Nonchiral-pool synthesis of (+)-hyacinthacine B1

Article abstract of DOI:10.1055/s-0028-1088147

The first nonchiral-pool total synthesis of (+)-hyacinthacine B₁ has been achieved. The synthesis uses as key steps an efficient [2+2] cycloaddition of dichloroketene to a chiral enol ether, two diastereoselective Bruylants-like alkylations, an

Full text of DOI:10.1055/s-0028-1088147

LETTER
1141
Nonchiral-Pool Synthesis of (+)-Hyacinthacine B1
S
ynthesis of (+
a
)
-Hyacinthiacine 1
B
di Venkatram Reddy, Peter Koos, Amaël Veyron, Andrew E. Greene, Philippe Delair*
Département de Chimie Moléculaire (SERCO) UMR-5250, ICMG FR-2607, CNRS Université Joseph Fourier, B. P. 53,
38041 Grenoble Cedex 9, France
Fax +33(4)76635754; E-mail: philippe.delair@ujf-grenoble.fr
Received 18 November 2008
To the memory of an excellent alkaloid chemist, Dr. Christian Marazano.
hibitor of b-glucosidase, b-galactosidase, and b-mannosi-
Abstract: The first nonchiral-pool total synthesis of (+)-hyacintha-
cine B1 has been achieved. The synthesis uses as key steps an effi-
cient [2+2] cycloaddition of dichloroketene to a chiral enol ether,
two diastereoselective Bruylants-like alkylations, and an effective
double Tamao–Fleming oxidation.
dase.11,12
OH
OH
OH
HO
H
N
H
N
H
1
7a
HO
OH
OH
OH
OH
OH
OH
Key words: stereoselective synthesis, natural products, azasugars,
cycloadditions, double Tamao–Fleming oxidation
5
3
N
HO
(+)-hyacinthacine A1 (1) (+)-hyacinthacine B1 (2) (+)-hyacinthacine C1 (3)
Figure 1 Examples of the three classes of hyacinthacines
The discovery of biologically active compounds with un-
usual mechanisms of action is important for confronting
the serious problem of multidrug resistance. Iminosugars1
effectively inhibit a-glycosidases, enzymes that are in-
volved in a large array of biological phenomena, and thus
are of potential use for the treatment of a variety human
diseases, inter alia, diabetes, cancers, malaria, and viral
infections.2 Among the naturally occurring iminosugars,
the rapidly expanding class of polyhydroxylated
pyrrolizidines3 has attracted significant attention because
of the selective inhibitory activity associated with several
of the alkaloids.1
We planned that hyacinthacine B1 would be secured from
the disilylated derivative III by an unusual double
Tamao–Fleming oxidation that would engender the two
hydroxymethyl units in a single step (Scheme 1). We
hoped that the C-5 silylmethyl substituent in III might be
introduced through a stereoselective Bruylants reaction of
the aminonitrile obtained by reductive cyanation of pyr-
rolizidinone II. Pyrrolizidinone II (P = H) had earlier
been prepared from enol ether I (R*OH = Stericol®).6
OH
OP
The hyacinthacines, a recently discovered pyrrolizidine
subgroup characterized by C-3 hydroxymethyl substitu-
tion, are divided into hyacinthacines A, B, and C based on
the number of hydroxyl and hydroxymethyl groups on the
second ring (cf. 1–3, Figure 1).4 Most reported synthetic
efforts toward these compounds have focused on the rela-
tively simple hyacinthacine A series and have either yield-
ed the racemic product or used chiral-pool starting
material or enzymatic techniques to obtain the natural
product.5 Very recently, we reported6 the first nonchiral-
pool synthesis of hyacinthacine A1 through the use of dia-
stereoselective dichloroketene–chiral enol ether cycload-
dition,7 a methodology previously applied for the prepara-
tion of a variety of other alkaloids.8–10 As an extension of
this work, we now describe the first nonchiral-pool prep-
aration of hyacinthacine B1, a pyrrolizidine characterized
by the presence of synthetically challenging hydroxy-
methyls at C-3 and C-5 and five stereocenters. Isolated in
low yield (12 mg/kg) by Asano and co-workers from im-
mature fruits and stalks of bluebells (Hyacinthoides non-
scripta), this alkaloid has been shown to be a selective in-
H
N
H
deprotection
OP
SiMe2Ph
OH
OH
N
HO
PhMe2Si
III
(+)-hyacinthacine B1 (2)
double Tamao–
Fleming oxidation
OP
H
OP
SiMe2Ph
OR*
N
O
II
I
reductive cyanation;
Bruylants reaction
Scheme 1 Retrosynthesis of (+)-hyacinthacine B1
The synthesis of hyacinthacine B1 thus started from the
commercially available chiral auxiliary (S)-(–)-Stericol®
413 (Scheme 2). This inductor allowed the preparation of
pyrrolizidinone 6, via lactam 510b,14 in a highly stereo-
selective manner, the key diastereoselective steps being: a
[2+2] cycloaddition of dichloroketene to a Stericol-
derived enol ether, a Bruylants-like addition of the silyl-
methyl substituent, and an endo-selective dihydroxyla-
tion.6
SYNLETT 2009, No. 7, pp 1141–1143
x
x.
x
x.
2
0
0
9
Advanced online publication: 20.03.2009
DOI: 10.1055/s-0028-1088147; Art ID: G34808ST
© Georg Thieme Verlag Stuttgart · New York

1142
P. V. Reddy et al.
LETTER
Triethylsilyl groups were chosen for protection of the C-1 signments, the minor diol was resilylated to provide the
and C-2 hydroxyl functions in 6 as they appeared to offer pure minor pyrrolizidine 9, which showed no significant
the best balance between easy of introduction/removal NOE between the hydrogens at C-3 and C-5, but one (1%)
and steric hindrance, which was expected to influence the between those at C-5 and C-7a.
stereoselectivity of the upcoming Bruylants15 C-5 alkyl-
Several different procedures have been developed for
ation. Triethylsilylation of 6 proceeded smoothly with tri-
ethylsilyl chloride in presence of imidazole to produce
lactam 7 (Scheme 2). The conversion of this lactam into
the corresponding aminonitrile16 in preparation for the
Bruylants reaction proved, though, problematic. Reduc-
tive cyanation with the often used DIBAL-H/KCN
system17 led invariably to significant amounts of over-
reduced material, while the use of Schwartz’s reagent
with TMSCN18 led primarily to recovered starting materi-
al. Fortunately, though, the DIBAL-H–n-BuLi ate com-
plex19 smoothly produced the desired hemiaminal, which,
following treatment in situ with TMSCN, gave in 89%
yield a 1.6:1 mixture of the epimeric aminonitriles 8.
silane oxidation,20 and some of them have been success-
fully used with a potentially oxidizable amino group in the
substrate.21 In a model study carried out using pyrrolizi-
dine 11, a lack of reactivity was observed under the basic
conditions developed by Smitrovich and Woerpel;21a in
contrast, the expected silanol was formed with tetrafluo-
roboric acid followed by a basic workup,21c but the subse-
quent oxidation with hydrogen peroxide in the presence of
potassium fluoride gave, disappointingly, only the pro-
todesilylated N-oxide derivative 12 (Scheme 3).
OH
OH
H
N
H
1. HBF4⋅OMe2; KOHaq
+ N
– O
2. H2O2, KF, DMF
61%
O
Ar
SiMe2Ph
ref. 6
12
OH
OH
11
HN
Scheme 3 Attempted Tamao–Fleming oxidation
O
5
(S)-(–)-Stericol (4)
It was hoped, however, that by eliminating the basic
workup, thereby leaving the nitrogen atom protonated, a
better result might be obtained in this Tamao–Fleming ox-
idation. To our considerable satisfaction, removal of
volatiles after treatment of pyrrolizidine 11 with tetrafluo-
roboric acid and then oxidation of the protonated silyl flu-
oride intermediate, indeed produced the corresponding
diol, without significant formation of the N-oxide.
OTES
H
H
TESCl, imid
94%
OH
OTES
5
N
N
O
O
SiMe2Ph
SiMe2Ph
7
6
OTES
OTES
H
N
DIBAL-H, BuLi;
TMSCN
PhMe2SiCH2MgCl
THF–Et2O
With this encouraging model-system result in hand, the
double Tamao–Fleming oxidation of 10 was next investi-
gated. While double Tamao–Fleming oxidations are rela-
tively few in the literature,22 a recent example reported by
Somfai and co-workers22g in their synthesis of (+)-alexine
allowed a degree of optimism. Under acidic conditions
[Hg(OTf)2, AcOOH, AcOH], they were able to obtain a
2:1 mixture of the expected diol and its N-oxide in 62%
combined yield. Much to our delight, by applying the
Tamao–Fleming protocol that had been successful in our
model system, 10 underwent clean double oxidation to af-
ford hyacinthacine B1 in 75% yield, without discernible
N-oxide formation (Scheme 4). The synthetically derived
natural product {[a]D +40} so obtained was spectroscopi-
cally and chromatographically indistinguishable from a
sample of the naturally derived material {[a]D +41.311}.23
89%
NC
SiMe2Ph
8
OH
H
OTES
H
TBAF
7a
OH
OTES
N
3
68% (from 8)
5
N
5:1
SiMe2Ph
PhMe2Si
SiMe2Ph
PhMe2Si
9
10
Ar = 2,4,6-triisopropylphenyl
Scheme 2 Preparation of bissilane 10
The mixture of aminonitriles reacted with dimethyl-
phenylsilylmethylmagnesium chloride in diethyl ether–
THF at room temperature to afford a 5:1 epimeric mixture
of alkylated pyrrolizidines 9. A sample of the major iso-
mer, separated with difficulty by silica gel chromatogra-
phy, provided 1H NMR data in agreement with the
depicted structure. Particularly diagnostic was the strong
NOE (10%) between the C-3 and C-5 hydrogens. The
TES groups were next removed from 9 by treatment with
TBAF, and the resultant mixture could now be easily sep-
arated by chromatography to give diol 10 in 68% overall
yield from 8. As further support for the stereochemical as-
OH
H
1. HBF4⋅OMe2
OH
N
10
2. H2O2, KF, DMF
75%
OH
(+)-hyacinthacine B1 (2)
HO
Scheme 4 Completion of the synthesis of (+)-hyacinthacine B1
Synlett 2009, No. 7, 1141–1143 © Thieme Stuttgart · New York

LETTER
Synthesis of (+)-Hyacinthacine B1
1143
(8) Pyrrolidines: (a) Kanazawa, A.; Gillet, S.; Delair, P.;
In summary, (+)-hyacinthacine B1 has been efficiently
prepared (4.4% overall yield) in enantiopure form through
an asymmetric cycloaddition approach. This approach,
which does not rely on chiral-pool substrates, is highly
flexible and should be useful for the synthesis of yet other
hyacinthacines.
Greene, A. E. J. Org. Chem. 1998, 63, 4660. (b) Delair, P.;
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M.; Delair, P.; Greene, A. E. J. Org. Chem. 2001, 66, 5438.
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8, 4739.
(10) Pyrrolizidines: (a) Roche, C.; Delair, P.; Greene, A. E. Org.
Lett. 2003, 5, 1741. (b) Roche, C.; Kadlecíková, K.; Veyron,
A.; Delair, P.; Philouze, C.; Greene, A. E.; Flot, D.;
Burghammer, M. J. Org. Chem. 2005, 70, 8352.
(11) Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.;
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank Professor N. Asano for a comparison sample of natural
hyacinthacine B1 and Professor P. Dumy for his interest in our
work. Financial support from the CNRS and the Université Joseph
Fourier is gratefully acknowledged.
(12) To the best of our knowledge, only a very recent synthesis of
hyacinthacine B1 starting from L-pyroglutamic acid has been
published prior to this report. See: Sengoku, T.; Satoh, Y.;
Oshima, M.; Takahashi, M.; Yoda, H. Tetrahedron 2008, 64,
8052.
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