Antibacterial Mimics of Natural Products by Side-Chain Functionalization of Bicyclic Tetramic Acids

Article abstract of DOI:10.1021/acs.joc.8b01453

Tetramic acids with unsaturated acyl chains are widely found in natural products possessing a range of biological activities, and bicyclic tetramates represent a suitable scaffold to prepare simple mimics of such complex molecules. An efficient route to functionalize the C(6)-acyl group of a bicyclic tetramate was developed and utilized to prepare a small chemical library with a range of saturated and unsaturated side-chains. The analogues with lipophilic residues possessed highly potent antibacterial activity, which was selective for Gram-positive bacteria, and the best compound was 37-fold more potent than the cephalosporin C control and with an appropriate therapeutic window.

Full text of DOI:10.1021/acs.joc.8b01453

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Article
Antibacterial Mimics of Natural Products by Side
Chain Functionalisation of Bicyclic Tetramic Acids
Laia Josa-Cullere, Alexander Pretsch, Dagmar Pretsch, and Mark Gerard Moloney
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01453 • Publication Date (Web): 20 Jul 2018
Downloaded from http://pubs.acs.org on July 20, 2018
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Antibacterial Mimics of Natural Products by Side Chain Functionalisation of Bicyclic
Tetramic Acids
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Laia JosaꢀCulleré,† Alexander Pretsch,‡ Dagmar Pretsch‡ and Mark G. Moloney*,†
†Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford,
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UK
‡Oxford Antibiotic Group, The Oxford Science Park, Magdalen Centre, Oxford OX4 4GA, UK
mark.moloney@chem.ox.ac.uk
TOC figure:
Abstract: Tetramic acids with unsaturated acyl chains are widely found in natural products possessing a range of
biological activities, and bicyclic tetramates represent a suitable scaffold to prepare simple mimics of such
complex molecules. An efficient route to functionalise the C(6)ꢀacyl group of a bicyclic tetramate was
developed, and utilised to prepare a small chemical library with a range of saturated and unsaturated sideꢀchains.
The analogues with lipophilic residues possessed highly potent antibacterial activity, which was selective for
Gramꢀpositive bacteria, and the best compound was 37ꢀfold more potent than the Cephalaosporin C control and
with an appropriate therapeutic window.
Introduction
Natural products have long provided valuable sources of inspiration for drug design,1 and may be considered to
be ‘privileged structures’ possessing large chemical diversity with effective biological activity, suitable for
therapies for a wide range of diseases.2,3 In the area of antiꢀinfectives, where the emergence of resistance to
known antibiotics has pointed to the need for new systems, the use of natural products represents a promising
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starting point for drug development. However, their long and low yielding synthetic routes which are frequently
required has hindered their use in drug discovery programmes. An alternative approach, which avoids the total
syntheses of the natural products, is to use their structure as inspiration to design simpler and more synthetically
accessible small molecules.4–6 Tetramic acids and hydroxylated pyrrolidinones are a widespread structural
motif in nature.7–10 Of interest are the 3ꢀacyl substituted variants, and in particular dienoyl and polyenoyl
derivatives, which have been reported to possess a range of biological properties including antibacterial,
antifungal and anticancer activities (Figure 1). This has, in turn, generated significant interest in their synthesis,
and approaches based upon Wittigꢀtype or acylative homologation11–17 or by late stage tetramisation18,19 have
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been reported.
O
ravenic acid
(antibacterial)
O
OH
H
O
O
N
OH
H
O
HO
O
O
6
O
CO2Me
O
N
O
N
N
Me
O
H
H
N
HO
CO2
H
O
O
harzianic acid
(antifungal)
synthetic bicyclic
tetramate 1
streptolydigin
(antibacterial)
O
OH
OH
virgaricin A
O
N
O
H
OH
O
OH
OH
pramanicin
(antibiotic, antifungal, anticancer)
O
N
H
OH
Figure 1. Structures and bioactivities of the natural products streptolydigin,20 ravenic acid,21 harzianic acid,22
vigaricin A23,24 and pramanicin.25,26
In the context of preparing simple versions of complex natural products, our group has identified bicyclic
tetramate 1 as an easily accessible scaffold from which mimics of such natural tetramates and pyrrolidinones
can be prepared. We have recently reported that functionalisation of the C(6) position of bicyclic tetramate 1
can be achieved via Grignard addition to Weinreb amide 2, providing alkyl, aryl, alkenyl and alkynyl
tricarbonyl compounds 4, and identified conditions for subsequent N,Oꢀacetal deprotection to 5 (Scheme 1).27
Moreover, we have also shown that reduction of the C(7) ketone group is possible in high diastereoselectivity
after hydrogenation with PtO2 followed by elimination, leading to alkenes 3.28 Therefore, key to the synthesis of
closer mimics of the natural products in Figure 1 is C(6)ꢀside chain manipulation allowing the introduction of
the dienoyl functionality, and we report here work which demonstrates that such side chain manipulation using a
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general approach based upon organometallic substitution is feasible on densely functional tetramate skeletons,
and that the derived products may exhibit antibacterial activity.
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R
O
O
O
O
OH
CO2Me
HO
R
N
CO2Me
CO2Me
ref 28
ref 27
O
O
O
N
N
N
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O
O
O
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ref 27
O
5 steps
R
CO2
H
HO
OH
H2N
L-serine
CO2Me
O
N
H
HO
5
Scheme 1. Reported synthetic transformations of the bicyclic tetramate via Weinreb amide 2.
Results and Discussion
Preparation of dienoyl-tetramates
We envisaged that a C(6)ꢀunsaturated chain could be introduced onto the bicyclic tetramate via isomerisation of
the corresponding ynone. Trost et al. have shown that such a transformation is possible with both aromatic and
aliphatic ketones, with the latter requiring higher temperatures.29 To assess the feasibility of this approach, we
treated Weinreb amide 2, prepared using our reported procedure from Lꢀserine,27,30 with heptynylmagnesium
bromide to form octynone 6 in good yield (Scheme 2). However, we found this compound to be unstable, and it
fully converted to tricycle 7 within hours at room temperature. Such degradation had been observed for similar
analogues,27 but at lower rates probably due to the presence of aromatic groups instead of the alkyl chain of 6,
which lowered the reactivity of the alkyne. Unfortunately, attempted isomerisation of the crude alkynone did not
give any desired product and only tricycle 7 was isolated.
Scheme 2. Grignard addition to Weinreb amide 2 and degradation product of 6.
We suspected that protection of the enol would avoid the isomerisation path described above, and therefore
Weinreb 2 was methylated via Mitsunobuꢀlike conditions with methanol.27 The expected methyl ether 8a was
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formed as a single regioisomer, as indicated by HMBC correlations (Scheme 3). Unfortunately, Grignard
addition to the protected enolate was much less efficient than with enol 2, and this was due to the formation of
several byꢀproducts, including enolꢀdeprotected amide 2 and alkynone 6, as well as isobutyl 10a and enamine
11a. Even though the formation of the latter was unexpected, similar outcomes had already been observed in the
addition of alkynes to Weinreb amides by Nielsen31 and Choudhury,32 who in fact did not obtain any of the
desired alkynone. The deprotected enols were likely to have originated from attack of the Grignard reagent onto
the methyl group, since the highly delocalised tricarbonyl system makes for a very good leaving group, and it
was envisaged that this deprotection could be impeded by employing a bulkier protecting group. Indeed, an
improvement was observed with the benzyl and isopropyl groups, but it was accompanied by a decrease in the
yield of the initial protection step (Table 1). With bulkier groups such as benzhydryl or tertꢀbutyl, there was low
or no conversion. The use of the isopropoxy enol ether provided a good balance, where the protection could be
achieved in acceptable yield and the Grignard addition proceeded with no detectable enol deprotection.
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O
O
N
OH
CO2Me
O
N
O
a: R=Me
b: R=Bn
c: R=iPr
2
ROH, PPh3, DEAD or DIAD
THF, 0 °C to rt, 13-24 h
69-80%
BrMg
H
C5H11
+
HMBC
O
O
O
OR
OR
CO2Me
N
C5H11
CO2Me
BrMg
C5H11
O
O
N
N
THF, -15 °C, 1 h
27-59%
O
O
8a-c
9a-c
O
O
N
O
OR
CO2Me
OR
CO2Me
O
N
O
N
O
O
10a-c
11a-c
Scheme 3. Enol protection of 2 and subsequent Grignard addition.
Table 1. Screen of enol protecting groups to optimise the formation of alkynes 9a-c.
Protection
Yield
8a, 80%
Grignard
Side products
9a, 27% 2, 6a, 10a, 11a
R
Time
Yield
13 h
Me
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18 h
8b, 71%
8c, 69%
9b, 35% 2, 6b, 10b, 11b
Bn
iPr
24 h
24 h
9c, 59%
10c, 11c
21%
ꢀ
ꢀ
CHPh2
8
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Recovered
starting material
tBu
24 h
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With alkynone 9c in hand, we were pleased to find that isomerisation to the dienone 12 occurred in high yields
provided stoichiometric amounts of triphenylphosphine were used at room temperature (Scheme 4); diene 12
was obtained as a single (E,E)ꢀregioisomer, evidenced by the large coupling constants and further confirmed by
NOE correlations. For the deprotection of the isopropyl enol ether group of 12, initial attempts with BBr3
resulted in low yields, partly due to concurrent N,Oꢀacetal deprotection. Alternatively, treatment with an excess
of NaHCO3 with stoichiometric Aliquat 336 under phaseꢀtransfer catalysis conditions successfully furnished
tetramate 13.
Scheme 4. Successful formation of dienoylꢀtetramate 13 via isomerisation and enol deprotection.
This sequence provided a reliable route to dienoneꢀtetramic acids, and was used to prepare analogues with
different chain lengths 13, 18, 19 (Scheme 5). The carboxymethyl group, which is not present in the natural
products, could also be removed via diastereoselective decarboxylation,27 and gave analogue 20. The
deprotected tetramic acids exist a mixture of tautomers, a characteristic that has been found and extensively
studied in related C(6)ꢀsubstituted tetramates;27,33–35 their double geometry was readily established by coupling
constant and NOE analysis, and no double bond isomerism was detected. The corresponding saturated
derivatives 21-23, readily available via direct Grignard reaction of Weinreb amide 2, were prepared to examine
the role of the diene functionality in biological activity.
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Scheme 5. Preparation of several dienoyl and saturated C(6)ꢀacyltetramic acids.
Further functionalisation of the acyl chain
For the preparation of analogues that mimic the acyl chain of pramanicin more closely, epoxidation of dienone
16 with mCPBA afforded epoxyꢀenone 24 with high regioselectivity, via reaction of the more electron rich
remote double bond, as a 1:1 mixture of diastereomers (Scheme 6). The position of the epoxide was indicated by
COSY and HMBC correlations. Enol deprotection under the optimised conditions provided tetramate 25.
Scheme 6. Preparation of epoxyꢀenone 25, a mimic of the acyl chain of pramanicin.
It was of interest to extend the scope of the method for the introduction of more polar sideꢀchains, for instance
through the addition of heterocycles such as oxazoles and thiazoles. The preparation of the required alkynes 34
and 40 was achieved starting from oxazole in 5 and 6 steps respectively (Scheme 7). After initial C(2)ꢀTIPS
protection,36 allylation of the less reactive C(5) position was achieved via lithiation followed by transmetallation
to the cuprate and reaction with allyl bromide.37 Hydroboration provided terminal alcohol 30 in good yield and
regioselectivity, which was a common intermediate for both alkyne lengths. The shorter alkyne 34 was accessed
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through oxidation to the aldehyde followed by SeyferthꢀGilbert homologation. For the longer one, the additional
carbon atom was introduced using a MitsunobuꢀWilk procedure38 to substitute the hydroxyl by a nitrile group.
Subsequent reduction with DIBALꢀH and treatment with Bestmann reagent yielded alkyne 40. The same
sequence was employed to access thiazole alkynes 35 and 41.
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Scheme 7. Preparation of alkynes 34,35 and 40,41 starting from oxazole and thiazole.
With the alkynes in hand, reaction with Weinreb amide 8c gave the alkynoyl analogues 42-45, along with the
enamine sideꢀproduct, which accounted for the moderate yields (Scheme 8). Interestingly, isomerisation of the
alkynes was achieved in high yield with the short analogues (n=1), but when n=2, a 1:1 mixture of alkene
isomers 50,52 and 51,53 was obtained. For the shorter systems 46 and 47, deprotection of both isopropyloxy
and TIPS groups yielded the target dieneꢀtetramates oxazole 48 and thiazole 49 without complication.
Unfortunately, the analogues bearing the additional methylene (52, 53), experienced degradation upon
deprotection of the enol group and no desired tetramate was isolated.
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Scheme 8. Preparation of heterocyclic dienes 48,49 and unsuccessful formation of 54,55.
Antibacterial activity
To study the influence of the side chain on antibacterial activity, the synthesised C(6)ꢀacyltetramates were tested
using the holeꢀplate method.39 Solutions of the compounds were loaded into 10 mm wells in agar plates
inoculated with either Gramꢀnegative Escherichia coli or Gramꢀpositive Staphylococcus aureus. The plates
were incubated for 20 h, and the resultant inhibition zones were measured and compared to the positive control
(Cephalosporin C). The compounds were initially tested at 4 mg/mL, and the most active ones diluted to obtain
a zone size smaller than 35 mm.
A
40
S. aureus
0.1
E. coli
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0.01
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13 18 19 21 22 23 25 48 49Ceph C
B
Compound
Compound
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Relative potency 2.3 36.7 2.5
7.3 85.7 2.1
0.4
0.3
0.3
4
5
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7
8
Figure 2. Antibacterial activity of the synthesised C(6)ꢀacyltetramates. (A) Zone size measured with the holeꢀ
plate method. The value above the bars indicates concentration of compound used in mg/mL; (B) Relative
potency of the compounds compared to Cephalosporin C in S. aureus.
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As indicated in Figure 2, the most active analogues against S. aureus were those with long lipophilic chains,
while heterocycles 48 and 49 proved to be only weakly active. Epoxide 25 was also less active than the
equivalent diene 18. The length of the chain was also influential for activity, and interestingly both the 10ꢀ
carbon analogues – diene 18 and saturated 22 – showed the biggest zone sizes at the lowest concentration
(0.1 mg/mL). Remarkably, these were 37ꢀ and 86ꢀfold more potent than the positive control respectively.
Conversely, only thiazole 49 displayed weak inhibition of Gramꢀnegative E. coli.
Given the high degree of unsaturation of the acyl chain in natural tetramic acids (Figure 1), the similar activities
of both the dienoyl and the saturated analogues was unexpected. In fact, Schobert and coꢀworkers have reported
similar observations, that a high degree of unsaturation on the side chain of 3ꢀacyltetramic acids is not a
prerequisite for antibacterial activity, as a saturated analogue of the ravenic acid was equally active than the
parent natural product (Figure 1).12
The selectivity of these compounds for Gramꢀpositive S. aureus has also been observed for structurally related
tetramates, with the less polar compounds found to be the most active against S. aureus.14,27 The low activity
against Gramꢀnegative systems is likely to be due to poor cell penetration or efficient efflux pump removal. By
comparison, the natural C(6)ꢀacyltetramate, kibdelomycin, was shown to inhibit DNA gyrase and topoisomerase
enzymes from both S. aureus and E. coli, but this inhibition only correlated with wholeꢀcell activity of the
former; the efficacy of the latter was probably limited by poor cell membrane uptake or by the active efflux
pump. In fact, the weakest C(6)ꢀacyl analogue tested herein, thiazole 51, was also the only one with some
activity against Gramꢀnegative E. coli, which could be ascribed to improved permeability.
Of interest is also that isopropoxyꢀprotected 17, precursor of the most active diene 18, was found to be
completely inactive, suggesting that the tetramic acid scaffold is required for biological activity. However, the
tetramate core itself is not sufficient for the antibacterial properties, as unsubstituted 1 and 2 are inactive,
revealing that appropriate functionalisation is required to obtain potent compounds.
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To support the results obtained with the holeꢀplate method, MIC values of the compounds were measured using
a broth dilution assay (Table 2). For S. aureus, the lowest values were confirmed to be for those compounds
with lipophilic side chains, and again only the most polar analogues displayed some inhibition against E. coli.
Importantly, we observed a good correlation between the activity values obtained from both assays, namely
holeꢀplate method and broth dilution (Figure 3); this is important, as the whole plate assay provides for a very
convenient initial screen.
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relative potency
Figure 3. Correlation between the results obtained with the holeꢀplate method (quantified as relative potency to
Cephalosporin C) and the broth dilution assay (MIC).
The most active analogues were also tested for antibacterial activity against Gramꢀpositive Enterococcus
faecalis and Gramꢀnegative Klebsiella pneumoniae and Pseudomonas aeruginosa, and antifungal activity
against Candida albicans, Candida krusei and Aspergillus fumigatus. Only activity against the bacterium E.
faecalis was found, consistent with the selective Gramꢀpositive activity noted above. With regards to antifungal
activity, most analogues showed some inhibition, but in particular undecyl 22.
Table 2. In vitro antibacterial and antifungal activity (MIC, ꢀg/mL) of C(6)ꢀacyltetramic acids.*
E.
S.
E.
S.
K.
P.
C.
C.
A.
coli
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
250
aureus faecalis pneumoniae pneumoniae aeruginosa albicans krusei fumigatus
31
1
16
1
31
1
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
–
n.a.
250
n.a.
500
n.a.
n.a.
–
250
250
500
500
250
250
–
250
250
500
500
250
250
–
250
62
13
18
19
21
22
23
48
2
2
2
n.a.
200
8
2
2
6
2
2
2
2
2
2
250
–
125
–
125
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62.5
–
62.5
–
–
–
–
–
49
4
5
*n.a. = not active; – = not determined. Ciprofloxacin used as positive control.
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The selectivity of the analogues to prokaryotic cells over mammalian cells was analysed by means of their EC50
values against HaCaT, an immortalised keratinocyte human cell line (Table 3). The therapeutic window was
estimated as the ratio of EC50 (HaCaT) to MIC (S. aureus). The best compound in this regard was decadiene 18,
with an 88ꢀfold selectivity, an excellent compromise between high potency and low toxicity. Therefore, despite
the similar potencies of both the unsaturated and saturated analogues, this data suggests that the latter might
suffer from bigger toxicities.
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Table 3. Assessment of human toxicity: therapeutic ratio between MIC (S. aureus) and EC50 (HaCat).
S. aureus
HaCat
Therapeutic
ratio
MIC [ꢀg/mL] EC50 [ꢀg/mL]
31
1
175
87.5
150
25
5.6
13
18
19
21
22
23
87.5
2
75.0
2
12.5
2
45
22.5
2
24
12.0
Conclusion
With this work, we have developed methods to rapidly and efficiently access dienoylꢀtetramates, a common
moiety in several complex natural products; this complements alternative approaches.12 We employed a simple
bicyclic tetramate scaffold and prepared several analogues with different lipophilic C(6)ꢀacyl chains, and we
were able to regioselectively epoxidise the dienoyl analogues. We further applied our methodology to access
more polar compounds, bearing heterocycles. These required the preparation of novel oxazole and thiazole
alkynes, which were accessed efficiently in high yields. Overall, this provides a flexible route to a variety of
mimics of pramanicin and of polyenoyl tetramates, some of which show antibacterial activity; although these
mimics may be considered to be distant from their parent natural products, they nonetheless help to define the
antibacterially active property space and, for example, the most active undecylidene 18 had an MIC value of 1
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ꢀg/mL. This activity is comparable to that of known therapeutic systems,40,41 and considering that MIC values
of <16 ꢁg/mL are acceptable as starting points for pharmaceutical development,42 these compounds could be
considered to be suitable for more detailed investigation.
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The highly potent activity of some of the synthesised analogues demonstrates the suitability of tetramates as 3Dꢀ
templates to prepare novel antibiotics and further supports the value of natural products as useful starting points
for antibacterial drug discovery.
Experimental section
General methods
All reagents were obtained from commercial sources and used without further purification. Anhydrous solvents
were dried by preꢀstoring them over activated 3 Å molecular sieves before being passed through an activated
alumina column on a solvent tower under N2 pressure. Reactions were conducted in ovenꢀdried glassware under
an inert atmosphere of nitrogen. Concentrations (c) in the general procedures refer to the limiting reagent and
are given in mmol/mL. Analytical thinꢀlayer chromatography (TLC) was carried out on Merck aluminium foil
backed sheets precoated with 0.2 mm Kielselgel 60 F254. The spots were visualised by UV irradiation (λ 254
nm) and by staining with a KMnO4 solution followed by heating. Flash column chromatography was performed
on Kielselgel 60 silica gel (230ꢀ400 mesh particle size). Optical rotations were recorded at 25 °C on a
polarimeter using the D line of sodium (589 nm) and a path length of 1 dm. Concentrations (c) are given in
g/100 mL and specific rotations ([ꢀ]ꢁꢂꢃ) are quoted in 10ꢀ1 deg cm2 gꢀ1. Melting points were measured with a
capillary melting point apparatus and are uncorrected. Infrared spectra were recorded on an FTꢀIR spectrometer;
1
absorption maxima (νmax) are reported in wavenumbers (cmꢀ1) and only selected peaks are reported. H NMR
spectra were recorded 400 and 500 MHz, and 13C NMR spectra at 101 and 125 MHz. Chemical shifts (δH and
δC) are reported in parts per million (ppm) and are referenced to the residual solvent peak (CDCl3: δ 7.26 for 1H
1
1
NMR and δ 77.2 for 13C NMR; C6D6: δ 7.16 for H NMR and δ 128.1 for 13C NMR; CD2Cl2: δ 5.32 for H
NMR and δ 54.0 for 13C NMR) and CDCl3. Coupling constants (J) are quoted in Hz. Twoꢀdimensional COSY,
NOE and HMBC experiments were recorded at 500 MHz. Low resolution mass spectra (m/z) were recorded
using electrospray ionisation (ESI); selected peaks are reported in Daltons and their intensities given as
percentages of the base peak. High resolution mass spectra (HRMS) were recorded using TOF (ESI). In the
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cases where the products exist as mixtures of tautomers or diastereomers, the ratio was calculated from the H
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NMR spectrum.
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7
1
For H and 13C NMR assignments of tetramates, the conventional IUPAC numbering has been used for the
8
bicyclic core; the C(6) side chain has been numbered with prime (’). For oxazoles and thiazoles, the prime (’ or
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’’) numbers correspond to the positions in the heterocycle.
Weinreb amide 2,27 oxazole 2636 and thiazole 2743 were prepared as reported.
General procedure A: Alkylation of C(6)ꢀacyltetramates
Diethyl azodicarboxylate (1.1 eq) was added to a solution of C(6)ꢀacyltetramate (1.0 eq), the required alcohol
(1.1 eq) and triphenylphosphine (1.1 eq) in anhydrous THF (c 0.1) at 0 °C. The mixture was stirred at room
temperature for 13ꢀ24 h and then concentrated under reduced pressure. The crude residue was purified by flash
column chromatography to give the alkyl ether.
General procedure B: Grignard reaction of enolꢀprotected Weinreb amide with alkynyl Grignard reagents
Isobutylmagnesium bromide (2 M in Et2O, 1.0 eq) was added dropwise to a solution of the 1ꢀalkyne (1.1 eq) in
anhydrous THF (c 0.7) at 0 °C. The suspension was then warmed to room temperature and heated at 40 °C for
5 h. The solution was used for the Grignard reaction directly at 40 °C.
The prepared Grignard reagent (2.5 eq) was added to enolꢀprotected Weinreb amide (1.0 eq) in anhydrous THF
dropwise at ꢀ15 °C. The reaction mixture was stirred at ꢀ15 °C for 1 h. The solution was quenched with
saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo and purified by flash column chromatography to give the C(7)ꢀalkynyl product.
General procedure C: Isomerisation of alkynones
Triphenylphosphine (1.0 eq, unless otherwise specified) was added to a solution of alkynone (1.0 eq) in
anhydrous toluene (c 0.2). The reaction mixture was stirred at room temperature for 24 h, concentrated in vacuo
and purified by flash column chromatography to give the dienone.
General procedure D: Deprotection of isopropoxy enol ethers
NaHCO3 (60 eq) was added to a biphasic solution of the enol ether (1.0 eq) and Aliquat 336 (1.1 eq) in 1:1
toluene/H2O (c 0.05). The mixture was heated at 80 °C for 6 h, quenched with saturated aqueous NH4Cl,
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extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was
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purified by flash column chromatography to give the deprotected tetramate.
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Methyl
(3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀmethoxyꢀ6ꢀ(methoxy(methyl)carbamoyl)ꢀ5ꢀoxoꢀ1H,3Hꢀpyrrolo[1,2ꢀ
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c]oxazoleꢀ7a(5H)ꢀcarboxylate (8a)
General procedure A with DIAD instead of DEAD (from 2, with methanol, for 13 h); yield 80% (342 mg);
colourless oil. Rf (25% EtOAc in DCM) 0.41; [ꢀ]ꢂꢁꢃ +74.6 (c 1.1, DCM); νmax/cmꢀ1 2959 (CꢀH), 1752 (C=O),
1719 (C=O), 1650 (C=O); δH (500 MHz, CDCl3, 4:1 mixture of rotamers, major A and minor B) 0.89 (9H, s,
C(CH3)3), 3.29 (3H, s, NCH3 A), 3.33 (3H, s, NCH3 B), 3.51 (1H, d, J 8.5, C(1)HAHB), 3.71 (3H, s, NOCH3 A),
3.79 (3H, s, CO2CH3), 3.87 (3H, s, NOCH3 B), 3.93 (3H, s, C(7)OCH3 A), 4.02 (3H, s, C(7)OCH3 B), 4.70 (1H,
s, C(3)H), 4.79 (1H, d, J 8.5, C(1)HAHB); δC (125 MHz, CDCl3) 24.7 (C(CH3)3), 32.5 (NCH3), 35.2 (C(CH3)3),
53.4 (CO2CH3), 60.2 (C(7)OCH3), 61.9 (NOCH3), 69.5 (C(1)), 74.4 (C(7a)), 97.3 (C(3)), 105.0 (C(6)), 163.0
(C(1’)), 168.3 (CO2CH3), 169.7 (C(7)), 174.9 (C(5)); m/z (ESI+) 357.1 (MH+, 100%), 379.1 (MNa+, 51%);
HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C16H25N2O7 357.1656; found 357.1651.
Methyl (3R,7aR)ꢀ7ꢀ(benzyloxy)ꢀ3ꢀ(tertꢀbutyl)ꢀ6ꢀ(methoxy(methyl)carbamoyl)ꢀ5ꢀoxoꢀ1H,3Hꢀpyrrolo[1,2ꢀ
c]oxazoleꢀ7a(5H)ꢀcarboxylate (8b)
General procedureGeneral procedure A (from 2, with benzyl alcohol, for 18 h); yield 71% (253 mg); yellow oil.
Rf (20% EtOAc in DCM) 0.57; [ꢀ]ꢂꢁꢃ +29.2 (c 1.0, DCM); νmax/cmꢀ1 2957 (CꢀH), 1751 (C=O), 1718 (C=O),
1646 (C=O); δH (400 MHz, CDCl3, 2:1 mixture of rotamers, major A and minor B) 0.89 (9H, s, C(CH3)3), 2.88
(3H, s, NCH3 B), 3.25 (3H, s, NCH3 A), 3.42 (3H, s, NOCH3 A), 3.57 (1H, d, J 8.6, C(1)HAHB), 3.77 (3H, s,
CO2CH3), 3.80 (3H, s, NOCH3 B), 4.68 (1H, s, C(3)H), 4.82 (1H, d, J 8.6, C(1)HAHB), 5.22 (1H, d, J 11.8,
C(7)OCHAHB A), 5.31 (1H, d, J 11.8, C(7)OCHAHB A), 5.22 (1H, d, J 12.4, C(7)OCHAHB B), 5.31 (1H, d, J
12.4, C(7)OCHAHB B), 7.22ꢀ7.24 (2H, m, Ar), 7.34ꢀ7.37 (3H, m, Ar); δC (100 MHz, CDCl3) 24.7 (C(CH3)3),
32.3 (NCH3), 35.2 (C(CH3)3), 53.2 (CO2CH3), 61.3 (NOCH3), 68.0 (C(1)), 74.5 (C(7)OC), 74.6 (C(7a)), 97.2
(C(3)), 105.7 (C(6)), 127.9, 128.7, 129.0, 134.5 (Ar), 162.6 (C(1’)), 168.2 (CO2CH3), 169.0 (C(7)), 174.7
(C(5)); m/z (ESI+) 433.1 (MH+, 58%), 455.1 (MNa+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for
C22H29N2O7 433.1969; found 433.1962.
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Methyl (3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀisopropoxyꢀ6ꢀ(methoxy(methyl)carbamoyl)ꢀ5ꢀoxoꢀ1H,3Hꢀpyrrolo[1,2ꢀ
c]oxazoleꢀ7a(5H)ꢀcarboxylate (8c)
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General procedure A (from 2, with 2ꢀpropanol, for 24 h); yield 69% (2.50 g); yellow oil. Rf (20% EtOAc in
DCM) 0.57; [ꢀ]ꢂꢁꢃ +57.4 (c 1.0, DCM); νmax/cmꢀ1 2959 (CꢀH), 1752 (C=O), 1716 (C=O), 1641 (C=O); δH (400
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MHz, CDCl3, 3:1 mixture of rotamers, major A and minor B) 0.90 (9H, s, C(CH3)3), 1.20 (3H, d, J 6.0, Pr),
1.28ꢀ1.34 (3H, m, iPr), 3.29 (3H, s, NCH3 A), 3.34 (3H, s, NCH3 B), 3.51 (1H, d, J 8.5, C(1)HAHB), 3.73 (3H, s,
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NOCH3 A), 3.79 (3H, s, CO2CH3), 3.82 (3H, s, NOCH3 B), 4.72 (1H, s, C(3)H), 4.72ꢀ4.77 (1H, m, Pr), 4.81
(1H, d, J 8.5, C(1)HAHB); δC (100 MHz, CDCl3) 21.1 (iPr), 22.2 (iPr), 24.7 (C(CH3)3), 32.4 (NCH3), 35.2
(C(CH3)3), 53.2 (CO2CH3), 61.8 (NOCH3), 69.4 (C(1)), 74.9 (C(7a)), 76.8 (iPr), 97.1 (C(3)), 104.4 (C(6)), 163.5
(C(1’)), 168.1, (CO2CH3), 168.3 (C(7)), 175.4 (C(5)); m/z (ESI+) 407.2 (MNa+, 100%); HRMS (ESIꢀTOF) m/z
[M+H]+ Calcd for C18H29N2O7 385.1969; found 385.1964.
Methyl (3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀmethoxyꢀ6ꢀ(octꢀ2ꢀynoyl)ꢀ5ꢀoxoꢀ1H,3Hꢀpyrrolo[1,2ꢀc]oxazoleꢀ7a(5H)ꢀ
carboxylate (9a)
General procedure B (from 8a, with 1ꢀheptyne); yield 27% (13 mg); yellow oil. Rf (DCM) 0.48; [ꢀ]ꢂꢁꢃ +120.0
(c 1.0, DCM); νmax/cmꢀ1 2958 (CꢀH), 2213 (C≡C), 1752 (C=O), 1720 (C=O), 1637 (C=O), 1604 (C=C); δH (500
MHz, CDCl3) 0.90 (3H, t, J 7.0, C(8’)H3), 0.90 (9H, s, C(CH3)3), 1.33 (2H, tq, J 7.5, 7.0, C(7’)H2), 1.39ꢀ1.45
(2H, m, C(6’)H2), 1.63 (2H, tt, J 7.5, 7.0, C(5’)H2), 2.44 (2H, t, J 7.0, C(4’)H2), 3.47 (1H, d, J 8.5, C(1)HAHB),
3.80 (3H, s, CO2CH3), 4.05 (3H, s, C(7)OCH3), 4.75 (1H, s, C(3)H), 4.82 (1H, d, J 8.5, C(1)HAHB); δC (125
MHz, CDCl3) 14.0 (C(8’)), 19.6 (C(4’)), 22.3 (C(7’)), 24.8 (C(CH3)3), 27.5 (C(5’)), 31.2 (C(6’)), 35.3
(C(CH3)3), 53.6 (CO2CH3), 63.5 (C(7)OCH3), 69.5 (C(1)), 73.8 (C(7a)), 81.9 (C(2’)), 97.8 (C(3)), 99.7 (C(3’)),
110.2 (C(6)), 168.0 (CO2CH3), 172.3 (C(1’)), 174.1 (C(5)), 175.6 (C(7)); m/z (ESI+) 392.1 (MH+, 42%), 414.1
(MNa+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C21H30NO6 392.2068; found 392.2066.
Methyl
(3R,7aR)ꢀ7ꢀ(benzyloxy)ꢀ3ꢀ(tertꢀbutyl)ꢀ6ꢀ(octꢀ2ꢀynoyl)ꢀ5ꢀoxoꢀ1H,3Hꢀpyrrolo[1,2ꢀc]oxazoleꢀ
7a(5H)ꢀcarboxylate (9b)
General procedure B (from 8b, with 1ꢀheptyne); yield 35% (18 mg); yellow oil. Rf (20% EtOAc in petrol) 0.58;
[ꢀ]ꢂꢁꢃ +105.6 (c 0.7, DCM); νmax/cmꢀ1 2957 (CꢀH), 2210 (C≡C), 1752 (C=O), 1721 (C=O), 1634 (C=O), 1598
(C=C); δH (500 MHz, CDCl3) 0.90 (9H, s, C(CH3)3), 0.91 (3H, t, J 7.2, C(8’)H3), 1.29ꢀ1.37 (2H, m, C(7’)H2),
1.38ꢀ1.44 (2H, m, C(6’)H2), 1.62 (2H, 77, J 7.5, 7.0, C(5’)H2), 2.44 (2H, t, J 7.0, C(4’)H2), 3.47 (1H, d, J 8.6,
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C(1)HAHB), 3.71 (3H, s, CO2CH3), 4.75 (1H, s, C(3)H), 4.81 (1H, d, J 8.6, C(1)HAHB), 5.19 (1H, d, J 12.0,
C(7)OCHAHB), 5.50 (1H, d, J 12.0, C(7)OCHAHB), 7.22ꢀ7.24 (2H, m, Ar), 7.35ꢀ7.37 (3H, m, Ar); δC (125 MHz,
CDCl3) 14.0 (C(8’)), 19.7 (C(4’)), 22.3 (C(7’)), 24.8 (C(CH3)3), 27.5 (C(5’)), 31.2 (C(6’)), 35.3 (C(CH3)3), 53.4
(CO2CH3), 69.6 (C(1)), 74.2 (C(7a)), 77.8 (C(7)OC), 81.9 (C(2’)), 97.8 (C(3)), 100.0 (C(3’)), 110.6 (C(6)),
128.3, 128.9, 129.3, 134.1 (Ar), 168.0 (CO2CH3), 172.6 (C(1’)), 174.1 (C(5)), 174.6 (C(7)); m/z (ESI+) 468.3
(MH+, 66%), 490.2 (MNa+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C27H34NO6 468.2381; found
468.2369.
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Methyl
(3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀisopropoxyꢀ6ꢀ(octꢀ2ꢀynoyl)ꢀ5ꢀoxoꢀ1H,3Hꢀpyrrolo[1,2ꢀc]oxazoleꢀ
7a(5H)ꢀcarboxylate (9c)
General procedure B (from 8c, with 1ꢀheptyne); yield 59% (657 mg); light yellow solid; m.p. 63ꢀ65 °C. Rf
(DCM) 0.43; [ꢀ]ꢂꢁꢃ +117.3 (c 1.0, DCM); νmax/cmꢀ1 2958 (CꢀH), 2211 (C≡C), 1754 (C=O), 1720 (C=O), 1634
(C=O), 1587 (C=C); δH (500 MHz, CDCl3) 0.90 (3H, t, J 7.2, C(8’)H3), 0.91 (9H, s, C(CH3)3), 1.17 (3H, d, J
6.0, iPr), 1.30ꢀ1.37 (2H, m, C(7’)H2), 1.32 (3H, d, J 6.0, iPr), 1.39ꢀ1.45 (2H, m, C(6’)H2), 1.63 (2H, tt, J 7.5, 7.0,
C(5’)H2), 2.45 (2H, t, J 7.0, C(4’)H2), 3.45 (1H, d, J 8.5, C(1)HAHB), 3.79 (3H, s, CO2CH3), 4.77 (1H, s,
i
C(3)H), 4.82 (1H, d, J 8.5, C(1)HAHB), 5.20 (1H, sept, J 6.0, Pr); δC (125 MHz, CDCl3) 14.0 (C(8’)), 19.7
(C(4’)), 21.1 (iPr), 22.3 (C(7’)), 22.3 (iPr), 24.8 (C(CH3)3), 27.5 (C(5’)), 31.2 (C(6’)), 35.3 (C(CH3)3), 53.4
(CO2CH3), 69.6 (C(1)), 74.4 (C(7a)), 79.7 (iPr), 81.9 (C(2’)), 97.8 (C(3)), 99.3 (C(3’)), 109.4 (C(6)), 168.1
(CO2CH3), 172.7 (C(1’)), 173.9 (C(5)), 174.6 (C(7)); m/z (ESI+) 420.2 (MH+, 61%), 442.2 (MNa+, 100%);
HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C23H34NO6 420.2381; found 420.2371.
Methyl (3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀisopropoxyꢀ6ꢀ(3ꢀmethylbutanoyl)ꢀ5ꢀoxoꢀ1H,3Hꢀpyrrolo[1,2ꢀc]oxazoleꢀ
7a(5H)ꢀcarboxylate (10c)
Sideꢀproduct from the reaction of isopropoxy Weinreb amide 8c with alkynyl Grignard reagents, yellow oil.
Rf (DCM) 0.40; [ꢀ]ꢂꢁꢃ +104.2 (c 1.0, CHCl3); νmax/cmꢀ1 2958 (CꢀH), 1754 (C=O), 1712 (C=O), 1681 (C=O),
1588 (C=C); δH (400 MHz, CDCl3) 0.90 (9H, s, C(CH3)3), 0.93 (3H, d, J 6.7, C(4’A)H3), 0.95 (3H, d, J 6.6,
C(4’B)H3), 1.10 (3H, d, J 6.1, OiPr), 1.30 (3H, d, J 6.1, OiPr), 2.19 (1H, n, J 6.7, C(3’)H), 2.77 (1H, dd, J 17.7,
6.7, C(2’)HAHB), 3.02 (1H, dd, J 17.7, 6.7, C(2’)HAHB), 3.45 (1H, d, J 8.4, C(1)HAHB), 3.77 (3H, s, CO2CH3),
4.73 (1H, s, C(3)H), 4.80 (1H, d, J 8.4, C(1)HAHB), 5.16 (1H, sept, J 6.1, OiPr); δC (100 MHz, CDCl3) 21.0
(OiPr), 22.3 (OiPr), 22.7 (C(4’B)), 22.8 (C(4’A)), 24.1 (C(3’)), 24.8 (C(CH3)3), 35.3 (C(CH3)3), 51.3 (C(2’)), 53.3
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(CO2CH3), 69.6 (C(1)), 74.7 (C(7a)), 78.9 (OiPr), 97.6 (C(3)), 110.1 (C(6)), 168.2 (CO2CH3), 173.1 (C(7)),
176.2 (C(5)), 198.2 (C(1’)); m/z (ESI+) 382.23 (MH+, 18%), 404.2 (MNa+, 74%); HRMS (ESIꢀTOF) m/z
[M+H]+ Calcd for C20H32NO6 382.2224; found 382.2226.
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Methyl
(3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀisopropoxyꢀ6ꢀ((Z)ꢀ3ꢀ(methoxy(methyl)amino)tetradecꢀ2ꢀenoyl)ꢀ5ꢀoxoꢀ
1H,3Hꢀpyrrolo[1,2ꢀc]oxazoleꢀ7a(5H)ꢀcarboxylate (11c’)
Sideꢀproduct (24%, 79 mg) from the Grignard reaction of isopropoxy Weinreb amide 8c and 1ꢀtridecyne,
General procedure B; colourless oil. Rf (20% EtOAc in petrol) 0.51; [ꢀ]ꢂꢁꢃ +114.1 (c 1.0, CHCl3); νmax/cmꢀ1
2925 (CꢀH), 1753 (C=O), 1708 (C=O), 1635 (C=O), 1585 (C=C); δH (500 MHz, CD2Cl2) 0.86ꢀ0.89 (3H, m,
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C(14’)H3), 0.88 (9H, s, C(CH3)3), 1.12 (3H, d, J 6.0, Pr), 1.26 (3H, d, J 6.0, Pr), 1.25ꢀ1.33 (14H, m,
C(7’ꢀ13’)H2), 1.40 (2H, tt, J 7.5, 6.5, C(6’)H2), 1.46ꢀ1.52 (2H, m, C(5’)H2), 2.79 (1H, dt, J 12.4, 7.4,
C(4’)HAHB), 2.94 (1H, dt, J 12.4, 8.1, C(4’)HAHB), 3.20 (3H, s, NCH3), 3.47 (1H, d, J 8.5, C(1)HAHB), 3.67
(3H, s, NOCH3), 3.76 (3H, s, CO2CH3), 4.68 (1H, s, C(3)H), 4.75 (1H, d, J 8.5, C(1)HAHB), 5.13 (1H, sept, J
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6.0, Pr), 5.73 (1H, s, C(10’)H); δC (125 MHz, CD2Cl2) 14.4 (C(14’)), 21.5 (iPr), 22.6 (iPr), 23.3 (C(13’)), 25.0
(C(CH3)3), 28.7 (C(5’)), 28.9 (C(4’)), 29.9, 30.0, 30.1, 30.2, 30.2, 30.3 (C(6’ꢀ11’)), 32.5 (C(12)), 35.6
(C(CH3)3), 37.2 (NCH3), 53.4 (CO2CH3), 60.4 (NOCH3), 70.2 (C(1)), 74.8 (C(7a)), 77.4 (iPr), 96.0 (C(2’)), 97.7
(C(3)), 113.7 (C(6)), 164.7 (C(3’)), 169.4 (CO2CH3), 169.8 (C(7)), 177.4 (C(5)), 183.7 (C(1’)); m/z (ESI+) 565.4
(MH+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C31H53N2O7 565.3847; found 565.3840.
Methyl
(3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀisopropoxyꢀ6ꢀ((2E,4E)ꢀoctaꢀ2,4ꢀdienoyl)ꢀ5ꢀoxoꢀ1H,3Hꢀpyrrolo[1,2ꢀ
c]oxazoleꢀ7a(5H)ꢀcarboxylate (12)
General procedure C (from 9c); yield 88% (574 mg); yellow oil. Rf (DCM) 0.39; [ꢀ]ꢂꢁꢃ +129.7 (c 1.0, DCM);
ν
max/cmꢀ1 2960 (CꢀH), 1754 (C=O), 1712 (C=O), 1652 (C=O), 1591 (C=C); δH (500 MHz, C6D6) 0.71 (3H, t, J
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7.4, C(8’)H3), 0.87 (3H, d, J 6.0, Pr), 1.02 (3H, d, J 6.0, Pr), 1.11 (9H, s, C(CH3)3), 1.13 (2H, sext, J 7.4,
C(7’)H2), 1.76 (2H, q, J 7.4, C(6’)H2), 3.05 (1H, d, J 8.4, C(1)HAHB), 3.29 (3H, s, CO2CH3), 4.84 (1H, d, J 8.4,
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15.0, 11.0, C(4’)H), 7.17 (1H, d, J 15.0, C(2’)H), 7.59 (1H, dd, J 15.0, 11.0, C(3’)H); δC (125 MHz, C6D6) 13.8
(C(8’)), 20.7 (iPr), 22.0 (iPr), 22.0 (C(7’)), 25.1 (C(CH3)3), 35.3 (C(6’)), 35.5 (C(CH3)3), 52.6 (CO2CH3), 69.7
(C(1)), 75.2 (C(7a)), 78.5 (iPr), 97.8 (C(3)), 110.5 (C(6)), 128.4 (C(2’)), 129.9 (C(4’)), 144.1 (C(3’)), 146.1
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(C(5’)), 168.6 (CO2CH3), 173.5 (C(7)), 176.3 (C(5)), 186.7 (C(1’)); m/z (ESI+) 420.3 (MH+, 47%), 442.2
(MNa+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C23H34NO6 420.2381; found 420.2371.
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Methyl (3R,7aR,Z)ꢀ3ꢀ(tertꢀbutyl)ꢀ6ꢀ((2E,4E)ꢀ1ꢀhydroxyoctaꢀ2,4ꢀdienꢀ1ꢀylidene)ꢀ5,7ꢀdioxodihydroꢀ1H,3Hꢀ
pyrrolo[1,2ꢀc]oxazoleꢀ7a(5H)ꢀcarboxylate (13)
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Method 1: BBr3 (1 M in DCM, 150 µL, 0.150 mmol) was added dropwise to a solution of isopropoxy 12 (63
mg, 0.15 mmol) in anhydrous DCM (1.5 mL). The solution was stirred at room temperature for 1 h, quenched
with H2O and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4 and
concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc), and the
product obtained was dissolved in EtOAc, washed with 2 M aqueous HCl, dried over anhydrous Na2SO4 and
concentrated in vacuo to give dienoyltetramate 13 (21 mg, 0.055 mmol, 37%).
Method 2: General procedure D (from 12); yield 56% (29 mg).
Orange oil; 3.5:1 mixture of tautomers. Rf (EtOAc) 0.42; [ꢀ]ꢂꢁꢃ +73.4 (c 0.4, CHCl3); νmax/cmꢀ1 2960 (CꢀH),
1752 (C=O), 1712 (C=O), 1654 (C=O), 1612 (C=C), 1557 (C=C); δH (500 MHz, CDCl3) major tautomer: 0.91ꢀ
0.94 (3H, m, C(8’)H3), 0.93 (9H, s, C(CH3)3), 1.48 (2H, sext, J 7.5, C(7’)H2), 2.22 (2H, q, J 7.5, C(6’)H2), 3.50
(1H, d, J 8.9, C(1)HAHB), 3.77 (3H, s, CO2CH3), 4.82 (1H, s, C(3)H), 4.85 (1H, d, J 8.9, C(1)HAHB), 6.32ꢀ6.40
(2H, m, C(4’)H + C(5’)H), 7.03 (1H, d, J 15.2, C(2’)H), 7.55ꢀ7.60 (1H, m, C(3’)H); δC (125 MHz, CDCl3)
major tautomer: 13.8 (C(8’)), 21.9 (C(7’)), 24.8 (C(CH3)3), 35.3 (C(CH3)3), 35.6 (C(6’)), 53.4 (CO2CH3), 68.5
(C(1)), 78.4 (C(7a)), 98.4 (C(3)), 99.6 (C(6)), 119.0 (C(2’)), 129.8 (C(4’)), 148.3 (C(3’)), 150.4 (C(5’)), 167.9
(CO2CH3), 177.4 (C(1’)), 180.9 (C(5)), 188.0 (C(7)); m/z (ESI+) 378.2 (MH+, 100%), 400.2 (MNa+, 66%), m/z
(ESIꢀ) 376.1 (MꢀHꢀ, 100%); HRMS (ESIꢀTOF) m/z [MꢀH]ꢀ Calcd for C20H26NO6 376.1766; found 376.1779.
Methyl
(3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀisopropoxyꢀ5ꢀoxoꢀ6ꢀ(undecꢀ2ꢀynoyl)ꢀ1H,3Hꢀpyrrolo[1,2ꢀc]oxazoleꢀ
7a(5H)ꢀcarboxylate (14)
General procedure B (from 8c, with 1ꢀdecyne); yield 54% (156 mg); yellow oil. Rf (DCM) 0.42; [ꢀ]ꢂꢁꢃ +99.3 (c
0.7, DCM); νmax/cmꢀ1 2957 (CꢀH), 2929 (CꢀH), 2211 (C≡C), 1754 (C=O), 1721 (C=O), 1634 (C=O), 1586
(C=C); δH (400 MHz, CDCl3) 0.84 (3H, t, J 6.9, C(11’)H3), 0.87 (9H, s, C(CH3)3), 1.13 (3H, d, J 6.0, iPr), 1.21ꢀ
1.27 (8H, m, C(7’ꢀ10’)H2), 1.29 (3H, d, J 6.0, iPr), 1.35ꢀ1.42 (2H, m, C(6’)H2), 1.65 (2H, quint, J 7.2, C(5’)H2),
2.42 (2H, t, J 7.2, C(4’)H2), 3.42 (1H, d, J 8.5, C(1)HAHB), 3.75 (3H, s, CO2CH3), 4.73 (1H, s, C(3)H), 4.78
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(1H, d, J 8.5, C(1)HAHB), 5.17 (1H, sept, J 6.0, Pr); δC (125 MHz, CDCl3) 14.2 (C(11’)), 19.6 (C(4’)), 21.0
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(iPr), 22.2 (iPr), 22.7 (C(10’)), 24.7 (C(CH3)3), 27.7 (C(5’)), 29.0 (C(6’)), 29.1, 29.2 (C(7’), C(8’)), 31.9 (C(9’)),
35.2 (C(CH3)3), 53.3 (CO2CH3), 69.5 (C(1)), 74.3 (C(7a)), 79.6 (iPr), 81.8 (C(2’)), 97.7 (C(3)), 99.2 (C(3’)),
109.3 (C(6)), 168.0 (CO2CH3), 172.5 (C(1’)), 173.8 (C(7)), 174.5 (C(5)); m/z (ESI+) 462.3 (MH+, 67%), 484.3
(MNa+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C26H40NO6 462.2850; found 462.2835.
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Methyl (3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀisopropoxyꢀ5ꢀoxoꢀ6ꢀ(tetradecꢀ2ꢀynoyl)ꢀ1H,3Hꢀpyrrolo[1,2ꢀc]oxazoleꢀ
7a(5H)ꢀcarboxylate (15)
General procedure B (from 8c, with 1ꢀtridecyne); yield 47% (141 mg); light yellow oil. Rf (20% EtOAc in
petrol) 0.52; [ꢀ]ꢂꢁꢃ +93.3 (c 1.0, CHCl3); νmax/cmꢀ1 2925 (CꢀH), 2211 (C≡C), 1754 (C=O), 1721 (C=O), 1633
(C=O), 1583 (C=C); δH (400 MHz, CDCl3) 0.85 (3H, t, J 6.8, C(14’)H3), 0.90 (9H, s, C(CH3)3), 1.15 (3H, d, J
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6.0, Pr), 1.22ꢀ1.29 (14H, m, C(7’ꢀ13’)H2), 1.31 (3H, d, J 6.0, Pr), 1.41 (2H, quint, J 7.2, C(6’)H2), 1.61 (2H,
quint, J 7.2, C(5’)H2), 2.44 (2H, t, J 7.2, C(4’)H2), 3.44 (1H, d, J 8.5, C(1)HAHB), 3.78 (3H, s, CO2CH3), 4.75
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(1H, s, C(3)H), 4.80 (1H, d, J 8.5, C(1)HAHB), 5.19 (1H, sept, J 6.0, Pr); δC (100 MHz, CDCl3) 14.2 (C(14’)),
19.7 (C(4’)), 21.1 (iPr), 22.3 (iPr), 22.8 (C(13’)), 24.8 (C(CH3)3), 27.8 (C(5’)), 29.1 (C(6’)), 29.2, 29.5, 29.6,
29.7, 29.7 (C(7’ꢀ11’)), 32.0 (C(12’)), 35.3 (C(CH3)3), 53.3 (CO2CH3), 69.6 (C(1)), 74.4 (C(7a)), 79.7 (iPr), 81.8
(C(2’)), 97.8 (C(3)), 99.3 (C(3’)), 109.4 (C(6)), 168.1 (CO2CH3), 172.6 (C(1’)), 173.9 (C(7)), 174.6 (C(5)); m/z
(ESI+) 526.3 (MNa+, 31%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C29H46NO6 504.3320; found 504.3320.
Methyl (3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ7ꢀisopropoxyꢀ5ꢀoxoꢀ6ꢀ((2E,4E)ꢀundecaꢀ2,4ꢀdienoyl)ꢀ1H,3Hꢀpyrrolo[1,2ꢀ
c]oxazoleꢀ7a(5H)ꢀcarboxylate (16)
General procedure C (from 14); yield 81% (129 mg); orange oil. Rf (10% EtOAc in petrol) 0.28; [ꢀ]ꢂꢁꢃ +126.0
(c 0.4, DCM); νmax/cmꢀ1 2957 (CꢀH), 2929 (CꢀH), 1755 (C=O), 1713 (C=O), 1663 (C=O), 1626 (C=C), 1591
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(C=C); δH (500 MHz, C6D6) 0.87 (3H, d, J 6.0, iPr), 0.89 (3H, t, J 7.2, C(11’)H3), 1.02 (3H, d, J 6.0, Pr), 1.07ꢀ
1.17 (6H, m, C(8’ꢀ10’)H2), 1.12 (9H, s, C(CH3)3), 1.21ꢀ1.26 (2H, m, C(7’)H2), 1.82 (2H, q, J 6.8, C(6’)H2), 3.04
(1H, d, J 8.4, C(1)HAHB), 3.29 (3H, s, CO2CH3), 4.85 (1H, d, J 8.4, C(1)HAHB), 4.89 (1H, s, C(3)H), 5.43 (1H,
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C(2’)H), 7.61 (1H, dd, J 15.2, 11.0, C(3’)H); δC (100 MHz, C6D6) 14.2 (C(11’)), 20.7 (iPr), 22.0 (iPr), 22.9
(C(10’)), 25.1 (C(CH3)3), 28.9, 29.2, 32.0 (C(7’ꢀ9’)), 33.4 (C(6’)), 35.5 (C(CH3)3), 52.5 (CO2CH3), 69.7 (C(1)),
75.2 (C(7a)), 78.5 (iPr), 97.9 (C(3)), 110.5 (C(6)), 128.0 (C(2’)), 129.7 (C(4’)), 144.2 (C(3’)), 146.3 (C(5’)),
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168.6 (CO2CH3), 173.6 (C(7)), 176.3 (C(5)), 186.7 (C(1’)); m/z (ESI+) 462.3 (MH+, 100%), 484.3 (MNa+, 79%);
HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C26H40NO6 462.2850; found 462.2853.
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pyrrolo[1,2ꢀc]oxazoleꢀ7a(5H)ꢀcarboxylate (17)
General procedure C (from 15); yield 75% (80 mg); orange oil. Rf (DCM) 0.32; [ꢀ]ꢂꢁꢃ +120.3 (c 1.0, DCM);
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max/cmꢀ1 2957 (CꢀH), 2926 (CꢀH), 1755 (C=O), 1714 (C=O), 1663 (C=O), 1626 (C=C), 1591 (C=C);
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δH (400 MHz, C6D6) 0.87 (3H, d, J 6.0, Pr), 0.93 (3H, t, J 7.0, C(14’)H3), 1.02 (3H, d, J 6.0, Pr), 1.11 (9H, s,
C(CH3)3), 1.13ꢀ1.35 (14H, m, C(7’ꢀ13’)H2), 1.84 (2H, q, J 6.8, C(6’)H2), 3.04 (1H, d, J 8.4, C(1)HAHB), 3.29
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(3H, s, CO2CH3), 4.85 (1H, d, J 8.4, C(1)HAHB), 4.89 (1H, s, C(3)H), 5.43 (1H, sept, J 6.0, Pr), 5.82 (1H, dt, J
15.2, 6.8, C(5’)H), 6.04 (1H, dd, J 15.2, 11.2, C(4’)H), 7.20 (1H, d, J 15.2, C(2’)H), 7.64 (1H, dd, J 15.2, 11.2,
C(3’)H); δC (100 MHz, C6D6) 14.4 (C(14’)), 20.6 (iPr), 22.0 (iPr), 23.1 (C(13’)), 25.1 (C(CH3)3), 28.9, 29.6,
29.8, 29.9, 30.0, 32.3 (C(7’ꢀ12’)), 33.4 (C(6’)), 35.5 (C(CH3)3), 52.6 (CO2CH3), 69.6 (C(1)), 75.2 (C(7a)), 78.5
(iPr), 97.8 (C(3)), 110.5 (C(6)), 128.0 (C(2’)), 129.7 (C(4’)), 144.2 (C(3’)), 146.4 (C(5’)), 168.6 (CO2CH3),
173.5 (C(7)), 176.3 (C(5)), 186.7 (C(1’)); m/z (ESI+) 504.4 (MH+, 100%), 526.3 (MNa+, 43%); HRMS (ESIꢀ
TOF) m/z [M+H]+ Calcd for C29H46NO6 504.3320; found 504.3322.
Methyl
(3R,7aR,Z)ꢀ3ꢀ(tertꢀbutyl)ꢀ6ꢀ((2E,4E)ꢀ1ꢀhydroxyundecaꢀ2,4ꢀdienꢀ1ꢀylidene)ꢀ5,7ꢀdioxodihydroꢀ
1H,3Hꢀpyrrolo[1,2ꢀc]oxazoleꢀ7a(5H)ꢀcarboxylate (18)
General procedure D (from 16); yield 48% (14 mg); orange oil; 1.9:1 mixture of tautomers. Rf (50% EtOAc in
petrol) 0.16; [ꢀ]ꢂꢁꢃ +62.9 (c 0.9, CHCl3); νmax/cmꢀ1 2960 (CꢀH), 1753 (C=O), 1712 (C=O), 1651 (C=O), 1613
(C=C), 1558 (C=C); δH (500 MHz, CDCl3) major tautomer: 0.88 (3H, t, J 6.9, C(11’)H3), 0.94 (9H, s, C(CH3)3),
1.24ꢀ1.35 (6H, m, C(8’ꢀ10’)H2), 1.42ꢀ1.48 (2H, m, C(7’)H2), 2.22ꢀ2.27 (2H, m, C(6’)H2), 3.51 (1H, d, J 8.9,
C(1)HAHB), 3.78 (3H, s, CO2CH3), 4.83 (1H, d, J 8.9, C(1)HAHB), 4.86 (1H, s, C(3)H), 6.32ꢀ6.40 (2H, m,
C(4’)H + C(5’)H), 7.03 (1H, d, J 15.3, C(2’)H), 7.58 (1H, dd, J 15.3, 10.2, C(3’)H); δC (125 MHz, CDCl3)
major tautomer: 14.2 (C(11’)), 22.7 (C(10’)), 24.8 (C(CH3)3), 28.6 (C(7’)), 29.0 (C(8’)), 29.9 (C(9’)), 33.7
(C(6’)), 35.4 (C(CH3)3), 53.4 (CO2CH3), 68.5 (C(1)), 78.4 (C(7a)), 98.4 (C(3)), 99.6 (C(6)), 118.9 (C(2’)), 129.7
(C(4’)), 148.4 (C(3’)), 150.8 (C(5’)), 167.9 (CO2CH3), 177.4 (C(1’)), 181.0 (C(5)), 188.0 (C(7)); m/z (ESIꢀ)
418.1 (MꢀHꢀ, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C23H34NO6 420.2381; found 420.2381.
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1H,3Hꢀpyrrolo[1,2ꢀc]oxazoleꢀ7a(5H)ꢀcarboxylate (19)
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General procedure D (from 17); yield 41% (30 mg); orange oil; 2.6:1 mixture of tautomers. Rf (70% EtOAc in
petrol) 0.26; [ꢀ]ꢂꢁꢃ +76.6 (c 1.0, CHCl3); νmax/cmꢀ1 2924 (CꢀH), 1754 (C=O), 1710 (C=O), 1654 (C=O), 1613
(C=C), 1556 (C=C); δH (500 MHz, CDCl3) major tautomer: 0.88 (3H, t, J 6.6, C(14’)H3), 0.93 (9H, s, C(CH3)3),
1.20ꢀ1.33 (12H, m, C(8’ꢀ13’)H2), 1.40ꢀ1.48 (2H, m, C(7’)H2), 2.24 (2H, q, J 6.3, C(6’)H2), 3.51 (1H, d, J 8.8,
C(1)HAHB), 3.78 (3H, s, CO2CH3), 4.83 (1H, d, J 8.8, C(1)HAHB), 4.86 (1H, s, C(3)H), 6.32ꢀ6.40 (2H, m,
C(4’)H + C(5’)H), 7.03 (1H, d, J 15.2, C(2’)H), 7.58 (1H, dd, J 15.2, 9.7, C(3’)H); δC (125 MHz, CDCl3) major
tautomer: 14.3 (C(14’)), 22.8 (C(13’)), 24.8 (C(CH3)3), 28.6 (C(7’)), 29.3, 29.4, 29.5, 29.6 (C(8’ꢀ11’)), 32.0
(C(12’)), 33.7 (C(6’)), 35.4 (C(CH3)3), 53.4 (CO2CH3), 68.5 (C(1)), 78.5 (C(7a)), 98.4 (C(3)), 99.6 (C(6)), 118.9
(C(2’)), 129.7 (C(4’)), 148.3 (C(3’)), 150.8 (C(5’)), 167.9 (CO2CH3), 177.4 (C(1’)), 180.9 (C(5)), 188.0 (C(7));
m/z (ESI+) 462.3 (MH+, 19%), 484.2 (MNa+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C26H40NO6
462.2850; found 462.2849.
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(3R,7aR,Z)ꢀ3ꢀ(tertꢀButyl)ꢀ6ꢀ((2E,4E)ꢀ1ꢀhydroxyundecaꢀ2,4ꢀdienꢀ1ꢀylidene)dihydroꢀ3H,5Hꢀpyrrolo[1,2ꢀ
c]oxazoleꢀ5,7(6H)ꢀdione (20)
Methyl ester 18 (41 mg, 0.098 mmol) and LiOH·H2O (20 mg, 0.50 mmol) in a 4:1:1 mixture of
THF/MeOH/H2O (1.4 mL) were heated at reflux for 8 h and then cooled to room temperature. The mixture was
diluted with brine, acidified with 2 M aqueous HCl, extracted with EtOAc, dried over Na2SO4 and concentrated
in vacuo. The residue was dissolved in MeCN and heated at reflux for 5 h, then cooled to room temperature.
The mixture was diluted with brine, acidified with 2 M aqueous HCl, extracted with EtOAc, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column
chromatography and the product thus obtained was dissolved in EtOAc, washed with 2 M aqueous HCl, dried
over anhydrous Na2SO4 and concentrated in vacuo to give the decarboxylated acyltetramate 20 (18 mg, 0.050,
51%) as an orange oil; 2.2:1 mixture of tautomers. Rf (80% EtOAc in petrol) 0.18; [ꢀ]ꢂꢁꢃ +136.4 (c 0.5, CHCl3);
νmax/cmꢀ1 2957 (CꢀH), 2927 (CꢀH), 1708 (C=O), 1650 (C=O), 1613 (C=O), 1557 (C=C); δH (500 MHz, CDCl3)
major tautomer: 0.86ꢀ0.90 (3H, m, C(11’)H3), 0.97 (9H, s, C(CH3)3), 1.25ꢀ1.34 (6H, m, C(8’ꢀ10’)H2), 1.45 (2H,
tt, J 7.0, 6.5, C(7’)H2), 2.23 (2H, td, J 7.0, 6.0, C(6’)H2), 3.45 (1H, dd, J 9.5, 8.3, C(1)HAHB), 4.15 (1H, dd, J
9.5, 7.0, C(7a)H), 4.26 (1H, dd, J 8.3, 7.0, C(1)HAHB), 4.95 (1H, s, C(3)H), 6.32ꢀ6.40 (2H, m, C(4’)H +
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C(5’)H), 7.07 (1H, d, J 15.5, C(2’)H), 7.53 (1H, dd, J 15.5, 10.0, C(3’)H); δC (125 MHz, CDCl3) major
tautomer: 14.2 (C(11’)), 22.7 (C(10’)), 24.9 (C(CH3)3), 28.6 (C(7’)), 29.0 (C(8’)), 31.8 (C(9’)), 33.6 (C(6’)),
36.1 (C(CH3)3), 67.0 (C(1)), 67.3 (C(7a)), 96.0 (C(3)), 101.1 (C(6)), 119.2 (C(2’)), 129.7 (C(4’)), 147.2 (C(3’)),
149.7 (C(5’)), 176.0 (C(1’)), 179.9 (C(5)), 191.8 (C(7)); m/z (ESIꢀ) 360.2 (MꢀHꢀ, 100%); HRMS (ESIꢀTOF) m/z
[MꢀH]ꢀ Calcd for C21H30NO4 360.2180; found 360.2180.
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Methyl
(3R,7aR,Z)ꢀ3ꢀ(tertꢀbutyl)ꢀ6ꢀ(1ꢀhydroxyoctylidene)ꢀ5,7ꢀdioxodihydroꢀ1H,3Hꢀpyrrolo[1,2ꢀ
c]oxazoleꢀ7a(5H)ꢀcarboxylate (21)
General procedure B (from 2, with 2 eq of 1ꢀbromoheptane); yield 60% (124 mg); orange oil; 3.4:1 mixture of
tautomers. Rf (EtOAc) 0.40; [ꢀ]ꢂꢁꢃ +67.4 (c 1.0, DCM); νmax/cmꢀ1 2958 (CꢀH), 2930 (CꢀH), 1758 (C=O), 1718
(C=O), 1657 (C=O), 1602 (C=C); δH (400 MHz, CDCl3) major tautomer: 0.84ꢀ0.89 (3H, m, C(8’)H3), 0.92 (9H,
s, C(CH3)3), 1.24ꢀ1.30 (8H, m, C(4’ꢀ7’)H2), 1.66 (2H, quint, J 7.6, C(3’)H2), 2.83 (2H, app td, J 7.6, 2.5,
C(2’)H2), 3.48 (1H, d, J 8.9, C(1)HAHB), 3.78 (3H, s, CO2CH3), 4.81 (1H, d, J 8.9, C(1)HAHB), 4.84 (1H, s,
C(3)H); δC (100 MHz, CDCl3) major tautomer: 14.2 (C(8’)), 22.7 (C(7’)), 24.8 (C(CH3)3), 26.0 (C(3’)), 28.9,
29.3 ((C(4’)), C(5’)), 31.7 (C(6’)), 33.2 (C(2’)), 35.3 (C(CH3)3), 53.4 (CO2CH3), 68.4 (C(1)), 78.4 (C(7a)), 98.4
(C(3)), 101.2 (C(6)), 167.6 (CO2CH3), 180.4 (C(5)), 187.9 (C(7)), 192.6 (C(1’)); m/z (ESI+) 382.2 (MH+, 81%),
404.3 (MNa+, 100%), m/z (ESIꢀ) 380.2 (MꢀHꢀ, 100%); HRMS (ESIꢀTOF) m/z [MꢀH]ꢀ Calcd for C20H30NO6
380.2079; found 380.2092.
Methyl
(3R,7aR,Z)ꢀ3ꢀ(tertꢀbutyl)ꢀ6ꢀ(1ꢀhydroxyundecylidene)ꢀ5,7ꢀdioxodihydroꢀ1H,3Hꢀpyrrolo[1,2ꢀ
c]oxazoleꢀ7a(5H)ꢀcarboxylate (22)
General procedure B (from 2, with 2 eq of 1ꢀbromodecane); yield 61% (119 mg); orange oil; 6:1 mixture of
tautomers. Rf (EtOAc) 0.35; [ꢀ]ꢂꢁꢃ +64.6 (c 1.0, DCM); νmax/cmꢀ1 2926 (CꢀH), 2856 (CꢀH), 1758 (C=O), 1719
(C=O), 1658 (C=O), 1602 (C=C); δH (400 MHz, CDCl3) major tautomer: 0.86 (3H, t, J 6.8, C(11’)H3), 0.91
(9H, s, C(CH3)3), 1.24ꢀ1.37 (14H, m, C(4’ꢀ10’)H2), 1.65 (2H, quint, J 7.5, C(3’)H2), 2.81ꢀ2.84 (2H, m, C(2’)H2),
3.48 (1H, d, J 8.8, C(1)HAHB), 3.77 (3H, s, CO2CH3), 4.81 (1H, d, J 8.8, C(1)HAHB), 4.83 (1H, s, C(3)H); δC
(100 MHz, CDCl3) major tautomer: 14.2 (C(11’)), 22.8 (C(10’)), 24.8 (C(CH3)3), 26.0 (C(3’)), 29.3, 29.3, 29.4,
29.5, 29.6 (C(4’ꢀ8’), 32.0 (C(9’)), 33.2 (C(2’)), 35.3 (C(CH3)3), 53.4 (CO2CH3), 68.5 (C(1)), 78.4 (C(7a)), 98.3
(C(3)), 101.1 (C(6)), 167.6 (CO2CH3), 180.4 (C(5)), 187.9 (C(7)), 192.6 (C(1’)); m/z (ESI+) 424.3 (MH+, 100%),
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446.3 (MNa+, 76%), m/z (ESIꢀ) 422.2 (MꢀHꢀ, 100%); HRMS (ESIꢀTOF) m/z [MꢀH]ꢀ Calcd for C23H36NO6
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(3R,7aR,Z)ꢀ3ꢀ(tertꢀbutyl)ꢀ6ꢀ(1ꢀhydroxytetradecylidene)ꢀ5,7ꢀdioxodihydroꢀ1H,3Hꢀpyrrolo[1,2ꢀ
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c]oxazoleꢀ7a(5H)ꢀcarboxylate (23)
General procedure B (from 2, with 2 eq of 1ꢀbromotridecane); yield 66% (102 mg); orange oil; 4.3:1 mixture of
tautomers. Rf (EtOAc) 0.46; [ꢀ]ꢂꢁꢃ +62.0 (c 1.0, DCM); νmax/cmꢀ1 2924 (CꢀH), 2854 (CꢀH), 1758 (C=O), 1719
(C=O), 1658 (C=O), 1603 (C=C); δH (400 MHz, CDCl3) major tautomer: 0.87 (3H, t, J 7.0, C(14’)H3), 0.92
(9H, s, C(CH3)3), 1.24ꢀ1.30 (18H, m, C(5’ꢀ13’)H2), 1.33ꢀ1.39 (2H, m, C(4’)H2), 1.66 (2H, quint, J 7.5, C(3’)H2),
2.82ꢀ2.85 (2H, m, C(2’)H2), 3.49 (1H, d, J 8.9, C(1)HAHB), 3.78 (3H, s, CO2CH3), 4.82 (1H, d, J 8.9,
C(1)HAHB), 4.84 (1H, s, C(3)H); δC (100 MHz, CDCl3) major tautomer: 14.3 (C(14’)), 22.8 (C(13’)), 24.8
(C(CH3)3), 26.0 (C(3’)), 29.3, 29.3, 29.5, 29.5, 29.7, 29.8, 29.8, 29.8 (C(4’ꢀ11’), 32.1 (C(12’)), 33.2 (C(2’)),
35.3 (C(CH3)3), 53.4 (CO2CH3), 68.4 (C(1)), 78.5 (C(7a)), 98.4 (C(3)), 101.2 (C(6)), 167.6 (CO2CH3), 180.4
(C(5)), 187.9 (C(7)), 192.7 (C(1’)); m/z (ESIꢀ) 464.3 (MꢀHꢀ, 100%); HRMS (ESIꢀTOF) m/z [MꢀH]ꢀ Calcd for
C26H42NO6 464.3007; found 464.3013.
Methyl
(3R,7aR)ꢀ3ꢀ(tertꢀbutyl)ꢀ6ꢀ((E)ꢀ3ꢀ(3ꢀhexyloxiranꢀ2ꢀyl)acryloyl)ꢀ7ꢀisopropoxyꢀ5ꢀoxoꢀ1H,3Hꢀ
pyrrolo[1,2ꢀc]oxazoleꢀ7a(5H)ꢀcarboxylate (24)
mCPBA (80%, 88 mg, 0.41 mmol) was added portionwise to a solution of diene 16 (64 mg, 0.14 mmol) in
anhydrous DCM (700 ꢀL) at 0 °C. The mixture was stirred at room temperature for 5 h and quenched with
saturated aqueous Na2S2O3. The aqueous phase was extracted with DCM, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was purified by flash column chromatography (10%
EtOAc in petrol) to give a 1:1 unseparable diastereomeric mixture of epoxide 24 (43 mg, 0.089 mmol, 64%) as a
light yellow oil. Rf (10% EtOAc in petrol) 0.19; νmax/cmꢀ1 2960 (CꢀH), 2931 (CꢀH), 1754 (C=O), 1711 (C=O),
1671 (C=O), 1618 (C=C), 1585 (C=C); δH (500 MHz, CDCl3, 1:1 mixture of diastereomers A and B) 0.88 (6H,
t, J 6.8, C(11’)H3 A + B), 0.91 (9H, s, C(CH3)3 A), 0.91 (9H, s, C(CH3)3 B), 1.09 (3H, d, J 6.0, iPr A), 1.09 (3H,
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d, J 6.0, Pr B), 1.25ꢀ1.37 (12H, m, C(8’ꢀ10’)H2 A + B), 1.31 (3H, d, J 6.0, Pr A), 1.32 (3H, d, J 6.0, Pr B),
1.40ꢀ1.49 (4H, m, C(7’)H2 A + B), 1.56ꢀ1.62 (4H, m, C(6’)H2 A + B), 2.94ꢀ2.97 (2H, m, C(5’)H A + B), 3.27ꢀ
3.29 (2H, m, C(4’)H A + B), 3.48 (1H, d, J 8.5, C(1)HAHB A), 3.48 (1H, d, J 8.5, C(1)HAHB B), 3.78 (3H, s,
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CO2CH3 A), 3.79 (3H, s, CO2CH3 B), 4.74 (2H, s, C(3)H A + B), 4.82 (1H, d, J 8.5, C(1)HAHB A), 4.82 (1H, d,
J 8.5, C(1)HAHB B), 5.16 (1H, sept, J 6.0, iPr A), 5.17 (1H, sept, J 6.0, iPr B), 6.59 (1H, dd, J 15.6, 8.0, C(3’)H
A), 6.65 (1H, dd, J 15.6, 7.3, C(3’)H B), 7.16 (1H, dd, J 15.6, 0.5, C(2’)H A), 7.23 (1H, dd, J 15.6, 0.5, C(2’)H
B); δC (125 MHz, CDCl3) 14.2 (C(11’) A + B), 20.9 (iPr A), 21.0 (iPr B), 22.3 (iPr A), 22.3 (iPr B), 22.7 (C(10’)
A + B), 24.8 (C(CH3)3 A + B), 25.9 (C(7’) A + B), 29.2 (C(8’) A + B), 31.8 (C(9’) A + B), 32.1 (C(6’) A), 32.1
(C(6’) B), 35.3 (C(CH3)3 A + B), 53.4 (CO2CH3 A + B), 56.9 (C(4’) A), 57.1 (C(4’) B), 61.6 (C(5’) A), 62.0
(C(5’) B), 69.6 (C(1) A + B), 74.9 (C(7a) A), 74.9 (C(7a) B), 79.2 (C(12’) A), 79.3 (C(12’) B), 97.7 (C(3) A),
97.7 (C(3) B), 109.0 (C(6) A), 109.0 (C(6) B), 130.3 (C(2’) A), 130.7 (C(2’) B), 144.5 (C(3’) A), 144.7 (C(3’)
B), 168.1 (CO2CH3 A + B), 174.2 (C(7) A), 174.3 (C(7) B), 176.1 (C(5) A), 176.2 (C(5) A), 185.5 (C(1’) A),
185.8 (C(1’) B); m/z (ESI+) 478.3 (MH+, 93%), 500.3 (MNa+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for
C26H40NO7 478.2799; found 478.2796.
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Methyl (3R,7aR,Z)ꢀ3ꢀ(tertꢀbutyl)ꢀ6ꢀ((E)ꢀ3ꢀ(3ꢀhexyloxiranꢀ2ꢀyl)ꢀ1ꢀhydroxyallylidene)ꢀ5,7ꢀdioxodihydroꢀ1H,3Hꢀ
pyrrolo[1,2ꢀc]oxazoleꢀ7a(5H)ꢀcarboxylate (25)
General procedure D (from 24); yield 77% (43 mg); orange oil. Rf (80% EtOAc in petrol) 0.32; νmax/cmꢀ1 2958
(CꢀH), 2930 (CꢀH), 1753 (C=O), 1715 (C=O), 1645 (C=O), 1616 (C=C), 1574 (C=C); δH (400 MHz, CDCl3, 1:1
mixture of diastereomers A and B) 0.85ꢀ0.90 (6H, m, C(11’)H3 A + B), 0.93 (18H, s, C(CH3)3 A + B), 1.23ꢀ1.36
(12H, m, C(8’ꢀ10’)H2 A + B), 1.42ꢀ1.48 (4H, m, C(7’)H2 A + B), 1.60ꢀ1.66 (4H, m, C(6’)H2 A + B), 2.95ꢀ3.00
(2H, m, C(5’)H A + B), 3.31ꢀ3.34 (2H, m, C(4’)H A + B), 3.51 (1H, d, J 8.8, C(1)HAHB A), 3.52 (1H, d, J 8.8,
C(1)HAHB B), 3.79 (3H, s, CO2CH3 A), 3.79 (3H, s, CO2CH3 B), 4.84 (2H, d, J 8.8, C(1)HAHB A + B), 4.87
(2H, s, C(3)H A + B), 6.94 (1H, dd, J 15.6, 7.6, C(3’)H A), 6.95 (1H, dd, J 15.6, 7.6, C(3’)H B), 7.34 (2H, d, J
15.6, C(2’)H A + B); δC (125 MHz, CDCl3) 14.2 (C(11’) A + B), 22.6 (C(10’) A + B), 24.8 (C(CH3)3 A + B),
25.9 (C(7’) A + B), 29.1 (C(8’) A + B), 31.8 (C(9’) A + B), 32.1 (C(6’) A + B), 35.3 (C(CH3)3 A + B), 53.5
(CO2CH3 A), 53.5 (CO2CH3 B), 57.0 (C(4’) A), 57.0 (C(4’) B), 62.3 (C(5’) A), 62.4 (C(5’) B), 68.3 (C(1) A +
B), 78.4 (C(7a) A + B), 98.5 (C(3) A), 98.5 (C(3) B), 100.4 (C(6) A + B), 122.6 (C(2’) A), 122.7 (C(2’) B),
148.5 (C(3’) A + B), 167.5 (CO2CH3 A), 167.6 (CO2CH3 B), 175.2 (C(1’) A + B), 180.3 (C(5) A + B), 187.8
(C(7) A + B); m/z (ESIꢀ) 434.2 (MꢀHꢀ, 100%); HRMS (ESIꢀTOF) m/z [MꢀH]ꢀ Calcd for C23H32NO7 434.2184;
found 434.2188.
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5ꢀAllylꢀ2ꢀ(triisopropylsilyl)oxazole (28)
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CuCN (495 mg, 5.52 mmol) and LiCl (485 mg, 11.4 mmol) were stirred at 130 °C under vacuum for 5 h. After
cooling to room temperature, anhydrous THF (10 mL) was added and stirring was continued for further 30 min.
To a solution of TIPSꢀprotected oxazole 26 (1.08 g, 4.80 mmol) in anhydrous THF (12 mL) was added nꢀBuLi
(1.6 M in hexanes, 3.3 mL, 5.3 mmol) dropwise at ꢀ78 °C. After stirring at this temperature for 30 min, the
CuCN·2LiCl solution was added by cannula (with another 2 mL of anhydrous THF) and the mixture was stirred
at ꢀ78 °C for 2 h. Allyl bromide (630 ꢁL, 7.28 mmol) was then added and the solution was stirred at ꢀ78 °C for
30 min and at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl,
extracted with Et2O and dried over anhydrous Na2SO4. The crude product was purified by flash column
chromatography (5% EtOAc in petrol) to give a 13:1 inseparable mixture of alkene 28 and remaining starting
material (1.21 g, 4.48 mmol, 93%) as a light yellow oil. Rf (5% EtOAc in petrol) 0.38; νmax/cmꢀ1 2944 (CꢀH),
2867 (CꢀH), 1464 (C=C); δH (400 MHz, CDCl3) 1.12 (18H, d, J 7.4, SiCH(CH3)2), 1.39 (3H, sept, J 7.4,
SiCH(CH3)2), 3.45 (2H, app dq, J 6.4, 1.2, C(1)H2), 5.11ꢀ5.13 (1H, m, C(3)HAHB), 5.14ꢀ5.16 (1H, m,
C(3)HAHB), 5.87ꢀ5.97 (1H, m, C(2)H), 6.83 (1H, t, J 1.2, C(4’)H); δC (100 MHz, CDCl3) 11.1 (SiCH(CH3)2),
18.5 (SiCH(CH3)2), 30.2 (C(1)), 117.5 (C(3)), 123.0 (C(4’)), 133.0 (C(2)), 152.6 (C(5’)), 167.9 (C(2’)); m/z
(ESI+) 266.2 (MH+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C15H28NOSi 266.1935; found 266.1935.
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CuCN (782 mg, 8.73 mmol) and LiCl (752 mg, 17.7 mmol) were stirred at 130 °C under vacuum for 5 h. After
cooling to room temperature, anhydrous THF (15 mL) was added and stirring was continued for further 30 min.
To a solution of protected oxazole 27 (1.92 g, 7.94 mmol) in anhydrous THF (20 mL) was added nꢀBuLi (1.6 M
in hexanes, 5.5 mL, 8.8 mmol) dropwise at ꢀ78 °C. After stirring at this temperature for 30 min, the
CuCN·2LiCl solution was added by cannula (with another 5 mL of anhydrous THF) and the mixture was stirred
at ꢀ78 °C for 2 h. Allyl bromide (1.0 mL, 12 mmol) was then added and the solution was stirred at ꢀ78 °C for 30
min and at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl,
extracted with Et2O and dried over anhydrous Na2SO4. The crude product was purified by flash column
chromatography (5% EtOAc in petrol) to give alkene 29 (1.92 g, 6.83 mmol, 86%) as an orange oil. Rf (5%
EtOAc in petrol) 0.37; νmax/cmꢀ1 2943 (CꢀH), 2866 (CꢀH), 1462 (C=C); δH (400 MHz, CDCl3) 1.13 (18H, d, J
7.5, SiCH(CH3)2), 1.42 (3H, sept, J 7.5, SiCH(CH3)2), 3.63 (2H, d, J 6.6, C(1)H2), 5.09ꢀ5.19 (2H, m, C(3)H2),
5.98 (1H, ddt, J 16.8, 10.0, 6.6, C(2)H), 7.80 (1H, s, C(4’)H); δC (100 MHz, CDCl3) 11.8 (SiCH(CH3)2), 18.7
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(SiCH(CH3)2), 31.2 (C(1)), 116.8 (C(3)), 136.1 (C(2)), 139.5 (C(5’)), 143.3 (C(4’)), 169.4 (C(2’)); m/z (ESI+)
282.1 (MH+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C15H28NSSi 282.1706; found 282.1704.
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9ꢀBBN (0.5 M in THF, 24 mL, 12 mmol) was added dropwise to a solution of alkene 28 (1.14 g, 3.98 mmol) in
anhydrous THF (16 mL) at 0 °C and the solution was stirred at room temperature for 13 h. The mixture was
then cooled to 0 °C and water (2.2 mL), aqueous NaOH (2 M, 20 mL, 40 mmol) and H2O2 (35% w/w, 3.4 mL,
40 mmol) were added dropwise. The biphasic mixture was stirred at room temperature for 6 h, diluted with
brine and extracted with EtOAc, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The
crude product was purified by flash column chromatography (30% EtOAc in DCM) to give alcohol 30 (1.02 g,
3.59 mmol, 90%) as a colourless oil. Rf (20% EtOAc in petrol) 0.33; νmax/cmꢀ1 3340 (OꢀH), 2944 (CꢀH), 2867
(CꢀH), 1464 (C=C); δH (400 MHz, CDCl3) 1.11 (18H, d, J 7.4, SiCH(CH3)2), 1.37 (3H, sept, J 7.4,
SiCH(CH3)2), 1.90 (2H, tt, J 7.4, 6.4, C(2)H2), 1.96 (1H, br s, OH), 2.79 (2H, t, J 7.4, C(3)H2), 3.68 (2H, t, J
6.4, C(1)H2), 6.81 (1H, s, C(4’)H); δC (100 MHz, CDCl3) 11.1 (SiCH(CH3)2), 18.5 (SiCH(CH3)2), 22.1 (C(3)),
30.8 (C(2)), 61.8 (C(1)), 122.5 (C(4’)), 154.3 (C(5’)), 167.7 (C(2’)); m/z (ESI+) 284.2 (MH+, 100%); HRMS
(ESIꢀTOF) m/z [M+H]+ Calcd for C15H30NO2Si 284.2040; found 284.2041.
3ꢀ(2ꢀ(Triisopropylsilyl)thiazolꢀ5ꢀyl)propanꢀ1ꢀol (31)
9ꢀBBN (0.5 M in THF, 41 mL, 20 mmol) was added dropwise to a solution of alkene 29 (1.92 g, 6.83 mmol) in
anhydrous THF (27 mL) at 0 °C and the solution was stirred at room temperature for 13 h. The mixture was
then cooled to 0 °C and water (3.8 mL), aqueous NaOH (2 M, 34 mL, 68 mmol) and H2O2 (35% w/w, 5.8 mL,
68 mmol) were added dropwise. The biphasic mixture was stirred at room temperature for 6 h, diluted with
brine and extracted with EtOAc, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The
crude product was purified by flash column chromatography (20% EtOAc in DCM) to give alcohol 31 (1.69 g,
5.65 mmol, 83%) as a yellow oil. Rf (20% EtOAc in DCM) 0.22; νmax/cmꢀ1 3348 (OꢀH), 2942 (CꢀH), 2866 (Cꢀ
H), 1462 (C=C); δH (400 MHz, CDCl3) 1.12 (18H, d, J 7.5, SiCH(CH3)2), 1.41 (3H, sept, J 7.5, SiCH(CH3)2),
1.90 (1H, br s, OH), 1.95 (2H, tt, J 7.6, 6.4, C(2)H2), 2.99 (2H, t, J 7.6, C(3)H2), 3.69 (2H, t, J 6.4, C(1)H2), 7.80
(1H, s, C(4’)H); δC (100 MHz, CDCl3) 11.7 (SiCH(CH3)2), 18.6 (SiCH(CH3)2), 23.2 (C(3)), 34.5 (C(2)), 61.7
(C(1)), 141.3 (C(5’)), 143.1 (C(4’)), 168.9 (C(2’)); m/z (ESI+) 300.2 (MH+, 100%); HRMS (ESIꢀTOF) m/z
[M+H]+ Calcd for C15H30NOSSi 300.1812; found 300.1811.
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To a solution of alcohol 30 (346 mg, 1.22 mmol) and NaHCO3 (115 mg, 1.37 mmol) in anhydrous DCM (6.1
mL) was added portionwise DessꢀMartin periodinane (767 mg, 1.81 mmol) at 0 °C. After stirring at room
temperature for 5 h, a 1:1 mixture of saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 was added and
the organic layer was extracted with Et2O, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography (5% EtOAc in DCM) to give aldehyde 32 (303 mg, 1.08
mmol, 89%) as a yellow oil. Rf (5% EtOAc in DCM) 0.36; νmax/cmꢀ1 2944 (CꢀH), 2867 (CꢀH), 1728 (C=O),
1465 (C=C); δH (400 MHz, CDCl3) 1.10 (18H, d, J 7.4, SiCH(CH3)2), 1.36 (3H, sept, J 7.4, SiCH(CH3)2), 2.80
(2H, t, J 7.6, C(2)H2), 3.02 (2H, t, J 7.6, C(3)H2), 6.83 (1H, s, C(4’)H), 9.82 (1H, s, C(1)H); δC (100 MHz,
CDCl3) 11.0 (SiCH(CH3)2), 18.5 (SiCH(CH3)2), 18.5 (C(3)), 41.7 (C(2)), 122.8 (C(4’)), 152.7 (C(5’)), 168.0
(C(2’)), 200.3 (C(1)); m/z (ESI+) 282.1 (MH+, 5%); HRMS (ESIꢀTOF) m/z [M+Na]+ Calcd for C15H27NNaO2Si
304.1703; found 304.1703.
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3ꢀ(2ꢀ(Triisopropylsilyl)thiazolꢀ5ꢀyl)propanal (33)
To a solution of alcohol 31 (358 mg, 1.19 mmol) and NaHCO3 (111 mg, 1.32 mmol) in anhydrous DCM (6 mL)
was added portionwise DessꢀMartin periodinane (766 mg, 1.81 mmol) at 0 °C. After stirring at room
temperature for 5 h, a 1:1 mixture of saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 was added and
the organic layer was extracted with Et2O, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography (2% EtOAc in DCM) to give aldehyde 33 (242 mg, 0.813
mmol, 68%) as a yellow oil. Rf (2% EtOAc in DCM) 0.24; νmax/cmꢀ1 2943 (CꢀH), 2865 (CꢀH), 2722 (CꢀH), 1727
(C=O), 1462 (C=C); δH (400 MHz, CDCl3) 1.12 (18H, d, J 7.5, SiCH(CH3)2), 1.41 (3H, sept, J 7.5,
SiCH(CH3)2), 2.87 (2H, td, J 7.4, 1.0, C(2)H2), 3.23 (2H, td, J 7.4, 0.8, C(3)H2), 7.82 (1H, t, J 0.8, C(4’)H), 9.83
(1H, t, J 1.0, C(1)H); δC (100 MHz, CDCl3) 11.8 (SiCH(CH3)2), 18.6 (SiCH(CH3)2), 19.5 (C(3)), 45.3 (C(2)),
139.7 (C(5’)), 143.4 (C(4’)), 169.6 (C(2’)), 200.4 (C(1)); m/z (ESI+) 298.1 (MH+, 4%); HRMS (ESIꢀTOF) m/z
[M+H]+ Calcd for C15H28NOSSi 298.1655; found 298.1654.
5ꢀ(Butꢀ3ꢀynꢀ1ꢀyl)ꢀ2ꢀ(triisopropylsilyl)oxazole (34)
Potassium carbonate (300 mg, 2.17 mmol) and a solution of the Bestmann reagent (250 mg, 1.30 mmol) in
MeOH (1.5 mL) were added to a solution of aldehyde 32 (295 mg, 1.05 mmol) in MeOH (9 mL). After stirring
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at room temperature for 14 h, the suspension was cooled to 0 °C, quenched with saturated aqueous NaHCO3 and
extracted with Et2O. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. The crude product was purified by flash column chromatography (5% EtOAc in petrol)
to give alkyne 34 (267 mg, 0.963 mmol, 92%) as a colourless oil. Rf (5% EtOAc in petrol) 0.24; νmax/cmꢀ1 3313
(CꢀH), 2944 (CꢀH), 2867 (CꢀH), 2123 (C≡C), 1465 (C=C); δH (400 MHz, CDCl3) 1.12 (18H, d, J 7.4,
SiCH(CH3)2), 1.38 (3H, sept, J 7.4, SiCH(CH3)2), 1.97 (1H, t, J 2.6, C(4)H), 2.53 (2H, td, J 7.4, 2.6, C(2)H2),
2.93 (2H, td, J 7.4, 0.8, C(1)H2), 6.90 (1H, t, J 0.8, C(4’)H); δC (100 MHz, CDCl3) 11.1 (SiCH(CH3)2), 17.7
(C(2)), 18.5 (SiCH(CH3)2), 25.2 (C(1)), 69.4 (C(4)), 82.7 (C(3)), 123.1 (C(4’)), 152.7 (C(5’)), 167.9 (C(2’)); m/z
(ESI+) 278.2 (MH+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C16H28NOSi 278.1935; found 278.1933.
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5ꢀ(Butꢀ3ꢀynꢀ1ꢀyl)ꢀ2ꢀ(triisopropylsilyl)thiazole (35)
Potassium carbonate (192 mg, 1.39 mmol) and a solution of the Bestmann reagent (160 mg, 0.835 mmol) in
MeOH (2.0 mL) were added to a solution of aldehyde 33 (204 mg, 0.685 mmol) in MeOH (4.9 mL). After
stirring at room temperature for 15 h, the suspension was cooled to 0 °C, quenched with saturated aqueous
NaHCO3 and extracted with Et2O. The combined organic layers were washed with brine, dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (5%
EtOAc in petrol) to give alkyne 35 (164 mg, 0.557 mmol, 81%) as a colourless oil. Rf (5% EtOAc in petrol)
0.26; νmax/cmꢀ1 3311 (CꢀH), 2943 (CꢀH), 2866 (CꢀH), 2122 (C≡C), 1463 (C=C); δH (400 MHz, CDCl3) 1.12
(18H, d, J 7.6, SiCH(CH3)2), 1.42 (3H, sept, J 7.6, SiCH(CH3)2), 2.02 (1H, t, J 2.6, C(4)H), 2.54 (2H, td, J 7.4,
2.6, C(2)H2), 3.12 (2H, t, J 7.4, C(1)H2), 7.87 (1H, s, C(4’)H); δC (100 MHz, CDCl3) 11.8 (SiCH(CH3)2), 18.6
(SiCH(CH3)2), 21.2 (C(2)), 26.3 (C(1)), 69.9 (C(4)), 82.9 (C(3)), 139.4 (C(5’)), 143.5 (C(4’)), 169.4 (C(2’)); m/z
(ESI+) 294.2 (MH+, 100%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C16H28NSSi 294.1706; found 294.1707.
4ꢀ(2ꢀ(Triisopropylsilyl)oxazolꢀ5ꢀyl)butanenitrile (36)
Triphenylphosphine (1.67 g, 6.37 mmol) and acetone cyanohydrin (580 ꢁL, 6.35 mmol) were added to a
solution of alcohol 30 (723 mg, 2.55 mmol) in anhydrous THF (10 mL). After stirring at room temperature for
10 min, the solution was cooled to 0 °C and diethyl azodicarboxylate (1.0 mL, 6.4 mmol) in anhydrous THF (3
mL) was added dropwise. The mixture was stirred at 0 °C for 1 h and for further 18 h at room temperature. The
solvent was then evaporated and the crude product was purified by flash column chromatography (10% to 20%
EtOAc in petrol) to give nitrile 36 (737 mg, 2.52 mmol, 99%) as a light yellow oil. Rf (20% EtOAc in petrol)
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0.30; νmax/cmꢀ1 2944 (CꢀH), 2867 (CꢀH), 2247 (C≡N), 1464 (C=C); δH (500 MHz, CDCl3) 1.12 (18H, d, J 7.5,
SiCH(CH3)2), 1.39 (3H, sept, J 7.5, SiCH(CH3)2), 2.03 (2H, quint, J 7.5, C(3)H2), 2.38 (2H, t, J 7.5, C(2)H2),
2.88 (2H, td, J 7.5, 1.0, C(4)H2), 6.89 (1H, t, J 1.0, C(4’)H); δC (125 MHz, CDCl3) 11.1 (SiCH(CH3)2), 16.6
(C(2)), 18.5 (SiCH(CH3)2), 24.0 (C(3)), 24.5 (C(4)), 119.0 (C(1)), 123.4 (C(4’)), 152.1 (C(5’)), 168.4 (C(2’));
m/z (ESI+) 293.2 (MH+, 100%), 315.2 (MNa+, 14%); HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C16H29N2OSi
293.2044; found 293.2042.
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4ꢀ(2ꢀ(Triisopropylsilyl)thiazolꢀ5ꢀyl)butanenitrile (37)
Triphenylphosphine (2.29 g, 8.74 mmol) and acetone cyanohydrin (800 ꢁL, 8.76 mmol) were added to a
solution of alcohol 31 (1.05 g, 3.50 mmol) in anhydrous THF (12 mL). After stirring at room temperature for 5
min, the solution was cooled to 0 °C and diethyl azodicarboxylate (1.4 mL, 8.9 mmol) in anhydrous THF (5
mL) was added dropwise. The mixture was stirred for 1 h at 0 °C and for further 18 h at room temperature. The
solvent was then evaporated and the crude product was purified by flash column chromatography (DCM) to
give nitrile 37 (1.00 g, 3.25 mmol, 93%) as a light yellow oil. Rf (DCM) 0.35; νmax/cmꢀ1 2943 (CꢀH), 2866 (Cꢀ
H), 2247 (C≡N), 1462 (C=C); δH (500 MHz, CDCl3) 1.13 (18H, d, J 7.5, SiCH(CH3)2), 1.42 (3H, sept, J 7.5,
SiCH(CH3)2), 2.05 (2H, quint, J 7.2, C(3)H2), 2.39 (2H, t, J 7.2, C(2)H2), 3.07 (2H, td, J 7.2, C(4)H2), 7.83 (1H,
s, C(4’)H); δC (125 MHz, CDCl3) 11.7 (SiCH(CH3)2), 16.6 (C(2)), 18.6 (SiCH(CH3)2), 25.7 (C(4)), 27.3 (C(3)),
119.1 (C(1)), 138.8 (C(5’)), 143.7 (C(4’)), 170.0 (C(2’)); m/z (ESI+) 309.2 (MH+, 100%), 331.1 (MNa+, 3%);
HRMS (ESIꢀTOF) m/z [M+H]+ Calcd for C16H29N2SSi 309.1815; found 309.1815.
4ꢀ(2ꢀ(Triisopropylsilyl)oxazolꢀ5ꢀyl)butanal (38)
DIBALꢀH (1 M in toluene, 3.7 mL, 3.7 mmol) was added dropwise to a solution of nitrile 36 (363 mg, 1.24
mmol) in anhydrous DCM (12 mL) at ꢀ78 °C. After stirring at this temperature for 3 h, EtOAc was added
followed by a saturated solution of Rochelle’s salt. After stirring at room temperature for 1 h, the aqueous layer
was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash column chromatography (20% EtOAc in petrol) to give
aldehyde 38 (286 mg, 0.969 mmol, 78%) as a colourless oil. Rf (20% EtOAc in petrol) 0.34; νmax/cmꢀ1 2944 (Cꢀ
H), 2867 (CꢀH), 1726 (C=O), 1464 (C=C); δH (500 MHz, CDCl3) 1.13 (18H, d, J 7.5, SiCH(CH3)2), 1.40 (3H,
sept, J 7.5, SiCH(CH3)2), 2.00 (2H, quint, J 7.2, C(3)H2), 2.50 (2H, td, J 7.2, 1.2, C(2)H2), 2.76 (2H, td, J 7.2,
0.7, C(4)H2), 6.86 (1H, s, C(4’)H), 9.78 (1H, t, J 1.2, C(1)H); δC (100 MHz, CDCl3) 11.1 (SiCH(CH3)2), 18.5
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