Approach to the hyacinthacines: First non-chiral pool synthesis of (+)-hyacinthacine A1

Article abstract of DOI:10.1039/b800445e

The first non-chiral pool total synthesis of (+)-hyacinthacine A ₁ is described. This synthesis is based on an effective [2 + 2] cycloaddition of dichloroketene to a Stericol-based enol ether, a diastereoselective dihydroxylation, and an efficient Tamao-Fleming oxidation. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b800445e

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Approach to the hyacinthacines: first non-chiral pool synthesis of
(+)-hyacinthacine A1†
P. Venkatram Reddy, Amae¨l Veyron, Peter Koos, Alexandre Bayle, Andrew E. Greene and Philippe Delair*
Received 11th January 2008, Accepted 15th February 2008
First published as an Advance Article on the web 28th February 2008
DOI: 10.1039/b800445e
The first non-chiral pool total synthesis of (+)-hyacinthacine
A1 is described. This synthesis is based on an effective [2 +
(IC50 value of 4.4 lM).8 To the best of our knowledge, only three
syntheses of this alkaloid have so far been reported in the literature,
one racemic13 and two from chiral pool material.12d
R
2] cycloaddition of dichloroketene to a Stericolꢀ-based enol
It was planned that hyacinthacine A1 would derive from the
protected pyrrolizidinone III by installation of the hydroxyl
functions and lactam reduction (Scheme 1). This pyrrolizidinone,
in turn, was seen as arising from lactam II by stereoselective
reductive alkylation with a latent hydroxymethyl group, followed
by oxidation and cyclization. Lactams of the general type II had
already been prepared in our group by stereoselective cycload-
dition of dichloroketene to chiral enol ethers I, Beckmann ring
expansion, and dechlorination.6c,7
ether, a diastereoselective dihydroxylation, and an efficient
Tamao–Fleming oxidation.
Glycosidases and glycotransferases are enzymes that catalyze
the degradation and the biosynthesis of oligosaccharides and
glycoconjugates (glycoproteines, glycolipids), which are involved
in a large array of biological phenomena. Inhibitors of these
enzymes can be considered as potential candidates for the
treatment of a variety human diseases, such as diabetes, cancers,
malaria, and viral infections.1 Iminosugars, structurally related to
carbohydrates, are among the most promising of the inhibitors,1,2
and within this group, the polyhydroxylated pyrrolizidines are
of particular interest because of their selectivity, as well as the
challenges associated with their stereoselective synthesis.3
Over the past few years, we have been studying the asymmet-
ric synthesis of alkaloids through the use of diastereoselective
dichloroketene–chiral enol ether cycloaddition.4 This method-
ology has been applied to the synthesis of naturally occurring
pyrrolidines,5 indolizidines,6 and, recently, pyrrolizidines.7 Am-
phorogynines A and D,7a two members of a new class of C-
1,C-6-substituted pyrrolizidines, and retronecine,7b a necine base
(C-1,C-7-substituted pyrrolizidine), have thus been efficiently
prepared. Another important pyrrolizidine class, exemplified by
hyacinthacine A1 (1),8,9 alexine (2),10 and casuarine (3),11 is
characterized by the presence of a hydroxymethyl group at C-
3.12 The first non-chiral pool total synthesis of (+)-hyacinthacine
A1 is now reported, which serves to underscore both the flexibility
and efficiency of our pyrrolizidine approach.
Scheme 1 Retrosynthesis of (+)-hyacinthacine A1.
R
The synthesis began from (S)-(−)-Stericolꢀ, a broadly effective
chiral auxiliary,14,15 which was converted into the known7 lactam
5 in 57% overall yield (Scheme 2).16 This was transformed into the
hemiaminalderivative7viaimide6in71%yieldbysuccessivetreat-
R
ment with Boc anhydride, Super Hydrideꢀ, and p-toluenesulfonic
acid in methanol in preparation for the introduction of a
hydroxymethyl equivalent. Initial attempts to achieve this end
through the reaction of 7 with a variety of hydroxymethylcuprate
derivatives (from ROCH2Li; R = Bn, p-MeOC6H4CH2, tert-
Bu, TBDMS)17 under different reaction conditions provided at
best only low yields of the desired adduct. Fortunately, however,
magnesio-(dimethylphenylsilylmethyl)cuprate18 reacted with 7 in
the presence of boron trifluoride etherate19 in 7:1 ether–dimethyl
sulfide to give a 6:1 mixture of difficult to separate pyrrolidines
(major isomer 8 shown) in 96% yield (in ether alone, the
diastereoselectivity was 3:1). The diastereomeric ratios and the
stereochemical assignments were established◦by careful analysis
of high-field 1H NMR spectra recorded at 85 C.
Hyacinthacine A1 was isolated in low yield (5 mg kg−1) from
the bulbs of Muscari armeniacum (Hyacinthaceae) and found to
exhibit selective inhibitory activity toward rat intestinal lactase
De´partement de Chimie Mole´culaire (SERCO) UMR-5250, ICMG FR-
2607, CNRS Universite´ Joseph Fourier, BP-53, 38041, Grenoble Cedex 9,
France. E-mail: philippe.delair@ujf-grenoble.fr; Fax: +33 4 76 63 57 54;
Tel: +33 4 76 63 54 42
† Electronic supplementary information (ESI) available: Characterization
data for compounds 1, 6–12, 15, 16 and NMR spectra for compounds 1,
6, 8–12, 15, 16. See DOI: 10.1039/b800445e
With a surrogate hydroxymethyl group now in place, the pyrro-
lidine derivatives were transformed into esters 9 by hydroboration,
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Scheme 4 Initial studies conducted with pyrrolizidine 13.
lactam 15.26 Since several modifications of the experimental con-
ditions did not fundamentally alter these disappointing results, the
above preparation of lactam 12 was conceived with the expectation
now that this considerably flatter bicycle would provide a highly
satisfactory stereochemical outcome.
Much to our delight, dihydroxylation of pyrrolidinone 12 under
similar conditions indeed proved highly stereoselective: the desired
diol 15 was formed exclusively in 99% yield (Scheme 5). The
primary hydroxyl group was next unmasked in 15 through a
Tamao–Fleming oxidation,27 which proceeded smoothly to afford
triol 16 in 82% yield. Completion of the synthesis was achieved
through borane reduction of 16 to give in 78% yield hyacinthacine
A1 ([a]D +43.9 (c 0.29, H2O)), which provided spectral data in
perfect agreement with those of the naturally derived product ([a]D
+38.2 (c 0.23, H2O)).8,28
Scheme 2 Preparation of silane 8.
21
oxidation,20,21 and esterification (Scheme 3). Conveniently, on
heating in toluene the free amines, obtained selectively from 9
with TMSOTf,22 only the major diastereomer cyclized, to provide
pyrrolizidinone 10 in 63% yield (2 steps). This fortuitous event
can most likely be ascribed to the significant steric interactions
that would be encountered in going from the minor pyrrolidine
to the diastereomeric pyrrolizidinone. The chiral auxiliary was
next cleaved with trifluoroacetic acid to provide pyrrolizidinol 11,
which could best be converted into olefin 12 by pyrolysis of the
corresponding methyl xanthate23 under published conditions.24
Scheme 5 Completion of the synthesis of (+)-hyacinthacine A1.
In conclusion, we have demonstrated through this efficient
synthesis of (+)-hyacinthacine A1 (6.5% overall yield) that the
dichloroketene–chiral enol ether cycloaddition approach to nat-
ural products can provide a stereocontrolled entry to another
important class of pyrrolizidines. Application of this novel
methodology for the preparation of more complex hyacinthacines
is currently under investigation.
Financial support from the CNRS and the Universite´ Joseph
Fourier (UMR 5250, ICMG FR 2607) is gratefully acknowledged.
We thank Professor P. Dumy for his interest in our work and a
referee for bringing to our attention two pertinent references.
Scheme 3 Preparation of pyrrolizidinone 12.
Notes and references
Efforts to stereoselectively introduce vicinal hydroxyl groups
proved interesting. In initial studies conducted with the
pyrrolizidine 1325 (Scheme 4), it had been found that catalytic
osmium tetroxide-mediated dihydroxylation with trimethylamine
N-oxide as the co-oxidant produced an equimolar mixture of cis
diols, which to our surprise was composed of the undesired b,b-diol
14 and the desired a,a-diol, the latter, however, as the over-oxidized
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Org. Biomol. Chem., 2008, 6, 1170–1172 | 1171
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25 Prepared from
8
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1172 | Org. Biomol. Chem., 2008, 6, 1170–1172
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The Royal Society of Chemistry 2008
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