Synthesis of the C19 methyl ether of aspercyclide A via germyl-Stille macrocyclisation and ELISA evaluation of both enantiomers following optical resolution

Article abstract of DOI:10.1039/c1ob05862b

Aspercyclide A (1) is a biaryl ether containing 11-membered macrocyclic natural product antagonist of the human IgE-FcεRI protein-protein interaction (PPI); a key interaction in the signal transduction pathway for allergic disorders such as asthma. Herein

Full text of DOI:10.1039/c1ob05862b

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PAPER
Synthesis of the C19 methyl ether of aspercyclide A via germyl-Stille
macrocyclisation and ELISA evaluation of both enantiomers following optical
resolution†
James L. Carr,a Jimmy J. P. Sejberg,a Fabienne Saab,b Mary D. Holdom,b Anna M. Davies,b
Andrew J. P. White,a Robin J. Leatherbarrow,a Andrew J. Beavil,b Brian J. Sutton,b Stephen D. Lindellc and
Alan C. Spivey*a
Received 31st May 2011, Accepted 4th July 2011
DOI: 10.1039/c1ob05862b
Aspercyclide A (1) is a biaryl ether containing 11-membered macrocyclic natural product antagonist of
the human IgE-FceRI protein-protein interaction (PPI); a key interaction in the signal transduction
pathway for allergic disorders such as asthma. Herein we report a novel approach to the synthesis of the
C19 methyl ether of aspercyclide A, employing a Pd(0)-catalysed, fluorous-tagged alkenylgermane/
arylbromide macrocyclisation (germyl-Stille reaction) as the key step, and evaluation of both
enantiomers of this compound via ELISA following optical resolution by CSP-HPLC. A crystal
structure for germyl hydride 27 is also reported.
The three compounds differed only in the nature of their ring
Introduction
A substituents R and R¢; aspercyclide A (1), for which R = CHO
In 2004, Singh et al. disclosed the structures of three biaryl ether
and R¢ = H, was shown via an enzyme-linked immunosorbent
containing 11-membered lactones [aspercyclides A (1), B (2) and C
assay (ELISA) to display the most potent antagonist activity
with an IC50 of 200 mM against the human IgE-FceRI protein-
protein interaction (PPI). This PPI constitutes a key link in the
(3)] that had been isolated following activity-guided fractionation
of a Tanzanian soil bacterium (Aspergillus sp.)1 (Fig. 1).
signal transduction pathway for human allergic reactions and
so compounds displaying such antagonistic activity constitute
interesting starting points for e.g. anti-asthma therapeutics.3–5
Following on from previous synthetic work on aspercyclides
B and C6 employing ring-closing metathesis (RCM) to effect
macrocyclisation,7,8 Fu¨rstner et al. reported the first synthesis of
(+)-aspercyclide A in 2009.9 They employed an intramolecular
Nozaki–Hiyama–Kishi (NHK) reaction to effect macrocyclisation
with concomitant anti-1,2-diol formation, although isolation of
clean product apparently proved troublesome. Subsequently, we
reported a synthesis of ( )-aspercyclide A and its C19 methyl
ether2 employing a Heck–Mizoroki macrocyclisation.10 We also
Fig. 1 Structures of natural (19R, 20S)-aspercyclides A–C (1–3).2
showed that the racemic C19 methyl ether derivative displayed
comparable activity to the synthetic racemic natural product using
aDepartment of Chemistry, South Kensington campus, Imperial College,
London, UK, SW7 2AZ. E-mail: a.c.spivey@imperial.ac.uk; Tel: +44 (0)20
75945841
an ELISA binding assay. We considered this finding significant as
our search for potentially more potent synthetic analogues of these
antagonists could therefore focus on C19 methyl ether derivatives
which, unlike those based on the natural product itself, would be
relatively easily accessible from commercially available acrolein
dimethylacetal with minimal protecting group manipulation.
To streamline our approach to the synthesis of analogues of
aspercyclide A C19 methyl ether having different substituent
patterns in both the A and B rings we were drawn to the possibility
of employing a fluorous-tagged germyl-Stille reaction to form
the macrocycle (instead of the Heck–Mizoroki reaction). This
bKing’s College London, The Randall Division of Cell and Molecular
Biophysics, New Hunt’s House, Guy’s Hospital Campus, London, UK, SE1
1UL
cBayer CropScience AG, Industriepark Ho¨chst G836, Frankfurt-am-Main,
D-65926, Germany
† Electronic supplementary information (ESI) available: crystallographic
analysis for compound 27 including CIF file and NMR spectra for
all new compounds. CCDC reference number 814148. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05862b
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Table 1 Optimisation of the Boeckman modified Takai–Utimoto
type of cross-coupling reaction features the use of a trialkylger-
manium group instead of the trialkylstannane group in a Pd(0)
mediated sp2–sp2-Stille-type bond forming reaction.11 Germanium
residues are essentially non-toxic (cf . tin residues),12 and C–Ge
bonds relatively apolar and therefore robust to basic/nucleophilic
conditions (cf . C–Sn and C–Si bonds),13 and we have previously
shown that these attributes facilitate synthetic strategies in which
a ‘safety-catch’ germanium group is introduced early in the
reaction sequence then activated for coupling when required.14,15
By incorporating a light-fluorous phase-tag as one of the germyl
substituents, parallel purification of intermediates by fluorous
solid phase extraction (F-SPE)16,17 prior to cross-coupling is
possible which is clearly advantageous for the rapid preparation
of analogues for structure–activity relationship (SAR) studies.
Moreover, when the fluorous-tagged germyl-Stille reaction is
employed as a cyclisation step, as envisioned here to install the
C16/C17 styrene linkage, then only cyclised products should be
‘released’ from the tag, thereby aiding their purification.
reaction
Isolated yield
of 8 (%)
Entry Modification
Scale (g)
d.r. (8 : 9)b
1
2
3
As precedenteda
TMSCl (6 eq.)
TMSCl (6 eq.), 60 h
0.1
1.0
1.0
6 : 1
9 : 1
7 : 1
9
41
56
a CrCl2 (0.07 eq.), Mn(0) (1.7 eq.), NaI (0.4 eq.), TMSCl (3.2 eq.), -30 ◦C,
16 h (ref. 18); b Determined by 1H NMR analysis.
electron rich para-quinol-derived A-ring at C16 this would couple
with a pendent alkenyl bromide/iodide. Consequently, our initial
target was ring A arylgermane/alkenyliodide 4a (Scheme 1). As
a fallback, we considered that the ‘reverse-polarity’ coupling
precursor comprising the ring A aryl bromide/alkenylgermane
4b constituted a promising alternative (Scheme 1). The C17
functionalised alkenes of both these precursors were envisaged
to be accessed from a C17–C18 alkyne which in turn would
be prepared by dibromination/bis-dehydrobromination of the
corresponding terminal alkene as used in our Heck–Mizoroki
macrocyclisation route.10
Herein, we describe our efforts to reduce this plan to practice.
Specifically, we describe our attempts to form a ring A C16
arylgermane/C17 alkenylbromide cyclisation precursor 4a and
our successful cyclisation of the ‘reversed polarity’ ring A C16
arylbromide/C17alkenylgermane substrate 4b to give macrocycle
5 using a germyl-Stille reaction (Scheme 1).
A Boeckman modified Takai–Utimoto condensation18–20 be-
tween hexanal and dimethyl acrolein was therefore used to access
the methyl ether protected anti-diol corresponding to the C17–C25
fragment of aspercyclide A C19 methyl ether (Table 1).10
In our hands, the published conditions18 failed to afford the
desired product efficiently but upon increasing the amount of
trimethylsilyl chloride (3.2 eq → 6 eq) and the reaction duration
(16 h → 60 h) allyl ether 8 was obtained with an acceptable crude
diastereoselectivity (7 : 1 d.r.) and subsequent isolated yield of 56%
(cf . 10.1 : 1 d.r. and yield 92% by Boeckman for the analogous
reaction of heptanal).18
Scheme 1 Two potential germyl-Stille macrocyclisations en route to
aspercyclide A C19 methyl ether.
We also attempted to perform an analogous condensation
between hexanal and the dimethyl acetal of propynal (data not
shown), which would have obviated the need for alkene to alkyne
conversion later in the synthesis, but this acetal was unreactive
under the reaction conditions and was recovered intact.21,22
2-Bromo-6-methyl benzoic acid (10),23 as required for esterifica-
tion to introduce ring B, is commercially available. This compound
was converted to the corresponding acid chloride 11 using oxalyl
chloride. Coupling of this compound with alcohol 8 via esterifi-
cation and subsequent dibromintion/bis-dehydrobromination24,25
was then carried out to give alkyne 17a (Scheme 2).
Although the macrocyclisation has not yet proved to be as
efficient as we would like, it has allowed for preparation of
aspercyclide A C19 methyl ether. Separation of the enantiomers
by chiral stationary phase (CSP) high performance liquid chro-
matography (HPLC) and evaluation of these via ELISA has also
been performed.
Results and discussion
Prior to the outset of this work we had shown that various aryl-
germanes could be activated by photo-oxidation in the presence
of a fluoride source to give difluorogermanes that participated
in efficient germyl-Stille cross-coupling with a variety of aryl
bromides, generating biaryls in moderate to excellent yields.14,15
Two reactivity trends were noted from this research: firstly, aryl
bromides are superior substrates to aryl iodides and, secondly,
electron-rich aryl germanes provide biaryls in higher yields than
electron deficient ones. Although we had not examined styrene
formation from the reaction of arylgermanes with alkenyl halides,
we anticipated that if we could install the germane on the
Esterification of alcohol 8 is difficult due to steric hindrance9
and required prior deprotonation using NaH then reflux with
acid chloride 11 (93% yield). Interestingly, bromination of alkene
12 at ambient temperature afforded a mixture of 1,2-dibromide
13 and 1,4-dibromide 14 in a 2 : 1 ratio. The latter compound
is presumably formed via intramolecular opening of the initial
bromonium ion by the ester carbonyl then ring-opening of the
resulting 1,3-dioxonium ion by bromide (Scheme 3).
We reasoned that cooling the reaction would lead to preferential
kinetic formation of the desired 1,2-dibromide 13. Gratifyingly,
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Scheme 4 Formation of alkenyl iodide 18.
Table 2 Optimisation of coupling to form model biaryl ether 22
Product distribution
Isolated yield
of 22 (%)
Entry
1a
Reagents (mol%)
(20 : 21 : 22)e
Pd(OAc)2 (3)
tert-Butyl XPhos (5)
K3PO4 (200)
Pd(OAc)2 (4)
Dave Phos (6)
NaH (220)
Cu2O (10)
Cs2CO3 (200)
Salox (20)
1 : 2.5 : 0
71% conversion
0
2b
3c
4d
1 : 2.5 : 0
71% conversion
0
Scheme 2 Formation of alkyne 17a.
0 : 1 : >20
70
72
(CuOTf)2·PhH (2.5)
Cs2CO3 (1.4)
EtOAc (5)
0 : 0 : 1
a 19 (1.2 eq.), toluene, 110 ◦C, 48 h (ref. 27).◦b 19 (1.2 eq.), toluene, 115 ◦C,
48 h (ref. 28). c 19 (1.5 eq.), acetonitrile, 110 C, 60 h (ref. 29). d 19 (1.4 eq.),
toluene, 110 ◦C, 60 h (ref. 30). e Determined by 1H NMR analysis.
sequently, we decided to perform preliminary optimisation of this
reaction using two model coupling partners: 2-tert-butylphenol 19
and iso-propyl benzoate 20 (Table 2).
Scheme 3 Plausible pathway for formation of 1,4-dibromide 14.
changing the solvent from chloroform to methylene chloride and
cooling the reaction to -78 ◦C resulted in a significantly improved
ratio in favour of 1,2-bromination (9 : 1, 13:14 → 72% and 8%
isolated yields, respectively). Treatment of 1,2-dibromide 13 with
DBU at room temperature resulted in rapid mono-elimination
affording alkenylbromides 15 and 16 in a 1 : 9 ratio. Microwave
irradiation (120 ◦C, 9 min) of this mixture resulted in complete
elimination of the major b alkenylbromide 16 to give the desired
terminal alkyne 17a (89% yield); the minor a-alkenylbromide 15
remained unaffected.
Although the plan for progressing alkyne 17a to give macro-
cyclisation precursor 4a was to effect biaryl ether formation with
a ring A phenol prior to conversion of the alkyne moiety to the
corresponding alkenyl iodide we considered it prudent to check
that alkenyl iodide formation was feasible at this stage. Pleasingly,
the transformation of chloroalkyne 17b to the corresponding (E)-
alkenyliodide 18 (58% yield) proceeded smoothly by sequential
addition of Schwartz’ reagent and molecular iodine26 (Scheme 4).
Our attention therefore turned to biaryl ether formation.
Cognisant that the proposed germyl-Stille macrocyclisation 4a →
5 (Scheme 1) requires ring A to contain the bulky trialkylgermane
unit ortho to the phenolic hydroxyl group we expected steric
hindrance to be a limiting factor in this coupling process. Con-
Thirteen sets of conditions employing palladium catalysts31
were explored in a parallel, but in no case was the desired
biaryl ether 22 produced (see ESI). In most cases no reaction
occurred, although in two cases oxidative addition was apparently
successful, with dehalogenated benzoate ester 2132 being isolated
(Table 2, entries 1 and 2). However, copper-catalysed Ullmann
biaryl ether formation33,34 was more successful: six variants of this
method were explored (see ESI), all gave some product and two
in particular gave clean conversion to product 22 (Table 2, entries
3 and 4), with the protocol developed by Buchwald30 providing
optimal results (biaryl ether 22 isolated in 72% yield, entry 4).
To assess the viability of using an ortho germyl phenol as a
substrate for this Ullmann coupling reaction, simple ring A model
compound 25 was prepared from 2-bromophenol 23 and fluorous-
tagged germylbromide 24 (Scheme 5).
Since direct bromine-germanium exchange on 2-bromophenol
23 proved impossible in our hands,21 germylation was achieved
via O-benzylation (97% yield), Barbier-type bromine-lithium
exchange/transmetallation with known germyl bromide 2414 (78%
yield), then debenzylation using borontribromide to give the target
germylphenol 25 (35% yield).35 This latter transformation was
extremely sensitive to trace amounts of HBr; the borontribromide
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Scheme 5 Synthesis of germylphenol 25 and subsequent attempted biaryl
ether formation.
was therefore stored over potassium carbonate and used immedi-
ately to limit the extent of ipso-protodegermylation.
Unfortunately, germylphenol 25 also proved too labile under
basic conditions to allow for Ullmann coupling to iso-propyl ester
20 under either the optimised Buchwald conditions (cf . Table
2, entry 4) or the conditions we subsequently employed during
our approach to aspercyclide A C19 methyl ether via Heck–
Mizoroki macrocyclisation using CuO and potassium carbonate
in pyridine.10,36 Under both conditions, rapid consumption of
germylphenol 25 was observed and control reactions established
that just cesium or potassium carbonate at elevated temperature
also resulted in degradation of germylphenol 25. It is likely that this
occurs via a [1,3]-germyl-Brook rearrangment37 and subsequent
protodegermylation to give phenol (cf . Scheme 5), although we
were unable to isolate the intermediate germylether.
Given this impasse, we decided to target the ‘reversed polarity’
coupling precursor 4b, containing the A ring aryl bromide and
alkenyl germane. For the synthesis of this macrocyclisation pre-
cursor it was envisaged that the alkenylgermane could be installed
prior to Ullmann biaryl ether formation via hydrogermylation of
alkyne 17a. The germyl hydride required for this hydrogermylation
reaction was prepared from the fluorous-tagged germylbromide
2410 by reduction with LiEt3BH38 (86% yield) and the alkyne
hydrogermylation itself was catalysed by Ru(CO)Cl(PPh3) under
conditions modified from those developed by Srebnik39 for hy-
droboration. The reaction proceeded to give alkenyl germane 28
in 57% yield with complete C17 regio and (E) stereocontrol as
judged by analysis of the 1H NMR spectrum of the crude reaction
mixture (Scheme 6).
Scheme 6 Synthesis of alkenylgermane 28, Ullmann coupling with
phenol 29, germyl-Stille macrocyclisation (4b → 5), and completion of
the synthesis of aspercyclide A C19 methyl ether (31).
Fig. 2 Molecular structure of germyl hydride 27 [HGe(CH22-Nap)2-
(CH2)2C8F17] (X-ray).
The structure of germyl hydride 27 was confirmed by a single
crystal X-ray structure determination (Fig. 2).
We were pleased to discover that alkenyl germane containing
aryl bromide 28 underwent chemoselective biaryl ether coupling
with functionalised phenol 29, using the CuO/K2CO3 in pyridine
conditions,10,36 to give macrocyclisation precursor 4b in 61% yield;
there was no evidence of alkenyl germane decomposition. The
stage was therefore set to examine the intramolecular germyl-Stille
reaction to form the C16/C17 styrene linkage.
After some experimentation, it was found that exposure of the
macrocyclisation substrate 4b to the photo-activation and germyl-
Stille cross-coupling conditions previously optimised by us for
biaryl formation [i.e. activation to the unisolated difluorogermane
using hn (pyrex filter), Cu(BF4)2 (2 ¥ 4.5 eq.), MeCN:MeOH (3 : 1),
2 ¥ 1 h, r.t., then immediate cross-coupling/macrocyclisation using
Pd(MeCN)2Cl2 (10 mol%), CuI (10 mol%), P(o-tol)3 (15 mol%),
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Table 3 Evaluation of the binding affinity of compounds (+)-31, (-)-31
and ( )-31 using IgE-FceRIa ELISAa
tagged methodology for the synthesis of this class of compound.
The enantiomers of aspercyclide A C19 methyl ether 31 have
also been separated by CSP-HPLC. ELISA studies on these
demonstrate that only the enantiomer (+)-31, having the same
(19R, 20S) configuration as natural (+)-aspercyclide A [(+)-1]
shows significant antagonist activity against the human IgE-
FceRI PPI (IC50 = 40 mM); the unnatural enantiomer (-)-31 is
at least 10-fold less active (IC50 = 483 mM).
Work is currently underway to optimise the structure of the
benzylic photoactivatable ligands on the alkenylgermane precur-
sor (cf. 2 ¥ 2-Nap groups currently) and the ensuing germyl-Stille
cross-coupling reaction conditions so as to allow for more efficient
macrocyclisations of the type 4b → 5 (cf . Scheme 6). It is hoped
that this will allow for preparation of arrays of synthetic analogues
aided by purification by fluorous SPE so as to aid our ongoing
experiments to map out the SAR for aspercyclide A and obtain
structural information about their interactions at the IgE-FceRI
PPI.
Entry
Compound (% e.e.)
IC50/mM
1
2
3
(+)-31 (98.4)
(-)-31 (98.8)
( )-31
40
483 105
56
1
2
a The ELISA binding assay was performed as described in the ESI. All the
titrations were performed twice in duplicate. The IC50 values were obtained
using KaleidagraphꢀR and calculated as described in the ESI.†
◦
TBAF (3.0 eq.), DMF, 48 h, 120 C]14,15 gave the desired
macrocycle 5, albeit along with degermylated product 30 in a
crude ratio of 1 : 2.2 and yields of 9% and 20%. Frustratingly,
no starting material could be recovered and the process has so far
resisted further optimisation despite the utility of fluorous SPE for
removing the fluorous-tagged germanium-containing by-product.
Finally, removal of the acetonide protecting group from macro-
cycle 5 to give ( )-aspercyclide B C19 methyl ether (aq. HCl,
94% yield) and then oxidation (MnO2, 84% yield) of the benzylic
alcohol furnished ( )-aspercyclide A C19 methyl ether 31 with
identical spectroscopic properties to those previously reported.10
Optical resolution of this racemic material by CSP-HPLC
using a Chiralpak IA column afforded (+)-aspercyclide A C19
methyl ether (+)-31 in 99.2 : 0.8 e.r. (i.e. 98.4% e.e.) as well
as its (-)-enantiomer (-)-31 in 99.4 : 0.6 e.r. (i.e. 98.8% e.e.).
Comparison of the CD spectra of these enantiomers with that
of natural (+)-aspercyclide A, as kindly supplied by Sheo B. Singh
(Merck Research Laboratories), confirmed that the dextrorotatory
(+)-enantiomer corresponded to the natural series, which has
previously been shown by Mosher ester derivatisation to have the
(19R, 20S) absolute configuration as drawn in Fig. 1.1
Experimental
For general experimental procedures and the single X-ray crystal
data please see the ESI.†
(3R*,4S*)-3-Methoxynon-1-en-4-ol (8)10 (Table 1, entry 3)
An oven-dried 250 mL round bottom flask was charged with
anhydrous CrCl2 (40 mg, 0.70 mmol), Mn(0) (930 mg, 16.97 mmol)
and NaI (300 mg, 2.00 mmol) in a nitrogen filled glove box.
Anhydrous THF (50 mL) was added and the resulting mixture
cooled to -30 ◦C for 20 min. Sequentially, via syringe, was added
freshly distilled TMS-Cl (7.65 mL, 59.88 mmol), freshly distilled
acrolein dimethyl acetal (30, 2.72 mL, 22.95 mmol) and freshly
distilled hexanal (1.20 mL, 9.98 mmol). The reaction mixture was
stirred at -30 ◦C for 60 h and then quenched at this temperature
with 1 M HCl (50 mL) before allowing to warm to r.t. The reaction
mixture was extracted with Et2O (3 ¥ 150 mL), with the organic
layers combined, washed with saturated aqueous sodium hydrogen
carbonate solution (50 mL), dried (Na2SO4), filtered, concentrated
in vacuo and purified by silica gel column chromatography, eluting
with EtOAc : petrol (1 : 50→1 : 25→1 : 10), to give diol derivative
810 as a colourless oil (962 mg, 5.59 mmol, 56%). IR (nmax, cm-1)
3470 (OH st, broad m), 2930 (s), 2860 (m), 1110 (s) and 760 (s);
1H NMR (400 MHz, CDCl3) dH 0.90 (t, 3H, J = 6.7 Hz, CH3),
1.27–1.54 (m, 8H, 4 ¥ CH2), 2.07 (broad s, 1H, OH), 3.33 (s, 3H,
OCH3), 3.52 (dd, 1H, J = 8.0 and 4.1 Hz, CH-OMe), 3.74-3.70
(dt, 1H, J = 7.6 and 4.1, CHOH), 5.22 (broad dd, 1H, J = 17.4 and
1.4 Hz, 1 ¥ CH2), 5.28 (dd, 1H, J = 10.4 and 1.4 Hz, 1 ¥ CH2)
and 5.74–5.83 (ddd, 1H, J = 17.4, 10.4 and 8.0 Hz, CH CH2);
13C NMR (100 MHz, CDCl3) dC 14.0 (q), 22.6 (t), 25.4 (t), 31.8
(t), 32.1 (t), 56.4 (q), 73.0 (d), 86.0 (d), 120.0 (t) and 134.2 (d). MS
(CI) m/z (rel. intensity) 238 (100%), 203 (30), 190 ([M+NH4]+, 90),
155 (20), 132 (40) and 114 (20); HRMS (CI+) Expected mass for
The ability of racemic aspercyclide A C19 methyl ether 31 and
both of its constituent enantiomers to inhibit the IgE-FceRI PPI
was assessed using ELISA as described previously (Table 3, see
also ESI).10
The dextrorotatory enantiomer (+)-31 was found to be an order
of magnitude more potent than the laevorotatory enantiomer
(-)-32 (IC50 = 40 mM cf . 483 mM; Table 3, entries 1 and 2).
We previously recorded racemic aspercyclide A C19 methyl ether
( )-31 as having an IC50 = 95 mM;10,40 when re-measured here in
parallel with its separated enantiomers we obtained a value of
56 mM (Table 3, entry 3). All these IC50 values are self-consistent
given the limitations of the assay and we interpret these data as
implicating the dextrorotatory enantiomer (+)-31, having the same
configuration as natural aspercyclide A [i.e. (+)-1] as being almost
exclusively responsible for the the antagonist activity towards the
IgE-FceRIa PPI (Table 3). That there is a significant difference in
the activity of the two enantiomers militates for a specific rather
than a non-specific binding event(s) underpinning their as yet
unknown mechanism of action at this important PPI interface.
+
Conclusions
C10H24NO2 (M+NH4 ) 190.1807, found 190.1809 (D = 1.1 ppm).
We have described a method for the preparation of aspercyclide
A C19 methyl ether 31 via an intramolecular germyl-Stille cross-
coupling macrocyclisation. Although this key step requires further
development if it is to be deployed for analogue preparation, the
synthesis provides proof of concept for the use of this fluorous-
2-Bromo-6-methylbenzoic acid (S*)-1-[(R*)-1-methoxy-allyl]hexyl
ester (12)10
To a stirred solution of diol derivative 8 (1.00 g, 5.92 mmol) in THF
(130 mL) at 0 ◦C was added sodium hydride (60% in mineral oil,
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1.39 g, 34.8 mmol). A solution of freshly prepared acid chloride
1110 (2.73 g, 11. 7 mmol) in THF (20 mL) was then added, and
the reaction mixture allowed to reach r.t. and then heated at reflux
for 2 h. The reaction mixture was then allowed to cool to r.t.,
diluted with Et2O (300 mL) and quenched with water (12 mL). The
mixture was washed with 0.1 M aq. HCl (250 mL) and saturated
aqueous sodium chloride solution (250 mL), and the organic layer
dried (MgSO4), filtered and concentrated in vacuo. Purification
of the resulting oil by silica gel column chromatography, eluting
with EtOAc : hexane (2 : 98), gave ester 12 a colourless oil (1.996
g, 5.40 mmol, 93%). A small sample was crystallised from Et2O
giving ester 1210 as colourless plates. Mp 31.1–33.9 ◦C (Et2O); IR
(nmax, cm-1) 2930 (m), 1730 (C O st, s), 1270 (s), 1100 (s) and 1070
(m); 1H NMR (400 MHz, CDCl3) dH 0.88 (t, 3H, J = 7.2 Hz, CH3),
1.24–1.45 (m, 4H, 2 ¥ CH2), 1.58–1.67 (m, 2H, CH2), 1.73–1.83
(m, 2H, CH2), 2.37 (s, 3H, ArCH3), 3.33 (s, 3H, OCH3), 3.85 (ddt,
1H, J = 8.2, 3.2 and 0.8 Hz, CH-OMe), 5.27 (dt, 1H, J = 8.2 and
3.7 Hz, CHOCOAr), 5.35 (ddd, 1H, J = 10.7, 1.2 and 0.8 Hz, 1 ¥
CH2), 5.35 (ddd, 1H, J = 17.0, 1.2 and 1.2 Hz, 1 ¥ CH2), 5.77
(ddd, 1H, J = 17.0, 10.7 and 7.6 Hz, CH CH2), 7.12 (d, 1H, J =
6.0 Hz, ArH), 7.13 (d, 1H, J = 3.1 Hz, ArH) and 7.38 (dd, 1H,
J = 6.0 and 3.1 Hz, ArH). 13C NMR (100 MHz, CDCl3) dC 14.0
(q), 19.7 (q), 22.5 (t), 25.2 (t), 28.8 (t), 31.6 (t), 56.6 (q), 76.8 (d),
83.5 (d), 118.8 (s), 119.8 (t), 128.9 (d), 129.9 (d), 130.2 (d), 134.3
(d), 136.3 (s), 136.9 (s) and 167.8 (s). MS (CI) m/z 388 [81BrM +
NH4]+ (90%), 386 [79BrM + NH4]+ (90), 371 [81BrM + H]+ (50),
369 [79BrM + H]+ (50), 355 (20), 339 [M - OMe]+ (20), 337 [M -
OMe]+ 308 (20), 291 (20), 276 (25), 202 (60), 199 [C8H781BrO] (20),
197 [C8H7 79BrO]+ (20) 155 [C10H19O]+ (100), 140 (30) and 52 (25).
HRMS (CI) Expected mass for C18H26O3Br (M + H+) 369.1059,
found 369.1065 (D = 1.6 ppm).
31.7 (t), 32.0 (t), 52.9 (d), 61.4 (q), 77.5 (d), 79.0 (d), 118.9 (s), 129.1
(d), 130.0 (d), 130.5 (d), 135.8 (s), 136.9 (s) and 167.2 (s). MS (CI)
m/z 548 ([79,81,81BrM+NH4]+, 30%), 546 ([79,79,81BrM+NH4]+, 30%),
388 ([81BrM+NH4-Br2]+, 100), 386 ([79BrM+NH4-Br2]+, 100), 371
([81BrM+H-Br2]+, 25), 369 ([79BrM+H-Br2]+, 25), 342 (15), 308
([M+NH4-Br3]+,15), 291 ([M+H-Br3]+, 20), 202 (30) and 155
+
(35). HRMS (CI) Expected mass for C18H29NO6Br3 (M+NH4 )
543.9698, found 543.9709 (D = 2.1 ppm).
1,4-Dibromide 14 as an undetermined single diastereomer and
as a colourless oil (6 mg, 0.01 mmol, 8%). IR (nmax, cm-1) 2930
(m), 1740 (C O st, s), 1450 (m), 1270 (s) and 1100 (s); 1H NMR
(400 MHz, CDCl3) dH 0.90 (t, 3H, J = 6.8 Hz, CH3), 1.31–
1.36 (m, 6H, 3 ¥ CH2), 1.87–2.05 (m, 2H, CH2), 2.40 (s, 3H,
ArCH3), 3.63 (s, 3H, OCH3), 3.72 (dd, 1H, J = 6.7 and 3.7 Hz,
CH-OMe), 3.74 (dd, 1H, J = 11.8 and 3.9 Hz, 1 ¥ CHBr), 3.91
(dd, 1H, J = 11.8 and 4.4 Hz, 1 ¥ CHBr), 4.19 (ddd, 1H, J =
6.7, 4.4 and 3.9 Hz, CHOCOAr), 5.51 (ddd, 1H, J = 6.0, 4.4
and 3.7 Hz, CHBr), 7.17 (d, 1H, J = 3.5 Hz, ArH), 7.17 (d,
1H, J = 5.5 Hz, ArH) and 7.41 (dd, 1H, J = 5.5 and 3.5 Hz,
ArH); 13C NMR (100 MHz, CDCl3) dC 14.0 (q), 19.7 (q), 22.5
(t), 27.2 (t), 30.5 (t), 31.2 (t), 35.5 (t), 55.3 (d), 62.0 (q), 75.8
(d), 82.2 (d), 118.8 (s), 129.0 (d), 129.9 (d), 130.7 (d), 135.4 (s),
136.8 (s) and 167.3 (s); MS (CI) m/z 548 ([79,81,81BrM+NH4]+,
100%), 546 ([79,79,81BrM+NH4]+, 100), 468 ([M+NH4-Br]+, 10),
388 ([81BrM+NH4-Br2]+, 20), 386 ([79BrM +NH4-Br2]+, 20),
371 ([81BrM +H-Br2]+, 30), 369 ([81BrM+H-Br2]+, 30), 339
([C10H26Br2O+NH4]+, 35), 337 ([C10H26Br2O+NH4]+, 35), 293 (30),
259 (10), 199 ([C8H681BrO]+, 25), 197 ([C8H679BrO]+, 25), 155
([C10H19O]+, 45), 140 ([C9H16O]+, 25), 124 (50), 119 (50) and 52
+
(30); HRMS (CI) Expected mass for C18H29NO6Br3 (M+NH4 )
543.9698, found 543.9708 (D = 1.9 ppm).
2-Bromo-6-methylbenzoic acid (S*)-1-[(S*)-2,3-dibromo-1-
methoxypropyl]hexyl ester (13) and 2-bromo-6-methylbenzoic acid
(2R*,3R*)-3-bromo-1-bromomethyl-2-methoxyoctyl ester (14)
2-Bromo-6-methylbenzoic acid (S*)-1-[(R*)-1-methoxyprop-2-
ynyl]hexyl ester (17a)
To a solution of 1,2-dibromide 13 (21 mg, 0.04 mmol) in
MeCN (200 mL) in a microwave vial was added DBU (36 mL,
0.24 mmol). Upon addition the reaction darkened significantly,
presumably as mono-elimination occurred. The vial was trans-
ferred to the microwave apparatus and heated to 100 ◦C for
30 min then 120 ◦C for 20 min. The reaction mixture was
diluted with Et2O (5 mL) and washed with saturated aqueous
ammonium chloride solution (2 ¥ 5 mL), dried (Na2SO4), filtered
and concentrated in vacuo. Purification of the resulting oil by
silica gel column chromatography, eluting with EtOAc : petrol
(0 : 1→1 : 100→1 : 50→3 : 100→1 : 25→1 : 20), gave alkyne 17a as
a colourless oil (13 mg, 0.04 mmol, 89%). IR (nmax, cm-1) 2930
(m), 1730 (C O st, s), 1450 (m), 1270 (s), and 1100 (s); 1H NMR
(400 MHz, CDCl3) dH 0.90 (t, 3H, J = 5.6 Hz, CH3), 1.28–1.38 (m,
6H, 3 ¥ CH2), 1.80–1.92 (m, 2H, CH2), 2.37 (s, 3H, ArCH3), 2.51
(app s, 1H, CH) 3.46 (s, 3H, OCH3), 4.31 (dd, 1H, J = 3.6 and
2.0 Hz, CH-OMe), 5.33 (dt, 1H, J = 8.8 and 3.6 Hz, CHOCOAr),
7.14 (d, 1H, J = 5.4 Hz, ArH), 7.14 (d, 1H, J = 4.2 Hz, ArH) and
7.38 (dd, 1H, J = 5.4 and 4.2 Hz, ArH). 13C NMR (100 MHz,
CDCl3) dC 14.0 (q), 19.7 (q), 22.5 (t), 25.2 (t), 28.8 (t), 31.5 (t),
57.0 (q), 72.4 (d), 76.0 (2d), 79.0 (s), 118.9 (s), 129.0 (d), 129.9
(d), 130.4 (d), 136.0 (s), 137.0 (s) and 167.6 (s). MS (EI) m/z 368
([81BrM]+, 15%), 366 ([81BrM]+, 15), 299 (20), 297 (20), 279 (15),
268 (15), 266 (15), 199 ([C8H681BrO]+, 100), 197 ([C8H679BrO]+,
To a cooled solution of alkene 12 (50 mg, 0.14 mmol) in CH2Cl2
(1 mL) at -78 ◦C was added, dropwise, a cooled solution of
Br2 (8 mL, 0.15 mmol) in CH2Cl2 (0.5 mL) at -78 ◦C via a
dry-ice cooled cannula. Upon complete addition the reaction
mixture was stirred at -78 ◦C for 1 h, before warming to r.t.
The reaction mixture was then stirred with saturated aqueous
sodium thiosulfate solution (5 mL) for 5 min before extraction
with Et2O (2 ¥ 5 mL). The organic layers were combined and
washed with saturated aqueous sodium chloride solution (10 mL),
dried (Na2SO4), filtered and concentrated in vacuo. Purification of
the resulting oil by silica gel column chromatography, eluting with
EtOAc : petrol (0 : 1→1 : 100→1 : 50→3 : 100→1 : 25), gave:
1,2-Dibromide 13 as an undetermined single diastereomer and
as a colourless oil (52 mg, 0.10 mmol, 72%). IR (nmax, cm-1) 2930
(s), 1730 (C O st, s), 1450 (m), 1270 (s), and 1100 (s); 1H NMR
(400 MHz, CDCl3) dH 0.91 (t, 3H, J = 7.0 Hz, CH3), 1.30–1.38 (m,
6H, 3 ¥ CH2), 1.78–1.87 (m, 1H, 1 ¥ CH), 1.99–2.08 (m, 1H, 1 ¥
CH), 2.38 (s, 3H, ArCH3), 3.67 (s, 3H, OCH3), 3.87–3.94 (m, 2H,
CH2Br), 3.98 (dd, 1H, J = 6.3 and 1.7 Hz, CH-OMe), 4.50 (ddd,
1H, J = 11.2, 4.8 and 1.7 Hz, CHBr), 5.92 (ddd, 1H, J = 7.6, 6.3 and
3.2 Hz, CHOCOAr), 7.17 (d, 1H, J = 5.2 Hz, ArH), 7.17 (d, 1H, J =
4.1 Hz, ArH) and 7.41 (dd, 1H, J = 5.2 and 4.1 Hz, ArH). 13C NMR
(100 MHz, CDCl3) dC 14.1 (q), 19.9 (q), 22.6 (t), 25.0 (t), 30.0 (t),
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100), 171 ([C7H681Br]+, 15), 169 ([C7H679Br]+, 15), 153 ([C10H17O]+,
20) and 90 (20); HRMS (EI) Expected mass for C18H23O3Br (M+)
366.0826, found 366.0831 (D = 1.2 ppm).
(s), 136.6 (s) and 167.4 (s); MS (CI) m/z 276 ([81BrM+NH4]+,
100%), 274 ([79BrM+NH4]+, 100), 259 ([81BrM+H]+, 20), 257
([79BrM+H]+, 20), 198 ([C8H681BrO]+, 10) and 196 ([C8H679BrO]+,
+
10); HRMS (CI) Expected mass for C11H17NO2Br (M+NH4 )
274.0456, found 274.0443 (D = 4.9 ppm).
2-Chloro-6-methylbenzoic acid (S*)-1-[(E)-(R*)-3-iodo-1-
methoxyallyl]hexyl ester (18)
2-(2-tert-Butylphenoxy)-6-methylbenzoic acid isopropyl ester (22)
(Table 2, entry 4)
To a cooled solution of alkyne 17b21 (27 mg, 0.08 mmol) in
THF (1 mL) at 0 ◦C was added Schwartz’s reagent (27 mg,
0.11 mmol) and the resulting mixture allowed to stir at this
temperature for 2 h. After this time a cooled solution of I2
(42 mg, 0.17 mmol) in THF (1 mL) at 0 ◦C was added via
cannula and the reaction mixture allowed to reach r.t. over
16 h. The reaction mixture was partitioned between hexane and
water (3 : 1 v/v, 20 mL), then washed with saturated aqueous
sodium sulfite solution (10 mL) and saturated aqueous sodium
chloride solution (10 mL). The organic layer was dried (Na2SO4),
filtered, concentrated in vacuo and purified by PLC eluting with
CH2Cl2 : heptane : toluene (3 : 6 : 1) to give alkenyl iodide 18 as a
colourless oil (22 mg, 0.05 mmol, 58%). IR (nmax, cm-1) 2930 (w),
An oven-dried reaction vial was charged with a stirrer bar, phenol
19 (54 mL, 0.35 mmol, 1.4 eq.), aryl bromide 20 (64 mg, 0.25 mmol,
1.0 eq.), (CuOTf)2·PhH (3.1 mg, 0.06 mmol, 2.5 mol%), EtOAc
(1 drop) and Cs2CO3 (114 mg, 0.35 mmol, 1.4 eq.). The vial
was equipped with a Suba-seal, then repeatedly evacuated and
purged with nitrogen (¥ 5) before addition of toluene (0.5 mL).
The Suba-seal was then replaced by a screw cap under a flow
of nitrogen, and the reaction mixture was heated at 110 ◦C
for 60 h. After this time the reaction was allowed to cool to
R
r.t., filtered through a pad of Celiteꢀ, washed with acetone
and concentrated in vacuo. Purification was accomplished by
silica gel column chromatography, eluting with EtOAc : heptane
(1 : 100→1 : 50→3 : 100→1 : 25→1 : 20), to give biaryl ether 22 as
a golden oil (59 mg, 0.18 mmol, 72%). IR (nmax, cm-1) 2960 (m),
1
1730 (C O st, s), 1270 (s), 1110 (s) and 1070 (m); H NMR
(500 MHz, CDCl3) dH 0.89 (t, 3H, J = 7.0 Hz, CH3), 1.27–1.37 (m,
4H, 2 ¥ CH2), 1.57–1.65 (m, 2H, CH2), 1.69–1.90 (m, 2H, CH2),
2.35 (s, 3H, ArCH3), 3.34 (s, 3H, OCH3), 3.80 (dd, 1H, J = 6.4 and
3.9 Hz, CH-OMe), 5.26 (dt, 1H, J = 9.2 and 3.9 Hz, CHOCOAr),
6.46 (d, 1H, J = 14.6 Hz, CHI), 6.52 (dd, 1H, J = 14.6 and 6.4 Hz,
CH CHI), 7.11 (dd, 1H, J = 4.5 and 5.3 Hz, ArH), 7.21 (d, 1H,
J = 5.3 Hz, ArH) and 7.22 (d, 1H, J = 4.5 Hz, ArH); 13C NMR
(125 MHz, CDCl3) dC 14.0 (q), 19.6 (q), 22.5 (t), 25.0 (t), 29.3 (t),
31.6 (t), 57.0 (q), 75.6 (d), 81.0 (d), 84.6 (d), 126.8 (d), 128.4 (d),
130.1 (d), 130.4 (s), 133.9 (s), 136.8 (s), 142.3 (d) and 167.0 (s); MS
(CI) m/z 470 ([37ClM+NH4]+, 30%), 468 ([35ClM+NH4]+, 90), 451
([35ClM+H]+, 10), 421 ([37ClM-OMe]+, 30), 419 ([35ClM-OMe]+,
90), 342 ([37ClM-I+NH4]+, 40), 340 ([35ClM-I+NH4]+, 90), 323
([M-I]+, 40), 153 ([C8H6OCl]+, 60) and 52 (100); HRMS (CI)
1
1730 (C O st, s), 1460 (m), 1270 (s) and 1100 (m); H NMR
(400 MHz, CDCl3) dH 1.26 (d, 6H, J = 6.2 Hz, CH(CH3)2), 1.40 (s,
9H, C(CH3)3), 2.38 (s, 3H, ArCH3), 5.23 (septet, 1H, J = 6.2 Hz,
CH(CH3)2), 6.61 (app d, 1H, J = 8.0 Hz, ArH), 6.81 (dd, 1H, J =
8.0 and 1.5 Hz, ArH), 6.92 (dt, 1H, J = 8.0 and 0.8 Hz, ArH),
7.03 (ddd, 1H, J = 7.5, 7.1 and 1.5 Hz, ArH), 7.12 (ddd, 1H, J =
8.0, 7.1 and 1.7 Hz, ArH), 7.17 (t, 1H, J = 8.0 Hz, ArH) and 7.37
(dd, 1H, J = 7.5 and 1.7 Hz, ArH); 13C NMR (100 MHz, CDCl3)
dC 19.2 (q), 21.8 (2q), 30.2 (3q), 34.7 (s), 68.9 (d), 115.8 (d), 120.0
(d), 123.2 (d), 124.5 (d), 127.0 (d), 127.1 (s), 127.2 (d), 130.1 (d),
136.7 (s), 140.6 (s), 154.4 (s), 155.9 (s) and 167.4 (s); MS (CI) m/z
344 (70%, [M + NH4]+), 327 (100, [M + H]+), 302 (10, [M + NH4
- C3H6]+), 251 (10), 216 (25), 148 (20) and 52 (10); HRMS (ES+)
Expected mass for C21H27O3 (M + H+) 327.1973, found 327.1960
(D = 4.0 ppm).
+
Expected mass for C18H28NO3ClI (M+NH4 ) 468.0802, found
468.0805 (D = 0.5 ppm).
2-Bromo-6-methylbenzoic acid isopropyl ester (20)
2-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)bis-
(naphthalen-2-ylmethyl)germylphenol (25)
To a stirred solution of benzoic acid 10 (3.02 g, 14.04 mmol) in
DMF (50 mL) at r.t. was added K2CO3 (5.81 g, 42.04 mmol)
and 2-bromopropane (1.90 g, 15.45 mmol, 1.1 eq.), and the
resulting mixture heated at 50 ◦C for 16 h. After this time the
reaction mixture was allowed to cool to r.t., diluted with water
(50 mL) and extracted with CH2Cl2 (2 ¥ 20 mL). The combined
organic fractions were then washed with saturated aqueous
sodium carbonate solution (3 ¥ 20 mL) and saturated aqueous
sodium chloride solution (3 ¥ 20 mL), dried (Na2SO4), filtered and
concentrated in vacuo. The resulting pale yellow oil was purified by
silica gel column chromatography, eluting with EtOAc : heptane
(1 : 50→3 : 100→1 : 25→1 : 20), to give isopropylester 20 as a
colourless oil (3.57 g, 13.88 mmol, 99%). IR (nmax, cm-1) 2980 (w),
Step 1. To a solution of 2-bromophenol 23 (670 mL, 5.78 mmol)
in DMF (10 mL) was added K2CO3 (879 mg, 6.36 mmol) and
benzyl bromide (687 mL, 5.78 mmol). The resulting suspension
was stirred at 60 ◦C for 16 h. After this time the reaction mixture
was diluted with Et2O (30 mL), washed with saturated aqueous
sodium hydrogen carbonate solution (2 ¥ 25 mL) and saturated
aqueous sodium chloride solution (5 ¥ 50 mL). The organic layer
was dried (Na2SO4), filtered and concentrated in vacuo and the
resulting oil purified by silica gel column chromatography, eluting
with Et2O : petrol (1 : 20), to give 1-bromo-2-benzyloxybenzene41 as
a pale yellow oil (1.47 g, 0.56 mmol, 97%). 1H NMR (400 MHz,
CDCl3) dH 5.17 (s, 2H, CH2Ar), 6.85 (dt, 1H, J = 7.7 and 1.5 Hz,
ArH), 6.94 (dd, 1H, J = 8.0 and 1.5 Hz, ArH), 7.24 (ddd, 1H,
J = 8.0, 7.7 and 1.7 Hz, ArH), 7.31–7.35 (m, 1H, ArH), 7.38–7.42
(m 2H, 2 ¥ ArH), 7.47–7.50 (m, 2H, 2 ¥ ArH) and 7.57 (dd, 1H,
J = 7.7 and 1.7 Hz, ArH); MS (EI) m/z 264 ([81BrM]+, 10%), 262
([79BrM]+, 10), 91 ([C7H7]+, 100) and 65 (20).
1
1730 (s), 1280 (s), 1100 (m) and 1070 (w); H NMR (400 MHz,
CDCl3) dH 1.40 (d, 6H, J = 5.7 Hz, CH(CH3)2), 2.34 (s, 3H,
ArCH3), 5.34 (septet, 1H, J = 5.7 Hz, CH(CH3)2), 7.13 (d, 1H,
J = 5.6 Hz, ArH), 7.14 (d, 1H, J = 3.2 Hz, ArH) and 7.39 (dd, 1H,
J = 5.6 and 3.2 Hz, ArH); 13C NMR (100 MHz, CDCl3) dC 19.5 (q),
21.8 (2q), 69.5 (d), 118.9 (s), 128.9 (d), 129.9 (d), 130.2 (d), 136.3
6820 | Org. Biomol. Chem., 2011, 9, 6814–6824
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Step 2. To a cooled solution of 1-bromo-2-benzyloxybenzene
(54 mg, 0.20 mmol) and germyl bromide 24 (150 mg, 0.17 mmol) in
THF (5 mL) was added, dropwise, a solution of t-BuLi in hexanes
(1.06 M, 384 mL, 0.408 mmol) at -78 ◦C. The resulting mixture was
HRMS (EI) Expected mass for C38H27O74GeF17 (M+) 896.1008,
found 896.1002 (D = 0.6 ppm).
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)bis-
(naphthalen-2-ylmethyl)germane (27)
◦
stirred vigorously at -78 C for 1 h. After this time the reaction
was allowed to warm to r.t., diluted with Et2O (20 mL) and washed
with saturated aqueous ammonium chloride solution (2 ¥ 20 mL)
and saturated aqueous sodium chloride solution (2 ¥ 20 mL). The
organic layer was dried (Na2SO4), filtered, concentrated in vacuo
and purified by silica gel column chromatography, eluting with
EtOAc : petrol (0 : 1→1 : 100→1 : 50→3 : 100→1 : 25→1 : 20), to
give (2-benzyloxyphenyl)bis-naphthalen-2-ylmethyl-(3,3,4,4,5,5,
6,6,7,7,8,8,9,9,10,10,11,11,11-nonadecafluoroundecyl)germane as
a pale yellow oil (130 mg, 0.131 mmol, 78%). IR (nmax, cm-1)
To a stirred solution of germyl bromide 2410 (396 mg, 0.45 mmol) in
R
THF (4 mL) was added a solution of LiEt3BH (Superhydrideꢀ) in
THF (494 mL, 0.45 mmol, 1.0 M) at r.t. The reaction mixture was
stirred for 3 h before being diluted with Et2O (5 mL), washed with
saturated aqueous sodium hydrogen carbonate solution (10 mL),
dried (Na2SO4), filtered and concentrated in vacuo. The resulting
white solid was recrystallized from hot hexane to give germyl
hydride 27 as colourless needles (310 mg, 0.39 mmol, 86%). Mp
62.8–68.4 ◦C (hexane); IR (nmax, cm-1) 2040 (w), 1200 (s), 1150 (s),
1110 (m) and 1070 (m); 1H NMR (400 MHz, CDCl3) dH 1.01–1.06
(m, 2H, GeCH2CH2), 1.84–1.97 (m, 2H, GeCH2CH2), 2.54 (dd,
2H, J = 12.8 and 2.9, CH2Nap), 2.59 (dd, 2H, J = 12.8 and 2.9 Hz,
CH2Nap), 4.28 (quintet, 1H, J = 2.9 Hz, GeH), 7.17 (dd, 2H, J =
8.4 and 2.0 Hz, 2 ¥ ArH), 7.39 (dt, 2H, J = 7.7 and 1.3 Hz, 2 ¥
ArH), 7.44 (br s, 2H, 2 ¥ ArH), 7.44 (dt, 2H, J = 7.7 and 1.5 Hz,
2 ¥ ArH), 7.68 (br d, 2H, J = 7.7 Hz, 2 ¥ ArH), 7.73 (br d, 2H,
J = 8.4 Hz, 2 ¥ ArH) and 7.78 (br d, 2H, J = 7.7 Hz, 2 ¥ ArH);
1
3060 (w), 1600 (w), 1440 (w), 1210 (s) and 1150 (m); H NMR
(400 MHz, CDCl3) dH 1.05–1.10 (m, 2H, GeCH2CH2), 1.71–1.85
(m, 2H, GeCH2CH2), 2.66 (d, 2H, J = 13.2 Hz, CH2Nap), 2.70 (d,
2H, J = 13.2 Hz, CH2Nap), 5.04 (s, 2H, CH2Ar), 6.95 (dd, 1H, J =
8.4 and 2.0 Hz, ArH), 7.02 (app d, 1H, J = 7.6 Hz, ArH), 7.04 (dd,
1H, J = 7.2 and 0.8 Hz, ArH), 7.21 (br s, 2H, 2 ¥ ArH), 7.36–7.45
(m, 12H, 12 ¥ ArH), 7.53 (dd, 2H, J = 9.2 and 1.6 Hz, 2 ¥ ArH),
7.60 (d, 2H, J = 8.4 Hz, 2 ¥ ArH) and 7.75 (dd, 2H, J = 7.2 and
1.6 Hz, 2 ¥ ArH); 19F NMR (376 MHz, CDCl3) dF -126.1 (s, 2F),
-123.5 (s, 2F), -122.7 (s, 2F), -122.0 (app s, 6F), -116.4 (quintet,
2F, J = 15.1 Hz), and -80.7 (t, 3F, J = 11.3 Hz). MS (EI) m/z
986 ([74GeM]+, 40%), 984 ([72GeM]+, 30), 982 ([70GeM]+, 20), 896
([74GeM-Bn]+, 20), 894 ([72GeM-Bn]+, 15), 892 ([70GeM-Bn]+,
10), 845 ([74GeM-CH2Np]+, 30), 843 ([72GeM-CH2Np]+, 20),
841 ([70GeM-CH2Np]+, 15), 530 (100), 515 (60), 337 (20), 231
(40), 219 (40), 141 ([CH2Np]+, 100) and 91 ([Bn]+, 80); HRMS
(EI) Expected mass for C45H33O74GeF17 (M+) 986.1479, found
986.1472 (D = 0.7 ppm).
13C NMR (100 MHz, CDCl3) dC 1.6 (t), 21.3 (2t), 27.4 (t, JC–F
=
23.0 Hz), 124.9 (2d), 125.4 (2d), 126.1 (2d), 127.0 (2d), 127.1 (2d),
127.6 (2d), 128.3 (2d), 131.3 (2 s), 133.8 (2 s) and 137.2 (2 s);
19F NMR (376 MHz, CDCl3) dF -126.1 (s, 2F), -123.6 (s, 2F),
-122.7 (s, 2F), -122.0 (app s, 4F), -121.8 (s, 2F), -116.2 (quintet,
2F, J = 15.1 Hz), and -80.8 (t, 3F, J = 9.8 Hz); MS (EI) m/z 804
([74GeM]+, 20%), 663 ([74GeM-C11H9]+, 5), 531 (10), 282 ([C22H18]+,
10), 215 ([C10H1174Ge]+, 45), 141 ([C11H11]+, 100), 115 (20), 84 (20)
and 49 (30); HRMS (EI) Expected mass for C32H23F1774Ge (M+)
804.0740, found 804.0737 (D = 0.4 ppm). A single crystal X-ray
structure determination was carried out on this compound (see
ESI).
Step 3. To a cooled solution of (2-benzyloxyphenyl)bis-
naphthalen-2-ylmethyl-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
nonadecafluoroundecyl)germane (92 mg, 0.093 mmol) at 0 ◦C
in CH2Cl2 (6 mL), was added a solution of boron tribromide
in CH2Cl2 (1 M, 186 mL, 0.186 mmol). The resulting solution
was stirred vigorously at 0 ◦C for 3 min. After this time solid
sodium hydrogen carbonate (250 mg) was added followed by
saturated aqueous sodium hydrogen carbonate solution (5 mL).
The aqueous layer was extracted with Et2O (3 ¥ 10 mL),
the combined organic fractions dried (Na2SO4), filtered and
concentrated in vacuo. The resulting reaction mixture was purified
by silica gel column chromatography, eluting with EtOAc : petrol
(1 : 20→1 : 10→3 : 20), to give germyl phenol 25 as a colourless
oil (29 mg, 0.032 mmol, 35%).42 1H NMR (400 MHz, CDCl3) dH
1.14–1.18 (m, 2H, GeCH2CH2), 1.80–1.93 (m, 2H, GeCH2CH2),
2.77 (s, 4H, 2 ¥ CH2Nap), 6.77 (dd, 1H, J = 8.0 and 1.0 Hz,
ArH), 6.94 (dt, 1H, J = 7.3 and 1.0 Hz, ArH), 7.08 (dd, 2H,
J = 8.6 and 1.6 Hz, 2 ¥ ArH), 7.25–7.40 (m, 8H, 8 ¥ ArH),
7.56 (dd, 2H, J = 8.0 and 1.2 Hz, 2 ¥ ArH), 7.63 (d, 2H, J =
8.6 Hz, 2 ¥ ArH) and 7.74 (dd, 2H, J = 7.6 and 1.6 Hz, 2 ¥ ArH);
19F NMR (376 MHz, CDCl3) dF -126.2 (s, 2F), -123.6 (s, 2F),
-122.8 (s, 2F), -122.0 (app s, 6F), -116.4 (quintet, 2F, J = 15.1
Hz), and -80.8 (t, 3F, J = 10.5 Hz); MS (EI) m/z 896 ([74GeM]+,
25%), 755 ([74GeM - C11H9]+, 60), 753 ([72GeM-C11H9]+, 50), 751
([70GeM-C11H9]+, 60), 530 (60), 515 (20), 327 (25), 281 (30), 251
(75), 153 (45), 142 ([C11H10]+, 100), 122 (45), 91 (55) and 77 (75);
Crystal data for 27. C32H23F17Ge, M = 803.09, triclinic, P1
˚
(no. 2), a = 6.09459(14), b = 7.56496(17), c = 33.7307(8) A, a =
84.8926(19), b = 87.4794(19), g = 88.9974(18)◦, V = 1547.35(6)
3
-3
-1
˚
A , Z = 2, Dc = 1.724 g cm , m(Cu-Ka) = 2.527 mm , T =
173 K, colourless needles, Oxford Diffraction Xcalibur PX Ultra
diffractometer; 5920 independent measured reflections (Rint
=
0.0312), F2 refinement, R1(obs) = 0.0517, wR2(all) = 0.1415, 4961
independent observed absorption-corrected reflections [|Fo| >
4s(|Fo|), 2qmax = 143◦], 494 parameters. CCDC 814148.
2-Bromo-6-methylbenzoic acid (S*)-1-{(E)-(R*)-3-[bis-naphtha-
len-2-ylmethyl-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-nonade-
cafluoro-undecyl)germanyl]-1-methoxyallyl}hexyl ester (28)
To a stirred solution of alkyne 17a (19 mg, 0.052 mmol) in
dichloroethane (3 mL), was added germyl hydride 27 (83 mg,
0.104 mmol) and Rh(CO)(PPh3)2Cl (7 mg, 0.01 mmol). The
reaction mixture was heated at reflux for 24 h, after which time
the reaction mixture was allowed to cool to r.t.. The reaction
R
mixture was filtered through a pad of Celiteꢀ, washed with CH2Cl2
(10 mL) and concentrated in vacuo. The resulting oil was purified
by silica gel column chromatography, eluting with EtOAc : petrol
(0 : 1→1 : 100→1 : 50→3 : 100→1 : 25→1 : 20), to give (E)-alkenyl
germane 28 as a colourless oil (35 mg, 0.030 mmol, 57%). IR
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(nmax, cm-1) 2930 (w), 1730 (m, C O st), 1240 (s), 1210 (s) and
1150 (s); 1H NMR (400 MHz, CDCl3) dH 0.89 (t, 3H, J = 7.0 Hz,
CH3), 1.01–1.04 (m, 2H, GeCH2CH2), 1.16–1.37 (m, 6H, 3 ¥ CH2),
1.65–1.73 (m, 2H, CH2), 1.90 (m, 2H, GeCH2CH2), 2.37 (s, 3H,
ArCH3), 2.61 (d, 4H, J = 5.6 Hz, 2 ¥ CH2Nap), 3.25 (s, 3H,
OCH3), 3.91 (ddd, 1H, J = 6.3, 2.9 and 0.6 Hz, CH-OMe), 5.25
(dt, 1H, J = 9.2 and 2.9 Hz, CHOCOAr), 5.91 (dd, 1H, J = 18.7
and 6.3 Hz, GeCH CH), 6.06 (dd, 1H, J = 18.7 and 0.6 Hz,
GeCH CH), 7.17–7.12 (m, 4H, 4 ¥ ArH), 7.39–7.47 (m, 7H,
7 ¥ ArH), 7.65 (br t, 2H, J = 6.8 Hz, 2 ¥ ArH), 7.71 (dd, 2H,
J = 8.4 and 4.0 Hz, 2 ¥ ArH) and 7.79 (d, 2H, J = 8.0 Hz, 2 ¥
ArH); 13C NMR (100 MHz, CDCl3) dC 2.5 (t), 13.9 (q), 19.7 (q),
22.5 (t), 22.6 (2t), 25.4 (t), 26.4 (t), 28.7 (t), 31.5 (t), 56.8 (q), 76.7
(d), 85.0 (d), 118.9 (s), 124.9 (2d), 125.5 (2d), 126.2 (2d), 127.0
(2d), 127.2 (2d), 127.6 (2d), 128.2 (2d), 129.0 (d), 129.8 (d), 130.0
(d), 130.3 (d), 131.3 (2 s), 133.8 (2 s), 136.2 (s), 136.5 (s), 136.8
(2 s), 143.7 (d) and 167.8 (s); 19F NMR (376 MHz, CDCl3) dF
-126.1 (s, 2F), -123.5 (s, 2F), -122.7 (s, 2F), -122.0 (app s, 6F),
-116.3 (quintet, 2F, J = 10.3 Hz), and -80.7 (t, 3F, J = 8.0 Hz); MS
(ES) m/z 1211 ([81Br74GeM+K]+, 50%), 1209 ([79Br74GeM+K]+,
55), 1195 ([81Br74GeM+Na]+, 60), 1193 ([79Br74GeM+Na]+, 70),
1191 ([79Br72GeM+Na]+, 60), 1140 (35), 1113 ([M-B +Na]+,
45), 1091 ([MH-Br]+, 15), 1071 ([81BrM-C11H9+K]+, 40), 1069
([79BrM-C11H9+K]+, 45), 1000 (15) and 338 (100); HRMS (ES)
Expected mass for C50H46O3Na79BrF1774Ge (M + Na+) 1193.1472,
found 1193.1468 (D = 0.3 ppm).
4.2 Hz, 2 ¥ ArH), 7.67 (dd, 2H, J = 7.9 and 4.2 Hz, 2 ¥ ArH)
and 7.79 (br d, 2H, J = 8.0 Hz, 2 ¥ ArH); 13C NMR (100 MHz,
CDCl3) dC 2.4 (t), 13.9 (q), 19.4 (q), 22.5 (t), 22.6 (t), 22.6 (t), 24.4
(q), 24.4 (q), 25.2 (t), 26.4 (t), 28.9 (t), 31.6 (t), 57.1 (q), 62.1 (t),
76.1 (d), 85.2 (d), 99.6 (s), 113.2 (d), 113.3 (d) 116.9 (s), 120.5 (s),
121.0 (d), 124.5 (d), 124.8 (2d), 125.3 (s), 125.5 (2d), 126.1 (2d),
126.9 (2d), 127.2 (2d), 127.6 (2d), 128.1 (2d), 129.2 (d), 130.1 (d),
131.2 (2 s), 133.7 (2 s), 136.5 (2 s), 137.1 (s), 144.1 (d), 146.2 (s),
148.7 (s), 154.6 (s) and 167.4 (s); 19F NMR (376 MHz, CDCl3) dF
-126.1 (s, 2F), -123.2 (s, 2F), -122.7 (s, 2F), -122.0 (app s, 6F),
-116.3 (quintet, 2F, J = 10.1 Hz), and -80.7 (t, 3F, J = 8.0 Hz);
MS (ES) m/z 1387 ([74GeM + K]+, 10%), 1371 ([74GeM+Na]+,
15), 1366 ([74GeM+NH4]+, 50), 573 (35), 391 (50), 279 (100) and
199 (65); HRMS (NES) Expected mass for C60H60O6N79BrF1770Ge
+
(M+NH4 ) 1361.2578, found 1361.2570 (D = 0.6 ppm).
(14R*,15S*,E)-14-Methoxy-1,11,11-trimethyl-15-pentyl-14,15-
dihydro-5H-benzo[b]10,12-dioxo[1,2-j][1,5]dioxacycloundecin-
17(9H)-one (5)10 and 2-(5-bromo-2,2-dimethyl-4H-benzo[1,3]-
dioxin-6-yloxy)-6-methylbenzoic acid (S*)-1-[(R*)-1-methoxy-
allyl]hexyl ester (30)10 (Table 3, entry 2)
To a solution of alkenyl germane 4b (6 mg, 0.004 mmol)
(0.076 mmol) in MeCN/MeOH (3/1 v/v, 2 mL) in a Pyrex
Schlenk tube (1 mm thick) was added powdered Cu(BF4)2·nH2O
(0.018 mmol). The resulting mixture was purged with argon for
30 min before irradiating using a 125 W high pressure Hg lamp for
1 h. A further portion of powdered Cu(BF4)2·nH2O (0.018 mmol)
was then added and the solution irradiated for a further 1 h. After
this time, the solvent was removed in vacuo, the residue was taken
up in CH2Cl2 (2.5 mL), washed with water (2 ¥ 1 mL) and dried
over MgSO4 to give the crude difluoroalkenylgermane.
2-(5-Bromo-2,2-dimethyl-4H-benzo[1,3]dioxin-6-yloxy)-6-methyl-
benzoic acid (S*)-1-{(E)-(R*)-3-[bis-naphthalen-2-ylmethyl-(3,3,
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-nonadecafluoroundecyl)-
germanyl]-1-methoxyallyl}hexyl ester (4b)
An oven-dried reaction vial was charged with a stirrer bar, phenol
29 (27 mg, 0.11 mmol), aryl bromide 28 (33 mg, 0.03 mmol), CuO
(0.8 mg, 0.01 mmol) and K2CO3 (18 mg, 0.13 mmol). The vial was
equipped with a Suba-seal, then repeatedly evacuated and purged
with nitrogen (¥ 5) before addition of pyridine (2 mL). The Suba-
seal was then replaced by a screw cap under a flow of nitrogen,
and the reaction mixture was heated for 24 h at 120 ◦C. After this
time the reaction mixture was allowed to cool to r.t., before being
A
solution of the crude difluoroalkenylgermane and
TBAF·3H2O (4 mg, 0.013 mmol) in degassed DMF (2 mL) was
prepared. PdCl2(MeCN)2 (0.1 mg, 0.0004 mmol) and P(o-tol)3
(0.2 mg, 0.0007 mmol) were dissolved in degassed DMF (1 mL)
and stirred at r.t. for 10 min to form the active catalytic species. This
catalyst solution was then added to the difluoroalkenylgermane
solution, followed by addition of CuI (1 mg, 0.005 mmol) and the
resulting mixture was heated at 120 ◦C for 48 h. After this time the
reaction mixture was allowed to cool to r.t., before being diluted
with Et2O (20 mL), washed with water (3 ¥ 10 mL), dried (MgSO4),
filtered and concentrated in vacuo. Fluorous-tagged by-products
were then removed by filtration through an F-SPE cartridge with
H2O/MeCN (1 : 1) and the filtrate concentrated in vacuo and then
purified by PLC, eluting with EtOAc : petrol to give:
R
diluted with Et2O (10 mL) and passed through a pad of Celiteꢀ.
Exhaustive washing with saturated aqueous ammonium chloride
solution (5 ¥ 5 mL) and aqueous hydrochloric acid (1 M; 3 ¥ 5 mL)
removed pyridine from the organic layer. The organic layer was
then dried (Na2SO4), filtered, concentrated in vacuo and purified
by PLC, eluting with a EtOAc : petrol (3 : 100), to give biaryl ether
4b as a colourless oil (23 mg, 0.02 mmol, 61%). IR (nmax, cm-1)
2930 (w), 1730 (m, C O st), 1460 (m), 1240 (s) and 1210 (s);
1H NMR (400 MHz, CDCl3) dH 0.77 (t, 3H, J = 7.0 Hz, CH3),
0.98 (m, 2H, GeCH2CH2), 1.35–1.46 (m, 6H, 3 ¥ CH2), 1.52 (s,
6H, C(CH3)2), 1.54–1.66 (m, 2H, CH2), 1.84 (m, 2H, GeCH2CH2),
2.39 (s, 3H, ArCH3), 2.54 (d, 4H, J = 5.6 Hz, 2 ¥ CH2Nap), 3.16
(s, 3H, OCH3), 3.82 (dd, 1H, J = 5.3 and 3.2 Hz, CH-OMe), 4.75
(s, 2H, ArCH2O), 5.23 (dt, 1H, J = 10.0 and 3.2 Hz, CHOCOAr),
5.95 (dd, 1H, J = 18.7 and 5.3 Hz,CH CHGe), 6.02 (d, 1H, J =
18.7 Hz, CH CHGe), 6.47 (d, 1H, J = 7.8 Hz, ArH), 6.76 (d, 1H,
J = 8.8 Hz, ArH), 6.90 (d, 1H, J = 7.8 Hz, ArH), 6.91 (d, 1H, J =
8.8 Hz, ArH), 7.08–7.12 (m, 2H, 2 ¥ ArH), 7.15 (t, 1H, J = 7.8 Hz,
ArH), 7.43–7.45 (m, 6H, 6 ¥ ArH), 7.62 (app dd, 2H, J = 8.0 and
Macrocycle 510 as off-white needles (0.6 mg, 0.0014 mmol, 9%).
Mp 119.9–125.6 ◦C (Et2O); IR (nmax, cm-1) 2930 (w), 1740 (m,
1
C
O st), 1460 (s), 1250 (s), 1240 (s) and 1100 (m); H NMR
(400 MHz, CDCl3) dH 0.91 (t, 3H, J = 7.0 Hz, CH3), 1.31–1.40 (m,
4H, 2 ¥ CH2), 1.53 (s, 3H, 1 ¥ C(CH3)2), 1.54 (s, 3H, 1 ¥ C(CH3)2),
1.58–1.70 (m, 2H, CH2), 1.98–2.07 (m, 2H, CH2), 2.35 (s, 3H,
ArCH3), 3.32 (s, 3H, OCH3), 3.58 (t, 1H, J = 9.3 Hz, CH-OMe),
4.63 (d, 1H, J = 15.6 Hz, 1 ¥ ArCH2O), 4.73 (d, 1H, J = 15.6 Hz,
1 ¥ ArCH2O), 5.25 (dt, 1H, J = 9.3 and 2.4 Hz, CHOCOAr),
5.89 (dd, 1H, J = 16.0 and 9.3 Hz, CH CHAr), 6.04 (d, 1H, J =
16.0 Hz, CH CHAr), 6.79 (d, 1H, J = 8.0 Hz, ArH), 6.79 (d,
1H, J = 8.8 Hz, ArH), 6.84 (d, 1H, J = 8.0 Hz, ArH), 7.11 (t, 1H,
J = 8.0 Hz, ArH) and 7.23 (d, 1H, J = 8.8 Hz, ArH). 13C NMR
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(100 MHz, CDCl3) dC 14.0 (q), 19.3 (q), 22.5 (t), 24.6 (q), 24.7 (q),
25.3 (t), 31.6 (t), 32.0 (t), 56.8 (q), 59.8 (t), 75.7 (d), 86.0 (d), 99.2 (s),
113.1 (d), 116.1 (d), 118.9 (s), 123.9 (d), 124.2 (d), 125.9 (d), 126.7
(s), 128.4 (s), 129.6 (d), 135.3 (s), 137.6 (d), 146.1 (s), 148.1 (s),
154.6 (s) and 167.8 (s). MS (CI) m/z 484 ([M + NH4]+, 60%), 467
([M + H]+, 10), 426 ([M - C3H6O]+, 5), 355 ([M - C3H6O - C4H6O
+ NH4]+, 100), 338 ([MH - C3H6O - C4H6O]+, 40), 327 (15), 97
(15) and 52 (85). HRMS (CI) Expected mass for C28H38NO6 (M +
7.58 (d, 1H, J = 8.8 Hz, ArH), 10.16 (s, 1H, ArCHO) and 11.54
(br s, 1H, OH); 13C NMR (126 MHz, CDCl3) dC 14.0 (q), 19.3
(q), 22.5 (t), 25.2 (t), 31.6 (t), 32.0 (t), 57.2 (q), 75.7 (d), 85.8 (d),
112.7 (d), 117.5 (d), 118.5 (s), 124.3 (d), 124.8 (d), 126.6 (s), 129.7
(d), 133.8 (d), 135.4 (s), 135.6 (s), 140.1 (d), 145.0 (s), 154.0 (s),
159.7 (s), 167.5 (s) and 195.4 (d); MS (EI) m/z 424 ([M]+, 10), 337
(10), 324 (40), 292 ([C17H24O4]+, 80), 281 (20), 277 (20), 264 (40),
255 ([C15H11O4]+, 20), 235 (20), 135 (20), 83 (25), 72 ([C4H8O]+,
75), 69 (35), 59 (100) and 55 (60); HRMS (EI) Expected mass for
C25H28O6 (M+) 424.1885, found 424.1886 (D = 0.2 ppm).
+
NH4 ) 484.2714, found 484.2699 (D = 3.1 ppm).
Bromo biaryl ether 3010 as a pale yellow oil (1.7 mg, 0.0030 mmol,
20%). IR (nmax, cm-1) 2960 (w), 1730 (C O st, m), 1460 (s), 1250
(s) and 1110 (m); 1H NMR (400 MHz, CDCl3) dH 0.78 (t, 3H, J =
7.0 Hz, CH3), 1.13–1.35 (m, 6H, 3 ¥ CH2), 1.54 (s, 6H, C(CH3)2),
1.57–1.67 (m, 2H, CH), 2.39 (s, 3H, ArCH3), 3.28 (s, 3H, OCH3),
3.76 (ddt, 1H, J = 7.6, 3.9 and 0.8 Hz, CH-OMe), 4.77 (s, 2H,
ArCH2O), 5.26 (dt, 1H, J = 9.2 and 3.9 Hz, CHOCOAr), 5.29 (ddd,
1H, J = 10.4, 1.6 and 0.8 Hz, 1 ¥ CH2), 5.30 (ddd, 1H, J = 17.2,
1.6 and 0.8 Hz, 1 ¥ CH2), 5.78 (ddd, 1H, J = 17.2, 10.4 and 7.6 Hz,
CH CH2), 6.48 (d, 1H, J = 8.2 Hz, ArH), 6.79 (d, 1H, J = 8.8 Hz,
ArH), 6.93 (app d, 2H, J = 8.8 Hz, 2 ¥ ArH) and 7.16 (t, 1H, J =
8.2 Hz, ArH); 13C NMR (100 MHz, CDCl3) dC 14.0 (q), 19.4 (q),
22.5 (t), 24.4 (q), 24.5 (q), 25.2 (t), 29.4 (t), 31.7 (t), 56.8 (q), 62.1 (t),
76.1 (d), 84.0 (d), 99.6 (s), 113.1 (d), 113.4 (s), 116.9 (d), 119.5 (t),
120.5 (s), 120.9 (d), 124.5 (s), 125.6 (d), 130.0 (d), 134.7 (d), 137.2
(s), 146.4 (s), 148.6 (s), 154.5 (s) and 167.4 (s); MS (CI) m/z 566
([81BrM+NH4]+, 30%), 564 ([79BrM+NH4]+, 30), 549 ([81BrM+H]+,
25), 547 ([79BrM+H]+, 25), 486 ([MNH4-Br]+, 20), 467 ([MH-Br]+,
30), 377 ([C18H1681BrO4]+, 10), 375 ([C18H1679BrO4]+, 10), 332 (10),
297 ([C18H16O4]+, 15), 274 (30), 228 ([C14H14NO2]+, 40), 220 (30),
218 (30), 190 (10), 155 ([C10H19O]+, 80), 140 (100) and 52 (75);
HRMS (ES) Expected mass for C28H35BrO6 (M+) 547.1714, found
547.1695 (D = 3.5 ppm).
Separation of enantiomers of ( )-aspercyclide A C19 methyl ether
(31)
Separation of enantiomers of racemic aspercyclide A C19 methyl
ether (31) by chiral HPLC was performed using an analytical
CHIRALPAK-IA column (5 mm; size: 0.46 cm I.D. ¥ 25 cm L.;
no. IA00CE-MB030) eluting with n-hexane/i-propanol (95 : 5) at
1 mL min-1 (24 ◦C, 41 bar) and detecting at UV 250 nm. Multiple
runs (injection size 6 mL; sample conc. 13 mg in 195 mL EtOAc/i-
propanol 125 : 70) gave:
(+)-(19R,20S)-aspercyclide A C19 methyl ether [(+)-31], 2.9 mg,
98.4% e.e., [a]D25 +232 (c. 0.25, CH2Cl2). UV lmax (n-hexane/i-
PrOH, 95 : 5)/nm 268, 351; CD lmax (MeOH, 0.02 mg mL-1)/nm
279 (+6). The Cotton effect for this enantiomer matched closely
that which we recorded for the natural (+)-aspercyclide A itself
(supplied by Sheo B. Singh, Merck Research Laboratories, Rah-
way Basic Chemistry NMR, NJ, USA: CD lmax (MeOH, 1.0
mg mL-1)/nm 278 (+6) (see ESI).
(-)-(19S,20R)-aspercyclide A C19 methyl ether [(-)-31], 3.3 mg,
98.8% e.e., [a]2D3 -176 (c. 0.136, CH2Cl2). UV lmax (n-hexane/i-
PrOH, 95 : 5)/nm 267, 356; CD lmax (MeOH, 0.02 mg mL-1)/nm
278 (-5).
( )-Aspercyclide A C19 methyl ether (31)10
Acknowledgements
A solution of acetonide 5 (14 mg, 0.030 mmol) in THF : 1M HCl
(1 : 1 v/v, 4 mL) was heated at 80 C for 3 h. After this time the
◦
The authors acknowledge Rebecca L. Beavil (KCL) for protein
production and Bayer CropScience AG, The EPSRC, Asthma
UK, The MRC, The European Commission (FP7 Marie Curie
Fellowship for JJPS) and Imperial College London for financial
support of this work.
solution was allowed to cool to r.t. before being extracted with
Et2O (3 ¥ 5 mL). The organic extracts were combined, washed
with saturated aqueous sodium chloride solution (10 mL), dried
(Na2SO4), filtered and concentrated in vacuo to a colourless oil
[( )-aspercyclide B C19 methyl ether, 12 mg, 94%]. To a solution
of this oil (9.4 mg, 0.022 mmol) in CH2Cl2 (9 mL) was added
activated Mn◦O2 (19 mg, 0.22 mmol). The resulting suspension was
heated at 40 C for 3 h, with additional activated MnO2 (23 mg,
0.26 mmol) added after 1 h. After this time the suspension was
Notes and references
1 S. B. Singh, H. Jayasuriya, D. L. Zink, J. D. Polishook, A. W.
Dombrowski and H. Zweerink, Tetrahedron Lett., 2004, 45, 7605–7608.
2 We use a different numbering system for the aspercyclides to that used
by Singh et al. (ref. 1). Our C19 corresponds to their C18.
3 H. J. Gould and B. J. Sutton, Nat. Rev. Immunol., 2008, 8, 205–
217.
4 B. J. Sutton, A. J. Beavil, R. L. Beavil and J. Hunt, in Allergy and
Alergic Diseases, ed. A. B. Kay, A. P. Kaplan, J. Bousquet and P. G.
Holt, Wiley-Blackwell, Chichester, 2008, vol. 1, pp. 103–118.
5 B. A. Helm, I. Sayers, J. Swan, L. J. C. Smyth, S. A. Cain, M. Suter,
D. C. Machado, A. C. Spivey and E. A. Padlan, Technol. Health Care,
1998, 6, 195–207.
6 A. Fu¨rstner and C. Mu¨ller, Chem. Commun., 2005, 5583.
7 C. V. Ramana, M. A. Mondal, V. G. Puranik and M. K. Gurjar,
Tetrahedron Lett., 2007, 48, 7524–7527.
8 K. R. Prasad, V. R. Gandi, J. E. Nidhiry and K. S. Bhat, Synthesis,
2010, 2521–2526.
R
allowed to cool to r.t. before being filtered through a pad of Celiteꢀ
and concentrated in vacuo to give aspercyclide A C19 methyl ether
(31)10 as an off-white solid (7.9 mg, 84%). Mp. 118.4–121.5 ◦C
(CH2Cl2); IR (nmax, cm-1) 2920 (w), 1740 (C O st, m), 1650 (m),
1
1460 (m), 1250 (s), 1240 (s), 1100 (m) and 730 (m); H NMR
(400 MHz, CDCl3) dH 0.92 (t, 3H, J = 7.0 Hz, CH3), 1.32–1.41
(m, 4H, 2 ¥ CH2), 1.49–1.55 (m, 2H, CH2), 1.62–1.71 (m, 1H,
1 ¥ CH2), 2.02–2.10 (m, 1H, 1 ¥ CH2), 2.36 (s, 3H, ArCH3), 3.35
(s, 3H, OCH3), 3.66 (app t, 1H, J = 9.4 Hz, CH-OCH3), 5.25 (dt,
1H, J = 9.4 and 2.7 Hz, CHOCOAr), 5.98 (dd, 1H, J = 16.0 and
9.4 Hz, CH CHAr), 6.51 (d, 1H, J = 16.0 Hz, CH CHAr),
6.70 (d, 1H, J = 7.9 Hz, ArH), 6.89 (d, 1H, J = 7.9 Hz, ArH),
6.98 (d, 1H, J = 8.8 Hz, ArH), 7.14 (t, 1H, J = 7.9 Hz, ArH),
9 J. Posp´ısˇil, C. Mu¨ller and A. Fu¨rstner, Chem.–Eur. J., 2009, 15, 5956–
5968.
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10 J. L. Carr, D. A. Offermann, M. D. Holdom, P. Dusart, A. J. P. White,
A. J. Beavil, R. J. Leatherbarrow, S. D. Lindell, B. J. Sutton and A. C.
Spivey, Chem. Commun., 2010, 46, 1824–1826.
11 A. C. Spivey, C. J. Gripton and J. P. Hannah, Curr. Org. Synth., 2004,
1, 211–226.
12 E. Lukevics and L. Ignatovich, in Chemistry of Organic Germanium,
Tin and Lead Compounds, ed. Z. Rappoport, Wiley, Chichester, 2002,
vol. 2 (Part 2), pp. 1653–1683.
25 T. Ohgiya, N. Kutsumura and S. Nishiyama, Synlett, 2008, 3091–
3105.
26 D. W. Hart, T. H. Blackburn and J. Schwartz, J. Am. Chem. Soc., 1975,
97, 679–680.
27 C. H. Burgos, T. E. Barder, X. Huang and S. L. Buchwald, Angew.
Chem., Int. Ed., 2006, 45, 4321–4326.
28 A. Aranyos, D. W. Old, A. Kiyomori, J. P. Wolfe, J. P. Sadighi and S. L.
Buchwald, J. Am. Chem. Soc., 1999, 121, 4369–4378.
29 H.-J. Cristau, P. P. Cellier, J.-F. Spindler and M. Taillefer, Org. Lett.,
2004, 6, 913–916.
13 A. C. Spivey, D. J. Turner, M. L. Turner and S. Yeates, Synlett, 2004,
111–115.
14 A. C. Spivey, C.-C. Tseng, J. P. Hannah, C. J. G. Gripton, P. de
Fraine, N. J. Parr and J. J. Scicinski, Chem. Commun., 2007, 2926–
2928.
15 A. C. Spivey, C. J. G. Gripton, J. P. Hannah, C.-C. Tseng, P. de Fraine,
N. J. Parr and J. J. Scicinski, Appl. Organomet. Chem., 2007, 21, 572–
589.
16 F-SPE is a form of reverse-phase chromatography that allows molecules
tagged with a ‘light’-fluorous group (e.g. a short fluorocarbon chain)
to be separated from those not containing such a tag. Fewer fluorine
atoms need be incorporated in a ‘light’ tag as compared to the >60%
by weight that are required in the original ‘heavy’ fluorous tags which
are separable by liquid–liquid extraction between aqueous/organic and
fluorocarbon phases.
17 W. Zhang and D. P. Curran, Tetrahedron, 2006, 62, 11837–11865.
18 R. K. Boeckman Jr. and R. A. Hudack Jr., J. Org. Chem., 1998, 63,
3524–3525.
30 J.-F. Marcoux, S. Doye and S. L. Buchwald, J. Am. Chem. Soc., 1997,
119, 10539–10540.
31 R. Frlan and D. Kikelj, Synthesis, 2006, 14, 2271–2285.
32 J. McNulty, J. J. Nair, S. Cheekoori, V. Larichev, A. Capretta and A. J.
Robertson, Chem.–Eur. J., 2006, 12, 9314–9322.
33 F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2008, 47, 3096–
3099.
34 F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 6954–
6971.
35 D. J. Hart, W. P. Hong and L. Y. Hsu, J. Org. Chem., 1987, 52, 4665–
4673.
36 N. N. Kulkarni, V. S. Kulkarni, S. R. Lele and B. D. Hosangadi,
Tetrahedron, 1988, 44, 5145–5149.
37 G. J. D. Peddle and J. E. H. Ward, J. Organomet. Chem., 1968, 14,
131–137.
38 B. H. Lipshutz, R. Keil and E. L. Ellsworth, Tetrahedron Lett., 1990,
31, 7257–7260.
39 S. Pereira and M. Srebnik, Tetrahedron Lett., 1996, 37, 3283–3286.
40 The IC50 value for natural (+)-aspercyclide A [(+)-1] was reported as
200 mM (ref. 1); however, our ELISA protocol does differ from that
reported (see ESI†) as noted in ref. 10.
19 K. Takai, K. Nitta and H. Utimoto, Tetrahedron Lett., 1988, 29, 5263–
5266.
20 A. Fu¨rstner, Chem. Rev., 1999, 99, 991–1045.
21 J. L. Carr, PhD Thesis, Imperial College London, 2009.
22 A. M. Montana, D. Fernandez, R. Pages, A. C. Filippou and G.
Kociok-Kohn, Tetrahedron, 2000, 56, 425–439.
41 M. Wolter, G. Nordmann, G. E. Job and S. L. Buchwald, Org. Lett.,
23 W. Sun and L. D. Cama, European Patent WO2004073612, 2004.
24 N. Kutsumura, T. Yokoyama, T. Ohgiya and S. Nishiyama, Tetrahedron
Lett., 2006, 47, 4133–4136.
2002, 4, 973–976.
42 This compound is rather unstable and we were unable to obtain a clean
13C NMR spectrum.
6824 | Org. Biomol. Chem., 2011, 9, 6814–6824
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