þ 256.1737, C13H26NO2Si re-
quires 256.1733; nmax/cmꢂ1 (film): 2959, 2930, 2859.
3.1.9. (ꢃ)-4-(3-(tert-Butyldimethylsilyloxy)-2-methylpropyl)-2-(trib-
utylstannyl)oxazole, 28. (ꢃ)-4-(3-(tert-Butyldimethylsilyloxy)-2-
methylpropyl)oxazole 27 (1.50 g, 5.9 mmol) was dissolved in an-
hydrous THF (35 mL) and treated with a 1 M solution of borane in
tetrahydrofuran (6.18 mL, 6.2 mmol). The solution was stirred un-
der argon at room temperature for 30 min and then cooled down to

9706
B.A. Egan et al. / Tetrahedron 67 (2011) 9700e9707
ether in petroleum ether) to yield (ꢃ)-3-(2-chlorooxazol-4-yl)-2-
methylpropan-1-ol, 32 (1.15 g, 95%) as a colourless oil.
d: 16.2, 28.9, 33.1, 65.3, 84.0, 124.3, 128.0, 129.8, 130.4, 134.4, 137.7,
140.2,140.5,146.9,164.8; m/z [EIþ (þve)] 307 [M(35Cl)]þ (100%), 309
35
1H NMR (CDCl3, 500 MHz)
d
: 0.92 (3H, d, J¼6.7 Hz), 1.97e2.06
[M(37Cl)]þ (35%); HRMS found [M]þ 307.0613, C15
H ClNO4 requires
14
(1H, m), 2.29 (1H, br s), 2.43 (1H, ddd, J¼14.7, 7.0, 0.8 Hz), 2.58 (1H,
ddd, J¼14.7, 6.2, 1.1 Hz), 3.47 (1H, dd, J¼11.0, 6.4 Hz), 3.54 (1H, dd,
J¼10.9, 5.4 Hz), 7.40 (1H, br t, J¼0.9 Hz); 13C NMR (CDCl3, 125 MHz)
307.0611; nmax/cmꢂ1 (film): 3399, 3134, 2976, 2934,1715,1518,1462.
Compound 34b. 1H NMR (CDCl3, 500 MHz)
: 1.13 (3H, d,
d
J¼6.7 Hz), 2.27e2.28 (1H, m), 2.56e2.65 (2H, m), 3.08 (1H, dd,
J¼11.2, 1.0 Hz), 4.21 (1H, dd, J¼9.1, 1.6 Hz), 4.76 (1H, d, J¼3.8 Hz),
7.46e7.47 (2H, m), 7.54 (1H, td, J¼7.6, 1.2 Hz), 7.66 (1H, td, J¼7.5,
d
: 16.6, 29.8, 35.0, 67.0, 137.4, 141.5, 146.6; m/z [EIþ (þve)] 175
[M(35Cl)]þ (100%), 177 [M(37Cl)]þ (100%); HRMS found [M]þ
35
175.0404, C7H ClNO2 requires 175.0400; nmax/cmꢂ1 (film): 3390,
1.3 Hz), 8.13 (1H, dd, J¼7.8, 1.3 Hz); 13C NMR (CDCl3, 125 MHz)
d:
10
2963, 2930, 2875, 1520.
15.1, 28.5, 33.1, 65.2, 83.7, 124.2, 128.1, 130.0, 130.5, 134.5, 137.9,
140.1,140.9, 146.4, 164.6; m/z [EIþ (þve)] 307 [M(35Cl)]þ (100%), 309
35
3.1.12. (ꢃ)-3-(2-Chlorooxazol-4-yl)-2-methylpropanal, 33. A solu-
tion of (ꢃ)-3-(2-chlorooxazol-4-yl)-2-methylpropan-1-ol 32
(1.15 mg, 6.6 mmol) in anhydrous DCM (30 mL) was treated se-
quentially with (diacetoxyiodo)benzene (2.54 g, 7.9 mmol) and
TEMPO (103 mg, 0.7 mmol). The resulting mixture was stirred at
room temperature under an atmosphere of argon for 16 h before
being diluted with DCM (250 mL) and washed with saturated so-
dium thiosulfate solution (2ꢄ60 mL), water (2ꢄ30 mL) and brine
(30 mL). The organic fraction was then dried over sodium sulfate
and concentrated under reduced pressure to afford a crude orange
oil. Purification of the crude residue by flash column chromatog-
raphy (silica gel, elution gradient 0e10% diethyl ether in petroleum
ether) afforded (ꢃ)-3-(2-chlorooxazol-4-yl)-2-methylpropanal 33
(1.09 g, 95%) as a colourless oil.
[M(37Cl)]þ (35%). HRMS found [M]þ 307.0616, C15
H ClNO4 requires
14
307.0611; nmax/cmꢂ1 (film): 3399, 3129, 2974, 2934, 1717, 1518.
3.1.14. Tributyl(prop-1-en-2-yl)stannane, 35. A round bottom flask
charged with magnesium turnings (175 mg, 7.2 mmol), was treated
with anhydrous THF (36 mL) followed by tributyltin chloride
(1.50 mL, 5.5 mmol). The heterogeneous mixturewas then sonicated
at room temperature under an argon atmosphere for 2 min before
being treated with the dropwise addition of 2-bromopropene
(639 mL, 7.2 mmol). The reaction mixture was sonicated for a fur-
ther 3 h by which time no magnesium turnings were longer visible.
The reaction was quenched by the addition of water (50 mL) and
extracted with diethyl ether (3ꢄ50 mL). The combined organics
were washed with water (15 mL) and brine (20 mL) before being
dried over sodium sulfate and concentrated under reduced pressure
to afford a crude colourless oil. Purification of the crude residue by
flash column chromatography (silica gel, petroleum ether) afforded
tributyl(prop-1-en-2-yl)stannane 35 (1.95 g, 96%) as a colourless oil.
1H NMR (CDCl3, 500 MHz)
d
: 1.15 (3H, d, J¼7.2 Hz), 2.53 (1H, ddd,
J¼14.9, 7.1, 0.9 Hz), 2.76e2.84 (1H, m), 2.93 (1H, ddd, J¼14.9, 6.6,
1.1 Hz), 7.42 (1H, t, J¼1.0 Hz), 9.71 (1H, d, J¼1.1 Hz); 13C NMR (CDCl3,
125 MHz) d
: 13.5, 27.1, 45.2, 137.7, 140.4, 146.9, 203.5; m/z [CIþ
(þve), isobutane] 174 [M(35Cl)þH]þ (100%), 176 [M(37Cl)þH]þ
(35%); HRMS found [MþH]þ 174.0321, C7H9NO235Cl requires
174.0322; nmax/cmꢂ1 (film): 2967, 2930, 2884, 2856, 1724.
1H NMR (CDCl3, 500 MHz)
d: 0.89e0.92 (15H, m), 1.30e1.35 (6H,
m), 1.47e1.54 (6H, m), 1.97 (3H, app t, J¼1.6 Hz), 5.09 (1H, dq, J¼3.0,
1.4 Hz), 5.69 (1H, dq, J¼3.1,1.7 Hz); 13C NMR (CDCl3,125 MHz)
d: 9.3,
13.9, 27.5, 27.6, 29.3, 125.7, 150.5. m/z [EIþ (þve)] 332 [M]þ (100%).
118
3.1.13. (ꢃ)-(3R,4R)-3-((S)-1-(2-Chlorooxazol-4-yl)propan-2-yl)-4-
hydroxyisochroman-1-one, 34a, and (ꢃ)-(3S,4S)-3-((S)-1-(2-
chlorooxazol-4-yl)propan-2-yl)-4-hydroxyisochroman-1-one,
34b. Using the same general procedure described for the synthesis
of 4-hydroxy-3-isochroman-1-ones 18a and 18b, a solution (ꢃ)-1-
methoxy-1,3-dihydroisobenzofuran 15 (1.36 mg, 9.08 mmol) in
anhydrous THF (45 mL) was treated with diisopropylamine
(2.67 mL, 19.1 mmol), n-butyllithium solution (1.6 M in hexanes,
11.9 mL, 19.1 mmol) and (ꢃ)-3-(2-chlorooxazol-4-yl)-2-
methylpropanal 33 (1.67 g, 9.63 mmol) to generate the putative
HRMS found [M]þ 332.1534, C15
H
Sn requires 332.1529; nmax/
32
cmꢂ1 (film): 2957, 2928, 2872, 2853, 1458.
3.1.15. (ꢃ)-4-(3-(tert-Butyldimethylsilyloxy)-2-methylpropyl)-2-
(prop-1-en-2-yl)oxazole, 30. (ꢃ)-4-(3-(tert-Butyldimethylsilyloxy)-
2-methylpropyl)-2-chlorooxazole (60 mg, 0.21 mmol), tribu-
tyl(prop-1-en-2-yl)stannane 31 (83 mg, 2.28 mmol) and bis(-
triphenylphosphine)palladium(II)dichloride (12 mg, 17 mmol) were
combined in an oven dried microwave vial and degassed anhydrous
DMF (2 mL) was added. The resulting heterogeneous solution was
heated under an atmosphere of argon under microwave irradiation
at 130 ꢁC for 12 h. The reactionwas cooled and the crude mixturewas
passed through a pad of Celite and eluted with diethyl ether (10 mL).
The organics were then washed with water (4ꢄ4 mL) and brine
(5 mL) before being dried over sodium sulfate. The solvent was
evaporated under reduced pressure to afford a crude colourless oil.
Purification of the crude residue by flash column chromatography
(silica gel, elution gradient 0e2% diethyl ether in petroleum ether)
afforded (ꢃ)-4-(3-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-
(prop-1-en-2-yl)oxazole, 30 (50 mg, 86%) as a colourless oil.
a
-hydroxyisobenzofuran intermediate. Oxidative rearrangement of
the crude intermediate was performed using 3-
chloroperoxybenzoic acid (77%, 2.24 g, 9.99 mmol) in anhydrous
DCM (45 mL) to afford the crude ketoelactols. Oxidation of the
lactol unit was performed in acetone (45 mL) using 2.5 M Jones
reagent (6 mL). Purification of the crude residue using flash chro-
matography (silica gel, elution gradient 0e20% diethyl ether in
petroleum ether) afforded the ketoelactone intermediates (1.60 g,
58%) as a 2:3 ratio of syn/anti diastereoisomers as a yellow oil.
Reduction of the ketoelactone intermediates was performed at
ꢂ78 ꢁC in methanol (25 mL) with sodium borohydride (243 mg,
6.68 mmol). The crude products were purified by flash column
chromatography (silica gel, elution gradient 0e1% methanol in
dichloromethane) to yield (ꢃ)-(3R,4R)-3-((S)-1-(2-chlorooxazol-4-
yl)propan-2-yl)-4-hydroxyisochroman-1-one, 34a (581 mg, 21%)
as a colourless oil. Further elution afforded (ꢃ)-(3S,4S)-3-((S)-1-(2-
chlorooxazol-4-yl)propan-2-yl)-4-hydroxyisochroman-1-one, 34b
(889 mg, 32%) also as a colourless oil.
1H NMR (CDCl3, 400 MHz)
d: 0.03 (6H, s), 0.89 (9H, s), 0.92 (3H,
d, J¼6.7 Hz),1.96e2.04 (1H, m), 2.15 (3H, dd, J¼1.5,1.0 Hz), 2.32 (1H,
ddd, J¼14.6, 7.9, 0.9 Hz), 2.64 (1H, ddd, J¼14.6, 6.1, 1.0 Hz), 3.45 (1H,
dd, J¼9.8, 5.9 Hz), 3.50 (1H, dd, J¼9.9, 5.5 Hz), 5.32 (1H, quint,
J¼1.5 Hz), 5.87e5.90 (1H, m), 7.30 (1H, s); 13C NMR (CDCl3,
100 MHz)
d
: ꢂ5.2, 16.8, 18.5, 19.3, 26.1, 29.9, 35.2, 67.5, 117.6, 132.0,
134.5, 140.7, 162.4; m/z [CIþ (þve),] 296 [MþH]þ (100%). HRMS
found [MþH]þ 296.2049, C16H30NO2Si requires 296.2046; nmax
cmꢂ1 (film): 2959, 2930, 2858, 1671, 1541, 1548, 1465.
/
Compound 34a. 1H NMR (CDCl3, 500 MHz)
d: 1.20 (3H, d,
J¼6.7 Hz), 2.56e2.65 (2H, m), 2.77e2.81 (1H, m), 3.05 (1H, br d,
J¼6.1 Hz), 4.25 (1H, dd, J¼8.5,1.7 Hz), 4.98 (1H, d, J¼1.6 Hz), 7.47 (1H,
s), 7.50 (1H, br d, J¼7.6 Hz), 7.53 (1H, td, J¼7.7, 1.2 Hz), 7.66 (1H, td,
J¼7.5, 1.3 Hz), 8.13 (1H, dd, J¼7.8, 1.3 Hz); 13C NMR (CDCl3, 125 MHz)
3.1.16. (ꢃ)-(3S,4S)-4-Hydroxy-3-((S)-1-(2-(prop-1-en-2-yl)oxazol-
4-yl)propan-2-yl)isochroman-1-one,
36. (ꢃ)-(3S,4S)-3-((S)-1-(2-
Chlorooxazol-4-yl)propan-2-yl)-4-hydroxyisochroman-1-one 34a

B.A. Egan et al. / Tetrahedron 67 (2011) 9700e9707
9707
(197 mg, 0.64 mmol), tributyl(prop-1-en-2-yl)stannane (251 mg,
0.69 mmol) and bis(triphenylphosphine)palladium(II) dichloride
(36 mg, 51 mmol) were combined together in an oven dried mi-
(1H, m), 3.19 (1H, d, J¼6.7 Hz), 4.23 (1H, dd, J¼7.9, 1.7 Hz), 4.79 (1H,
d, J¼5.0 Hz), 7.34 (1H, s), 7.47 (1H, d, J¼7.5 Hz), 7.52 (1H, td, J¼7.5,
1.2 Hz), 7.64 (1H, td, J¼7.5, 1.3 Hz), 8.14 (1H, dd, J¼7.8, 1.1 Hz); 13C
crowave vial with degassed, anhydrous DMF (3.2 mL) and heated
120 ꢁC under microwave for 12 h under an atmosphere of argon for
12 h. The crude mixture was passed through a pad of Celite and
eluted with diethyl ether (50 mL). The organics were then washed
with water (2ꢄ10) and brine (10 mL) before being dried over so-
dium sulfate. The solvent was evaporated under reduced pressure
to afford the crude product as a yellow oil. Purification by flash
column chromatography (silica gel, elution gradient 0e10% diethyl
ether in DCM) afforded (ꢃ)-(3S,4S)-4-hydroxy-3-((S)-1-(2-(prop-1-
en-2-yl)oxazol-4-yl)propan-2-yl)isochroman-1-one 36 (140 mg,
70%), as a pale yellow oil.
NMR (CDCl3, 125 MHz) d: 16.2, 20.5, 20.6, 28.2, 28.6, 34.1, 65.9, 84.2,
124.5, 128.1, 129.9, 130.6, 134.4, 134.6, 138.3, 140.6, 165.0, 168.9; m/z
[CIþ (þve)] 316 [MþH]þ (100%); HRMS found [MþH]þ 316.1551,
C18H22NO4 requires 316.1549; nmax/cmꢂ1 (film): 3374, 2972, 2936,
2878, 1717, 1605, 1566.
3.2. Crystallographic data collection and refinement details
X-ray data for 20 were collected at 100 K on a Rigaku R-Axis
RAPID Image Plate diffractometer equipped with an Oxford Cry-
osystems Cryostream low-temperature device and using graphite
1H NMR (CDCl3, 500 MHz)
d
: 1.16 (3H, d, J¼6.7 Hz), 2.12 (3H, br
ꢀ
monochromated Mo K
a
radiation (
l
¼0.71075 A) radiation. Data
s), 2.53e2.63 (2H, m), 2.93 (1H, d, J¼6.8 Hz), 3.13e3.16 (1H, m), 4.23
(1H, dd, J¼8.5, 1.6 Hz), 4.79 (1H, d, J¼5.4 Hz), 5.32 (1H, t, J¼1.5 Hz),
5.89 (1H, s), 7.39 (1H, s), 7.46 (1H, d, J¼7.7 Hz), 7.52 (1H, td, J¼7.6,
1.2 Hz), 7,64 (1H, td, J¼7.5, 1.4 Hz), 8.14 (1H, dd, J¼7.7, 1.2 Hz); 13C
reduction and an empirical absorption correction were carried out
using CrystalClear [CRYSTALCLEAR 1.4.0. Rigaku, 9009 New Trails
Dr., The Woodlands, Texas 77381, USA, 1998]. The structure was
solved by direct methods using the program SHELXS97 [SHELX,
Sheldrick, G. M., 2008. Acta Crystallogr. A64, pp 112e122] and re-
fined using full-matrix least-squares refinement on F2 using
SHELXL97 [SHELX Sheldrick, G. M., 2008. Acta Crystallogr. A64, pp
112e122] within the WinGX program suite [Farrugia, L. J., . J. Appl.
Cryst. 1999, 32, pp 837e838]. All non-hydrogen atoms were refined
anisotropically. Hydrogen atoms modelled as riding atoms and
placed on calculated positions.
NMR (CDCl3, 125 MHz) d: 15.9, 19.2, 28.4, 33.9, 65.7, 84.1, 117.9,
124.5, 128.1, 130.0, 130.6, 131.8, 134.5, 135.1, 139.7, 140.5, 162.5,
164.9; m/z [CIþ (þve)] 314 [MþH]þ (100%). HRMS found [MþH]þ
314.1390, C18H20NO4 requires 314.1392; nmax/cmꢂ1 (film): 3372,
2961, 2928, 2880, 1713, 1666, 1605, 1556, 1463.
3.1.17. (ꢃ)-(3S,4S)-4-Hydroxy-3-((R)-1-(2-(prop-1-en-2-yl)oxazol-
4-yl)propan-2-yl)isochroman-1-one,
37. (ꢃ)-(3S,4S)-3-((R)-1-(2-
Crystal data for 20: C15H15NO4, Mr¼273.28, monoclinic, C2/c,
Chlorooxazol-4-yl)propan-2-yl)-4-hydroxyisochroman-1-one 34b
(93 mg, 0.3 mmol), tributyl(prop-1-en-2-yl)stannane (127 mg,
0.3 mmol) and bis(triphenylphosphine)palladium(II) dichloride
ꢀ
a¼13.5059(9), b¼9.3899(6), c¼21.6502(17) A,
b
¼105.593(3)ꢁ,
T¼100(2) K, Z¼8, R¼0.0783 for 1726 data with F0>2
s(F),
wR2¼0.2634 for 3031 unique data (all data 18,041), GOF¼1.132.
CCDC832199 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(17 mg, 24 mmol) were combined in an oven dried microwave vial
and suspended in anhydrous, degassed DMF (3 mL). The heteroge-
neous suspensionwas heated to 120 ꢁC under microwave irradiation
under an atmosphere of argon for 12 h. The crude mixture was
passed through a pad of Celite and eluted with diethyl ether (30 mL).
The organics were then washed with water (2ꢄ5) and brine (5 mL)
before being dried over sodium sulfate. The solvent was evaporated
under reduced pressure toyield a crudeyellowoil. Purification of the
crude residue by flash column chromatography (silica gel, elution
gradient 0e10% diethyl ether in DCM) afforded (ꢃ)-(3S,4S)-4-
hydroxy-3-((R)-1-(2-(prop-1-en-2-yl)oxazol-4-yl)propan-2-yl)iso-
chroman-1-one, 37 (79 mg, 83%), as a pale yellow oil.
Acknowledgements
We would like to thank the EPSRC Pharma Synthesis Network
and Pfizer for postgraduate support (B.A.E.). The authors also thank
Dr. Ian Sword and the EPSRC and Pfizer for funding.
1H NMR (CDCl3, 400 MHz)
d
: 1.27 (3H, d, J¼6.7 Hz), 2.10 (3H, s),
References and notes
2.56e2.74 (3H, m), 4.18 (1H, d, J¼9.5 Hz), 5.04 (1H, d, J¼2.4 Hz), 5.36
(1H, d, J¼4.6 Hz), 5.38 (1H, s), 5.93 (1H, s), 7.41 (1H, s), 7.48e7.53
(2H, m), 7.64 (1H, d, J¼7.0 Hz), 8.13 (1H, d, J¼7.7 Hz); 13C NMR
€
1. Wenzel, S. C.; Muller, R. In Comprehensive Natural Products Chemistry II; Moore,
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2. Weissman, K. J.; Muller, R. Bioorg. Med. Chem. 2009, 17, 2121e2136.
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3. (a) Jansen, R.; Kunze, B.; Reichenbach, H.; Hofle, G. Eur. J. Org. Chem. 2002,
(CDCl3, 100 MHz)
d 18.1, 19.0, 28.6, 33.0, 64.8, 85.3, 119.0, 124.8,
€
917e921; (b) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot. 2004,
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[FABþ (þve)] 314 [MþH]þ (100%). HRMS found [MþH]þ 314.1397,
C18H20NO4 requires 314.1392; nmax/cmꢂ1 (film): 3342, 2964, 2934,
2919, 2877, 1710, 1606, 1532, 1456.
57, 151e155.
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4-yl)propan-2-yl)isochroman-1-one, 38. A solution of (ꢃ)-(3S,4S)-4-
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chroman-1-one 36 (72 mg, 230 mmol) in absolute ethanol (3 mL)
10. The atomic coordinates for 20 (CCDC deposition number CCDC832199) are
available upon request from the Cambridge Crystallographic Centre, University
Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
The crystallographic numbering system differs from that used in the text;
therefore, any request should be accompanied by the full literature citation of
this paper.
was charged with palladium on carbon (10% Pd on activated carbon,
11 mg). The suspension was then stirred under an atmosphere of
hydrogen at room temperature until TLC analysis indicated reaction
completion (4 h). The suspension was filtered through a plug of
Celite and silica and the filtrate concentrated under reduced pres-
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oxazol-4-yl)propan-2-yl)isochroman-1-one 38 (71 mg, 98%) as
a colourless oil without the need of any further purification.
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1H NMR (CDCl3, 500 MHz)
J¼6.9 Hz), 2.50e2.57 (2H, m), 3.02 (1H, sept, J¼7.0 Hz), 3.11e3.16
d
: 1.15 (3H, d, J¼6.7 Hz), 1.30 (6H, d,