Total synthesis of (±)-aspercyclide A and its C19 methyl ether

Article abstract of DOI:10.1039/b923528k

The total syntheses of (±)-aspercyclide A (1) and its C19 methyl ether (15a) featuring Heck-Mizoroki macrocyclisation to form the 11-membered (E)-styrenyl biaryl ether lactone core are described. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b923528k

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Total synthesis of (ꢀ)-aspercyclide A and its C19 methyl etherw
James L. Carr,a Daniel A. Offermann,a Mary D. Holdom,b Philip Dusart,b
Andrew J. P. White,a Andrew J. Beavil,b Robin J. Leatherbarrow,a Stephen D. Lindell,c
Brian J. Suttonb and Alan C. Spivey*a
Received (in Cambridge, UK) 11th November 2009, Accepted 14th December 2009
First published as an Advance Article on the web 23rd December 2009
DOI: 10.1039/b923528k
The total syntheses of (ꢀ)-aspercyclide A (1) and its C19 methyl
ether (15a) featuring Heck–Mizoroki macrocyclisation to form
the 11-membered (E)-styrenyl biaryl ether lactone core are
described.
Allergic disorders such as asthma are caused by inflammatory
mediators (e.g. leukotrienes) released by mast cells and
basophils.1 Binding of allergen specific soluble immunoglobin E
(IgE) to its membrane bound high affinity receptor (FceRI) on
these cells, and then cross-linking of these complexes by
multivalent allergens, is the trigger for the inflammatory
mediator release.2 Blocking of the IgE–FceRI protein–protein
interaction (PPI) therefore constitutes a strategy for therapeutic
intervention.3 In 2005 the European Commission approved
the humanised monoclonal anti-IgE antibody omalizumab
(Xolairs, Novartis/Genentech), which has this mode of
action, for the treatment of severe asthma in all member
states.4 However, the antibody is expensive to manufacture
and requires subcutaneous injection every 2–4 weeks; a
comparably efficacious small molecule antagonist could have
tremendous potential for the treatment of asthma and other
allergic disorders.5
Several peptides,6a oligonucleotides6b and fluorescein dyes6c
have been reported to block the IgE–FceRI PPI, but arguably
the most promising small molecule antagonist for drug
development reported to date is the fungal metabolite asper-
cyclide A (1).7 This natural product is the most active member
(IC50 = 200 mM) of three closely related 11-membered biaryl
ether lactones (aspercyclides A–C, 1–3) that were isolated and
characterised by Singh et al. following enzyme-linked
immunosorbent assay (ELISA)-guided fractionation of
Aspergillus sp. found in soil extracts collected in Tanzania
and published in 2004 (Fig. 1).7
Fig. 1 Structures of aspercyclides A–C.
(RCM) to effect macrocyclisation (- 5 : 1, E : Z).8a In 2007,
Ramana et al. reported a similar approach to this natural
product via the corresponding anti-1,2-diol-PMB ether
(prepared from D-ribose) then RCM using the Furstner
¨
conditions.8b They obtained the E-isomer exclusively and
oxidative deprotection of the PMB ether proved higher
yielding than for the PMP congener but they were unable
to isolate clean aspercyclide C following the final C11 aryl
methyl ether deprotection using BBr3. Very recently,
Furstner et al. disclosed the first syntheses of (+)-aspercyclides
¨
A and B from (S)-glycidol employing an intramolecular
Nozaki–Hiyama–Kishi (NHK) reaction to effect macrocyclisation
and form the anti-1,2-diol motif (>90% de). (+)-Aspercyclide
B was fully characterised but (+)-aspercyclide A proved labile
to chromatography and no spectral data were reported.8c
We report here our synthesis and full characterisation of
(ꢀ)-aspercyclide A and ELISA studies that demonstrate that
synthetic aspercyclide A (1) and its C19 methyl ether (15a)
display comparable antagonist activity against the IgE–FceRI
PPI. A single crystal X-ray structure determination on methyl
ether 15a has also been obtained.
Our synthesis of (ꢀ)-aspercyclide A differs significantly
from Furstner’s in that we employ a Heck–Mizoroki reaction
¨
to effect macrocyclisation. We have explored routes that
deploy both methyl and PMB ether protection of the eventual
C19 hydroxy group. The synthetic sequences are similar and
both start with a Boeckman modified Takai–Utimoto acrolein
acetal–hexanal condensation,9 that is catalytic in Cr(II) and
stoichiometric in Mn(0), to access mono-protected anti-diols
5a (56% yield)z and 5b (64% yield).y Esterification in the case
of alcohol 5a was accomplished by deprotonation with n-BuLi
followed by addition of benzoyl chloride 6z at ꢁ78 1C and
warming to RT (- 7a in 66% yield). For the PMB congener,
NaH was employed in place of n-BuLi as this gave superior
The synthesis of (+)-aspercyclide C was reported by Furstner
¨
and Muller in 2005 and featured Duthaler–Hafner asymmetric
¨
oxy-allylation of hexanal to prepare an anti-1,2-diol-PMP
ether derivative (>90% de, 92% ee) then ring-closing metathesis
a Department of Chemistry, South Kensington campus, Imperial
College, London, UK SW7 2AZ. E-mail: a.c.spivey@imperial.ac.uk;
Tel: +44 (0)20 75945841
b King’s College London, The Randall Division of Cell & Molecular
Biophysics, New Hunt’s House, Guy’s Hospital Campus, London,
UK SE1 1UL
c BayerCropScience AG, Industriepark Hochst G836,
¨
Frankfurt-am-Mein, D-65926, Germany
yields (- 7b in 85% yield). We, like Furstner, then selected to
¨
w Electronic supplementary information (ESI) available: Experimental
procedures and all 1H–13C NMR spectra. CCDC 747376, 747377 and
747554. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b923528k
use acetonide protected bromobenzoquinol 88 as our ring A
precursor. We were unable to identify useful Pd-mediated
conditions for biaryl ether formation and Cu-mediated
ꢂc
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Ullmann coupling protocols resulted in dehalogenation except
when pyridine was employed as the solvent as described by
Kulkarni et al.10 Using their protocol, biaryl ethers 9a and 9b
could be isolated in 70% and 54% yields, respectively
(Scheme 1).
Our initial investigation of the Heck–Mizoroki11 macro-
cyclisation reaction focussed on the Me ether containing
arylbromide 9a. This substrate was found to form dibenzofuran
13a (via direct arylation),12 more readily than the desired
macrocycle 12a under many conditions assayed, typically
giving a B4 : 1 ratio of these two products. The best
conversions (>90%) were obtained using conditions modified
from those reported by Nolan et al.13 but using the novel
diazabutadiene (DAB) ligand 11. Cognisant, that the rate of
direct arylation might be suppressed by the addition of
stoichiometric iodide,12 AgI was explored as an additive.
Use of 100 mol% indeed reversed the product ratio but we
could not find conditions that also allowed acceptable
conversion (e.g. - 13a : 12a, B1 : 5; 31% conv. at 72 h).
A copper-mediated aromatic Finkelstein halogen exchange
process14 was therefore applied to arylbromide 9a to give the
corresponding aryliodide 10a (94% yield). Pleasingly, this
substrate underwent Heck–Mizoroki macrocyclisation under
identical conditions with improved selectivity and conversion
(i.e. - 13a : 12a, B1 : 10; 74% conv. at 48 h) to afford
macrocycle 12a in 52% isolated yield (Scheme 1).
Interestingly, the PMB protected substrates 9b and 10b
(10b obtained from 9b in 88% yield by an aromatic Finkelstein
halogen exchange process) were not prone to dibenzofuran
formation. This allowed reduced amounts of Pd(acac)2
to be deployed and for the AgI to be omitted from the
Heck–Mizoroki macrocyclisation but the isolated yields from
both these PMB ether arylbromide and iodide substrates were
comparable with those from the corresponding Me ethers
(9b - 12b, 34%; 10b - 12b, 47%).
Acid catalysed acetal deprotection of both macrocycles 12a
and 12b proceeded smoothly affording diols 14a and 14b in
94% yield and 82% yield respectively. Oxidation of benzyl
alcohol 14a with MnO2 afforded (ꢀ)-aspercyclide A methyl
ether 15a in 42% yield. Conversion of methyl ether 15a to
(ꢀ)-aspercyclide A itself did not prove possible in our hands.
However, oxidation of benzyl alcohol 14b with MnO2 then
immediate C19 PMB ether removal using BF3ꢃEt2O gave
(ꢀ)-aspercyclide A (1)** in 72% yield (from 14b). We did
not observe this compound to be unstable or sensitive to flash
chromatography.8c
Methyl ether 15a was subject to a single crystal X-ray
structure determination which confirmed the styrene stereo-
chemistry as being E as required and the presence of an
intramolecular H-bond between the ring A aldehyde oxygen
and the phenol OH as expected (Fig. 2).
The overall conformation of the macrocycle in the crystal
lattice is similar to that predicted by Singh et al.7 for (+)-
aspercyclide A by computation based on NMR nOe data.
It is also similar to that of (+)-aspercyclide C C11 methyl
ether8b and its C19 PMP ether,8c suggesting that the ring A
substitution pattern has little influence on the macrocycle
Scheme 1 Synthetic route to aspercyclide A (1) and derivatives.
Reagents and conditions: [a] CrCl2, TMS–Cl, NaI, Mn(0), THF,
ꢁ30 1C, 56% (5a), 64% (5b); [b] 5a, n-BuLi, THF, ꢁ78 1C then acid
chloride 6, ꢁ78 1C - rt, 66% (7a); [c] 5b, NaH, acid chloride 6, THF
reflux, 85% (7b); [d] Phenol 9, CuO, K2CO3, pyridine, 120 1C, 70%
(9a), 54% (9b); [e] CuI, NaI, N,N-dimethylethylenediamine, 1,4-dioxane,
110 1C, 94% (10a), 88% (10b); [f] Pd(acac)2, 11, Cs2CO3, AgI,
1,4-dioxane, 120 1C, 52% (12a), 47% (10b - 12b), 34% (9b - 12b);
[g] 2 M HCl–THF (1
:
1), 60 1C, 94% (14a); [h] p-TSAꢃH2O,
THF–MeOH (1 : 3), 40 1C, 82% (14b); [i] MnO2, CH2Cl2, 40 1C,
42% (15a); [j] BF3ꢃEt2O, CH2Cl2, rt, 72% (14b - 1).
Fig. 2 Single crystal X-ray structure of (ꢀ)-aspercyclide A C19
methyl ether (15a).
ꢂc
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conformation and that this is largely dictated by the out-of-
plane sterically hindered ring B benzoate, the anti-diol and the
E-alkene moieties.
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The ability of compounds (ꢀ)-1 and (ꢀ)-15a to block the
IgE–FceRI PPI was investigated using an ELISA binding
assay (see ESIw). Interestingly, aspercyclide A (1) and its
methyl ether 15a were found to be comparably potent antagonists
of the IgE–FceRI PPI [(ꢀ)-15a IC50 = 95 ꢀ 10 mM; (ꢀ)-1
IC50 = 110 ꢀ 10 mM].ww Since the synthesis of methyl ether
15a benefits from having commercially available acetal 4a as
starting material, analogues of this compound may prove
useful for future structure–activity relationship (SAR) studies.
In summary, we have developed a short synthesis of (ꢀ)-
aspercyclide A (7 steps, 6% yield overall) that employs a
Boeckman modified Takai–Utimoto acrolein acetal–hexanal
condensation to establish the anti-diol motif and a Heck–
Mizoroki reaction to close the 11-membered ring. We plan to
use this route to prepare more analogues and build up SAR
data. We also plan to employ surface plasmon resonance
(SPR) direct binding studies with both protein partners to
establish the binding site of these derivatives as a prelude to
trying to obtain co-crystals with the appropriate protein
partner.
4 See: http://www.xolair.com/.
5 For an excellent review of the challenges of developing small
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studentship), are thanked for financial support of this work.
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Notes and references
z The anti stereochemistry of the major diastereomer was confirmed
by obtaining a single crystal structure determination on its ester
derivative 7a. See ESI.w
y PMB-acetal 4b was prepared from acrolein and the TMS-ether of
4-methoxybenzyl alcohol. See ESI.w
z The benzoic acid precursor to acid chloride 6 is commercially
available. We employed (COCl)2 and DMF (cat.) in CH2Cl2 for its
conversion to acid chloride 6. See ESI.w
8 Synthesis of bromoquinol 8 was via bromination of gentisaldehyde
(Br2, CHCl3), reduction (NaBH4, NaOHaq) and protection (DMP, CSA).
The regioselectivity of the bromination was verified by a single crystal
structure determination on the benzoate of bromoquinol 8. See ESI.w
** The 1H and 13C NMR spectra of synthetic (ꢀ)-1 matched those of
the natural (+)-aspercyclide A, a sample of which was kindly supplied
by Sheo B. Singh, Merck Research Laboratories, Rahway Basic
Chemistry NMR, NJ, USA.
ww These IC50 values are for racemic samples for which the unnatural
(ꢁ)-enantiomer is expected to be inactive. They are lower than that
reported for the natural (+)-aspercyclide (IC50 200 mM, ref. 7) but our
ELISA protocol does differ from that reported, see ESI.w
8 (a) A. Furstner and C. Muller, Chem. Commun., 2005, 5583;
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M. K. Gurjar, Tetrahedron Lett., 2007, 48, 7524; (c) J. Pospısil,
C. Muller and A. Furstner, Chem.–Eur. J., 2009, 15, 5956.
´
¨
¨
9 (a) R. K. Boeckman Jr. and R. A. Hudack Jr., J. Org. Chem., 1998,
63, 3524; (b) K. Takai, K. Nitta and H. Utimoto, Tetrahedron
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¨
10 N. N. Kulkarni, V. S. Kulkarni, S. R. Lele and B. D. Hosangadi,
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ꢂc
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