Total synthesis and biological evaluation of seven new anti-inflammatory oxacyclododecindione-type macrolactones

Article abstract of DOI:10.1039/d0ob00958j

Through variation of our previously published total synthesis of two highly active anti-inflammatory macrolactones from the oxacyclododecindione family (J. Tauber, M. Rohr, T. Walter, G. Erkel and T. Opatz, Org. Biomol. Chem., 2015, 13, 7813-7821), seven new representatives of this compound class were prepared. Substitution of the 14-hydroxy group in oxacyclododecindione with a methyl substituent provided a readily accessible non-natural analogue which has similar pharmacological properties to the scarcely available natural product. Since the producible amount of substance is therefore no longer restricted by low fermentation yields, extensive in vivo studies become possible for the first time. Based on this finding, further investigations on structure-activity relationships were undertaken by variation of the halogen atom, which showed that exchange or omission of the chloro substituent led to significantly lower binding affinities. Furthermore, it was found that elongation of the crucial and characteristic aliphatic side chain at C-10 also increased the IC50 value in the biological assays of interest.

Full text of DOI:10.1039/d0ob00958j

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Vierengel, T. Walter, T. Behrendt, T. Lucas, G. Erkel and T. Opatz, Org. Biomol. Chem., 2020, DOI:
10.1039/D0OB00958J.
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DOI: 10.1039/D0OB00958J
ARTICLE
Total synthesis and biological evaluation of seven new anti-
inflammatory oxacyclododecindione-type macrolactones
Carina Weber,a,† Nina Vierengel,a,† Thorsten Walter,b Torsten Behrendt,a Tobias Lucas,a Gerhard
Received 00th January 20xx,
Accepted 00th January 20xx
Erkelb and Till Opatz*a
DOI: 10.1039/x0xx00000x
Through variation of our previously published total synthesis of two highly active anti-inflammatory macrolactones from the
oxacyclododecindione family (Org. Biomol. Chem., 2015, 7813-7821), seven new representatives of this compound class
were prepared. Substitution of the 14-hydroxy group in oxacyclododecindione with a methyl substituent provided a readily
accessible non-natural analogue which has similar pharmacological properties as the scarcely available natural product.
Since the producible amount of substance is therefore no longer restricted by low fermentation yields, extensive in vivo
studies become possible for the first time. Based on this finding, further investigations on structure-activity relationships
were undertaken by variation of the halogen atom, which showed that exchange or omission of the chloro substituent led
to significantly lower binding affinities. Furthermore, it was found that prolongation of the crucial and characteristic aliphatic
side chain at C-10 also increased the IC50 value in the biological assays of interest.
Introduction
O
8
O
Me
OH
O
O
Me
15
14
Cl
4
Cl
1
Me
Me
HO
HO
Me
Me
The twelve-membered macrolactones oxacyclododecindione
(1), 14-deoxyoxacyclododecindione (2) and the 13-hydroxy
isomer 3 are secondary metabolites of the imperfect fungus
10
OH
O
OH
O
1
2
Exserohilum rostratum.1-4 Compounds
1 and 2 showed
Steglich
exceptionally high anti-inflammatory activities in reporter gene
assays and therefore represent potential lead structures for the
development of anti-inflammatory drugs.3, 5 Indeed, 1 proved to
be effective in an in vivo mouse model for the chronic
autoimmune disease systemic lupus erythematosus (SLE).6
With the previously reported synthesis of macrolactone 2, we
disclosed the first total synthesis of an oxacyclododecindione-
type macrolactone. Furthermore, its unexpected absolute
configuration (14S,15R) could be deduced from the comparison
of the optical rotations of the pure synthetic enantiomers of 2
with the respective value of the natural product.4, 7
esterification
X
O
O
Me
R1
O
O
Me
Me
Me
Cl
Me
R2
HO
HO
OH
Wittig
olefination
OH
O
OH
O
FriedelCrafts
3
acylation
Figure 1 – Structures of the natural macrolactones 1–3 and retrosynthetic approach to
the derivatives described herein.
gain a better insight into structure-activity relationships
between the macrolactones and their still unknown biological
target(s), we investigated the effect of structural variation at C-
14. By installing a second methyl group in this position, we
aimed to investigate the role of the 14-hydroxy group – a main
handicap for the total synthesis of 1. This would also simplify
the molecule by eliminating one of the two stereocenters.
Furthermore, the effects of a halogen exchange at C-4 and of
the size of the substituent at C-10 should be determined.
However, further pharmacological evaluation of 1 and 2 was
impeded by low fermentation yields.1 Accordingly, total
synthetic access to either oxacyclododecindione (1) itself or a
derivative with comparable biological properties is highly
desirable.
Herein, the racemic total synthesis of seven new
oxacyclododecindione-type macrolactones is presented. To
a. Department of Chemistry, Johannes Gutenberg-University, Duesbergweg 10-14,
55128 Mainz, Germany. E-mail: opatz@uni-mainz.de
b.Department of Molecular Biotechnology & Systems Biology, University of
Kaiserslautern, Erwin-Schrödinger Str. 70, Building 70, 67663 Kaiserslautern
Germany.
Results and discussion
Although various ring closure strategies have been extensively
studied, intramolecular Friedel–Crafts acylation at low
† Both authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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O
OH
OH
View Article Online
DOI: 10.1039/D0OB00958J
1) MeI, LiHMDS, THF,
–78 °C, 1 h, 89%
1) MeLi, THF,
0 °C, 1 h, 98%
Me
Me
O
O
Me
OTr
2) DIBAL-H, nHex/CH2Cl2,
–78 °C, 30 min, 94%
2) TrCl, NEt3, CH2Cl2,
0 °C  r.t., 18 h, 93%
Me Me
O
(±)-6
(±)-5
4
OH
PPh3
1)
OAll
O
O
Me
O
O
Me
7
Me
1) p-TsOH, MeOH
50 °C  r.t., 18 h, 98%
10
BnO
OBn
O
BnO
Me
BnO
Me
CH2Cl2, r.t., 42 h, 89%
Me
Me
DCC, DMAP, CH2Cl2
0 °C  r.t., 24 h, 83%
2) 1,3-dimethylbarbituric acid,
15 mol% Pd(PPh3)4, PPh3,
THF, r.t., 18 h, quant.
2) PCC, CH2Cl2,
18 h, 86%
OBn
OTr
OBn
O
(±)-9
(±)-8
O
O
Me
Me
Me
Me
O
O
Me
O
O
Me
Me
Cl
TFA/TFAA,
CH2Cl2,
–8 °C, 48 h, 90%
HO
Me
Me
BnO
Me
1) BCl3, CH2Cl2,
–78 °C, 1 h, 88%
BnO
Me
R
2) NCS, TFA,
DMF, r.t., 48 h
OH
O
OBn HO
OBn
O
Me
(a)
(±)-13
(±)-14
: R = H 75%
: R = Cl 17%
(±)-12
(±)-11
O
Scheme 1 – Total synthesis of 14-deoxy-14-methyloxacyclododecindionecyclododecindione (±)-13 and 6-chloro-14-deoxy-14-methyloxacyclododecindionecyclododecindione (±)-14.
(a) Yield of (±)-13 varied, the value given is an average for two runs.
substrate concentration (c = 0.65 mM) proved to be the only crystallography, revealing an L-shaped conformation with the
suitable method for the construction of the twelve-membered ester being (Z)-configured and the enone unit being nearly
lactone ring in the oxacyclododecindione series to date.7-10 The perpendicular to the aromatic ring (Figure 2). These three
reason for this counterintuitive observation is probably the findings also apply to the previously published X-ray structure
steric bulk of the C-10 methyl group and the strain of the of natural product 2 and might play a role for their biological
macrocyclic ring which lead to a perpendicular arrangement of properties.4 As shown in the biological evaluation section
the arene and the enone moiety. As shown in Figure 1, the below, compound (±)-13, bearing a second methyl group at C-
required precursors for ring closure are synthesized through 14, showed strong inhibitory activity in the transcriptional
Steglich esterification and Wittig olefination of suitable building reporter gene assays of interest which were similar to its natural
blocks.11-13 For the synthesis of 14-deoxy-14-methyl derivative parent compound 1 and to 14-deoxyoxacyclododecindione (2).
(±)-13, trityl protected alcohol (±)-6 was obtained from
commercial δ-valerolactone (4) by double α-methylation,
subsequent reduction to lactol (±)-5,14 and ring-opening
initiated by methyllithium (Scheme 1). Installation of a trityl
O
O
Me
Me
Me
Me
F
group allowed selective Steglich esterification of the secondary
hydroxyl group with 2-(3,5-bis(benzyloxy)phenyl)acetic acid 7,
which was prepared in five steps from dimethyl 1,3-
HO
Selectfluor, TFA, DMF
r.t., 96 h, 28%(a)
acetonedicarboxylate using
a
known procedure.15-18 The
OH
O
obtained ester (±)-8 was transformed into aldehyde (±)-9 by
detritylation and subsequent oxidation of the primary alcohol
under Corey–Suggs conditions.19 The aldehyde was reacted
with the previously established Wittig ylide allyl 2-
(triphenylphosphoranylidene)-propanoate (10), prepared in
three steps from 2-bromopropionic acid according to Blum.20
Pd0-catalysed deallylation furnished carboxylic acid (±)-11 as
precursor for the Friedel–Crafts cyclization. Ring closure using
TFA/TFAA in dichloromethane proceeded smoothly, producing
lactone (±)-12 in 90% yield. The reaction sequence was
concluded by BCl3-mediated debenzylation and electrophilic
aromatic substitution with N-chlorosuccinimide (NCS) providing
oxacyclododecindione derivative (±)-13 in twelve linear steps
with an overall yield of 30%. As a byproduct of this last
conversion, the dichlorinated compound (±)-14 was isolated in
17% yield. Target compound (±)-13 was characterized by X-ray
O
O
Me
Me
Me
Me
(±)-16
HO
(±)-15
O
OH
O
O
Me
Me
Br
Me
Me
NBS, TFA, DMF,
r.t., 96 h
HO
R
OH
O
(±)-17
(±)-18
: R = H 50%
: R = Br 36%
Scheme 2 – Variation of the last step in the synthesis of (±)-13 gave access to the
(a)
fluorinated and brominated derivatives (±)-16 and (±)-17. Most of (±)-16 was
obtained in a hardly separable mixture with (±)-15, the yield stated was calculated
based on 1H NMR.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0OB00958J
1) allyl bromide,
DCC, DMAP,
CH2Cl2, 0 °C, 4
h, 94%
Br
PPh3
NaOH, CH2Cl2/H2O,
r.t., 2 h, 98%
Br
Et
OH
OAll
Me
Et
O
(±)-19
2) PPh3, H2O,
reflux, 18 h, 94%
O
(±)-20
PPh3
O
O
O
O
Me
OAll
Et
1) 1,3-dimethylbarbituric acid,
5 mol% Pd(PPh3)4, THF,
r.t., 18 h, quant.
BnO
Me
Me
BnO
Me
21
O
Me
CH2Cl2, r.t., 72 h, 67%
2) TFA/TFAA, CH2Cl2,
0 °C, 48 h, 79%
OBn
OAll
OBn
O
Et
(±)-9
(±)-22
O
O
O
Me
Et
Me
Me
O
O
Me
Et
Me
Me
Cl
BnO
1.) BCl3, CH2Cl2
–78 °C, 24 h, 87%
HO
2.) NCS, TFA, DMF
r.t., 7 d, 75%
OBn
O
OH
O
(±)-24
(±)-23
Scheme 3 – Total synthesis of 14-deoxy-10-ethyl-14-methyloxacyclododecindionecyclododecindione (±)-24.
Considering these results and the lability of the 14-hydroxy
group in protected or unprotected form in the Friedel-Crafts
reaction (data not shown), (±)-13 is a useful starting point for
further modifications of the macrolactone scaffold. It is known
that the absence of the chloro-substituent at C-4 leads to a
significant loss of bioactivity for the oxacyclododecindione-type
macrolactones.7 To further evaluate the role of the halogen
substituent, chloride was replaced by fluoride and bromide
(Scheme 2). After debenzylation of (±)-12, compound (±)-15
was fluorinated with Selectfluor® to give 4-dechloro-14-deoxy-
4-fluoro-14-methyl-oxacyclododecindione ((±)-16) in a hardly
separable 3:2 mixture with (±)-15. Based on 1H NMR, a yield of
28% (±)-16 was calculated. Nevertheless, the purest fractions of
the HPLC run could be isolated to obtain a sample pure enough
for biological evaluation. Along the same lines, bromination was
performed using N-bromosuccinimide (NBS). However, due the
limited chemo-selectivity of the latter reaction, a mixture of 4-
bromo-4-dechloro-14-deoxy-14-methyloxacyclododecindione
((±)-17, 50% yield) and the dibrominated product 4,6-dibromo-
4-dechloro-14-deoxy-14-methyloxacyclododecindione ((±)-18,
36% yield) was obtained.
In previous studies on oxacyclododecindione- and
dehydrocurvularine-type macrolactones, the enone unit on the
aromatic ring proved to be associated with the bent three-
dimensional structure of this compound class and its biological
activity.5, 7, 8 To evaluate the tolerance for a sterically more
demanding group, the methyl substituent at C-10 was replaced
by an ethyl group. The latter was introduced using the higher
homologue of phosphoranylidene 10 in the Wittig olefination
(Scheme 3). Starting from 2-bromobutyric acid ((±)-19), a
sequence comprising esterification with allyl alcohol and
reaction with triphenylphosphane provided phosphonium
salt (±)-20 which was subsequently deprotonated to provide
ylide 21 in three steps with an overall yield of 87%. Wittig
Figure 2 – X-ray crystal structure of ((±)-13) as an ORTEP ellipsoid in two different
perspectives (30% probability) C: gray, H: white, O: red, Cl: green. For the X-ray
molecular structures of compounds (±)-12 and (±)-23, please refer to the Supporting
Information.
This journal is © The Royal Society of Chemistry 20xx
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olefination with aldehyde (±)-9 gave the (E)-configured,
unsaturated ester (±)-22 in 67% yield. Following the established
route, benzyl-protected macrolactone (±)-23 was obtained
through deallylation and subsequent ring closure.
Debenzylation and chlorination led to 14-deoxy-10-ethyl-14-
methyloxacyclododecindione (±)-24 after twelve linear steps
with an overall yield of 18%.
Biological evaluation
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As indicated above, macrolactones 1 andD2OaI:re10p.1o0t3e9n/Dt0inOhB0ib0i9to58rJs
of TGF-β and IL-4 signalling pathways in mammalian cells.1, 3, 5
As with the natural compounds and synthetic derivatives
investigated previously, the seven new compounds described
herein were examined for their inhibitory activity on IL-4-
inducible STAT6-dependent and TGF-β-inducible Smad2/3-
dependent transcriptional luciferase reporters in transiently
Table 1 – Effect of natural and synthetic macrolactones in two relevant reporter gene assays.a
(CAGA)9x-MLP-Luc
(Smad2/3)
pGL3-TK-7xN4
(STAT6)
IC50 (nM)
IC50 (nM)
Oxacyclododecindione (1)
135.6 ± 13.6
90.1 ± 9.6
67.8 ± 5.4
20.1 ± 1.4
(14S/15R)-14-Deoxyoxacyclododecindione (2)
14-Deoxy-14-methyloxacyclododecindione ((±)-13)
30.0 ± 10.9
4623 ± 13
79.1 ± 27.3
1017 ± 17
6-Chloro-14-deoxy-14-methyloxacyclododecindione ((±)-14)
4-Dechloro-14-deoxy-14-methyloxacyclododecindione ((±)-15)
4-Dechloro-14-deoxy-4-fluoro-14-methyloxacyclododecindione ((±)-16)
4-Bromo-4-dechloro-14-deoxy-14-methyloxacyclododecindione ((±)-17)
4,6-Dibromo-4-dechloro-14-deoxy-14-methyloxacyclododecindione ((±)-18)
14-Deoxy-10-ethyl-14-methyloxacyclododecindione ((±)-24)
87.2 ± 30.1
1264 ± 11
264.7 ± 21.1
442.4 ± 28.5
177.5 ± 4.9
379.4 ± 12.2
105.0 ± 23.6
381.7 ± 26.7
852.7 ± 10.2
519.9 ± 13.1
aHepG2 cells were transiently transfected with the indicated reporter gene construct and the constitutively active pRL-EF1α reporter gene and stimulated with 5 ng mL−1
TGF-β or 5 ng mL−1 IL-4 with or without the test compounds for 16 h as described in Materials and methods. To exclude unspecific cytotoxic effects, the results were
normalized against the constitutive active EF1α-promoter in front of the luciferase gene in order as described previously.1, 5
transfected HepG2 cells (Table 1). The racemate of the synthetic reduced the inhibitory activity on the STAT6-pathway by a
derivative 14-deoxy-14-methyloxa-cyclododecindione ((±)-13) factor of 2, the Smad2/3 dependant transcriptional reporter
exhibits potent inhibition of TGF-β-inducible Smad2/3- as well was reduced by 14.5-fold. On the other hand, the introduction
as IL-4-inducible STAT6-dependent reporter gene expression of chlorine into (±)-15 led to an almost 3-fold increase of the
with IC50 values of 30.0 nM (Smad2/3) and 79.1 nM (STAT6), inhibitory activity in the same system.
respectively. Therefore, it can be concluded that exchanging the
hydroxy group in 1 for a methyl substituent leads to an increase
of the inhibitory activity in the signalling pathways of interest.
Conclusion
Moreover, only the (14S,15R)-enantiomer of 2 shows the
tabulated IC50 values in the lower nanomolar range, while its
(14R,15S)-enantiomer is much less active. Thus, it can be
assumed that the activity of enantiopure (15R)-13 is even higher
and already the racemate is by far the strongest inhibitor of
Smad2/3 signalling in the series.
It has been observed that a dechlorinated derivative of 2 is not
as active as the latter.7 The same trend was found in the newly
synthesized series. Furthermore, the fluorinated and
brominated derivatives (±)-16 and (±)-17 as well as the
dihalogenated species (±)-14 and (±)-18 show practically no
inhibitory activity on TGF-β induced Smad2/3 signalling and very
weak inhibitory activity in the IL-4 reporter gene expression,
which is in strong contrast to the excellent bioactivity of (±)-13.
The C-10-ethyl derivative (±)-24 showed only a weak response
in the TGF-β reporter assay but was only a little less active in the
IL-4 assay. The significant loss of both kinds of activity upon
exchange of the chlorine substituent in (±)-13 to fluorine
appears particularly remarkable. While the introduction of
fluorine into the non-halogenated compound (±)-15 only
The general synthetic approach to oxacyclododecindione-type
macrolactones through Friedel-Crafts-cyclization provided a
broad and reliable access to further derivatives of this
compound class through variation of the building blocks. Seven
new derivatives were obtained and investigated with respect to
their biological activity to gain insight into structure-activity
relationships. A convenient and scalable total synthesis of 14-
deoxy-14-methyl-oxacyclododecindione ((±)-13) with an overall
yield of 30% in twelve linear steps could be devised. (±)-13
proved to be a remarkably potent inhibitor of TGF-β dependent
Smad2/3 and IL-4 dependent STAT6 signalling in in vitro studies
with IC50 values comparable to the natural product
oxacyclododecindione (1). While attempts to synthesize 1 have
met with little success so far, this is the first report of a synthetic
oxacyclododecindione-type macrolactone which surpasses the
impressive biological activity of the most potent natural
products of the series known so far in the TGF-β-inducible
Smad2/3-dependent reporter gene assay. The synthesis could
be performed (up to 100 mg) and makes further in vivo
experiments independent from fermentation yields.
4 | J. Name., 2012, 00, 1-3
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using positive ionization mode. X-ray crystallographic analysis
View Article Online
DOI: 10.1039/D0OB00958J
was kindly provided by the Department of Crystal Structure
Analysis of the Central Analytical Department of the
Department of Chemistry, Mainz.
Experimental section
Biological assays
Materials and methods
HepG2 cells (DSMZ ACC 180) were maintained in DMEM
medium supplemented with 10% fetal calf serum (FCS) and
65 μg mL–1 penicillin G and 100 μg mL–1 streptomycin sulfate
under a humidified atmosphere. The STAT6-driven reporter
plasmid pGL3-TK-7xN4 contains the herpes simplex virus
thymidine kinase promoter under the control of seven copies of
the palindromic sequence TTC(N)4GAA.1 The STAT6 expression
plasmid (TOPO-STAT6) has been previously described.21 The
reporter plasmid (AGCCAGACA)9-MLP-Luc contains nine
tandem copies of the CAGA Smad binding element upstream of
the adenovirus major late promoter driving luciferase
expression.22 The plasmid was kindly provided by Prof. S. Dooley
(University of Mannheim, Germany). The control reporter
vector pRL-EF1α for data normalization was purchased from
Promega (Dual-Luciferase-Reporter-Assay). Luciferase-based
reporter gene expression was thereby normalized for
transfection variability and cytotoxicity against renilla
expression of the constitutively active control vector (pRL-EF1α)
assayed in the same sample. HepG2 cells were transiently
transfected by electroporating (Bio-Rad, Gene-Pulser) 1 × 107
cells per mL in DMEM together with the indicated constructs
(50 μg) and the internal control pRL-EF1α vector at 500 V cm–1.
After electroporation the cells were seeded at 2 × 105 cells per
mL and allowed to recover for 16 h. For the induction of
reporter gene expression, the cells were treated either with
5 ng mL–1 TGF-β or 5 ng mL–1 IL-4 with or without the test
compounds in DMEM containing 5% FCS. Luciferase activity was
measured 16 h after induction using the luciferase assay system
(Promega, Mannheim, Germany) according to the
manufacturer’s instructions with a luminometer.
Unless stated otherwise, all solvents and reagents were
obtained from commercial suppliers and used without prior
purification. Dichloromethane, chloroform and triethylamine
were distilled from calcium hydride right bevor use. Diethyl
ether, benzene and toluene were distilled from sodium and
benzophenone. Anhydrous tetrahydrofuran was obtained by
distillation from potassium. Acetonitrile, N,N-dimethyl-
formamide and dimethyl sulfoxide were obtained from
commercial suppliers as extra dry solvents stored over
molecular sieve 3 Å and were used without further purification.
Reactions requiring anhydrous conditions were performed
under argon atmosphere in flame-dried glassware. Reactions at
–78 °C were carried out in a dry ice/acetone cooling bath. For
thin-layer chromatography (TLC), 0.25 mm silica plates (60F254
)
from Merck were used. Visualization of the compounds on the
TLC-plates was accomplished with UV light (λ = 254 nm) and/or
by staining with vanillin reagent (solution of vanillin (1.0 g),
methanol (100 mL), glacial acetic acid (12 mL) and conc. sulfuric
acid (4 mL)) and heat. Flash-chromatographic purifications (0.2–
0.4 bar nitrogen) were performed on silica gel (35–70 μm, Acros
Organics). The compositions of all eluents are stated in v/v-
ratios. Analytical HPLC separations were carried out on an ACE3-
C18-PFP-column (particle size: 3 μm, length: 15 cm, diameter:
4.6 mm, column temperature: 40 °C column, flow rate:
1 mL/min–1) temperature and with UV-DAD detection.
Preparative HPLC separations were performed using two high-
pressure gradient K-1800 pumps and an S-260-UV-DAD
detection. The eluents were mixtures given in v/v-ratios of
acetonitrile (HPLC grade) and Milli-Q® water. The separations
were carried out on an ACE5-C18-PFP-column (particle size:
5 μm, length: 15 cm, diameter: 30 mm, flow rate: 37.5 mL/
min–1). NMR spectra were, if not stated otherwise, recorded at
23 °C on a 300 MHz Bruker Avance-III HD (1H: 300 MHz, 13C: 75.5
MHz), a 400 MHz Bruker Avance-II (1H: 400 MHz, 13C: 100.6
MHz) or 600 MHz Bruker Avance-III (1H: 600 MHz, 13C: 151.1
MHz) spectrometer. All chemical shifts were referenced to the
signal of the residual solvent (CDCl3: 7.26 ppm & 77.16 ppm,
DMSO-d6: 2.50 ppm & 39.52 ppm, CD3OD: 3.31 ppm & 49.00
3,3-Dimethyltetrahydro-2H-pyran-2-one.14, 23
A solution of LiHMDS in anhydrous THF (1 M, 100 mL, 100 mmol,
2.20 eq.) was added dropwise within one hour to a precooled
solution (–78 °C) of δ-valerolactone (4, 4.55 g, 45.5 mmol,
1.00 eq.) and iodomethane (6.2 mL, 0.10 mmol, 2.20 eq.) in
anhydrous THF (80 mL). The mixture was stirred at –40 °C for
2 h before it was warmed to room temperature and acidified
with 1 N HCl (aq.). After adding diethyl ether (200 mL), layers
were separated, and the aqueous layer was extracted with
diethyl ether (3 x 40 mL). The combined organic layers were
washed with brine (50 mL), saturated aqueous sodium
bicarbonate (20 mL), again with brine (2 x 25 mL) and dried over
sodium sulfate. The solvent was removed carefully under
reduced pressure and the residue was purified by flash
chromatography (cyclohexane/EtOAc 4:1) yielding 3,3-
Dimethyltetrahydro-2H-pyran-2-one as a slightly yellow oil
(5.13 g, 40.0 mmol, 89%). Rf: 0.26 (cyclohexane/EtOAc 3:1).
1H-NMR, COSY (300 MHz, CDCl3): δ/ppm = 4.36–4.32 (m, 2H,
H-6), 1.92–1.86 (m, 2H, H-5), 1.77–1.73 (m, 2H, H-4), 1.30–1.29
1
ppm, CD3CN: 1.94 ppm & 1.32 ppm for H NMR and 13C NMR
respectively) and reported in parts per million (ppm, δ) relative
to tetramethylsilane (TMS). Infrared spectra were recorded on
a FT-IR spectrometer (Bruker Tensor 27) with a diamond ATR
unit. Low resolution electron spray ionization (ESI) mass spectra
were recorded on a LC/MSD trap XCT spectrometer. HRMS
spectra were recorded either on a Waters Q-ToF Ultima III
instrument with an ESI source using a suitable external calibrant
(reported high resolution masses refer to neutral molecules
since the mass of the electron was considered during
calibration) or on an Agilent 6545 QTOF-LC/MS with ESI, APCI or
APPI source. Unless stated otherwise, spectra were recorded
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 12
ARTICLE
Journal Name
(m, 6H, 2 x CH3). 13C-NMR, HSQC, HMBC (75.5 MHz, CDCl3): 1105, 1068, 1055, 1030, 912. HRMS (ESI): m/z calcd. for
View Article Online
+
DOI: 10.1039/D0OB00958J
δ/ppm = 177.1 (C-2), 70.6 (C-6), 38.8 (C-3), 35.1 (C-4), 27.8 (2 x [C8H18O2Na] : 169.1204; found: 169.1218.
CH3), 20.6 (C-5). IR (ATR): /cm–1 = 2968, 2871, 1726, 1474,
휈
1458, 1400, 1386, 1296, 1276, 1137, 1077, 1016. HRMS (ESI):
m/z calcd. for [C7H12O2Na]+: 153.0891; found: 153.0898. The
analytical data are consistent with those reported in the
literature.14, 23
1-Trityloxy-4,4-dimethylhexan-5-ol ((±)-6).
Compound (±)-6 was prepared according to a procedure by
Yasukouchi and Kanematsu.25
A
solution of 4,4-
3,3-Dimethyltetrahydro-2H-pyran-2-ol ((±)-5).24
dimethylhexane-1,5-diol (3.12 g, 21.3 mmol, 1.0 eq.) in
dichloromethane (80 mL) was treated with triethylamine, which
was freshly distilled from calcium hydride (7.4 mL, 53.2 mmol,
2.5 eq.). The solution was cooled to 0 °C before a solution of
trityl chloride (6.53 g, 23.4 mmol, 1.1 eq.) in dichloromethane
(30 mL) was added dropwise. The mixture was stirred at room
temperature overnight. The solvent was removed under
reduced pressure and the residue was purified by flash
chromatography (cyclohexane/EtOAc 10:1) yielding trityl ether
(±)-6 as colourless, highly viscous oil (7.73 g, 19.9 mmol, 93%).
Rf: 0.51 (cyclohexane/EtOAc 2:1). 1H-NMR, COSY (400 MHz,
CDCl3): δ/ppm = 7.48–7.44 (m, 6H, o-HTr), 7.33–7.29 (m, 6H,
m-HTr), 7.26–7.22 (m, 3H, p-HTr), 3.55 (q, 1H, J = 6.4 Hz, H-5),
3.06 (t, 2H, J = 6.8 Hz, H-1), 1.67–1.55 (m, 2H, H-2), 1.34–1.18
A solution of DIBAL-H in n-hexane (1 M, 38.2 mL, 38.2 mmol,
1.10 eq.) was added dropwise at –78 °C within 30 min to a
solution of 3,3-dimethyltetrahydro-2H-pyran-2-one (4.45 g,
34.7 mmol, 1.00 eq.) in anhydrous dichloromethane (80 mL).
After 2 h, the mixture was warmed to room temperature and
treated with methanol (15 mL), ethyl acetate (130 mL) and a
saturated aqueous potassium sodium tartrate solution (12 mL)
until the suspension cleared and a coarse-grained precipitate
sedimented (30 min). The suspension was filtered over a pad of
celite® and the aqueous layer was extracted with ethyl acetate
(3 x 30 mL). The combined organic layers were washed with
brine (50 mL), dried over sodium sulfate and the solvents were
removed under reduced pressure. 3,3-Dimethyltetrahydro-2H-
pyran-2-ol ((±)-5) was obtained as a colourless oil (4.23 g,
A
(m, 3H, H-3, OH), 1.12 (d, 3H, J = 6.4 Hz, H-6), 0.87 (s, 3H, CH3 ),
B
0.84 (s, 3H, CH3 ). 13C-NMR, HSQC, HMBC (101 MHz, CDCl3):
1
32.5 mmol, 94%). Rf: 0.29 (cyclohexane/EtOAc 3:1). H-NMR,
144.5 (ipso-CTr), 128.7 (o-CTr), 127.7 (m-CTr), 126.8 (p-CTr), 86.4
(CPh3), 74.3 (C-5), 64.6 (C-1), 37.1 (C-4), 34.9 (C-2), 24.5 (C-3),
COSY (300 MHz, CDCl3): δ/ppm = 4.45 (s, 1H, H-2), 4.01–3.93
(m, 1H, HA-6), 3.54–3.46 (m, 1H, HB-6), 1.66–1.56 (m, 2H. HA-4,
HA-5), 1.54–1.43 (m, 1H, HB-5), 1.37–1.21 (m, 1H, HB-4), 0.96 (s,
22.5 (CH3 ), 22.4 (CH3 ), 17.7 (C-6). IR (ATR): /cm–1 = 3407,
3086, 3058, 3032, 2963, 2872, 1491, 1448, 1386, 1220, 1183,
1155, 1072, 912, 900, 746, 705, 633. HRMS (ESI): m/z calcd. for
[C27H32O2Na]+: 411.2305; found: 411.2300.
B
A
휈
3H, CH3 ), 0.93 (s, 3H, CH3 ). 13C-NMR, HSQC, HMBC (75.5 MHz,
CDCl3): δ/ppm = 100.7 (C-2), 64.2 (C-6), 34.7 (C-4), 34.2 (C-3),
A
B
25.8 (CH3 ), 22.0 (C-5), 20.4 (CH3 ). IR (ATR): /cm–1 = 3398,
2946, 2927, 2856, 1478, 1453, 1383, 1364, 1274, 1137, 1081,
1028, 978, 950. HRMS (ESI): m/z calcd. for [C7H14O2Na]+:
153.0891; found: 153.0898. The analytical data are in
accordance with those reported in the literature.24
B
A
휈
3,3-Dimethyl-6-(trityloxy)hexan-2-yl [3,5-bis(benzyloxy)-phenyl]-
acetate ((±)-8).
According to a previously published procedure,7 to an ice cold
solution of 1-trityloxy-4,4-dimethylhexan-5-ol ((±)-6, 940 mg,
2.42 mmol, 1.00 eq.), (3,5-bis(benzyloxy)-phenyl)acetic acid (7,
843 mg, 2.42 mmol, 1.00 eq.) and 4-(dimethylamino)pyridine
(58.9 mg, 482 µmol, 20.0 mol% ) in dichloromethane (80 mL)
was slowly added a solution of N,N’-dicyclohexylcarbodiimide
(598 mg, 2.90 mmol, 1.20 eq.) in dichloromethane (15 mL). The
mixture was stirred for 3 h at 0 °C and for 16 h at room
temperature. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography
(cyclohexane/EtOAc 20:1) yielding ester (±)-8 as colourless oil
(1.44 g, 2.00 mmol, 83%). Rf: 0.51 (cyclohexane/EtOAc 4:1).
1H-NMR, COSY (400 MHz, CDCl3): δ/ppm = 7.47–7.22 (m, 25H,
HTr, HBn), 6.56–6.55 (m, 2H, H-2’, H-6’), 6.53–6.52 (m, 1H, H-4’ ),
4.99 (s, 4H, PhCH2), 4.78 (q, 1H, J = 6.4 Hz, H-2’’), 3.59–3.51 (m,
2H, H-2), 3.08–2.99 (m, 2H, H-6’’), 1.59–1.53 (m, 2H, H-5’’),
1.31–1.23 (m, 2H, H-4’’), 1.13 (d, 3H, J = 6.4 Hz, H-1’’), 0.85 (s,
6H, 2 x CH3). 13C-NMR, HSQC, HMBC (101 MHz, CDCl3): δ/ppm =
170.9 (C-1), 159.9 (C-3’, C-5’), 144.5 (ipso-CTr), 136.9 (ipso-CBn),
136.4 (C-1’), 128.7 (o-CTr), 128.6 (m-CBn), 128.0 (p-CBn), 127.8 (m-
CTr), 127.5 (o-CBn), 126.9 (p-CTr), 108.5 (C-2’, C-6’), 100.9 (C-4’),
86.4 (CPh3), 77.1 (C-2’’), 70.0 (PhCH2), 64.4 (C-6’’), 42.1 (C-2),
4,4-Dimethylhexane-1,5-diol.
A solution of methyllithium in diethyl ether (1.6 M, 24.6 mL,
39.4 mmol, 1.23 eq.) was added dropwise within 30 min to an
ice cold solution of 3,3-dimethyltetrahydro-2H-pyran-2-ol
((±)-5, 3.01 g, 32.1 mmol, 1.00 eq.) in THF (300 mL). After
warming to room temperature, the reaction mixture was
quenched with methanol/water (1:1 v/v, 50 mL). The organic
solvents were removed under reduced pressure and the
aqueous phase was extracted with diethyl ether (5 x 20 mL). The
organic solution was dried over sodium sulfate before the
solvent was removed under reduced pressure. The residue was
purified by flash chromatography (cyclohexane/EtOAc 2:1)
yielding 4,4-dimethylhexane-1,5-diol as colourless oil (3.32 g,
1
22.6 mmol, 98%). Rf: 0.23 (cyclohexane/EtOAc 1:2). H-NMR,
COSY (300 MHz, CDCl3): δ/ppm = 3.66–3.61 (m, 2H, H-1), 3.56
(q, 1H, J = 6.4 Hz, H-5), 1.64–1.46 (m, 4H, H-2, 2x OH), 1.43–1.34
(m, 1H, HA-3), 1.30–1.19 (m, 1H, HB-3), 1.13 (d, 3H, J = 6.4 Hz,
A
B
H-6), 0.87 (s, 3H, CH3 ), 0.85 (s, 3H, CH3 ). 13C-NMR, HSQC,
HMBC (75.5 MHz, CDCl3): δ/ppm = 74.2 (C-5), 63.9 (C-1), 37.2
B
A
(C-4), 34.7 (C-3), 27.1 (C-2), 22.8 (CH3 ), 22.4 (CH3 ), 17.8 (C-6).
A
B
IR (ATR): /cm–1 = 3374, 2949, 2872, 1474, 1453, 1386, 1366,
휈
36.5 (C-3’’), 35.2 (C-4’’), 24.5 (C-5’’), 23.2 (CH3 ), 22.7 (CH3 ),
14.6 (C-1’’). IR (ATR): /cm–1 = 3087, 3061, 3033, 2964, 2945,
휈
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
2872, 1727, 1595, 1491, 1449, 1378, 1291, 1156, 1116, 1061, (ipso-CBn), 136.3 (C-1’), 128.6 (m-CBn), 128.0 (p-CBn), 127.5
View Article Online
Bn
1030, 745, 736, 698. HRMS (ESI): m/z calcd. for [C49H50O5Na]+: (o-C ), 108.5 (C-2’, C-6’), 100.8 (C-4’), 76.6 (C-2’’), 70.0 (PhCH2),
741.3556; found: 741.3585.
DOI: 10.1039/D0OB00958J
B
42.1 (C-2), 38.9 (C-5’’), 36.2 (C-3’’), 30.0 (C-4’’), 23.1 (CH3 ), 23.0
A
(CH3 ), 14.6 (C-1’’). IR (ATR): /cm–1 = 2966, 2939, 2875, 2722,
휈
6-Hydroxy-3,3-dimethylhexan-2-yl [3,5-bis(benzyloxy)-phenyl]-
acetate.
1723, 1594, 1452, 1378, 1291, 1216, 1154, 1058, 834, 738, 698.
HRMS (ESI): m/z calcd. for [C30H34O5Na]+: 497.2298; found:
497.2300.
p-Toluenesulfonic acid monohydrate (19 mg, 0.10 mmol, 5.0
mol%) was added to a suspension of trityl ether (±)-8 (1.40 g,
1.95 mmol, 1.0 eq.) in methanol (250 mL). The mixture was
warmed to 50 °C for 2 h, whereas the starting material dissolved
Allyl (2E)-7-([[3,5-Bis(benzyloxy)phenyl]acetyl]oxy)-2,6,6-tri-
methyloct-2-enoate.
completely within a few minutes. After stirring overnight at According to a previously published procedure,7 phosphonium
room temperature, the solvent volume was decreased to 1/3 of ylide 10 (76.2 mg, 204 µmol, 1.14 eq.) was added to a solution
the initial volume by evaporation under reduced pressure. of aldehyde (±)-9 (84.5 mg, 178 µmol, 1.00 eq.) in dichloro-
Saturated aqueous sodium bicarbonate (100 mL) was added methane (10 mL). The mixture was stirred at room temperature
and the aqueous layer was extracted with ethyl acetate (4 x overnight. As conversion of aldehyde (±)-9 was incomplete,
50 mL). The organic solution was washed with brine (50 mL), further ylide 10 (7.0 mg, 18 µmol, 0.10 eq.) was added. Stirring
dried over magnesium sulfate. The solvent was removed under was continued for 24 h at room temperature, then the solvent
reduced pressure and the residue was purified by flash was removed under reduced pressure. The residue was purified
chromatography (cyclohexane/EtOAc 3:1) yielding 6-Hydroxy- by flash chromatography (cyclohexane/EtOAc 12:1) yielding the
3,3-dimethylhexan-2-yl [3,5-bis(benzyloxy)phenyl]acetate as unsaturated, (E)-configured allyl ester as colourless oil (92.1 mg,
1
colourless oil (912 mg, 1.91 mmol, 98%). Rf: 0.07 161 µmol, 89%). Rf: 0.18 (cyclohexane/EtOAc 12:1). H-NMR,
(cyclohexane/EtOAc 4:1). 1H-NMR, COSY (400 MHz, CDCl3): COSY (400 MHz, CDCl3): δ/ppm = 7.42–7.30 (m, 10H, HBn), 6.73–
δ/ppm = 7.43–7.30 (m, 10H, HBn), 6.56–6.55 (m, 2H, H-2’, H-6’), 6.69 (m, 1H, H-3), 6.54–6.52 (m, 3H, H-2’’, H-4’’, H-6’’), 5.94
6.53–6.52 (m, 1H, H-4’), 5.02 (s, 4H, PhCH2), 4.74 (q, 1H, J = (ddt, 1H, J = 17.2, 10.5, 5.6 Hz, OCH2CH=CH2), 5.34–5.29 (m, 1H,
E
Z
6.4 Hz, H-2’’), 3.53–3.48 (m, 4H, H-2, H-6’’), 1.47–1.40 (m, 2H, OCH2CH=CH2 ), 5.24–5.20 (m, 1H, OCH2CH=CH2 ), 5.01 (s, 4H,
H-5’’), 1.28–1.15 (m, 2H, H-4’’ ), 1.12 (d, 3H, J = 6.4 Hz, H-1’’), PhCH2), 4.76 (q, 1H, J = 6.4 Hz, H-7), 4.62–4.60 (m, 2H,
0.84 (s, 3H, CH3 ), 0.82 (s, 3H, CH3 ). 13C-NMR, HSQC, HMBC OCH2CH=CH2), 3.57–3.50 (m, 2H, H-2’), 2.14–2.00 (m, 2H, H-4),
(101 MHz, CDCl3): δ/ppm = 170.8 (C-1), 160.0 (C-3’, C-5’), 136.8 1.81 (s, 3H, 2-CH3), 1.39–1.31 (m, 1H, HA-5), 1.29–1.21 (m, 1H,
(ipso-CBn), 136.5 (C-1’), 128.6 (m-CBn), 128.0 (p-CBn), 127.5 HB-5), 1.12 (d, 3H, J = 6.4 Hz, H-8), 0.86 (s, 6H, 2 x 6-CH3).
(o-CBn), 108.6 (C-2’, C-6’), 100.7 (C-4’), 77.2 (C-2’’), 70.1 (PhCH2), 13C-NMR, HSQC, HMBC (101 MHz, CDCl3): δ/ppm = 170.8 (C-1’),
63.6 (C-6’’), 42.2 (C-2), 36.4 (C-3’’), 34.6 (C-4’’), 27.1 (C-5’’), 22.9 167.7 (C-1), 160.0 (C-3’’, C-5’’), 142.7 (C-3), 136.8 (ipso-HBn),
A
B
2 x CH3), 14.6 (C-1’’). IR (ATR): /cm–1 = 3432, 3065, 3034, 2943, 136.3 (C-1’’), 132.6 (OCH2CH=CH2), 128.6 (m-HBn), 128.0 (p-HBn),
휈
2873, 1725, 1595, 1498, 1453, 1378, 1292, 1158, 1058, 737, 127.5 (o-HBn), 127.4 (C-2), 117.8 (OCH2CH=CH2), 108.5 (C-2’’,
698. HRMS (ESI): m/z calcd. for [C30H36O5Na]+: 499.2460; found: C-6’’), 100.8 (C-4’’), 76.8 (C-7), 70.0 (PhCH2), 65.1
499.2473.
(OCH2CH=CH2), 42.1 (C-2’), 37.2 (C-5), 36.7 (C-6), 23.3 (C-4), 23.0
A
B
–
휈
(6-CH3 ), 22.8 (6-CH3 ), 14.6 (C-8), 12.3 (2-CH3). IR (ATR): /cm
1 = 3066, 3033, 2966, 2936, 2875, 1711, 1648, 1595, 1452, 1378,
1290, 1260, 1158, 1060, 736, 698. HRMS (ESI): m/z calcd. for
[C36H42O6Na]+: 593.2879; found: 593.2892.
3,3-Dimethyl-6-oxohexan-2-yl [3,5-bis(benzyloxy)phenyl]acetate
(±)-9.
According to procedures by Nokami et al.26 and Opatz et al.,7
pyridinium chlorochromate (276 mg, 1.28 mmol, 1.51 eq.) was
added under argon atmosphere to a solution of 6-Hydroxy-3,3-
dimethylhexan-2-yl [3,5-bis(benzyloxy)phenyl]acetate (404 mg,
847 µmol, 1.00 eq.) in dichloromethane (20 mL). After stirring
at room temperature overnight, the solvent was removed
under reduced pressure and the residue was filtered rapidly
over silica (cyclohexane/EtOAc 4:1). Aldehyde (±)-9 was
obtained as a colourless oil (349 mg, 735 µmol, 86%). Note: The
product is prone to oxidation and should be stored under an
inert gas atmosphere at –25 °C or used immediately after
(2E)-7-([[3,5-Bis(benzyloxy)phenyl]acetyl]oxy)-2,6,6-trimethyloct-
2-enoic acid ((±)-11).
According to a procedure by Kunz and März,27 allyl (2E)-7-
([[3,5-bis(benzyloxy)phenyl]acetyl]oxy)-2,6,6-trimethyloct-
2-enate (356 mg, 627 µmol, 1.0 eq.), 1,3-dimethylbarbituric
acid (116 mg, 743 µmol, 1.2 eq.), tetrakis(triphenylphosphine)-
palladium(0)
(69 mg,
60 µmol,
10 mol%)
and
triphenylphosphane (178 mg, 678 µmol, 1.1 eq.) were solved
under argon in THF (35 mL) and stirred overnight at room
temperature. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography
(cyclohexane/EtOAc 6:1 + 1% HOAc). Carbonic acid (±)-11 was
obtained as colourless oil (327 mg, 616 µmol, 98%). Rf: 0.22
(cyclohexane/EtOAc 3:1 + 1% HOAc). 1H-NMR, COSY (400 MHz,
CDCl3): δ/ppm = 7.42–7.29 (m, 10H, HBn), 6.80–6.76 (m, 1H,
H-3), 6.56–6.52 (H-2’’, H-4’’, H-6’’), 5.01 (s, 4H, PhCH2), 4.75 (q,
1
production. Rf: 0.28 (cyclohexane/EtOAc 4:1). H-NMR, COSY
(400 MHz, CDCl3): δ/ppm = 9.65 (t, 1H, J = 1.6 Hz, CHO), 9.44–
9.26 (m, 10H, HBn), 6.55–6.53 (m, 3H, H-2’, H-4’, H-6’), 5.02 (s,
4H, PhCH2), 4.73 (q, 1H, J = 6.4 Hz, H-2’’), 3.58–3.50 (m, 2H, H-2),
2.38–2.23 (m, 2H, H-5’’), 1.61–1.52 (m, 1H, HA-4’’), 1.51–1.41
A
(m, 1H, HB-4’’), 1.13 (d, 3H, J = 6.4 Hz, H-1’’), 0.85 (s, 3H, CH3 ),
B
0.82 (s, 3H, CH3 ). 13C-NMR, HSQC, HMBC (101 MHz, CDCl3):
δ/ppm = 202.3 (CHO), 170.8 (C-1), 160.0 (C-3’, C-5’), 136.8
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
1H, J = 6.5 Hz, H-7), 3.57–3.49 (m, 2H, H-2’), 2.10–2.05 (m, 2H, solvent under reduced pressure. After flash chromatography
View Article Online
H-4), 1.80–1.79 (m, 3H, 2-CH3), 1.38–1.31 (m, 1H, HA-5), 1.28– (cyclohexane/EtOAc 4:1) and preparative HPLC (C18-PFP,
DOI: 10.1039/D0OB00958J
1.20 (m, 1H, HB-5), 1.13 (d, 3H, J = 6.5 Hz, H-8), 0.87 (s, 3H, MeCN/H2O 40:60, 30 min), macrolactone (±)-15 was obtained
6-CH3 ), 0.86 (s, 3H, 6-CH3 ). 13C-NMR, HSQC, HMBC (101 MHz, as colourless oil (20 mg, 60 µmol, 88%). Rf: 0.20
CDCl3): δ/ppm = 172.2 (C-1), 170.8 (C-1’), 160.0 (C-3’’, C-5’’), (cyclohexane/EtOAc 2:1). tR (HPLC): 9.1 min (C18-PFP,
A
B
145.1 (C-3), 136.8 (ipso-CBn), 136.3 (C-1’’), 128.5 (m-CBn), 127.9 MeCN/H2O 40:60). H-NMR, COSY, NOESY (600 MHz, CD3OD):
1
(p-CBn), 127.5 (o-CBn), 126.7 (C-2), 108.5 (C-2’’, C-6’’), 100.8 δ/ppm = 6.42 (s, 1H, H-11), 6.27 (s, 1H, H-4), 6.24–6.23 (m, 1H,
(C-4’’), 77.2 (C-7), 70.0 (PhCH2), 42.1 (C-2’), 37.1 (C-5), 36.7 H-6), 4.50 (q, 1H, J = 6.3 Hz, H-15), 3.27–3.24 (m, 1H, HA-2),
A
B
(C-6), 23.4 (C-4), 23.0 (6-CH3 ), 22.8 (6-CH3 ), 14.6 (C-8), 11.9 3.20–3.17 (m, 1H, HB-2), 2.54–2.27 (m, 2H, H-12), 1.91–1.85 (m,
(2-CH3). IR (ATR): /cm–1 = 3067, 3033, 2965, 2932, 2875, 1725, 4H, 10-CH3, HA-13), 1.50–1.47 (m, 1H, HB-13), 1.06 (d, 3H, J =
1685, 1595, 1452, 1291, 1160, 1060, 737, 635. HRMS (ESI): m/z 6.3 Hz, 15-CH3), 0.91 (s, 3H, 14-CH3 ), 0.90 (s, 3H, 14-CH3 ).
calcd. for [C33H38O6Na]+: 553.2566; found: 553.2542.
휈
A
B
13C-NMR, HSQC, HMBC (151 MHz, CD3OD): δ/ppm = 200.8 (C-9),
170.0 (C-1), 158.5 (C-5), 155.6 (C-7), 154.1 (very broad, C-11),
134.8 (C-10), 132.7 (C-3), 118.4 (C-8), 106.6 (C-4), 100.4 (C-6),
77.6 (C-15), 38.3 (C-2), 35.3 (C-14), 33.5 (very broad, C-13), 24.9
(very broad, C-12), 23.8 (very broad, 2 x 14-CH3), 12.7 (15-CH3),
5,7-Bis(benzyloxy)-4-dechloro-14-methyl-14-deoxy-
oxacyclododecindione ((±)-12).
According to procedures from Roberts et al.9 and Opatz et al.,7
a solution of trifluoroacetic acid (12 mL) and trifluoroacetic
anhydride (6 mL) in dichloromethane (160 mL) was precooled
to –8 °C. A solution of carboxylic acid (±)-11 (63 mg, 0.12 mmol)
in dichloromethane (3 mL) was added and the flask was left to
stand at –8 °C for 48 h. The solution was neutralized by cautious
washing with saturated aqueous sodium bicarbonate (3 x
80 mL). The organic layer was dried over sodium sulfate and the
solvent was removed under reduced pressure. After flash
8.6 (10-CH3). IR (ATR): /cm–1 = 3351, 2962, 2924, 2873, 2854,
휈
1703, 1619, 1461, 1333, 1302, 1269, 1159, 845, 757. HRMS
(ESI): m/z calcd. for [C19H24O5Na]+: 355.1516; found: 355.1524.
14-Methyl-14-deoxyoxacyclododecindione ((±)-13).
According to previously published procedures,7 a solution of
macrolactone (±)-15 (115 mg, 346 µmol, 1.0 eq.) and N-chloro-
succinimide (46 mg, 0.34 mmol, 1.0 eq.) in N,N-dimethylform-
amide (14 mL) was treated with trifluoroacetic acid (42 µL,
0.55 mmol, 1.6 eq.). After 48 h, the solvent was removed under
reduced pressure and the residue was co-evaporated with
toluene (2 x 2 mL). After flash chromatography (cyclo-
hexane/EtOAc 3:1 + 1% HOAc) and preparative HPLC (C18-PFP,
MeCN/H2O 35:65, 30 min), compound (±)-13 was obtained as
colourless oil (100 mg, 273 µmol, 79%). It should be noted that
in a smaller batch (20 mg of starting material), a yield of 70%
was obtained. Rf: 0.12 (cyclohexane/EtOAc 2:1). tR (HPLC):
chromatography (cyclohexane/EtOAc 15:1
+ 1% HOAc),
macrolactone (±)-12 was obtained as colourless oil (55 mg,
11 mmol, 90%). Rf: 0.33 (cyclohexane/EtOAc 4:1). 1H-NMR,
COSY, NOESY (600 MHz, CD3OD): δ/ppm = 7.40–7.38 (m, 2H,
HBn), 7.36–7.33 (m, 2H, HBn), 7.31–7.24 (m, 6H, HBn), 6.65 (d, 1H,
J = 2.1 Hz, H-6), 6.57–6.56 (m, 1H, H-4), 6.39–6.37 (m, 1H, H-11),
5.11–5.05 (m, 2H, 5-OCH2Ph), 5.05–5.00 (m, 2H, 7-OCH2Ph),
4.48 (q, 1H, J = 6.3 Hz, H-15), 3.30–3.21 (m, 2H, H-2), 2.43–2.29
(m, 2H, H-12), 1.87 (s, 3H, 10-CH3), 1.82–1.78 (m, 1H, HA-13),
1.46–1.42 (m, 1H, HB-13), 0.96 (d, 3H, J = 6.3 Hz, 15-CH3), 0.87
1
10.5 min (C18-PFP, MeCN/H2O 40:60). H-NMR, COSY, NOESY
(s, 3H, 14-CH3 ), 0.86 (s, 3H, 14-CH3 ). 13C-NMR, HSQC, HMBC
(151 MHz, CD3OD): δ/ppm = 199.3 (C-9), 169.6 (C-1), 159.3
(C-5), 156.0 (C-7), 155.0 (C-11), 136.2 (ipso-C5-Bn), 136.1 (ipso-C7-
Bn), 134.7 (C-10), 132.3 (C-3), 127.4 (m-CBn), 127.3 (m-CBn), 126.8
(p-CBn), 126.7 (p-CBn), 126.4 (o-C5-Bn), 126.2 (o-C7-Bn), 123.1 (C-8),
106.9 (C-4), 99.5 (C-6), 77.9 (C-15), 69.5 (5-OCH2Ph), 69.2 (7-
OCH2Ph), 38.2 (C-2), 35.3 (C-14), 34.1 (very broad, C-13), 24.9
(C-12), 23.9 (very broad, 2 x 14-CH3), 12.8 (15-CH3), 8.1 (10-CH3).
A
B
(600 MHz, CD3CN, 343 K): δ/ppm = 7.32 (s, 2H, 2x OH), 6.52 (s,
1H, H-6), 6.43–6.40 (m, 1H, H-11), 4.75 (q, 1H, J = 6.5 Hz, H-15),
3.52 (d, 1H, J = 16.5 Hz, HA-2), 3.31 (d, 1H, J = 16.5 Hz, HB-2),
2.52–2.45 (m, 1H, HA-12), 2.22–2.16 (m, 1H, HB-12), 1.91–1.87
(m, 1H, HA-13), 1.87–1.86 (m, 3H, 10-CH3), 1.44–1.40 (m, 1H,
A
HB-13), 1.04 (d, 3H, J = 6.5 Hz, 15-CH3), 0.88 (s, 3H, 14-CH3 ),
B
0.86 (s, 3H, 14-CH3 ). 13C-NMR, HSQC, HMBC (151 MHz, CD3CN,
293 K): δ/ppm = 197.4 (C-9), 167.5 (C-1), 153.7 (C-11), 152.5 (2x
COH), 134.1 (C-10), 131.0 (C-3), 121.2 (C-8), 111.6 (C-4), 101.6
(C-6), 76.9 (C-15), 37.4 (C-2), 35.3 (C-14), 32.4 (C-13), 25.9 (14-
IR (ATR): /cm–1 = 3033, 2925, 2873, 1726, 1652, 1635, 1604,
휈
1583, 1455, 1432, 1329, 1297, 1156, 1135, 1066, 904, 730, 650.
HRMS (ESI): m/z calcd. for [C33H36O5]+: 513.2641; found:
513.2647.
A
B
CH3 ), 25.2 (C-12), 23.8 (14-CH3 ), 13.3 (15-CH3), 8.6 (10-CH3). IR
(ATR): /cm–1 = 3355, 2963, 2926, 2874, 1730, 1705, 1619,
휈
1438, 1368, 1336, 1301, 1275, 1242, 1178, 1066, 1016, 843,
655. HRMS (ESI): m/z calcd. for [C19H23(35Cl)O5Na]+: 389.1126;
found: 389.1129.
4-Dechloro-14-methyl-14-deoxy-
oxacyclododecindione ((±)-15).
According to Opatz et al.,7 a solution of boron trichloride in
dichloromethane (1 M, 0.70 mL, 0.70 mmol, 10 eq.) was added
at –78 °C to a solution of benzyl protected macrolactone (±)-12
(34 mg, 68 µmol, 1.0 eq.) in dichloromethane (10 mL). After 1 h,
saturated aqueous sodium bicarbonate (15 mL) was added
upon warming to room temperature. The aqueous layer was
extracted with dichloromethane (7 x 10 mL). The organic
solution was dried over sodium sulfate before removal of the
6-Chloro-14-methyl-14-deoxyoxacyclododecindione ((±)-14).
Double-chlorinated compound (±)-14 was obtained as minor
byproduct from the above stated chlorination reaction. Rf: 0.24
(cyclohexane/EtOAc 2:1). tR (HPLC): 13.4 min (C18-PFP,
1
MeCN/H2O 36:65). H-NMR, COSY, NOESY (600 MHz, CD3CN):
δ/ppm = 7.51 (s, 1H, 5-OH), 7.20 (s, 1H, 7-OH), 6.45–6.43 (m,
1H, H-11), 4.71 (q, 1H, J = 6.5 Hz, H-15), 3.50–3.47 (m, 1H, HA-2),
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
3.31–3.19 (m, 1H, HB-2), 2.56–2.44 (m, 1H, HA-12), 2.16–2.11 completely consumed after 4 d. The solvent was removed
View Article Online
(m, 1H, HB-12), 1.92–1.87 (m, 1H, HA-13), 1.85–1.83 (m, 3H, under reduced pressure and the residue was purified by flash
DOI: 10.1039/D0OB00958J
10-CH3), 1.38–1.34 (m, 1H, HB-13), 0.99 (d, 3H, J = 6.5 Hz, chromatography (cyclohexane/EtOAc 4:1 + 1% HOAc) and
15-CH3), 0.85 (s, 3H, 14-CH3 ) 0.81 (s, 3H, 14-CH3 ). 13C-NMR, subsequent preparative HPLC (C18-PFP, MeCN/H2O 40:60),
HSQC, HMBC (151 MHz, CD3CN): δ/ppm = 196.1 (C-9), 167.1 yielding mono-brominated macrolactone (±)-17 (12.3 mg,
(C-1), 155.0 (C-11), 148.4 (C-7), 147.9 (C-5), 133.7 (C-10), 128.8 29.9 µmol, 50%, brown oil) as major product. Rf: 0.17 (cyclo-
(C-3), 121.5 (C-8), 112.7 (C-4), 107.4 (C-6), 77.0 (C-15), 37.2 hexane/EtOAc 2:1). tR (HPLC): 8.3 min (C18-PFP, MeCN/H2O
A
B
A
(C-2), 35.3 (C-14), 32.1 (C-13), 26.1 (14-CH3 ), 25.3 (C-12), 23.6 40:60). 1H-NMR, COSY, NOESY (600 MHz, CD3CN): δ/ppm = 7.45
B
(14-CH3 ), 13.3 (15-CH3), 8.5 (10-CH3). IR (ATR): /cm–1 = 3368, (s, 2H, 2 x OH), 6.48 (s, 1H, H-6), 6.43 (d, 1H, J = 11.3 Hz, H-11),
ν
2965, 2874, 1714, 1625, 1589, 1433, 1370, 1333, 1296, 1272, 4.74 (q, 1H, J = 6.5 Hz, H-15), 3.48 (d, 1H, J = 6.7 Hz, HA-2), 3.29–
1179, 1094, 1065, 951, 738. HRMS (ESI): m/z calcd. for 3.25 (m, 1H, HB-2), 2.53–2.46 (m, 1H, HA-12), 2.18–2.12 (m, 1H,
[C19H23(35Cl)2O5]+: 401.0923; found: 401.0917.
HB-12), 1.91–1.86 (m, 1H, HA-13), 1.82 (s, 3H, 10-CH3), 1.38–1.33
(m, 1H, HB-13), 1.01 (d, 3H, J = 6.5 Hz, 15-CH3), 0.85 (s, 3H, 14-
CH3 ), 0.81 (s, 3H, 14-CH3 ). 13C-NMR, HSQC, HMBC (151 MHz,
CD3CN): δ/ppm = 197.4 (C-9), 167.4 (C-1), 153.9 (C-11), 153.4
(COH), 153.0 (COH), 134.0 (C-10), 132.5 (C-3), 121.7 (C-8), 102.4
(C-4), 101.2 (C-6), 76.9 (C-15), 39.7 (C-2), 35.3 (C-14), 32.4
A
B
4-Fluoro-14-methyl-14-deoxyoxacyclododecindione ((±)-16).
A
solution of macrolactone (±)-15 (13.1 mg, 40.6 µmol,
1.00 eq.), Selectfluor® (20.8 mg, 58.7 µmol, 1.44 eq.) and tri-
fluoroacetic acid in N,N-dimethylformamide (2.2 mL) was
stirred at room temperature for 7 d. Water (3 mL) was added
and the aqueous layer was extracted with diethyl ether (6 x
3 mL). The organic layers were washed with water (2 x 2 mL)
and brine (2 mL), dried over sodium sulfate and the solvent was
removed under reduced pressure. After flash chromatography
(cyclohexane/EtOAc 2:1) and subsequent preparative HPLC
(C18-PFP, MeCN/H2O 35:65), ), a 3:2 mixture of fluorinated
compound (±)-16 and the starting material (±)-15 due to
incomplete conversion was obtained as a brown oil (in total
6.45 mg containing 3.93 mg of (±)-16, 11.2 µmol, 28%
(calculated based on 1H NMR)). The purest fractions were used
for biological evaluation (0.57 mg, please refer to the
supporting information). Rf: 0.19 (cyclohexane/EtOAc 2:1).
tR (HPLC): 12.2 min (C18-PFP, MeCN/H2O 35:65). 1H-NMR, COSY,
NOESY (600 MHz, CD3OD): δ/ppm = 6.53–6.49 (m, 1H, H-11),
6.39 (d, 1H, J = 7.2 Hz, H-6), 4.67 (q, 1H, J = 6.4 Hz, H-15), 3.48–
3.43 (m, 1H, HA-2), 3.16–3.11 (m, 1H, HB-2), 2.56–2.48 (m, 1H,
HA-12), 2.29–2.26 (m, 1H, HB-12), 1.94–1.84 (m, 4H, 10-CH3,
HA-13), 1.49–1.46 (m, 1H, HB-13), 1.07 (m, 3H, J = 6.4 Hz,
A
B
(C-13), 25.9 (14-CH3 ), 25.2 (C-12), 23.9 (14-CH3 ), 13.3 (15-CH3),
8.5 (10-CH3). IR (ATR): /cm–1 = 3341, 2965, 2928, 2872, 1728,
휈
1703, 1620, 1432, 1336, 1300, 1241, 1176, 1065, 1015, 948,
841. HRMS (ESI): m/z calcd. für [C19H24(79Br)O5]+: 411.0802;
found: 411.0789.
4,6-Dibromo-4-dechloro-14-methyl-14-deoxy-
oxacyclododecindione ((±)-18).
Dibrominated compound (±)-18 (10.7 mg, 21.8 µmol, 36%) was
obtained as minor product from the bromination reaction
described above as brown oil. Rf: 0.36 (cyclohexane/EtOAc 2:1).
tR (HPLC): 12.5 min (C18-PFP, MeCN/H2O 40:60). 1H-NMR, COSY,
NOESY (600 MHz, CD3CN): δ/ppm = 7.37 (s, 1H, OH), 7.15 (s, 1H,
OH), 6.47 (d, 1H, J = 11.2 Hz, H-11), 4.77 (q, 1H, J = 6.5 Hz, H-15),
3.50 (d, 1H, J = 16.8 Hz, HA-2), 3.35–3.32 (m, 1H, HB-2), 2.58–
2.50 (m, 1H, HA-12), 2.17–2.13 (m, 1H, HB-12), 1.96–1.89 (m, 1H,
HA-13), 1.87–1.86 (m, 3H, 10-CH3), 1.43–1.37 (m, 1H, HB-13),
A
1.04 (d, 3H, J = 6.5 Hz, 15-CH3), 0.87 (s, 3H, 14-CH3 ), 0.84 (s, 3H,
14-CH3 ). 13C-NMR, HSQC, HMBC (151 MHz, CD3CN): δ/ppm =
196.3 (C-9), 167.0 (C-1), 155.0 (C-11), 150.2 (COH), 149.6 (COH),
B
15-CH3), 0.90 (s, 3H, 14-CH3 ), 0.87 (s, 3H, 14-CH3 ). 13C-NMR,
HSQC, HMBC* (151 MHz, CD3OD): δ/ppm = 201.1 (C-9), 170.7
(C-1), 157.5 (very broad, C-11), 152.3 (C-5), 145.5 (d, J = 237.8
Hz, C-4), 137.0 (C-10), 121.4 (d, J = 15.7 Hz, C-8), 104.8 (C-6),
79.6 (C-15), 37.4 (C-14), 34.7 (C-2), 30.8 (br, C-13), 27.0 (C-12),
A
B
133.7 (C-10), 131.2 (C-3), 122.1 (C-8), 103.3 (C-4), 97.7 (C-6),
A
77.1 (C-15), 39.1 (C-2), 35.3 (C-14), 32.2 (C-13), 26.1 (14-CH3 ),
B
25.4 (C-12), 23.8 (14-CH3 ), 13.3 (15-CH3), 8.5 (10-CH3). IR (ATR):
/cm–1 = 3401, 2966, 2925, 2872, 1719, 1626, 1581, 1423, 1367,
휈
A
B
25.8 (14-CH3 ), 15.1 (15-CH3), 14.7 (br, 14-CH3 ), 10.4 (10-CH3).
1293, 1271, 1174, 1065, 1017. HRMS (ESI): m/z calcd. for
[C19H23(79Br)2O5]+: 488.9912; found: 488.9907.
IR (ATR): /cm–1 = 3340, 2966, 1725, 1621, 1455, 1266, 1156,
휈
1118, 1067, 736. HRMS (ESI, neg.): m/z calcd. for [C19H22FO5]–:
349.1444; found: 349.1451.
*The resonances of C-3 and C-7 could not be assigned due to
missing HMBC crosspeaks.
Allyl 2-bromobutanoate.
On the basis of a previously published procedure,7 a solution of
4-(dimethylamino)pyridine (1.22 g, 9.98 mmol, 5.0 mol%),
2-bromobutyric acid ((±)-19, 21.0 mL, 195 mmol, 1.00 eq.) and
allyl alcohol (16.4 mL, 240 mmol, 1.23 eq.) in dichloromethane
(150 mL) was treated at 0 °C with a solution of N,N’-dicyclo-
hexylcarbodiimide (40.2 g, 194 mmol, 1.00 eq.) in dichloro-
methane (30 mL). After stirring for 4 h at 0 °C, the mixture was
filtered over celite®. The solvent was removed carefully under
reduced pressure. Distillation yielded allyl 2-bromobutanoate
as colourless liquid (37.5 g, 181 mmol, 94%). Bp: 79–82 °C
(18 mbar), lit.: 189–193 °C (atm.)28. Rf: 0.30 (cyclohexane).
1H-NMR, COSY (300 MHz, CDCl3): δ/ppm = 5.92 (ddt, 1H, J =
4-Bromo-4-dechloro-14-methyl-14-deoxyoxacyclododecindione
((±)-17).
A 0.06 M solution of N-bromosuccinimide in N,N-dimethyl-
formamide (0.50 mL, 30 µmol, 0.50 eq.) was added to a solution
of macrolactone (±)-15 (20.0 mg, 60.2 µmol, 1.0 eq.) and
trifluoroacetic acid (10 µL, 0.13 mmol, 2.2 eq.) in N,N-dimethyl-
formamide (3 mL). Portions of NBS solution (each time 0.25 mL,
15 µmol, 0.25 eq.) were added to the mixture three times in
intervals of 24 h, until the starting material (±)-15 was
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J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
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2
17.3, 10.4, 5.7 Hz, OCH2CH=CH2), 5.40–5.33 (m, 1H, (OCH2CH=CH2), 133.1 (d, J = 9.3 Hz, o-CPh), 132V.2ie–w1A3rti1cl.e4On(lmine,
E
Z
3
Ph
1
OCH2CH=CH2 ), 5.29–5.24 (m, 1H, OCH2CH=CH2 ), 4.72–4.60 (m, p-CPh), 128.7 (d, J = 11.8 Hz, m-C ), 127.0 (d, J = 89.8 Hz,
2H, OCH2CH=CH2), 4.20–4.16 (m, 1H, H-2), 2.19–1.93 (m, 2H, ipso-CPh), 114.9 (OCH2CH=CH2), 61.6 (OCH2CH=CH2), 40.3 (d, 1J =
H-3), 1.02 (t, 3H, J = 7.3 Hz, H-4). 13C-NMR, HSQC, HMBC 178.1 Hz, C-2), 20.5 (d, 2J = 12.2 Hz, C-3), 18.5 (C-4). Rotamer B:
(75.5 MHz, CDCl3): δ/ppm = 169.4 (C-1), 131.3 (OCH2CH=CH2), 1H-NMR, COSY (400 MHz, DMSO-d6): δ/ppm = 7.65–7.54 (m,
118.9 (OCH2CH=CH2), 66.3 (OCH2CH=CH2), 47.5 (C-2), 28.4 (C-3), 15 H, HPh), 5.20–5.11 (m, 1H, OCH2CH=CH2), 4.61–4.57 (m, 1H,
DOI: 10.1039/D0OB00958J
11.9 (C-4). IR (ATR): /cm–1 = 3088, 2974, 2939, 2879, 1737, OCH2CH=CH2 ), 4.49–4.43 (m, 1H, OCH2CH=CH2 ), 4.03–4.00 (m,
1650, 1457, 1382, 1372, 1300, 1256, 1234, 1205, 1149, 1076, 2H, OCH2CH=CH2), 1.88–1.77 (m, 2H, H-3), 0.80–0.72 (m, 3H,
984, 931, 809, 750. HRMS (APPI): m/z calcd. for [C7H11(81Br)O2]+: H-4). 13C-NMR, HSQC, HMBC (101 MHz, DMSO-d6): δ/ppm =
205.9937; found: 205.9935.
(1-Allyloxy-1-oxobutan-2-yl)triphenylphosphonium bromide ((±)-
Z
E
휈
2
167.8 (d, J = 13.8 Hz, C-1), 134.2 (OCH2CH=CH2), 133.1 (d, J =
9.6 Hz, o-CPh), 132.2–131.4 (m, p-CPh), 128.7 (d, J = 11.8 Hz,
3
1
m-CPh), 127.7 (d, J = 89.6 Hz, ipso-CPh), 114.7 (OCH2CH=CH2),
20).
1
2
61.6 (OCH2CH=CH2), 39.0 (d, J = 169.0 Hz, C-2), 19.3 (d, J =
11.7 Hz, C-3), 17.7 (C-4). IR (ATR): /cm–1 = 3057, 2948, 2920,
2861, 1625, 1599, 1483, 1437, 1362, 1312, 1267, 1178, 1100,
1089, 1060, 1028, 736, 714, 694, 576, 519. HRMS (ESI): m/z
calcd. for [C25H26O2P]+: 389.1665; found: 389.1673.
Allyl 2-bromobutyrate (2.00 g, 7.40 mmol, 1.00 eq.) was added
under an argon atmosphere dropwise within 2 h to a boiling
suspension of triphenylphosphane (1.94 g, 7.40 mmol, 1.00 eq.)
in degassed water (32 mL). The resulting mixture was refluxed
for 18 h and washed with diethyl ether (2 x 2 mL). The aqueous
layer containing the phosphonium salt was evaporated to
dryness under reduced pressure, yielding (±)-20 as colourless
foam (3.27 g, 6.97 mmol, 94%). 1H-NMR, COSY (300 MHz,
휈
Allyl (2E)-7-([[3,5-Bis(benzyloxy)phenyl]acetyl]oxy)-2-ethyl-6,6-di-
methyloct-2-enoate ((±)-22).
CD3OD): δ/ppm = 7.95–7.73 (m, 15H, HPh), 5.69 (ddt, 1H, J = According to a previously published procedure,7 phosphonium
17.2, 10.3, 6.2 Hz, OCH2CH=CH2), 5.30–5.19 (m, 2H, ylide 21 (102 mg, 263 µmol, 1.00 eq.) was added to a solution
OCH2CH=CH2), 5.05 (ddd, 1H, J = 13.3, 11.4, 3.0 Hz, H-2, signal of aldehyde (±)-9 (83.5 mg, 175 µmol, 1.00 eq.) in dichloro-
vanishes after a few hours in CD3OD due to C-H acidity related methane (10 mL). The mixture was stirred at room temperature
deuterium exchange), 4.58–4.44 (m, 2H, OCH2CH=CH2), 2.21– overnight. As conversion of aldehyde (±)-9 was incomplete,
2.04 (m, 1H, HA-3), 2.02–1.87 (m, 1H, HB-3), 1.21–1.16 (m, 3H, further ylide 21 (14.6 mg, 37.5 µmol, 0.21 eq.) was added.
H-4). 13C-NMR, HSQC, HMBC (75.5 MHz, CD3OD): δ/ppm = Stirring was continued for 4 d at room temperature, then the
4
3
166.6 (C-1), 134.5 (d, J = 3.2 Hz, p-CPh), 133.3 (d, J = 10.0 Hz, solvent was removed under reduced pressure. The residue was
m-CPh), 129.8 (OCH2CH=CH2), 129.4 (d, 2J = 13.0 Hz, o-CPh), 118.7 purified by flash chromatography (cyclohexane/EtOAc 20:1)
(OCH2CH=CH2), 116.4 (d, 1J = 86.3 Hz, ipso-CPh), 66.4 yielding the unsaturated, (E)-configurated allyl ester as
(OCH2CH=CH2), 41.9 (very broad, C-2), 21.9 (d, 2J = 2.8 Hz, C-3), colourless oil (70.1 mg, 120 µmol, 67%). Rf: 0.59
10.9 (d, J = 15.2 Hz, C-4). IR (ATR): /cm–1 = 3407, 3053, 2985, (cyclohexane/EtOAc 3:1). 1H-NMR, COSY (600 MHz, CDCl3):
3
휈
2937, 2877, 2823, 1730, 1646, 1622, 1587, 1485, 1438, 1326, δ/ppm = 7.42–7.40 (m, 4H, o-HBn), 7.39–7.37 (m, 4H, m-HBn),
1270, 1221, 1178, 1109, 996, 754, 725, 692, 530, 515. HRMS 7.34–7.31 (m, 2H, p-HBn), 6.67 (t, 1H, J = 7.5 Hz, H-3), 6.55–6.54
(APCI): m/z calcd. for [C25H26O2P]+: 389.1665; found: 389.1659. (m, 2H, H-2’’, H-6’’), 6.53–6.52 (m, 1H, H-4’’), 5.95 (ddt, 1H, J =
17.2, 10.5, 5.6 Hz, OCH2CH=CH2), 5.34–5.30 (m, 1H,
E
Z
Allyl 2-(triphenylphosphoranylidene)butanoate (21).
OCH2CH=CH2 ), 5.23–5.21 (m, 1H, OCH2CH=CH2 ), 5.02 (s, 4H,
PhCH2), 4.76 (q, 1H, J = 6.4 Hz, H-7), 4.62–4.61 (m, 2H,
OCH2CH=CH2), 3.56–3.51 (m, 2H, H-2’), 2.29 (q, 2H, J = 7.5 Hz,
2-CH2CH3), 2.14–2.04 (m, 2H, H-4), 1.38–1.33 (m, 1H, HA-5),
1.29–1.24 (m, 1H, HB-5), 1.13 (d, 3H, J = 6.4 Hz, H-8), 1.00 (t, 3H,
J =7.5 Hz, 2-CH2CH3), 0.87 (s, 6H, 2 x 6-CH3). 13C-NMR, HSQC,
HMBC (151 MHz, CDCl3): δ/ppm = 170.8 (C-1’), 167.4 (C-1),
159.9 (C-3’’, C-5’’), 142.4 (C-3), 136.8 (ipso-CBn), 136.3 (C-1’’),
133.7 (C-2), 132.5 (OCH2CH=CH2), 128.6 (m-CBn), 128.0 (p-CBn),
127.5 (o-CBn), 117.8 (OCH2CH=CH2), 108.4 (C-2’’, C-6’’), 100.8
(C-4’’), 76.8 (C-7), 70.0 (PhCH2), 65.0 (OCH2CH=CH2), 42.1 (C-2’),
On the basis of a previously published procedure,7 a solution of
phosphonium bromide (±)-20 (3.08 g, 6.56 mmol) in
dichloromethane (150 mL) and aqueous sodium hydroxide
(0.1 M, 150 mL) was mixed at 0 °C. The biphasic system was
vigorously stirred for 2 h at room temperature. The aqueous
layer was extracted with dichloromethane (2 x 30 mL) and the
the organic solution was dried over magnesium sulfate. After
solvent removal under reduced pressure, phosphonium ylide
(±)-20 was obtained as yellow solid (2.50 g, 6.44 mmol, 98%).
Mp: 93–100 °C (dichloromethane). NMR-spectra of compound
(±)-20 in DMSO-d6 exhibit at room temperature a twofold set of
signals resulting from two rotamers A and B at the ratio of
1.1:1.0. However, an assignment of the 13C signals to the
corresponding rotamer was not possible in the range
132.0-131.4 ppm. Rotamer A: 1H-NMR, COSY (400 MHz,
DMSO-d6): δ/ppm = 7.65–7.54 (m, 15 H, HPh), 5.97–5.88 (m, 1H,
A
B
37.7 (C-5), 36.7 (C-6), 23.0 (6-CH3 ), 22.9 (C-4), 22.8 (6-CH3 ),
20.0 (2-CH2CH3), 14.6 (C-8), 14.0 (2-CH2CH3). IR (ATR): /cm
3033, 2967, 2936, 2874, 1710, 1594, 1453, 1291, 1247, 1228,
1157, 1059, 989, 934, 833, 736, 698. HRMS (ESI): m/z calcd. for
[C37H44O6Na]+: 607.3030; found: 607.3015.
–1
휈
=
E
(2E)-7-([[3,5-Bis(benzyloxy)phenyl]acetyl]oxy)-2-ethyl-6,6-tri-
methyloct-2-enoic acid.
According to a procedure by Kunz and März,27 allyl ester (±)-22
(363 mg, 629 µmol, 1.0 eq.), 1,3-dimethylbarbituric acid
OCH2CH=CH2), 5.31–5.26 (m, 1H, OCH2CH=CH2 ), 5.15–5.10 (m,
Z
1H, OCH2CH=CH2 ), 4.40–4.37 (m, 2H, OCH2CH=CH2), 1.88–1.77
(m, 2H, H-3), 0.80–0.72 (m, 3H, H-4). 13C-NMR, HSQC, HMBC
(101 MHz, DMSO-d6): δ/ppm = 169.3 (d, 2J = 19.0 Hz, C-1), 135.6
10 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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(116 mg, 743 µmol, 1.2 eq.), tetrakis(triphenylphosphine)- 122.8 (C-8), 105.6 (C-4), 99.0 (C-6), 77.6 (C-15), 69.1 (5-OCH2Ph),
View Article Online
palladium(0) (37 mg, 32 µmol, 5.0 mol%) and triphenyl- 68.9 (7-OCH2Ph), 37.9 (C-2), 35.3 (C-14),D3O2I:.810(.1C0-3193/D),02O6B.0509(1584J-
A
B
phosphane (182 mg, 694 µmol, 1.1 eq.) were solved under CH3 ), 24.8 (C-12), 22.9 (14-CH3 ), 16.8 (10-CH2CH3), 12.4
argon in THF (35 mL) and stirred overnight at room (15-CH3), 11.6 (10-CH2CH3). IR (ATR): /cm–1 = 3032, 2965, 2933,
휈
temperature. The solvent was removed under reduced pressure 2873, 1724, 1649, 1630, 1602, 1581, 1454, 1431, 1377, 1300,
and the residue was purified by flash chromatography 1277, 1264, 1226, 1154, 1135, 1054, 838, 749, 696. HRMS (ESI):
(cyclohexane/EtOAc 7:1 + 1% HOAc), yielding (2E)-7-([[3,5-Bis- m/z calcd. for [C34H39O5]+: 527.2792; found: 527.2774.
(benzyloxy)phenyl]acetyl]oxy)-2-ethyl-6,6-trimethyloct-2-enic
acid as colourless oil (327 mg, 616 µmol, 98%). Rf: 0.43 (cyclo-
hexane/EtOAc 3:1 + 1% AcOH). 1H-NMR, COSY (400 MHz, 4-Dechloro-10-ethyl-14-methyl-14-deoxy-
CDCl3): δ/ppm = 7.42–7.29 (m, 10H, HBn), 6.75 (t, 1H, J = 6.8 Hz, oxacyclododecindione.
H-3), 6.55–6.53 (m, 3H, H-2’’, H-4’’, H-6’’), 5.01 (s, 4H, PhCH2), According to previously published procedures,7 a solution of
4.76 (q, 1H, J = 6.4 Hz, H-7), 3.53 (s, 2H, H-2’), 2.27 (q, 2H, J = boron trichloride in dichloromethane (1 M, 3.70 mL, 3.70 mmol,
7.5 Hz, 2-CH2CH3), 2.13–2.06 (m, 2H, H-4), 1.39–1.21 (m, 2H, 9.95 eq.) was added dropwise at –78 °C to a solution of
H-5), 1.15 (d, 3H, J = 6.4 Hz, H-8), 1.00 (t, 3H, J = 7.5 Hz, 2- macrolactone (±)-23 (196 mg, 372 µmol, 1.00 eq.) in
CH2CH3), 0.87 (s, 6H, 2 x 6-CH3). 13C-NMR, HSQC, HMBC (101 dichloromethane (80 mL). After 1 h, saturated aqueous sodium
MHz, CDCl3): δ/ppm = 172.2 (C-1), 170.8 (C-1’), 160.0 (C-3’’, bicarbonate (50 mL) was added upon warming to room
C-5’’), 144.8 (C-3), 136.8 (ipso-CBn), 136.3 (C-1’’), 133.0 (C-2), temperature. The aqueous layer was extracted with
128.6 (m-CBn), 128.0 (p-CBn), 127.5 (o-CBn), 108.5 (C-2’’, C-6’’), dichloromethane (4 x 20 mL) and the combined organic layers
100.8 (C-4’’), 76.7 (C-7), 70.0 (PhCH2), 42.1 (C-2’), 37.5 (C-5), were dried over magnesium sulfate. The solvent was removed
A
B
36.7 (C-6), 23.1 (C-4), 23.0 (6-CH3 ), 22.8 (6-CH3 ), 19.7 (2- under reduced pressure and the residue was purified by flash
CH2CH3), 14.6 (C-8), 13.9 (2-CH2CH3). IR (ATR): /cm–1 = 3064, chromatography (cyclohexane/EtOAc 4:1), yielding 4-Dechloro-
휈
3033, 2967, 2935, 2874, 1723, 1681, 1594, 1452, 1377, 1292, 10-ethyl-14-methyl-14-deoxyoxacyclododecindione as colour-
1256, 1151, 1058, 947, 833, 735, 697. HRMS (ESI): m/z calcd. for less oil (112 mg, 323 µmol, 87%). Rf: 0.18 (cyclohexane/EtOAc
[C34H40O6Na]+: 567.2717; found: 567.2710.
2:1). 1H-NMR, COSY (300 MHz, CD3OD): δ/ppm = 6.42–6.41 (m,
1H, H-11), 6.28–6.26 (m, 1H, H-4), 6.25–6.24 (m, 1H, H-6), 4.52
(q, 1H, J = 6.4 Hz, H-15), 3.32–3.19 (m, 2H, H-2), 2.51–2.36 (m,
4H, H-12, 10-CH2CH3), 1.94–1.84 (m, 1H, HA-13), 1.51–1.43 (m,
1H, HB-13), 1.10–1.04 (m, 6H, 10-CH2CH3, 15-CH3), 0.91 (s, 6H, 2
x 14-CH3). 13C-NMR, HSQC, HMBC (75.5 MHz, CD3OD): δ/ppm =
200.4 (C-9), 170.0 (C-1), 158.3 (COH), 154.8 (COH), 153.2 (C-11),
140.7 (C-10), 132.8 (C-3), 118.5 (very broad, C-8), 106.6 (C-4),
100.4 (C-6), 77.7 (C-15), 38.1 (C-2), 35.4 (C-14), 34.6 (very broad,
5,7-Bis(benzyloxy)-4-dechloro-10-ethyl-14-methyl-14-deoxy-
oxacyclododecindione ((±)-23).
According to procedures from Roberts et al.9 and Opatz et al.,7
five round bottom flasks were each equipped with
dichloromethane (60 mL), trifluoroacetic acid (12 mL) and
trifluoroacetic anhydride (6 mL) and precooled to –8 °C. To
every flask, solutions of 53.4 mg (2E)-7-([[3,5-Bis(benzyloxy)-
phenyl]acetyl]oxy)-2-ethyl-6,6-trimethyloct-2-enic acid (267
mg, 489 µmol in total) in dichloromethane (1 mL) were added
and the flasks were left to stand at –8 °C for 4 d. The reaction
mixtures were combined, cautiously neutralized by washing
with saturated aqueous sodium bicarbonate (3 x 250 mL),
washed with brine (250 mL) and dried over magnesium sulfate.
The solvent was removed under reduced pressure and the
C-13), 24.6 (C-12), 24.1 (very broad, 2 x 14-CH3) 17.5 (10-
–1
휈
CH2CH3), 12.7 (15-CH3), 11.6 (10-CH2CH3). IR (ATR): /cm
=
3356, 2967, 2933, 2875, 1729, 1701, 1614, 1593, 1451, 1251,
1156, 1067, 1025, 842, 735, 701, 643, 591. HRMS (ESI): m/z
calcd. for [C20H27O5]+: 347.1853; found: 347.1854.
10-Ethyl-14-methyl-14-deoxyoxacyclododecindione ((±)-24).
According to a previously published procedure,7 a solution of
4-Dechloro-10-ethyl-14-methyl-14-deoxyoxacyclododecindi-
one (77.8 mg, 224 µmol, 1.0 eq.), N-chlorosuccinimide
(29.4 mg, 225 µmol, 1.0 eq.) and trifluoroacetic acid (17 µL,
0.34 mmol, 1.5 eq.) in N,N-dimethylformamide (9 mL) was
stirred for 8 d at room temperature under an argon
atmosphere. More N-chlorosuccinimide (6.0 mg, 45 µmol,
0.2 eq.) was added and stirring was continued for 3 d. The
solvent was removed under reduced pressure and the residue
was purified by flash chromatography (cyclohexane/EtOAc 3:1
+ 1% HOAc) and subsequent preparative HPLC (C18-PFP,
MeCN/H2O 40:60) yielding compound (±)-24 as colourless oil
(64.3 mg, 169 µmol, 75%). Rf: 0.08 (cyclohexane/EtOAc 4:1 + 1%
HOAc). tR (HPLC): 10.8 min (C18-PFP, MeCN/H2O 40:60).
1H-NMR, COSY, NOESY (600 MHz, CD3CN): δ/ppm = 6.50 (s, 1H,
H-6), 6.44 (s, 1H, H-11), 4.72 (q, 1H, J = 6.5 Hz, H-15), 3.50 (d,
1H, J = 16.7 Hz, HA-2), 3.28–3.20 (m, 1H, HB-2), 2.55–2.49 (m, 1H,
residue
was
purified
by
flash
chromatography
(cyclohexane/EtOAc 10:1) yielding macrolactone (±)-23 as
colourless solid (203 mg, 385 µmol, 79%). Mp: 112–113 °C
(cyclohexane/EtOAc). Rf: 0.58 (cyclohexane/EtOAc 3:1).
1H-NMR, COSY, NOESY (600 MHz, CD3OD): δ/ppm = 7.42–7.41
(m, 2H, HBn), 7.38–7.34 (m, 2H, HBn), 7.32–7.25 (m, 6H, HBn),
6.69–6.68 (m, 1H, H-6), 6.50–6.46 (m, 1H, H-4), 6.44–6.42 (m,
1H, H-11), 5.13–5.01 (m, 4H, PhCH2), 4.51–4.46 (m, 1H, H-15),
3.37–3.33 (m, 1H, HA-2), 3.21–3.19 (m, 1H, HB-2), 2.69–2.58 (m,
1H, HA-12), 2.52–2.47 (m, 1H, 10-CH2 CH3), 2.38–2.35 (m, 1H,
A
B
10-CH2 CH3), 2.27–2.18 (m, 1H, HB-12), 1.85–1.81 (m, 1H,
HA-13), 1.42–1.40 (m, 1H, HB-13), 1.02 (t, 3H, J = 7.5 Hz, 10-
CH2CH3), 0.88–0.83 (m, 9H, 2 x 14-CH3, 15-CH3). 13C-NMR, HSQC,
HMBC (151 MHz, CD3OD): δ/ppm = 199.2 (C-9), 169.3 (C-1),
159.3 (C-5), 156.0 (C-11), 155.9 (C-7), 140.0 (C-10), 136.2
(ipso-C5-Bn), 136.1 (ipso-C7-Bn), 132.2 (C-3), 127.4 (m-CBn), 127.2
(m-CBn), 126.9 (p-CBn), 126.7 (p-CBn), 126.4 (o-CBn), 126.2 (o-CBn),
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Journal Name
HA-12), 2.41–2.33 (m, 1H, 10-CH2CH3), 2.21–2.13 (m, 1H, HB-12), 10. E. J. Bourne, M. Stacey, J. C. Tatlow and J. M. Tedder, J. Chem.
View Article Online
1.89–1.85 (m, 1H, HA-13), 1.39–1.31 (m, 1H, HB-13), 1.21–0.99
Soc., 1951, 718-720.
DOI: 10.1039/D0OB00958J
(m, 6H, 10-CH2CH3, 15-CH3), 0.84 (s, 6H, a x 14-CH3). 13C-NMR, 11. B. Neises and W. Steglich, Angew. Chem. Int. Ed., 1978, 17,
HSQC, HMBC (151 MHz, CD3CN): δ/ppm = 197.3 (C-9), 167.5 522-524.
(C-1), 153.5 (C-11), 153.0 (C-5), 152.8 (C-7), 140.1 (C-10), 130.9 12. G. Wittig and U. Schöllkopf, Chem. Ber., 1954, 87, 1318-1330.
(C-3), 120.7 (C-8), 111.6 (C-4), 101.8 (C-6), 76.9 (C-15), 37.4 13. B. Neises and W. Steglich, Angew. Chem., 1978, 90, 556-557.
A
(C-2), 35.4 (C-14), 33.1 (C-13), 25.1 (14-CH3 ), 24.9 (C-12), 24.3 14. J. E. Boehmer, M. Phadte, A. Longstaff, J. A. Morris, T. R.
B
(14-CH3 ), 17.1 (10-CH2CH3), 13.4 (15-CH3), 12.2 (10-CH2CH3). IR
Desson, M. B. Hotson, A. J. Dowling, W. G. Whittingham, A. J.
Dalencon, P. J. De Fraine, R. J. G. Mondiere, S. Hachisu, A. J.
Thompson, V. G. Gopalsamuthiram (Syngenta International
AG), international patent, WO/2015/18434, 2015.
15. S. Elzner, D. Schmidt, D. Schollmeyer, G. Erkel, T. Anke, H.
Kleinert, U. Foerstermann and H. Kunz, ChemMedChem, 2008,
3, 924-939.
16. B. Bycroft and J. Roberts, J. Chem. Soc., 1962, 2063-2084.
17. J. R. Rachele, J. Org. Chem., 1963, 28, 2898-2898.
18. W. Theilacker and W. Schmid, Justus Liebigs Annalen der
Chemie, 1950, 570, 15-33.
(ATR): /cm–1 = 3338, 2968, 2935, 2875, 1727, 1612, 1436,
휈
1340, 1303, 1236, 1177, 1141, 1065, 1016, 946, 843, 667, 590.
HRMS (ESI, neg.): m/z calcd. for [C20H24(35Cl)O5]–: 379.1318;
found: 379.1321.
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was supported by the Rhineland Palatinate Natural
Products Research Center. We thank Dr. J. C. Liermann (Mainz)
for NMR spectroscopy, Dr. C. Kampf (Mainz) for high resolution
mass spectrometry and Dr. D. Schollmeyer (Mainz) for X-ray
crystal structure analysis. Parts of this research were conducted
using the supercomputer Mogon and/or advisory services
offered by Johannes Gutenberg University Mainz (hpc.uni-
mainz.de), which is a member of the AHRP (Alliance for High
Performance
Computing
in
Rhineland
Palatinate,
www.ahrp.info) and the Gauss Alliance e.V.
The authors gratefully acknowledge the computing time
granted on the supercomputer Mogon at Johannes Gutenberg
University Mainz (hpc.uni-mainz.de) and thank Jonathan Groß
for assistance on NMR elucidation.
Notes and references
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