Total synthesis of (-)-ulapualide A, a novel tris-oxazole macrolide from marine nudibranchs, based on some biosynthesis speculation

Article abstract of DOI:10.1039/b801036f

A new, second generation, total synthesis of ulapualide A (1), whose stereochemistry was recently determined from X-ray analysis of its complex with the protein actin, is described. The synthesis is designed and based on some speculation of the biosynthet

Full text of DOI:10.1039/b801036f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Total synthesis of (−)-ulapualide A, a novel tris-oxazole macrolide from
marine nudibranchs, based on some biosynthesis speculation†
Gerald Pattenden,* Neil J. Ashweek, Charles A. G. Baker-Glenn, James Kempson, Gary M. Walker and
James G. K. Yee
Received 21st January 2008, Accepted 6th February 2008
First published as an Advance Article on the web 6th March 2008
DOI: 10.1039/b801036f
A new, second generation, total synthesis of ulapualide A (1), whose stereochemistry was recently
determined from X-ray analysis of its complex with the protein actin, is described. The synthesis is
designed and based on some speculation of the biosynthetic origin of the contiguous tris-oxazole unit
in ulapualide A, alongside that of the related co-metabolites that contain only two oxazole rings, e.g. 6
and 7. The mono-oxazole carboxylic acid 67b and the mono-oxazole secondary alcohol 55b which,
together, contain all of the 10 asymmetric centres in the natural metabolite, were first elaborated using a
combination of contemporary asymmetric synthesis protocols. Esterification of 67b with 55b under
Yamaguchi conditions gave the ester 77 which was then converted into the x-amino acid 18a following
simultaneous deprotection of the t-butyl ester and the N-Boc protecting groups. Macrolactamisation of
18a, using HATU, now gave the key intermediate macrolactam 17, containing two of the three oxazole
rings in ulapualide A (1). A number of procedures were used to introduce the third oxazole ring in
ulapualide A from 17, including: a) cyclodehydration to the oxazoline 78a followed by oxidation using
nickel peroxide leading to 76; b) dehydration to the enamide 79, followed by conversion into the
methoxyoxazoline 78b, via 80, and elimination of methanol from 78b using camphorsulfonic acid. The
tris-oxazole macrolide 76 was next converted into the aldehyde 82b in four straightforward steps, which
was then reacted with N-methylformamide, leading to the E-alkenylformamide 83. Removal of the
TBDPS protection at C3 in 83 finally gave (−)-ulapualide A, whose 1H and 13C NMR spectroscopic
data were indistinguishable from those obtained for naturally derived material. It is likely that the
tris-oxazole unit in ulapualide A (1) is derived in nature from a cascade of cyclodehydrations from an
acylated tris-serine precursor, e.g. 9, followed by oxidation of the resulting tris-oxazoline intermediate,
i.e. 10. It is also plausible to speculate that the biosynthesis of metabolites related to ulapualide A, e.g.
the bis-oxazole 6 and the imide 7, involve cyclisations of just two of the serine units in 9. These
speculations were given some credence by carrying out pertinent interconversions involving the
bis-oxazole amide 24, the enamide 25, the imide 26, the oxazoline 27 and the tris-oxazole 30 as model
compounds. An alternative strategy to the tris-oxazole macrolide intermediate 76 was also examined,
involving preliminary synthesis of the aldehyde 73, containing a shortened (C25–C34) side chain from
67b and 47b. A Wadsworth–Emmons olefination reaction between 73 and the phosphonate ester 74 led
smoothly to the E-alkene 75, but we were not able to reduce selectively the conjugated enone group in
75 to 76 without simultaneous reduction of the oxazole alkene bond, using a variety of reagents and
reaction conditions.
and halichondramides 5,2–4 together with a number of congeners
Introduction
where the tris-oxazole unit has been severed, e.g. 6, or modified
as an imide, e.g. 7.5 The ulapualides show antifungal activity
The “ulapualides” are a unique family of macrolides isolated from
sponges and nudibranchs (sea slugs). They show structures which
and ichthyotoxic properties, together with modest activity against
feature three contiguously linked oxazoles embedded within the
L1210 leukemia cells.
macrocycle, and a substituted polyol side chain terminated by
At the time ulapualide A was isolated in the late 1980s,
oxazoles had rarely been reported as secondary metabolides,
let alone those containing contiguously linked oxazoles. The
an unusual N-formyl enamine unit. Ulapualide A (1) was the
first of their number to be characterised1, and the family now
includes the mycalolides, e.g. 2, kabiramides 3, halishigamides 4
burgeoning family of polyoxazole-based secondary metabo-
lites now includes the phorboxazoles,6 hennoxazoles,7 dia-
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD,
England
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures; crystal structure data. See DOI: 10.1039/b801036f
zonamide A,8 several azole-based cyclic peptides9, the tetra-
oxazole YM-216391,10 and the intriguing hepta-oxazole telomes-
tatin.11
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The juxtaposition of several nitrogen and oxygen ligand-
binding sites in the ulapualides encouraged us earlier to carry
out a molecular mechanics study of a hypothetical metal-chelated
complex of ulapualide A.12 This study led us to assign the relative
stereochemistry shown in structure 8 for ulapualide A,13 and in
1998 we described a total synthesis of this compound. Much to
our chagrin, although the synthetic ulapualide A showed identical
at C32. Contemporaneously, Panek and Fusetani,14 and their col-
laborators, using a combination of degradation studies, together
with reconnective and total synthesis, established that the related
metabolite mycalolide A had the stereochemistry shown in the
structure 2. The stereochemistry established for mycalolide A
differed from the one we had tentatively assigned to ulapualide A
at no less than five stereocentres, i.e. C28, C29, C30, C32 and C3.
This was uncanny, even somewhat bewildering, in view of the close
similarityofmuchoftheNMRspectroscopicdatarecordedforour
synthetic and natural ulapualide A. To cap it all, in 2004, Rayment
et al.15 presented an X-ray crystal structure of ulapualide A bound
to the protein actin which showed that the metabolite had the
stereochemistry shown in structure 1. Thus, ulapualide A (1) and
1
chromatographic behaviour, as well as chiroptical and H NMR
spectroscopic data, with those of the natural product, very small
differences were observed in the 13C NMR spectra, associated with
the C32–C34 portions, of the structures. We therefore concluded
that we had synthesised a diastereoisomer of natural ulapualide
A, which, apart from other features, was almost certainly epimeric
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mycalolide A (2) have identical stereochemistries at C3, and along
their C28–C33, and indeed C37–C39, side chains. As synthetic
chemists, driven by curiosity and desirous of completeness, it
became imperative for us to undertake a new, second generation,
total synthesis of ulapualide A. This paper presents full details
of these new synthetic endeavours,16 which are interweaved with
an exploration of the biosynthetic interrelationship between the
contiguously linked tris-oxazole containing metabolites 1–5 and
those congeners, 6 and 7, with incomplete tris-oxazole motifs.
discussing this total synthesis of ulapualide A (1) in detail,
however, we first describe some complementary synthetic inter-
conversions with some model substrates, which give credence to
the speculation regarding the biosynthetic relationships between
the ulapualides 1–5, and their congeners, 6 and 7, having modified
tris-oxazole units.18
Using the truncated tris-oxazole 30, together with the bis-
oxazole amide 24 and the oxazoline bis-oxazole 27, as model
compounds, we first prepared the known substituted oxazoles 21
and 22a18 starting from readily available derivatives of serine. The
oxazole-oxazolidine 21 was next doubly deprotected, using 4 M
HCl in dioxane, and the resulting secondary amine 23 was then
acylated with the acid chloride 22b, produced from 22a, leading
to the bis-oxazole serine amide derivative 24 (Scheme 3).
Treatment of 24 with SOCl2 in DCM next gave the corre-
sponding alkyl chloride, which underwent dehydrochlorination
in the presence of DBU to produce the enamide 25 (Scheme 3).
Oxidative cleavage of the alkene bond in 25, using catalytic RuO2
and NaIO4 then gave the imide 26, cf. the natural product 7. In
a separate sequence, the bis-oxazole serine amide 24 underwent
cyclodehydration when treated with DAST,19 producing the bis-
oxazole oxazoline 27 in 99% yield. Oxidation of the oxazoline
27 in the presence of NiO2 in hot benzene,20 or better, using
BrCCl3–DBU,21 then led to the contiguously linked tris-oxazole
30. The same tris-oxazole 30 was also produced from the enamide
25 following conversion to the methoxy-substituted oxazoline 29
via the methoxy-bromide 28, and treatment with camphorsulfonic
acid in toluene (Scheme 3).22 The aforementioned synthetic
interconversions, involving the amide 24, the enamide 25, the
imide 26, together with the oxazolines 27 and 29 and the tris-
oxazole 30, not only provide a plausible biogenetic link between
the ulapualide natural products 1–7, but also set some precedent
for the more demanding synthetic work towards ulapualide A that
we were about to embark upon.
Discussion and synthetic strategy
In the absence of biosynthetic studies, it is likely that the tris-
oxazole unit 11 in the ulapualides is derived from a cascade of
cyclodehydrations from an acylated tris-serine precursor, e.g. 9,
followed by oxidation of the resulting tris-oxazoline intermediate
10.17 It is also plausible that a similar cyclodehydration–oxidation
process involving just two of the serine units in 9 would lead to
the bis-oxazole amide 12 (Scheme 1). The amide 12 could then
act as precursor to the tris-oxazole 11, and also to the enamide
13, and then to the open-chain ester-amide 15, by a sequence
involving oxidation to the imide 14 and hydrolysis. Indeed, based
on this speculation we designed our second generation synthesis
of ulapualide A (1) involving macrolactamisation of an x-amino
acid intermediate, viz. 18a, as a key step, followed by elaboration of
the central oxazole ring in the natural product from a macrolide-
macrolactam, viz. 17a,18 as a late step in the overall synthesis. This
approach required a synthesis of the ester 18a from the carboxylic
acid 20a and the alcohol 19, which, together, contain all of the ten
stereocentres in ulapualide A. The terminal formyl enamine unit
in 1 would be introduced as a late step in the synthesis, following
manipulation of the functionality and the protecting groups in
the tris-oxazole macrolide 16a, leading to the aldehyde 16b,
and treatment of the latter with N-methylformamide. Before
Scheme 1
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Scheme 2
Scheme 3 Reagents and conditions: i, 22, 23, DCM, 87%; ii, SOCl2, DCM, 98%; iii, DBU, DCM, 99%; iv, RuO2, NaIO4, CCl4, H2O, MeCN, 50%; v,
DAST, DCM, −78 ◦C, 99%; vi, NiO2, benzene, reflux, 40% or BrCCl3, DBN, 81%; vii, NBS, MeOH, 96%; viii, Cs2CO3, dioxane, 88%; ix, CSA, toluene,
Dean–Stark, 95%.
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Scheme 4
Synthesis of the oxazole-substituted C25–C41 (55) and C25–C34
(47) side chains
by X-ray crystallography.26 Deprotection of the silyl ether in 49b
and oxidation of the resulting alcohol, using TPAP, next gave the
aldehyde 50b. A Wadsworth–Emmons reaction between the alde-
hyde 50 and the phosphonate ester 51 we had used in our synthesis
of the diastereoisomer of ulapualide A,13 using Ba(OH)2 as base27
then gave the E-alkene 52, which, in one step was converted into
the alcohol 53a following hydrogenation/hydrogenolysis in the
presence of Pearlman’s catalyst28 The primary alcohol in 53a was
now protected as its TBDPS ether 53b, and the dimethylacetal
In our synthesis of the diastereoisomer 8 of ulapualide A, we
applied a range of contemporary synthetic methods in asymmetric
synthesis, and examined a variety of OH protecting groups to
prepare the C26–C41 (top chain) portion in 8. Pertinent to these
studies was the use of methoxymethyl, t-butyldimethylsilyl and
t-butyldiphenylsilyl ether protecting groups at C30, C38 and C41
respectively, and their sequential and selective deprotection using
Me2BBr (for MeOCH2O–), Me3SiOTf (for C38, sec-OH), HF–
C5H5N (for C41, primary OH).
We investigated two separate approaches to the advanced
intermediate 16a en route to ulapualide A. In the first of these
approaches we planned to synthesise the tris-oxazole based
macrolide 31 containing a shortened (C25–C34) side chain,
derived ultimately from 19b and 20, via 18b, and then to elaborate
31 to 16a via an olefination reaction, producing 32, followed by
selective reduction of the C34–C35 alkene bond (Scheme 4). In the
second, more convergent, approach we proposed incorporating the
entire C25–C41 top chain in the natural product at an earlier stage
in the overall synthesis, i.e. starting with the oxazole substituted
intermediate 19a.
The (shortened) C25–C34 side chain 47 was synthesised
starting from 3-benzyloxypropanal 33, (R)-2-benzyl-3-propionyl-
2-oxazolidinone 34, and the (R)-pentenoyloxazolidin-2-one 40,
using conventional Evans aldol chemistry23 to introduce the syn
stereochemistry at C32–C33 (i.e. 34 → 35) and the anti- stere-
ochemistry at C29–C30 (i.e. 40 → 41), and by applying Brown’s
allylboration chemistry24 to install the b-orientated hydroxyl group
at C28 (viz. 43 → 44a) (Scheme 5). Protection of the hydroxyl
group in 44a as its methyl ether 44b, followed by oxidative cleavage
of the alkene bond, next gave the corresponding aldehyde 45. A
Wittig reaction between the aldehyde 45 and the phosphorus ylide,
derived in situ from the oxazolemethyl bromide 46a25 and Bu3P,
using DBU as base, gave the E-vinyloxazole 47a with the C25–C34
side chain present in ulapualide A. The methyl ether group in 47a
was then converted into the corresponding alcohol in two steps
leading to 47b in readiness for coupling to the carboxylic acid 20
en route to the macrolide 31.
◦
group was then unmasked selectively using Me2BBr at −78 C29
to give the aldehyde 54 in excellent yield (Scheme 6). Finally, a
straightforward Wittig reaction between 54 and the phosphonium
salt 46b, under the same conditions as those used to synthesise 47a
from 45, led to the E-2-alkenyloxazole 55a, which was selectively
deprotected using Me2BBr in CH2Cl2 at −78 ◦C to provide the
corresponding C30-alcohol 55b.
Synthesis of the oxazole-substituted carboxylic acid 20
In our (first generation) synthesis of the diastereoisomer 8 of
ulapualide A we introduced the methyl group at C9 as a late step in
the overall synthesis using a 1,4-addition reaction of methylcopper
lithium to an C8,9-unsaturated enone precursor. This conjugate
addition showed poor selectivity (3:2, a:b) and accordingly we
examined an alternative strategy to synthesise the C9(S)-methyl,
C3(S) oxy-protected carboxylic acid 20 (Scheme 2).30 This syn-
thesis was based on a little-used chromium-mediated coupling
reaction between the C4 (S) oxy-protected alkyl iodide 59 and the
C3(S) methyl substituted aldehyde 65, in the presence of vitamin
B12.31
Thus, asymmetric reduction of the known b-keto ester 56a32
using (S)-Ru[BINAP]33 first gave the (S)-hydroxy ester 57a (97%
ee), which was next selectively protected as its C6-TBS, C3-TBDPS
bis-silyl ether 58a (Scheme 7). The absolute stereochemistry of 57a
was confirmed by comparison with the same compound prepared
from 56b using Noyori’s asymmetric hydrogenation protocol,
followed by hydrogenolysis of the benzyl ether protecting group
([a]D +21.9; [a]D +22.7 synthetic).34 Selective deprotection of the
TBS group in 58a, using camphorsulfonic acid in MeOH, followed
by iodination of the resulting primary alcohol 58a then gave the
(S)-iodide 59 in 83% overall yield over two steps.
The oxazole-substituted compound 55b, containing the entire
C25–C41 top chain in ulapualide A, was also synthesised from the
intermediate 44b following exchange of TBS for MOM, oxidative
cleavage of the alkene bond in 48b and protection of the resulting
aldehyde as the corresponding dimethylacetal 49b (Scheme 6). The
absolute stereochemistry of the dimethylacetal 49b was established
The substituted aldehyde 65 was prepared from Garner’s
aldehyde starting with an E-selective Wittig reaction, leading to
the a,b-unsaturated ester 60,35 followed by chelation-controlled
syn-addition of lithium dimethylcuprate producing the adduct 61a
(9:1 syn selectivity).35 Successive functional group interconversions
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Scheme 5 Reagents and conditions: i, Bu2BOTf, Et3N, DCM, −78 ◦C, 72%; ii, LiBH4–MeOH, THF; iii, TBDPS-Cl, imidazole, DMF, 94%; iv, NaHMDS,
MeI, THF, 0 ◦C, 90%; v, Pd(OH)2/C, H2, EtOAc, 92%, vi, DMSO, (COCl)2, DCM, Et3N, −78 ◦C, 96%; vii, ethoxycarbonylmethylenetriphenylphos-
phorane, DCM, 68%; viii, LiOH, THF, H2O, 95%; ix, (COCl)2, DMF, DCM, 99%; x, n-BuLi, 4-phenylmethyl-2-oxazolidone, −78 ◦C, 95%; xi, 37,
Bu2BOTf, Et3N, DCM, −78 ◦C, 58%, xii, LiBH4–MeOH, THF, 99%; xiii, MsCl, DIPEA, DCM, −40 ◦C; xiv, LiBH4–MeOH, THF, 85%; xv, TBSOTf,
2,6-lutidine, DCM, 85%; xvi, O3, DCM, PPh3, −78 ◦C, 93%; xvii, allylmagnesium bromide, Et2O, −78 ◦C, (−)-B-chlorodiisopinocamphenylborane, 91%;
xviii, NaHMDS, MeI, THF, −15 ◦C, 91%; xix, O3, DCM, PPh3, −78 ◦C, 94%; xx, PBu3, then 45, DBU, DMF, 0 ◦C, 91%; xxi, HF–pyridine, THF,
pyridine, 91%, then TBDPSCl, imidazole, DMF, 63%.
next led to the amino alcohol 62, which was then reacted with
Garner’s acid36 to deliver the corresponding amide 63 (Scheme 8).
Oxidation of the primary OH group in 63 followed by a Robinson–
Gabriel cyclisation37 of the resulting keto-aldehyde gave the
substituted oxazole 64, which was then elaborated to the C7-
aldehyde 65 in two straightforward steps.
The oxazole-substituted aldehyde 65 was coupled to the iodide
59 in degassed DMF in the presence of chromium chloride and
vitamin B12 to give a 1:1 mixture of C7 epimers of the alcohol
66 in 88% yield. Finally, oxidation of the alcohol 66 using Swern
conditions, followed by saponification of the ester group in the
resulting 6-ketoester 67a, using LiOH/MeOH, gave the carboxylic
acid 67b.
in a position to examine their combination and conversion to
the tris-oxazole macrolide 72. The esterification of the carboxylic
acid 67b with the alcohol 47b proceeded smoothly under Ya-
maguchi conditions38 to give the ester 68 in an excellent 96%
yield (Scheme 9). The t-butyl ester and the N-Boc protecting
groups in 68 were then removed simultaneously using TMSOTf
in the presence of Et3N39 to give the amino acid 69, which was
immediately treated with DPPA and iPr2NEt40 in DMF at room
temperature, leading to the macrolactam 70 in 50–70% yield over
two steps. When the macrolactam 70 was treated with DAST
at −78 ◦C it underwent smooth cyclodehydration and gave the
corresponding oxazoline 71 in 92% yield. The oxidation of the
oxazoline 71 to the tris-oxazole macrolide 72 however did not turn
out to be straightforward. Where most oxidants such as DDQ,
MnO2 and activated NiO2 worked reasonably well with model
systems, both DDQ or MnO2 failed to oxidise 71 to 72, and NiO2
needed to be used in considerable excess (60 equiv), with recovery
and recycling of unoxidised oxazoline, before a respectable 55%
yield of the tris-oxazole macrolide 72a could be realised.
Synthesis of the tris-oxazole macrolide 72a containing a C25–C34
side chain
With concise syntheses of the oxazole-containing carboxylic acid
67b and the oxazole-containing C30 alcohol 47b, we were now
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Scheme 6 Reagents and conditions: i, PPTS, EtOH, reflux, 77%; ii, MOM-Cl, DIPEA, DCM, reflux, 95%; iii, O3, DCM, PPh3, −78 ◦C, 99%; iv,
trimethylorthoformate, MeOH, pTSA, 89%; v, TBAF, THF 99%; vi, TPAP, NMO, DCM, 78%; vii, 50b, Ba(OH)2, THF, H2O, 68%; viii, Pd(OH)2/C,
H2, EtOAc, 96%; ix, TBDPS-Cl, imidazole, DMF, 93%; x, Me2BBr, DCM, −78 ◦C, 98%; xi, 46a, PBu3, then 54, DBU, DMF, 75%; xii, Me2BBr, Et2O,
−78 ◦C, 79%.
a regioselective reduction of the C34–C35 alkene in 75 in the
presence of the C25–C26 (vinyloxazole) double bond, leading to 76
(Scheme 10).
Thus, selective deprotection of the TBDPS ether of the primary
alcohol group in 72a using HF–pyridine, followed by oxidation
of the resulting alcohol 72b with Dess–Martin periodinane,41 first
gave the aldehyde 73. A Wadsworth–Emmons reaction between
the aldehyde 73 and the phosphonate ester 74, produced in two
steps from 51 using Ba(OH)2 as base, next gave the E-alkene 75 in
60% yield over two steps.
Selective reduction of the conjugated enone alkene, at C34–
C35 in the presence of the vinyloxazole alkene at C25–C26 in
75, leading to the target 76 (cf. 16a), was not straightforward. A
plethora of methods for selective 1,4-reductions of enones abound
Scheme 7 Reagents and conditions: ia, S-Ru[BINAP], MeOH, H2, 80
bar, 92%; ib, S-Ru[Binap], MeOH, H2, 80 bar, 86%; ii, TBS-Cl, imidazole,
DMF, 81%; iii, TBDPS-Cl, imidazole, DMF, 90%; iv, CSA, MeOH, DCM,
97%; v, PPh3, I2, imidazole, DCM, 0 ◦C, 86%.
in the literature, with transition-metal-catalysed hydrosilylations
and “copper hydride” reductions amongst the most attractive.
Using model systems alongside the substrate 75, we investigated
R
the scope for (PPh3·CuH)6 and PhSiH3,42 Red-Alꢀ and CuBr or
Synthesis of the tris-oxazole macrolide 16a containing the entire
C25–C41 top chain and its C34–C35 dehydro analogue 75, and
completion of the total synthesis of ulapualide A (1)
CuI,43 Mo(Co)6 and Ph3SiH3,44 H2 and Pd(OH)2 on C,28 and
CuCl, Bu4NF, PPh3 with PhMe2SiH.45 To our chagrin, in all cases,
we either recovered starting material or observed simultaneous
reduction of both conjugated enone and vinyloxazole alkene
bonds in 75. At this stage therefore we abandoned our first
approach to the advanced intermediate 76 (cf. 16a) towards
ulapualide A (1), and instead focused on our second approach,
i.e. incorporating the entire C25–C41 top chain in the natural
In our first approach to the advanced intermediate 16a en
route to ulapualide A (Scheme 2), we planned to elaborate
the aldehyde 73, containing a shortened C25–C34 side chain,
to the corresponding alkene 75 using an olefination reaction
with the substituted phosphonate ester 74, and then to effect
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Scheme 8 Reagents and conditions: i, Me2CuLi, TMS-Cl, THF, 81%; ii, DIBAL-H, THF, 100%; iii, NaH, BnBr, TBAI, THF, 78%; iv HCl, dioxane; v,
Garner’s acid, EDC, 4-methylmorpholine, THF, HOBt, 79%; vi DMSO, (COCl)2, Et3N, DCM, −78 ◦C, 97%; vii PPh3, 1,2 dibromotetrachloroethane,
2,6-di-t-butylpyridine, DCM, DBU, MeCN, 72%; viii, Pd/C, EtOAc, H2, 81%; ix, DMSO, (COCl)2, Et3N, DCM, −78 ◦C, 87%; x, 59, vitamin B12, CrCl2,
DMF, 88%; xi, DMSO, (COCl)2, Et3N, DCM, −78 ◦C, 85%; xii, LiOH, MeOH, H2O, 88%.
Scheme 9 Reagents and conditions: i, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene, DMAP, 0 ◦C, 96%; ii, TMSOTf, Et3N, DCM, 0 ◦C; iii, DIPEA,
DPPA, DMF, 68%; iv, DAST, DCM, −78 ◦C, 92%; v, NiO2, benzene, reflux, 55%; vi, HF–pyridine, THF, pyridine, 45%.
product, starting from the already synthesised oxazole-substituted
C30 alcohol 55b.
Thus, esterification of the carboxylic acid 67b with the alcohol
55b, using Yamaguchi’s conditions, followed by removal of the
t-butyl ester and N-Boc protecting groups in the product 77, first
gave the corresponding x-amino acid 18a (Scheme 11). Instead of
DPPA–iPr2NEt used in the macrolactamisation of the analogue
69 to 70, we treated 18a with HATU46 at 0 ◦C, which resulted
in an equally efficient macrolactamisation and gave 17 in an
The synthesis of 76 from the C30 alcohol 55b and the carboxylic
acid 67b was relatively straightforward and proceeded along a
pathway essentially identical to that followed in our synthesis of
the ester 68 and the macrolide 71 with a shorter side chain, from
47b and 67b.
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Scheme 10 Reagents and conditions: i, NaHCO3, Dess–Martin periodinane, DCM; ii, Ba(OH)2·8H2O, THF, H2O, 36% over two steps.
Scheme 11 Reagents and conditions: i, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene, DMAP, 0 ◦C, 93%; ii, TMSOTf, Et3N, DCM, 0 ◦C; iii, HATU,
Et3N, DCM, 0 ◦C, 67%; iv, DAST, DCM, −78 ◦C, 89%; v, NiO2, benzene, reflux, 25%; vi, MsCl, DIPEA, DCM, DBU, 0 ◦C, 75%; vii NBS, MeOH,
DCM, 92%; viii, Cs2CO3, dioxane, 60 ◦C, 92%; ix, CSA, benzene, 5 A mol. sieves, reflux, 58%.
˚
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Scheme 12 Reagents and conditions: i, TMSOTf, DCM, −78 ◦C, 85%; ii, acetic anhydride, DMAP, DCM, pyridine, 84%; iii, HF–pyridine, DCM,
pyridine, 61%; iv, Dess–Martin periodinane, DCM, 80%; v, N-methylformamide, PPTS, benzene, reflux, 40%; vi, HF–pyridine, THF, 60%.
agreeable 67% yield (over 2 steps). Treatment of 17 with DAST
at −78 ◦C next gave the oxazoline 78a (89%), but the subsequent
oxidation of 78a to the corresponding tris-oxazole 76 (cf. 16a),
using NiO2 in benzene under reflux, was unreliable and seldom
gave yields above 25%. A more reliable route to 76 from 17 was
via the enamide 79, and based on our earlier model studies with
25 (Scheme 3). Thus, mesylation of 17 followed by elimination of
MeSO2H from the intermediate mesylate in the presence of DBU
first gave the enamide 79 in 75% yield over two steps. Treatment
of 79 with NBS in MeOH next led to the methoxybromide 80,
selective deprotection of the TBDPS ether of the C41 primary
alcohol, using HF–pyridine (1.5 h only) next gave the alcohol
82a, which was then oxidised to the aldehyde 82b using Dess–
Martin periodinane. Although not without some difficulties, when
a solution of the aldehyde 82b in benzene was heated under reflux
with N-methylformamide) (22 equiv.) in the presence of PPTS
(0.25 equiv) for 6–10 h (t.l.c. monitoring with further additions
of N-methylformamide) workup and chromatography gave the
E-alkenyl formamide 83 which was isolated as a 3:2 mixture
of rotamers, in 25–40% yield. Finally, removal of the TBDPS
protection at C3 in 83, using HF–pyridine in THF (12 h), gave
(−)-ulapualide A as a colourless viscous oil, in 60% yield.
22
which underwent dehydrobromination in the presence of Cs2CO3
producing the methoxyoxazoline 78b. Finally, treatment of 78b
with camphorsulfonic acid in benzene, heated under reflux, gave
the same tris-oxazole macrolide 76 to that obtained using the NiO2
oxidation route.
The final six steps in the synthesis of ulapualide A (1) from the
tris-oxazole macrolide 76 had already been established in our first
generation total synthesis of the diastereoisomic ulapualide A (8).
Thus, selective deprotection of the TBS group in 76 using TMSOTf
at −78 ◦C, followed by acetylation of the resulting secondary
alcohol 81a first led to the C38-acetate 81b (Scheme 12). A second,
26
The synthetic ulapualide A had [a]D −52.8 (c 0.11 in MeOH)
(lit. [a]D −42.9 (c 0.16 in MeOH)) and displayed 1H and 13C
NMR spectroscopic data which were indistinguishable from those
obtained for naturally derived material.1 Significantly, chemical
shift data for the C32, C34 and C33-Me carbon atoms in synthetic
1 were superimposable on those obtained for natural ulapualide A.
This is in contrast to the synthetic diastereoisomer 8 which
displayed small differences in the chemical shifts of these same
three carbon atoms in its 13C NMR spectrum (Table 1) yet closely
Table 1 13C NMR data (dC in ppm) for the C32–C34 unit in synthetic and natural ulapualide A, and in the synthetic diastereoisomer 8
Carbon atom
Natural ulapualide A
Synthetic ulapualide A
Diastereoisomer 8 of ulapualide A
32
34
C33-Me
81.8
27.6
15.5
81.8
27.7
15.6
81.0
26.6
14.2
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Table 2 13C NMR data (dC in ppm) for natural and synthetic ulapualide A
Carbon atom
Natural ulapualide A
Synthetic ulapualide A
Carbon atom
Natural ulapualide A
Synthetic ulapualide A
1
2
3
4
5
6
7
8
9
10
12
14
15
17
19
20
22
24
25
26
27
28
29
30
31
172.6
43.0
68.4
37.2
20.8
43.9
210.5
48.1
172.6
43.0
68.6
37.3
20.8
43.9
210.5
48.3
32
33
34
35
36
37
38
39
40
81.8
40.4
27.6
39.8
211.8
48.6
77.3
37.0
112.2
110.5
129.6
125.5
162.2
161.0
33.1
19.5
170.1
20.9
13.4
15.5
58.1
9.1
81.8
40.5
27.7
39.9
211.7
48.7
77.6
37.0
112.2
110.5
129.6
125.6
162.2
161.0
33.1
19.5
170.1
21.0
13.4
15.6
58.2
9.1
28.2
27.9
146.5
154.2
133.5
131.7
156.2
137.4
130.2
162.7
137.8
117.2
139.9
33.7
146.5
154.3
133.5
131.8
156.3
137.4
130.4
162.8
137.8
117.3
139.8
33.6
41
43
44
45
C38-OCOMe
C38-OCOMe
46
47
C32-OMe
48
C28-OMe
49
80.0
34.6
73.0
32.1
80.0
34.6
73.0
32.2
57.8
18.9
57.8
18.9
similar chemical shift data for all other carbon atoms.13 The 13C
NMR spectroscopic data for synthetic (−)-ulapualide A (1) and
naturally derived material, recorded on the same spectrometer
during the same period of time, are collected in Table 2.
materials to “sacrifice” in the exercise! This concept of “mixed”
NMR spectra is akin to mixed melting point measurements which,
after all, were used routinely and with great accuracy for decades
by our synthetic chemistry ancestors!
Summary and comment
Experimental
Our total synthesis of (−)-ulapualide A complements the recent
X-ray studies made by Rayment et al.15 on an actin–ulapualide A
complex. The synthesis also emphasises how vigilant and cautious
synthetic chemists should be in relying on NMR spectroscopy
when comparing data for complex natural products and their
synthetic counterparts. Our present studies have shown that
profound changes in the stereochemistry of a natural product
(compare structures 1 and 8 which differ at five stereocentres) are
not always adequately reflected in a significant way in their NMR
spectroscopic, and other, data.47 It could be argued that apart
from the usual comparisons of mass spectrometric, chiroptical,
and chromatography data, the unambiguous proof of identity of
a complex natural product with a synthetic compound should
General details
1H NMR spectra were recorded on Bruker DPX 360 (360 MHz),
Varian Inova 400 (400 MHz), or Bruker DRX 500 (500 MHz)
spectrometers. Chemical shifts are quoted in parts per million
(ppm) downfield of tetramethylsilane, and the spectra are refer-
enced to residual protonated solvent (d 7.27 for CDCl3 and 7.15
for C6D6). Abbreviations used in the description of resonances
are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
app (apparent) and br (broad). Coupling constants (J) are quoted
to the nearest 0.1 Hz. 13C NMR spectra were recorded on Bruker
DPX 360 (360 MHz), Varian Inova 400 (400 MHz) or Bruker DRX
500 (500 MHz) spectrometers. Chemical shifts are quoted in parts
per million (ppm) downfield of tetramethylsilane, and spectra are
referenced to residual protonated solvent (d 77.1 for CDCl3, 128.6
for C6D6); multiplicities were determined using a DEPT sequence.
1
always be ascertained by recording “mixed” H and 13C NMR
spectra. This proposition assumes of course, that there are
sufficient quantities (i.e. 0.5–1 mg) of both natural and synthetic
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Abbreviations used in the description of resonances are: s (singlet,
quaternary), d (doublet, CH), t (triplet, CH2), q (quartet CH3).
Where required, 1H–1H COSY and 1H–13C COSY were recorded
on Bruker DPX 360 (360 MHz), Varian Inova 400 (400 MHz) or
Bruker DRX 500 (500 MHz) spectrometers.
Infra-red spectra were recorded on a Perkin-Elmer 1600 series
FT-IR spectrometer as a dilute solution in chloroform. Absorp-
tions (mmax) are reported in wavenumbers (cm−1).
Mass spectra were recorded on VG Autospec, MM-701CF,
or Micromass LCT spectrometers, using electron ionisation (EI)
or electrospray (ES) techniques. High-resolution mass spectra
were calculated from the molecular formula corresponding to the
observed signal using the lowest atomic weights of isotopes of each
element, to 4 decimal places.
Optical rotations were recorded on a JASCO DIP 370 polarime-
ter. [a]D values are recorded in units of 10−1 deg cm2 g−1. Melting
points were recorded on a Stuart Scientific SMP3 apparatus and
are uncorrected. Thin layer chromatography (TLC) was performed
on Merck DC-Alufolien 60PF254 0.2 mm precoated plates. Product
3398, 1737 and 1682; 1H NMR (360 MHz, CDCl3) d 2.50 (3H, s,
CH3CN), 3.93 (3H, s, CH3O), 4.04 (1H, dd, J 11.3, 4.7 Hz, CHH),
4.12 (1H, dd, J 11.3, 4.7 Hz, CHH), 5.78 (1H, app dt, J 8.7,
4.7 Hz, CONHCH), 7.73 (1H, d, J 8.7 Hz, NH), 8.13 (1H, s,
CHCCONH), 8.25 (1H, s, CHCCO2Me); 13C NMR (90.6 MHz,
CDCl3) d 13.9 (q), 45.2 (t), 48.3 (d), 52.4 (q), 133.8 (s), 135.2
(s), 141.6 (d), 144.7 (d), 160.4 (s), 161.3 (s), 161.5 (s), 161.7 (s);
m/z (EI) 336.0393 (M+ + Na), C12H12ClN3O5 + Na requires
336.0363.
1,8-Diazabicyclo[5.4.0]undec-7-ene (485 ll, 3.20 mmol) was
added dropwise over 5 min to a stirred solution of the alkyl chloride
(1.18 g, 3.20 mmol) in dry dichloromethane (13 ml) at room
temperature under a nitrogen atmosphere. The orange mixture
was stirred at room temperature for 3 h and then concentrated in
vacuo. Ethyl acetate (100 ml) and 2 M hydrochloric acid (80 ml)
were added to the residue and the separated organic phase was then
washed with 2 M hydrochloric acid (2 × 80 ml), dried (MgSO4),
and concentrated in vacuo. The residue ◦was recrystallised from
ethyl acetate–light petroleum (bp 40–60 C) to give the enamide
(0.88 g, 99%) as colourless crystals, mp 150–151 ◦C: mmax (soln,
CHCl3)/cm−1 3366, 1747 and 1689; (found, C, 51.8%; H, 3.9%;
N, 15.0%; C12H11N3O5 requires C, 52.0%; H, 4.0%; N, 15.2%); 1H
NMR (360 MHz, CDCl3) d 2.53 (3H, s, CH3CN), 3.95 (3H, s,
CH3O), 5.86 (1H, s, CCHH), 6.64 (1H, s, CCHH), 8.15 (1H, s,
CHCCONH), 8.24 (1H, s, CHCCO2Me), 9.29 (1H, s, NH); 13C
NMR (90.6 MHz, CDCl3) d 13.9 (q), 52.4 (q), 105.1 (t), 127.9
(s), 134.0 (s), 136.0 (s), 141.5 (d), 144.5 (d), 158.9 (s), 159.7 (s),
161.3 (s), 161.7 (s); m/z (EI) 278.0754 (M+ + H), C12H11N3O5 + H
requires 278.0777.
spots were visualised by the quenching of UV fluorescence (kmax
=
254 nm) and subsequently developed using vanillin solution,
molybdophosphoric acid solution, or potassium permanganate
solution, as appropriate. Flash column chromatography was
carried out on silica gel (Merck silica gel 60 (230–400 mesh
ASTM)).
Unless stated otherwise, reactions requiring anhydrous condi-
tions were conducted in an inert atmosphere of nitrogen in flame-
dried or oven-dried apparatus. Combined solvent extracts were
dried over MgSO4 prior to evaporation, unless stated otherwise.
Several reagents were purified prior to use. Triethylamine,
pyridine and diisopropylethylamine were distilled from calcium
hydride. Dimethylboron bromide was prepared according to the
procedure of Guindon et al.29 and stored as a solution in dry
dichloromethane at −20 ◦C. Nickel peroxide was reactivated
according to the procedure of Konaka et al.48 The concentrations
of alkylation reagents were determined by titration against 1,3-
diphenylacetone p-tosylhydrazone. Molecular sieves were stored in
a warm oven before use. All other commercially available reagents
were used as received.
When necessary, solvents were dried prior to use. Benzene,
toluene, diethyl ether and tetrahydrofuran (THF) were distilled
from sodium and benzophenone ketyl. Dichloromethane was dis-
tilled from calcium hydride. Methanol was distilled from magne-
sium methoxide and ethanol was distilled from magnesium ethox-
ide. Anhydrous dimethylformamide was obtained from Aldrich.
2-[(2-Methyloxazole-4-carbonyl)carbamoyl]oxazole-4-carboxylic
acid methyl ester (26)
Ruthenium(IV) oxide hydrate (2.3 mg, 0.02 mmol) and sodium
periodate (618 mg, 2.89 mmol) were added sequentially to a
stirred solution of the enamide 25 (200 mg, 0.72 mmol) in carbon
tetrachloride (7.3 ml), water (7.3 ml) and acetonitrile (0.4 ml) at
room temperature. The mixture was stirred vigorously for 30 min,
then chloroform (10 ml) and water (10 ml) were added. The
separated aqueous phase was extracted with chloroform (2 ×
10 ml) and the combined organic extracts were then washed with
saturated aqueous sodium thiosulfate solution (10 ml) and brine
(10 ml), dried (MgSO4) and concentrated in vacuo. The residue
was purified by chromatography on silica using ethyl acetate–light
petroleum (bp 40–60 ◦C) (3:2) as eluent to give the imide (99 mg,
50%), which recrystallised from ethyl acetate–light petroleum (bp
40–60 ◦C) as colourless crystals, mp 254–256 ◦C: mmax (soln,
2-{1-[(2-Methyloxazole-4-carbonyl)amino]vinyl}-2,3-
1
CHCl3)/cm−1 1764; H NMR (360 MHz, CDCl3) d 1.58 (3H, s,
dihydrooxazole-4-carboxylic acid methyl ester (25)
CH3CN), 3.98 (3H, s, CH3O), 8.31 (1H, s, CHCCONH), 8.44
(1H, s, CHCCO2Me), 10.80 (1H, s, NH); 13C NMR (90.6 MHz,
CDCl3) d 13.9 (q), 52.8 (q), 134.4 (s), 134.8 (s), 143.8 (d), 147.3 (d),
151.4 (s), 154.1 (s), 157.8 (s), 160.4 (s), 162.1 (s); m/z (EI) 280.0567
(M+ + H), C11H9N3O5 + H requires 280.0570.
Thionyl chloride (320 ll, 4.40 mmol) was added dropwise over
5 min to a stirred solution of the hydroxy amide 24 (144 mg,
0.49 mmol) in dry dichloromethane (3.5 ml) at 0 ◦C under a
nitrogen atmosphere. The solution was stirred at room temper-
ature for 12 h and then concentrated in vacuo. Ethyl acetate
(36 ml) and water (20 ml) were added to the residue and the
separated aqueous phase was then extracted with ethyl acetate
(2 × 20 ml). The combined organic extracts were dried (MgSO4)
and then concentrated in vacuo to leave the corresponding alkyl
chloride (160 mg, 98%) as a yellow oil: mmax (soln, CHCl3)/cm−1
Methyl 2-(2-(2-methyloxazol-4-yl)oxazol-4-yl)oxazole-4-
carboxylate (30)
Procedure A. A solution of the oxazoline 27 (2.5 mg,
0.009 mmol) in dry degassed benzene (1 ml) was heated under
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reflux in the presence of nickel peroxide (30 mg, 0.33 mmol) and
409.9965 (M+ + Na) 355.9899 (M+ − MeOH + H), C13H14BrN3O6
˚
4 A molecular sieves (10 mg) for 30 min. The mixture was filtered
+ Na requires 409.9964.
through celite and the filter cake was washed with ethyl acetate (3 ×
5 ml). The combined ethyl acetate washings were concentrated in
vacuo and the residue was purified by chromatography on silica
using ethyl acetate–light petroleum (bp 40–60 ◦C) (1:1) as eluent
to give the tris-oxazole (1 mg, 40%) as a crystalline solid.
Methyl 2-(4,5-dihydro-4-methoxy-2-(2-methyloxazol-4-yl)oxazol-
4-yl)oxazole-4-carboxylate (29)
Caesium carbonate (18 mg, 0.06 mmol) was added in one portion
to a stirred solution of the bromide 28 (11 mg, 0.03 mmol) in
dry dioxane (1 ml) at 60 ◦C under a nitrogen atmosphere. The
mixture was stirred at 60 ◦C for 12 h and then concentrated
in vacuo. Dichloromethane (10 ml) and 10% aqueous citric acid
solution (10 ml), were added and the separated aqueous phase was
then extracted with dichloromethane (2 × 5 ml). The combined
organic extracts were dried (Na2SO4) and then concentrated in
vacuo. The residue was purified by chromatography on silica using
ethyl acetate–light petroleum (bp 40–60 ◦C) (1:1) as eluent to
give the oxazoline (7.4 mg, 88%) as a solid, which recrystallised
from ethyl acetate–light petroleum (bp 40–60 ◦C) as colourless
crystals, mp 135–137 ◦C: mmax (soln, CHCl3)/cm−1 1743, 1725, 1674
Procedure B. Bromotrichloromethane (99 ll, 1.0 mmol) was
added to a stirred solution of the oxazoline 27 (90 mg, 0.32 mmol)
in dry dichloromethane (3 ml) at 0 ◦C under a nitrogen atmo-
sphere and the mixture was stirred at 0 ◦C for 10 min. 1,8-
Diazabicyclo[5.4.0]undec-7-ene (150 ll, 1.0 mmol) was added
dropwise over 5 min and the mixture was allowed to warm to
room temperature overnight. The mixture was concentrated in
vacuo and the residue was then partitioned between ethyl acetate
(5 ml) and 10% aqueous citric acid solution (5 ml). The separated
organic extract was washed with saturated sodium bicarbonate
solution (5 ml), then dried (MgSO4) and concentrated in vacuo.
The residue was purified by chromatography on silica using ethyl
1
and 1584; H NMR (360 MHz, CDCl3) d 2.53 (3H, s, CH3CN),
◦
acetate–light petroleum (bp 40–60 C) (1:1) as eluent to give the
3.45 (3H, s, CH3OCH2), 3.92 (3H, s, CH3O2C), 4.67 (1H, d, J
10.5 Hz, CHHO), 5.05 (1H, d, J 10.5 Hz, CHHO), 8.15 (1H, s,
CHCCONH), 8.28 (1H, s, CHCCO2Me); 13C NMR (90.6 MHz,
CDCl3) d 13.8 (q), 51.6 (q), 52.3 (q), 74.8 (t), 99.6 (s), 129.7 (s),
133.3 (s), 142.4 (d), 145.0 (d), 161.3 (s), 162.2 (s), 162.5 (s), 162.9
(s); m/z (EI) 308.0861 (M+ + H), 330.0674 (M+ + Na), 276.0614
(M+ − MeOH + H), C13H13N3O6 + H requires 308.0883.
tris-oxazole (70 mg, 81%) as a solid, which recrystallised from
ethyl acetate–light petroleum (bp 40–60 ◦C) as colourless crystals,
mp 217–220 ◦C.
Procedure C. A solution of the oxazoline 29 (13 mg,
0.04 mmol) and CSA (10 mg, 0.04 mmol) in dry toluene (10 ml) was
heated under reflux using a Dean–Stark apparatus for 12 h. The
mixture was concentrated in vacuo and the residue was purified
by chromatography on silica using ethyl acetate–light petroleum
(bp 40–60 ◦C) (1:1) as eluent to give the tris-oxazole (12 mg,
95%), which recrystallised from ethyl acetate–light petroleum (bp
40–60 ◦C) as colourless crystals, mp 216–219 ◦C; mmax (soln,
CHCl3)/cm−1 1732, 1655 and 1586; 1H NMR (360 MHz, CDCl3) d
2.57 (3H, s, CH3CN), 3.95 (3H, s, CH3O), 8.26 (1H, s, CHOCCH3),
8.33 (1H, s, CHCCNCCO2Me) 8.42 (1H, s, CHCCO2Me); 13C
NMR (90.6 MHz, CDCl3) d 13.9 (q), 52.4 (q), 129.7 (s), 130.9 (s),
134.5 (s), 139.3 (d), 139.3 (d), 143.9 (d), 155.6 (s), 156.4 (s), 161.4
(s), 163.1 (s); m/z (EI) 276.0618 (M+ + H), 298.0499 (M+ + Na),
C12H9N3O5 + H requires 276.0620.
(S)-4-[(1S,7S)-7-(tert-Butyldiphenylsilanyloxy)-3-hydroxy-8-
methoxycarbonyl-1-methyloctyl]-2ꢀ,2ꢀ-dimethyl-4ꢀ,5ꢀ-dihydro-
[2,4ꢀ]bioxazolyl-3ꢀ-carboxylic acid tert-butyl ester (66)
A solution of the aldehyde 65 (500 mg, 1.5 mmol) and the
iodide 59 (3 g, 5.9 mmol) in dry dimethylformamide (12 ml) was
added dropwise over 15 min to a stirred suspension of chromium
chloride (1.8 g, 14.7 mmol) and vitamin B12 (160 mg, 0.12 mmol)
(both weighed in a glove bag under an argon atmosphere), in
dry dimethylformamide (21 ml) at room temperature with argon
bubbling through the solution. The mixture was stirred at room
temperature for 3 days and then diluted with water (40 ml)
and diethyl ether (210 ml). The separated organic extract was
washed with water (3 × 40 ml) and brine (62 ml), then dried
(MgSO4) and concentrated in vacuo. The residue was purified
by chromatography on silica using diethyl ether–light petroleum
(bp 40–60 ◦C) (1:1 to 1:0) as eluent to give a 1:1 mixture of
diastereoisomers of the alcohol (760 mg, 72%) as a colourless oil:
Methyl 2-(1-(2-methyloxazole-4-carboxamido)-2-bromo-1-
methoxyethyl)oxazole-4-carboxylate (28)
N-Bromosuccinimide (14 mg, 0.08 mmol) was added in one
portion to a stirred solution of the enamide 25 (20 mg, 0.07 mmol)
in dry methanol (2 ml) at room temperature under a nitrogen
atmosphere. The mixture was stirred at room temperature for 15 h
whereupon a colourless solid precipitated. The solid was filtered
and washed with cold methanol to leave the bromide (26 mg,
96%) which recrystallised from ethyl acetate–light petroleum (bp
40–60 ◦C) as colourless crystals, mp 140–142 ◦C: mmax (soln,
CHCl3)/cm−1 3374, 1732 and 1693; 1H NMR (360 MHz, CDCl3)
d 2.53 (3H, s, CH3CN), 3.24 (3H, s, CH3OCNH), 3.95 (3H, s,
CH3O2C), 4.11 (1H, d, J 10.7 Hz, CHHBr), 4.82 (1H, d, J 10.7 Hz,
CHHBr), 8.13 (1H, s, CHCCONH), 8.34 (1H, s, CHCCO2Me),
8.35–8.42 (1H, br, NH); 13C NMR (90.6 MHz, CDCl3) d 13.9
(q), 33.1 (t), 52.5 (q), 52.5 (q), 85.4 (s), 133.3 (s), 135.5 (s), 141.8
(d), 145.6 (d), 160.2 (s), 160.5 (s), 161.1 (s), 161.7 (s); m/z (EI)
22
[a]D −21.2 (c 1.03 in CHCl3); mmax (soln, CHCl3)/cm−1 3368, 1732
1
and 1699; H NMR (360 MHz; C6D6, 333 K) d 1.16–1.30 (16H,
m, (CH3)3CSi, CH3CH, CH2CH2CHOH), 1.36 (9H, s, (CH3)3CO),
1.39–1.64 (7H, m, CH3C, CH2CHOSi, CH2CHCH3), 1.87 (3H, s,
CH3C), 2.52 (1H, dd, J 14.9, 4.6 Hz, CHHCO2Me), 2.54 (1H, dd,
J 14.9, 6.8 Hz, CHHCO2Me), 2.95 (1H, ddq, J 7.0, 6.9, 6.8 Hz,
CHCH3), 3.33 (3H, s, CH3O), 3.42–3.52 (1H, m, CHOH), 3.76
(1H, dd, J 8.8, 6.7 Hz, CHHCHN), 3.88 (1H, dd, J 8.8, 2.6 Hz,
CHHCHN), 4.37 (1H, app pentet, J 5.8 Hz, CHOSi), 4.79–4.91
(1H, m, CHN), 6.99 (1H, s, CHCN), 7.24–7.28 (6H, m, ArH),
7.78–7.83 (4H, m, ArH); 13C NMR (90.6 MHz; C6D6, 333 K) d
19.9 (q), 20.7 (s), 21.7 (t), 25.0 (q), 26.0 (q), 27.7 (3q), 28.7 (3q),
28.8 (d), 38.0 (t), 38.3 (t), 42.5 (t), 45.1 (t), 51.2 (q), 56.0 (d), 67.9
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(t), 69.3 (d), 71.5 (d), 80.3 (s), 95.5 (s), 128.2 (2d), 128.3 (2d), 130.3
(2d), 133.8 (d), 135.0 (s), 135.2 (s), 136.7 (4d), 146.6 (s), 151,9 (s),
162.2 (s), 171.7 (s); m/z (EI) 723.4001 (M+ + H), 745.3893 (M+ +
Na), C40H58N2O8Si + H requires 723.4041.
and 5.7 Hz, CHHCO), 3.11–3.27 (3H, m), 3.24 (3H, OMe), 3.26
(3H, OMe), 3.57 (1H, dd, J 10.0 and 6.2 Hz, CHHOSi), 3.67
(1H, dd, J 10.0 and 6.1 Hz, CHH OSi), 4.03–4.27 (3H, m), 4.98
(0.7H, dd, J 6.2 and 3.4 Hz, CHN), 5.04–5.15 (1.3H, m, CHN
=
=
and CH.OC O), 6.4 (1H, d, J 16 Hz, CH CHCH2), 6.78 (1H,
=
=
dt, J 16 and 7.5 Hz, CH CHCH2), 7.27 (0.3H, OCH CHMe),
(S)-4-[(1S,7S)-7-(tert-Butyldiphenylsilanyloxy)-8-
=
7.31 (0.7H, OCH CHMe), 7.36–7.47 (12H, m), 7.65–7.72 (8H, m,
methoxycarbonyl-1-methyl-3-oxooctyl]-2ꢀ,2ꢀ-dimethyl-4ꢀ,5ꢀ-
dihydro-[2,4ꢀ]bioxazolyl-3ꢀ-carboxylic acid tert-butyl ester (67a)
ArH), 8.01 (1H, OCH ); 13C NMR (90 MHz, CDCl3)(rotamers)
=
9.3 (q), 12.2 (q), 18.7 (q), 19.2 (s), 19.3 (s), 19.3 (q), 24.3 (q), 25.1
(q), 26.7 (d), 26.9 (q), 28.1 (q), 28.2 (q), 28.3 (q), 32.9 (t),34.9 (t),
36.0 (t), 38.7 (d), 40.1 (d), 41.7 (t), 42.8 (t), 48.2 (t), 55.2 (d), 57.7
(q), 58.6 (q), 65.0 (t), 67.4 (t), 69.5 (d), 72.9 (d), 78.5 (d), 80.1 (s),
80.8 (d), 82.0 (s), 94.4 (s), 94.9 (s), 118.2 (d), 127.6 (2 × d), 129.6
(d), 129.7 (2 × d), 133.1 (d), 133.3 (d), 133.7 (2 × s), 133.9 (s),
135.3 (s), 135.5 (2 × d), 135.8 (d), 135.9 (d), 137.7 (d), 142.5 (d),
145.0 (s), 151.2 (s), 151.9 (s), 160.5 (s), 161.2 (s), 162.6 (s), 162.8
(s), 170.6 (s), 208.5 (s), 208.8 (s). m/z (ESI) 1354.7366 (M+ + H),
C77H108N3O14Si2 requires 1354.7370.
DMSO (2.1 ml, 29.5 mmol) was added dropwise over 10 min
to a stirred solution of oxalyl chloride (1.55 ml, 17.8 mmol)
in dry dichloromethane (10 ml) at −78 ◦C under a nitrogen
atmosphere. The solution was stirred at −78 ◦C for 15 min
and then a solution of the alcohol 66 (984 mg, 11.8 mmol) in
dry dichloromethane (10 ml) was added dropwise over 15 min.
◦
The mixture was stirred at −78 C for 1.5 h, then triethylamine
(9.4 ml, 67.3 mmol) was added dropwise over 15 min. The mixture
was allowed to warm to room temperature, then diluted with
water (10 ml). The separated aqueous phase was extracted with
dichloromethane (2 × 20 ml) and the combined dichloromethane
extracts were then dried (MgSO4) and concentrated in vacuo. The
residue was purified by chromatography on silica using diethyl
ether–light petroleum (bp 40–60 ◦C) (1:1) as eluent to give the
The bis-oxazole macrolactam (70)
The macrolactam was prepared from the ester 68 using TMSOTf–
Et3N in CH2Cl2 at 0 ◦C to give, first, the corresponding amino
acid 69. The amino acid was then treated with DPPA–Et3N in
22
ketone (869 mg, 87%) as a colourless oil: [a]D −69.4 (c 1.90
◦
in CHCl3); mmax (soln, CHCl3)/cm−1 1731 and 1699; (Found: C,
66.8; H, 7.8; N, 3.9; C40H56N2O8Si requires C, 66.6; H, 7.8; N,
3.9%); 1H NMR (400 MHz; C6D6, 333 K) d 1.10–1.16 (12H,
m, (CH3)3CSi, CH3CH), 1.34 (9H, s, (CH3)3CO), 1.41–1.48 (4H,
m, CH2CH2CHOSi), 1.58 (3H, s, CH3C), 1.81–1.91 (5H, m,
CH2COCH2CHCH3, CH3C), 2.13–2.22 (1H, m, CHHCHCH3),
2.37 (1H, dd, J 14.9, 5.7 Hz, CHHCO2Me), 2.51 (1H, dd,
J 14.9, 6.6 Hz, CHHCO2Me), 2.57 (1H, dd, J 16.5, 6.2 Hz,
CHHCHCH3), 3.23 (1H, ddq, J 6.8, 6.7, 6.6 Hz, CHCH3), 3.33
(3H, s, CH3O), 3.81 (1H, dd, J 8.9, 6.5 Hz, CHHCHN), 3.89 (1H,
dd, J 8.9, 3.3 Hz, CHHCHN), 4.32 (1H, app pentet, J 5.4 Hz,
CHOSi), 4.84–5.01 (1H, m, CHN), 6.98 (1H, s, CHCN), 7.23–
7.27 (6H, m, ArH), 7.74–7.80 (4H, m, ArH); 13C NMR (90.6 MHz;
C6D6, 333 K) d 19.3 (t), 19.5 (q), 19.5 (s), 24.7 (q), 25.6 (q), 27.3
(3q), 27.4 (d), 28.3 (3q), 36.9 (t), 41.9 (t), 42.7 (t), 48.5 (t), 50.9
(q), 55.7 (d), 67.6 (t), 70.7 (d), 79.8 (s), 95.1 (s), 127.8 (2d), 127.9
(2d), 129.9 (2d), 133.3 (d), 134.5 (s), 134.6 (s), 136.2 (2d), 136.3
(2d), 145.8 (s), 151,5 (s), 163.3 (s), 171.1 (s), 207.0 (s); m/z (EI)
721.3845 (M+ + H), 745.3893 (M+ + Na), C40H56N2O8Si + H
requires 721.3884.
DMF at 0 C (cf. HATU–Et3N in CH2Cl2 used in the synthesis
of 17 from 75), to give the macrolactam (68%) as a viscous oil,
[a]D22 +2.2 (c 0.55 in CHCl3); mmax (soln, CHCl3, cm−1) 3646, 3398,
1718, 1670; 1H NMR (360 MHz, CDCl3), 0.81 (3H, d, J 6.9 Hz,
CH3 CH), 0.84 (3H, d, J 6.9 Hz, CH3CH), 1.03 (9H, CMe3),
1.04 (9H, CMe3), 1.24 (3H, d, J 7.0 Hz, CH3CH), 1.38–162 (6H,
m), 1.77–1.86 (2H, m), 2.08–2.26 (2H, m), 2.36 (1H, dd, J 16.2
=
and 5.1 Hz, CHHC O), 2.4–2.59 (4H, m), 2.86 (1H, dd, J 16.2
=
and 9.2, CHH.C O), 3.06–3.15 (2H, m, 2 × CHOMe), 3.2 (3H,
OMe), 3.28 (3H, OMe), 3.27–3.34 (1H, m), 3.41 (1H, brt, J 5.8 Hz,
OH), 3.54 (1H, dd, J 9.9 and 6.3 Hz, CHHOSi), 3.62 (1H, dd, J
9.9 and 6.0 Hz, CHH OSi), 3.99–4.13 (3H, m), 5.0–5.06 (1H, m),
5.35 (1H, dt, J 8.1 and 3.9 Hz, CHNH), 6.34 (1H, d, J 16 Hz,
=
=
CH CH.CH2), 6.81 (1H, dt, J 16 and 7.5, CHCH2), 7.32–7.46
(13H, m), 7.64–7.69 (8H, m, ArH), 7.88 (1H, d, J 8.1 Hz, NH),
8.09 (1H, OCH ). 13C NMR (90 MHz, CDCl3), 9.4 (q), 12.0 (q),
=
18.6 (q), 19.2 (2 × s), 19.9 (q), 26.9 (d), 26.9 (2 × q), 32.4 (t), 33.7
(t), 35.6 (t), 38.7 (d), 39.7 (d), 42.0 (t), 43.2 (t), 48.3 (t), 49.0 (d),
57.4 (q), 58.6 (q), 64.2 (t), 64.9 (t), 69.5 (d), 72.4 (d), 78.4 (d), 80.6
(d), 118.1 (d), 127.6 (d), 129.6 (2 × d), 129.7 (2 × d), 133.7 (2 × s),
133.8 (s), 133.9 (s), 134.5 (d), 135.5 (d), 135.6 (d), 135.8 (d), 136.1
(s), 137.3 (d), 140.5 (d), 144.1 (s), 160.8 (s), 161.1 (s), 170.1 (s),
209.6 (s). m/z (ESI) 1140.5806 (M+ + H), C65H86N3O11Si2 requires
1140.5801.
The bis-oxazole ester (68)
The ester was prepared from the carboxylic acid 67b (150 mg,
0.212 mmol) and the alcohol 47b (118 mg, 0.18 mmol) under
Yamaguchi conditions, using the procedure described for the
synthesis of the ester 75 from 55b and 67b. It was purified by
chromatography on silica, using diethyl ether–light pretroleum
The oxazoline bis-oxazole macrolide (71)
The oxazoline was prepared from the macrolactam 70 using
DAST in CH2Cl2, and following the procedure described for the
synthesis of the analogous oxazoline 76a from 17. It was purified
by chromatography on silica, using diethyl ether–light petroleum
(bp 40–60 ◦C) (1:1 to 1:99) as eluent, and was obtained as a viscous
◦
(bp 40–60 C) (1:1 to 1:3) as eluent, and was obtained as an oil
22
(96%), which showed, [a]D −21.3 (c 1.50 in CHCl3); mmax (soln,
CHCl3, cm−1) 1717, 1703; 1H NMR (360 MHz, CDCl3) (rotamers)
d 0.88 (3H, d, J 6.6 Hz, CH3 CH), 0.90 (3H, d, J 6.7 Hz, CH3CH),
1.05 (9H, SiCMe3), 1.07 (9H, SiCMe3), 1.21 (3H, d, J 6.6 Hz,
CH3 CH), 1.27–1.65 (27H, m), 1.68–1.93 (5H, m), 2.13 (2H, t,
J 7.6 Hz, CH2CH2CO), 2.36–2.58 (5H, m), 2.73 (1H, dd, J 17.0
22
oil (92%) which showed [a]D + 64.5 (c 0.4 in CHCl3); mmax (soln,
CHCl3, cm−1) 1716, 1679; 1H NMR (360 MHz, CDCl3) 0.81 (3H,
d, J 6.9 Hz, CHMe), 0.89 (3H, d, J 7.0 Hz, CHMe), 1.02 (9H,
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CMe3), 1.08 (9H, CMe3), 1.18–1.23 (1H, m), 1.23 (3H, d, J 7.0 Hz,
CHMe), 1.35–1.56 (5H, m), 1.67–1.77 (2H, m), 1.79–1.94 (2H, m),
acetate (1:1, then 1:99) as eluent, and was obtained as a viscous
oil which was used immediately in the next step.
=
2.19 (1H, dd, J 16.4 and 4.3 Hz, CHH.C O), 2.37 (2H, d, J 6.2 Hz,
=
CH2 CO2), 2.46–2.64 (2H, m, CHCH2), 2.85 (1H, dd, J 16.5 and
The tris-oxazole macrolide conjugated enone (75)
=
9.5 Hz, CHHC O), 3.07 (1H, td, J 6.3 and 2.8 Hz, CHOMe),
3.31–3.18 (2H, m), 3.31 (3H, OMe), 3.34 (3H, OMe), 3.58 (1H,
dd, J 10.1 and 6 Hz, CHHOSi), 3.64 (1H, dd, J 10.1 and 6.2 Hz,
CHH OSi), 3.97–4.05 (1H, m), 4.68 (1H, dd, J 9.5 and 8.8 Hz,
Powdered sodium hydrogencarbonate (7.1 mg, 84 l mol) and
Dess–Martin periodinane (7.4 mg, 17 lmol) were added to a
solution of the alcohol 72b (7.4 mg, 8.4 lmol) in dichloromethane
(800 l) at room temperature and the mixture was stirred for
2h. More Dess–Martin periodinane (3.7 mg) was added and
the mixture was stirred at room temperature for a further 1h.
Saturated sodium thiosulfate (500 ll) and saturated sodium
hydrogencarbonate (500 ll), followed by ether (2 ml), were
added and the separated aqueous phase was then extracted with
diethyl ether (3 × 2 ml). The combined organic extracts were
washed with brine (1 ml) then dried and evaporated in vacuo.
The residue containing the aldehyde 73 was reacted with the b-
ketophosphonate 74 (5.3 mg, 11 lmol) in THF-H2O (180 ll) in
the presence of Ba(OH)2·8H2O (2.8 mg, 9 ll), using the procedure
described for the synthesis of the conjugated enone 52 from 50b
and 51. Chromatography on silica, using diethyl ether as eluent,
=
CHHCHN), 4.98 (1H, dd, J 8.7 and 4.4 Hz, CH.OC O), 5.05
(1H, dd, J 6.7 and 8.8 Hz, CHH.CHN), 5.43 (1H, dd, J 9.9 and
=
6.4 Hz, CHN), 6.43 (1H, d, J 16.2 Hz, CH CH.CH2), 6.85 (1H,
=
=
ddd, J 16.2, 8.1 and 6.5 Hz, CH2CH CH), 7.35 (1H, CH ), 7.35–
7.50 (12H, m), 7.62–7.75 (8H, m), 8.01 (1H, OCH ); 13C NMR
=
(90 MHz, CDCl3) 9.1 (q), 12.1 (q), 18.3 (t), 19.3 (2 × s), 26.4 (q),
26.5 (d), 26.8 (q), 26.9 (q), 32.1 (t), 32.5 (t), 35.6 (t), 38.6 (q), 39.1
(q), 41.5 (t), 43.2 (t), 47.8 (t), 57.2 (q), 59.2 (q), 63.3 (d), 65.0 (t),
69.3 (d), 7.10 (t), 72.0 (d), 78.5 (d), 81.6 (d), 118.9 (d), 237.5 (d),
127.6 (d), 129.6 (d), 129.8 (d), 130.8 (s), 133.7 (2 × 5), 133.8 (s),
134.0 (s), 134.2 (d), 135.5 (d), 135.6 (d), 135.8 (d), 135.9 (d), 136.4
(d), 140.2 (d), 144.3 (s), 159.4 (s), 161.9 (s), 162.7 (s), 169.9 (s),
209.7 (s); m/z (ESI) 1122.5674 (M+ + H) C65H84N3O10Si2 requires
1122.5695.
22
gave the enone (4.1 mg, 36%) as an oil, [a]D −27.3 (c 0.41 in
CHCl3); mmax (soln, CHCl3, cm−1) 1732, 1709; 1H NMR (500 MHz,
CDCl3) d−0.10 (3H, SiMe), 0.04 (3H, SiMe), 0.80 (3H, d, J 7.0 Hz,
CH3 CH), 0.81 (9H, CMe3), 0.87 (3H, d, J 6.8 Hz, CH3CH), 0.97
(3H, d, J 7.5 Hz, CH3CH), 0.99 (3H, d, J 7.4 Hz, CH3CH), 1.03
(9H, CMe3), 1.05 (9H, CMe3), 1.28 (3H, d, J 6.9 Hz, CH3CH),
1.41–1.53 (3H, m), 1.70–1.80 (5H, m), 1.83–1.93 (2H, m), 2.24–
2.36 (2H, m), 2.39 (1H, dd, J 16.7 and 5.6 Hz, CHH.CO), 2.40–
2.47 (1H, m), 2.54 (1H, dd, J 15.6 and 6.4 Hz, CHH.CO2), 2.59
(dd, J 15.6 and 5 Hz, CHH CO2), 2.57–2.7 (2H, m), 2.98 (1H, app.
The tris-oxazole macrolide (72b)
The tris-oxazole 72a was produced by oxidation of the oxazoline
bis-oxazole 71, using NiO2 in benzene, following the procedure
described for the preparation of the analogous tris-oxazole 76
from 78a. Recovered 78a was continuously recycled to produce the
22
tris-oxazole (55%) as an oil, which showed [a]D +14.5 (c 0.24 in
CHCl3); mmax (soln, CHCl3, cm−1) 1728, 1714; 1H NMR (500 MHz,
CDCl3) 0.80 (3H, d, J 6.9 Hz, CHMe), 0.85 (3H, d, J 6.9 Hz,
CHMe), 1.02 (9H, CMe3), 1.04 (9H, CMe3), 1.29 (3H, d, J 6.9 Hz,
CHMe), 1.46 (1H, ddd, J 14.4, 10.0 and 1.9 Hz, CHH.CHOMe),
1.58 (1H, ddd, J 14.4, 10.3 and 1.7 Hz, CHH.CHOMe), 1.65–
1.79 (4H, m), 1.83–1.91 (2H, m), 2.27–2.30 (1H, m), 2.35 (1H, d,
J 6.1 Hz, CHH.CO), 2.38 (1H, d, J 5.7, CHH.CO), 2.46 (1H,
=
qn, J 7.5 Hz, CH3CH.C O), 3.04 (1H, ddd, J 9.9, 4.1 and 2.1 Hz,
CH2CH OMe), 3.15 (1H, dd, J 16.7 and 7.7 Hz, CHHCO), 3.16–
3.20 (1H, m), 3.28 (3H, OMe), 3.31 (3H, OMe), 3.4 (1H, app. sx,
=
J 6.7 Hz, CH3CH.CH2C O), 3.64 (1H, app. dt, J 9.1 and 5.6 Hz,
CHH.OSi), 3.75 (1H, ddd, J 10.4, 7.6 and 5.3 Hz, CHH.OSi), 3.92
(1H, dd, J 8.1 and 2.2 Hz, CH2OTBS), 4.29 (2H, app. qn, J 5.3 Hz,
=
=
app, dt, J 15.1 and 8.3 Hz, CHH.CH ), 2.50 (1H, dd, J 15.9 and
CH2CHOSi), 5.10 (1H, dd, J 9.6, 7.0 and 2.0, CHOC O), 6.17
=
6.9 Hz, CHH.CO2), 2.57 (1H, dd, J 15.9 and 5.2 Hz, CHH.CO2),
2.59–2.66 (1H, m), 3.14 (1H, dd, J 16.6 and 7.7 Hz, CHH.CO),
3.2–3.24 (1H, m), 3.25 (3H, OMe), 3.27 (3H, OMe), 3.40 (1H,
(1H, dd, J 16.0 and 1.0 Hz, CH.C O), 6.34 (1H, d, J 15.9 Hz,
=
=
CH2CH =CH), 6.87 (1H, dd, J 15.9 and 6.5 Hz, CH CH.C O),
=
7.07 (1H, ddd, J 15.7, 8.4 and 6.2 Hz, CH2CH ), 7.30–7.46 (13H,
=
=
=
app. sex, J 6.7 Hz, CH3CHCH2C O), 3.52 (1H, dd, J 10.0 and
6.5 Hz, CHHOSi), 3.63 (1H, dd, J 10.0 and 6.2 Hz, CHHOSi),
4.29 (1H, app. qn, J 5.4 Hz, CH2CHOSi), 5.06 (1H, ddd, J 8.0, 5.7
m), 7.65–7.73 (8H, m, ArH), 8.05(1H, OCH ), 8.05(1H, OCH );
13C NMR (125 MHz, CDCl3) d −4.3 (q), −4.0 (q), 8.6 (q), 14.3 (q),
14.6 (q), 16.6 (q), 18.4 (s) 19.2 (s), 19.4 (s), 19.5 (t), 19.7 (q), 26.2
(q), 26.9 (q), 27.1 (q), 32.6 (t), 32.7 (d), 33.1 (t), 33.5 (t), 36.3 (t)
38.3 (d), 39.3 (d), 41.4 (t), 44.1 (t), 47.6 (t), 48.4 (d), 57.4 (q), 58.1
(q), 62.2 (q), 69.7 (d), 72.6 (d), 78.5 (d), 80.4 (d), 80.9 (d), 117.2
(d), 127.6 (d), 127.7 (d), 129.6 (d), 130.4 (d), 130.6 (s), 131.9 (s),
133.5 (d), 134.0 (s), 134.1 (s), 134.2 (s), 135.6 (d), 135.9 (d), 136.0
(d), 137.0 (d), 137.3 (d), 138.8 (d), 146.5 (s), 147.8 (d), 154.2 (s),
156.5 (s), 162.4 (s), 170.4 (s), 203.2 (s), 210.4 (s); m/z 1405.7489
(M+ + H2O). C80H111O13N3Si2 requires 1405.7425.
=
=
and 2.3 Hz, CHO.C O), 6.35 (1H, d, J 15.9 Hz, CH2CH CH),
=
7.10 (1H, ddd, J 15.9, 8.6 and 6.0 Hz, CH2CH ), 7.30–7.43 (13H,
m), 7.63–7.73 (8H, m), 8.05 (2H, OCH ); 13C NMR (125 MHz,
=
CDCl3) 8.70 (q), 12.0 (q), 19.2 (s), 19.3 (s), 19.4 (t), 19.7 (q), 26.9
(q) 27.0 (q and d), 33.0 (2 × t), 36.2 (t), 39.0 (d), 41.5 (t), 44.0 (t),
47.5 (t), 57.3 (q), 58.8 (q), 65.1 (t), 69.6 (d), 72.8 (t) 78.4 (d), 80.5
(d), 117.3 (d), 127.5 (d), 127.6 (d), 129.5 (d), 130.5 (s), 131.8 (s),
133.4 (d), 133.8 (2 × s), 134.1 (s), 134.2 (s), 135.5 (d), 135.6 (d),
135.8 (d), 135.9 (d), 136.9 (d), 137.2 (d), 138.7 (d), 146.5 (s), 154.1
(s), 156.4 (s), 162.3 (s), 170.5 (s), 210.5 (s). m/z (ESI) 1120.5569
(M+ + H). C65H82N3O10Si2 requires 1120.5539.
The bis-oxazole macrolactam (17) (P = TBDPS; Pꢀ = TMS)
The corresponding alcohol 72b was prepared from the silyl
ether 72a, using HF–pyridine complex in dry THF, following the
procedure described for the deprotection of 47a to 47b. It was
purified by chromatography on silica, using diethyl ether–ethyl
Trimethylsilyl trifluroromethanesulfonate (258 ll, 1.42 mmol), was
added dropwise over 5 min to a stirred solution of the acetonide
77 (117 mg, 0.072 mmol) and triethylamine (229 ll, 1.64 mmol) in
dry dichloromethane (14 ml) at 0 ◦C under a nitrogen atmosphere.
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The solution was allowed to warm to room temperature and
stirred at this temperature for 48 h. Saturated aqueous ammonium
chloride solution (700 ll) and diethyl ether (250 ml) were added
and the mixture was stirred vigorously at room temperature for
30 min. The separated organic phase was dried (Na2SO4) and then
concentrated in vacuo to leave the crude amino alcohol 18a (Pꢀ =
TBS) as an oil.
then allowed to warm to room temperature and stirred at this
temperature for a further 10 min. The mixture was quenched with
saturated sodium bicarbonate solution (2 ml) and the separated
organic phase was then dried (Na2SO4) and concentrated in vacuo.
The residue was purified by chromatography on silica using diethyl
ether–light petroleum (bp 40–60 ◦C) (2:3) as eluent to give the
26
oxazoline (43 mg, 89%) as a colourless oil: [a]D +22.9 (c 2.9 in
HATU (36 mg, 0.095 mmol) was added in one portion to a
stirred solution of crude amino alcohol and triethylamine (13 ll,
0.095 mmol) in dry dichloromethane (35 ml) at 0 ◦C, under a
nitrogen atmosphere. The solution was allowed to warm to room
temperature and stirred at this temperature for six days. Saturated
aqueous sodium bicarbonate solution (10 ml) was added and the
separated aqueous phase was then extracted with dichloromethane
(3 × 30 ml). The combined organic extracts were dried (Na2SO4)
and then concentrated in vacuo. The residue was purified by
chromatography on silica using diethyl ether–light petroleum (bp
40–60 ◦C) (1:1 to 0:1) as eluent to give the macrocycle (68 mg,
67%) as a colourless oil, which crystallised from diethyl ether,
light petroleum (bp 40–60 ◦C) as colourless crystals, mp 57–
CHCl3); mmax (soln, CHCl3)/cm−1 2931, 2858, 1714, 1679 and 1598;
1H NMR (400 MHz, CDCl3) d−0.03 (3H, s, CH3Si), 0.09 (3H, s,
CH3Si), 0.76 (3H, d, J 7.2 Hz, CH3-29), 0.80 (3H, d, J 6.8 Hz, CH3-
39), 0.82–0.90 (3H, m, CH3-33), 0.86 (9H, s, (CH3)3CSi(CH3)2),
0.95 (3H, d, J 6.8 Hz, CH3-37), 1.00 (9H, s, (CH3)3CSi(Ph)2), 1.05
(9H, s, (CH3)3CSi(Ph)2), 1.20 (3H, d, J 7.2 Hz, CH3-9), 1.24–1.49
(7H, m, CHH H-40, H-31, H-4, H-5), 1.62–1.92 (6H, m, CHH H-
40, H-39, H-33, H-29, H-34), 2.17 (1H, dd, J 16.5, 4.3 Hz, CHH
H-6), 2.22–2.31 (1H, m, CHH H-8), 2.31–2.40 (1H, m, CHH H-2),
2.37 (1H, dd, J 9.2, 6.3 Hz, CHH H-2), 2.41–2.63 (5H, m, CHH
H-6, H-27, H-35), 2.70–2.81 (1H, m, H-37), 2.81–2.87 (2H, m, H-
32, CHH H-8), 3.08 (1H, app dt, J 6.4, 2.9 Hz, H-28), 3.21–3.41
(1H, m, H-9), 3.30 (3H, s, CH3OC-32), 3.35 (3H, s, CH3OC-28),
3.59–3.69 (1H, m, CHH H-41), 3.71–3.79 (1H, m, CHH H-41),
3.85 (1H, dd, J 8.0, 2.4 Hz, H-38), 3.97 (1H, dddd, J 5.3, 5.2,
5.1, 5.0 Hz, H-3), 4.65 (1H, dd, J 10.0, 8.4 Hz, CHH H-19), 4.97
(1H, ddd, J 4.7, 4.6, 4.5 Hz, H-30), 5.03 (1H, dd, J 8.4, 6.4 Hz,
CHH H-19), 5.40 (1H, dd, J 10.0, 6.4 Hz, H-15), 6.40 (1H, d, J
16.2 Hz, H-25), 6.82 (1H, dt, J 16.2, 6.4 Hz, H-26), 7.33 (1H, s,
H-14), 7.35–7.52 (12H, m, ArH), 7.61–7.75 (8H, m, ArH), 8.01
(1H, s, H-24); 13C NMR (90.6 MHz, CDCl3) d −4.2 (q), −4.1 (q),
9.31 (q), 14.2 (q), 15.7 (q), 16.2 (q), 18.3 (t), 18.4 (s), 19.3 (s), 19.3
(s), 20.5 (q), 24.4 (t), 26.2 (3q), 26.6 (3q), 26.9 (3q), 30.1 (t), 32.6
(t), 33.1 (d), 33.8 (t), 34.2 (d), 35.6 (t), 38.8 (d), 41.5 (t), 42.5 (t),
43.3 (t), 47.8 (t), 50.1 (d), 57.3 (q), 58.3 (q), 62.2 (t), 63.4 (d), 69.5
(d), 71.0 (t), 72.1 (d), 78.6 (d), 81.6 (d), 82.1 (d), 118.9 (d), 127.6
(d), 127.7 (8d), 129.6 (3d), 129.9 (d), 130.8 (s), 133.8 (2 s), 134.0 (2
s), 134.1 (s), 134.3 (d), 135.6 (4d), 135.9 (2d), 136.1 (2d), 136.7 (d),
140.3 (d), 144.3 (s), 159.5 (s), 162.0 (s), 170.0 (s), 209.8 (s), 214.0
(s); m/z (EI) 1414.7398 (M+ + Na), C80H113N3O12Si3 + Na requires
1414.7530.
59 ◦C: [a]D −6.4 (c 1.0 in CHCl3); mmax (soln, CHCl3)/cm−1 3399,
31
2931, 2857, 1715, 1671 and 1596; (Found: C, 68.0; H, 8.4; N,
2.9 C80H115N3O13Si3 requires C, 68.1; H, 8.2; N, 3.0%); 1H NMR
(400 MHz, CDCl3) d− 0.04 (3H, s, CH3Si), 0.07 (3H, s, CH3Si),
0.77 (3H, d, J 6.8 Hz, CH3-29), 0.84 (3H, d, J 7.3 Hz, CH3-39),
0.88 (9H, s, (CH3)3CSi(CH3)2), 0.90 (3H, d, J 7.2 Hz, CH3-33),
0.95 (3H, d, J 7.0 Hz, CH3-37), 1.07 (9H, s, (CH3)3CSi(Ph)2), 1.08
(9H, s, (CH3)3CSi(Ph)2), 1.25 (3H, d, J 6.9 Hz, CH3-9), 1.33–1.38
(1H, m, CHH H-40), 1.40–1.48 (4H, m, H-31, H-4), 1.53–1.63
(2H, m, H-5), 1.68–1.89 (5H, m, CHH H-40, H-33, H-29, H-34),
1.95 (1H, m, H-39), 2.11–2.29 (2H, m, H-6), 2.37 (1H, dd, J 16.3,
5.0 Hz, CHH H-8), 2.47 (2H, app d, J 6.4 Hz, H-2), 2.51 (2H, t, J
7.6 Hz, H-35), 2.55–2.64 (2H, m, H-27), 2.74–2.85 (2H, m, H-37,
H-32), 2.88 (1H, dd, J 16.3, 9.2 Hz, CHH H-8), 3.13 (1H, m, H-
28), 3.24 (3H, s, CH3OC-32), 3.30–3.35 (1H, m, H-9), 3.34 (3H, s,
CH3OC-28), 3.60–3.70 (1H, m, CHH H-41), 3.72–3.79 (1H, m,
CHH H-41), 3.82 (1H, dd, J 8.1, 2.3 Hz, H-38), 4.00–4.15 (1H, m,
H-3), 4.02 (1H, dd, J 11.3, 3.9 Hz, CHH H-19), 4.06–4.14 (1H,
m, CHH H-19), 5.03–5.13 (1H, m, H-30), 5.35 (1H, app dt, J 8.1,
3.9 Hz, H-15), 6.34 (1H, d, J 16.0 Hz, H-25), 6.82 (1H, dt, J 16.0,
7.2 Hz, H-26), 7.35–7.49 (13H, m, ArH & H-14), 7.65–7.73 (8H,
m, ArH), 7.88 (1H, d, J 8.1 Hz H-16), 8.12 (1H, s, H-24); 13C NMR
(125 MHz, CDCl3) d −1.4 (q), −1.1 (q), 9.5 (q), 14.1 (q), 15.6 (q),
16.2 (q), 18.4 (s), 18.6 (t), 19.2 (s), 19.3 (s), 19.9 (q), 24.4 (t), 26.2
(3q), 26.9 (3q), 27.0 (3q), 30.8 (t), 33.1 (d), 33.8 (2t), 34.1 (d), 35.6
(t), 39.8 (d), 42.0 (t), 42.5 (t), 43.3 (t), 48.4 (t), 49.1 (d), 50.0 (d),
57.5 (q), 57.9 (q), 62.1 (t), 64.3 (t), 69.6 (d), 72.5 (d), 78.6 (d), 80.6
(d), 81.7 (d), 118.2 (d), 125.6 (d), 127.7 (8d), 129.6 (2d), 129.8 (2d),
133.8 (s), 134.9 (2 s), 134.0 (2 s), 134.6 (d), 135.6 (4d), 135.9 (2d),
135.9 (2d), 136.2 (s), 137.5 (d), 140.6 (d), 144.2 (s), 160.9 (s), 161.2
(s), 170.1 (s), 209.7 (s), 214.0 (s); m/z (EI) 1410.7807 (M+ + H),
1432.7594 (M+ + Na), C80H115N3O13Si3 + H requires 1410.7816.
The tris-oxazole macrolide (76)
Procedure A. A solution of the oxazoline 78a (14 mg,
˚
0.01 mmol), nickel peroxide (34 mg, 0.38 mmol) and 4 A molecular
sieves (20 mg) in dry degassed benzene (1 ml) was heated under
reflux for 12 h. The mixture was filtered through celite and the filter
cake was washed with ethyl acetate (3 × 5 ml). The combined ethyl
acetate washings were concentrated in vacuo and the residue was
then purified by chromatography on silica using ethyl acetate–
light petroleum (bp 40–60 ◦C) (1:9 to 2:3) as eluent to give the
tris-oxazole (3.6 mg, 25%), which recrystallised from ethyl acetate–
light petroleum (bp 40–60 ◦C) as colourless crystals, mp 72–75 ◦C:
[a]D26–24.8 (c 1.0 in CHCl3); mmax (soln, CHCl3)/cm−1 2931, 2858
1
and 1713; H NMR (400 MHz, CDCl3) d-0.07 (3H, s, CH3Si),
0.04 (3H, s, CH3Si), 0.78 (3H, d, J 6.8 Hz, CH3-29), 0.82–0.86
(3H, m, CH3-39), 0.85 (9H, s, (CH3)3CSi(CH3)2), 0.87 (3H, d, J
7.0 Hz, CH3-33), 0.94 (3H, d, J 7.0 Hz, CH3-37), 1.03 (9H, s,
(CH3)3CSi(Ph)2), 1.05 (9H, s, (CH3)3CSi(Ph)2), 1.25–1.40 (1H, m,
CHH H-40), 1.28 (3H, d, J 7.0 Hz, CH3-9), 1.38–1.62 (5H, m,
CHH H-4, H-31, H-33, CHH H-34), 1.65–1.82 (5H, m, CHH
The oxazoline bis-oxazole macrolide (78a)
(Diethylamino)sulfur trifluoride (7 ll, 0.053 mmol) was added in
one portion to a stirred solution of the macrocycle 17 (48 mg,
0.035 mmol) in dry dichloromethane (1 ml) at −78 ◦C under a
nitrogen atmosphere. The mixture was stirred at −78 ◦C for 2 h,
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H-4, H-5, CHH H-34, CHH H-40), 1.83–1.95 (2H, m, H-29, H-
39), 2.21–2.46 (2H, m, H-6), 2.38 (1H, dd, J 16.6, 5.5 Hz, CHH
H-8), 2.44–2.54 (3H, m, CHH H-27, H-35), 2.57 (2H, app dd, J
5.4, 3.7 Hz, CHH H-2), 2.65 (1H, ddd, J 16.9, 6.4, 4.1 Hz, CHH
H-27), 2.75 (1H, dq, J 8.0, 7.0 Hz, H-37), 2.88–2.96 (1H, m, H-32),
3.15 (1H, dd, J 16.6, 7.8 Hz, CHH H-8), 3.18–3.25 (1H, m, H-28),
3.28 (3H, s, CH3OC-32), 3.32 (3H, s, CH3OC-28), 3.41 (1H, app
q, J 7.0 Hz, H-9), 3.64 (1H, ddd, J 14.5, 9.8, 4.5 Hz CHH H-41),
3.74 (1H, ddd, J 9.8, 6.4, 4.4 Hz, CHH H-41), 3.83 (1H, dd, J
8.0, 2.4 Hz, H-38), 4.29 (1H, dddd, J 5.5, 5.4, 5.3, 5.2 Hz, H-3),
5.11 (1H, ddd, J 9.0, 6.2, 1.2 Hz, H-30), 6.35 (1H, d, J 15.3 Hz,
H-25), 7.09 (1H, ddd, J 15.3, 8.6, 6.4 Hz, H-26), 7.30–7.49 (13H,
m, ArH, H-14), 7.64–7.76 (8H, m, ArH), 8.05 (2H, s, H-19, H-24);
13C NMR (90.6 MHz, CDCl3) d-4.4 (q), -4.1 (q), 8.8 (q), 14.1 (q),
15.7 (q), 16.2 (q), 18.4 (s), 19.2 (t), 19.4 (q), 19.5 (s), 19.8 (s), 24.5
(t), 26.2 (3q), 26.9 (3q), 27.1 (3q), 27.1 (d) 31.6 (t), 33.0 (d), 33.1
(t), 33.8 (t), 34.2 (d), 36.3 (t), 39.3 (d), 41.5 (t), 42.6 (t), 44.1 (t),
47.6 (t), 50.0 (d), 57.4 (q), 58.0 (q), 62.2 (t), 69.8 (d), 72.8 (d),
78.6 (d), 80.5 (d), 81.9 (d), 117.3 (d), 127.6 (4d), 127.7 (4d), 129.6
(4d), 130.6 (s), 131.8 (s), 133.5 (d), 134.0 (2 s), 134.2 (2 s), 135.6
(4d), 135.9 (2d), 136.0 (2d), 137.0 (d), 137.3 (d), 138.9 (d), 146.5
(s), 154.2 (s), 156.5 (s), 162.4 (s), 170.5 (s), 210.5 (s), 214.0 (s);
m/z (EI) 1412.7352 (M+ + Na), 1444.7628 (M+ + MeOH + Na),
C80H111N3O12Si3 + Na requires 1412.7373.
the combined organic extracts were washed with 1 M hydrochloric
acid (40 ml) and saturated aqueous sodium bicarbonate solution
(40 ml), then dried (Na2SO4) and concentrated in vacuo. The
residue was purified by chromatography on silica using ethyl
acetate–light petroleum (bp 40–60 ◦C) (1:5 to 1:1) as eluent to give
23
the enamide (131 mg, 75%) as a colourless oil: [a]D −8.4 (c 1.0
in CHCl3); mmax (soln, CHCl3)/cm−1 3364, 2932, 2858, 1715, 1675
1
and 1588; H NMR (400 MHz, CDCl3) d−0.06 (3H, s, CH3Si),
0.05 (3H, s, CH3Si), 0.75 (3H, d, J 6.8 Hz, CH3-29), 0.86 (3H, d,
J 6.3 Hz, CH3-39), 0.87 (9H, s, (CH3)3CSi(CH3)2), 0.88 (3H, d,
J 7.2 Hz, CH3-33), 0.95 (3H, d, J 7.0 Hz, CH3-37), 1.03 (9H, s,
(CH3)3CSi(Ph)2), 1.06 (9H, s, (CH3)3CSi(Ph)2), 1.14–1.24 (1H, m,
CHH H-34), 1.27 (3H, d, J 6.9 Hz, CH3-9), 1.30–1.45 (1H, m,
CHH H-40), 1.46–1.58 (4H, m, H-31, H-4), 1.58–1.83 (6H, m, H-
5, H-29, H-33, CHH H-34, CHH H-40), 1.89 (1H, app dp, J, 6.3,
3.5 Hz, H-39), 2.35 (2H, t, J 6.8 Hz, H-6), 2.36 (1H, dd, J 16.4,
6.6 Hz, CHH H-8), 2.41–2.55 (5H, m, H-2, CHH H-27, H-35),
2.59 (1H, ddd, J 11.6, 7.8, 5.1 Hz, CHH H-27), 2.73–2.83 (2H,
m, H-32, H-37), 2.92 (1H, dd, J 16.4, 7.3 Hz, CHH H-8), 3.16
(1H, ddd, J 8.9, 5.1, 1.1 Hz, H-28), 3.25 (3H, s, CH3OC-32), 3.32
(3H, s, CH3OC-28), 3.37 (1H, app dd, J 13.7, 6.9 Hz, H-9), 3.64
(1H, ddd, J 10.0, 8.9, 5.6 Hz, CHH H-41), 3.75 (1H, ddd, J 10.0,
6.3, 4.2 Hz, CHH H-41), 3.84 (1H, dd, J 8.1, 2.5 Hz, H-38), 4.04–
4.13 (1H, m, H-3), 5.07 (1H, ddd, J 9.9, 6.5, 1.5 Hz, H-30), 5.70
(1H, s, CHH H-19), 6.39 (1H, d, J 16.0 Hz, H-25), 6.51 (1H, s,
CHH H-19), 6.82 (1H, dt, J 16.0, 7.8 Hz, H-26), 7.30–7.47 (13H,
m, ArH, H-14), 7.62–7.71 (8H, m, ArH), 8.15 (1H, s, H-24), 9.45
(1H, s, H-16); 13C NMR (90.6 MHz, CDCl3) d-4.3 (q), -4.1 (q),
10.0 (q), 14.2 (q), 15.7 (q), 16.2 (q), 18.5 (s), 19.3 (q), 19.3 (s), 19.4
(t), 19.4 (s), 24.4 (t), 26.2 (3q), 27.0 (3q), 27.0 (3q), 27.2 (d), 31.5
(t), 33.1 (d), 33.8 (t), 34.1 (d), 34.2 (t), 36.0 (t), 39.9 (d), 42.5 (t),
42.6 (t), 43.5 (t), 48.1 (t), 50.1 (d), 57.6 (q), 57.9 (q), 62.2 (t), 69.5
(d), 72.7 (d), 78.6 (d), 80.8 (d), 81.8 (d), 102.2 (t), 118.4 (d), 127.7
(8d), 128.6 (s), 129.7 (2d), 129.8 (2d), 133.7 (2 s), 134.0 (2 s), 134.6
(d), 135.6 (4d), 135.9 (4d), 137.0 (s), 137.8 (d), 140.7 (d), 145.9 (s),
157.8 (s), 159.5 (s), 160.7 (s), 170.1 (s), 209.7 (s), 214.0 (s); m/z
(EI) 1392.7658 (M+ + H), 1414.7449 (M+ + Na), C80H113N3O12Si3
+ H requires 1392.7710.
Procedure B. A solution of the oxazoline 78b (124 mg,
˚
0.087 mmol), CSA (105 mg, 0.45 mmol) and 5 A molecular
sieves (100 mg) in dry benzene (15 ml) was heated under reflux
using a Dean–Stark apparatus for 22 h. The mixture was filtered
through celite and the filter cake was washed with ethyl acetate
(3 × 5 ml). The combined ethyl acetate washings were diluted
with saturated aqueous sodium bicarbonate solution (10 ml) and
the separated aqueous phase was then extracted with ethyl acetate
(3 × 20 ml). The combined organic extracts were dried (Na2SO4)
and then concentrated in vacuo. The residue was purified by
chromatography on silica using ethyl acetate–light petroleum (bp
40–60 ◦C) (1:9 to 2:3) as eluent to give the tris-oxazole (70 mg,
58%), which showed analytical and spectroscopic data which were
identical to those obtained by procedure A.
The bis-oxazole enamide (79)
The bis-oxazole (80)
N,N-Diisopropylethylamine (49 ll, 0.28 mmol), and methanesul-
fonyl chloride (10 ll, 0.13 mmol) were added sequentially to a
stirred solution of the alcohol 17 (177 mg, 0.13 mmol) in dry
dichloromethane (4.5 ml) at 0 ◦C under a nitrogen atmosphere.
The mixture was stirred at 0 ◦C for 1 h, then quenched with
1 M aqueous potassium carbonate solution (30 ml) and stirred at
room temperature for 10 min. The separated aqueous phase was
extracted with dichloromethane (3 × 30 ml) and the combined
organic extracts were then dried (Na2SO4) and concentrated in
vacuo to leave the corresponding methanesulfonate as an oil, which
was used without further purification.
1,8-Diazabicyclo[5.4.0]undec-7-ene (19 ll, 0.13 mmol) was
added dropwise over 5 min to a stirred solution of the crude
methanesulfonate (187 mg, 0.13 mmol) in dry dichloromethane
(10 ml) at 0 ◦C under a nitrogen atmosphere. The mixture was
allowed to warm to room temperature, stirred for 2 h and then
diluted with water (40 ml) and ethyl acetate (40 ml). The separated
aqueous phase was extracted with ethyl acetate (2 × 40 ml) and
N-Bromosuccinimide (16 mg, 0.09 mmol) was added in one
portion to a stirred mixture of the enamide 79 (126 mg, 0.09 mmol)
and 4 A molecular sieves (40 mg) in dry methanol (7 ml) and dry
˚
dichloromethane (7 ml) at 0 ◦C under a nitrogen atmosphere. The
mixture was allowed to warm to room temperature over 15 h, and
then filtered through celite. The filter cake was washed with ethyl
acetate (3 × 15 ml) and the combined ethyl acetate washings were
then diluted with saturated aqueous sodium thiosulfate solution
(10 ml). The separated aqueous phase was extracted with ethyl
acetate (2 × 30 ml) and the combined organic extracts were
washed with brine (10 ml), then dried (Na2SO4) and concentrated
in vacuo. The residue was purified by chromatography on silica
◦
using ethyl acetate–light petroleum (bp 40–60 C) (1:5 to 1:1) as
eluent to give the bromide (134 mg, 92%) as a colourless oil and a
24
mixture of diastereoisomers: [a]D −9.8 (c 3.7 in CHCl3); mmax (soln,
1
CHCl3)/cm−1 3364, 2932, 2858, 1714, 1675 and 1591; H NMR
(400 MHz, CDCl3) d −0.06 (6H, s, CH3Si), 0.05 (6H, s, CH3Si),
0.75 (6H, d, J 6.6 Hz, CH3-29), 0.82–0.87 (6H, m, CH3-39), 0.87
1494 | Org. Biomol. Chem., 2008, 6, 1478–1497
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©

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(18H, s, (CH3)3CSi(CH3)2), 0.88 (6H, d, J 7.3 Hz, CH3-33), 0.96
(6H, d, J 6.9 Hz, CH3-37), 1.02 (18H, s, (CH3)3CSi(Ph)2), 1.06
(18H, s, (CH3)3CSi(Ph)2), 1.29 (6H, d, J 6.9 Hz, CH3-9), 1.15–1.25
(2H, m, CHH H-34), 1.33–1.60 (10H, m, H-4, H-31, CHH H-40),
1.61–1.84 (12H, m, H-5, H-29, H-33, CHH H-34, CHH H-40),
1.84–1.95 (2H, m, H-39), 2.31–2.55 (14H, m, H-2, H-6, CHH H-8,
H-35), 2.55–2.69 (4H, m, H-27), 2.73–2.84 (4H, m, H-32, H-37),
2.93 (2H, dd, J 16.4, 7.9 Hz, CHH H-8), 3.13–3.20 (2H, m, H-28),
3.11 (3H, s, CH3OC-15), 3.14 (3H, s, CH3OC-15), 3.25 (6H, s,
CH3OC-32), 3.31 (3H, s, CH3OC-28), 3.33 (3H, s, CH3OC-28),
3.34–3.45 (2H, m, H-9), 3.64 (2H, ddd, J 10.1, 7.1, 4.0 Hz, CHH
H-41), 3.75 (2H, ddd, J 10.1, 6.3, 4.4 Hz, CHH H-41), 3.84 (2H,
dd, J 8.0, 2.2 Hz, H-38), 3.98 (1H, d, J 10.4 Hz, CHH H-19), 4.00
(1H, d, J 10.4 Hz, CHH H-19), 4.01–4.11 (2H, m, H-3), 4.91 (1H,
d, J 10.4 Hz, CHH H-19), 4.96 (1H, d, J 10.4 Hz, CHH H-19),
5.07 (2H, ddd, J 10.3, 6.3, 1.9 Hz, H-30), 6.39 (1H, d, J 16.0 Hz,
H-25), 6.40 (1H, d, J 16.0 Hz, H-25), 6.73–6.92 (2H, m, H-26),
7.30–7.48 (24H, m, ArH), 7.51 (2H, s, H-14), 7.61–7.74 (16H, m,
ArH), 8.16 (2H, s, H-24), 8.74 (1H, s, H-16), 8.76 (1H, s, H-16);
13C NMR (90.6 MHz, CDCl3) d −4.3 (2q), −4.1 (2q), 9.8 (q), 10.0
(q), 14.2 (2q), 15.7 (q), 16.2 (2q), 18.4 (2 s), 19.0 (q), 19.2 (t), 19.3
(2 s), 19.4 (2 s), 19.5 (t), 19.5 (2q), 24.4 (2t), 26.2 (6q), 26.9 (6q),
27.0 (6q), 27.4 (2d), 31.3 (t), 31.7 (2t), 32.6 (t), 33.0 (2t), 33.1 (2d),
33.8 (2t), 33.9 (d), 34.0 (d), 34.1 (t), 34.2 (t), 36.0 (2t), 39.8 (d), 39.9
(d), 42.5 (t), 42.6 (t), 43.5 (t), 43.7 (t), 48.1 (t), 48.2 (t), 50.1 (2d),
52.4 (2q), 57.5 (2q), 57.9 (2q), 62.1 (t), 62.2 (t), 69.5 (d), 69.6 (d),
72.8 (2d), 78.6 (2d), 80.7 (d), 80.8 (d), 81.7 (2d), 85.8 (2 s), 118.3
(d), 118.4 (d), 127.7 (16d), 129.6 (4d), 129.8 (4d), 133.6 (4 s), 134.0
(4 s), 135.6 (8d), 135.9 (8d), 136.0 (s), 136.1 (s), 137.7 (2d), 137.9
(2d), 141.0 (2d), 144.6 (s), 145.0 (s), 159.0 (s), 159.1 (s), 160.2 (2
s), 160.8 (2 s), 170.0 (s), 170.1 (s), 209.5 (s), 209.6 (s), 214.0 (2 s);
m/z (EI) 1524.6863 (M+ + Na), C81H116BrN3O13Si3 + Na requires
1524.6897.
(2H, t, J 10.0 Hz, H-6), 2.08 (2H, t, J 10.0 Hz, H-6), 2.20 (1H,
dd, J 16.6, 5.2 Hz, CHH H-8), 2.21–2.30 (1H, m, CHH H-8), 2.36
(2H, dd, J 9.4, 7.0 Hz, CHH H-2), 2.39 (2H, dd, J 7.0, 1.5 Hz,
CHH H-2), 2.47–2.62 (4H, m, H-27, H-35), 2.72–2.95 (6H, m,
CHH H-8, H-32, H-37), 3.08 (2H, ddd, J 8.8, 6.8, 3.8 Hz, H-
28), 3.21–3.30 (2H, m, H-9), 3.26 (3H, s, CH3OC-32), 3.31 (3H, s,
CH3OC-32), 3.32 (3H, s, CH3OC-28), 3.33 (3H, s, CH3OC-28),
3.47 (3H, s, CH3OC-15), 3.49 (3H, s, CH3OC-15), 3.61–3.69 (2H,
m, CHH H-41), 3.75 (2H, ddd, J 9.7, 5.9, 4.0 Hz, CHH H-41),
3.84 (2H, dd, J 8.1, 2.3 Hz, H-38), 3.95–4.08 (2H, m, H-3), 3.49
(1H, d, J 9.9 Hz, CHH H-19), 4.54 (1H, d, J 9.9 Hz, CHH H-19),
4.75 (1H, d, J 9.9 Hz, CHH H-19), 4.99 (2H, ddd, J 10.6, 4.5,
1.2 Hz, H-30), 5.03 (1H, d, J 9.9 Hz, CHH H-19), 6.38 (1H, d, J
16.0 Hz, H-25), 6.43 (1H, d, J 16.0 Hz, H-25), 6.88 (2H, ddd, J
16.0, 6.9, 6.8 Hz, H-26), 7.31–7.49 (26H, m, ArH, H-14), 7.59–7.76
(16H, m, ArH), 8.06 (1H, s, H-24), 8.08 (1H, s, H-24); 13C NMR
(90.6 MHz, CDCl3) d −4.4 (2q), −4.2 (2q), 9.6 (q), 9.2 (q), 14.1
(2q), 15.6 (q), 15.7 (q), 16.2 (2q), 18.4 (2 s), 18.5 (t), 19.1 (t), 19.2
(2 s), 19.3 (2 s), 19.9 (2q), 24.4 (2t), 26.2 (6q), 26.3 (3q), 26.6 (3q),
26.9 (3q), 27.1 (3q), 27.3 (2d), 30.1 (t), 30.4 (t), 32.6 (t), 33.0 (2d),
33.2 (t), 33.8 (2t), 34.2 (2d), 35.4 (t), 35.6 (t), 38.8 (d), 39.2 (d), 41.4
(t), 41.5 (t), 42.5 (2t), 43.2 (t), 43.6 (t), 47.9 (t), 48.0 (t), 50.1 (2d),
52.0 (q), 52.1 (q), 57.2 (q), 57.3 (q), 58.1 (q), 58.3 (q), 62.0 (t), 62.1
(t), 69.5 (d), 69.8 (d), 72.1 (d), 72.5 (d), 74.7 (t), 75.3 (t), 77.3 (d),
78.6 (d), 81.3 (d), 81.6 (d), 81.8 (d), 82.0 (d), 100.2 (s), 100.3 (s),
118.3 (d), 118.8 (d), 127.6 (8d), 127.7 (8d), 129.6 (2d), 129.7 (2d),
129.8 (2d), 130.6 (2 s), 133.7 (2 s), 133.8 (2 s), 133.9 (2 s), 134.0
(2 s), 134.3 (d), 134.8 (d), 135.6 (8d), 135.9 (4d), 136.0 (4d), 137.0
(2d), 137.7 (2d), 141.2 (d), 141.3 (d), 144.4 (s), 145.5 (s), 160.9 (s),
161.3 (s), 161.6 (s), 161.7 (s), 162.1 (s), 162.2 (s), 169.9 (s), 170.1
(s), 209.8 (s), 210.2 (s), 214.0 (2 s); m/z (EI) 1444.7632 (M+ + Na),
C81H115N3O13Si3 + Na requires 1444.7635.
The C3 TBDPS ether of ulapualide A (83)
The methoxyoxazoline bis-oxazole macrolide (78b)
Pyridinium p-toluenesulfonate (0.8 mg, 0.003 mmol) and N-
methylformamide (17 ll, 0.29 mmol) were added sequentially to
a stirred solution of the aldehyde 82b (14 mg, 0.013 mmol) in dry
benzene (30 ml) and the mixture was then heated under reflux for
4 h in a nitrogen atmosphere. The solution was cooled to room
temperature and another portion of N-methylformamide (12 ll,
0.21 mmol) was added, and the mixture was heated under reflux
for a further 6 h. The mixture was cooled to room temperature,
and then diluted with ethyl acetate (10 ml) and water (5 ml). The
separated organic phase was washed with brine (5 ml), then dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
chromatography on silica using ethyl acetate–light petroleum (bp
40–60 ◦C) (1:1 to 3:1) as eluent to give the N-methyl-N-alkenyl
formamide (5.6 mg, 40%), as a colourless oil, which was used
without further purification; 1H NMR (500 MHz, CDCl3) d 0.78
(3H, d, J 6.7 Hz, CH3-33), 0.83 (3H, d, J 6.8 Hz CH3-29), 1.00–
1.04 (3H, m, CH3-39), 1.02 (9H, s, (CH3)3CSi(Ph)2), 1.07 (3H, d,
J 6.9 Hz, CH3-37), 1.17–1.25 (1H, m, CHH H-34), 1.28 (3H, d,
J 7.0 Hz, CH3-9), 1.37–1.59 (4H, m, H-4, H-31), 1.65–1.77 (4H,
m, H-5, H-33, CHH H-34), 1.84–1.93 (1H, m, H-29), 2.00 (3H, s,
CH3CO), 2.20–2.35 (2H, m, H-6), 2.38 (1H, dd, J 16.5, 5.4 Hz,
CHH H-8), 2.43–2.57 (4H, m, CHH H-27, H-35, H-39), 2.60–2.64
(2H, m, H-2), 2.64–2.69 (1H, m CHH H-27), 2.71–2.80 (1H, m,
H-37), 2.88–2.93 (1H, m, H-32), 3.08 (3.04) (3H, s, NCH3), 3.13
Caesium carbonate (176 mg, 0.49 mmol) was added in one portion
to a stirred solution of the a-methoxy bromide 80 (250 mg,
0.016 mmol) in dry dioxane (25 ml) at 60 ◦C under a nitrogen
atmosphere. The mixture was stirred at 60 ◦C for 5 h and then
concentrated in vacuo. Ethyl acetate (20 ml) and 10% aqueous citric
acid solution (10 ml), were added and the separated aqueous phase
was then extracted with ethyl acetate (3 × 20 ml). The combined
organic extracts were dried (Na2SO4) and then concentrated in
vacuo. The residue was purified by chromatography on silica
using ethyl acetate–light petroleum (bp 40–60 ◦C) (1:2 to 1:1)
as eluent to give the oxazoline (196 mg, 92%) as a colourless foam
24
and a mixture of diastereoisomers: [a]D +0.8 (c 2.5 in CHCl3);
mmax (soln, CHCl3)/cm−1 2931, 2857, 1714 and 1676; H NMR
1
(400 MHz, CDCl3) d −0.06 (6H, s, CH3Si), 0.05 (6H, s, CH3Si),
0.77 (3H, d, J 7.1 Hz, CH3-29), 0.79 (3H, d, J 7.7 Hz, CH3-29),
0.80 (3H, d, J 7.2 Hz, CH3-39), 0.81 (3H, d, J 6.8 Hz, CH3-39),
0.85 (18H, s, (CH3)3CSi(CH3)2), 0.88 (6H, d, J 7.1 Hz, CH3-33),
0.95 (3H, d, J 6.9 Hz, CH3-37), 0.96 (3H, d, J 6.9 Hz, CH3-37),
1.00 (9H, s, (CH3)3CSi(Ph)2), 1.03 (9H, s, (CH3)3CSi(Ph)2), 1.05
(18H, s, (CH3)3CSi(Ph)2), 1.16–1.28 (2H, m, CHH H-34), 1.21
(3H, d, J 6.9 Hz, CH3-9), 1.24 (3H, d, J 6.9 Hz, CH3-9), 1.29–1.56
(14H, m, H-4, H-5, H-31, CHH H-40), 1.63–1.82 (6H, m, H-33,
CHH H-34, CHH H-40), 1.83–1.94 (4H, m, H-29, H-39), 2.07
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(1H, dd, J 16.5, 8.2 Hz, CHH H-8), 3.18–3.24 (1H, m, H-28),
3.26 (3H, s, CH3OC-32), 3.31 (3H, s, CH3OC-28), 3.35–3.44 (1H,
m, H-9), 4.24–4.32 (1H, m, H-3), 4.98 (1H, dd, J 14.4, 9.2 Hz,
H-40), 5.05–5.11 (1H, m, H-30), 5.14 (2H, dd, J 8.9, 3.8 Hz, H-
38), 6.35 (1H, d, J 15.7 Hz, H-25), 7.01–7.13 (1H, m, H-26), 7.17
(6.50) (1H, d, J 14.4 Hz, H-41), 7.29–7.44 (7H, m, ArH, H-14),
7.65–7.75 (4H, m, ArH), 8.05 (2H, s, H-19, H-24), 8.29 (8.08)
(1H, s, CHO); m/z (EI) 1141.5544 (M+ + Na), C60H79N3O13Si +
Na requires 1141.5545.
References
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26
(1.8 mg, 60%), as a colourless oil; [a]D −52.8 (c 0.11 in MeOH);
1H NMR (500 MHz, CDCl3) d 0.83 (3H, d, J 6.8 Hz, CH3-33), 0.91
(3H, d, J 6.9 Hz CH3-29), 1.05 (3H, d, J 6.8 Hz, CH3-39), 1.08 (3H,
d, J 7.0 Hz, CH3-37), 1.27–1.31 (1H, m, CHH H-34), 1.33 (3H, d,
J 7.0 Hz, CH3-9), 1.46–1.63 (4H, m, H-4, H-31), 1.67–1.87 (5H,
m, H-5, H-29, H-33, CHH H-34), 2.02 (3H, s, CH3CO), 2.43–2.57
(9H, m, H-2, H-6, CHH H-8, CHH H-27, H-35, H-39), 2.63–2.71
(1H, m CHH H-27), 2.71–2.80 (1H, m, H-37), 2.95–2.99 (1H, m,
H-32), 2.99 (1H, dd, J 15.0, 7.2 Hz, CHH H-8), 3.08 (3.04) (3H, s,
NCH3), 3.28–3.34 (1H, m, H-28), 3.32 (3H, s, CH3OC-32), 3.39
(3H, s, CH3OC-28), 3.39–3.48 (1H, m, H-9), 4.20–4.29 (1H, m,
H-3), 4.46–4.52 (1H, br, OH), 4.95–5.03 (1H, m, H-40), 5.14 (2H,
dd, J 8.8, 3.7 Hz, H-38), 5.25–5.30 (1H, m, H-30), 6.41 (1H, d,
J 16.1 Hz, H-25), 6.97–7.05 (1H, m, H-26), 7.17 (6.50) (1H, d, J
14.3 Hz, H-41), 7.41 (1H, s, H-14), 8.06 (2H, s, H-19, H-24), 8.30
(8.09) (1H, s, CHO); 13C NMR (125 MHz, CDCl3) d 9.1 (q), 13.4
(q), 15.6 (q), 18.9 (q), 19.5 (q), 20.8 (t), 21.0 (q), 27.7 (t), 27.9 (d),
32.2 (t), 33.1 (q), 33.6 (t), 34.6 (d), 37.0 (d), 37.3 (t), 39.9 (t), 40.5
(d), 43.0 (t), 43.9 (t), 48.3 (t), 48.7 (d), 57.8 (q), 58.2 (q), 68.6 (d),
73.0 (d), 77.6 (d), 80.0 (d), 81.8 (d), 110.5 (d), 112.2 (d), 117.3 (d),
125.6 (d), 129.6 (d), 130.4 (s), 131.8 (s), 133.5 (d), 137.4 (d), 137.8
(d), 139.8 (d), 146.5 (s), 154.3 (s), 156.3 (s), 161.0 (d), 162.2 (d),
162.8 (s), 170.1 (s), 172.6 (s), 210.5 (s), 211.7 (s); m/z (EI) 903.4385
(M+ + Na), C46H64N4O13 + Na requires 903.4368.
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Acknowledgements
We thank the late Professor Scheuer for a sample of natural
ulapualide A and Gregory Chaume for carrying out some
experiments on the attempted reduction of the enone 75 to 76.
We also thank AstraZeneca (studentship to JK) and Pfizer Ltd
(sponsorship for GMW) for their support towards this research
program.
26 We thank Professor A. J. Blake of this department for this X-ray
analysis, which has been deposited at the Cambridge Crystallographic
1496 | Org. Biomol. Chem., 2008, 6, 1478–1497
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