Towards a total synthesis of ulapualide A. Concise synthetic routes to the tris-oxazole ring system and tris-oxazole macrolide core in ulapualides, kabiramides, halichondramides, mycalolides and halishigamides

Article abstract of DOI:10.1039/b000750L

A range of methods for the synthesis of mono-, bis- and tris-2,4-disubstituted oxazoles were evaluated, which led ultimately to a concise synthesis of the three contiguous oxazole ring system 26 in the ulapualide family of 25-membered macrolides, e.g. 1, found in marine organisms. The tris-oxazole macrolide core 30 in ulapualide A (1) was also synthesised based on a macrolactamisation strategy from the two functionalised mono-oxazole precursors 28 and 29, followed by oxazoline 45 and oxazole ring formation, exploiting the methodologies established in the synthesis of linear bis- and tris-oxazoles in the formation of 18 and 26. The tris-oxazole 26 was converted into the corresponding phosphonium salt 5 in readiness for elaboration to ulapualide A (1). The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b000750L

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Towards a total synthesis of ulapualide A. Concise synthetic routes
to the tris-oxazole ring system and tris-oxazole macrolide core in
ulapualides, kabiramides, halichondramides, mycalolides and
halishigamides
1
Shital K. Chattopadhyay, James Kempson, Alan McNeil, Gerald Pattenden,* Michael Reader,
David E. Rippon and David Waite
School of Chemistry, The University of Nottingham, Nottingham, UK NG7 2RD
Received (in Cambridge, UK) 27th January 2000, Accepted 3rd February 2000
Published on the Web 21st June 2000
A range of methods for the synthesis of mono-, bis- and tris-2,4-disubstituted oxazoles were evaluated, which led
ultimately to a concise synthesis of the three contiguous oxazole ring system 26 in the ulapualide family of
25-membered macrolides, e.g. 1, found in marine organisms. The tris-oxazole macrolide core 30 in ulapualide
A (1) was also synthesised based on a macrolactamisation strategy from the two functionalised mono-oxazole
precursors 28 and 29, followed by oxazoline 45 and oxazole ring formation, exploiting the methodologies
established in the synthesis of linear bis- and tris-oxazoles in the formation of 18 and 26. The tris-oxazole 26
was converted into the corresponding phosphonium salt 5 in readiness for elaboration to ulapualide A (1).
The “ulapualides”, which include the halichondramides,
kabiramides, mycalolides and halishigamides are a novel family
of marine metabolites which show structures based on the
presence of three contiguous oxazole rings incorporated in a
25-membered macrolide ring, to which is attached an acyclic
side chain that terminates in an N-methyl-N-alkenyl formamide
group.1–4 The structures, e.g. ulapualide A 1,1 differ from each
other largely according to the oxidation patterns and alkyl
group substitutions found in their aliphatic portions, e.g.
mycalolide B (2).4 Interestingly, other ulapualides are known
which contain incomplete tris-oxazole chromophores e.g. 33
and 4.5
unprecedented. Indeed, in earlier overtures we have even
suggested that some of the unique biological properties of these
molecules are associated with their capacity to sequester and
transport metal ions, i.e. behave as ionophores, using the several
oxazole nitrogen and side chain oxygen ligand binding sites
present in their structures.7 The combination of a unique and
unprecedented chemical structure with novel biological proper-
ties lured us to attempt a total synthesis of the founder member,
ulapualide A (1), of this intriguing family of marine metabolites.8
In this paper we focus our attention on the development of
suitable synthetic routes to the three contiguous oxazole ring
system in the natural product, specifically the doubly function-
alised tris-oxazole 5,9 and in the accompanying paper we
describe the extension of this work culminating in a total
Although oxazoles are now found quite commonly in nature,6
the tris-oxazole unit present in the ulapualides remains
DOI: 10.1039/b000750l
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428
This journal is © The Royal Society of Chemistry 2000
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synthesis of ulapualide A, with the relative stereochemistry
shown in structure 1.10
oxidation steps, instead of the more ambitious one-pot, 7→6,
approach.9
The tris-oxazole unit 6 (cf. 5) in the ulapualides is most likely
derived in nature by cyclodehydration of an appropriately
substituted tris-serine precursor, e.g. 7, leading to the corre-
sponding tris-oxazoline, followed by enzymic oxidation.11
A related bis-oxazole unit is found in the natural product
hennoxazole A 8 isolated from Polyfibrospongia sp.,6 and
muscoride A 9 found in the freshwater cyanobacterium Nostac
muscorum6 shows a bis-oxazole core which is formally derived
from two threonine residues. Our first approach to the differ-
entially functionalised tris-oxazole 5 was indeed based on
the aforementioned biogenetic pathway but utilised three
molecules of serine in three sequential oxazoline cyclisation–
Thus, condensation between serine ethyl ester hydrochloride
10 and ethyl acetimidate hydrochloride 11 in the presence of
triethylamine first led to the oxazoline 12 (Scheme 1),12 which
on oxidation with nickel peroxide in hot benzene, according to
the method of Meyers et al.,13 gave the mono-oxazole ester 13a.
The same substituted oxazole 13a could also be obtained from
ethyl acetimidate hydrochloride following condensation with
glycine ester hydrochloride leading to 14, followed by formyl-
ation (to 15) and acid-catalysed cyclisation, as described by
Cornforth and Cornforth.14 Saponification of 13a, followed
by conversion of the resulting carboxylic acid 13b into the
corresponding acid chloride 13c and treatment with a second
Scheme 1
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Scheme 2
molecule of serine ester hydrochloride next provided the
With the tris-oxazole 26 to hand, treatment with N-bromo-
mono-oxazole serine amide 16a. Treatment of 16a with thionyl
chloride at 0 ЊC then led to the alkyl chloride 16b which could
be cyclised to the oxazole-oxazoline 17a in the presence of 1.2
equivalents of silver triflate.15 Oxidation of 17a using nickel
peroxide in hot benzene then provided the bis-oxazole 18 as
colourless crystals, albeit in only 27% yield. More satisfactory
methods for the “oxidation” of 17a to 18 were either to use
N-bromosuccinimide with irradiation from a sun lamp,16 or
alternatively to convert 17a into the corresponding phenyl-
selenyl derivative 17b, then oxidise the latter to the selenoxide
and eliminate the elements of phenylselenic acid.17 Finally, the
same bis-oxazole ester 18 could be produced from the alkyl
chloride 16b following conversion into the alkene 19, bromin-
ation–dehydrobromination of 19 to the vinyl bromide 20, and
cyclisation of the latter in the presence of copper() bromide
and caesium carbonate.18
Repetition of the sequences detailed above i.e. acid chloride
21b formation (from 18), reaction with serine ester hydro-
chloride (to 22a), chlorination (to 22b), cyclisation to 23a and
oxidation (direct or via 23b), or alternatively conversion of 22b
into 24 followed by bromination–dehydrobromination (to 25)
and cyclisation, was then applied to convert the bis-oxazole ester
18 into the target tris-oxazole ester 26 (Scheme 2), which was
secured as a white solid, mp 222–224 ЊC. In a slight modific-
ation to the synthesis of 18 and 26 from similar starting
materials, the amide 13d derived from 13c could be converted
into the oxazole-oxazoline 17c in one step by condensation with
serine ethyl ester hydrochloride in the presence of triethyloxo-
nium tetrafluoroborate, and likewise the amide 21c into 23c by
similar chemistry.
succinimide and AIBN with irradiation from a 300 W sun
lamp at reflux in carbon tetrachloride for 24 h, next led to the
corresponding oxazolylmethyl bromide 27 which, on reaction
with triphenylphosphine, finally led to the target tris-
oxazole phosphonium salt 5 in readiness for elaboration to
ulapualide A. These studies are described in the accompanying
paper.10
Preliminary details of the aforementioned synthesis of the
tris-oxazole unit 26 in the ulapualides were described in 1990.9
Other approaches to the same unit have been described more
recently, which highlight the scope for the Hantzsch oxazole
synthesis19 and for [3 ϩ 2] cycloaddition reactions of acyl
carbenes to nitriles20 in the elaboration of oxazoles. Like our
own approach however, these alternative methods are used in a
linear, step-wise fashion. A more attractive proposition would
be to develop a convergent approach to the tris-oxazole unit in
the ulapualides, which would permit the elaboration of the
central oxazole ring as a final step and in an intramolecular
fashion. We felt this objective could be achieved based on a
macrolactamisation strategy from two appropriately function-
alised mono-oxazole precursors, followed by oxazoline and
oxazole ring formation exploiting the methodologies we had
established in the synthesis of the polyoxazoles 18 and 26; this
sequence is shown diagramatically in Scheme 3. Such an
approach would offer an attractive alternative strategy for
elaboration of the tris-oxazole macrolide core in the ulapu-
alides. Accordingly, we examined the scope for this approach
using the substituted mono-oxazoles 28 and 29 as key pre-
cursors, with a view to the synthesis of the model tris-oxazole
macrolide 30 (Scheme 4).
Scheme 3
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428
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Scheme 4
Scheme 5 Reagents and conditions: i, SerineOMeؒHCl, Et3N, 0 ЊC then DCC, 74%; ii, Burgess’ reagent, THF, 75%, iii, BrCCl3, DBU, 0–25 ЊC, 75%;
iv, DIBAL-H; v, PySO3 in DMSO, Et3N, 60%; vi, Ba(OH)2ؒ8H2O, 14, THF, 71%; vii, Me2CuLi, Et2O, Ϫ5 ЊC, 55%; viii, LiOH, THF, H2O, 98%.
Thus, treatment of the serine-derived oxazolidine carboxylic
acid 31 (Garner’s acid)21 with serine methyl ester hydrochloride
first gave the corresponding amide 32 which on reaction
with Burgess’ reagent22 led to the oxazoline 33 as a mixture of
diastereoisomers (Scheme 5). “Oxidation” of this mixture using
BrCCl3–DBU23 then gave the oxazole 34a which, following
reduction to the corresponding aldehyde 34b and Wadsworth–
Emmons olefination using the ketophosphonate 35,24 was
converted into the E-enone 36. The addition of lithium dimeth-
ylcuprate to the enone 36 next led to an unresolved mixture of
diastereoisomers of the ketoester 37 which on saponification
gave the carboxylic acid 29, in readiness for esterification with
the oxazole substituted primary alcohol 28.
The oxazole substituted primary alcohol 28 was prepared
from the known 2-methyloxazole 13a following initial conver-
sion into the corresponding phosphonium salt 38, followed by a
Wittig reaction between 38 and 5-tert-butyldimethylsilyl-
Scheme 6 Reagents and conditions: i, NBS–AIBN, 41%; ii, PPh3, 82%;
pentanal 3925 using butyllithium as base, to produce the
iii, BuLi, Et2O, Ϫ78 ЊC; iv, 5-tert-butyldimethylsilylpentanal 39, 45%; v,
E-alkene 40a almost exclusively. Saponification of 40a followed
by protection of the resulting carboxylic acid 40b as the corre-
sponding allyl ester 41 and removal of the tert-butyldimeth-
ylsilyl protection then gave the oxazole substituted primary
alcohol 28, suitably protected at the oxazole carboxylic ester
terminus for deprotection under mild palladium(0) catalysis
(Scheme 6).26
Esterification of the mono-oxazole carboxylic acid 29 with
the mono-oxazole alcohol 28 in the presence of l-ethyl-3-[3-
(dimethylamino)propyl]carbodiimide hydrochloride containing
4-(dimethylamino)pyridine next led to the ester 42 in a satis-
factory 73% yield (Scheme 7), which was then deprotected
sequentially using palladium(0) pyrrolidine (70% to the carb-
oxylic acid) followed by 50% trifluoroacetic acid, leading to the
trifluoroacetate salt of the amino acid 43.
LiOH, THF–H2O, 99%; vi, Allylbromide, NaHCO3, H2O, 51%; vii,
AcOH, THF, H2O, 91%.
unoptimised 20% yield, by treatment with diphenylphosphoryl
azide in the presence of diisopropylethylamine under high
dilution.27 Cyclodehydration of 44 using Burgess’ reagent
followed by oxidation of the resulting oxazole-oxazoline-
oxazole macrolide 45 in the presence of nickel peroxide, finally
led to target tris-oxazole macrolide 30 (Scheme 7). This altern-
ative approach to the macrolide core found in the ulapualides,
kabiramides, halichondramides, mycalolides, and halishig-
amides has many attractions over the linear approach to
tris-oxazoles used in our total synthesis of the ulapualide A
stereostructure 1. We have plans in place to develop this
protocol in a second generation synthesis of the ulapualides,
which will be described in due course.
The macrolactamisation of 43 to 44 was accomplished, in an
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Scheme 7 Reagents and conditions: i, EDCؒHCl, DMAP, 0 ЊC, 73%; ii, Pd(0)–pyrrolidine, 70%; iii, 50% TFA solution in CH2Cl2; iv, DPPA, DIPEA,
DMF, 20%; v, Burgess’ reagent, THF; vi, NiO2, C6H6, 46%.
Commonly used organic solvents were dried by distillation
from the following: THF (sodium benzophenone ketyl),
dichloromethane (calcium hydride) and methanol (magnesium
methoxide). Other organic solvents and reagents were purified
by accepted literature procedures. Solvents were removed on
a Büchi rotary evaporator using water aspirator pressure.
Petrol refers to light petroleum with distillation range 40–60 ЊC.
Where necessary, reactions requiring anhydrous conditions
were performed in a flame dried apparatus under a nitrogen
atmosphere. A Büchi GKR-50 Kugelröhr apparatus was used
for bulb-to-bulb distillations.
Experimental
General details
[All mps were determined on a Kofler hot stage apparatus and
are uncorrected. Optical rotations were measured on a JASCO
DIPA-370 polarimeter; [α]D values are recorded in units of 10Ϫ1
deg cm2 gϪ1. Ultraviolet spectra were recorded on a Philips PU
8720 spectrophotometer as dilute solutions in spectroscopic
grade ethanol; ε values are recorded in units of dm3 molϪ1 cmϪ1
.
Infrared spectra were obtained using a Perkin-Elmer 1600
series FT-IR instrument as either potassium bromide discs,
liquid films or as dilute solutions in spectroscopic grade chloro-
form. Proton NMR spectra were recorded on either a Bruker
WM250 (250 MHz), a Bruker AM400 (400 MHz), a Bruker
DRX (500 MHz) or a JEOL EX-270 (270 MHz) spectrometer
as dilute solutions in deuterochloroform or d6-dimethyl sulf-
oxide. Chemical shifts are recorded relative to a solvent
standard and the multiplicity of a signal is designated by one of
the following abbreviations: s = singlet; d = doublet; t = triplet;
q = quartet; br = broad; m = multiplet. All coupling constants,
J, are reported in Hertz. Carbon-13 NMR spectra were
recorded on either a Bruker AM400 (100.6 MHz) or JEOL
EX-270 (67.8 MHz) instrument. The spectra were recorded as
dilute solutions in deuterochloroform or d6-dimethyl sulfoxide
with chemical shifts reported relative to a solvent standard on a
broad band decoupled mode and the multiplicities obtained
using a DEPT sequence. The following symbolisms are used for
the multiplicities in carbon-13 spectra: q = primary methyl;
t = secondary methylene; d = tertiary methine; s = quarternary.
Where required, assignment for 1H and 13C NMR spectra were
confirmed by two-dimensional homonuclear (1H) and/or
heteronuclear (1H/13C) correlation spectroscopy. Matrix dimen-
sions for two dimensional spectra were either 1024 points × 256
columns (homonuclear 1H) or 2048 points × 128 columns
2-Methyl-4,5-dihydro-1,3-oxazole-4-carboxylic acid ethyl ester
12
A solution of triethylamine (10.1 g, 100 mmol) in dry CH2Cl2
(25 ml) was added dropwise over 30 min to a stirred suspension
of ethyl acetimidate hydrochloride (6.2 g, 50 mmol) and
-serine ethyl ester hydrochloride (8.45 g, 50 mmol) in dry
CH2Cl2 (100 ml) at 25 ЊC. The mixture was stirred overnight
and then the solvents were removed in vacuo. The residue was
washed with diethyl ether (3 × 25 ml) and the ethereal solution
was then dried (MgSO4) and evaporated to dryness. The residue
was purified by Kugelröhr distillation under reduced pressure
to give the oxazoline (5.89 g, 75%) as a pale yellow oil, bp
100–110 ЊC at 11 mmHg (lit. bp12 98.5–100 ЊC at 11 mmHg);
νmax(film)/cmϪ1 1735 and 1665; δH(250 MHz, CDCl3) 4.8–4.2
(3H, m), 4.21 (2H, q, J 7 Hz), 2.0 (3H, s) and 1.35 (3H, t, J 7 Hz).
[(1-Ethoxyethylidene)amino]acetic acid ethyl ester 14
Using a modification of the Cornforth procedure,14 a cooled
(0 ЊC) suspension of ethyl acetimidate hydrochloride 11 (25.0 g,
0.2 mol) in ether (100 ml) was shaken for 5 min in a separating
funnel with a cooled (0 ЊC) solution of potassium carbonate
(33.1 g, 0.24 mol) in water (70 ml). The separated aqueous
phase was extracted with diethyl ether (30 ml) and a cooled
(0 ЊC) solution of glycine ethyl ester hydrochloride (28.2 g,
0.2 mol) in water (30 ml) was then added to the combined ether
extracts with further shaking for 15 min. The separated
aqueous layer was once again extracted with diethyl ether
(30 ml) and the combined ether phases were washed with water
(3 × 30 ml), then dried (MgSO4) and evaporated in vacuo to
leave a yellow oil which was distilled to give the imino ether
(20.7 g, 59%) as a colourless liquid, bp 90 ЊC at 10 mmHg (lit.
bp14 85–86 ЊC at 7.5 mmHg); νmax(film)/cmϪ1 1745 and 1677;
δH(250 MHz, CDCl3) 4.24–4.09 (4H, m), 4.04 (2H), 1.88 (:CMe)
and 1.31–1.24 (6H, m); δC(69.2 MHz, CDCl3) 171.2 (q), 164.8
1
(heteronuclear H/13C), and were recorded on a JEOL EX-270
instrument. Mass spectra were recorded on a AE1 MS-902,
MM-70E or VG Autospec spectrometer using electron ionis-
ation (EI) or fast atom bombardment (FAB) techniques.
Microanalytical data were obtained on a Perkin-Elmer 240B
elemental analyser. Flash chromatography was performed on
Merck silica gel 60 as the stationary phase and the solvents
employed were either of analytical grade or were distilled before
use. All reactions were monitored by TLC using Merck silica
gel 60 F254 precoated plastic backed plates, which were visual-
ised with ultraviolet light and then with either vanillin solution,
basic potassium permanganate solution, or phosphomolybdic
acid solution.
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428
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(q), 60.9 (d), 60.8 (d), 51.3 (d), 15.2 (t), 14.2 (t) and 14.2 (t)
in vacuo, and the residue was then azeotroped with toluene to
(Found: m/z (EI) 173.1072. C8H15NO3 requires M, 173.1052).
give the corresponding acid chloride 13c as a cream solid, which
was used immediately without further purification. A solution
of the acid chloride in dry dichloromethane (25 ml) was added
dropwise over 15 min to a stirred solution of -serine methyl
ester hydrochloride (7.15 g, 46 mmol) and triethylamine (12.8
ml, 92 mmol) in dry dichloromethane (50 ml) under a nitrogen
atmosphere at 0 ЊC. The mixture was stirred for 20 h at ambient
temperature and then evaporated in vacuo. The residue was
diluted with saturated sodium hydrogen carbonate solution
(30 ml), then extracted with ethyl acetate (4 × 30 ml) and the
combined organic phases were washed with saturated brine
(30 ml), then dried (MgSO4) and evaporated in vacuo to leave
the oxazole serine derivative (7.3 g, 77%) as a light brown solid.
A small portion was purified by chromatography on silica to
give the product as a white crystalline solid, mp 97–98 ЊC (ethyl
acetate–petrol) (Found: C, 47.2; H, 5.4; N, 12.1. C9H12N2O5
requires C, 47.4; H, 5.3; N, 12.3%); λmax(EtOH)/nm 222 (3330)
and 233sh (3290); νmax(CHCl3)/cmϪ1 3405 br, 1746, 1674, 1601,
1509 and 1106; δH(250 MHz, CDCl3) 8.09 (1H, s, 5Ј-H), 7.70
(1H, br d, J 7.4 Hz, NH), 4.81 (1H, ddd, J 7.4, 3.7 and 3.7 Hz,
4-H), 4.15–3.95 (2H, m, 5-H), 3.81 (3H, s, CO2Me), 2.91 (1H, br
t, J 5.6 Hz, OH) and 2.48 (3H, s, 2Ј-Me); δC(67.8 MHz, CDCl3)
170.5 (s, 2-C), 161.6 (s, CO2Me), 160.8 (s, 2Ј-C), 141.3 (d, 5Ј-C),
135.3 (s, 4Ј-C), 62.7 (t, 5-C), 54.3 (d, 4-C), 52.6 (q, CO2Me)
and 13.6 (q, 2Ј-Me); m/z (EI) 210 (Mϩ Ϫ H20, 4%), 198 (17), 197
(7), 169 (21), 110 (100) and 82 (11) (Found: m/z 198.0592
(Mϩ Ϫ H2O). C8H10N2O4 requires M, 198.0582).
2-Methyl-1,3-oxazole-4-carboxylic acid ethyl ester 13a
(a) Using a modification of the Cornforth procedure,14 a solu-
tion of the imino ether 14 (69.1 g, 0.40 mol) in dry THF (150
ml) was added dropwise over 40 min to a stirred suspension of
potassium tert-butoxide (49.2 g, 0.44 mol) in dry THF (150 ml)
under a nitrogen atmosphere at Ϫ10 ЊC. Ethyl formate (35.5 ml,
0.44 mol) was added sequentially and after stirring at Ϫ10 ЊC
for 1 h, dry diethyl ether (100 ml) was added to the brown
solution. The mixture was held at this temperature for 1 h and
was then evaporated in vacuo to leave the potassium enolate
salt 15 as a hygroscopic yellow solid. Hot acetic acid (110 ml)
was added to the vigorously stirred residue and reflux was
maintained for 15 min before the mixture was cooled to room
temperature. The resulting orange solid was dissolved in water
(500 ml) and the solution was then basified cautiously with
solid potassium carbonate before the aqueous mixture was
extracted with diethyl ether (3 × 300 ml). The combined organic
phases were washed with saturated brine (100 ml), then dried
(MgSO4) and evaporated in vacuo to leave a yellow liquid.
Distillation of the crude material gave the oxazole ester (50.4 g,
81%), as a straw coloured liquid, bp 106–110 ЊC at 20 mmHg
(lit. bp14 106–110 ЊC at 12 mmHg) (Found: C, 54.2; H, 5.8; N,
8.8. C7H9NO3 requires C, 54.2; H, 5.8; N, 9.0%); λmax(EtOH)/
nm 217 (4760); νmax(film)/cmϪ1 1738, 1592 and 1109; δH(270
MHz, CDCl3) 8.12 (1H, s, 5-H), 4.37 (2H, q, J 7 Hz, OCH2-
CH3), 2.50 (3H, s, 2-Me) and 1.37 (3H, t, J 7 Hz, OCHCH3);
δC(67.8 MHz, CDCl3) 162.0 (s, CO), 160.9 (s, 2-C), 143.4 (d,
5-C), 133.1 (s, 4-C), 60.7 (t, OCH2CH3), 13.9 (q, OCH2CH3)
and 13.4 (q, 2-Me); m/z (EI) 155 (Mϩ, 21%), 126 (2), 110 (57)
and 82 (12) (Found: m/z 155.0619. C7H9NO3 requires M
155.0582).
3-Chloro-2-[(2-methyl-1,3-oxazol-4-ylcarbonylamino]propionic
acid methyl ester 16b
Thionyl chloride (3 ml) was added cautiously to the oxazole
serine derivative 16a (1.0 g, 4.4 mmol) under a nitrogen atmos-
phere at 0 ЊC and the solution was then stirred at ambient
temperature for 12 h. The excess thionyl chloride was evapor-
ated in vacuo to leave a residue which was quenched with water
(25 ml). The aqueous mixture was extracted with ethyl acetate
(3 × 30 ml) and the combined organic extracts were washed
with saturated brine (30 ml), then dried (MgSO4) and evapor-
ated in vacuo to leave the oxazole serine chloride (1.04 g, 96%) as
a cream solid. A small portion was recrystallised to give a white
crystalline solid, mp 104–105 ЊC (from ethyl acetate–petrol)
(Found: C, 43.9; H, 4.6; N, 11.5. C9H11ClN2O4 requires C, 43.8;
H, 4.5; N, 11.4%); λmax(EtOH)/nm 214 (10240); νmax(CHCl3)/
cmϪ1 3401, 1751, 1678, 1600, 1505 and 1107; δH(250 MHz,
CDCl3) 8.07 (1H, s, 5Ј-H), 7.64 (1H, br d, J 7.8 Hz, NH), 5.09
(1H, ddd, J 7.8, 3.6 and 3.4 Hz, 4-H), 4.01 (1H, dd, J 11.3 and
3.4 Hz, 5-H), 3.90 (1H, dd, J 11.3 and 3.6 Hz, 5-H), 3.78 (3H, s,
CO2Me) and 2.44 (3H, s, 2Ј-Me); δC(67.8 MHz, CDCl3) 168.8
(s, 2-C), 161.5 (s, CO2Me), 160.3 (s, 2Ј-C), 141.1 (d, 5Ј-C), 135.3
(s, 4Ј-C), 52.9 (d, 4-C), 52.6 (q, CO2Me), 44.8 (t, 5-C) and 13.6
(q, 2Ј-Me); m/z (EI) 211 (Mϩ Ϫ Cl, 9%), 210 (9), 189 (32), 187
(82), 151 (42), 123 (18) and 110 (100) (Found: m/z 194.0283.
C8H9N2O3 requires M, 194.0275).
(b) Nickel peroxide (5 × 1 g) was added portionwise over 2 h
to a stirred refluxing solution of the oxazoline 12 (5.1 g, 33
mmol) in dry hexane (60 ml) under a nitrogen atmosphere. The
mixture was stirred at reflux for a further 2 h and the hot
solution was filtered through a Celite pad and then washed with
hot ethyl acetate. The combined filtrates were evaporated in
vacuo, and the residue was purified by distillation to give the
oxazole (2.1 g, 41%) as an oil which showed identical spectro-
scopic data to those described under (a).
2-Methyl-1,3-oxazole-4-carboxylic acid 13b
Using a modification of the Cornforth procedure,14 a solution
of potassium hydroxide (4.34 g, 77 mmol) in water (20 ml) was
added in one portion to ethyl 2-methyl-1,3-oxazole-4-carb-
oxylate 13a (10 g, 64 mmol) and the mixture was then heated
under reflux for 1 h. The mixture was cooled to ambient
temperature over 1 h and then evaporated in vacuo. The residue
was acidified with concentrated hydrochloric acid (to pH 1) and
then cooled in ice for 30 min. The precipitate was filtered and
freeze dried to leave the oxazole acid (5.4 g, 66%) as a white
crystalline solid, mp 180–181 ЊC (water) (lit. mp14 183–184 ЊC)
(Found: C, 47.3; H, 4.1; N, 10.9. C5H5NO3 requires C, 47.2; H,
4.0; N, 11.0%); λmax(EtOH)/nm 213 (5610); νmax(KBr disc)/cmϪ1
3436, 1718, 1590, 1164, 1107 and 984; δH(270 MHz, d6-DMSO)
12.96 (1H, br s, CO2H), 8.58 (1H, s, 5-H) and 2.43 (3H, s,
2-Me); δC(67.8 MHz, d6-DMSO) 162.5 (s, CO2H), 162.2 (s,
2-C), 145.2 (d, 5-C), 133.5 (s, 4-C) and 13.7 (q, 2-Me); m/z (EI)
127 (Mϩ, 54%), 110 (11) and 82 (7) (Found: m/z 127.0287.
C5H5NO3 requires M, 127.0269).
2-[(2-Methyl-1,3-oxazol-4-ylcarbonyl)amino]acrylic acid methyl
ester 19
1,8-Diazabicyclo[5.4.0]undec-7-ene (4.3 ml, 28.6 mmol) was
added dropwise over 10 min to a stirred solution of the serine
chloride 16b (7.1 g, 28.6 mmol) in dry dichloromethane (70
ml) under a nitrogen atmosphere at ambient temperature. The
yellow solution was stirred for 3 h, then washed with dilute
hydrochloric acid (2 M, 2 × 30 ml) and the separated organic
layer was dried (MgSO4) and then evaporated in vacuo to leave
the olefin (1.6 g, 95%) as a white solid; a small sample was
recrystallised from 1:1 ether–hexane, mp 128–129 ЊC (Found:
C, 51.3; H, 4.7; N, 13.1. C9H10N2O4 requires C, 51.4; H, 4.8;
N, 13.3%); λmax(EtOH)/nm 222 (11260) and 259 (11640);
νmax(CHCl3)/cmϪ1 3370, 1724, 1685, 1592, 1519 and 1106;
3-Hydroxy-2-[(2-methyl-1,3-oxazol-4-ylcarbonyl)amino]-
propionic acid methyl ester 16a
Thionyl chloride (25 ml) was added to the oxazole acid 13b (5.3
g, 42 mmol) with stirring, and the mixture was then heated
under reflux for 4 h. The excess thionyl chloride was removed
2420
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428

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δH(250 MHz, CDCl3) 9.19 (1H, br s, NH), 8.12 (1H, s, 5Ј-H),
6.71 (1H, s, 5-H), 5.97 (1H, s, 5-H), 3.89 (3H, s, CO2Me) and
2.50 (3H, s, 2Ј-Me); δC(67.8 MHz, CDCl3) 163.9 (s, 2-C), 161.3
(s, CO2Me), 159.0 (s, 2Ј-C), 141.1 (d, 5Ј-C), 135.9 (s, 4Ј-C),
130.7 (s, 4-C), 108.9 (t, 5-C), 52.8 (q, CO2Me) and 13.5 (q,
2Ј-Me); m/z (EI) 210 (Mϩ, 31%), 195 (5), 179 (3), 178 (10), 151
(4) and 110 (100).
eluent to give the selenide (433 mg, 45%) as a yellow oil;
νmax(thin film)/cmϪ1 1729, 1644, 1597 and 1439; δH(270 MHz,
CDCl3) 8.01 (1H, s), 7.75–7.53 (2H, m), 7.30–7.17 (3H, m), 4.78
(1H, d, J 10.6 Hz, CHH), 4.56 (1H, d, J 10.6 Hz, CHH), 3.7
(3H, s, OMe) and 2.42 (3H, 2Ј-Me); δC(67.8 MHz, CDCl3) 169.8
(s), 162.3 (s), 159.8 (s), 143.5 (s), 141.7 (d), 139.2 (s), 137.7 (d),
129.7 (d), 128.9 (d), 126.3 (s), 75.5 (t), 53.0 (q) and 13.7 (q); m/z
(FAB) (Found: m/z 209 (Mϩ Ϫ PhSe). C9H9O4N2 requires M
209, 20%), 103 (52), 81 (48) and 43 (100). The selenide was
found to partially oxidise and eliminate to the bi-oxazole ester
18 upon standing overnight.
3-Bromo-2-[(2-methyl-1,3-oxazol-4-ylcarbonyl)amino]acrylic
acid methyl ester 20
A solution of bromine (0.4 ml, 7.7 mmol) in dry dichlorometh-
ane (12 ml) was added dropwise over 2 h to a stirred solution of
the olefin 19 (1.6 g, 7.7 mmol) in dry dichloromethane (49 ml)
under a nitrogen atmosphere at Ϫ78 ЊC. Triethylamine (1.1 ml,
7.7 mmol) was added in one portion and the mixture was then
warmed to ambient temperature over 2 h. The mixture was
washed with saturated brine (30 ml), then dried (MgSO4) and
evaporated in vacuo to leave an orange gum. Purification by
chromatography on silica using 2:1 diethyl ether–petrol as
eluent gave the vinyl bromide (2.1 g, 91%) as a white crystalline
solid, mp 107–108 ЊC (ether–petrol) (Found: C, 37.6; H, 3.2; N,
2Ј-Methyl-4,5-dihydro-2,4Ј-bi(1,3-oxazolyl)-4-carboxylic acid
ethyl ester 17c
Triethyloxonium tetrafluoroborate (11 ml of a 1 M solution in
CH2Cl2, 11 mmol) was added to a suspension of 2-methyl-
oxazole-4-carboxamide28 (1.26 g, 10 mmol) in dry dichloro-
methane (25 ml) and the resulting solution was stirred under
nitrogen atmosphere for 6 h. -Serine ethyl ester hydrochloride
(1.70 g, 10 mmol) and triethylamine (2.80 ml, 22 mmol) were
introduced and the mixture was then stirred overnight at ambi-
ent temperature. The mixture was evaporated to dryness in
vacuo to leave an off-white solid which was preadsorbed onto
silica and purified by flash chromatography using 2% methanol
in chloroform as eluent to give the product (210 mg, 10%) as a
pale yellow oil (starting material (720 mg, 43%) was also
recovered); νmax(film)/cmϪ1 1735, 1670 and 1585; δH(400 MHz,
CDCl3) 8.08 (1H, s, 5Ј-H), 4.90 (1H, dd, J 11 and 8 Hz, 4-H),
4.66 (1H, dd, J 9 and 11 Hz, 5-H), 4.58 (1H, dd, J 11 and 9 Hz,
5-H), 4.25 (2H, m, CH2CH3), 2.51 (3H, s, 2Ј-Me) and 1.31 (3H,
t, J 7 Hz, CH2CH3); δC(67.8 MHz, CDCl3) 170.7 (s), 162.4 (s),
159.9 (s), 141.1 (d), 129.9 (s), 69.6 (t), 68.5 (d), 61.7 (t), 14.0 (q)
and 13.6 (q) (Found: m/z 224.0788. C10H12N2O4 requires M,
224.0795).
9.9. C9H9BrN2O4 requires C, 37.4; H, 3.1; N, 9.7%); λmax
-
(EtOH)/nm 222 (4560) and 255 (4570); νmax(CHCl3)/cmϪ1 3376,
1737, 1696, 1625, 1595 and 1111; δH(270 MHz, CDCl3) 8.30
(1H, br s, NH), 8.15 (1H, s, 5Ј-H), 7.19 (1H, s, 5-H), 3.83 (3H, s,
CO2Me) and 2.50 (3H, s, 2Ј-Me); δC(67.8 MHz, CDCl3) 162.0
(s, 2-C), 161.4 (s, CO2Me), 157.8 (s, 2Ј-C), 141.7 (d, 5Ј-C), 134.7
(s, 4Ј-C), 131.3 (s, 4-C), 113.3 (d, 5-C), 52.6 (q, CO2Me) and
13.4 (q, 2Ј-Me); m/z (EI) 259, 257 (Mϩ Ϫ OMe, 2 and 2%), 209
(88), 110 (100) and 82 (20).
2Ј-Methyl-4,5-dihydro-2,4Ј-bi(1,3-oxazolyl)-4-carboxylic acid
methyl ester 17a
Silver trifluoromethanesulfonate (13.7 g, 53 mmol) was added
in one portion to a stirred solution of the oxazole serine chlor-
ide 16b (11.15 g, 45 mmol) in dry benzene (225 ml) at room
temperature under a nitrogen atmosphere. The suspension was
heated under reflux for 6 h, then cooled to ambient temperature
and evaporated in vacuo. The residue was partitioned between
ethyl acetate (300 ml) and saturated sodium bicarbonate solu-
tion (300 ml), with vigorous stirring for 30 min. The separated
aqueous layer was extracted with ethyl acetate (3 × 200 ml) and
the combined organic phases were then washed with saturated
sodium bicarbonate solution (3 × 150 ml). The second aqueous
extract was washed further with ethyl acetate (3 × 100 ml) and
the combined organic phases were then dried (MgSO4) and
evaporated in vacuo to leave the oxazole-oxazoline (9.50 g, 99%)
as a straw coloured oil; νmax(CHCl3)/cmϪ1 2956, 1741, 1675,
1587, 1216 and 1108; δH(250 MHz, CDCl3) 8.07 (1H, s, 5Ј-H),
4.93 (1H, dd, J 10.5 and 7.9 Hz, 4-H), 4.68 (1H, dd, J 8.6 and
7.9 Hz, 5-H), 4.56 (1H, dd, J 10.5 and 8.6 Hz, 5-H), 3.80 (3H, s,
CO2Me) and 2.50 (3H, s, 2Ј-Me); δC(67.8 MHz, CDCl3) 170.1
(s, 2-C), 161.5 (s, CO2Me), 158.9 (s, 2Ј-C), 140.3 (d, 5Ј-C), 128.7
(s, 4Ј-C), 68.6 (t, 5-C), 67.1 (d, 4-C), 51.4 (q, CO2Me) and 12.4
(q, 2Ј-Me); m/z (EI) 210 (Mϩ, 5%), 151 (61), 126 (100), 110 (25)
and 82 (14) (Found: m/z 210.0651. C9H10N2O4 requires M,
210.0648).
2Ј-Methyl-2,4Ј-bi(1,3-oxazolyl)-4-carboxylic acid methyl ester
18a
(a) Nickel peroxide (5 × 790 mg, Aldrich) was added portion-
wise over 2.5 h to a stirred refluxing solution of the oxazole-
oxazoline 17a (3.9 g, 18.8 mmol) in dry benzene (25 ml) under a
nitrogen atmosphere. The reflux was maintained for a further 2
h and the hot mixture was filtered through a Celite pad which
was then washed with hot ethyl acetate (3 × 50 ml). The com-
bined extracts were evaporated in vacuo and the residue was
then purified by chromatography on silica using ethyl acetate as
eluent to give the bi-oxazole (0.76 g, 27%) as a white solid,
along with some recovered oxazole-oxazoline and the olefin 19
in varying amounts.
(b) Distilled 1,4-dioxane (12.8 ml) was added to a stirred
mixture of caesium carbonate (10.4 g, 31.9 mmol), copper()
bromide (100 mg) and the vinyl bromide 20 (4.6 g, 15.9 mmol)
under a nitrogen atmosphere. The slurry was heated to 40 ЊC for
22 h, next cooled to ambient temperature and ethyl acetate (100
ml) was then added. The mixture was washed with saturated
brine (2 × 50 ml). The combined organic phases were dried
(MgSO4) and evaporated in vacuo to leave a residue which was
then purified by chromatography on silica using ethyl acetate as
eluent to give the bi-oxazole (1.35 g, 40%) as a white solid.
(c) N-Bromosuccinimide (7.3 g, 41 mmol) was added to a
stirred solution of the oxazole-oxazoline 17a (8.6 g, 41 mmol)
in dry benzene (860 ml) under a nitrogen atmosphere at room
temperature. The solution was irradiated (sun lamp, 300 W) for
18 h at 25 ЊC and then evaporated in vacuo to leave a brown
residue. Purification by chromatography on silica using two
columns, the first with ethyl acetate as eluent and the second
using 1% methanol–chloroform gave the bi-oxazole (4.78 g,
56%) as colourless crystals, mp 130–131 ЊC (ethyl acetate)
(Found: C, 51.6; H, 3.8; N, 13.2. C9H8N2O4 requires C, 51.9; H,
3.9; N, 13.5%); λmax(EtOH)/nm 208 (9990) and 246 (11030);
2Ј-Methyl-4-phenylselenyl-4,5-dihydro-2,4Ј-bi(1,3-oxazolyl)-4-
carboxylic acid methyl ester 17b
A solution of potassium hexamethyldisilazide in toluene (1.8
ml, 1.5 M, 2.7 mmol) was added dropwise to a stirred solution
of the oxazoline ester 17a (540 mg, 2.6 mmol) in dry THF (5
ml) at Ϫ78 ЊC under an atmosphere of nitrogen. The resulting
orange solution was quenched with a solution of phenylselenyl
bromide (728 mg, 3.1 mmol) in dry THF (2 ml), and then
allowed to warm to ambient temperature. The solvent was
evaporated in vacuo to leave a brown oil that was purified
by column chromatography using hexane–diethyl ether (1:1) as
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428
2421

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νmax(CHCl3)/cmϪ1 1744, 1725, 1688, 1641 and 1588; δH(270
MHz, CDCl3) 8.28 (1H, s, 5-H), 8.26 (1H, s, 5Ј-H), 3.94 (3H, s,
CO2Me) and 2.55 (3H, s, 2Ј-Me); δC(67.8 MHz, CDCl3) 162.6
(s, CO2Me), 161.1 (s, 2-C), 155.6 (s, 2Ј-C), 143.4 (d, 5-C), 139.0
(d, 5Ј-C), 133.9 (s, 4-C), 129.4 (s, 4Ј-C), 52.0 (q, CO2Me) and
13.5 (q, 2Ј-Me); m/z (EI) 208 (Mϩ, 100%), 177 (4), 149 (8) and
110 (75) (Found: m/z 208.0458. C9H8N2O4 requires M,
208.0452).
(d) Pyridine (0.18 ml, 2.2 mmol) and 30% aqueous hydrogen
peroxide (0.5 ml, 4.4 mmol) were added sequentially to a stirred
solution of the selenide 17b (404 mg, 1.1 mmol) in dichloro-
methane (5 ml). The mixture was stirred vigorously for 1 h and
then 1 M HCl (5 ml) and chloroform (10 ml) were added
sequentially, and the mixture was partitioned. The organic
extract was dried and evaporated in vacuo to leave an off-white
solid which was purified by chromatography on silica using
chloroform–methanol (100:1) as eluent to give the bi-oxazole
(216 mg, 94%) as a white solid, mp 130–132 ЊC (ethyl acetate)
which showed identical spectroscopic data to those recorded
previously.
solution of the acid chloride in dry dichloromethane (90 ml)
was added dropwise over 20 min to a stirred solution of -
serine methyl ester hydrochloride (5.5 g, 35 mmol) and triethyl-
amine (10 ml, 71 mmol) in dry dichloromethane (62 ml) under a
nitrogen atmosphere at 0 ЊC. The brown solution was stirred at
ambient temperature for 14 h, evaporated in vacuo, and then
diluted with saturated sodium bicarbonate solution (200 ml).
The aqueous mixture was extracted with ethyl acetate (4 × 200
ml) and the combined organic extracts were washed with satur-
ated brine (100 ml), then dried (MgSO4) and evaporated in
vacuo to leave the amide (8.4 g, 88%) which crystallised as a
cream solid, mp 141–142 ЊC (ethyl acetate) (Found: C, 48.5; H,
4.5; N, 14.2. C12H13N3O6 requires C, 48.8; H, 4.4; N, 14.2%);
λmax(EtOH)/nm 222 (13640), 235 (13380) and 254 (13970);
νmax(CHCl3)/cmϪ1 3402 br, 1746, 1676, 1596, 1508 and 1115;
δH(250 MHz, CDCl3) 8.23 (1H, s, 5Ј-H), 8.14 (1H, s, 5"-H), 7.80
(1H, br d, J 7.9 Hz, NH), 4.87 (1H, ddd, J 7.9, 3.8 and 3.8 Hz,
4-H), 4.20–3.95 (2H, m, 5-H), 3.81 (3H, s, CO2Me), 2.80 (1H, br
m, OH) and 2.57 (3H, s, 2"-Me); δC(67.8 MHz, CDCl3) 170.4
(s, 2-C), 163.1 (s, CO2Me), 160.3 (s, 2Ј-C), 154.9 (s, 2Љ-C), 141.2
(d, 5Ј-C), 139.0 (d, 5Љ-C), 136.5 (s, 4Ј-C), 129.4 (s, 4Љ-C), 62.7
(t, 5-C), 54.4 (d, 4-C), 52.5 (q, CO2Me) and 13.7 (q, 2Љ-Me);
m/z (EI) 295 (Mϩ, 7%), 277 (4), 265 (71), 264 (25), 236 (87), 177
(100), 149 (24) and 110 (32) (Found: m/z 236.0641. C10H10N3O4
requires M, 236.0639).
2Ј-Methyl-2,4Ј-bi(1,3-oxazolyl-4-carboxylic acid ethyl ester 18b
Freshly prepared nickel peroxide (5 × 1g) was added portion-
wise every 0.5 h to a stirred solution of crude oxazoline 17c
(1.44 g, 6.42 mmol) in dry benzene (25 ml) heated under reflux.
The mixture was heated under reflux for a further 2.5 h then
cooled and filtered through a Celite pad. The Celite pad was
washed with ethyl acetate (3 × 20 ml) and the solvents were then
removed in vacuo to leave the crude product as an off-white
solid. Purification by flash chromatography on silica using 2%
methanol in chloroform as eluent afforded unreacted starting
material (150 mg, 11%), (eluted second) and the bi-oxazole
(0.67 g, 47%) as a white solid, mp 129–130 ЊC (ethyl acetate–
petrol) (Found: C, 54.1; H, 4.5; N, 12.7. C10H10N2O4 requires C,
54.05; H, 4.5; N, 12.6%); νmax(CHCl3)/cmϪ1 3000, 1730, 1640
and 1580; δH(400 MHz, CDCl3) 8.28 (1H, s, 5-H), 8.27 (1H, s,
5Ј-H), 4.42 (2H, q, J 7 Hz, CH2CH3), 2.56 (3H, s, 2Ј-Me) and
1.40 (3H, t, J 7 Hz, CH2CH3); δC(67.8 MHz, CDCl3) 162.8 (s),
161.0 (s), 155.7 (s), 143.5 (d), 139.3 (d), 134.7 (s), 129.8 (s), 61.3
(t), 14.4 (q) and 13.7 (q) (Found: m/z 222.0651. C10H10N2O4
requires M, 222.0641).
3-Chloro-2-[2Ј-methyl-2,4Ј-bi(1,3-oxazolyl)-4-ylcarbonyl-
amino]propionic acid methyl ester 22b
Thionyl chloride (45 ml) was added cautiously to the bi-oxazole
serine derivative 22a (8.4 g, 28 mmol) under a nitrogen atmos-
phere at 0 ЊC. The solution was stirred for 12 h at ambient
temperature and the excess thionyl chloride was then evapor-
ated in vacuo. The residue was quenched with water (200 ml)
and the aqueous layer was then extracted with ethyl acetate
(4 × 200 ml). The combined organic phases were washed with
saturated brine (100 ml), then dried (MgSO4) and evaporated in
vacuo to leave the bi-oxazole serine chloride (8.7 g, 97%) which
crystallised as a cream solid, mp 137–138 ЊC (diethyl ether)
(Found: C, 46.0; H, 4.0; N, 13.1; Cl, 11.0. C12H12ClN3O5
requires C, 46.0; H, 3.9; N, 13.4; Cl, 11.3%); λmax(EtOH)/nm
218 (10440) and 255 (10270); νmax(CHCl3)/cmϪ1 3401, 1748,
1681, 1650 and 1588; δH(270 MHz, CDCl3) 8.24 (1H, s, 5Ј-H),
8.16 (1H, s, 5Љ-H), 7.75 (1H, br d, J 7.9 Hz, NH), 5.16 (1H, ddd,
J 7.9, 4.0 and 3.6 Hz, 4-H), 4.04 (1H, dd, J 11.2 and 3.6 Hz, 5-
H), 3.93 (1H, dd, J 11.2 and 4.0 Hz, 5-H), 3.82 (3H, s, CO2Me)
and 2.56 (3H, s, 2Љ-Me); δC(67.8 MHz, CDCl3) 168.5 (s, 2-C),
162.9 (s, CO2Me), 159.8 (s, 2Ј-C), 154.9 (s, 2Љ-C), 141.2
(d, 5Ј-C), 139.0 (d, 5Љ-C), 136.1 (S, 4Ј-C), 129.4 (s, 4Љ-C), 52.7 (d,
4-C), 52.7 (q, CO2Me), 44.4 (t, 5-C) and 13.5 (q, 2Љ-Me); m/z
(EI) 315 (Mϩ, 1.5%), 3.3 (4), 278 (15), 256 (41), 254 (88), 177
(100), 149 (21) and 110 (28) (Found: m/z 313.4532. C12H12-
ClN3O5 requires M, 313.4528).
2Ј-Methyl-2,4Ј-bi(1,3-oxazolyl)-4-carboxylic acid 21a
A solution of potassium hydroxide (3.4 g, 60 mmol) in water
(50 ml) was added to the bi-oxazole 18a (10.4 g, 50 mmol), and
the mixture was heated under reflux for 1 h. The mixture was
cooled to ambient temperature, evaporated in vacuo, then acid-
ified with concentrated hydrochloric acid (pH 1) and cooled in
ice for 30 min. The precipitate was filtered, then washed with
water (20 ml) and freeze dried to leave the bi-oxazole acid (6.25
g, 64%) as a cream solid, mp > 210 ЊC (decomp.) (Found: C,
49.3; H, 3.0; N, 14.4. C8H6N2O4 requires C, 49.2; H, 2.9; N,
14.4%); λmax(EtOH)/nm 208 (6430), 247 (7700) and 254 (7750);
νmax(KBr disc)/cmϪ1 3143, 1681, 1644 and 1122; δH(270 MHz,
d6-DMSO) 8.75 (1H, s, 5-H), 8.72 (1H, s, 5Ј-H) and 2.44 (3H,
s, 2Ј-Me); δC(67.8 MHz, d6-DMSO) 162.6 (s, CO2H), 161.8 (s,
2-C), 155.1 (s, 2Ј-C), 144.9 (d, 5-C), 140.4 (d, 5Ј-C), 134.2 (s, 4-
C), 129.0 (s, 4Ј-C) and 13.4 (q, 2Ј-Me); m/z (EI) 194 (Mϩ, 13%),
150 (12), 110 (100) and 82 (10) (Found: m/z 194.0299.
C8H6N2O4 requires M, 194.0328).
2-[2Ј-Methyl-2,4Јbi(1,3-oxazolyl)-4-ylcarbonylaminoacrylic
acid methyl ester 24
1,8-Diazabicyclo[5.4.0]undec-7-ene (900 µl, 6 mmol) was added
dropwise to a stirred solution of the chloride 22b (1.87 g,
6 mmol), in dry dichloromethane (20 ml), at room temperature
under a nitrogen atmosphere. The mixture was stirred for 3 h
and then washed with 2 M hydrochloric acid (2 × 10 ml) and
the layers were separated. The organic phase was dried
(MgSO4) and the solvent was removed in vacuo to leave the
olefin (1.52 g, 92%) as an off-white solid. A small portion was
recrystallised from diethyl ether–hexane (1:1) and had mp 148–
149 ЊC (Found: C, 52.0; H, 4.06; N, 15.5. C12H13N3O6 requires
C, 52.0; H, 4.0; N, 15.2%); νmax(CHCl3) cmϪ1 3383, 1715, 1694,
1582, 1515 and 1203; δH(270 MHz, CDCl3) 9.12 (1H, br s, NH),
3-Hydroxy-2-[(2Ј-methyl-2,4Ј-bi(1,3-oxazolyl)-4-
ylcarbonylamino)propionic acid methyl ester 22a
Thionyl chloride (50 ml) was added to the bi-oxazole acid 21a
(6.25 g, 32 mmol), and the stirred suspension was then heated
under reflux for 6 h. The excess thionyl chloride was evaporated
in vacuo and the residue was next azeotroped with toluene to
leave the corresponding acid chloride 21b as a cream solid
which was used immediately without further purification. A
8.20 (1H, s, 5-H), 8.12 (1H, s, 5Ј-H), 6.66 (1H, s, E᎐CH), 5.94
᎐
(1H, d, J 1 Hz, Z᎐CH), 3.82 (3H, s, CO Me) and 2.49 (3H, s,
᎐
2
2422
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2-Me); δC(67.8 MHz, CDCl3) 164.2 (s, CO), 163.2 (s, CO), 158.9
(s, 2-C), 154.7 (s, 2Ј-C), 141.6 (d, 5-C), 139.3 (d, 5Ј-C), 137.3 (s,
4-C), 130.9 (s, 4Ј-C), 129.9 (s, CCO2Me), 110.1 (t, CCH2), 53.1
(q, CO2Me) and 13.9 (q, 2-Me); m/z (EI) 277 (Mϩ, 51%) and
177 (100).
selenyl bromide (275 mg, 1.2 mmol) in dry THF (3 ml), and
then allowed to warm to room temperature. The solvent was
then evaporated in vacuo to leave the selenide as a brown oil
(145 mg, 43%) which was used directly without purification.
2Љ-Methyl-2,4Ј:2Ј,4Љ-ter(1,3-oxazole)-4-carboxylic acid methyl
ester 26a
3-Bromo-2-[2Ј-methyl-2,4Ј-bi(1,3-oxazolyl)-4-ylcarbonylamino-
acrylic acid methyl ester 25
(a) Solid N-bromosuccinimide (3.6 g, 20 mmol) was added to a
stirred solution of the bi-oxazole-oxazoline 23a (5.7 g, 20
mmol) in dry benzene (565 ml) under a nitrogen atmosphere at
room temperature. The solution was irradiated for 23 h (sun
lamp, 300 W) at 25 ЊC before the solvent was evaporated in
vacuo to leave a brown residue. Purification by chromatography
on silica using 1% methanol–chloroform as eluent gave the
ter-oxazole (2.8 g, 50%) which crystallised as colourless needles,
mp 217–218 ЊC (ethyl acetate–petrol) (Found: C, 51.9; H, 3.2;
N, 15.2. C12H9N3O5 requires C, 52.3; H, 3.3; N, 15.3%);
λmax(EtOH)/nm 202 (10010), 249 (13130) and 255 (13600);
νmax(CHCl3)/cmϪ1 1747 (CO), 1654, 1605, 1588 and 1115;
δH(250 MHz, CDCl3) 8.41 (1H, s, 5-H), 8.31 (1H, s, 5Ј-H), 8.25
(1H, s, 5Љ-H), 3.94 (3H, s, CO2Me) and 2.56 (3H, s, 2Љ-Me);
δC(67.8 MHz, CDCl3) 163.0 (s, CO2Me), 161.3 (s, 2-C), 156.3
(s, 2Ј-C), 155.5 (s, 2Љ-C), 143.8 (d, 5-C), 139.2 (s, 5Ј-C), 134.4 (s,
5Љ-C), 130.7 (s, 4-C), 129.6 (2 × s, 4Ј and 4Љ-C), 52.3 (q, CO2Me)
and 13.8 (q, 2Љ-Me); m/z (EI) (Found: Mϩ, 275.0491.
C12H9N3O5 requires M, 275.0542, 100%), 244 (10), 216 (2), 149
(11), 124 (3) and 110 (63). This same ter-oxazole was produced
from the same oxazoline 23a using nickel peroxide in 40% yield
according to the procedure described for the preparation of the
bi-oxazole 18.
A solution of the alkene 24 (1.52 g, 5.5 mmol) in dry dichloro-
methane (50 ml) was cooled to Ϫ78 ЊC under a nitrogen atmos-
phere and then a solution of bromine (282 µl, 5.5 mmol) in dry
dichloromethane (3.0 ml) was slowly added dropwise. Triethyl-
amine (840 µl, 5.5 mmol) was added and the resulting mixture
was then allowed to warm to room temperature over 2 h. The
mixture was washed with brine (15 ml), dried (MgSO4) and
concentrated in vacuo. The semi-solid residue was purified by
flash chromatography on silica gel using ether–petrol (1:1) as
eluent to give the vinyl bromide (1.73 g, 88%) as a white crystal-
line solid, mp 140 ЊC (Found: C, 40.4; H, 2.8; N, 11.55; Br,
22.3. C12H10BrN3O5 requires C, 40.45; H, 2.8; N, 11.8; Br,
22.5%); νmax(CHCl3)/cmϪ1 3367, 1730, 1691, 1587, 1470 and
1113; λmax(EtOH)/nm 221.5 (1602), 235.2 (1562) and 256.1
(1667); δH(250 MHz, CDCl3) 8.30 (1H, br s, NH), 8.22 (1H, s,
5-H), 8.09 (1H, s, 5-H), 7.20 (1H, d, J 1 Hz, CHBr), 3.70 (3H, s,
2-Me) and 2.44 (3H, s, C2-Me); δC(67.8 MHz, CDCl3) 163.2
(s, CO), 162.2 (s, CO), 157.8 (s, 2-C), 155.5 (s, 2Ј-C), 141.9 (d,
5-C), 139.2 (d, 5Ј-C), 136.1 (s, 4-C), 131.2 (s, 4Ј-C), 129.5
(s, CCO2Me), 115.1 (d, CHBr), 52.9 (q, CO2Me) and 13.8 (q,
2-Me); m/z (EI) 358 and 356 (Mϩ, 0.6%), 326 and 324
(Mϩ Ϫ OMe, 3) and 276 (Mϩ Ϫ Br, 100).
(b) Distilled 1,4-dioxane (800 µl) was added to a mixture of
caesium carbonate (348 mg, 1.1 mmol), copper() bromide
(2 mg, 0.006 mmol) and the vinyl bromide 25 (190 mg, 0.5
mmol), under an atmosphere of nitrogen and the mixture was
then heated to 40 ЊC for 22 h. The mixture was cooled to room
temperature, then diluted with ethyl acetate (10 ml) and washed
with 1 M hydrochloric acid (2 × 5 ml). The separated aqueous
washings were back extracted with ethyl acetate (3 × 10 ml),
and the combined organic phases were dried (MgSO4) and
concentrated in vacuo to leave the crude product as a pale
orange solid. Purification by flash chromatography on silica gel
using ethyl acetate as eluent afforded the ter-oxazole as a white
solid (76 mg, 62%), mp 217–218 ЊC, which showed identical
spectroscopic properties to those described earlier.
(c) Pyridine (0.04 ml, 0.5 mmol) and hydrogen peroxide (0.11
ml, 1.1 mmol) were added sequentially to a stirred solution of
the selenide 23b (106 mg, 0.2 mmol) in dichloromethane (5 ml).
The mixture was stirred vigorously for 1 h and then 1 M HCl
(5 ml) and chloroform (10 ml) were added sequentially and the
mixture was partitioned. The organic extract was dried and
evaporated in vacuo to leave an off-white solid which was puri-
fied by chromatography on silica using chloroform–methanol
(100:1) as eluent to give the ter-oxazole (48 mg, 71%) as a white
solid, mp 218–220 ЊC (ethyl acetate–petrol), which showed
identical spectroscopic data to those recorded previously.
2ЈЈ-Methyl-4,5-dihydro-2,4Ј:2Ј,4Љ-ter(1,3-oxazole)-4-carboxylic
acid methyl ester 23a
Silver trifluoromethanesulfonate (12.5 g, 49 mmol) was added
in one portion to a stirred solution of the bi-oxazole serine
chloride 22b (10.0 g, 41 mmol) in dry benzene (100 ml) under a
nitrogen atmosphere, and the slurry was then heated under
reflux for 6 h. The mixture was cooled to ambient temperature,
evaporated in vacuo, and then the grey residue was slurried in
ethyl acetate (300 ml) and saturated sodium bicarbonate (200
ml) with vigorous stirring for 30 min. The separated aqueous
layer was extracted with ethyl acetate (3 × 100 ml) and the
combined organic phases were washed with sodium hydrogen
carbonate (3 × 100 ml). The second aqueous extract was
washed with further ethyl acetate (3 × 100 ml) and the total
combined organic phases were dried (MgSO4) and evaporated
in vacuo to leave the bi-oxazole-oxazoline (5.3 g, 62%) which
crystallised as a pale yellow solid, mp 181–182 ЊC (ethyl
acetate); λmax(EtOH)/nm 240 (13520) and 255 (13940);
νmax(CHCl3)/cmϪ1 1742, 1682, 1639, 1586 and 1113; δH(250
MHz, CDCl3) 8.26 (1H, s, 5Ј-H), 8.22 (1H, s, 5Љ-H), 4.95 (1H,
dd, J 10.6 and 7.9 Hz, 4-H), 4.71 (1H, dd, J 8.7 and 7.9 Hz, 5-
H), 4.60 (1H, dd, J 10.6 and 8.7 Hz, 5-H), 3.80 (3H, s, CO2Me)
and 2.54 (3H, s, 2Љ-Me); δC(67.8 MHz, CDCl3) 170.9 (s, 2-C),
162.6 (s, CO2Me), 159.6 (s, 2Ј-C), 155.8 (s, 2Љ-C), 141.0 (d,
5Ј-C), 139.2 (d, 5Љ-C), 130.9 (s, 4Ј-C), 129.5 (s, 4Љ-C), 69.7 (t, 5-
C), 68.3 (d, 4-C), 52.5 (q, CO2Me) and 13.6 (q, 2Љ-Me); m/z (EI)
277 (Mϩ, 14%), 218 (100), 208 (24), 190 (78), 177 (37), 149 (11)
and 110 (35) (Found: m/z 277.0653. C12H11N3O5 requires M,
277.0699).
2Ј-Methyl-2,4Ј-bi(1,3-oxazolyl)-4-carboxylic acid amide 21c
Liquid ammonia (2 ml) was added to a cooled (Ϫ20 ЊC) solu-
tion of the bi-oxazole ester 18 (0.11 g, 0.5 mmol) in methanol
and the reaction flask was then lightly stoppered, allowed to
warm to room temperature over ca. 2 h, and then left to stand
overnight. The solution was evaporated to dryness in vacuo to
leave the amide (96 mg, 99%) which recrystallised from ethyl
acetate–petrol as white needles, mp 224–230 ЊC (decomp.)
(Found: C, 49.5; H, 3.6; N, 21.8. H7N3O3 requires C, 49.7; H,
3.6; N, 21.8%); νmax(Nujol)/cmϪ1 3480, 3410, 3200, 1660, 1610,
1585, 1400 and 1100; δH(400 MHz, CDCl3 ϩ CD3OD) 8.45
(2H, br s) and 2.6 (3H, s) (Found: m/z 193.0522. C8H7N3O3
requires M, 193.0557).
2Љ-Methyl-4-phenylselenyl-4,5-dihydro-2,4Ј:2Ј,4Љ-teroxazole-4-
carboxylic acid methyl ester 23b
A 1.5 M solution of potassium hexamethyldisilazide in toluene
(0.54 ml, 0.8 mmol) was added dropwise to a stirred solution of
the oxazoline ester 23a (215 mg, 0.8 mmol) in dry THF (5 ml) at
Ϫ78 ЊC under an atmosphere of nitrogen. The resulting orange
solution was immediately quenched with a solution of phenyl-
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428
2423

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2Љ-Methyl-4,5-dihydro-2,4Ј:2Ј,4Љ-ter(1,3-oxazole)-4-carboxylic
acid ethyl ester 23c
1% methanol–chloroform to give the methyl bromide (202 mg,
46% based on recovered starting material) as a white solid
(methanol), mp > 230 ЊC (decomp.) (Found: C, 40.9; H, 2.3; N,
(a) Silver trifluoromethanesulfonate (1.19 g, 4.62 mmol) was
added to a stirred solution of the ethyl ester corresponding to
the chloride 22b (0.69 g, 2.10 mmol) in dry benzene (25 ml),
under a nitrogen atmosphere, and the resulting solution was
then stirred and heated under reflux for 6 h. The solution was
cooled to 25 ЊC and the solvent was then removed in vacuo. The
residual grey sticky solid was dissolved in ethyl acetate (50 ml)
and the solution was then washed with saturated aqueous
sodium bicarbonate (3 × 25 ml) and saturated brine (3 × 25
ml). The aqueous washings were re-extracted separately with
ethyl acetate (3 × 25 ml), and the combined organic extracts
were then dried and evaporated in vacuo to leave the crude
product (0.60 g, 98%) as a yellow solid. Chromatography on
silica using ethyl acetate as eluent gave the bi-oxazole-oxazoline
as a white solid, mp 157–158 ЊC (ethyl acetate); νmax(KBr)/cmϪ1
3105, 3070, 1725, 1670, 1640 and 1590; δH(400 MHz, CDCl3)
8.21 (1H, s), 8.17 (1H, s), 4.88 (1H, dd, J 11 and 9 Hz), 4.64
(1H, t, J 9 Hz), 4.55 (1H, dd, J 11 and 9 Hz), 4.20 (2H, m), 2.49
(3H, s) and 1.26 (3H, t, J 7 Hz); δC(67.8 MHz, CDCl3) 170.6 (s),
162.8 (s), 159.8 (s), 156.0 (s), 141.2 (d), 139.4 (d), 131.1 (s), 129.7
(s), 69.9 (t), 68.6 (d), 61.9 (t), 14.1 (q) and 13.8 (q) (Found: m/z
291.0833. C13H13N3O5 requires M, 291.0854).
(b) Triethyloxonium tetrafluoroborate (1.1 ml of a 1 M
solution in DCM, 1.1 mmol) was added to a suspension of the
bi-oxazole amide 21c (0.1 g, 1 mmol) in dry dichloromethane
(10 ml) and the resulting solution was stirred under an atmos-
phere of nitrogen for 6 h. -Serine ethyl ester hydrochloride
(0.19 g, 1.1 mmol) and triethylamine (0.31 ml, 2.2 mmol) were
introduced and the mixture was then stirred overnight at
ambient temperature. The mixture was evaporated to dryness in
vacuo to leave an off-white solid which was preadsorbed onto
silica and purified by flash chromatography using 2% methanol
in chloroform as eluent to give the product (35 mg, 12%) as a
pale yellow oil. Starting material (74 mg, 39%) was also
recovered. The product showed identical spectroscopic
properties to those described above.
11.9. C12H8BrN3O5 requires C, 40.7; H, 2.3; N, 11.9%); λmax
-
(EtOH)/nm 245 (17345) and 255 (19310); νmax(CHCl3)/cmϪ1
1729, 1654, 1577, 1114 and 1100; δH(400 MHz, CDCl3) 8.43
(1H, s, 5-H), 8.37 (1H, s, 5Ј-H), 8.32 (1H, s, 5Љ-H), 4.52 (2H, s,
CH2Br) and 3.95 (3H, s, CO2Me); δC(67.8 MHz, d6-DMSO)
161.1 (s, CO2Me), 161.0, 155.4 and 155.0 (3 × s, 2, 2Ј and 2Љ-C),
145.9, 142.3 and 141.3 (3 × d, 5, 5Ј and 5Љ-C), 133.5, 130.2
and 129.8 (3 × s, 4, 4Ј and 4Љ-C), 52.2 (q, CO2Me) and 21.1 (t,
CH2Br); m/z (EI) (Found: m/z 354.9656, (16%). C12H8BrN3O5
requires M, 354.9627, 353 (17), 274 (100) and 242 (5).
4Љ-Methoxycarbonyl-4,2Ј:4Ј,2Љ-ter(1,3-oxazolyl)-2-ylmethyltri-
phenylphosphonium bromide 5
A stirred solution of the oxazole bromide 27 (159 mg, 0.45
mmol) and triphenylphosphine (236 mg, 0.90 mmol) in distilled
benzene (20 ml) was heated under reflux for 17 h in a nitrogen
atmosphere. The mixture was cooled to ambient temperature
and the precipitate was then filtered off and washed with dry
diethyl ether (50 ml). The residue was dried in vacuo to give the
phosphonium salt (210 mg, 76%) as a hygroscopic, cream
powder; δH(400 MHz, CDCl3) 8.35 (1H, s, 5-H), 8.30 (1H, s,
5Ј-H), 8.21 (1H, s, 5Љ-H), 7.94 (6H, m, Ar), 7.80 (3H, m, Ar),
7.68 (6H, m, Ar), 6.20 (2H, d, J 14.9 Hz, CH2P) and 3.94 (3H, s,
CO2Me); δC(67.8 MHz, CDCl3) 162.2 (s, CO2Me), 155.3 and
155.2 (3 × s, 2, 2Ј and 2Љ-C), 143.9, 142.1 and 139.4 (3 × d, 5, 5Ј
and 5Љ-C), 135.4 (d, Ar), 134.4 and 130.8 (3 × s, 4, 4Ј and 4Љ-C),
134.2 (d, Ar), 134.1 (d, Ar), 130.5 (d, Ar), 130.3 (d, Ar), 117.7
(s, Ar), 116.9 (s, Ar), 52.3 (q, CO2Me) and 26.6 (CH2, d, JP-C
54 Hz, CH2P) which was used directly without further
purification.
4-(2-Hydroxy-1-methoxycarbonylethylcarbamoyl)-2,2-dimethyl-
1,3-oxazolidine-3-carboxylic acid tert-butyl ester 32
Triethylamine (1.81 ml, 13.0 mmol) was added dropwise, over
2 min, to a stirred solution of serine methyl ester hydrochloride
(0.58 g, 3.7 mmol) in dry dichloromethane (15 ml) at 0 ЊC under
a nitrogen atmosphere. A solution of GarnerЈs acid 3121 (0.91 g,
3.7 mmol) in dry dichloromethane (5 ml) was added in one
portion followed by HOBt (0.54 g, 4.0 mmol) and the resulting
suspension was then stirred at room temperature for 15 min.
A solution of DCC (0.83 g, 4.0 mmol) in dry dichloromethane
(5 ml) was added to the suspension over 10 min and the mixture
was then stirred at room temperature for 17 h. The mixture was
evaporated in vacuo to leave a solid which was taken up in ethyl
acetate (20 ml), washed with saturated aqueous sodium
bicarbonate solution (3 × 15 ml), 10% aqueous citric acid solu-
tion (3 × 15 ml) and brine (2 × 10 ml). The organic layer was
dried (MgSO4) and evaporated in vacuo to leave a residue which
was purified by chromatography on silica using a 3:1 ethyl
acetate–petrol as eluent to give the amide (0.9 g, 74%) as a straw
coloured oil; νmax(CHCl3)/cmϪ1 3423, 2980, 1743, 1681, 1456,
1368, 1094 and 1053; δH (360 MHz, d6-DMSO at 80 ЊC) 7.81
(1H, dd, J 24.4 and 7.6 Hz, NH), 4.87 (1H, br s, OH), 4.46–4.39
(2H, m, 2-H and 2Ј-H), 4.15–4.08 (1H, m, 1Ј-H), 3.93–3.87 (1H,
m, 1-H), 3.81–3.72 (1H, m, 1-H), 3.68–3.63 (1H, br m, 1-H),
3.68 (3H, s, OCH3), 1.58 (3H, s, CH3), 1.48 (3H, s, CH3) and
2Љ-Methyl-2,4Ј:2Ј,4Љ-ter(1,3-oxazole)-4-carboxylic acid ethyl
ester 26b
Freshly prepared nickel peroxide (5 × 3.55 g) was added
portionwise every 0.5 h to a stirred solution of the bi-oxazole-
oxazoline 23c (2.70 g, 9.28 mmol) in dry benzene (100 ml)
heated under reflux. The mixture was heated under reflux for a
further 2.5 h then cooled and filtered through a Celite pad. The
Celite pad was washed with ethyl acetate (3 × 30 ml) and the
solvents were then removed in vacuo to leave the crude product
as an off-white solid. Purification by flash chromatography on
silica using 2% methanol in chloroform as eluent gave
unreacted starting material (41 mg, 15%) (eluted second) and
the ter-oxazole (1.02 g, 38%) as a white solid, mp 222–224 ЊC
(ethyl acetate–petrol); λmax(EtOH)/nm 244; νmax(CHCl3)/cmϪ1
3170, 2920, 1725, 1645 and 1575; δH(400 MHz, CDCl3) 8.41
(1H, s), 8.31 (1H, s), 8.27 (1H, s), 4.43 (2H, q, J 7 Hz), 2.57 (1H,
s) and 1.41 (3H, t, J 7 Hz); δC(67.8 MHz, CDCl3) 162.6 (s),
160.6 (s), 156.0 (s), 155.1 (s), 143.4 (d), 138.9 (2 × d), 134.3 (s),
130.5 (s), 129.3 (s), 61.1 (t), 13.8 (q) and 13.5 (q) (Found: m/z
289.0685. C13H11N3O5 requires M, 289.0697).
t
1.41 (9H, s, Bu); δC(100 MHz, CDCl3) 177.0 (175.4), 153.0
2Љ-Bromomethyl-2,4Ј:2Ј,4Љ-ter(1,3-oxazole)-4-carboxylic acid
methyl ester 27
(151.3), 95.3 (94.8), 81.8 (80.8), 66.2 (65.7), 60.5 (59.2), 28.3
26.2, 25.0, 24.9 and 24.4; m/z (FAB) (Found: Mϩ ϩ 1, 347.1813
(35%). C15H27O7N2 requires M, 347.1818).
A stirred solution of the ter-oxazole 26a (0.89 g, 3.2 mmol),
N-bromosuccinimide (633 mg, 3.6 mmol) and AIBN (45 mg) in
distilled carbon tetrachloride (178 ml) was irradiated (sun lamp,
300 W) under reflux for 23 h in a nitrogen atmosphere. The
mixture was cooled to ambient temperature, then evaporated in
vacuo, and the residue was purified by chromatography on silica
eluting with 7:1 dichloromethane–diethyl ether and then with
2Ј,2Ј-Dimethyl-2Ј,3Ј,4Ј,5Ј-tetrahydro-2,4Ј-bi(1,3-oxazolyl)-4,3Ј-
dicarboxylic acid 3Ј-tert-butyl ester 4-methyl ester 34a
A solution of BurgessЈ reagent (0.77 g, 3.2 mmol)22 in dry THF
(10 ml) was added to a solution of the amide 32 (0.96 g, 2.8
mmol) in dry THF (20 ml) and the mixture was heated under
2424
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428

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reflux for 2 h in a nitrogen atmosphere. The mixture was
evaporated to dryness in vacuo and the residue was purified by
chromatography on silica using 1:1 petrol (bp 40–60 ЊC)–ethyl
acetate as eluent to give the corresponding oxazoline 33
(6.1 g, 61%) as an oil; δH(360 MHz, CDCl3 at 50 ЊC, single
diastereomer) 4.83–4.79 (1H, m, 2Ј-H), 4.61–4.56 (2H, m, 1Ј-H
and 2-H), 4.43 (1H, dd, J 10.4 and 8.8 Hz, 1Ј-H), 4.16 (1H, dd,
J 9.1 and 6.9 Hz, 1-H), 4.04 (1H, dd, J 9.0 and 3.2 Hz, 1-H),
3.78 (3H, s, CO2Me) and 1.67–1.44 (15H, m, 2 × Me and tBu);
δC(125 MHz, CDCl3, single diastereomer) 171.4, 169.1, 151.3,
106.4, 95.2, 80.4, 70.2, 68.3, 66.7, 55.0, 52.8, 52.4, 28.4, 25.2 and
24.3; m/z (EI) (Found: Mϩ Ϫ CH3, 313.1395 (11%). C14H21N2O6
requires M, 313.1400).
and evaporated in vacuo. The residue was purified by chrom-
atography on silica using ethyl acetate as eluent to give the
oxazole aldehyde (0.4 g, 79%) as a colourless oil. δH(360 MHz,
CDCl3, major rotamer) 9.95 (1H, s), 8.24 (1H, s), 5.20–5.07
(1H, m), 4.31–4.12 (2H, m), 1.76 (3H, s), 1.58 (3H, s) and 1.31
(9H, s), which was used without further characterisation.
8-(Diethoxyphosphoryl)-7-oxooctanoic acid ethyl ester 35
A solution of n-butyllithium (2.35 M in hexane, 14.4 ml) was
added dropwise, over 10 min to a stirred solution of dimethyl
methylphosphonate in dry THF (80 ml) under a nitrogen
atmosphere at Ϫ78 ЊC. The mixture was stirred at Ϫ78 ЊC for
30 min and a solution of diethyl pimelate (5.0 g, 23.1 mmol) in
dry THF (40 ml) was then added. The mixture was stirred at
Ϫ78 ЊC for 2 h and then quenched with saturated ammonium
chloride solution (100 ml). The separated aqueous layer was
extracted with diethyl ether (2 × 50 ml) and the combined
organic phases were washed with saturated brine (50 ml), then
dried (MgSO4) and evaporated in vacuo. The residue was
purified by chromatography on silica using ethyl acetate as
eluent to give the β-ketophosphonate (1.6 g, 24%) as a straw
coloured oil; νmax(CHCl3)/cmϪ1 3477, 2953, 1730, 1259 and
1185; δH (360 MHz, CDCl3) 4.08 (2H, q, J 7.1 Hz, OCH2CH3),
3.77 (3H, s, POCH3), 3.74 (3H, s, POCH3), 3.05 (2H, d, JP-H
22.7 Hz, 8-H), 2.59 (2H, t, J 7.2 Hz, 6-H), 2.26 (2H, t, J 7.5 Hz,
2-H), 1.64–1.53 (4H, m, 4-H and 5-H), 1.34–1.25 (2H, m, 3-H)
and 1.22 (3H, t, J 7.1 Hz, OCH2CH3); δC(90 MHz, CDCl3)
201.3 (s), 201.2 (s), 173.1 (s), 59.7 (t), 52.6 (q), 52.5 (q), 43.4 (t),
40.8 (d), 33.6 (t), 27.9 (t), 24.2 (t), 22.5 (t) and 13.8 (q); m/z (EI)
294 (Mϩ, 2%), 249 (Mϩ Ϫ OEt, 15%) and 231 (Mϩ Ϫ (OMe)2,
26%).
DBU (0.53 ml, 3.5 mmol) was added dropwise, over 2 min, to
a stirred solution of the oxazoline (1.04 g, 3.2 mmol) in dry
dichloromethane (30 ml) at 0 ЊC under a nitrogen atmosphere.
Bromotrichloromethane (0.34 ml, 3.5 mmol) was added drop-
wise over 10 min and the mixture allowed to warm to room
temperature over 24 h.23 The mixture was quenched with
saturated ammonium chloride (2 × 20 ml), and the separated
aqueous phase was then extracted with ethyl acetate (2 × 20
ml). The combined organic extracts were dried (MgSO4), and
then evaporated in vacuo to leave a residue which was purified
by chromatography on silica using 1:1 petrol–ethyl acetate as
eluent to give the oxazole (0.8 g, 75%) as a mixture of rotamers;
νmax(CHCl3)/cmϪ1 2980, 1703, 1368, and 1110; δH(360 MHz,
CDCl3, major rotamer) 8.21 (1H, s), 5.20–5.07 (1H, m, 2-H),
4.29–4.09 (2H, m, 1-H), 3.93 (3H, s, CO2Me), 1.75 (3H, s, CH3),
t
1.60 (3H, s, CH3) and 1.30 (9H, s, Bu); δC(125 MHz, CDCl3,
major rotamer) 164.0 (s), 161.3 (s), 150.9 (s), 143.6 (d), 133.4
(s), 95.1 (s), 80.5 (s), 67.4 (t), 55.0 (d), 52.1 (q), 28.0 (q), 25.1 (q)
and 23.9 (q); m/z (FAB) (Found: Mϩ ϩ 1, 327.1531 (11%).
C15H23N2O6 requires M, 327.1556).
4-(8-Ethoxycarbonyl-3-oxooct-1-enyl)-2Ј,2Ј-dimethyl-2Ј,3Ј,4Ј,5Ј-
tetrahydro-2,4Ј-bi(1,3-oxazolyl)-3Ј-carboxylic acid tert-butyl
ester 36
4-Hydroxymethyl-2Ј,2Ј-dimethyl-,2Ј,3Ј,4Ј,5Ј-tetrahydro-2,4Ј-
bi(1,3-oxazolyl)-3Ј-carboxylic acid tert-butyl ester
Barium hydroxide octahydrate (0.4 g, 1.4 mmol) was added in
one portion to a stirred solution of the β-ketophosphonate 35
(0.4 g, 1.4 mmol) in dry THF (8 ml) under a nitrogen atmos-
phere at room temperature. The suspension was stirred for 30
min and a solution of the aldehyde 34b (0.4 g, 1.4 mmol) in
40:1 THF–H2O (2 ml) was then added in one portion. The
mixture was stirred at room temperature for 3 h then quenched
with saturated sodium bicarbonate solution (20 ml) and
extracted with dichloromethane (3 × 20 ml). The combined
organic extracts were washed with brine (20 ml), dried (MgSO4)
and evaporated in vacuo to leave a viscous oil. Purification by
chromatography on silica using 2:1 petrol–ethyl acetate as
eluent gave the alkene (0.5 g, 71%) as a yellow oil; νmax(CHCl3)/
cmϪ1 2936, 1698, 1627, 1379, 1368 and 1097; δH(360 MHz,
CDCl3, major rotamer) 7.77 (1H, s, 14-H), 7.36 (1H, d, J 15.6
Hz, 9-H), 6.91 (1H, d, J 15.6 Hz, 8-H), 5.15–5.00 (1H, m,
15-H), 4.29–4.22 (1H, m, 19-H), 4.15–4.09 (1H, br m, 19-H),
4.12 (2H, q, J 7.2 Hz, OCH2CH3), 2.64–2.60 (2H, m, 6-H), 2.30
(2H, t, J 7.4 Hz, 2-H), 1.76–1.54 (9H, m, 3-H, 4-H, 5-H and
A solution of DIBAL-H (1.5 M in toluene, 5.1 ml) was added
dropwise, over 30 min, to a stirred solution of the oxazole ester
34a (1.0 g, 3.06 mmol) in dry dichloromethane (10 ml) at 0 ЊC
under a nitrogen atmosphere and the mixture was stirred at
0 ЊC for 4 h. The mixture was quenched with methanol (20 ml)
followed by magnesium sulfate (20 g) and the filtered suspen-
sion was evaporated in vacuo to leave a viscous yellow residue.
The residue was added to a saturated solution of potassium
sodium tartrate and the mixture was stirred vigorously for 2 h.
The mixture was extracted with ethyl acetate (2 × 200 ml), and
the combined organic extracts were then dried (MgSO4) and
evaporated in vacuo to leave a yellow residue. The residue was
purified by chromatography on silica using 1:1 petrol–ethyl
acetate as eluent to give the oxazole alcohol (0.55 g, 61%) as a
yellow oil; δH(360 MHz, CDCl3, major rotamer) 7.55 (1H, s),
5.13–4.98 (1H, m, 2-H), 4.58 (2H, br s, CH2OH), 4.26–4.04
(3H, m, 1-H), 2.78 (1H, br s, OH), 1.73 (3H, s, CH3), 1.59 (3H,
t
s, CH3) and 1.29 (9H, s, Bu); δC(125 MHz, CDCl3) 163.7 (s),
t
151.2 (s), 140.6 (s), 134.9 (d), 95.0 (s), 80.4 (s), 67.4 (t), 56.7 (t),
55.1 (d), 28.1 (q), 25.2 (q) and 24.2 (q); m/z (EI) (Found: Mϩ,
298.1535 (1.26%) C14H22N2O5 requires M, 298.1529).
OCH2CH3) and 1.49–1.21 (15H, m, 2 × CH3 and Bu); δC(125
MHz, CDCl3) 200.0 (s), 173.8 (s), 160.2 (s), 151.3 (s), 139.4 (s),
137.7 (s), 129.3 (s), 127.3 (s), 95.3 (s), 81.3 (s), 67.3 (t), 60.2 (t),
55.1 (d), 41.5 (t), 34.1 (t), 28.7 (t), 28.1 (q), 25.2 (q), 24.7 (t), 24.2
(q), 23.7 (t) and 14.2 (q).
4-Formyl-2Ј,2Ј-dimethyl-2Ј,3Ј,4Ј,5Ј-tetrahydro-2,4Ј-bi(1,3-oxa-
zolyl)-3Ј-carboxylic acid tert-butyl ester 34b
4-(8-Ethoxycarbonyl-1-methyl-3-oxooctyl)-2Ј,2Ј-dimethyl-
2Ј,3Ј,4Ј,5Ј-tetrahydro-2,4Ј-bi(1,3-oxazolyl)-3Ј-carboxylic acid
tert-butyl ester 37
A solution of pyridine–sulfur trioxide complex (0.87 g, 5.49
mmol) in DMSO (5 ml) was added dropwise, over 2 min, to a
stirred solution of the alcohol (from above) (0.50 g, 1.7 mmol),
DMSO (5 ml) and triethylamine (4.71 ml, 33.8 mmol) at room
temperature under a nitrogen atmosphere. The mixture was
stirred at room temperature for 2 h and then quenched with a
10% solution of potassium hydrogen sulfate (10 ml). The separ-
ated aqueous layer was extracted with diethyl ether (3 × 25 ml)
and the combined organic extracts were then dried (MgSO4),
A solution of methyllithium (1.6 M in diethyl ether, 6.7 ml, 10.7
mmol) was added dropwise over 20 min to a stirred suspension
of copper iodide (1.0 g, 5.4 mmol) in dry diethyl ether (20 ml) at
Ϫ5 ЊC under an argon atmosphere and the resulting yellow
solution was stirred at Ϫ5 ЊC for 30 min. A solution of the
enone 36 (300 mg, 0.65 mmol) in dry diethyl ether (15 ml) was
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428
2425

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added dropwise over 10 min to the cuprate solution at Ϫ5 ЊC
and the mixture was stirred at Ϫ5 ЊC for 3 h. The mixture
was quenched with a 1:1 mixture of saturated ammonium
chloride–ammonium hydroxide solution (20 ml) and the separ-
ated aqueous layer was then extracted with diethyl ether (2 × 30
ml). The combined organic phases were washed with saturated
brine (30 ml), then dried (MgSO4) and evaporated in vacuo. The
residue was purified by chromatography on silica using 1:1
petrol–ethyl acetate as eluent to give the 3-methyl ketone (168
mg, 55%) as a viscous oil; νmax(CHCl3)/cmϪ1 1696; δH(360 MHz,
CDCl3) 7.30 (1H, s, 14-H), 5.29–4.95 (1H, m, 15-H), 4.22–4.16
(1H, m, 19-H), 4.13–4.02 (1H, br m, 19-H), 4.11 (2H, q, J 7.1
Hz, OCH2CH3), 3.30–3.24 (1H, m, 9-H), 2.83 (1H, dd, J 6.0
and 16.9 Hz, 8-H), 2.51 (1H, dd, J 8.1 and 17.2 Hz, 8-H), 2.36
(2H, t, J 7.3 Hz, 6-H), 2.27 (2H, t, J 7.4 Hz, 2-H), 1.72–1.41
(9H, m, 3-H, 4-H, 5-H and OCH2CH3) and 1.31–1.09 (18H, m,
14.9 Hz, CH2P), 4.28 (2H, q, J 7.1 Hz, OCH2CH3) and 1.32
(3H, t, J 7.1 Hz, OCH2CH3), which was used without further
characterisation.
2-[6-(tert-Butyldimethylsilyloxy)hex-1-enyl]-1,3-oxazole-4-
carboxylic acid ethyl ester 40a
A solution of butyllithium (2.35 M) in hexane (1.68 ml, 2.69
mmol) was added dropwise over 10 min to a stirred suspension
of the phosphonium salt 38 (1.67 g, 2.69 mmol) in dry THF
(40 ml) at Ϫ30 ЊC under a nitrogen atmosphere. The deep red
solution was stirred at room temperature for 30 min, and
was then cooled to Ϫ78 ЊC. A solution of 5-tert-butyldimeth-
ylsilylpentanal 39 (0.87 g, 4.04 mmol) in dry THF (9 ml) was
added dropwise over 5 min to the ylide solution at Ϫ78 ЊC and
the mixture was allowed to warm to room temperature
overnight. The mixture was quenched with saturated aqueous
ammonium chloride solution (20 ml) and the separated
aqueous layer was then extracted with diethyl ether (2 × 30 ml).
The combined organic phases were washed with saturated brine
(20 ml), then dried (MgSO4) and evaporated in vacuo. The
residue was purified by chromatography on silica using 5:1
petrol–ethyl acetate as eluent to give the olefin (0.4 g, 41%) as a
viscous oil (Found: C, 60.9; H, 9.3; N, 3.9. C18H31O4NSi
requires C, 61.1; H, 8.9; N, 4.0%); νmax(CHCl3)/cmϪ1 1730, 1664,
1318 and 1114; δH(360 MHz, CDCl3) 8.12 (1H, s, 5-H), 6.85
(1H, dt, J 16.0 and 7.0 Hz, 2Ј-H), 6.32 (1H, d, J 16.0 Hz, 1Ј-H),
4.39 (2H, q, J 7.1 Hz, OCH2CH3), 3.65–3.61 (2H, m, 6Ј-H),
2.30–2.28 (2H, m, 3Ј-H), 1.58–1.54 (4H, m, 4Ј and 5Ј-H), 1.39
(3H, t, J 7.1 Hz, OCH2CH3), 0.90 (9H, s, tBu) and 0.05 (6H, s, 2,
CH3); δC(67.5 MHz, CDCl3) 161.6 (CO), 160.4 (2-C), 142.9
(5-C), 142.5 (2Ј-C), 133.3 (4-C), 115.8 (1Ј-C), 62.7 (6Ј-C), 61.2
(OCH2CH3), 32.5 (3Ј-C), 32.1 (5Ј-C), 25.9 (tBu), 24.7 (4Ј-C),
18.3 (q-C), 14.3 (OCH2CH3) and Ϫ5.3 (Si-Me); m/z (FAB)
(Found: Mϩ ϩ 1, 354.2119 (77%) C18H32O4NSi requires M,
354.2101).
t
2 × CH3, Bu and 9-CH3); δC(90 MHz, CDCl3) 209.2 (s), 173.6
(s), 162.8 (s), 151.2 (s), 133.1 (s), 94.9 (s), 80.1 (s), 67.5 (t), 60.2
(t), 55.2 (d), 48.3 (t), 42.9 (t), 34.1 (t), 28.6 (t), 28.1 (q), 26.8 (d),
25.1 (q), 24.6 (t), 24.5 (q), 23.1 (t), 19.4 (q) and 14.2 (q); m/z
(FAB) (Found: Mϩ ϩ 1, 481.2944 (10%). C25H41O7N2 requires
M, 481.2915).
4-(8-Carboxy-3-oxooct-1-enyl)-2Ј,2Ј-dimethyl-2Ј,3Ј,4Ј,5Ј-
tetrahydro-2,4Ј-bi(1,3-oxazolyl)-3Ј-carboxylic acid tert-butyl
ester 29
Lithium hydroxide (22 mg, 0.5 mmol) was added in one
portion to a solution of the ester 37 (60 mg, 0.17 mmol) in a 3:1
mixture of THF–H2O (4 ml), and the mixture was then stirred
at ambient temperature for 2 h. Water (2 ml) was added,
followed by ethyl acetate (10 ml) and the mixture was then
acidified to pH 1 with 2 M HCl (0.5 ml added dropwise). The
separated aqueous layer was extracted with ethyl acetate (3 × 10
ml), and the combined organic extracts were then washed with
brine (20 ml), dried (MgSO4) and evaporated in vacuo to leave
the carboxylic acid (20 mg, 99%) as a viscous oil; δH(360 MHz,
CDCl3) 7.32 (1H, s, 14-H), 5.12–4.98 (1H, m, 15-H), 4.24–4.15
(1H, m, 19-H), 4.13–4.03 (1H, m, 19-H), 3.32–3.26 (1H, m,
9-H), 2.88–2.82 (1H, m, 8-H), 2.58–2.46 (1H, m, 8-H), 2.40–
2.27 (4H, m, 2-H and 6-H) and 1.73–1.12 (18H, m, 2 × CH3,
tBu and 9-CH3).
2-[6-(tert-Butyldimethylsilyloxy)hex-1-enyl]-1,3-oxazole-4-
carboxylic acid 40b
Lithium hydroxide (22 mg, 0.51 mmol) was added in one
portion to a solution of the ester 40a (60 mg, 0.17 mmol) in a
3:1 mixture of THF–H2O (4 ml), and the mixture was then
stirred at room temperature for 2 h. Water (2 ml) was added,
followed by ethyl acetate (10 ml) and the mixture was cooled to
0 ЊC and then acidified to pH 1 with 2 M HCl (0.5 ml added
dropwise). The separated aqueous layer was extracted with
ethyl acetate (3 × 10 ml) and the combined organic extracts
were then washed with saturated brine (20 ml), dried (MgSO4)
and evaporated in vacuo to leave the carboxylic acid (20 mg,
99%) as a white solid, mp 210–212 ЊC (from ethanol);
νmax(CHCl3)/cmϪ1 3697, 2930, 1716, 1601 and 1110; δH(360
MHz, CDCl3) 8.21 (1H, s, 5-H), 6.89 (1H, dt, J 16.0 and 7.0 Hz,
2Ј-H), 6.33 (1H, dt, J 16.0 and 1.4 Hz, 1Ј-H), 3.66–3.63 (2H, m,
6Ј-H), 2.32–2.30 (2H, m, 3Ј-H), 1.59–1.56 (4H, m, 4Ј and 5Ј-H),
4-Ethoxycarbonyl-1,3-oxazol-2-ylmethyltriphenylphosphonium
bromide 38
Solid N-bromosuccinimide (6.9 g, 39 mmol) and AIBN (400
mg, 20% w/w) were added to a stirred solution of the oxazole
ester 13a (2.0 g, 13 mmol) in carbon tetrachloride (40 ml) and
the suspension was then heated under reflux in a nitrogen
atmosphere for 17 h. The mixture was cooled to room temper-
ature, then evaporated to dryness in vacuo to leave a solid
residue. Purification by chromatography on silica using 1:1
toluene–ethyl acetate as eluent gave the corresponding
bromomethyloxazole (1.23 g, 41%) as a yellow oil; νmax(CHCl3)/
cmϪ1 1726, 1580, 1317, 1114 and 664; δH(360 MHz, CDCl3) 8.25
(1H, s, 5-H), 4.49 (2H, s, CH2Br), 4.39 (2H, q, J 7.2 Hz,
OCH2CH3), 1.40 (3H, t, J 7.2 Hz, OCH2CH3); δC(67.5 MHz,
CDCl3) 160.5 (CO), 159.9 (2-C), 144.7 (5-C), 134.1 (4-C), 61.3
(OCH2CH3), 19.3 (CH2Br) and 14.0 (OCH2CH3); m/z (EI) 235,
233 (Mϩ, 6, 6%), 190, 188 (15, 15), 154 (91), 110 (4) and 82 (7).
A solution of triphenylphosphine (2.4 g, 9.2 mmol) in dry
diethyl ether (17 ml) was added to a solution of the
bromomethyloxazole (1.1 g, 4.6 mmol) in dry diethyl ether (5
ml) under a nitrogen atmosphere and the solution was then
stirred at room temperature for 24 h. The mixture was evapor-
ated to dryness in vacuo to leave a yellow solid which was
triturated in pentane (3 × 30 ml). The residue was evaporated to
dryness in vacuo to leave the phosphonium salt (1.9 g, 82%) as a
pale yellow solid, mp >300 ЊC (decomp.); δH(360 MHz, CDCl3),
8.07 (1H, s, 5-H), 7.94–7.53 (15H, m, 3 Ar), 6.10 (2H, d, JP-H
t
0.90 (9H, s, Bu) and 0.06 (6H, s, 2 × CH3); δC(67.5 MHz,
CDCl3) 165.3 (CO2H), 162.5 (2-C), 144.3 (5-C), 143.6 (2Ј-C),
133.9 (4-C), 116.0 (1Ј-C), 63.2 (6Ј-C), 32.9 (3Ј-C), 32.6 (5Ј-C),
26.4 (tBu), 25.1 (4Ј-C), 18.8 (q-C) and Ϫ4.9 (Si-Me); m/z (ES)
(Found: m/z (Mϩ ϩ 1), 326.2583. C16H28O4NSi requires
(Mϩϩ1) 326.1787).
2-[6-(tert-Butyldimethylsilyloxy)hex-1-enyl]-1,3-oxazole-4-
carboxylic acid allyl ester 41
A solution of tricarpylmethylammonium chloride (77 mg, 0.2
mmol) and allyl bromide (23 mg, 0.2 mmol) in dichloromethane
(0.3 ml) was added in one portion to a stirred suspension of the
carboxylic acid 40b (62 mg, 0.2 mmol) and sodium hydrogen
carbonate (16 mg, 0.2 mmol) in water (0.3 ml) at room temper-
ature. The mixture was stirred vigorously at room temperature
for 24 h, and then extracted with dichloromethane (3 × 10 ml).
2426
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428

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The combined organic phases were dried (MgSO4) and evapor-
ated in vacuo. The residue was purified by chromatography on
silica using 5:1 petrol–ethyl acetate as eluent to give the olefin
(35 mg, 51%) as a colourless oil; νmax(CHCl3)/cmϪ1 1731, 1664,
1578, 1462, 1369, 1317, 1092 and 989; δH(360 MHz, CDCl3)
141.8, 133.8 (s), 133.1, 131.7, 119.0 (t), 116.1, 94.9 (s), 80.1 (s),
67.4 (t), 65.7 (t), 63.8 (t), 55.1, 48.3 (t), 42.9 (t), 34.0 (t), 32.2 (t),
29.6 (t), 28.6 (t), 28.2, 28.1, 28.0 (t), 26.8, 25.0, 24.7 (t), 24.6,
24.2, 23.1 (t), 19.3 (q); m/z (FAB) (Found: Mϩ ϩ 1, 686.3677
(100%). C36H52O10N3 requires M, 686.3654).
8.14 (1H, s, 5-H), 6.85 (1H, dt, J 16.0 and 7.0 Hz, HC᎐
᎐
Bis-oxazole amino acid ester 43
CHCH ), 6.32 (1H, d, J 16.0 Hz, CH᎐CHCH ), 6.01 (1H, ddt,
᎐
2
2
J 17.1, 10.4 and 5.9 Hz, CH CH᎐CH ), 5.39 (1H, dd, J 17.2 and
᎐
2
2
Pyrrolidine (33.1 µl, 0.4 mmol) was added in one portion to a
stirred solution of the ester (42) (0.18 g, 0.3 mmol), tetrakis-
(triphenylphosphine)palladium (18 mg, 0.016 mmol) and
triphenylphosphine (4.1 mg, 0.016 mmol) in dichloromethane
(2 ml) at 0 ЊC under a nitrogen atmosphere. The mixture was
stirred at 0 ЊC for 4 h, diluted with dichloromethane (10 ml) and
then washed with 1 M HCl (3 ml). The separated organic layer
was then dried (MgSO4) and evaporated in vacuo. The residue
was purified by chromatography on silica using 9:1 dichloro-
methane–methanol as eluent to give the acid (0.11 g, 70%) as an
opaque oil. A 50% solution of trifluoroacetic acid in dichloro-
methane (1 ml) was added to the acid (20 mg, 0.03 mmol) and
the resulting mixture was stirred at room temperature for 1 h.
The mixture was then evaporated in vacuo to leave the TFA salt
which was not purified further.
1.4 Hz, ᎐CHH), 5.29 (1H, dd, J 10.4 and 1.1 Hz, ᎐CHH), 4.82
᎐
᎐
(2H, d, J 5.9 Hz, CH ᎐CH), 3.66–3.61 (2H, m, 6Ј-H), 2.31–2.28
᎐
2
(2H, m, 3Ј-H), 1.57–1.42 (4H, m, 4Ј and 5Ј-H), 0.89 (9H, s, tBu)
and 0.05 (6H, s, 2 × CH3); δC(67.5 MHz, CDCl3) 161.7 (CO),
161.0 (2-C), 143.0 (5-C), 142.6 (2Ј-C), 133.7 (4-C), 131.7, 119.0,
115.8 (1Ј-C), 65.7, 62.7 (6Ј-C), 32.5 (3Ј-C), 32.1 (5Ј-C), 25.9
(tBu), 24.7 (4Ј-C), 18.3 and Ϫ5.4 (Si-Me); m/z (FAB) (Found:
Mϩ ϩ 1, 366.2094 (66%). C19H32O4NSi requires M, 366.2101).
2-(6-Hydroxyhex-1-enyl)-1,3-oxazole-4-carboxylic acid allyl
ester 28
A solution of the silyl ether 41 (115 mg, 0.3 mmol) in a 3:1:1
mixture of AcOH–THF–H2O (3.0 ml) was stirred at room tem-
perature for 2 h. The mixture was basified with saturated
sodium hydrogen carbonate solution and the separated aque-
ous phase was then extracted with dichloromethane (3 × 10
ml). The combined organic phases were dried (MgSO4) and
evaporated in vacuo. The residue was purified by chroma-
tography on silica using 5:1 petrol–ethyl acetate as eluent to
give the corresponding alcohol (70 mg, 91%) as a straw coloured
oil; νmax(CHCl3)/cmϪ1 2936, 1732, 1664, 1316, 1116, 990 and
663; δH(360 MHz, CDCl3) 8.14 (1H, s 5-H), 6.85 (1H, dt, J 16.0
and 7.0 Hz, 2Ј-H), 6.32 (1H, d, J 16.0 Hz, 1Ј-H), 6.01 (1H, ddt,
4-Hydroxymethyl-9-methyl-6,18,26-trioxa-3,28,29-triazatri-
cyclo[23.2.1.15,8]nonacosa-1(27),5(29),7,23,25(28)-pentaene-
2,11,17-trione 44
Diisopropylethylamine (37 mg, 0.29 mmol) was added in one
portion to a stirred solution of the salt 43 (51 mg, 0.08 mmol) in
dry DMF (16 ml) under a nitrogen atmosphere at 0 ЊC. The
solution was stirred at 0 ЊC for 15 min and then diphenylphos-
phoryl azide (0.034 g, 0.12 mmol) was added and the mixture
was stirred for a further 3 min and then left at room temper-
ature for 5 days. The mixture was diluted with ethyl acetate (20
ml) and poured into ice-cold water. The separated aqueous
layer was extracted with ethyl acetate (3 × 20 ml) and the com-
bined organic extracts were washed with water (6 × 30 ml) and
brine (30 ml), then dried (MgSO4) and evaporated in vacuo. The
residue was purified by chromatography on silica using ethyl
acetate as eluent to give the amide (14 mg, 36%) as an oil;
νmax(CHCl3)/cmϪ1 3399, 1715, 1688 and 1596; δH(500 MHz,
CDCl3, major rotamer) 8.20 (1H, s, 29-H), 8.02 (1H, d, J 7.4 Hz,
NH), 7.45 (1H, s, 21-H), 6.93 (1H, dt, J 16.2 and 6.8 Hz, 2-H),
6.37 (1H, m, 1-H), 5.46–5.42 (1H, m, 22-H), 4.27–4.10 (4H, m,
23-H and 6-H), 3.42–3.37 (1H, m, 15-H), 3.03 (1H, dd, J 16.7
and 11.0 Hz, 14-H), 2.62–2.56 (1H, m, 14-H), 2.54–2.35 (6H, m,
12-H, 8-H and 3-H), 1.84–1.61 (4H, m, 4-H and 5-H), 1.50–1.22
(6H, m, 9-H, 10-H and 11-H) and 0.97–0.91 (3H, m, 16-H);
δC(125 MHz, CDCl3) 209.5 (s), 173.6 (s), 161.0 (s), 160.8 (s),
145.3 (s), 144.4 (s), 141.7 (d), 140.5 (d), 136.1 (s), 134.2 (d),
132.1 (d), 128.6 (d), 116.0 (d), 64.6 (t), 63.8 (t), 48.3 (t), 43.0 (t),
34.4 (t), 31.9 (t), 29.7 (t), 28.6 (t), 27.8 (t), 24.7 (t), 23.4 (t), 19.4
(q); m/z (EI) (Found: Mϩ Ϫ H2O, 469.2223 (100%). C25H31O6N3
requires M, 469.2167).
J 17.1, 10.4 and 5.9 Hz, CH CH᎐CH ), 5.39 (1H, dd, J 17.2 and
᎐
2
2
1.4 Hz, ᎐CHH), 5.29 (1H, dd, J 10.4 and 1.1 Hz, ᎐CHH), 4.82
᎐
᎐
(2H, d, J 5.9 Hz, CH CH᎐CH ), 3.66–3.61 (2H, m, 6Ј-H),
᎐
2
2
2.31–2.28 (2H, m, 3Ј-H) and 1.57–1.42 (4H, m, 4Ј and 5Ј-H);
δC(90 MHz, CDCl3) 161.8 (CO), 161.0 (2-C), 143.1 (5-C), 142.2
(2Ј-C), 133.9 (4-C), 131.7, 119.1, 116.0 (1Ј-C), 65.8, 62.5 (6Ј-C),
32.5 (3Ј-C), 32.0 (5Ј-C) and 24.6 (4Ј-C).
4-{8-[6-(4-Allyloxycarbonyl-1,3-oxazol-2-yl)hex-5-enyloxycarb-
onyl]-1-methyl-3-oxooctyl}-2Ј,2Ј-dimethyl-2Ј,3Ј,4Ј,5Ј-tetra-
hydro-2,4Ј-bi(1,3-oxazolyl)-3Ј-carboxylic acid tert-butyl
ester 42
1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide
hydro-
chloride (37 mg, 0.19 mmol) was added in one portion to a
stirred solution of the acid 29 (77 mg, 0.18 mmol) and the
alcohol 28 (50 mg, 0.20 mmol) in dichloromethane (6 ml) at
0 ЊC containing 4-(dimethylamino)pyridine (11 mg, 0.09
mmol). The mixture was stirred at 0 ЊC for 2 h and then at room
temperature overnight before it was evaporated to dryness in
vacuo. The residue was diluted with ethyl acetate (10 ml) and
water (2 ml), and the organic layer was then separated, washed
with saturated sodium bicarbonate (15 ml) and water (15 ml),
dried (Na2SO4) and evaporated in vacuo. The residue was
purified by chromatography on silica using 1:1 petrol–ethyl
acetate as eluent to give the ester (89 mg, 73%) as an oil;
νmax(CHCl3)/cmϪ1 3156, 2253, 1793, 1730, 1720, 1368, 1096 and
889; δH(360 MHz, CDCl3) 8.14 (1H, s, 9-H), 7.31 (1H, s, 30-H),
6.83 (1H, dt, J 16.0 and 7.0 Hz, 11-H), 6.33 (1H, d, J 16.0 Hz,
The oxazole-oxazoline-oxazole macrolide 45
A solution of Burgess’ reagent (4.5 mg, 0.02 mmol) in dry THF
(0.2 ml) was added to a solution of the amide 44 (8 mg, 0.02
mmol) in dry THF (0.4 ml) and the mixture was heated under
reflux for 2 h in a nitrogen atmosphere. The cooled mixture was
evaporated to dryness in vacuo and the residue was purified by
chromatography on silica using 1:1 petrol–ethyl acetate as eluent
to give the oxazoline (5.5 mg, 72%); δH(360 MHz, CDCl3) 8.01
(1H, d, J 8.8 Hz, 8-H), 7.33 (1H, d, J 14.6 Hz, 14-H), 6.98–6.84
(1H, m, 5-H), 6.29 (1H, d, J 15.9 Hz, 6-H), 5.48–5.35 (1H, m,
12-H), 4.77–4.58 (2H, m, 2 × 11-H), 4.16–3.98 (2H, m, 1-H),
3.40 (1H, apparent d, J 4.8 Hz, 16-H), 3.33–3.25 (1H, m,
18-H), 2.96–2.87 (1H, m, 18-H), 2.46–2.15 (6H, m, 20-H, 24-H
and 4-H), 1.87–1.35 (4H, m, 2-H and 3-H), 1.29–1.03 (6H, m,
23-H, 22-H and 21-H) and 0.90–0.76 (3H, m, 17-H).
10-H), 6.01 (1H, ddt, J 17.1, 10.4 and 5.9 Hz, CH CH᎐CH ),
᎐
2
2
5.37 (1H, dd, J 10.4 and 1.4 Hz, ᎐CHH), 5.27 (1H, dd, J 10.4
᎐
and 1.1 Hz, ᎐CHH), 5.08–4.96 (1H, m, 31-H), 4.82 (2H, dt,
᎐
J 5.6 and 1.3 Hz, 3-H), 4.23–4.03 (4H, m, 32-H and 15-H),
3.31–3.26 (1H, m, 24-H), 2.83 (1H, dd, J 16.8 and 5.8 Hz,
23-H), 2.51 (1H, dd, J 16.9 and 7.8 Hz, 23-H), 2.40–2.27 (6H,
m, 12-H, 17-H and 21-H), 1.73–1.55 (10H, m, 13-H, 14-H and
t
2 × CH3), 1.48–1.08 (15H, m, 18-H, 19-H, 20-H and Bu) and
0.90–0.80 (3H, m, 25-H); δC(360 MHz, CDCl3) 210.5 (s), 173.6
(s), 162.8 (s), 161.7 (s), 160.9 (s), 151.2 (s), 144.9 (s), 143.1,
J. Chem. Soc., Perkin Trans. 1, 2000, 2415–2428
2427

View Online
J. Antibiot., 1984, 37, 354; and calyculin A: Y. Kato, N. Fusetani,
The ter-oxazole macrolide 30
S. Matsunaga, K. Hashimoto, S. Fujita and T. Furuya, J. Am. Chem.
Soc., 1986, 108, 2780; the bis-oxazoles: hennoxazole A, T. Ichiba,
W. Y. Yoshida, P. J. Scheuer, T. Higa and D. G. Gravalos, J. Am.
Chem. Soc., 1991, 113, 3173; muscoride A, A. Nagatsu, H. Kajitani
and J. Sakakibara, Tetrahedron Lett., 1995, 36, 4097; diazonamide:
N. Lindquist, W. Fenical, G. D. Van Duyne and J. Clardy, J. Am.
Chem. Soc., 1991, 113, 2303.
7 For a review of this topic see: J. P. Michael and G. Pattenden, Angew.
Chem., Int. Ed. Engl., 1993, 32, 1.
8 (a) S. K. Chattopadhyay and G. Pattenden, Synlett, 1997, 1345; (b)
S. K. Chattopadhyay and G. Pattenden, Tetrahedron Lett., 1998, 39,
6095 and references cited therein.
9 D. W. Knight, G. Pattenden and D. E. Rippon, Synlett, 1990, 1, 36.
10 See the following paper S. K. Chattopadhyay and G. Pattenden,
J. Chem. Soc., Perkin Trans. 1, 2000, DOI: 10.1039/b000751j.
11 For a discussion on this topic see: (a) R. E. Moore, G. M. L.
Patterson, S. Mynderse, J. Barchi, T. R. Norton, E. Furusawa and
S. Furusawa, Pure Appl. Chem., 1986, 58, 263; (b) M. Ishibashi,
R. E. Moore, G. M. L. Patterson, C. Xu and J. Clardy, J. Org.
Chem., 1986, 51, 5300.
12 A. I. Meyers, R. K. Smith and C. E. Whitten, J. Org. Chem., 1979,
44, 2250.
13 A. I. Meyers, D. L. Evans, D. K. Minster, U. Jordis, S. M. Hecht
and A. L. Muzzu, J. Org. Chem., 1979, 44, 497.
Freshly prepared nickel peroxide (150 mg) was added in three
portions to a refluxing solution of the oxazoline 45 (50 mg) in
dry benzene (3 ml) at one hour intervals. The mixture was
heated under reflux for 2 h, and then filtered through Celite.
The filtrate was concentrated in vacuo to leave a viscous mass.
Purification by chromatography on silica using ethyl acetate as
eluent gave the ter-oxazole macrolide as a white solid mp 140–
142 ЊC (EtOAc); λmax(EtOH)/nm 263 (1888); νmax(CHCl3)/cmϪ1
3019, 2929, 1715 and 1215; δH(500 MHz, CDCl3) 8.07 and 8.06
(2 × 1H, s, 8 and 11-H), 7.40 (1H, s, 14-H), 7.19 (1H, dt, J 15.9
and 7.1 Hz, 5-H), 6.31 (1H, dt, J 15.9 and 1.5 Hz, 6-H), 4.08
(2H, 2 × dt, J 22.0 and 10.8 Hz, 1-H), 3.43–3.39 (1H, m, 16-H),
3.29 (1H, dd, J 17.2 and 6.0 Hz, 18-H), 2.63–2.57 (1H, m,
18-H), 2.49–2.35 (6H, m, 20-H, 24-H and 4-H), 1.80–1.60 (4H,
m, 2-H and 3-H), 1.46–1.16 (6H, m, 23-H, 22-H and 21-H) and
0.93–0.78 (3H, m, 17-H); δC(125 MHz, CDCl3) 210.25 (s),
173.86 (s), 162.77 (s), 156.57 (s), 154.26 (s), 146.65 (s), 143.23
(d), 137.27 (d), 137.02 (d), 133.40 (d), 131.76 (s), 130.39 (s),
115.21 (d), 65.86 (t), 48.08 (t), 43.64 (t), 34.58 (t), 31.13 (t),
29.70 (t), 29.15 (t), 27.44 (d), 26.88 (t), 25.06 (t), 24.45 (t) and
18.96 (q); m/z (FAB) (Found: Mϩ ϩ 1, 468.2154 (7%).
C25H30O6N3 requires M, 468.2134).
14 J. W. Cornforth and R. H. Cornforth, J. Chem. Soc., 1947, 96.
15 Y. Hamada, M. Shibata and T. Shioiri, Tetrahedron Lett., 1985, 26,
6501.
16 A. I. Meyers and F. Tavares, Tetrahedron Lett., 1994, 35, 2481.
17 D. C. Waite, PhD Thesis, University of Nottingham, 1993.
18 A. McNeill, University of Nottingham, unpublished work.
19 (a) J. S. Panek, R. T. Beresis and C. A. Celatka, J. Org. Chem., 1996,
61, 6494; (b) J. S. Panek and R. T. Beresis, J. Org. Chem., 1996, 61,
6496; (c) P. Liu, C. A. Celatka and J. S. Panek, Tetrahedron Lett.,
1997, 38, 5445; (d) C. A. Celatka, P. Liu and J. S. Panek, Tetrahedron
Lett., 1997, 38, 5449.
Acknowledgements
We thank the EPSRC for support of this work via Studentships
(to M. R., D. E. P. and D. W.) and a Post-doctoral Fellowship
(to S. K. C.), and Zeneca for a Research Studentship (to J. K).
We also thank Pfizer and Zeneca for their generous financial
support of our research program.
20 S.-K. Yoo, Tetrahedron Lett., 1992, 33, 2159. cf. K. J. Doyle and C. J.
Moody, Tetrahedron, 1994, 50, 3761.
21 (a) P. Garner and J. M. Park, J. Org. Chem., 1987, 52, 2361; (b)
A. McKillop, R. J. K. Taylor, R. J. Watson and N. Lewis, Synthesis,
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Synthesis, 1998, 12, 1707.
22 G. M. Atkins, Jr. and E. M. Burgess, J. Am. Chem. Soc., 1968, 90,
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23 D. R. Williams, P. D. Lowder, Y.-G. Gu and D. A. Brooks,
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24 M. Reader, PhD Thesis, University of Nottingham, 1995.
25 S. J. Danishefsky and W. H. Pearson, J. Org. Chem., 1983, 48, 3865.
26 R. Deziel, Tetrahedron Lett., 1987, 28, 4371.
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