The first enantioselective total synthesis of (-)-arisugacin A

Article abstract of DOI:10.1016/S0040-4039(02)02094-4

The first enantioselective synthesis of (-)-arisugacin A in 17 steps is described here, featuring a CBS asymmetric ketone reduction and a highly stereoselective formal [3+3] cycloaddition approach. This concise synthesis of the enantiomer unambiguously confirms the original assignment of the absolute configuration.

Full text of DOI:10.1016/S0040-4039(02)02094-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8791–8793
The first enantioselective total synthesis of (−)-arisugacin A
Kevin P. Cole and Richard P. Hsung*,†
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Received 9 September 2002; accepted 12 September 2002
Abstract—The first enantioselective synthesis of (−)-arisugacin A in 17 steps is described here, featuring a CBS asymmetric ketone
reduction and a highly stereoselective formal [3+3] cycloaddition approach. This concise synthesis of the enantiomer unambigu-
ously confirms the original assignment of the absolute configuration. © 2002 Elsevier Science Ltd. All rights reserved.
(+)-Arisugacin A (1) was isolated from Penicillium sp.
Fo-4259 and identified as an inhibitor of acetyl-
cholinesterase (AChE) with the highest potency and
selectivity among all known inhibitors of AChE,
thereby possessing significance in treatment of demen-
tias.1,2 Given such biological relevance and its unique
structural features, arisugacin A (1) has attracted much
ours.4 While we have explored a number of different
synthetic routes toward 1,5 our eventual 20-step racemic
synthesis4 featured a key formal [3+3] cycloaddition
reaction6–9 of a,b-unsaturated iminium salt 3 with 2-
pyrone 4 that proceeds through a highly stereoselective
6p-electron electrocyclic ring-closure10 (Scheme 1). This
stepwise cycloaddition methodology has proven to be
highly useful for constructing complex 2H-pyrans7 and
dihydropyridines.8 To continue our efforts in shorten-
ing the synthesis as well as achieving an enantioselective
synthesis, we chose to pursue ent-arisugacin A (2)
because of inherent advantages of possessing the enan-
tiomer from medicinal and stereochemical perspectives.
We communicate here the first enantioselective total
synthesis of (−)-arisugacin A and confirmation of its
absolute stereochemistry.
attention from the synthetic community leading to total
3
0
syntheses of racemic material from Omura’s group and
Scheme 1.
Scheme 2. (a) CH3CCCO2H, DCC, DMAP, CH2Cl2, 0°C to
rt. (b) n-decane, reflux, 23 h. (c) m-CPBA, CH2Cl2, 0°C, 48 h.
(d) 2.0 equiv. AlCl3 in THF at −78°C, and added 4.0 equiv.
LAH soln, and then added 9, −78°C to rt, 2 h. (e) 5 mol%
TPAP, 1.4 equiv. NMO, molecular sieves, CH2Cl2, rt.
* Corresponding author.
† A recipient of 2001 Camille Dreyfus Teacher-Scholar and 2001–
2003 McKnight New Faculty Awards.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02094-4

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K. P. Cole, R. P. Hsung / Tetrahedron Letters 43 (2002) 8791–8793
To achieve synthesis of (−)-arisugacin A, (R)-6 was
obtained readily from 2-methyl-1,3-cyclohexanedione
(7) in four steps with an overall yield of 46%, featuring
vinylogous ester formation, Stork–Danheiser double
alpha methylation,11,12 vinyl Grignard addition fol-
lowed by acidic work-up,11 and an asymmetric CBS
reduction (Scheme 2).13,14 The level of enantiomeric
excess (ee) for (R)-6 was found to be in the range of
85–95% using 1H NMR ratios of corresponding
diastereomeric naproxen esters.15 By comparing with
optical rotation of the known (S)-6 ([h]2D3 −53.0 (c 1.0,
CHCl3)) with an ee>90% using Mosher’s esters,14a opti-
cal rotation of (R)-6 ([h]2D3 +53.2 (c 1.0, CHCl3)) also
confirms its level of ee as well as absolute configuration
at C1.
yield, although some lactolization of 11 was observed at
higher temperatures or in acidic mediums.
The key formal [3+3] cycloaddition reaction of the
enal 11 with the pyrone 417 under the standard condi-
tions4,6–8 using
L-proline as the initiator for the forma-
tion of the iminium salt from 11 led to the desired
pentacycle 12 in 54% yield a single diastereomer
(Scheme 3). To render L-proline useful in the iminium
formation, solubility was an issue, and thus, THF was
used in place of EtOAc which was frequently used in
our previous studies.7,8 Subsequent TPAP oxidation of
12 led to the keto pentacycle 13 in 92% yield, and a
directed reduction of 13 using NMe4BH(OAc)3 in
AcOH gave exclusively the diol pentacycle 14 in 94%
yield with b-C1-OH. The optically enriched pentacycles
12–14 matched spectroscopically with the racemic
standards.4a,b
DCC/DMAP mediated esterification of 2-butynoic acid
using (+)-(R)-6 followed by intramolecular Diels–Alder
cycloaddition of the resulting ester in refluxing decane
(conc. 0.07 M) provided the tricyclic lactone 8 in 60%
overall yield (Scheme 2). Epoxidation of 8 using non-
buffered m-CPBA led to the b-epoxy lactone 9 (or
ent-5) in 64% yield. The b-epoxy lactone 9 is highly
crystalline unlike the racemic form. Further recrystal-
lization from 1:1 mixture of EtOAc and hexane pro-
vided 9 with >97% ee. A successful one-pot reduction
of 9 using AlH3 carefully generated in situ16 gave the
triol 10 in 90% yield. A selective Ley’s TPAP oxidation
of the triol 10, without protecting either the C1- or
C4a-hydroxyl group, afforded the key enal 11 in 73%
Dihydroxylation4c of 14 in pyridine, a protocol used for
our racemic synthesis was found to be difficult here
mainly in the isolation of the tetraol product. We
elected to go with the epoxidation protocol4c using
various peroxy acetic acids,3 and the best result gave
the desired product 15 in 21% yield in addition to a
hexacycle4a,b in 28% yield.
Subsequent removal of the C12 hydroxyl group in 15
using Et3SiH and TFA4c gave the diol acetate pentacy-
cle 16 in 83% yield. Deacylation of 16 followed by
TPAP oxidation of the triol 17 gave the pentacycle 18
in 73% overall yield. Schlosser’s base (LDA generated
in the presence of KOt-Bu) was effective in the selena-
tion,3,4 and subsequent oxidative elimination of the
selenide using H2O2 afforded in 67% overall yield (−)-
arisugacin A (2) that matched spectroscopically (co-
spectra of 1H NMR in pyridine-d5) and analytically
(TLC: in 2:1 EtOAc:hexane; 2:1 ether:hexane; 1:9 ace-
tone:CHCl3] with the natural as well as racemic sample.
The optical rotation of synthetic (−)-arisugacin A (2)
([h]2D3 −79.0 (c 0.1, CHCl3)) confirms the originally
assigned absolute configuration for the natural (+)-
arisugacin A ([h]2D3 +72.0 (c 0.1, CHCl3)).
We have described here a 17-step total synthesis of
(−)-arisugacin A with an overall yield of 4.3%. This
enantioselective synthesis features a CBS asymmetric
reduction, a highly stereoselective formal [3+3] cycload-
dition, and a key bisoxygenation–deoxygenation proto-
col to install the desired C12a-OH, and confirms the
absolute configuration of the natural (+)-arisugacin A.
Supporting Information Available: NMR spectra of title
compounds reported here are given.
Scheme 3. (a) 0.5 equiv.
L
-proline, THF, 65°C, 1.5 equiv. of
Acknowledgements
4. (b) 5 mol% TPAP, 1.4 equiv. NMO, CH2Cl2, 3 h. (c)
NMe4BH(OAc)3, AcOH, rt, 30 min. (d) 20 equiv. CH3CO3H,
pH 7 buffer, CH2Cl2, rt. (e) Et3SiH, TFA, CH2Cl2, rt, 4 h. (f)
K2CO3, MeOH, rt, 2 h. (g) 5 mol%, TPAP, 1.4 equiv. NMO,
CH2Cl2, 3 h. (h) i. LDA, KOt-Bu, HMPA, THF, −78°C,
PhSeBr; ii. 10 equiv. H2O2, AcOH, THF, 0°C to rt, 1.5 h.
R.P.H. thanks National Institutes of Health (NS38049)
and American Chemical Society PRF-Type-G for
financial support. We thank Professor S. Omura for a
0
generous sample of (+)-arisugacin A.

K. P. Cole, R. P. Hsung / Tetrahedron Letters 43 (2002) 8791–8793
8793
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