Formal synthesis of galantinic acid by oxo-Diels-Alder methodology

Article abstract of DOI:10.1002/ejoc.201001296

This communication presents a simple and efficient enantioselective route to galantinic acid. The strategy is based on a highly enantioselective hetero-Diels-Alder (HDA) reaction of 3-(4-methoxybenzyloxy)propanal with Danishefsky's diene followed by selec

Full text of DOI:10.1002/ejoc.201001296

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001296
Formal Synthesis of Galantinic Acid by Oxo-Diels–Alder Methodology
Wojciech Chaładaj[a] and Janusz Jurczak*[a,b]
Keywords: Natural products / Cycloaddition / Oxygen heterocycles / Chromium
This communication presents a simple and efficient enantio-
selective route to galantinic acid. The strategy is based on a
highly enantioselective hetero-Diels–Alder (HDA) reaction of
3-(4-methoxybenzyloxy)propanal with Danishefsky’s diene
followed by selective introduction of further stereogenic cen-
ters thanks to the rigidity of the dihydropyran ring. The key
HDA reaction is catalyzed by a new salen CrIII complex bear-
ing a 1,1-diphenylethyl substituent at the 3-position of the
salicyliden moiety.
activity, galantinic acid has attracted the attention of a
number of synthetic chemists.[5,6] Most of the reported
Introduction
Galantinic and galantinamic acids (1 and 2, respectively) methodologies are based on a chiral pool approach.[5] Only
are nonproteogenic amino acid components of galantin,[1] two approaches utilize enantioselective processes – Jacob-
a peptide antibiotic isolated from Bacillus pulvifaciens sen’s hydrolytic kinetic resolution of epoxides[6a] and the
(Scheme 1).[2] The initially proposed structure[3] of galan- Sharpless epoxidation[6b] – but they suffer from low overall
tinic acid (i.e., 3) turned out to be incorrect and was revised yields (5.6 and 5.7%, respectively).
in the early 1990s by Sakai and Ohfune,[4] who reported the
Herein we present an enantioselective formal synthesis of
first, and so far the only, total synthesis of galantin. Due galantinic acid (1) based on an enantioselective oxo-Diels–
to its unusual polyol structure and its potential biological Alder reaction with Danishefsky’s diene, taking advantage
Scheme 1. Galantin and its nonproteogenic amino acid components.
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax: +48-22-632-66-81
of the rigidity of the resulting dihydropyran ring for selec-
tive introduction of further stereogenic centers (Scheme 2).
Acid 1 can be derived from aldehyde 4, the cyclic hemiacet-
al form of which 5 is a product of hydrolysis of aziridine 6.
Azidirine 6 can be obtained from dihydropyranon 7
through sequential reduction of the carbonyl group fol-
E-mail: jurczak@icho.edu.pl
[b] Department of Chemistry, Warsaw University,
Pasteura 1, 02-093 Warsaw, Poland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001296.
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W. Chaładaj, J. Jurczak
SHORT COMMUNICATION
Scheme 2. Retrosynthetic analysis of galantinic acid.
lowed by aziridination, or through a synthetically equiva-
lent transformation. Dihydropyranon 7, in turn, is an obvi-
ous product of condensation of Danishefsky’s diene with
properly protected 3-hydroxypropanal 8. 3-(4-Methoxy-
benzyloxy)propanal (9) was chosen as a starting material
for the synthesis due to the possibility of facile deprotection
of the hydroxy function under oxidative or hydrogenolytic
conditions as well as orthogonality to common aziridine
protection, such as carbamide or sulfonamide.
Table 1. Enantioselective reaction of aldehyde 9 with Danishefsky’s
diene.
Entry
Catalyst
[mol-%]
Diene
[equiv.]
Yield
[%]
ee[a]
[%]
Results and Discussion
1
2
3
4
5
10a (2)
10b (2)
1
1
1
1
1.5
74
81
93
68
90
78
86
94
94
94
We started our investigation of the above-presented syn-
thetic route by optimizing the key reaction of 3-(4-methoxy-
benzyloxy)propanal with Danishefsky’s diene. Considering
the choice of catalyst, we focused our attention on stable,
inexpensive, and well-defined salen chromium(III) com-
plexes, which have proven their eficiency in enantioselective
HDA reactions,[7] in particular in the reaction with Danish-
efsky’s diene.[8] Classic complex 10a proved to be a moder-
ately good catalyst for the reaction investigated, leading un-
der the reaction conditions developed by Jacobsen[8a] to de-
sired dihydropyrone 11 in high yields and with high
enantioselectivities (Table 1, Entry 1). As expected, based
on our previous observations, the application of sterically
modified catalyst 10b[8d,8e,9] improved both the yield and
the enantioselectivity (Table 1, Entry 2). Hoping for further
improvements in the reaction outcome, we synthesized
complex 10c (Figure 1) bearing a 1,1-diphenylethyl substit-
uent at the 3-position of the salicyliden moiety (Scheme 3).
Catalyst 10c proved its efficiency, leading to dihydropyrone
11 in excellent yield with 94%ee (Table 1, Entry 3). De-
creased catalyst loading, down to as little as 0.5 mol-%,
resulted in virtually no change in selectivity but to a lower
yield; however, this can be suppressed by the use of
1.5 equiv. of Danishefsky’s diene with respect to the alde-
hyde (Table 1, Entries 4 and 5).
10c (2)
10c (0.5)
10c (0.5)
[a] Determined by HPLC with an AD-H column.
Dihydropyranone 11 was reduced by using Luche meth-
odology[10] to corresponding allyl alcohol 16, which was
further acetylated to yield 17 (Scheme 4). Note that the Lu- 14.
Figure 1. ORTEP diagrams of chromium complex 10c and ligand
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Formal Synthesis of Galantinic Acid by Oxo-Diels–Alder Methodology
Scheme 3. Synthesis of sterically modified complex 10c. Reagents
and conditions: (a) 1,1-diphenylethane, H2SO4, CH2Cl2, room
temp.; (b) (HCHO)n, SnCl4, Bu3N, toluene, 110 °C; (c) (S,S)-1,2-
diammoniumcyclohexane d-tartrate, K2CO3, EtOH/H2O, reflux;
(d) 1. CrCl2, THF; 2. air.
Figure 2. ORTEP diagram of iodosulfonamide 18.
structurally resembles galantinic acid; in particular it bears
all stereogenic centers in the proper configuration. Protec-
tion of two hydroxy groups (including primary) as an iso-
propylidene acetal, followed by hydrogenolytic cleavage of
the p-methoxybenzyl ether produced compound 22, which
only differs in terms of the protection of the amine group
from the precursor of galantinic acid applied by Sakai and
Ohfune in the original synthesis of galantine. What is more,
2-(trimethylsilyl)ethylsulfonyl (SES) protection,[12] similarly
to the original Boc group, seems to be orthogonal to all
other protection groups used in the reported total synthe-
che reduction proceeded in a completely diastereoselective
fashion to the cis product. Moreover, both the reduction
and the acetylation were virtually quantitative and gave suf-
ficiently pure products after the usual extractive workup.
Employing the methodology developed by Danishefsky,[11]
allyl acetate 17 was converted into iodosulfonamide 18,
which after crystallization gave enantiomerically pure prod-
uct with almost 50% yield. Unfortunately, monocrystals of
18 were not suitable for X-ray analysis; however, indepen-
dently obtained racemic form of 18 did produce material of
sufficient quality. The structure of 18 determined by X-ray
crystallographic analysis of rac-18 is depicted in Figure 2
and unquestionably confirms the expected relative configu-
ration of iodosulfonamide 18.
Scheme 4. Reagents and conditions: (a) CeCl3·7H2O, NaBH4,
MeOH, –20 °C; (b) AcCl, Et3N, CH2Cl2; (c) I(coll-sym)2PF6,
SESNH2, CH2Cl2.
Compound 18, possessing iodine and sulfonamide
groups in a 1,2-diaxial orientation, easily cyclizes under ba-
sic conditions to the corresponding aziridine, which was in
turn hydrolytically opened (Scheme 5). Resulting hemiacet-
al 19 was further reduced to open-chain monoprotected
tetrol 20. All the above-described reactions enabling conver-
sion of 18 into 20 were performed as a one-pot sequence,
Scheme 5. Reagents and conditions: (a) Et3N, THF/H2O, room
temp., 12 h; (b) NaBH4, THF/H2O/Et3N, 60 °C, 3 h; (c) 2,2-di-
yielding polyol 20 in 83% overall yield. Compound 20 methoxypropane, acetone, TsOH, 30 min; (d) H2, Pd/C, MeOH.
Eur. J. Org. Chem. 2011, 1223–1226
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W. Chaładaj, J. Jurczak
SHORT COMMUNICATION
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Conclusions
In conclusion we have shown a short, enantioselective
route to galantinic acid. Enantiomerically pure, properly
protected direct precursor 22 was synthesized in eight steps
in 25% overall yield. The exceptionally high yield and
enantioselectivity of the key reaction with Danishefsky’s
diene was achieved by application of a new, sterically modi-
fied salen chromium complex.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and crystallographic data.
CCDC-781845 (for 10c), -781846 (for 14), and -781847 (for rac-
18) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Acknowledgments
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Financial support for W.Ch. from the Foundation for Polish Sci-
ence is gratefully acknowledged. The X-ray measurements were un-
dertaken in the Crystallographic Unit of the Physical Chemistry
Laboratory at the Chemistry Department of the University of War-
saw (10c and 14) or at the Institute of Organic Chemistry PAS (rac-
18).
[9] For application of 10b in other reactions, see: a) P. Kwiatkow-
ski, W. Chaładaj, J. Jurczak, Synlett 2005, 2301–2304; b) R.
Kowalczyk, P. Kwiatkowski, J. Skarzewski, J. Jurczak, J. Org.
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[12] SES protection is sometimes hardly removable. In this case, the
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strated by deprotection of the amine group in compound 20,
and by trapping the free amine as a Boc derivative. The conver-
sion of 20 into the corresponding Boc derivative was ac-
complished in 39% yield in an non-optimized protocol.
Received: September 16, 2010
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Published Online: January 27, 2011
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Eur. J. Org. Chem. 2011, 1223–1226