Total synthesis of the proposed structure of 8-deshydroxyajudazol a: A modified approach to 2,4-disubstituted oxazoles

Article abstract of DOI:10.1021/jo302055w

The total synthesis of the proposed structure for the minor myxobacterial metabolite 8-deshydroxyajudazol A (3) is described. The isochromanone moiety present in the eastern fragment was constructed by an intramolecular-Diels-Alder (IMDA). Difficulties were encountered with the formation of the 2,4-disubstituted oxazole, so this was synthesized via a modified approach. This involved selective acylation of the diol 7 with acid 8, azide displacement of the secondary alcohol, and subsequent azide reduction in the presence of base which induced an O,N shift to give the hydroxyamide 23. Cyclodehydration then gave the desired oxazole 24 and deprotection followed by mesylation and elimination produced the C15 alkene 5. Sonogashira coupling with the eastern fragment vinyl iodide 6 and partial reduction yielded 8-deshydroxyajudazol A (3).

Full text of DOI:10.1021/jo302055w

Article
pubs.acs.org/joc
Total Synthesis of the Proposed Structure of 8‑Deshydroxyajudazol
A: A Modified Approach to 2,4-Disubstituted Oxazoles†
Stephen Birkett, Danny Ganame, Bill C. Hawkins, Sebastien Meiries, Tim Quach, and Mark A. Rizzacasa*
́
School of Chemistry, The Bio21 Institute, The University of Melbourne, Victoria 3010, Australia
S
* Supporting Information
ABSTRACT: The total synthesis of the proposed structure for the minor myxobacterial metabolite 8-deshydroxyajudazol A (3)
is described. The isochromanone moiety present in the eastern fragment was constructed by an intramolecular-Diels−Alder
(IMDA). Difficulties were encountered with the formation of the 2,4-disubstituted oxazole, so this was synthesized via a modified
approach. This involved selective acylation of the diol 7 with acid 8, azide displacement of the secondary alcohol, and subsequent
azide reduction in the presence of base which induced an O,N shift to give the hydroxyamide 23. Cyclodehydration then gave the
desired oxazole 24 and deprotection followed by mesylation and elimination produced the C15 alkene 5. Sonogashira coupling
with the eastern fragment vinyl iodide 6 and partial reduction yielded 8-deshydroxyajudazol A (3).
however, the absolute configurations of 1 and 2 were not
determined. The ajudazols are inhibitors of the mitochondrial
respiratory energy metabolism of beef heart submitochondrial
particles (SMP). For ajudazol A (1), NADH oxidation in SMP
was inhibited at an IC50 of 13.0 ng/mL (22.0 nM), while
ajudazol B (2) had an IC50 of 10.9 ng/mL (18.4 nM).9
INTRODUCTION
■
Myxobacteria are a life form at the interface between single and
multicellular organisms. They live in places that are rich in
organic matter and are otherwise known as gliding bacteria
owing to the fact that they move by gliding over a solid
surface.1 These microorganisms have astonishing life cycles
culminating in multicellular fruiting body formation upon
starvation and are a rich source of potentially useful secondary
metabolites.2 Indeed, myxobacteria produce an amazing array
of natural products with structural diversity not seen in other
single-celled organisms. This could be due to a combination of
their organic rich living environments as well as the
sophisticated enzyme machinery. For example, the myxobacte-
rium Sorangium cellulosum produces the potent anticancer
compounds the epothilones,3 the isochromanone-containing
icumazols,4 as well as the complex spiroketal natural product
spirangien A.5 S. cellulosum has the largest bacterial genome
sequenced to date (>13 Mb),6 much of which is dedicated to
regulation to support the complex lifecycle of this organism. In
addition, there are 17 secondary metabolite loci,6 which
explains the array of natural products isolated from this species.
Extracts of Chondromyces crocatus have also afforded a number
of diverse compounds including the crocacins7 and the
ajudazols.8 Ajudazol A (1) (Figure 1) possesses a novel
structure that includes an isochromanone fragment, a 2,4-
disubstituted oxazole, and a polyene chain terminating in a
tertiary enamide moiety. Ajudazol B (2) differs from compound
1 at C15 whereby a methyl group and additional asymmetric
center is present rather than the 1,1-disubstituted alkene;
Muller and co-workers have proposed that the final stages of
̈
the biosynthesis of ajudazols A (1) and B (2) involve a series of
post polyketide synthase (PKS) cytochrome P450 mediated
oxidations of the putative biosynthetic precursors 8-deshydrox-
yajudazol A (3) and B (4).10 Two mutant forms of C. crocatus
were produced in which the genes that encode for the P450
enzymes AjuJ (C8 oxidation) or AjuI (C15 oxidation/
elimination) were removed by mutagenesis. The AjuI knockout
produced only ajudazol B (2), while the AjuJ knockout
produced deshydroxyajudazol A (3). Thus, the final stages of
the biosynthesis of 1 and 2 begin with the post-PKS tailoring of
deshydroxyajudazol B (4) by P450-mediated oxidations to
produce either ajudazol B (2) (AjuJ) or deshydroxyajudazol A
(3) (AjuI) (Figure 1). Further oxidation of deshydroxyajudazol
A (3) by AjuJ then gives ajudazol A (1). However, it appears
that ajudazol B (2) is not a substrate for AjuI-mediated
desaturation to form ajudazol A (1). This accounts for the
presence of both ajudazols A (1) and B (2) and the higher
proportion of 1 is presumably because AjuI is a more efficient
Special Issue: Robert Ireland Memorial Issue
Received: September 19, 2012
Published: November 6, 2012
© 2012 American Chemical Society
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deshydroxyajudazol A (3) is shown in Scheme 1. It was
envisaged that the C18−19 bond could be formed by an
efficient Sonogashira coupling16 between the alkyne−oxazole
western fragment 5 and labile vinyliodide eastern fragment 6.13
Partial reduction of the resultant enyne would then form the
Z,Z-diene and yield 8-deshydroxyajudazol A (3).
The alkyne−oxazole 5 would arise from ester formation
between diol 7 and the acid 8 followed by O,N-shift, oxidation,
and cyclodehydration,17 while the 1,1-disubstituted alkene
could be formed by elimination of a mesylate derived from
the alcohol arising from acid 8. The isochromanone in fragment
7 can be formed by an intramolecular Diels−Alder (IMDA)18
cyclization followed by aromatization and bromine−oxygen
exchange.
This approach to deshydroxyajudazol A (3) is based on our
synthesis of 15R deshydroxyajudazol B (4), which is
summarized in Scheme 2.15 Compound 10 was secured by a
IMDA reaction of dienyne 9, which on aromatization afforded
the isochromanone. Br−O exchange via Pd-mediated cross-
coupling19 with pinacol borane and oxidative workup gave the
phenol 11. Further functionalization gave diol 7, which was
then converted into the oxazole 12 using a modified protocol
(see below). Sonagashira coupling with iodide 6 followed by
partial reduction the P2−Ni gave 15R deshydroxyajudazol B
(4).
Figure 1. Structures of the ajudzols A (1) and B (2) and 8-
deshydroxyajudzols A (3) and B (4) and the proposed final stages of
the biosynthesis.
Since no NMR data were measured for deshydroxyajudazol B
(4), we compared data for the synthetic material with that
reported for the C1−10 western fragment of deshydroxyaju-
dazol A (3)10 and the C11−29 eastern fragment of ajudazol B
(2).7b Because of the possible effects of conjugation of the exo-
methylene at C15 on some of the chemical shifts, C11−C14
were included in the eastern fragment for the purpose of this
analysis. These compared very well with our synthetic material
but since no chiroptical data was available, we were unable to
confirm the C15 stereochemistry or the absolute configuration.
Eastern Fragment Vinyl Iodide Synthesis. The full detail
of the synthesis of the required vinyl iodide fragment 6 is
shown in Scheme 3.13 This began with the known volatile
alcohol 1320 (Scheme 2). PCC oxidation and Wittig extension
gave the α,β-unsaturated ester 14 with high E selectivity in 73%
yield for the two steps. DIBAL-H reduction of ester 14 gave
allylic alcohol 15, which was converted into the bromide 16.
Treatment of bromide with methylamine in THF gave the
secondary amine 17 which was coupled with the known
unsaturated acid 1812,21 to give the vinyl iodide fragment 6 in
good yield. Key to the success of this peptide coupling was the
use of EDCl·MeI and 20 mol % HOBt in DMF solvent.
Modified Approach to the 2,4-Disubstituted Oxazole.
The failure to produce a protected amino alcohol from diol 7
required for amide formation and cyclodehydration to the
oxazole in our original approach to the deshyroxyajudazols
catalyst than AjuJ for the selective oxidation of deshydrox-
yajudazol B (4). Both 8-deshydroxyajudazols A (3) and B (4)
were detected in small amounts in the extracts of wild type C.
crocatus and deshydroxyajudazol B (4) is present in trace
amounts in both AjuI and AjuJ mutants.10 However, only
compound 3 had it is structure assigned by NMR analysis while
the structure of 8-deshydroxyajudazol B (4) was inferred by MS
analysis. Muller and co-workers have also investigated the
̈
biosynthesis of the unusual isochomanone moiety and have
suggested that this is produced by an unusual thioesterase and
not a terminal cyclase.11
A number of synthetic approaches to the C12−C29 fragment
of ajudazol A (1)12,13 and (2) have been reported as well as an
approach to the isochromanone fragment.14 We have recently
reported the total synthesis of a the minor metabolite and
putative biosynthetic precursor to the ajudazols, 15R-8-
deshydroxyajudazol B (4)15 and now describe the first total
synthesis of the structure proposed for 8-deshydroxyajudazol A
(3) which utilizes a modified approach to the 2,4-disubstituted
oxazole.
RESULTS AND DISCUSSION
Retrosynthetic Analysis of 8-Deshydroxyajudazol A
(3). Our initial retrosynthetic analysis of the 15R isomer of 8-
■
Scheme 1. Retrosynthetic Analysis of 8-Deshydroxyajudazol A (3)
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Scheme 2. Total Synthesis of 8-Deshydroxyajudazol B (4)15
formation of 2,4-disubstituted oxazoles from alkenes via
dihydroxylation with a wide array of substituents.
Scheme 3. Synthesis of Vinyl Iodide 6
Western Fragment Oxazole Synthesis. The synthesis of
the acid coupling partner and oxazole for the production of
deshydroxyajudazol A (3) is detailed in Scheme 5. Mono-
Scheme 5. Synthesis of the Western Fragment Oxazole 25
via a Modified Approach
forced us to reconsider a modified protocol.15 2,4-Disubstituted
oxazoles are present in a number of myxobacteria metabolites2
and a synthetic approach to this functionality from a non-amino
acid precursor, especially in the present case, would be
desirable.22 The focus in the present case would be on the
synthesis of this system, which circumvents the need for the
isolation of an amine but could be adaptable to the construction
of 2,4-disubstituted oxazoles with a wide variety of substituents.
This modified approach is detailed in Scheme 4 and begins
with selective acylation of a vicinal diol A with acid B to give a
Scheme 4. Modified Approach to 2,4-Disubstituted Oxazoles
silylation26 of the known diol 19, readily available via alkylation
of dimethylmalonate with propargyl bromide followed by
reduction,27 gave the alcohol 20. Oxidation with Dess−Martin
periodinane followed by Pinnick oxidation then afforded
racemic acid 8 in high yield and selective acylation of the
primary alcohol in diol 715 with 8 gave ester 21 which was
transformed to the azide 22 by a Mitsunobu reaction using
Zn(N3)2·pyridine as a stable azide source.23 Reduction and O,N
shift was best achieved with 1,3-propanedithiol28 to give
hydroxyamide 23 as a complex mixture of four diaster-
eoisomers. Dess−Martin periodinane oxidation of the hydrox-
yamide 23 resulted in some over oxidation so we resorted to a
Parikh−Doering oxidation to the aldehyde and subsequent
cyclodehydration using the Wipf protocol18b to give the oxazole
24 in a serviceable yield as a mixture of two inseparable
monoester C. Azide displacement23 of the secondary alcohol
affords an azide which upon reduction under basic conditions
would induce a O,N acyl shift24 to form the hydroxyamide
directly without the need for isolation of an amine intermediate
and subsequent peptide coupling. Oxidation give the aldehyde
ready for cyclodehydration to give a 2,4-disubstituted oxazole.
This approach is an alternative to the aza-Wittig type
approaches to oxazolines and oxazoles25 and allows for the
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diastereoisomers. Desilylation then yielded alcohol 25 ready for
elimination to produce the C15 alkene.
confirmation of the structure for synthetic 3 was achieved
through examination of the 2D spectra for synthetic 3 (COSY,
gHSQC and gHMBC), but at this stage, confirmation of the
composition of natural material remains to be achieved beyond
reasonable doubt.
Total Synthesis of Deshydroxyajudazol A (3). In our
early model studies,13 the C15 1,1-disubstituted alkene was
installed after the Sonogashira coupling and partial reduction;
however, for a more convergent approach, we elected to form
this double bond prior to coupling. Mesylation of alcohol 25
followed by removal of the PMB ether under acidic conditions
gave the mesylate 26 in high yield (Scheme 6). Immediate
CONCLUSION
■
In conclusion, we have completed the first total synthesis of the
reported structure for the minor metabolite 8-deshydroxyaju-
dazol A (3), the proposed biosynthetic precursor to ajudazol A
(1). Key steps included an IMDA reaction and subsequent
aromatization to construct the isochromanone western frag-
ment, late stage installation of the sensitive 1,1-disubstituted
alkene and a Sonagashira coupling to form the C18−C19 bond.
In addition, a modified approach to the 2,4-disubstituted
oxazole was developed which utilized a selective acylation and
O,N shift to form a hydroxyamide which could be oxidized and
cyclodehydrated to the oxazole. Experiments directed toward
the application of synthetic 3 for the investigation of the
interesting biogenesis of these compounds as well as the total
synthesis of ajudazols A (1) and B (2) using a similar approach
are underway.33
Scheme 6. Completion of the Total Synthesis of 8-
Deshydroxyajudazol A (3)
EXPERIMENTAL SECTION
■
General Methods. Proton nuclear magnetic resonance spectra
(1H NMR, 400 MHz, 500 MHz, and 600 MHz) and proton-decoupled
carbon nuclear magnetic resonance spectra (13C NMR, 100 MHz, 125
MHz, and 150 MHz) were obtained in deuterochloroform with
residual chloroform as internal standard unless otherwise noted.
COSY, gHMQC, and gHMBC spectra (1H 500/13C 125 MHz) were
recorded in methanol-d4. Chemical shifts are followed by multiplicity,
coupling constant(s) (J, Hz), integration, and assignments where
possible. Optical rotations were recorded for a 1 mL solution, and
units are deg cm2 g−1. Flash chromatography was carried out on silica
gel 60. Analytical thin-layer chromatography (TLC) was conducted on
aluminum-backed 2 mm thick silica gel 60 GF254, and chromatograms
were visualized with 20% w/w phosphomolybdic acid in ethanol.
High-resolution mass spectra (HRMS) were obtained by ionizing
samples via electron spray ionization (ESI) on a Finnigan LTQ
Fourier transform hybrid linear ion trap ICR mass spectrometer.
Anhydrous THF and CH2Cl2 were used from a solvent cartridge
system. Dry methanol was distilled from magnesium methoxide. All
other solvents were purified by standard methods. Petrol used refers to
petroleum ether 40−60 °C boiling range. All other commercially
available reagents were used as received. The standard workup refers
to extraction with a particular solvent (3×), washing with water and
brine, drying with MgSO4, and concentration under reduced pressure.
(2E,6Z)-Methyl 7-iodohepta-2,6-dienoate (14). To a solution of
the alcohol 1319 (7.0 g, 33.01 mmol) in CH2Cl2 (160 mL) was added
PCC (17.30 g, 82.53 mmol), and the resulting mixture was stirred at rt
under Ar for 2 h. The mixture was filtered through Florisil, and the
solvent was carefully removed under reduced pressure to give the
volatile crude aldehyde (6.50 g), which was dissolved in CH2Cl2 (200
mL). To this solution was added (triphenylphosphoranylidene)-
propionaldehyde (25.87 g, 77.39 mmol), and the resulting mixture was
stirred at rt under Ar for 24 h. The solvent was concentrated under
reduced pressure, and the crude mixture was filtered through a plug of
silica gel with 10% EtOAc/petroleum ether. Purification of the residue
left on evaporation of the solvent, by flash chromatography eluting
with 2.5% EtOAc/petroleum ether gave the methyl ester 14 (6.0 g,
73%) as a brown oil: IR νmax (film) 3068, 2989, 2949, 2846, 1720,
1656 cm−1; 1H NMR (400 MHz) δ 2.24−2.33 (m, 4H), 3.68 (s, 3H),
5.82 (ddd, J = 14.6, 1.3, 1.3 Hz, 1H), 6.14 (dq, J = 6.4 Hz, 1H,), 6.24
(d, J = 7.2 Hz, 1H), 6.29 (dt, J = 15.6, 6.6 Hz, 1H); 13C NMR (75
MHz) δ 30.1, 32.8, 51.1, 83.7, 121.4, 139.0, 147.2, 166.3; HRMS (ESI)
m/z [MH + Na]+ calcd for C8H12INaO2 289.9785, found 289.9777.
DBU-mediated elimination29 of 26 smoothly formed the 1,1-
disubstituted alkene 5. This compound proved to be reasonably
stable, however acidic conditions or prolonged exposure to
silica gel resulted in substantial isomerization to the conjugated
enyne.
Sonagashira coupling of alkyne 5 with iodide 6 produced the
coupled product, but unfortunately, this could not be separated
from the excess 6 used in the reaction by chromatography so
we proceeded with the mixture. Partial reduction proved
challenging and we eventually resorted to exposure of the
mixture to Cu/Ag activated Zn30 which gave deshydroxyaju-
dazol A (3) after purification by HPLC. These partial reduction
conditions proved superior to the P2−Ni/H2/EDA31 proce-
dure utilized for dehydroxyajudazol B as over reduction was
completely suppressed.
1
The H and 13C NMR spectral data for 3 in methanol-d4
were compared to that quoted for natural material10 (Table 1).
1
The H and 13C NMR spectra matched very well with those
reported; however, a few exceptions were observed. Most
notable were the signals in the unsaturated amide C25−C29
region especially for NCH3, 28-OCH3, and H25 which
appeared slightly further downfield than reported,10 although
these resonances were significantly broadened due to restricted
rotation. These minor discrepancies between synthetic and
natural 3 values could be due to concentration and/or
temperature effects.32 In addition, as can be seen in Table 1,
there are some missing peaks in the quoted spectra as well as
misassigned resonances for NCH3, C7, and C10. Thus, the only
major difference is the 13C NMR chemical shift for 28-OCH3.
Unfortunately, due to the small amount of natural 3 isolated, an
authentic sample was not available for direct comparison and
no copies of the original spectra were provided in the
Supporting Information of the original publication.10 Further
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1
Table 1. Comparison of the H and 13C Spectra of Synthetic and Natural Deshydroxyajudazol A (3) in Methanol-d4
atom
δH nat
δH syn
ΔδH
δC nat
δC syn
171.9
ΔδC
1
2
3
4
a
108.8
161.4
125.9
15.4
160.9
126.0
15.3
+0.5
−0.1
+0.1
−0.3
+0.3
4-CH3
2.22
2.21
−0.01
+0.01
+0.01
5
7.33
6.72
7.34
6.73
138.4
118.6
138.1
118.9
138.8
29.3
6
a
7
108.6
8
3.01
3.02
+0.01
+0.01
0
30.4
84.7
−0.9
−0.1
9
4.5
4.51
84.6
b
10
2.33
2.33
34.8
37.7
10-CH3
11
1.03
1.04
+0.01
0/+0.03
15.2
34.0
15.3
+0.1
−0.9
−0.1
+0.2
−0.3
−0.1
−0.1
−0.7
−0.5
−0.6
0
2.54/2.89
2.54/2.91
33.1
12
140.9
136.9
163.7
136.1
118.6
31.2
140.8
137.1
163.4
136.0
118.5
30.5
13
7.64
7.65
+0.01
14
15
15-CH2
16
5.40/5.95
3.35
5.40/5.96
3.37
0/+0.01
+0.02
+0.02
+0.01
+0.01
+0.02
+0.01
+0.14
+0.28
+0.11
+0.02
+0.27
17
5.54
5.56
128.9
126.9
124.9
133.3
27.6
128.4
126.3
124.9
133.6
28.2
18
6.35
6.36
19
6.34
6.35
20
5.48
5.48
+0.3
+0.6
−1.0
−1.5
21
2.28
2.29
22
2.03
2.17
31.8
30.8
23
5.33
5.61
130.8
c
129.3
128.4/128.7
50.3/53.4
34.0/35.8
170.2/170.4
92.2
24
5.39
5.50
25
3.92
3.94
50.1
+0.2
b
NCH3
26
2.66
2.90/2.97
38.0
c
27
5.26
5.28
+0.02
92.3
169.2
18.9
49.9
- 0.1
+0.8
+0.2
+5.8
28
170.0
19.1
29
2.10
3.53
2.11
3.62
+0.01
+0.09
28-OCH3
55.7
a
b
c
Signal misassigned to C7 in original report and should be for C2.10 Signal misassigned to C10 in original report and should be for NCH3. Peak
not quoted for natural 3.10
(1E,5Z)-1-Iodohepta-1,5-dien-7-ol (15). To a solution of the
methyl ester 14 (150 mg, 0.563 mmol) in CH2Cl2 (5 mL) at 0 °C
under Ar was added dropwise a solution of DIBAL-H in THF (1 M,
2.81 mL, 2.81 mmol), and the mixture was then warmed to rt and
stirred for 2.5 h. Et2O and 0.5 M potassium tartrate solution were
added, and the mixture was allowed to stir for 30 min. The aqueous
phase was extracted with Et2O, and the combined organic extracts
were washed with water and brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification of the crude
product by flash chromatography eluting with 25% EtOAc/petroleum
ether gave alcohol 15 (112 mg, 83%) as a colorless oil: IR νmax (film)
6.60 mL, 13.29 mmol), and the resulting solution was stirred for 2 h.
The solvent and excess MeNH2 was removed under reduced pressure.
Purification by chromatography on alumina with a 1:1:0.1 mixture of
CH2Cl2/petroleum ether/MeOH gave the secondary amine 17 (0.50
g, 75%) as an oil: IR νmax (film) 3284, 2927, 2842, 2786, 1652, 1608,
1440 cm−1; 1H NMR (400 MHz) δ 2.02−2.14 (m, 4H, H21−22), 2.29
(s, 3H), 3.04 (d, J = 4.4 Hz, 2H), 5.40−5.52 (m, 2H), 6.04−6.11 (m,
2H); 13C NMR (100 MHz) δ 30.3, 34.0, 35.6, 53.2, 82.6, 128.9, 130.6,
140.2; HRMS (ESI) m/z [M + H]+ calcd for C8H15IN 252.0249,
found 252.0247.
(E)-N-((2E,6Z)-7-Iodohepta-2,6-dien-1-yl)-3-methoxy-N-methyl-
but-2-enamide (6). To a solution of the amine 17 (57.5 mg, 0.229
mmol) in CH2Cl2 (15 mL) were added the acid 1721 (29.2 mg, 0.252
mmol), EDC·MeI (122 mg, 0.412 mmol), and HOBt (6.2 mg, 0.046
mmol), and the mixture was stirred at rt for 18 h. The solvent was
evaporated to give the crude product, which was purified by column
chromatography eluting with 40% EtOAc/petroleum ether to give the
amide 6 (63.5 mg, 79%) as a yellow oil: IR νmax (film) 3462, 2920,
1
3308, 2921, 2852, 1671, 1608, 1438 cm−1; H NMR (400 MHz) δ
2.10−2.23 (m, 4H), 2.42 (s, 1H), 4.03 (s, 2H), 5.58−5.69 (m, 2H,),
6.12−6.19 (m, 2H); 13C NMR (100 MHz) δ 30.2, 34.0, 63.1, 82.9,
129.7, 131.0, 140.1; HRMS (ESI) m/z [M + Na]+ calcd for
C7H11INaO 260.9752, found 260.9747.
(1E,5Z)-1-Iodo-N-methylhepta-1,5-dien-7-amine (17). To a sol-
ution of the above allylic alcohol (30 mg, 0.126 mmol) in CH2Cl2 (6
mL) at 0 °C under Ar were added PPh3 (319 mg, 1.21 mmol) and
CBr4 (242 mg, 0.730 mmol), and the resulting mixture was stirred for
1.5 h. The solvent was concentrated under reduced pressure, and
purification of the crude product by flash chromatography eluting with
100% petroleum ether gave bromide 16 (172 mg, 93%) as a light
yellow oil which was used immediately in the next reaction. To a
solution of the allylic bromide 16 (800 mg, 2.65 mmol) in THF (15
mL) at 0 °C under Ar was added a solution of MeNH2 in THF (2 M,
1
2846, 1647, 1604, 1438 cm−1; H NMR (400 MHz, 40 °C) δ 2.13−
2.22 (m, 7H), 2.93 (br s, 3H), 3.58 (s, 3H), 3.87 (br s, 1H), 3.96 (br s,
1H), 5.15 (s, 1H), 5.42 (dt, J = 15.6, 6.0 Hz, 1H), 5.57 (dt, J = 15.6,
6.0 Hz, 1H), 6.14 (dt, J = 6.8, 6.8 Hz, 1H), 6.20 (d, J = 7.2 Hz, 1H);
13C NMR (100 MHz) δ 18.7, 30.4, 34.2, 35.5, 52.0, 54.8, 83.1, 91.1,
125.6, 126.2, 131.5, 132.0, 140.1, 168.5; HRMS (ESI) m/z [M + Na+]
calcd for C13H20INNaO2 372.0436, found 372.0434.
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2-((tert-Butyldimethylsilyloxy)methyl)pent-4-yn-1-ol (20). A sol-
ution of diol 1927 (1.08 g, 9.46 mmol) in THF (12 mL) was added at
0 °C to a suspension of NaH (228 mg, 7.00 mmol) in THF (20 mL).
After 5 min, TBSCl (1.43 g, 9.49 mmol) was added slowly and the
mixture stirred at 0 °C for 1 h before being allowed to warm to rt and
stirred for a further 1.5 h. The mixture was diluted (Et2O) and
quenched (H2O) before the usual workup into Et2O gave the crude
alcohol, which was purified by flash chromatography (10% EtOAc/
petroleum ether) to afford alcohol 20 (1.39 g, 87%) as a colorless oil:
IR νmax (film) 3314, 2955, 2930, 2858, 2119, 1472, 1432, 1390, 1362,
1253, 1068, 1034, 939, 834, 775 cm−1; 1H NMR (500 MHz) δ 0.08 (s,
6H,), 0.90 (s, 9H), 1.93 (m, 1H), 1.98 (t, J = 2.7 Hz, 1H), 2.30 (m,
2H), 2.41 (t, J = 5.6 Hz, 1H), 3.72−3.87 (m, 4H); 13C NMR (125
MHz) δ −5.44, −5.40, 17.6, 18.3, 26.0, 41.7, 65.1, 69.7, 82.6; HRMS
(ESI) m/z [M + H]+ calcd for C12H25O2Si 229.16183, found
229.16180.
0.110 mmol) in toluene (2.0 mL) were added PPh3 (89.0 mg, 0.339
mmol) and Zn(N3)2·2Py23 (50.1 mg, 0.163 mmol) at rt. The reaction
was cooled to 0 °C, and DIAD (90 μL, 0.457 mmol) was added
dropwise. The reaction was allowed to warm to rt and stirred for a
further 4.5 h before being filtered through Celite (washing with
EtOAc) and concentrated under reduced pressure. Flash chromatog-
raphy (20% EtOAc/peroleum ether) afforded the desired azide 22
(49.6 mg, 69%) as a colorless oil: IR νmax (film) 3288, 2954, 2930,
2857, 2113, 1729, 1613, 1515, 1464, 1375, 1249, 1170, 1119, 1036,
836, 778 cm−1; 1H NMR (500 MHz) δ 0.05 (s, 3H), 0.06 (s, 3H), 0.88
(m, 9H), 1.12 (m, 3H), 1.39 (m, 0.5H), 1.50 (m, 0.5H), 1.87 (m, 1H),
2.00 (m, 1H), 2.06 (m, 0.5H), 2.12 (m, 0.5H), 2.26 (s, 3H), 2.59 (m,
2H), 2.77−2.84 (m, 2H), 2.95 (m, 1H), 3.74 (m, 0.5H), 3.80 (m,
0.5H), 3.81 (s, 3H), 3.92 (m, 2H), 4.07 (m, 0.5H), 4.12−4.20 (m,
1.5H), 4.33 (m, 1H), 4.95 (m, 2H), 6.88−6.92 (m, 3H), 7.33 (dd, J =
7.6, 3.0 Hz, 1H), 7.44 (m, 2H). 13C NMR (125 MHz) δ −5.40, −5.39,
15.0, 15.1, 15.3, 15.4, 16.25, 16.32, 16.5, 17.5, 18.3, 21.78, 21.82, 21.86,
21.91, 22.1, 22.3, 31.4, 31.6, 31.7, 32.78, 32.82, 33.36, 33.40, 33.5, 33.7,
33.8, 33.9, 34.0, 34.1, 34.5, 34.6, 47.06, 47.07, 47.11, 55.4, 58.6, 58.69,
58.74, 58.8, 59.6, 59.7, 62.20, 62.22, 62.3, 66.8, 67.0, 67.55, 67.64, 70.1,
70.2, 75.7, 81.28, 81.32, 81.34, 81.6, 81.8, 81.9, 82.0, 113.92, 113.92,
118.6, 122.59, 122.63, 129.5, 130.6, 130.67, 130.70, 132.6, 132.7,
136.10, 136.13, 136.2, 138.8, 138.9, 139.1, 139.2, 159.0, 159.1, 159.7,
162.6, 162.8, 172.1, 172.2; HRMS (ESI) m/z [M + Na]+ calcd for
C35H47N3NaO7Si 672.30755, found 672.30757.
2-((tert-Butyldimethylsilyloxy)methyl)pent-4-ynoic Acid (8). To a
solution of alcohol 20 (540.6 mg, 2.37 mmol) in CH2Cl2 (23 mL) at 0
°C was added Dess−Martin periodinane (1.30 g, 3.07 mmol) and the
reaction stirred for 5 min before being allowed to warm to rt and
stirred for a further 1 h. The mixture was diluted (Et2O) and quenched
(satd aq NaHCO3, followed by 2 M Na2S2O3) before the usual workup
into Et2O to provide the crude aldehyde (534.4 mg, 2.36 mmol, quant
yield) which was used in the next step without further purification.
t
The aldehyde was dissolved in BuOH (59 mL) before 2-methyl-2-
butene (9.8 mL) was added. A solution of NaClO4 (843 mg, 9.32
mmol) and NaH2PO4·H2O (1.29 g, 9.35 mmol) in H2O (14 mL) was
added dropwise and the resultant mixture stirred at rt overnight. Et2O
and H2O were added, and the mixture was acidified to pH ∼2 with 1.2
M HCl before the usual workup into Et2O yielded the desired acid 8
(510 mg, 89%) as a waxy solid: IR νmax (film) 3314, 2957, 2932, 2857,
2-((tert-Butyldimethylsilyloxy)methyl)-N-((4S)-1-hydroxy-4-((R)-8-
(4-methoxybenzyloxy)-7-methyl-1-oxoisochroman-3-yl)pentan-2-
yl)pent-4-ynamide (23). To a solution of azide 22 (41.2 mg, 63.4
μmol) in MeOH (1.5 mL) were added 1,3-propanedithiol (40 μL, 0.40
mmol) and NEt3 (70 μL, 0.50 mmol). The mixture was heated at 55
°C for 24 h before being allowed to cool to rt and was subsequently
diluted (EtOAc) and quenched (H2O). The product was extracted
(EtOAc), washed (H2O, then brine), dried (Na2SO4), filtered, and
concentrated under reduced pressure to furnish the desired crude
product, which was purified by flash chromatography (60% EtOAc/
peroleum ether) providing 23 (34.5 mg, 87%) as a mixture of
diastereomers as a clear oil: IR νmax (film) 3305, 2932, 2855, 1723,
1653, 1515, 1464, 1249, 1171, 1114, 1038, 1030, 963, 837, 780 cm−1;
1H NMR (500 MHz) δ 0.10 (m, 6H), 0.90 (m, 9H), 1.09 (m, 3H),
1.32 (m, 0.5H), 1.44 (m, 0.5H), 1.91−2.06 (m, 3H), 2.25 (s, 1.5H),
2.26 (s, 1.5H), 2.42 (m, 1H), 2.68 (m, 2H), 2.62−2.73 (m, 0.5H),
2.76−2.84 (m, 1.5H), 2.92 (m, 1H), 3.56−3.64 (m, 1H), 3.69 (m,
1H), 3.81 (s, 3H), 3.85 (m, 2H), 4.07 (m, 1H), 4.19 (m, 1H), 4.95 (m,
2H), 6.34 (d, J = 8.7 Hz, 0.25H), 6.46 (d, J = 8.4 Hz, 0.25H), 6.63 (d, J
= 8.0 Hz, 0.25H), 6.70 (d, J = 7.9 Hz, 0.25H), 6.87−6.90 (m, 3H),
7.32 (d, J = 7.6, Hz, 1H), 7.43 (m, 2H); 13C NMR (125 MHz) δ −5.4,
−5.3, 15.28, 15.31, 16.00, 16.02, 16.5, 18.1, 18.2, 18.3, 18.36, 18.40,
18.43, 22.1, 26.0, 31.20, 31.23, 31.7, 31.8, 33.78, 33.83, 33.9, 34.1, 34.4,
48.0, 48.1, 48.3, 48.4, 49.4, 49.5, 50.1, 50.2, 55.4, 63.1, 63.2, 63.3, 63.5,
64.8, 65.0, 66.7, 66.8, 70.26, 70.29, 70.31, 70.5, 75.7, 81.6, 81.77, 81.82,
81.9, 82.1, 82.2, 113.9, 118.55, 118.63, 118.7, 122.67, 122.71, 129.5,
129.6, 130.6, 130.7, 132.6, 136.1, 136.2, 139.1, 159.0, 159.1, 159.7,
162.9, 163.0, 173.2, 173.3, 173.66, 173.68; HRMS (ESI) m/z [M +
H]+ calcd for C35H50NO7Si 624.3351, found 624.3350.
(3R)-3-((2S)-1-(2-(1-(tert-Butyldimethylsilyloxy)pent-4-yn-2-yl)-
oxazol-4-yl)propan-2-yl)-8-(4-methoxybenzyloxy)-7-methylisochro-
man-1-one (24). Amide alcohol 23 (33.9 mg, 54.3 μmol) was
dissolved in a 1:1 mixture of DMSO (0.5 mL, 7.0 mmol) and CH2Cl2
(0.5 mL) before being cooled to 0 °C. NEt3 (50 μL, 0.359 mmol) and
SO3·pyridine (49.9 mg, 0.314 mmol) were added, and the resultant
mixture was stirred at 0 °C for 90 min. The reaction was quenched
(MeOH), the mixture was diluted (CH2Cl2), and the usual workup
into CH2Cl2 afforded the crude aldehyde, which was used without
further purification. The aldehyde was dissolved in CH2Cl2 (2.5 mL)
and cooled to 0 °C. PPh3 (45.0 mg, 0.172 mmol), 2,6-di-tert-butyl-4-
methylpyridine (61.1 mg, 0.298 mmol), and (BrCl2C)2 (55.9 mg,
0.172 mmol) were added, and the mixture was stirred at 0 °C for 5
min before being allowed to warm to rt and stirred for a further 90
min. i-Pr2NEt (52 μL, 0.299 mmol) was added, and after 90 min the
solvent was removed under reduced pressure. Flash chromatography
1
1715, 1472, 1430, 1258, 1117, 838, 779, 668 cm−1; H NMR (500
MHz) δ 0.09 (s, 6H), 0.89 (s, 9H), 2.00 (t, J = 2.6 Hz, 1H), 2.53 (ddd,
J = 17.0, 8.2, 2.6 Hz, 1H), 2.62 (ddd, J = 17.0, 5.6, 2.6 Hz, 1H), 2.76
(m, 1H), 3.92 (dd, J = 10.0, 5.8 Hz, 1H), 3.98 (dd, J = 10.0, 5.2 Hz,
1H); 13C NMR (125 MHz) δ 5.4, 17.2, 18.3, 25.9, 46.5, 62.2, 70.2,
81.2, 177.1; HRMS (ESI) m/z [M + H]+ calcd for C12H23O3Si
243.14110; Found 243.14108.
(S)-((2R,S-4S)-2-Hydroxy-4-((R)-3-(4-methoxybenzyloxy)-4-meth-
yl-1-oxoisochroman-9-yl)pentyl 2-((tert-Butyldimethylsilyloxy)-
methyl)pent-4-ynoate (21). To a solution of diol 7 (76.4 mg, 0.191
mmol) and acid 8 (52.1 mg, 0.215 mmol) in CH2Cl2 (3.5 mL) at rt
was added DMAP (3.9 mg, 31.9 μmol). The solution was subsequently
cooled to −45 °C, and DIC (53 μL, 0.34 mmol) was added dropwise.
The reaction was stirred at −45 °C for 40 min before being allowed to
warm to rt and stirred for a further 3 h. The reaction was quenched
(MeOH) before being concentrated under reduced pressure. The
crude product was purified by flash chromatography (30% EtOAc/
peroleum ether) to afford the desired ester 21 (94.9 mg, 80%) as a
colorless oil: IR νmax = 3486, 3294, 2949, 2930, 2856, 1726, 1613,
1515, 1464, 1425, 1389, 1249, 1171, 1120, 1036, 966, 837, 779 cm−1;
1H NMR (500 MHz) δ 0.06 (s, 6H), 0.87 (s, 9H), 1.12 (m, 3H), 1.36
(ddd, J = 12.7, 10.1, 2.5 Hz, 0.5H), 1.52 (m, 0.5H), 1.81 (m, 1H), 2.02
(m, 1H), 2.12 (m, 0.5H), 2.22 (m, 0.5H), 2.26 (s, 3H), 2.31 (d, J = 2.7
Hz, 0.25H), 2.37 (d, J = 3.8 Hz, 0.25H), 2.39 (d, J = 4.1 Hz, 0.25H),
2.44 (d, J = 3.1 Hz, 0.25H), 2.56 (m, 2H), 2.70−2.83 (m, 2H), 2.97
(m, 1H), 3.81 (s, 3H), 3.91 (m, 2H), 3.98−4.08 (m, 2H), 4.19−4.26
(m, 2H), 4.96 (m, 2H), 6.88−6.90 (m, 3H), 7.32 (dd, J = 7.7, 3.3 Hz,
1H), 7.44 (d, J = 8.6 Hz); 13C NMR (125 MHz) δ −5.3, 15.39, 15.41,
16.3, 16.4, 16.5, 17.6, 17.7, 18.4, 23.7, 26.0, 31.3, 33.35, 33.36, 34.30,
34.32, 34.96, 35.03, 36.1, 47.20, 47.23, 47.3, 55.4, 62.68, 62.71, 62.8,
67.4, 67.5, 68.5, 68.6, 68.95, 69.02, 69.5, 69.6, 70.2, 75.7, 81.66, 81.68.
81.97, 82.02, 82.1, 113.93, 113.94, 118.7, 122.62, 122.64, 129.57,
129.59, 130.66, 130.69, 130.71, 132.4, 132.5, 136.00, 136.04, 139.1,
139.32, 139.33, 159.0, 159.7, 162.9, 163.1, 172.49, 172.52, 172.6;
HRMS (ESI) m/z [M + Na]+ calcd for C35H48NaO8Si 647.30107,
found 647.30109.
(S)-((2R,S-4S)-2-Azido-4-((R)-8-(4-methoxybenzyloxy)-7-methyl-
1-oxoisochroman-3-yl)pentyl) 2-((tert-Butyldimethylsilyloxy)-
methyl)pent-4-ynoate (22). To a solution of alcohol 21 (69.0 mg,
121
dx.doi.org/10.1021/jo302055w | J. Org. Chem. 2013, 78, 116−123

The Journal of Organic Chemistry
Article
(25% EtOAc/petroleum ether) yielded the desired oxazole 24 (21.4
mg, 65% from alcohol 23) as a clear oil: IR νmax (film) 3299, 2955,
2929, 2857, 1723, 1613, 1579, 1515, 1464, 1427, 1373, 1248, 1170,
160.7, 161.1, 170.5; HRMS (ESI) m/z [M + H]+ calcd for C21H22NO4
352.15433, found 352.15430.
(9R,10S)-8-Deshydroxyajudazol A (3). Enyne 5 (7.5 mg, 21.3
μmol) and vinyl iodide 6 (9.8 mg, 28.1 μmol) were dried
azeotropically from toluene before being dissolved in CH3CN (1.0
mL). Pd(PPh3)2Cl2 (1.4 mg, 2.0 μmol) and CuI (1.0 mg, 5.3 μmol)
were added, and the mixture was degassed with Ar before being cooled
to 0 °C. NEt3 (12 μL, 86.6 μmol) was added and the mixture stirred at
0 °C for 1 h before being allowed to warm to rt and stirred for a
further 24 h. The mixture was diluted (EtOAc) and quenched (pH 7
buffer) before the usual workup into EtOAc to give the crude alkyne,
which was flushed through a plug of silica and taken through to the
next step without further purification. Zn dust (2.50 g, 38.2 mmol) was
suspended in H2O (15 mL) and the mixture degassed with Ar for 15
min. Cu(OAc)2·H2O (0.25 g, 1.25 mmol) was added and the mixture
stirred for 15 min before AgNO3 (0.25 g, 1.47 mmol) was added and
the mixture stirred for an additional 30 min. The solid was filtered and
washed with H2O, MeOH, acetone and Et2O. The slightly Et2O wet
solid was transferred to a round-bottom flask and suspended in a 1:1
mixture of H2O/MeOH (10 mL). 8 mL of the resultant mixture was
added to a solution of the crude alkyne in MeOH (1 mL) and the
mixture stirred at rt for 24 h. The mixture was filtered through Celite,
eluting with MeOH, followed by EtOAc. The crude product was
filtered through a plug of silica before purification by HPLC (5 μm
silica semipreparative column: 10 × 250 mm, 60% EtOAc/petroleum
ether eluent, flow rate: 2.00 mL/min, tR 18.8 min) afforded pure
deshydroxyajudazol A (3) (2.4 mg, 20% from alkyne 5) as a clear oil:
[α]26D +11.5 (c 0.14, CH2Cl2); IR νmax (film) 3390, 2922, 2848, 1667,
1645, 1595, 1454, 1427, 1383, 1292, 1253, 1200, 1174, 1135, 1071,
972, 805, 742 cm−1; 1H NMR (500 MHz, d4-methanol) δ 1.04 (d, J =
6.9 Hz, 3H, C10−CH3), 2.11 (br s, 3H, H29), 2.14−2.21 (m, 5H,
ArCH3 and H22), 2.29 (dt, J = 7.3, 7.2 Hz, 2H, H21), 2.33 (m, 1H,
H10), 2.54 (dd, J = 14.5, 8.9 Hz, 1H, H11), 2.89−2.93 (m, 2.5H, H11
and NCH3), 2.97 (br s, 1.5H, NCH3), 3.02 (m, 2H, H8), 3.37 (d, J =
7.4 Hz, 2H, H16), 3.60 (br s, 1.5H, OCH3), 3.64 (br s, 1.5H, OCH3),
3.94 (m, 2H, H25), 4.51 (ddd, J = 9.1, 6.4, 6.2 Hz, 1H, H9), 5.27 (br s,
0.5H, H27), 5.30 (m, 0.5H, H27), 5.41 (d, J = 1.0 Hz, 1H, C15−CH2),
5.46−5.65 (m, 4H, H17, H20, H23 and H24), 5.96 (d, J = 0.8 Hz, 1H,
C15−CH2), 6.32−6.39 (m, 2H, H18 and H19), 6.73 (d, J = 7.5 Hz,
H6), 7.33 (d, J = 8.2 Hz, H5), 7.65 (s, 1H, H13); 13C NMR (125
MHz) δ 15.3, 15.4, 19.0, 28.2, 29.3, 30.0, 30.5, 30.8, 31.3, 33.1, 33.2,
34.0, 35.8, 37.7, 53.4, 54.8, 55.7, 84.6, 92.3, 108.8, 118.5, 118.9, 124.9,
125.9, 126.3, 126.4, 126.6, 126.7, 128.4, 128.7, 129.3, 133.0, 133.7,
134.6, 136.0, 137.1, 138.1, 138.8, 140.8, 161.4, 163.4, 170.1, 170.2,
170.4, 170.9, 171.2, 171.9; HRMS (ESI) m/z [M + Na]+ calcd for
C34H42NaN2O6 597.29351, found 597.29349.
1
1124, 1037, 962, 836, 778 cm−1; H NMR (500 MHz) δ −0.01 (m,
6H), 0.82 (s, 9H), 1.03 (d, J = 6.9 Hz, 3H), 1.88 (t, J = 2.7 Hz, 0.5H),
1.89 (t, J = 2.9 Hz, 0.5H), 2.26 (s, 3H), 2.29 (m, 1H), 2.51 (m, 1H),
2.69 (m, 2H), 2.81−2.89 (m, 2H), 2.97 (dd, J = 15.1, 12.7 Hz, 1H),
3.20 (m, 1H), 3.81 (s, 3H), 3.93 (ddd, J = 9.9, 6.5, 1.0 Hz, 1H), 3.96
(dd, J = 10.0, 5.5 Hz, 1H), 4.24 (ddd, J = 12.1, 6.1, 2.6 Hz, 1H), 4.94
(d, J = 10.1 Hz, 1H), 4.98 (d, J = 10.1 Hz, 1H), 6.87−6.90 (m, 3H),
7.32 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H), 7.46 (m, 2H); 13C NMR (125
MHz) δ −5.4, 14.1, 15.4, 16.5, 18.3, 19.0, 25.9, 28.5, 31.2, 36.5, 41.7,
55.4, 63.4, 69.9, 75.7, 81.3, 81.4, 81.47, 81.51, 113.9, 118.8, 122.6,
129.6, 130.7, 132.4, 135.0, 136.0, 138.6, 139.3, 159.0, 159.7, 163.1,
163.8; HRMS (ESI) m/z [M + H]+ calcd for C35H46NO6Si 604.3089,
found 604.3088.
(3R)-3-((2S)-1-(2-(1-Hydroxypent-4-yn-2-yl)oxazol-4-yl)propan-2-
yl)-8-(4-methoxybenzyloxy)-7-methylisochroman-1-one (25). A sol-
ution of TBS ether 24 (17.9 mg, 29.6 μmol) in THF (2.0 mL) was
added to a flask containing TBAF·3H2O (15.0 mg, 47.5 μmol). The
resultant mixture was allowed to stir at rt for 6 h before being
concentrated under reduced pressure to afford the crude product.
Flash chromatography (50 − 60% EtOAc/petroleum ether) gave
alcohol 25 (14.4 mg, quant) as a colorless oil: IR νmax (film) 3305,
2926, 1720, 1612, 1564, 1515, 1481, 1463, 1424, 1371, 1301, 1249,
1
1171, 1129, 1037, 825 cm−1; H NMR (500 MHz) δ 1.04 (d, J = 6.9
Hz, 3H), 1.97 (t, J = 2.7 Hz, 0.5H), 1.99 (t, J = 2.7 Hz, 0.5H), 2.26−
2.27 (m, 4H), 2.53 (dd, J = 14.6, 8.5 Hz, 1H), 2.68 (m, 2H), 2.83−
2.90 (m, 2H), 2.97 (dd, J = 16.0, 11.9 Hz, 1H), 3.13 (m, 1H), 3.19 (m,
1H), 3.82 (s, 3H), 4.02 (m, 2H), 4.21 (m, 1H), 4.94 (d, J = 10.0 Hz,
1H), 4.98 (d, J = 10.1 Hz, 1H), 6.89−6.91 (m, 3H), 7.33 (d, J = 7.6
Hz, 1H), 7.40 (s, 1H), 7.46 (m, 2H); 13C NMR (125 MHz) δ 15.6,
16.5, 19.4, 28.5, 29.9, 31.5, 36.5, 40.4, 55.4, 62.8, 70.59, 70.63, 75.7,
80.8, 81.37, 81.38, 113.9, 118.7, 122.7, 129.6, 130.7, 132.6, 135.3,
136.1, 138.6, 139.2, 159.0, 159.8, 163.0, 164.2; HRMS (ESI) m/z [M +
H]+ calcd for C29H32NO6 490.2224, found 490.2223.
(R)-8-(4-Methoxybenzyloxy)-7-methyl-3-((S)-1-(2-(pent-1-en-4-
yn-2-yl)oxazol-4-yl)propan-2-yl)isochroman-1-one (5). NEt3 (5 μL,
36 μmol) and freshly distilled MsCl (5 μL, 65 μmol) were added to a
solution of the alcohol 25 (14.4 mg, 29.4 μmol) in CH2Cl2 (1.0 mL)
at 0 °C, and the resultant mixture was stirred at 0 °C for 1 h before
being allowed to warm to rt and stirred for an additional 1 h. The
mixture was diluted (EtOAc) and quenched (H2O) before the usual
workup into EtOAc to provide the crude mesylate, which was used
without further purification.
The crude mesylate was dissolved in a 1:1 mixture of MeOH (0.5
mL) and CH2Cl2 (0.5 mL) before being cooled to 0 °C. 10-CSA (8.5
mg, 36.6 μmol) was added, and after 5 min the mixture was allowed to
warm to rt and stirred for a further 13 h. The reaction mixture was
diluted (EtOAc) and quenched (H2O) before the usual workup into
EtOAc provided the crude phenol, which was purified by flash
chromatography (40−100% EtOAc/peroleum ether) to give mesylate
26 (12.7 mg, 28.4 μmol, 97% from alcohol 25) as a clear oil. This was
used immediately in the elimination reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of the H and 13C NMR spectra of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
DBU (13.0 μL, 86.9 μmol) was added to a solution of the mesylate
26 (12.7 mg, 28.4 μmol) in CH2Cl2 (1.0 mL) at 0 °C and the resultant
mixture stirred for 50 min before being allowed to warm to rt and
stirred for a further 2.5 h. The mixture was diluted with EtOAc and
quenched (satd aq NH4Cl) before the usual workup into EtOAc gave
the crude product. Flash chromatography (20% EtOAc/peroleum
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: masr@unimelb.edu.au.
Notes
The authors declare no competing financial interest.
ether) yielded alkene 5 (7.5 mg, 75%) as a colorless oil: [α]23 +38.7
D
(c 0.46, CH2Cl2); IR νmax (film) 3299, 2968, 2923, 1671, 1622, 1592,
1532, 1508, 1459, 1427, 1383, 1293, 1253, 1174, 1136, 919, 805 cm−1;
1H NMR (600 MHz) δ 1.06 (d, J = 6.9 Hz, 3H), 2.20 (t, J = 2.6 Hz,
1H), 2.24 (s, 3H), 2.36 (m, 1H), 2.56 (dd, J = 14.5, 8.4 Hz, 1H),
2.83−2.91 (m, 2H), 3.00 (dd, J = 16.1, 12.2 Hz, 1H), 3.45 (s, 2H),
4.45 (ddd, J = 12.1, 6.4, 3.4 Hz, 1H), 5.82 (s, 1H), 6.10 (s, 1H), 6.62
(d, J = 7.3 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.39 (s, 1H), 11.21 (s,
1H); 13C NMR (125 MHz) δ 15.3, 15.6, 22.3, 28.6, 29.8, 36.6, 72.0,
80.1, 82.9, 107.9, 117.5, 118.4, 125.4, 130.8, 135.4, 136.8, 137.0, 139.6,
ACKNOWLEDGMENTS
■
We thank the Australian Research Council Discovery Grants
Scheme (DP110100112) for financial support.
DEDICATION
■
†Dedicated to the memory of Professor Robert E. Ireland, a
great scientist and mentor.
122
dx.doi.org/10.1021/jo302055w | J. Org. Chem. 2013, 78, 116−123

The Journal of Organic Chemistry
Article
(29) Doi, T.; Yoshida, M.; Shin-ya, K.; Takahashi, T. Org. Lett. 2006,
8, 4165.
(30) Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. Helv. Chim. Acta
REFERENCES
■
(1) Reichenbach, H J. Ind. Microbiol. Biotechnol. 2001, 27, 149.
(2) Weissman, K. J.; Muller, R. Biorg. Med. Chem. Lett. 2009, 17,
2129.
̈
1987, 70, 1025.
(31) Brown, C. A.; Ahuja, V. K. J. Chem. Soc. Chem. Commun. 1973,
553.
(3) Hofle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
̈
Reichenbach, H. Angew. Chem., Int. Ed. 1996, 35, 1567.
(32) The original structures assigned to the ajudzols A (1) and B (2)
in ref 5 have the C27 double bond in the E-configuration, i.e., OMe
group is trans to the amide which was assigned based on NOE analysis.
The structures depicted for compounds 1−4 in ref 10 have the 27Z
geometry. We assume these are in error and the correct configuration
for these compounds is 27E.
(33) Note added in proof: A total synthesis of (+)-ajudazol B (2)
was reported following the acceptance of this manuscript which
confirmed the absolute configurations of the ajudazols and
deshydroxyajudazols as enantiomeric to those shown in Figure 1
(4) Barbier, J.; Jansen, R.; Irschik, H.; Benson, S.; Gerth, K.;
Bohlendorf, B.; Hofle, G.; Reichenbach, H.; Wegner, J.; Zeilinger, C.;
̈
̈
Kirschning, A.; Muller, R. Angew. Chem., Int. Ed. 2011, 51, 1256.
̈
(5) Niggemann, J.; Bedorf, N.; Florke, U.; Steinmetz, H.; Gerth, K.;
Reichenbach, H.; Hofle, G. Eur. J. Org. Chem. 2005, 23, 5013.
(6) Schneiker, S.; Perlova, O.; Kaiser, O.; Gerth, K.; Alici, A.;
Altmeyer, M. O.; Bartels, D.; Bekel, T.; Beyer, S.; Bode, E.; Bode, H.
B.; Bolten, C. J.; Choudhuri, J. V.; Doss, S.; Elnakady, Y. A.; Frank, B.;
Gaigalat, L.; Goesmann, A.; Groeger, C.; Gross, F.; Jelsbak, L.; Jelsbak,
L.; Kalinowski, J.; Kegler, C.; Knauber, T.; Konietzny, S.; Kopp, M.;
Krause, L.; Krug, D.; Linke, B.; Mahmud, T.; Martinez-Arias, R.;
see: Essig, S.; Bretzke, S.; Muller, R.; Menche, D. J. Am. Chem. Soc.
̈
2012, DOI: 10.1021/ja309685n.
McHardy, A. C.; Merai, M.; Meyer, F.; Mormann, S.; Munoz-Dorado,
J.; Perez, J.; Pradella, S.; Rachid, S.; Raddatz, G.; Rosenau, F.; Ruckert,
C.; Sasse, F.; Scharfe, M.; Schuster, S. C.; Suen, G.; Treuner-Lange, A.;
̃
̈
Velicer, G. J.; Vorholter, F.-J.; Weissman, K. J.; Welch, R. D.; Wenzel,
̈
S. C.; Whitworth, D. E.; Wilhelm, S.; Wittmann, C.; Blocker, H.;
̈
Puhler, A.; Muller, R. Nat. Biotechnol. 2007, 25, 1281.
̈
̈
(7) (a) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot.
1994, 47, 881. (b) Jansen, R.; Washausen, P.; Kunze, B.; Reichenbach,
H.; Hofle, G. Eur. J. Org. Chem. 1999, 1085.
(8) Jansen, R; Kunze, B; Reichenbach, H.; Hofle, G. Eur. J. Org.
̈
Chem. 2002, 917.
(9) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot.
2004, 57, 151.
(10) Buntin, K.; Rachid, S.; Scharfe, M.; Blocker, H.; Weissman, K. J.;
̈
Muller, R. Angew. Chem., Int. Ed. 2008, 47, 4595.
̈
(11) Buntin, K.; Weissman, K. J.; Muller, R. ChemBioChem 2010, 11,
1137.
(12) Krebs, O.; Taylor, R. J. K. Org. Lett. 2005, 7, 1063.
(13) Ganame, D.; Quach, T.; Poole, C.; Rizzacasa, M. A. Tetrahedron
Lett. 2007, 48, 5841.
(14) (a) Hobson, S. J.; Parkin, A.; Marquez, R. Org. Lett. 2008, 10,
2813. (b) Egan, B. A.; Paradowski, M.; Thomas, L. H.; Marquez, R.
Tetrahedron 2011, 67, 9700.
(15) Birkett, S.; Ganame, D.; Hawkins, B. C.; Meiries, S.; Quach, T.;
Rizzacasa, M. A. Org. Lett. 2011, 13, 1964.
́
(16) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
(17) (a) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(b) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
(18) For the synthesis of a benzomacrolactone by an IMDA reaction,
see: (a) Graetz, B. R.; Rychnovsky, S. D. Org. Lett. 2003, 5, 3357.
Intermolecular Diels−Alder synthesis of benzomacrolactones: (b) Zhi-
Qiang Yang, Z.-Q.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125,
9602. (c) Geng, Z.; Danishefsky, S. J. Org. Lett. 2004, 6, 413.
Intermolecular Diels−Alder isochromanone synthesis: (d) Ghosh, A.
K.; Cappiello, J. Tetrahedron Lett. 1998, 39, 8803.
(19) Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008, 73, 5589.
(20) Yenjai, C.; Isobe, M. Tetrahedron 1998, 54, 2509.
(21) Smissman, E. E.; Voldeng, A. N. J. Org. Chem. 1964, 29, 3161.
(22) Palmer, D. C.; Venkatraman, S. Oxazoles: Synthesis, Reactions,
and Spectroscopy, Part A; John Wiley & Sons, Inc.: Hoboken, 2003.
(23) Viaud, M. C.; Rollin, P. Synthesis 1990, 130.
(24) (a) Denis, J.-N.; Green, A. E.; Serra, A. A.; Luche, M.-J. J. Org.
Chem. 1986, 51, 46. (b) Popsavin, M.; Torovic,
́ ̌ ́
L.; SvircevKojic, V.;
Bogdanovic, G.; Popsavin, V. Biorg. Med. Chem. Lett. 2006, 16, 2773.
́
(25) Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S.; Eguchi, S. J.
Org. Chem. 1989, 54, 431.
(26) Mc Dougal, P.; Rico, J.; Oh, Y. -I.; Condon, B. J. Org. Chem.
1986, 51, 3388.
(27) Dotz, K. H.; Popall, M. Tetrahedron 1985, 41, 5797.
(28) Bayley, H.; Standring, D. N.; Knowles, J. R. Tetrahedron Lett.
1978, 39, 3633.
123
dx.doi.org/10.1021/jo302055w | J. Org. Chem. 2013, 78, 116−123