Stereoselective syntheses of the glycosidase inhibitors hyacinthacine A2, hyacinthacine A3 and 5-epi-hyacinthacine A3

Article abstract of DOI:10.1016/j.tet.2009.06.046

Stereoselective syntheses of the naturally occurring glycosidase inhibitors hyacinthacines A₂ and A₃ are reported. In the case of hyacinthacine A₂, the pyrrolizidine system was created from an acyclic precursor via a doubl

Full text of DOI:10.1016/j.tet.2009.06.046

Tetrahedron 65 (2009) 6965–6971
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Tetrahedron
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Stereoselective syntheses of the glycosidase inhibitors hyacinthacine A2,
hyacinthacine A3 and 5-epi-hyacinthacine A3
,
Celia Ribes a, Eva Falomir a, Miguel Carda a, J. Alberto Marco b
*
a
´
´
´
´
Depart. de Q. Inorganica y Organica, Univ. Jaume I, Castellon, E-12080 Castellon, Spain
b
´
Depart. de Q. Organica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 May 2009
Received in revised form 6 June 2009
Accepted 12 June 2009
Available online 18 June 2009
Stereoselective syntheses of the naturally occurring glycosidase inhibitors hyacinthacines A2 and A3 are
reported. In the case of hyacinthacine A2, the pyrrolizidine system was created from an acyclic precursor
via a double cyclization procedure with a one-pot formation of two C–N bonds. In the case of hyacin-
thacine A3, the two C–N bonds were created in separate steps. In addition, the non-natural epimer at C-5
of hyacinthacine A3 was obtained.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
enantiomer.7 Four of these syntheses used commercial sugar de-
rivatives as the chirality source,7a–d whereas the remaining one
Pyrrolizidine alkaloids have been isolated from species of many
terrestrial plants.1 Polyhydroxylated representatives have been
found in genera belonging to the Leguminosae and a few other
families. For instance, hyacinthacine A1 (1), hyacinthacine A2 (2)
and hyacinthacine A3 (3) (Fig. 1) were isolated in 2000, together
with further related alkaloids, from Muscari armeniacum Leichtl. ex
Baker (Hyacinthaceae).2 From these, compound 1 showed a strong
relied on the enzymatic resolution of a racemic aminoacid for the
preparation of the chiral starting material.7e An enzymatic meth-
odology was also used in the synthesis of the enantiomer of hya-
cinthacine A2.7f With respect to hyacinthacine A3 (3), only one
synthesis has been reported so far, with a sugar derivative also
being the starting material.8
In the present paper, we describe stereoselective syntheses of 2
and 3. The retrosynthetic plan for 2, shown in Scheme 1, relies on
that followed in our recent syntheses of the natural pyrrolidines
broussonetines D and M, because all these compounds share the
b
-galactosidase activity whereas 2 and, to a lesser extent, 3 were
found to be selective inhibitors of the amyloglucosidase from
Aspergillus niger.
HO
1
HO
HO
H
N
1
H
N
2
H
N
3
7
HO
OH
H
OBn OH
HO
OH
R
7a
6
HO
HO
HO
HO
HO
5
2
O
O
3
5
N
N
H
NBoc OBn
OH
HO
8
HO
HO
I
2
4
Figure 1. Structures of hyacinthacines A1 (1), A2 (2) and A3 (3).
The diverse array of potentially useful biological activities3 and
the high degree of functionality embedded in these alkaloids make
them attractive targets for stereoselective synthesis.4 As regards
the hyacinthacine family, several of its members have been so far
the object of total synthesis. In most cases, simple carbohydrates
already having several of the final stereocentres were the ultimate
source of chirality.5,6 As for 2 and 3, five syntheses of the former
have appeared in the bibliography, as well as one of the non-natural
OBn OH
O
Garner´s (R)-aldehyde
H
O
NBoc OBn
5
NBoc
HO
OH
OBn OH
H
O
N
HO
NBoc OBn
O
3
6
* Corresponding author. Tel.: þ34 96 3544337; fax: þ34 96 3544328 (J.A.M.).
E-mail address: alberto.marco@uv.es (J.A. Marco).
Scheme 1. Retrosynthetic analysis of 2 and 3.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.046

6966
C. Ribes et al. / Tetrahedron 65 (2009) 6965–6971
common fragment I.9 Thus, pyrrolizidine 2 may be referred to diol 4
via one-pot or stepwise cleavage of two C–N bonds.10 In the syn-
thetic sense, this corresponds to activation of the hydroxyl groups
and oxazolidine ring opening, followed by two nucleophilic sub-
followed by alkalinization with aq methanolic ammonia. This
yielded pyrrolizidine 2, which showed spectroscopic data consis-
tent with those reported for both natural2 and synthetic7 hyacin-
thacine A2.
stitutions. Diol
4
in turn should be readily prepared from
Scheme 3 depicts the synthesis of hyacinthacine A3 (3). Our
initial idea was to convert alcohol 5 into methyl ketone 6, followed
by mesylation to 12 and subsequent cyclization. On the basis of that
observed in the previous synthesis of 38 and in our synthesis of
radicamine B,9b we expected that hydrogenation of 12 in an acidic
medium would give rise to cleavage of N-protecting groups, intra-
molecular nucleophilic substitution and reductive ring closure with
formation of the pyrrolizidine system of 3. Indeed, Wacker oxida-
tion12 of 5 gave moderate yields of ketone 6, which was then
mesylated to 12. Unfortunately, all attempts at converting 12 into 3
were unsuccessful, mixtures of ill-defined products being the only
observed result.
compound 5, for which an efficient synthesis from Garner’s (R)-
aldehyde has been recently reported by our group.9a Likewise,
pyrrolizidine 3 may also be referred to alcohol 5 through a similar
sequence of reactions via ketone 6.
2. Results and discussion
Scheme 2 shows in detail the synthesis of hyacinthacine A2 (2).
Compound 5 can be prepared in 6 steps and ca. 59% overall yield
from Garner’s (R)-aldehyde.9a Attempts at oxidative cleavage of the
olefinic bond in 5 gave unsatisfactory yields. Much better results
were observed after protection of the free OH as the triethylsilyl
(TES) ether to yield 7. Thus, oxidative cleavage of the C]C bond in 7
to give alcohol 8 was achieved in 70% overall yield by means of
OBn OH
OBn OH
PdCl2, CuCl,
aq DMF, O2
O
O
O
50%
NBoc
OBn
NBoc OBn
5
a
three-step osmylation/periodate oxidation/NaBH4 reduction
procedure.10 Desilylation of the TES group in 8 with tetra-n-butyl-
ammonium fluoride (TBAF) furnished diol 9 in almost quantitative
yield. The latter reacted with mesyl chloride to give dimesylate 10.
6
2 steps
MsCl, py
ref. [9a]
OMs
OBn
BnO
OH
OBn
O
1: OsO4, NMO, tBuOH
aq THF, RT, 2h
O
NBoc OBn
N
R
2: aq NaIO4, RT, 2 h
OBn OR
3: NaBH4, MeOH, 0 °C
1.5 h (70% overall)
OBn OTES
12
CbzCl, Na2CO3,
aq THF, RT, 93%
13
Boc2O,
NEt3
(68%)
R = H
14 R = Cbz
15 R = Boc
O
O
NBoc OBn
NBoc OBn
OH
3
PdCl2, CuCl, 88% from 14
8
86% from 15
aq DMF, O2
TESCl, Et3N, CH2Cl2
RT, 16 h, 87%
5 R = H
7 R = TES
HO
TBAF, THF
H
N
aq HCl:MeOH 1:10
H2, Pd/C, RT
BnO
OBn
RT, 40 min (99%)
HO
5
3
+
variable proportions
O
3
3
/ 5-epi- (see text)
OBn OMs
N
R
OBn OH
MsCl, Et3N
CH2Cl2, 0°C, 2 h
HO
OH
3
-
5-
epi
16
R = Cbz
O
O
17 R = Boc
NBoc OBn
OMs
NBoc OBn
OH
TPSCl,
10
9
88-90%
BnO
imidazole
aq HCl:MeOH 1:10
H2, Pd/C, RT, 2d
TFA, CH2Cl2
0 °C, 2 h (55%
overall from 9)
OBn
5-epi-3
1: 6M HCl/MeOH 1:10, 10% Pd/C, H2, 40 h, RT
2: NH4OH, MeOH (62% overall from 9)
(75% from 18)
O
N
R
aq HCl:MeOH 1:10
H2, Pd/C, RT, 2d
TPSO
BnO
BnO
H
N
3
+ 5-epi-3
18
R = Cbz
19 R = Boc
HO
H
19
)
(from
11
Scheme 3. Stereoselective synthesis of 3 and 5-epi-3.
HO
N
HO
HO
NOE
H3
N
2
In view of these drawbacks, we decided to build up the two
required C–N bonds of the pyrrolizidine system in two separate
steps. Compound 5 was converted into pyrrolidine 13 in two steps
as reported in our recent synthesis of broussonetines D and M.9a
Conversion of 13 into its N-Cbz and N-Boc derivatives, 14 and 15,
followed by Wacker oxidation gave methyl ketones 16 or 17, re-
spectively. When subjected to hydrogenolytic conditions, either of
these two ketones gave separable mixtures of hyacinthacine A3 (3)
and its epimer at C-5 (5-epi-3).13 The relative configuration of the
new stereocentre (C-5) was confirmed in both cases with the aid of
NOE studies. For 3, a NOE was observed between H-1 and the
methyl group bound to C-5. This NOE was not detected in 5-epi-3
but, in contrast, a NOE was visible between H-7a and the afore-
mentioned methyl group.
H1
OBn
BnO
OH
NOE
Scheme 2. Stereoselective synthesis of 2.
H7a
H2
Treatment of 10 with trifluoroacetic acid (TFA) in CH2Cl2 at 0 ꢀC
provided pyrrolizidine 11 in a one-pot process which encompasses
the cleavage of the Boc and the aminoacetal groups followed by the
sequential formation of two C–N bonds through intramolecular 5-
exo-tet nucleophilic substitutions.11 NOE studies were performed
on compound 11 in order to confirm the configuration at the newly
formed stereocentre C-7a (Scheme 2). While compound 11 was
amenable to conversion into 2 by means of hydrogenolytic depro-
tection of the two benzyl groups, it proved much more practical to
stir crude 10 in an acidic medium under an H2 atmosphere,
The relative proportion of the two pyrrolizidines was markedly
dependent on the experimental procedure. For instance, hydro-
genolysis under neutral conditions until disappearance of the
starting compound (TLC monitoring), followed by addition of acid

C. Ribes et al. / Tetrahedron 65 (2009) 6965–6971
6967
(aq HCl/MeOH) and further stirring under a H2 atmosphere affor-
ded a mixture of 3 and 5-epi-3 with a slight predominance of the
former (dr w1.2:1). In contrast, when the acid was added from the
beginning of the hydrogenolysis, 5-epi-3 was practically the sole
product detected, even though the formation of small amounts of 3
cannot be completely excluded.
were freshly distilled from KOH. Toluene was freshly distilled from
sodium wire. Commercially available reagents were used as received.
Unless detailed otherwise, ‘work-up’ means pouring the reaction
mixture into brine, followed by extraction with the solvent indicated
in parenthesis. If the reaction medium was acidic, an additional
washing with 5% aq NaHCO3 was performed. If the reaction medium
was basic, an additional washing with aq NH4Cl was performed. New
washing with brine, drying over anhyd Na2SO4 and elimination of the
solvent under reduced pressurewere followed bychromatographyon
On the basis of that reported in the previous synthesis of 3,8 we
wondered whether the presence of a free hydroxyl group might
exert some influence14 on the stereochemical outcome of the hy-
drogenation step. Thus, ketones 16 and 17 were first converted into
their respective silylated derivatives 18 and 19 (Scheme 3,
TPS¼tert-butyldiphenylsilyl). Compound 19 showed spectral data
coincident with those reported for an intermediate in the previous
synthesis of 3.8,15 When 18 was subjected to hydrogenolysis under
the same conditions described above for 16 and 17 (acid added from
the beginning), however, 5-epi-3 was the main product, whereas 19
yielded a mixture of 3 and 5-epi-3 (dr w1:1). Further variations in
the reaction conditions (modification of temperature or reaction
time, etc.) caused changes in the relative proportion of 5-epi-3 to 3
but did not give rise to the formation of pure 3.
The reasons of these stereochemical differences and of the di-
vergence of our results from those reported in the previous
synthesis8 of 3 are not clear. trans-2,5-Disubstituted pyrrolidine
derivatives with a 3-oxoalkyl chain at C-2 and a further substituent
at C-5 (pyrrolidine numbering) have often been shown to undergo
ring closure via intramolecular reductive amination to yield a pyr-
rolizidine system.16 Furthermore, the stereoisomers formed in
a predominant or exclusive manner were found to display the same
relative configuration at C-3, C-5 and C-7a as does 5-epi-3. This has
been attributed to a face-selective reduction of the intermediate
bicyclic iminium cation controlled by an interplay of stereo-
electronic and steric factors.17 Therefore, preferential formation of
5-epi-3 rather than 3 is the expected result in the present case.
However, the fact that small variations in the reaction conditions
cause marked changes in the stereoisomer composition suggests
that other subtle factors may also play a role.
a silica gel column (60–200 mm) and elution with the indicated sol-
vent mixture. Where solutions were filtered through a Celite pad, the
pad was additionally washed with the same solvent used, and the
washings incorporated to the main organic layer.
3.1.1. tert-Butyl (R)-4-[(1R,2S,3S)-1,2-bis(benzyloxy)-3-
(triethylsilyloxy)hept-6-enyl]-2,2-dimethyloxazolidine-3-
carboxylate (7)
A solution of alcohol 59a (1.05 g, 2 mmol) in dry CH2Cl2 (10 mL)
was cooled to 0 ꢀC under N2 and treated with Et3N (1.12 mL,
8 mmol, 2 equiv) and TESCl (0.4 mL, 2.4 mmol, 1.2 equiv). The re-
action mixture was stirred at room temperature for 16 h. Work-up
(extraction with CH2Cl2, 3ꢁ15 mL) and column chromatography on
silica gel (hexanes/EtOAc, 95:5) afforded 1.11 g (87%) of silyl ether 7:
oil; [
a
]
D þ42.3 (c 1.65, CHCl3); 1H NMR (500 MHz, DMSO-d6, 70 ꢀC):
d¼7.35–7.25 (br m, 10H), 5.80 (ddt, J¼17.2, 10.3, 6.4 Hz, 1H), 5.00
(dd, J¼17.2, 1.7 Hz, 1H), 4.95 (dd, J¼10.3, 1.7 Hz, 1H), 4.68 (d,
J¼11.2 Hz, 1H), 4.62 (m, 3H), 4.24 (br s, 1H), 4.10 (dd, J¼8.6, 4.2 Hz,
1H), 4.06 (m, 1H), 3.90–3.85 (m, 2H), 3.34 (dd, J¼6.4, 4.9 Hz, 1H),
2.15 (br m, 1H), 2.04 (br m, 1H), 1.80 (br m, 1H), 1.56 (br m, 1H), 1.47
(s, 9H), 1.42 (s, 3H), 1.40 (s, 3H), 0.92 (t, J¼7.8 Hz, 9H), 0.57 (q,
13
J¼7.8 Hz, 6H); C NMR (125 MHz, DMSO, 70 ꢀC):
d
¼152.6
*
, 139.2,
139.1, 94.0
*
, 80.1 (Cq), 139.3, 128.7 (ꢁ2), 128.6 (ꢁ2), 128.2 (ꢁ2),
* * *
128.0,127.9 (ꢁ2),127.8, 83.9, 78.2
, 72.0, 59.2
(CH), 75.1, 73.9, 63.9
,
32.2
*
, 30.2, 5.2 (ꢁ3) (CH2), 28.8 (ꢁ3), 26.4
*
, 25.0
*
, 7.2 (ꢁ3) (CH3)
(starred signals are low and broad); IR nmax 3065 (C]C–H), 1692
(C]O) cmꢂ1
;
HRFABMS m/z 640.4039 (MþHþ). Calcd for
In summary, the two bioactive, naturally occurring pyrrolizidine
alkaloids 2 and 3 and the non-natural alkaloid 5-epi-3 have been
prepared in enantiopure form from the commercially available
C37H58NO6Si: 640.4033.
3.1.2. tert-Butyl (R)-4-[(1R,2S,3S)-1,2-bis(benzyloxy)-6-hydroxy-3-
(triethylsilyloxy)hexyl]-2,2-dimethyloxazolidine-3-carboxylate (8)
Compound 7 (448 mg, 0.7 mmol) was dissolved at room tem-
perature in a mixture of THF (1.5 mL), t-BuOH (3.75 mL) and water
(0.5 mL). The solution was then treated with NMO (100 mg, ca.
0.84 mmol, 1.2 equiv) and OsO4 (4% aq solution, 0.18 mL,
0.028 mmol, 0.04 equiv) and stirred at room temperature for 2 h.
Subsequently, a solution of NaIO4 (214 mg, ca. 1 mmol, 1.4 equiv) in
water (1 mL) was added dropwise, followed by further stirring at
room temperature for 2 h. The reaction mixture was then treated
with satd aq Na2SO3 (5 mL), stirred for 5 min and extracted with
CH2Cl2 (3ꢁ20 mL). The organic layers were washed with brine and
dried on anhyd Na2SO4. After filtration and solvent removal under
reduced pressure, the oily residue was used as such in the next step.
The residue from above was dissolved in MeOH (8 mL), cooled to
0 ꢀC and treated with NaBH4 (80 mg, 2.1 mmol, 3 equiv). The re-
action mixture was then stirred at 0 ꢀC for 1.5 h. Work-up (extrac-
tion with EtOAc, 2ꢁ15 mL) and column chromatography on silica
aminoacid D
-serine via Garner’s aldehyde.18
3. Experimental
3.1. General
1H/13C NMR spectra were recorded at 500/125 MHz in the in-
dicated solvent at 30 ꢀC if not stated otherwise. Molecules with Cbz or
Boc protecting groups were measured at higher temperatures in
those cases where this was necessary to have reasonably sharp sig-
nals. When sharp, separate signals for the two rotamers were ob-
served at 30 ꢀC, the signals of one of the rotamers are indicated in
italics. The signals of the deuterated solvent were taken as the
reference (for DMSO-d6,
d
2.50 and 39.5 ppm for 1H and 13C NMR,
respectively). For spectra measured in D2O, sodium 3-(trimethylsilyl)-
propanesulfonate-d6 (DSS) was the reference for
d
¼0 (1H and 13C
NMR). Carbon atom types (C, CH, CH2, CH3) were determined with the
DEPT pulse sequence. Mass spectra were run by the electron impact
mode (EIMS), by the fast atom bombardment mode (FABMS, m-
nitrobenzyl alcohol matrix) or by the electrospray injection mode
(ESMS). IR data are given only for compounds with significant func-
tions (OH, C]O) and were recorded as oily films on NaCl plates (oils)
or as KBr pellets (solids). Optical rotations were measured at 25 ꢀC.
Reactions which required an inert atmosphere were carried out un-
der N2 with flame-dried glassware. Et2O and THF were freshly dis-
tilled from sodium/benzophenone ketyl and transferred via syringe.
Dichloromethane was freshly distilled from CaH2. Tertiary amines
gel (hexanes/EtOAc, 8:2) furnished alcohol 8 (316 mg, 70%): oil; [a]
D
þ46 (c 2.25, CHCl3); 1H NMR (500 MHz, CDCl3, 55 ꢀC):
¼7.35–7.20
d
(br m, 10H), 4.75–4.70 (m, 2H), 4.64 (s, 2H), 4.40 (br s, 1H), 4.22 (dd,
J¼8.8, 4.2 Hz, 1H), 4.20 (br s, overlapped, 1H), 3.90 (m, 2H), 3.63 (br
t, J¼5.6 Hz, 2H), 3.38 (dd, J¼7.2, 4.5 Hz, 1H), 1.90 (br m, 2H), 1.70 (m,
2H), 1.50 (br s,12H), 1.47 (s, 3H), 0.95 (t, J¼8 Hz, 9H), 0.57 (q, J¼8 Hz,
6H) (hydroxyl signal not detected); 13C NMR (125 MHz, CDCl3,
55 ꢀC):
(ꢁ2), 127.8 (ꢁ2), 127.7 (ꢁ2), 127.5, 127.2, 84.7, 78.1
75.5, 74.3, 63.9
, 63.0, 29.2 (ꢁ2), 5.1 (ꢁ3) (CH2), 28.6 (ꢁ3), 26.2
d
¼152.8
*
, 139.1, 138.8, 94.0
*
, 80.2 (Cq), 128.3 (ꢁ2), 128.1
*
, 72.4, 59.0 (CH),
*
*
*
,

6968
C. Ribes et al. / Tetrahedron 65 (2009) 6965–6971
24.9
*
, 6.9 (ꢁ3) (CH3) (starred signals are low and broadened); IR
dissolved in MeOH (3 mL) and the solution was brought to basic pH
with dropwise addition of 33% aq NH3. After stirring for 10 min at
room temperature, the solvent was removed under reduced pres-
sure. The residue was then put on the top of a ion-exchange resin
column (DowexÒ 50Wx4 200–400 mesh, pre-acidified with 0.5 M
HCl). Elution with water (50 mL) to remove salts and then with 1 M
aq NH3 until elution of the product (TLC monitoring), followed by
removal of the volatiles of the latter fraction under reduced pres-
sure, gave a brownish residue which was subjected to column
chromatography on silica gel (CHCl3/MeOH/aq NH3, gradient from
90:10:1 to 10:10:1). This yielded hyacinthacine A2 (2) (19 mg, 62%
nmax 3490 (br, OH), 1691 (C]O) cmꢂ1; HRFABMS m/z 644.3998
(MþHþ). Calcd for C36H58NO7Si: 644.3982.
3.1.3. tert-Butyl (R)-4-[(1R,2R,3S)-1,2-bis(benzyloxy)-3,6-
dihydroxyhexyl]-2,2-dimethyloxazolidine-3-carboxylate (9)
A solution of compound 8 (258 mg, 0.4 mmol) in dry THF (3 mL)
was treated under N2 with TBAF trihydrate (152 mg, 0.48 mmol,
1.2 equiv). The reaction mixture was stirred at room temperature
for 45 min. Solvent removal under reduced pressure and column
chromatography of the residue on silica gel (hexanes/EtOAc, 1:1)
provided diol 9 (209 mg, 99%): oil; [
NMR (500 MHz, CDCl3, 55 ꢀC):
a
]
þ51.8 (c 0.8, CHCl3); 1H
overall yield from 9): oil; [
a
]
D þ12.1 (c 0.3, H2O), lit.2
[
a
]
D þ20.1 (c
D
d
¼7.35–7.20 (br m, 10H), 4.78 (d,
0.44, H2O), lit.7a
H2O), lit.7c
lit.7e
[
a
]
D
þ12.5 (c 0.4, H2O), lit.7b
[a]
D
þ12.7 (c 0.13,
J¼11.2 Hz, 1H), 4.76 (d, J¼11.3 Hz, 1H), 4.67 (d, J¼11.3 Hz, 1H), 4.58
(d, J¼11.2 Hz, 1H), 4.32 (br s, overlapped, 1H), 4.30 (dd, J¼8.8,
3.5 Hz, 1H), 4.15 (br s, 1H), 3.96 (dd, J¼8.8, 7.5 Hz, 1H), 3.72 (br m,
1H), 3.60 (m, 2H), 3.30 (dd, J¼6, 3 Hz, 1H), 2.50 (br s, OH, 2H), 1.70–
1.50 (br m, overlapped, 4H), 1.57 (s, 3H), 1.51 (s, 9H), 1.48 (s, 3H); 13C
NMR (125 MHz, CDCl3, 55 ꢀC):
128.3 (ꢁ2),128.2 (ꢁ4),127.9 (ꢁ2),127.7,127.5, 82.2
(CH), 75.0, 74.6
[
a
]
þ10.5 (c 0.6, H2O), lit.7d
[
a
]
D
þ19.9 (c 0.97, MeOH),
D
[a
]
D þ11.2 (c 0.52, H2O), lit.7f for the non-natural enantiomer,
[a
]
D ꢂ11 (c 1, MeOH); IR nmax 3470 (br, OH) cmꢂ1. For NMR data and
their comparison with literature values for natural and synthetic
samples, see Supplementary data.
d
¼152.9
*
,138.5,138.2, 93.9
*
, 80.4 (C),
, 71.1, 58.8
, 24.3
*
, 78.2
*
3.1.6. tert-Butyl (R)-4-[(1R,2R,3S)-1,2-bis(benzyloxy)-3-hydroxy-6-
oxoheptyl]-2,2-dimethyloxazolidine-3-carboxylate (6)
*
, 63.5, 62.7, 31.4, 29.6 (CH2), 28.5 (ꢁ3), 26.4
*
*
(CH3) (starred signals are low and broadened); IR nmax 3430 (br,
OH), 1688 (C]O) cmꢂ1; HRFABMS m/z 530.3118 (MþHþ). Calcd for
C30H44NO7: 530.3117.
A solution of compound 5 (263 mg, 0.5 mmol) in a 10:1 DMF/
H2O mixture (11 mL) was treated with PdCl2 (35 mg, 0.2 mmol) and
CuCl (248 mg, 2.5 mmol). The reaction mixture was then stirred
under O2 at room temperature for 24 h. Work-up (extraction with
Et2O, 3ꢁ10 mL) and column chromatography on silica gel (hexanes/
3.1.4. [(1R,2R,3R,7aR)-1,2-Bis(benzyloxy)hexahydro-1H-pyrrolizin-
3-yl] methanol (11)
EtOAc, 8:2 to 7:3) afforded 135 mg (50%) of methyl ketone 6: oil;
1
A solution of diol 9 (185 mg, 0.35 mmol) in dry CH2Cl2 (3 mL)
was cooled to 0 ꢀC under N2 and treated with DMAP (6 mg,
0.05 mmol), Et3N (0.3 mL, 2.1 mmol, 6 equiv) and methanesulfonyl
chloride (0.11 mL, 1.4 mmol, 4 equiv). The reaction mixture was
stirred at 0 ꢀC for 2 h. Work-up (extraction with CH2Cl2, 3ꢁ10 mL)
and removal of all volatiles under reduced pressure gave crude
dimesylate 10, which was divided into two identical aliquots and
used as such in the two next reactions.
One of the aliquots of the crude dimesylate from above was
dissolved in CH2Cl2 (1 mL), cooled to 0 ꢀC and treated with TFA
(1 mL). The mixture was stirred at the same temperature for 2 h.
After removal of all volatiles under reduced pressure, the residue
was dissolved in MeOH (2 mL) and the solution was brought to
basic pH with dropwise addition of 33% aq NH3. After stirring for
10 min at room temperature, the solvent was removed under re-
duced pressure. The residue was then subjected to column chro-
matography on silica gel (EtOAc/MeOH, 9:1) to yield pyrrolizidine
[
d
a
]
þ42 (c 1.2, CHCl3); H NMR (500 MHz, DMSO-d6, 90 ꢀC):
D
¼7.35–7.20 (br m, 10H), 4.70–4.55 (br m, 4H), 4.45 (br s, 1H), 4.25
(br d, Jw6.5 Hz, 1H), 4.20–4.00 (br m, 2H), 3.90 (m, 1H), 3.60 (m,
1H), 3.30 (br dd, Jw6.5, 4 Hz, 1H), 2.60–2.40 (br m, 2H), 2.04 (s, 3H),
1.85–1.60 (br m, 2H), 1.45 (s, 9H), 1.40 (s, 3H), 1.39 (s, 3H); 13C NMR
(125 MHz, DMSO-d6, 90 ꢀC):
d
¼207.8, 151.8, 138.7 (ꢁ2), 93.0, 79.1
(Cq) (10 overlapped aromatic CH signals), 83.2, 77.7 , 69.0, 58.3
*
(CH), 74.0, 73.2, 63.0, ca. 40.5 (overlapped by solvent, CH2CO), 29.2
(CH2), 28.0 (ꢁ3), 26.7, 25.6 (CH3) (the starred signal is low and
broadened); IR nmax 3440 (br, OH), 1690 (C]O) cmꢂ1; HRESMS m/z
564.2944 (MþNaþ). Calcd for C31H43NNaO7: 564.2937.
3.1.7. tert-Butyl (R)-4-[(1R,2R,3S)-1,2-bis(benzyloxy)-3-
(methanesulfonyloxy)-6-oxoheptyl]-2,2-dimethyloxazolidine-3-
carboxylate (12) and attempts at the synthesis of 3
A solution of compound 6 (108 mg, 0.2 mmol) in dry CH2Cl2
(2 mL) was cooled to 0 ꢀC under N2 and treated with DMAP (1 mg,
11 (34 mg, 55% overall yield from 9): oil; [
a
]
þ17.7 (c 0.8, CHCl3);
ca. 0.01 mmol), Et3N (84
mL, 0.6 mmol) and methanesulfonyl chlo-
D
1H NMR (500 MHz, CDCl3):
d¼7.40–7.25 (br m, 10H), 4.78 (d,
ride (31
m
L, 0.4 mmol). The reaction mixture was stirred at 0 ꢀC for
J¼11.2 Hz, 1H), 4.65 (d, J¼11.2 Hz, 1H), 4.62 (d, J¼11.8 Hz, 1H), 4.56
(d, J¼11.8 Hz, 1H), 4.12 (br t, Jw6 Hz, 1H), 3.82 (br t, Jw5.8 Hz, 1H),
3.62 (dd, J¼11.1, 2.3 Hz, 1H), 3.58 (dd, J¼11.1, 2.8 Hz, 1H), 3.46 (br q,
Jw6.5 Hz, 1H), 2.96 (br dt, Jw10.5, 6.3 Hz, 1H), 2.85 (m, 1H), 2.80 (br
s, 1H, OH), 2.68 (br dt, Jw10.5, 6.3 Hz, 1H), 2.05–2.00 (m, 1H), 1.90–
1.80 (m, 1H), 1.80–1.75 (m, 1H), 1.75–1.65 (m, 1H); 13C NMR
2 h and then further 30 min at room temperature. Work-up (ex-
traction with CH2Cl2, 3ꢁ10 mL) and removal of all volatiles under
reduced pressure gave crude mesylate 12.
The crude 12 from above was dissolved in MeOH (10 mL) and
treated with 6 M HCl (1 mL). The mixture was stirred at room
temperature for 30 min. After addition of Degussa-type 10% Pd/C
(100 mg), the mixture was stirred at room temperature under an H2
atmosphere until no UV-absorbing product was visible in a TLC
plate (ca. 48 h). Following this, the mixture was filtered through
a pad of Celite (MeOH), and the solvent was removed under re-
duced pressure. The obtained residue was dissolved in MeOH
(3 mL) and the solution was brought to basic pH with dropwise
addition of 33% aq NH3. After stirring for 10 min at room temper-
ature, the solvent was removed under reduced pressure. The resi-
due was then put on the top of a ion-exchange resin column
(DowexÒ 50Wx4 200–400 mesh, pre-acidified with 0.5 M HCl).
Elution with water (50 mL) to remove salts and then with 1 M aq
NH3 until elution of the product (TLC monitoring), followed by
removal of the volatiles of the latter fraction under reduced pres-
sure, gave a brownish residue which was subjected to column
(125 MHz, CDCl3):
d
¼138.3, 138.1 (Cq), 128.5 (ꢁ2), 128.4 (ꢁ2), 127.8
(ꢁ4), 127.7 (ꢁ2), 88.8, 84.5, 69.5, 67.5 (CH), 73.0, 72.0, 60.6, 53.9,
31.9, 25.7 (CH2); IR nmax 3440 (br, OH) cmꢂ1; HRFABMS m/z
354.2076 (MþHþ). Calcd for C22H28NO3: 354.2069.
3.1.5. (1R,2R,3R,7aR)-3-(Hydroxymethyl)hexahydro-1H-
pyrrolizine-1,2-diol, hyacinthacine A2 (2)
The second aliquot of the crude dimesylate 10 was dissolved in
MeOH (10 mL) and treated with 6 M HCl (1 mL). The mixture was
stirred at room temperature for 30 min. After addition of Degussa-
type 10% Pd/C (100 mg), the mixture was stirred at room temper-
ature for 40 h under an H2 atmosphere. Following this, the mixture
was filtered through a pad of Celite (MeOH), and the solvent was
removed under reduced pressure. The obtained residue was

C. Ribes et al. / Tetrahedron 65 (2009) 6965–6971
6969
chromatography on silica gel (CHCl3/MeOH/aq NH3, gradient from
90:9:1 to 70:29:1). After solvent removal, NMR examination of the
chromatographic fractions showed only ill-defined products but
not the desired 3.
1H; OH), 4.60–4.50 (br m, 4H together; benzyl CH2), 4.22 and 4.18
(br s, 1H; CH–OBn), 3.95–3.85 and 3.75–3.70 (m, 4H together;
CHOBn, 2CHN and CH2OH), 3.35–3.25 (m, 1H; CH2OH), 2.45–2.35
(br m, 2H; CH2CO), 2.15–2.05 (br m, 1H; CH2CH2CO), 2.04 and 1.94
(two s, 3H together; COMe), 1.80–1.65 (br m, 1H; CH2CH2CO); 13C
3.1.8. Benzyl [(2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-(but-3-enyl)-5-
(hydroxymethyl)]pyrrolidine-1-carboxylate (14)
NMR (125 MHz, DMSO-d6, 30 ꢀC):
d
¼207.6 and 207.4, 153.8 and
153.7, 138, 137.9, 136.8 and 136.7 (Cq), 128.3–127.4 (15 overlapped
aromatic CH signals), 83.4, 82.6, 82.4, 81.8, 65.7, 65.2, 63.9, 63.4 (CH),
70.3, 70.2 (2ꢁbenzyl CH2), 66.1, 66.0 (Cbz CH2), 59.6, 58.6 (CH2OH),
ca. 40.5 (overlapped by solvent, CH2CO), 25.7, 24.3 (CH2CH2CO)
(CH2), 29.4, 29.3 (CH3); IR nmax 3440 (br, OH), 3065, 3032 (C]C–H),
1698 (C]O) cmꢂ1; HRESMS m/z 540.2363 (MþNaþ). Calcd for
C31H35NO6Na: 540.2362.
A solution of pyrrolidine 139a (441 mg, 1.2 mmol) in a 1:1 THF/
H2O mixture (12 mL) was cooled to 0 ꢀC under N2 and treated with
CbzCl (257 mL, 1.8 mmol, 1.5 equiv) and solid Na2CO3 (510 mg,
4.8 mmol, 4 equiv). The reaction mixture was stirred at room
temperature for 8 h. Work-up (extraction with EtOAc, 3ꢁ15 mL)
and column chromatography on silica gel (hexanes/EtOAc, 7:3)
provided 560 mg (93%) of compound 14: oil; [
a
]
ꢂ27 (c 1.5,
D
1
CHCl3); H NMR (500 MHz, DMSO-d6, 30 ꢀC):
d¼7.40–7.25 (br m,
3.1.11. tert-Butyl [(2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-
15H together, aromatic), 5.78 and 5.62 (ddt, J¼17.2, 10.3, 6 Hz, 1H;
olefinic CH), 5.15 and 5.14 (d, J¼12.2 Hz, 1H; Cbz CH2), 5.05 and
5.02 (d, J¼12.2 Hz, 1H; Cbz CH2), 5.05–4.85 (br m, 2H together;
olefinic CH2), 4.65–4.50 (br m, 4H together; benzyl CH2), 4.24 and
4.21 (br s, 1H; CHOBn), 3.96 (s, 1H; CHOBn), 3.95–3.85 and 3.80–
3.70 (m, 3H together; 2CHN and CH2OH), 3.35–3.25 (m, 1H;
(hydroxymethyl)-5-(3-oxobutyl)]pyrrolidine-1-carboxylate (17)
A solution of compound 15 (467 mg, ca. 1 mmol) in a 10:1
DMF/H2O mixture (22 mL) was treated with PdCl2 (71 mg,
0.4 mmol) and CuCl (495 mg, 5 mmol). The reaction mixture was
then stirred under O2 at room temperature for 24 h. Work-up
(extraction with Et2O, 3ꢁ20 mL) and column chromatography on
silica gel (hexanes/EtOAc, 7:3) afforded 416 mg (86%) of methyl
CH2OH), 2.10–1.55 (several br m, 4H together; CH2CH2) (OH signal
13
not detected); C NMR (125 MHz, DMSO-d6, 30 ꢀC):
d
¼153.7,
ketone 17: oil; [
DMSO-d6, 90 ꢀC):
a
d
]
ꢂ32.7 (c 1.4, CHCl3); 1H NMR (500 MHz,
¼7.40–7.20 (br m, 10H), 4.70 (br s, 1H, OH),
D
153.5, 138.0, 137.6, 136.8, 136.6 (4C together, Cq), 137.8 (olefinic),
128.4–127.4 (15 overlapped aromatic CH signals), 83.1, 82.4, 81.8,
65.7, 65.1, 64.0, 63.3 (4C together) (CH), 115.1, 114.9 (1ꢁolefinic
CH2), 70.3, 70.2 (2ꢁbenzyl CH2), 66.1, 65.9 (1ꢁCbz CH2), 59.7, 58.6,
30.2, 29.9, 29.8, 28.6 (3C together) (CH2); IR nmax 3450 (br, OH),
3065, 3032 (C]C–H), 1698 (C]O) cmꢂ1; HREIMS m/z (rel int.)
501.2523 (Mþ, 1), 471 (4), 426 (6), 91 (100). Calcd for C31H35NO5:
501.2515.
4.60–4.45 (br m, 4H; 2 benzyl CH2), 4.15 (br s, 1H), 3.88 (br s, 1H),
3.78 (m, 1H), 3.62 (m, 1H), 3.30 (m, 1H), 3.10 (m, 1H), 2.37 (t,
J¼12 Hz, 2H), 2.03 (s, 3H), 2.05–1.95 (m, 1H), 1.80–1.70 (m, 1H),
13
1.50 (s, 9H); C NMR (125 MHz, DMSO-d6, 90 ꢀC):
d
¼206.8, 153.0,
137.8, 137.7, 78.5 (Cq), 128.0–127.0 (10 partially overlapped aro-
matic CH signals), 83.3 , 82.2 , 65.2, 63.3 (CH), 70.2, 70.1, 59.4 , ca.
40.5 (overlapped by solvent), 25.0
(CH2), 29.0, 27.8 (ꢁ3) (CH3)
*
*
*
*
(starred signals are low and broadened); IR nmax 3450 (br, OH),
3.1.9. Benzyl [(2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-(but-3-enyl)-5-
(hydroxymethyl)]pyrrolidine-1-carboxylate (15)
3065 (C]C–H), 1689 (C¼O) cmꢂ1
; HRESMS m/z 506.2517
(MþNaþ). Calcd for C28H37NNaO6: 506.2519.
A solution of pyrrolidine 13 (551 mg, 1.5 mmol) in dry THF
(5 mL) was cooled to 0 ꢀC under N2 and treated first with Et3N
(0.42 mL, 3 mmol, 2 equiv) and then dropwise with a solution of
Boc2O (360 mg, 1.65 mmol, 1.1 equiv) in THF (3 mL). The reaction
mixture was stirred at room temperature for 18 h. Work-up (ex-
traction with EtOAc, 3ꢁ25 mL) and column chromatography on
silica gel (hexanes/EtOAc, 7:3) provided 477 mg (68%) of compound
3.1.12. Benzyl [(2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-(tert-
butyldiphenyl-silyloxy)methyl-5-(3-oxobutyl)]pyrrolidine-1-
carboxylate (18)
A solution of compound 16 (103 mg, 0.2 mmol) in dry DMF
(2 mL) was treated with tert-butyldiphenylsilyl chloride (62 mL,
0.24 mmol, 1.2 equiv) and imidazole (33 mg, 0.48 mmol). The re-
action mixture was then stirred under N2 at room temperature for
18 h. Work-up (extraction with Et2O, 3ꢁ10 mL) and column
chromatography on silica gel (hexanes/EtOAc, 8:2) provided
15: oil; [
90 ꢀC):
a
]
þ16 (c 0.6, CHCl3); 1H NMR (500 MHz, DMSO-d6,
D
d
¼7.40–7.25 (br m, 10H), 5.80 (ddt, J¼17, 10, 6.2 Hz, 1H), 5.00
(br dd, Jw17, 1.7 Hz, 1H), 4.94 (br dd, J¼10, 1.7 Hz, 1H), 4.57 (d,
J¼12 Hz, 2H), 4.52 (d, J¼12 Hz, 2H), 4.02 (br d, J¼1.8 Hz, 1H), 4.00
(br d, J¼1.2 Hz, 1H), 3.80 (br t, J¼3.5 Hz, 1H), 3.67 (dd, J¼5, 3.5 Hz,
1H), 3.33 (br dt, J¼6.5, 3.5 Hz, 1H), 3.05 (m, 1H, overlapped by water
133 mg (88%) of the silylated derivative 18: oil; [
a
]
ꢂ9.7 (c 1.05,
D
CHCl3); 1H NMR (500 MHz, DMSO-d6, 30 ꢀC):
d
¼7.60–7.10 (several
m, 25H together, aromatic), 5.10 and 4.95 (d, J¼12.5 Hz, 1H to-
gether; Cbz CH2), 4.97 and 4.87 (d, J¼12 Hz, 1H together; Cbz CH2),
4.65–4.60 (br m, 2H; benzyl CH2), 4.50–4.40 (AB system, J¼12 Hz,
2H; benzyl CH2), 4.31 and 4.29 (br s, 1H together; CH–OBn), 4.12
and 4.06 (br dd, J¼9, 4.5 Hz, 1H together; CH–N), 4.05–3.95 (br m,
1H; CH–OBn), 3.91 (br dd, J¼9, 4.5 Hz, 1H; CH2OH), 3.70 and 3.67
(br dd, J¼10, 2.5 Hz; 1H together; CH–N), 3.55 (br q, J¼9 Hz, 1H;
CH2OH), 2.50–2.35 (br m, 2H; CH2CO), 2.10 and 1.80–1.70 (br m,
2H together; CH2CH2CO), 2.04 and 1.94 (s, 3H together; COMe),
0.97 and 0.92 (s, 9H together; Sit-Bu); 13C NMR (125 MHz, DMSO-
signal or hydroxyl signal), 2.15–2.00 (br m, 2H), 1.65–1.40 (br m,
13
2H), 1.42 (s, 9H); C NMR (125 MHz, DMSO-d6, 90 ꢀC):
d
¼152.7,
138.2, 138.1, 81.1 (Cq), 138.3, 128.0–127.0 (10 overlapped aromatic
CH signals), 88.8, 86.1, 67.6, 60.2 (CH), 114.2, 70.8, 70.7, 60.8, 32.7,
30.0 (CH2), 27.2 (ꢁ3) (CH3); IR nmax 3390 (br, OH), 1686
(C]O) cmꢂ1; HRESMS m/z 468.2757 (MþHþ). Calcd for C28H38NO5:
468.2750.
3.1.10. Benzyl [(2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-
(hydroxymethyl)-5-(3-oxobutyl)]pyrrolidine-1-carboxylate (16)
A solution of compound 14 (501 mg, ca. 1 mmol) in a 10:1 DMF/
H2O mixture (22 mL) was treated with PdCl2 (71 mg, 0.4 mmol) and
CuCl (495 mg, 5 mmol). The reaction mixture was then stirred
under O2 at room temperature for 24 h. Work-up (extraction with
Et2O, 3ꢁ20 mL) and column chromatography on silica gel (hexanes/
d6, 30 ꢀC):
135.0 (ꢁ4), 130.0, 129.9, 128.5 (ꢁ4), 128.3 (ꢁ4), 128.0–127.4 (11
overlapped aromatic CH signals), 83.3 , 82.5, 82.0, 81.6 (2C to-
gether; CH–O), 65.1, 64.6, 64.0, 63.6 (2C together; CH–N) (CH),
70.5, 70.3 (2ꢁbenzyl CH2), 66.2 and 66.0 (Cbz CH2), 62.0 and 61.0
(CH2OH), ca. 40.5 (overlapped by solvent, CH2CO), 25.8 and 24.2
(CH2, CH2CH2CO), 29.6 (COCH3), 26.6 (3ꢁCH3) (starred signals are
d
¼207.7, 153.5, 137.8 (ꢁ2), 136.5, 132.8 (ꢁ2), 18.7 (Cq),
*
*
*
EtOAc, 7:3) afforded 455 mg (88%) of methyl ketone 16: oil; [a]
D
1
ꢂ20.9 (c 2, CHCl3); H NMR (500 MHz, DMSO-d6, 30 ꢀC):
d¼7.40–
low and broadened); IR nmax 3065 (C]C–H), 1701 (C]O) cmꢂ1
;
7.25 (br m, 15H together, aromatic), 5.13 and 5.06 (br d, Jw12.5 Hz,
1H; Cbz CH2), 5.13 and 5.04 (d, Jw12.2 Hz, 1H; Cbz CH2), 4.90 (br s,
HRFABMS m/z 756.3721 (MþHþ). Calcd for C47H54NO6Si:
756.3720.

6970
C. Ribes et al. / Tetrahedron 65 (2009) 6965–6971
3.1.12.1. tert-Butyl [(2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-(tert-butyldi-
phenyl-silyloxy)methyl-5-(3-oxobutyl)]pyrrolidine-1-carboxylate
(19). A solution of compound 17 (97 mg, ca. 0.2 mmol) in dry DMF
(2 mL) was treated under N2 with tert-butyldiphenylsilyl chloride
When the reaction was carried out with pyrrolizidine 17 instead
of 16, a similar result was observed. Under the same reaction
conditions,18 gave 5-epi-3 in 75% yield and 19 afforded a mixture of
3 and 5-epi-3.
(62 mL, 0.24 mmol, 1.2 equiv) and imidazole (33 mg, 0.48 mmol).
The reaction mixture was then stirred at room temperature for
24 h. Work-up (extraction with Et2O, 3ꢁ10 mL) and column chro-
matography on silica gel (hexanes/EtOAc, 8:2) provided 94 mg of
the silylated derivative 19 (65%, 90% based on recovered 17) as well
as unreacted 17 (27 mg). The NMR spectra of 19 were coincident
with those reported.8
Acknowledgements
Financial support has been granted by the Ministerio de
´
Educacion
y
Ciencia (projects CTQ2005-06688-C02-01 and
CTQ2005-06688-C02-02), by the BANCAJA-UJI foundation (projects
P1-1A-2005-15 and P1-1B-2005-30) and by the Generalitat
Valenciana (projects ACOMP07/023 and ACOMP07/025). C.R.
3.1.13. (1R,2R,3R,5R,7aR)-3-(Hydroxymethyl)-5-methylhexahydro-
1H-pyrrolizine-1,2-diol, hyacinthacine A3 (3) and
´
thanks the Ministerio de Educacion y Ciencia for a FPU fellowship.
(1R,2R,3R,5S,7aR)-3-(hydroxymethyl)-5-methylhexahydro-1H-
pyrrolizine-1,2-diol, 5-epi-hyacinthacine A3 (5-epi-3)
Supplementary data
Pyrrolidine 16 (104 mg, ca. 0.2 mmol) was dissolved in MeOH
(8 mL). After addition of Degussa-type 10% Pd/C (100 mg), the
mixture was stirred at room temperature for 24 h under an H2 at-
mosphere until disappearance of the starting compound (TLC
monitoring, UV-absorbing products were still present). The mix-
ture was then filtered through a pad of Celite (MeOH), and the
solvent was removed under reduced pressure. After this, the resi-
due was dissolved in MeOH (6 mL), followed by addition of 6 M HCl
(0.6 mL) and Degussa catalyst (100 mg). The mixture was sub-
sequently stirred for 32 h under an H2 atmosphere until no UV-
absorbing products were observed in TLC plates.
Following this, the mixture was filtered through a pad of Celite
(MeOH), and the solvent was removed under reduced pressure. The
obtained residue was dissolved in MeOH (2 mL) and the solution
was brought to basic pH with dropwise addition of 33% aq NH3.
After stirring for 10 min at room temperature, the solvent was re-
moved under reduced pressure. The residue was then put on the
top of a ion-exchange resin column (DowexÒ 50Wx4 200–400
mesh, pre-acidified with 0.5 M HCl). Elution with water (50 mL) to
remove salts and then with 1 M aq NH3 until elution of the product
(TLC monitoring), followed by removal of the volatiles of the latter
fraction under reduced pressure, gave a brownish residue which
was subjected to column chromatography on silica gel (CHCl3/
MeOH/aq NH3, gradient from 90:9:1 to 70:29:1). This yielded
hyacinthacine A3 (3) (17 mg, 45% yield from 16) and 5-epi-hyacin-
thacine A3 (5-epi-3) (14 mg, 37% yield from 16).
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.06.046.
References and notes
1. For general reviews on pyrrolizidine alkaloids, see: Liddell, J. R. Nat. Prod. Rep.
2002, 19, 773–781 and the previous papers in this series.
2. Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson,
A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1–8.
3. For further reviews on the chemistry and biology of pyrrolizidine alkaloids, see:
(a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645–1680; (b) Mroczek, T.; G1owniak, K. Proc. Phytochem. Soc. Eur.
2002, 47, 1–46; (c) Fu, P. P.; Xia, Q.; Lin, G.; Chou, M. W. Drug Metab. Rev. 2004,
36, 1–55; (d) Pyne, S. G.; Tang, M. Curr. Org. Chem. 2005, 9, 1393–1418.
4. For recent reviews on syntheses of this compound class: (a) Yoda, H. Curr. Org.
Chem. 2002, 6, 223–243; (b) Ayad, T.; Genisson, Y.; Baltas, M. Curr. Org. Chem.
2004, 8, 1211–1233.
5. For representative examples, see: (a) Toyao, A.; Tamura, O.; Takagi, H.; Ishiba-
shi, H. Synlett 2003, 35–38; (b) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett.
2005, 7, 2587–2590; (c) Kaliappan, K. P.; Das, P. Synlett 2008, 841–844; (d)
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F. Tetrahedron 2008, 64, 4613–4618.
6. For the use of non-sugar chiral starting materials, see for example: (a) Reddy, P.
K.; Veyron, A.; Koos, P.; Bayle, A.; Greene, A. E.; Delair, P. Org. Biomol. Chem.
2008, 6, 1170–1172; (b) Sengoku, T.; Satoh, Y.; Oshima, M.; Takahashi, M.; Yoda,
H. Tetrahedron 2008, 64, 8052–8058; (c) Donohoe, T. J.; Thomas, R. E.;
Cheeseman, M. D.; Rigby, C. L.; Bhalay, G.; Linney, I. D. Org. Lett. 2008, 10, 3615–
3618; (d) Chandrasekar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem. 2008, 73,
7826–7828.
7. For previous syntheses of hyacinthacine A2 (2) see: (a) Rambaud, L.; Com-
pain, P.; Martin, O. R. Tetrahedron: Asymmetry 2001, 12, 1807–1809; (b) Car-
dona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A. Tetrahedron Lett. 2003,
44, 2315–2318; (c) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asym-
´
metry 2003, 14, 3933–3935; (d) Desvergnes, S.; Py, S.; Vallee, Y. J. Org. Chem.
3.1.13.1. Compound 3. oil; [
a
]
þ15.1 (c 0.35, H2O), lit.2
[
a
]
þ19.2
2005, 70, 1459–1462; (e) Dewi-Wu¨ lfing, P.; Blechert, S. Eur. J. Org. Chem. 2006,
1852–1856; (f) Calveras, J.; Casas, J.; Parella, T.; Joglar, J.; Clape`s, P. Adv. Synth.
Catal. 2007, 349, 1661–1666 (synthesis of ent-2, the non-natural enantiomer
of hyacinthacine A2).
8. For a previous synthesis of hyacinthacine A3 (3) see: Izquierdo, I.; Plaza, M. T.;
Franco, F. Tetrahedron: Asymmetry 2002, 13, 1581–1585.
9. (a) Ribes, C.; Falomir, E.; Murga, J.; Carda, M.; Marco, J. A. Org. Biomol. Chem.
2009, 7, 1355–1360; (b) For a recent synthesis of radicamine B, a further pyr-
rolidine alkaloid which also contains the structural fragment I, see: Ribes, C.;
Falomir, E.; Carda, M.; Marco, J. A. J. Org. Chem. 2008, 73, 7779–7782.
10. Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956, 21,
478–479.
11. In our recent synthesis of the pyrrolizidine alkaloid australine, all three C–N
bonds of the heterobicyclic system were formed in a one-pot procedure: Ribes,
C.; Falomir, E.; Carda, M.; Marco, J. A. Org. Lett. 2007, 9, 77–80.
D
D
(c 0.43, H2O), lit.8 [
a]
D þ14 (c 0.55, H2O); IR nmax 3370 (br, OH) cmꢂ1
;
HRESMS m/z 188.1282 (MþHþ). Calcd for C9H18NO3: 188.1287. For
NMR data and their comparison with literature values for natural
and synthetic samples, see Supplementary data.
3.1.13.2. Compound 5-epi-3. oil; [
a
]
þ22 (c 0.3, H2O), lit.5c
[a]
D
D
þ24.8 (c 14, H2O), lit.5d
[
a]
ꢂ162 (c 0.5, H2O); IR nmax 3390 (br,
D
OH) cmꢂ1; HRESMS m/z 188.1285 (MþHþ). Calcd for C9H18NO3:
188.1287. For NMR data and their comparison with literature values
for previous synthetic samples, see Supplementary data.
12. (a) Tsuji, J. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Win-
terfeldt, E., Eds.; Pergamon: Oxford, 1993; Vol. 7, pp 449–468; (b) Takacs, J. M.;
Jiang, X.-T. Curr. Org. Chem. 2003, 7, 369–396; (c) Cornell, C. N.; Sigman, M. S.
Inorg. Chem. 2007, 46, 1903–1909.
3.1.14. (1R,2R,3R,5S,7aR)-3-(Hydroxymethyl)-5-methylhexahydro-
1H-pyrrolizine-1,2-diol, 5-epi-hyacinthacine A3 (5-epi-3)
Pyrrolidine 16 (52 mg, ca. 0.1 mmol) was dissolved in MeOH
(3 mL) and treated with 6 M HCl (0.3 mL). After addition of
Degussa-type 10% Pd/C (50 mg), the mixture was stirred for 48 h at
room temperature under an H2 atmosphere until no UV-absorbing
products were observed in TLC plates.
Following this, the mixture was processed in the same way as
above. Column chromatography on silica gel (CHCl3/MeOH/aq NH3,
gradient from 90:9:1 to 70:29:1) furnished 5-epi-hyacinthacine A3
(5-epi-3) (13 mg, 69% yield from 16).
13. For previous syntheses of 5-epi-3, see Refs. 5c and d.
14. Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307–1370.
15. The compound reported in Ref. 8 (numbered 4 there) is a dehydro derivative of
19 showing an additional C]C bond in the side chain. In the reaction condi-
tions described by the authors, this compound was assumed to undergo hy-
drogenation to 19 (numbered 5) in a neutral medium as the first step. The acid
was added to the reaction medium only after this initial step had taken place.
16. (a) Lathbury, D. C.; Shaw, R. W.; Bates, P. A.; Hursthouse, M. B.; Gallagher, T. J.
Chem. Soc., Perkin Trans. 1 1989, 2415–2424; (b) Provot, O.; Ce´le´rier, J.-P.; Petit,
H.; Lhommet, G. J. Org. Chem. 1992, 57, 2163–2166; (c) Oppolzer, W.; Bochet, C.
G.; Merifield, E. Tetrahedron Lett. 1994, 35, 7015–7018; (d) Dhimane, H.;

C. Ribes et al. / Tetrahedron 65 (2009) 6965–6971
6971
Vanucci-Bacque´, C.; Hamon, L.; Lhommet, G. Eur. J. Org. Chem. 1998, 1955–1963;
(e) Takahata, H.; Takahashi, S.; Azer, N.; Eldefrawi, A. T.; Eldefrawi, M. E. Bioorg.
Med. Chem. Lett. 2000, 10, 1293–1295.
18. For 2, the complete sequence includes 16 steps from
D
-serine with ca. 21%
overall yield. This compares well with the overall yields of the previous syn-
theses, which were with one exception7d in the range 3–11% from commercial
precursors. For 3 and 5-epi-3, the sequence contains 15 steps along the re-
spective synthetic routes 5/16/3 and 5/16/5-epi-3. The overall yields
were ca. 14% and 21%, respectively.
17. (a) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032–7035; (b)
Stevens, R. V.; Lee, A. W. M. J. Chem. Soc., Chem. Commun. 1982, 102–103; (c)
Stevens, R. V.; Lee, A. W. M. J. Chem. Soc., Chem. Commun. 1982, 103–104.