Enantioselective synthesis of (+)-aspercyclide A

Article abstract of DOI:10.1016/j.tetlet.2013.07.038

An efficient synthesis of the natural IgE-FcεRI PPI inhibitor (+)-aspercyclide A (1) was achieved through the use of a Krische iridium-catalyzed diastereo- and enantioselective alkoxyallylation to form the key mono-protected anti-diol intermediate 4, in high optical purity. A derivative of the natural product (15), containing an oxathiazine dioxide ring in place of the ring-A hydroxyaldehyde unit has also been prepared and found to display comparable ELISA activity to the parent compound, indicating that the aldehyde group is not the key determinant of activity.

Full text of DOI:10.1016/j.tetlet.2013.07.038

Tetrahedron Letters 54 (2013) 4970–4972
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective synthesis of (+)-aspercyclide A
Jimmy J. P. Sejberg a, Lucy D. Smith a, Robin J. Leatherbarrow a, Andrew J. Beavil b, Alan C. Spivey a,
⇑
a Department of Chemistry, Imperial College, London SW7 2AZ, United Kingdom
b King’s College London, The Randall Division of Cell and Molecular Biophysics, New Hunt’s House, Guy’s Hospital Campus, London SE1 1UL, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of the natural IgE-Fc
e
RI PPI inhibitor (+)-aspercyclide A (1) was achieved through
Received 13 May 2013
Revised 26 June 2013
Accepted 5 July 2013
Available online 15 July 2013
the use of a Krische iridium-catalyzed diastereo- and enantioselective alkoxyallylation to form the key
mono-protected anti-diol intermediate 4, in high optical purity. A derivative of the natural product
(15), containing an oxathiazine dioxide ring in place of the ring-A hydroxyaldehyde unit has also been
prepared and found to display comparable ELISA activity to the parent compound, indicating that the
aldehyde group is not the key determinant of activity.
Keywords:
Aspercyclide
IgE
Ó 2013 Elsevier Ltd. All rights reserved.
Krische oxyallylation
anti-Diol
Heck macrocyclization
R'
In 2004, Singh et al. isolated (+)-aspercyclide A (1) and congen-
ers B and C, through activity-guided fractionation of an Aspergillus
sp. soil bacterium sourced from Tanzania (Fig. 1).1 Aspercyclide A
was shown, via an enzyme-linked immunosorbent assay (ELISA),
to inhibit the binding of human IgE to its high affinity receptor
R''
15
A
R
O
19 OH
C5H11
B
O
Fc
e
RI with an IC50 of ꢀ200
lM. Therefore, aspercyclide A and its
analogues constitute interesting leads for the development of
O
anti-asthma and anti-allergic therapeutics.2
1, R = H, R' = OH, R'' = CH=O, (+)-aspercyclide A
R = H, R' = OH, R'' = CH2OH, aspercyclide B
R = OH, R' = H, R'' = H, (+)-aspercyclide C
In 2005, Fürstner and co-workers reported the first synthesis of
(+)-aspercyclide C in which the chirality was introduced via a
Duthaler–Hafner alkoxyallylation reaction employing stoichiome-
tric (S,S)-taddol and macrocyclization was via ring-closing metath-
esis (RCM).3a Similar syntheses of (+)-aspercyclide C and its C12
methyl ether, also deploying RCM macrocyclization but using
Figure 1. Structures of the aspercyclides, with numbering system and anti-diol unit
highlighted.
D-ribose and L-tartaric acid as the sources of chirality, were
subsequently reported by the Ramana3b and Prasad3c groups,
respectively. In 2009, Fürstner and co-workers reported an ap-
proach to (+)-aspercyclide A employing (S)-glycidol to establish
the C20 stereocentre and an intramolecular Nozaki–Hiyama–Kishi
(NHK) reaction to effect macrocyclization with concomitant diaste-
reoselecive anti-1,2-diol formation.4 Subsequently, we reported a
synthesis of ( )-aspercyclide A and its C19 methyl ether employing
a diastereoselective Takai–Utimoto alkoxyallylation to establish
the anti-1,2-diol function followed by either a Heck–Mizoroki5 or
a germyl-Stille macrocyclization reaction.6 Most recently, Sato
and co-workers reported the first asymmetric synthesis of (+)-
aspercyclide A (14 steps from salicylic acid, 20% overall yield).7
Their route featured a Sharpless asymmetric epoxidative desym-
metrization catalyzed by sub-stoichiometric (À)-DIPT to establish
the anti-1,2-diol motif, and using an elegant and potentially biomi-
metic intramolecular oxidative diaryl etherification to close the
macrocycle.
Herein, we describe an enantioselective synthesis of (+)-asper-
cyclide A and also a ring-A derivative in which the intramolecularly
hydrogen-bonded C14 phenol and C15 aldehyde have been
replaced by an oxathiazine dioxide ring moiety. Our synthesis
employs an iridium-catalyzed diastereo- and enantioselective
anti-alkoxyallylation developed by Krische and co-workers to
establish the two stereocentres.8 This group have developed proto-
cols for diastereo- and enantioselective carbonyl allylation/crotyla-
tion and related reactions9 via the iridium-catalyzed transfer
hydrogenation.10 We envisaged using their anti-alkoxyallylation
⇑
Corresponding author. Tel./fax +44 (0)20 759 45841.
E-mail address: a.c.spivey@imperial.ac.uk (A.C. Spivey).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.038

J. J. P. Sejberg et al. / Tetrahedron Letters 54 (2013) 4970–4972
4971
Br
method, wherein an allyl gem-dicarboxylate acts as the allyl
donor,8 to obtain optically pure mono-protected anti-diol 4, which
could then be taken through to (+)-aspercyclide A by a route anal-
ogous to that which we developed in our racemic synthesis.5 Due
to problems with migration of an acetyl protecting group during
the initial optimization of the reaction, the method described by
Krische and co-workers involves acylative capping of the crude
mono-protected diol to give diester products.8 However, we sus-
pected that the migration would not occur with the mono-benzo-
ate. Gratifyingly, this was indeed the case, eliminating the need for
a potentially difficult selective deprotection of the homoallylic
alcohol over the allylic alcohol. Thus, in our hands, treatment of
n-hexanal with gem-dibenzoate 2 and iridium catalyst 3 furnished
mono-protected anti-diol 4 in moderate to good yields (47–61%)
and high optical purity (98.0–99.6% ee) on both small and medium
scale (i.e., 20–400 mg of hexanal) (Scheme 1).
5
Cl
Br
O
NaH
OBz
O
OBz
C5H11
THF
reflux, 2.5 h
(80%)
O
HO
C5H11
4
6
K2CO3, MeOH
rt, 17 h then 50 oC, 1 h
(93%)
PMBBr
KHMDS
Br
Br
O
O
THF
OPMB
C5H11
OH
C5H11
-78 oC, 1 h
then rt, 1.5 h
(quant.)
O
O
8
7
(1:4 mixture of rotamers)
Initially, we carried this Bz-protected anti-diol forward in the
synthesis, but we were unable to achieve Heck–Mizoroki macro-
Scheme 2. Synthesis of Ullmann coupling precursor 8.
cyclization, possibly due to p-allyl palladium formation. We there-
fore decided to switch protecting groups early on in the synthesis.
Thus, treatment of anti-diol 4 with sodium hydride and 2-bromo-
6-methylbenzoyl chloride (5) furnished benzoic ester 6 in good
yield. Removal of the benzoate protecting group was achieved by
treatment with K2CO3 in methanol11 giving alcohol 7 as what we
believe to be a mixture of rotamers (1:4) in excellent yield
(Scheme 2).12
The presence of these rotamers is likely due to hindered rota-
tion about the aryl–carbonyl carbon bond, the magnitude of the
barrier for which is presumably amplified by internal hydrogen
bonding between the OH and the carbonyl group (cf. compounds
6 and 8). Re-protection of the alcohol as the PMB ether by treat-
ment with KHMDS in the presence of PMBBr13 furnished Ullmann
coupling precursor 8 in quantitative yield (Scheme 2). Cu-mediated
Ullmann coupling with functionalized phenol 95 proceeded in
moderate yield using 30 mol % of either a Cu(I) or Cu(II) catalyst
in pyridine.14 However, employing a mixed Cu(I)/Cu(II) catalyst
system (1:1, 30 mol % copper in total) resulted in an improved
yield of 72% of biaryl ether 10 (Scheme 3).
O
O
X
O
O
CuO, Cu2O
K2CO3
O
O
8
O
pyridine
reflux, 19 h
(72%)
Br
OH
C5H11
CuI, NaI
OH
9
10
11
X = Br
N,N-dimethylethylenediamine
1,4-dioxane, 120 oC, 45 h
(86%)
X = I
12
Pd(acac)2,
, Cs2CO3, AgI
1,4-dioxane, reflux, 25 h
(53%)
MeO
N
N
OMe
12
O
O
OH OH
Copper-mediated aromatic Finkelstein halogen exchange15 then
gave the corresponding aryl iodide 11, which underwent the
Heck–Mizoroki16 macrocyclization in the presence of AgI (to
suppress dibenzofuran formation through direct arylation via
C–H activation17) to afford macrocycle 13 in 53% isolated yield.
p-TsOH-catalyzed acetonide removal proceeded smoothly to afford
diol 14 in good yield. Oxidation of the benzyl alcohol with MnO2
followed by removal of the PMB ether with BF3ÁEt2O gave (+)-
aspercyclide A (1) in 54% yield from 14 (Scheme 3). The optical
rotation measured for our material (+278) is higher than that
reported by Singh et al. (+191)1 and Sato and co-workers (+196)7,
p-TsOH-H2O
O
O
O
O
OPMB
C5H11
OPMB
C5H11
O
THF-MeOH
35 oC, 17 h
(77%)
O
13
14
1. MnO2, CH2Cl2, 40 oC, 5 h
2. BF3 Et O, CH2Cl , rt, 3 min
(54% ove2r 2 steps) 2
1 (+)-aspercyclide A
Scheme 3. Completion of the synthesis of (+)-aspercyclide A (1).
3
(5 mol%)
K3PO4, iPrOH
however the circular dichroism (CD) spectra recorded for our
material match that recorded for an original sample of (+)-aspercy-
clide A (kindly provided by Merck). The overall yield from hexanal
was 4.8–6.2% over the 10 steps.
OBz
O
THF
C5H11
BzO
OBz
HO
C5H11
60 oC, 48 h
(47-61%)
4
(98.0-99.6% ee)
2
A significant concern about the utility of (+)-aspercyclide A as a
lead for further development towards a therapeutic agent for asth-
ma and allergy is the presence of the ring-A aldehyde moiety. Alde-
hydes can potentially react with protein lysine side chains to form
Schiff bases leading to unselective irreversible toxicity.18 To dis-
count this mode of reactivity as being responsible for the
bioactivity of (+)-aspercyclide A we decided also to prepare a
derivative of aspercyclide A which did not contain an aldehyde
group—compound 15. We targeted a cyclic structure designed to
loosely mimic ring-A plus the six-membered ring formed by the
intramolecularly H-bonded hydroxyaldehyde motif. We envisaged
O
Ph Ph
P
O
O
Ir
O
P
O
Ph
Ph
O
CN
NO2
3
Scheme 1. Synthesis of optically pure anti-diol 4.

4972
J. J. P. Sejberg et al. / Tetrahedron Letters 54 (2013) 4970–4972
O
O
References and notes
S
O
N
OH
O
O
1. Singh, S. B.; Jayasuriya, H.; Zink, D. L.; Polishook, J. D.; Dombrowski, A. W.;
Zweerink, H. Tetrahedron Lett. 2004, 45, 7605–7608.
O
O
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Blackwell, Chichester 2008, 1, 103–118; (c) Helm, B. A.; Sayers, I.; Swan, J.;
Smyth, L. J. C.; Cain, S. A.; Suter, M.; Machado, D. C.; Spivey, A. C.; Padlan, E. A.
Technol. Health Care 1998, 6, 195–207.
3. (a) Furstner, A.; Muller, C. Chem. Commun. 2005, 5583–5585; (b) Ramana, C. V.;
Mondal, M. A.; Puranik, V. G.; Gurjar, M. K. Tetrahedron Lett. 2007, 48, 7524; (c)
Prasad, K. R.; Gandi, V. R.; Nidhiry, J. E.; Bhat, K. S. Synthesis 2010, 2521.
4. Pospíšil, J.; Müller, C.; Fürstner, A. Chem. Eur. J. 2009, 15, 5956–5968.
5. Carr, J. L.; Offermann, D. A.; Holdom, M. D.; Dusart, P.; White, A. J. P.; Beavil, A.
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S
Cl
NH2
O
O
OH
OH
DMA
O
O
rt, 23 h
(21%)
C5H11
C5H11
O
15
1 (+)-aspercyclide A
Scheme 4. Synthesis of non-aldehydic derivative 15 of (+)-aspercyclide A.
benzoxathiazine-2,2-dioxide analogue 15 to be accessible through
treatment of (+)-aspercyclide A with sulfamoyl chloride,19 as
described by Du Bois and co-workers.20
6. Carr, J. L.; Sejberg, J. J. P.; Saab, F.; Holdom, M. D.; Davies, A. M.; White, A. J. P.;
Leatherbarrow, R. J.; Beavil, A. J.; Sutton, B. J.; Lindell, S. D.; Spivey, A. C. Org.
Biomol. Chem. 2011, 9, 6814–6824.
Thus, benzoxathiazine analogue (+)-15 was obtained in 21%
yield by treatment of (+)-aspercyclide A (1) with sulfamoyl chlo-
ride in dry dimethylacetamide (DMA) at room temperature
(Scheme 4).20
7. Yoshino, T.; Sato, I.; Hirama, M. Org. Lett. 2012, 14, 4290–4292.
8. Han, S. B.; Han, H.; Krische, M. J. J. Am. Chem. Soc. 2010, 132, 1760–1761.
9. (a) Gao, X.; Townsend, I. A.; Krische, M. J. J. Org. Chem. 2011, 76, 2350–2354; (b)
Bechem, B.; Patman, R. L.; Hashmi, A. S. K.; Krische, M. J. J. Org. Chem. 2010, 75,
1795; (c) Kim, I. S.; Han, S. B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2514–
2520; (d) Han, S. B.; Gao, X.; Krische, M. J. J. Am. Chem. Soc. 2010, 132, 9153; (e)
Han, S. B.; Hassan, A.; Kim, I. S.; Krische, M. J. J. Am. Chem. Soc. 2010, 132, 15559;
(f) Han, S. B.; Kim, I. S.; Han, H.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 6916.
10. For reviews of this type of reaction, see: (a) Bower, J. F.; Kim, I. S.; Patman, R. L.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34; (b) Han, S. B.; Kim, I. S.;
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J.; Linsell, M. S. 2011, WO 2011044501; Chem. Abstr. 2011, 154, 435160.
12. The rotamers of alcohol 7 can be separated by silica gel chromatography. Each
rotamer was taken through the synthesis to (+)-aspercyclide A. After PMB-
protection (? 8), all 1H and 13C NMR data and optical rotations of
intermediates were identical irrespective of the starting rotamer.
Furthermore, CD spectra of the material obtained from both rotamers were
identical and matched that 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. Resubjection of a pure sample of the minor
rotamer from the Bz-deprotection step, to the deprotection conditions (K2CO3
in MeOH, 50 °C, 1 h), resulted in the isolation of a 4:10 mixture favoring the
major isomer from the Bz-deprotection step. This supports the notion that the
two isomers are rotamers.
The ability of compound (+)-15 to inhibit the human IgE-FceRIa
protein–protein interaction (PPI) was assessed using an ELISA (see
Supplementary data) which revealed that it displayed only margin-
ally reduced potency as compared to the parent natural product:
(+)-15, IC50 = 160–460 lM, cf. (+)-1, IC50 = 50–200 l
M.1,6
In conclusion, an efficient route to (+)-aspercyclide A of high
optical purity has been developed. The route features a Krische
iridium-catalyzed diastereo- and enantioselective anti-alkoxyally-
lation to establish the two stereocentres (C19 and C20) and a
Heck macrocyclization. A derivative of the natural product (15),
lacking the benzaldehyde ring-A moiety has been found to exhi-
bit comparable inhibition of the human IgE-FceRI PPI to that of
the parent natural product in an ELISA, which indicates that
the activity of (+)-aspercyclide A cannot be attributed to non-
specific irreversible Schiff base formation with protein lysine
residues.
13. Sanchez, C. C.; Keck, G. E. Org. Lett. 2005, 7, 3053–3056.
14. Kulkarni, N. N.; Kulkarni, V. S.; Lele, S. R.; Hosangadi, B. D. Tetrahedron 1988, 44,
5145–5149.
We are currently in the process of preparing a number of addi-
tional aspercyclide A analogues to enable further studies into the
structure activity relationship (SAR) of aspercyclide A. The results
of these studies will be reported in due course.
15. (a) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844–14845; For a
review see: (b) Sheppard, T. D. Org. Biomol. Chem. 2009, 7, 1043–1052.
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44; (b) Grasa, G. A.; Singh, R.; Stevens, E. D.; Nolan, S. P. J. Organomet. Chem.
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Acknowledgments
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references therein.
19. Chen, J.; Sperl, G.; Gullo, V.; Sista, L.; Hughes, D.; Peng, Y.; Pierceall, W.;
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The European Commission FP7 Marie Curie Actions and the
Imperial College ICB-CDT are acknowledged for financial support
of this work. We also wish to thank Sheo B. Singh, Merck Research
Laboratories, for kindly providing us with a sample of natural
(+)-aspercyclide A.
20. Litvinas, N. D.; Brodsky, B. H.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 4513–
4516.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.038.