Total synthesis of (+)-hyacinthacine A1, (+)-7a-epi- hyacinthacine A1, (6R)-6-hydroxyhyacinthacine A1 and (6S)-6-hydroxy-7a-epi-hyacinthacine A1

Article abstract of DOI:10.1002/ejoc.201101096

The total synthesis of natural (+)-hyacinthacine A₁ (6), (+)-7a-epi-hyacinthacine A₁ (7) and their 6-hydroxy analogues 21 and 16 was achieved using a nitrone cycloaddition strategy with D-ribose-derived cyclic nitrone 8 as the dipole

Full text of DOI:10.1002/ejoc.201101096

FULL PAPER
DOI: 10.1002/ejoc.201101096
Total Synthesis of (+)-Hyacinthacine A1, (+)-7a-epi-Hyacinthacine A1,
(6R)-6-Hydroxyhyacinthacine A1 and (6S)-6-Hydroxy-7a-epi-hyacinthacine A1
Giampiero D’Adamio,[a] Andrea Goti,*[a] Camilla Parmeggiani,[a] Elena Moreno-Clavijo,[b]
Inmaculada Robina,[b] and Francesca Cardona*[a]
Keywords: Natural products / Total synthesis / Alkaloids / Nitrogen heterocycles / Cycloaddition / Enzyme inhibitors /
Biological activity
The total synthesis of natural (+)-hyacinthacine A1 (6), (+)-
7a-epi-hyacinthacine A1 (7) and their 6-hydroxy analogues
21 and 16 was achieved using a nitrone cycloaddition strat-
the pyrrolizidinols 20 and 15, respectively. Evaluation of the
synthesized compounds against a panel of 12 commercially
available glycosidases showed that hyacinthacine A1 (6) and
its (6R)-hydroxy analogue 21 are good inhibitors of amyloglu-
cosidase; the non-natural compound 21 is also a strong inhib-
itor of β-glucosidase, while 6 showed only moderate inhibi-
tion. The non-natural (+)-7a-epi-hyacinthacine A1 (7) is a
moderate inhibitor of amyloglucosidase and α-L-fucosidase;
the presence of the (6S)-hydroxy group in 16 led to di-
minished activity.
egy with D-ribose-derived cyclic nitrone 8 as the dipole and
tert-butyl acrylate as the dipolarophile. After separation of
the adducts, reductive cleavage of the N–O bond followed
by lactam reduction and deprotection afforded the two non-
natural hydroxy analogues in excellent yields. The synthesis
of (+)-hyacinthacine A1 (6) and of (+)-7a-epi-hyacinthacine
A1 (7), which required deoxygenation at C(6), was ac-
complished by DIBAL-H reduction of mesylate derivatives of
nitrone 5 (Scheme 1) as the key building block.[5] Their ac-
tivity as inhibitors of commercial and human glycosidases
and trehalases have been evaluated.[6]
Introduction
In 1988, Fleet and co-workers reported the isolation of
alexine (1, Figure 1) from the seedpods of Alexia leiopet-
ala,[1] the first example of a novel type of polyhydroxylated
pyrrolizidine alkaloid bearing a carbon substituent at C(3).
Since then, several related polyhydroxylated pyrrolizidines
have been isolated from various plant families (eg, com-
pounds 2–4, Figure 1), and this structural motif has proven
to be a rich source of glycosidase inhibitors.[2] Iminosugar
glycosidase inhibitors are valuable targets for synthesis[3]
since they are the focus of growing attention as possible
therapeutic agents for the treatment of tumor metastasis,
viral infections, as antidiabetic agents and in the oral treat-
ment of lysosomal storage disorders.[4] Our group recently
achieved the total synthesis of a number of these natural
alkaloids, including hyacinthacine A2 (2), casuarine (3),
(–)-uniflorine A (4) and their structural analogues using a
nitrone cycloaddition strategy[3d] and a d-arabinose derived
Figure 1. Naturally occurring pyrrolizidine alkaloids.
[a] Dipartimento di Chimica “Ugo Schiff”, Università di Firenze,
Polo Scientifico e Tecnologico,
via della Lastruccia 3–13, 50019 Sesto Fiorentino, Firenze,
Italia
Fax: 39-055-457-3531
E-mail: francesca.cardona@unifi.it
[b] Departmento de Química Orgánica, Facultad de Química, Uni-
versidad de Sevilla,
c/ Prof. García González 1, 41012 Sevilla, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101096.
Scheme 1. Nitrone 8 as the key building block for the synthesis of
(+)-hyacinthacine A1 (6) and 7a-epi-hyacinthacine A1 (7).
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The natural product (+)-hyacinthacine A1 (6, Scheme 1) anti with respect to the CH2OBn substituent at C(5), which
was isolated in 2000 from the bulbs of Muscari armeniacum clearly plays a crucial role in determining stereoselectivity
(Hyacinthaceae) in less than 0.0005% yield.[2a] Since then, on steric grounds. The two adducts 10 and 11 were obtained
several total syntheses of this alkaloid have been reported, in a 1.5:1 ratio,[11,12] and were isolated in 50% and 38%
either using the chiral pool approach[7] or the enantioselec- yield, respectively. Their structures were unambiguously as-
1
tive non chiron approach.[8,9] This alkaloid was found to be signed on the basis of H NMR, 13C NMR, COSY, HSQC
a good inhibitor of β-galactosidase from rat intestinal lact- and 1D NOESY spectra.
ase (IC50 = 4.4 μm) and a moderate inhibitor of α-l-fucosi-
This modest diastereoselectivity[13] proved, nevertheless,
dase from rat epididymis (IC50 = 46 μm).[2a] It also is a mod- to be convenient for the synthesis of both 7a-epi-hy-
erate inhibitor of amyloglucosidase from Aspergillus niger acinthacine A1 (7), (+)-hyacinthacine A1 (6) and their struc-
(IC50 = 25 μm)[2a] although in our hands, potent inhibition tural analogues. Reductive N-O ring cleavage, performed by
of the latter enzyme was measured (see below).
heating a mixture of 10 with Zn in CH3COOH/H2O, 9:1 as
Based on our previous findings in the total synthesis of reported for similar cycloadducts to nitrone 5,[5,6] gave er-
indolizidine and pyrrolizidine alkaloids, we envisaged that ratic results. Indeed, using the usual temperature conditions
the nitrone cycloaddition strategy could be suited for the (60–65 °C), only formation of the open chain pyrrolidine 12
1
total synthesis of pyrrolizidine alkaloids bearing the C(1)– was observed, as clearly shown by the H NMR spectrum
C(2) cis stereochemistry of (+)-hyacinthacine A1 if the d- (Scheme 3). Ring closure and formation of desired lactam
ribose derived nitrone 8 was employed (Scheme 1).[10]
13 was achieved by refluxing the mixture for 3 d, but con-
The main challenge of this synthetic strategy rested in comitant formation of acetylated lactam 14 was also ob-
the stereoselectivity of the cycloaddition reaction to nitrone served (see Supporting Information). Treatment of the
8, which had not been investigated before. We report here crude mixture with the strongly basic resin Ambersep 900
our results leading to the total synthesis of (+)-hyacinthac- OH afforded, in good overall yield, target compound 13 in
ine A1 (6), 7a-epi-hyacinthacine A1 (7), and two new 6-hy- 90% yield from 10 (Scheme 3). The structure of 13, confir-
droxy analogues 16 and 21. The biological activity of the matory of the structure of its precursor 10, was assigned on
1
synthesized compounds was then evaluated using a panel the basis of H NMR, 13C NMR, COSY, HSQC and 1D
of 12 commercially available glycosidases.
NOESY spectra. In particular, 1D NOESY spectra showed
strong NOESY correlation peaks between H(6) and H(7a)
and between H(1) and one of the two hydrogen atoms at
C(7).
Results and Discussion
Nitrone 8 was synthesized from commercially available
2,3,5-tri-O-benzyl-d-ribofuranose as recently reported in
the literature.[10a] The cycloaddition reaction of nitrone 8
was performed in dichloromethane at room temperature
using tert-butylacrylate (9) as the dipolarophile (Scheme 2).
As reported for analogous cycloadditions to nitrone 5,[5] the
reaction was completely regioselective and only 5-substi-
tuted isoxazolidines were generated. However, in consider-
ing the issue of stereoselectivity, two main adducts 10 and
11 were formed; both result from an exo-approach of the
dipolarophile (Scheme 2).
Scheme 3. Synthesis of lactam 13. Reaction conditions: a) Zn,
CH3COOH/H2O, 9:1, 60–65 °C, 3 h; b) Zn, CH3COOH/H2O, 9:1,
reflux, 3 d; c) Ambersep 900 OH, MeOH, room temp., 10 h, 90%
over two steps from 10.
Reduction of the C=O bond of 13 was achieved with
LiAlH4 in refluxing THF, to afford protected pyrrolizidine
15 in 82% yield (Scheme 4); subsequent removal of the
benzyl groups, performed by catalytic hydrogenolysis under
acidic conditions, afforded non-natural (6S)-6-hydroxy-7a-
epi-hyacinthacine A1 (16) in excellent overall yield after ion
Scheme 2. The cycloaddition reaction.
Major adduct 10, whose structure was confirmed on the exchange chromatography of the corresponding ammonium
basis of 1D NOESY NMR spectra, results from an exo salt (Scheme 4).
approach of acrylate anti to the vicinal OBn of the nitrone.
Deoxygenation at C(6) of lactam 13, required for the syn-
Significant formation of adduct 11, resulting from an exo- thesis of 7a-epi-hyacinthacine A1 (7), was not trivial. First,
syn approach of the dipolarophile to nitrone 8, was ob- a radical deoxygenation, namely the Barton–McCombie re-
served. A similar syn approach had not been observed be- action,[14] previously useful in our hands for the deoxygen-
fore in cycloadditions to nitrone 5. This result can be ex- ation of indolizidine alkaloids,[15] was attempted on a thio-
plained by the peculiar stereochemistry of 8. Indeed, a syn carbonylimidazolide derivative, readily obtained from 13 in
approach to the vicinal OBn at C(3) of the nitrone occurs 97% yield (see Supporting Information). However, treat-
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Total Synthesis of (+)-Hyacinthacine A1 and Related Congeners
correlation peaks between H(6) and H(7a) and between
H(7a) and H(2). Reduction of the lactam C=O in 19 and
further catalytic hydrogenolysis of compound 20 afforded
(6R)-6-hydroxyhyacinthacine A1 (21) in 96% yield after ion
exchange chromatography of the corresponding ammonium
salt (Scheme 6).
Scheme 4. Synthesis of (6S)-6-hydroxy-7a-epi-hyacinthacine A1
(16). Reaction conditions: a) LiAlH4, dry THF, reflux, 2 h, 82%;
b) H2, MeOH, HCl, room temp., 3 d; c) DOWEX 50WX8–200,
100% over two steps.
ment of the thiocarbonylimidazolide with Bu3SnH in re-
fluxing THF afforded only a complex mixture of products.
Attempts to deoxygenate the corresponding mesylate ob-
tained from 13 in 82% yield (see Supporting Information)
with LiAlH4 in refluxing THF, successful for the deoxygen-
ation of similar pyrrolizidines,[5,6e] failed, giving predomi-
nantly alcohol 15. Inspired by these observations we then
changed our strategy by first reducing the double bond to
afford secondary alcohol 15 which was then transformed
into corresponding mesylate derivative 17 in 88% yield
(Scheme 5).
Scheme 6. Synthesis of (6R)-6-hydroxyhyacinthacine A1 (21). Reac-
tion conditions: a) Zn, CH3COOH/H2O, 9:1, reflux, 24 h; b) Am-
bersep 900 OH, MeOH, room temp., 10 h, 92% over two steps
from 11; c) LiAlH4, dry THF, reflux, 2 h, 79%; d) H2, MeOH, HCl,
room temp., 3 d; e) DOWEX 50WX8–200, 96% over two steps.
In a fashion analogous to previous observations with lac-
tam 13, mesylation of lactam 19 (see Supporting Infor-
mation) and subsequent treatment with LiAlH4 in refluxing
THF afforded predominantly pyrrolizidinol 20. Thus, the
total synthesis of (+)-hyacinthacine A1 (6) was undertaken
from pure 20. Reaction of 20 with MsCl and NEt3 in dry
CH2Cl2 gave mesylate 22 in 100% yield (Scheme 7). Reac-
tion with DIBAL-H in toluene at reflux afforded com-
pound 23 in 56% yield. Finally, catalytic hydrogenation and
treatment with the basic resin gave (+)-hyacinthacine A1 (6)
in 95% yield (Scheme 7). The spectroscopic data and
physicochemical properties of the synthesized compound
were identical to those of natural (+)-hyacinthacine A1 (6).
Scheme 5. Synthesis of (+)-7a-epi-hyacinthacine A1 (7). Reaction
conditions: a) MsCl, NEt3, CH2Cl2, room temp., 2 h, 88%; b)
DIBAL-H, toluene, reflux, 3 h, 27%; c) H2, MeOH, HCl, room
temp., 2 d, 100% over two steps; d) DOWEX 50WX8–200.
Synthetic 6 showed a specific optical rotation of [α]D24
=
Reduction of mesylate 17 with the less reactive DIBAL-
H in refluxing toluene afforded desired pyrrolizidine 18, al-
beit in 27% yield. Final catalytic hydrogenation gave (+)-
7a-epi-hyacinthacine A1 (7) as its hydrochloride salt in
quantitative yield. Due to the limited amount of compound
available, only a small portion of the hydrochloride salt
was passed on ion exchange resin DOWEX 50WX8–200
+35.6 (c = 0.32, H2O) that is in good agreement with that
reported for the natural sample: [α]D = +38.2 (c = 0.23,
H2O).[2a]
obtaining analytically pure
7
for biological tests
(Scheme 5).[16,17]
Starting from minor exo-syn cycloadduct 11, an analo-
gous reaction sequence gave (6R)-6-hydroxyhyacinthacine
A1 (21) (Scheme 6). N-O reductive cleavage of the isoxazol-
idine adduct and ring closure to lactam 19 was easier, re-
quiring heating in a refluxing 9:1 CH3COOH/H2O mixture
for only 24 h instead of the 3 d required for the major ad-
duct 10; using these conditions, compound 19 was obtained
in 92% isolated yield after treatment with the strongly basic
resin Ambersep 900 OH. Such treatment was found to be
convenient since, as previously observed with major isomer
10 (Scheme 3), partial acetylation of 19 occurred under the
reaction conditions. The structure of 19 (and thus, indi-
Scheme 7. Synthesis of (+)-7a-hyacinthacine A1 (6). Reaction con-
ditions: a) MsCl, NEt3, CH2Cl2, room temp., 2 h, 100%; b)
DIBAL-H, toluene, reflux, 3 h, 56%; c) H2, MeOH, HCl, room
temp., 2 d; d) DOWEX 50WX8–200, 95% over two steps.
Biological Evaluation of Hyacinthacine
Derivatives towards Glycosidases
1
rectly, of cycloadduct 11) was assigned on the basis of H
(+)-Hyacinthacine A1 (6), 7a-epi-hyacinthacine A1 (7),
NMR, 13C NMR, COSY, HSQC and 1D NOESY spectra. and the two new structural analogues 16 and 21 were as-
In particular, 1D NOESY spectra showed strong NOESY sayed for their ability to inhibit 12 commercially available
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A. Goti, F. Cardona et al.
FULL PAPER
glycosidases.[18] At 1 mm concentration and under enzyme- hyacinthacine A1 (6) showed a strong mixed inhibition of
optimized pH none of the compounds inhibited α-galactos- amyloglucosidase from Aspergillus niger and moderate in-
idase from coffee beans, β-galactosidase from Escherichia hibitory activity against β-glucosidase from almonds. Its
coli, α-glucosidase from yeast and rice, α-mannosidase from non-natural (6R)-hydroxy analogue 21 was a strong com-
Jack beans, β-mannosidase from snail, β-xylosidase from petitive inhibitor of both amyloglucosidase from Aspergillus
Aspergillus niger and β-N-acetylglucosaminidase from Jack niger and β-glucosidase from almonds. The C-7a epimer,
beans. Table 1 summarizes the inhibitory activity measured 7a-epi-hyacinthacine A1 (7) displayed only moderate inhibi-
towards α-l-fucosidase from bovine kidney, β-galactosidase tion of amyloglucosidase from Aspergillus niger. The pres-
from Aspergillus orizae, amyloglucosidase from Aspergillus ence of the hydroxy group at C-6 (compound 16) in this
niger and β-glucosidase from almonds. (+)-Hyacinthacine case was detrimental to enzyme inhibition activity.
A1 (6) showed a strong mixed type of inhibition (see Sup-
porting Information for Lineweaver–Burk plot) towards
Experimental Section
amyloglucosidase from Aspergillus niger. The much better
inhibitory activity for 6 found relative to that described pre-
viously by Asano and co-workers[2a] (IC50 one order of
magnitude lower) may be attributable to the use of different
assay conditions. Compound 6 also displayed moderate in-
hibitory activity against β-glucosidase from almonds and
weak inhibitory activity against α-l-fucosidase and β-galac-
tosidase. The non-natural (6R)-hydroxy analogue 21 was
also found to be a strong inhibitor of amyloglucosidase
from A. niger; competitive inhibition was observed in this
case. Compound 21 also was found to display potent com-
petitive inhibition of β-glucosidase from almonds.
General Methods: Commercial reagents were used as received. All
reactions were magnetically stirred and monitored by TLC on
0.25 mm silica gel plates (Merck F254) and column chromatography
was carried out on Silica Gel 60 (32–63 μm). Yields refer to spectro-
scopically and analytically pure compounds unless otherwise
stated. 1H NMR spectra were recorded with a Varian Mercury-400
or Varian INOVA-400. 13C NMR spectra were recorded with a
Varian Gemini-200. Infrared spectra were recorded with a Perkin–
Elmer Spectrum BX FT-IR System spectrophotometer. Mass spec-
tra were recorded with a QMD 1000 Carlo Erba instrument by
direct inlet; relative percentages are shown in brackets. ESI full MS
were recorded with a Thermo LTQ instrument by direct inlet; rela-
tive percentages are shown in brackets. Elemental analyses were
performed with a Perkin–Elmer 2400 analyzer. Optical rotation
measurements were performed with a JASCO DIP370 polarimeter.
Table 1. Inhibitory activities of hyacinthacine derivatives 6, 7, 16
and 21 against glycosidases. Percentage inhibition at 1 mm, IC50
(in parenthesis, μm) and Ki (bold, μm) if measured. Optimal pH,
37 °C.[a,b,c]
Cycloaddition of Nitrone 8 to Dipolarophile 9: A solution of nitrone
8
(700 mg, 1.68 mmol) and tert-butylacrylate (9, 366 μL,
Entry Comp. α-l-Fuc-ase β-Gal-ase Amyloglucosidase β-Glc-ase
2.52 mmol) in 1.7 mL CH2Cl2 was stirred at room temp. under ni-
trogen atmosphere for 3 d, monitoring the reaction by TLC analy-
sis (AcOEt/PE, 3:1). At completion of the reaction, the solvent was
removed under reduced pressure and the crude mixture was puri-
fied by flash column chromatography (eluent AcOEt/PE, 1:3) af-
fording pure 10 (Rf = 0.23, 463 mg, 0.85 mmol, 50% yield) as a
white solid, and pure 11 (Rf = 0.14, 346 mg, 0.63 mmol, 38% yield)
as a colourless oil.
1
2
3
4
6
7
16
21
17
64
60
–
43
–
–
99 (2.3); 3.9 (M)
75 (346)
58
84; (180)
–
–
–
99 (7.7); 3.6 (C)
99 (14.5); 7.7 (C)
[a] For conditions of measurements see ref.[18] and the Supporting
Information. [b] (C): competitive inhibition (M): mixed type of in-
hibition from Lineweaver–Burk plots, ni: no inhibition at 1 mm
concentration of the inhibitor. [c] α-l-Fuc-ase: α-l-fucosidase from
bovine kidney, β-Gal-ase: β-galactosidase from Aspergillus orizae,
amyloglucosidase is from Aspergillus niger, β-Glc-ase: β-glucosidase
from almonds.
tert-Butyl
(2S,3aS,4S,5R,6R)-4,5-Bis(benzyloxy)-6-[(benzyloxy)-
methyl]-hexahydro-pyrrolo[1,2-b]isoxazole-2-carboxylate (10): M.p.
58–59 °C. [α]2D4 = +43.6 (c = 1.06, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.23 (m, 15 H, Ar), 4.71–4.60 (AB system, J =
12.2 Hz, 2 H, Bn), 4.61–4.51 (AB system, J = 11.7 Hz, 4 H, Bn),
4.28 (dd, J = 8.3, 4.8 Hz, 1 H, 2-H), 4.00 (dd, J = 7.8, 5.9 Hz, 1
H, 5-H), 3.95 (dd, J = 9.2, 3.9 Hz, 1 H, 8-Ha), 3.85–3.76 (m, 2 H,
3a-H, 6-H), 3.80 (dd, J = 9.2, 5.4 Hz, 1 H, 8-Hb), 3.70 (dd, J =
5.9, 4.4 Hz, 1 H, 4-H), 2.74 (ddd, J = 12.7, 7.8, 4.9 Hz, 1 H, 3-Ha),
2.31 (ddd, J = 12.7, 8.8, 2.4 Hz, 1 H, 3-Hb), 1.45 (s, 9 H, tBu) ppm.
13C NMR (50 MHz, CDCl3): δ = 170.4 (s, C=O), 138.5, 138.0,
137.8 (s, C-Ar), 128.4–127.3 (d, 15 C, C-Ar), 81.8 (d, C-4), 81.8 (s,
OtBu), 79.3 (d, C-5), 75.0 (d, C-2), 73.2, 72.5, 72.2 (t, C-Bn), 70.8
(d, C-6), 69.9 (d, C-3a), 67.9 (t, C-8), 37.7 (t, C-3), 28.2 (q, 3 C,
The inversion of configuration at C-7a in 6 to give 7a-epi-
hyacinthacine A1 (7) diminished inhibitory potential against
amyloglucosidase from Aspergillus niger, abolished activity
against β-glucosidase from almonds, and slightly improved
activity against α-l-fucosidase. The presence of the hydroxy
group at C-6 (compound 16) was found to be detrimental
for activity against amyloglucosidase from Aspergillus niger,
while slight inhibition against α-l-fucosidase was found to
be retained.
tBu) ppm. IR (CDCl ): ν = 3518, 3088, 3065, 3032, 3004, 2869,
˜
3
1741, 1454, 1368, 1241, 1153, 1027 cm–1. MS (ESI): m/z (%) =
568.24 (51) [M + Na]+. C33H39NO6 (545.67): calcd. C 72.64, H
7.20, N 2.57; found C 72.69, H 7.36, N 2.56.
Conclusions
In conclusion, the total synthesis of (+)-hyacinthacine A1
(6), (+)-7a-epi-hyacinthacine A1 (7) and two new 6-hydroxy
analogues 16 and 21 was achieved by the nitrone cycload-
dition strategy employing a d-ribose-derived nitrone 8 and
tert-Butyl (2R,3aR,4S,5R,6R)-4,5-Bis(benzyloxy)-6-[(benzyloxy)-
methyl]-hexahydro-pyrrolo[1,2-b]isoxazole-2-carboxylate (11): [α]2D4
= –20.8 (c = 1.06, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.35–
7.25 (m, 15 H, Ar), 4.71 (d, J = 12.2 Hz, 1 H, Bn), 4.61–4.49 (m,
tert-butyl acrylate (9) as dipolarophile. In our assays, (+)- 5 H, Bn), 4.56 (t, J = 7.8 Hz, 1 H, 2-H), 3.99 (t, J = 5.4 Hz, 1 H,
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Total Synthesis of (+)-Hyacinthacine A1 and Related Congeners
4-H), 3.91 (t, J = 5.4 Hz, 1 H, 5-H), 3.92–3.86 (m, 1 H, 3a-H), 3.65
146.5 °C. [α]2D2 = +38.3 (c = 0.96, CHCl3). 1H NMR (400 MHz,
(dd, J = 9.8, 3.9 Hz, 1 H, 8-Ha), 3.57 (dd, J = 9.8, 5.4 Hz, 1 H, 8- CDCl3): δ = 7.35–7.25 (m, 15 H, Ar), 4.62–4.48 (AB system, J =
Hb), 3.44–3.41 (m, 1 H, 6-H), 2.91 (ddd, J = 12.2, 7.3, 4.4 Hz, 1 12.2 Hz, 2 H, Bn), 4.60–4.52 (AB system, J = 11.7 Hz, 2 H, Bn),
H, 3-Ha), 2.21 (ddd, J = 12.2, 9.3, 2.9 Hz, 1 H, 3-Hb), 1.47 (s, 9 4.53–4.44 (AB system, J = 11.7 Hz, 2 H, Bn), 4.36–4.31 (m, 1 H,
H, tBu) ppm. 13C NMR (50 MHz, CDCl3): δ = 171.4 (s, C=O),
138.2, 138.0, 137.9 (s, C-Ar), 128.4–127.5 (d, 15 C, C-Ar), 81.8 (s,
OtBu), 78.5 (d, C-5) 77.8 (d, C-4), 76.5 (d, C-2), 73.5, 73.0, 72.4 (t,
C-Bn), 70.5 (d, C-6), 69.9 (t, C-8), 65.9 (d, C-3a), 34.6 (t, C-3), 28.2
6-H), 4.06 (t, J = 5.4 Hz, 1 H, 2-H), 3.79 (t, J = 4.9 Hz, 1 H, 1-H),
3.77–3.73 (m, 1 H, 8-Ha), 3.68–3.62 (m, 1 H, 7a-H), 3.60–3.54 (m,
2 H, Hb-8, 3-H), 3.04 (dd, J = 10.7, 4.9 Hz, 1 H, 5-Ha), 2.96–2.90
(m, 1 H, 5-Hb), 2.55 (br. s, 1 H, OH), 2.24 (ddd, J = 13.6, 8.3,
(q, 3 C, tBu) ppm. IR (CDCl ): ν = 3472, 3018, 2997, 1738, 1521,
5.8 Hz, 1 H, 7-Ha), 1.52 (dt, J = 13.2, 5.4 Hz, 1 H, 7-Hb) ppm. 13
C
˜
3
1453, 1368, 1219, 1156, 1047 cm–1. MS (ESI): m/z (%) = 568.25 NMR (50 MHz, CDCl3): δ = 138.1 (s, 2 C, C-Ar), 137.5 (s, C-Ar),
(100) [M + Na]+. C33H39NO6 (545.67): calcd. C 72.64, H 7.20, N
2.57; found C 72.34, H 7.63, N 2.47.
128.4–127.6 (d, 15 C, C-Ar), 81.5 (d, C-1) 78.8 (d, C-2), 73.4 (t, C-
Bn), 72.6 (d, C-6), 72.3, 71.7 (t, C-Bn), 67.9 (d, C-7a), 67.4 (t, C-
8), 63.6 (d, C-3), 55.6 (t, C-5) 39.3 (t, C-7) ppm. IR (CDCl ): ν =
˜
3
N–O Ring Cleavage of Cycloadduct 10: To a solution of 10 (162 mg,
0.30 mmol) in 4 mL of a 9:1 CH3COOH/H2O mixture, Zn dust
(78 mg, 1.12 mmol) was added. The suspension was heated at re-
flux and stirred for 3 d then a TLC analysis (AcOEt/PE, 3:1)
showed the disappearance of the starting material (Rf = 0.80) and
formation of two new products (Rf = 0.30 and 0.58). After cooling
to room temp. and filtration through cotton the mixture was con-
centrated at reduced pressure and then saturated aqueous solution
of NaHCO3 was added at 0 °C until basic pH. After extraction
with AcOEt (3ϫ25 mL), the organic layers were dried on Na2SO4
and concentrated at reduced pressure affording a crude brown oil
(140 mg) that resulted, after 1H NMR 200 MHz spectra analysis,
in a mixture of the desired product 13 and its acetylated derivative
in 1.5:1 ratio. This crude was then stirred at room temp. with Am-
bersep 900 OH (500 mg) in 20 mL of MeOH for 10 h, then a TLC
analysis (AcOEt/PE, 3:1) showed conversion of the two products
(Rf = 0.30 and 0.58) in 13 (Rf = 0.30). The resin was filtered off and
the solvent removed under reduced pressure affording 13 (128 mg,
0.27 mmol, 90% yield over two steps) as a pale yellow oil enough
pure to be used in the next steps. A small amount of the product
was purified by flash column chromatography (eluent AcOEt/PE,
2:1) affording analytically pure material.
3426, 3090, 3064, 3031, 2913, 2866, 1453, 1358, 1206, 1114,
1045 cm–1. MS (ESI): m/z (%) = 460.32 (50) [M + H]+. C29H33NO4
(459.24): calcd. C 75.79, H 7.24, N 3.05; found C 75.37, H 7.31, N
3.56.
(1S,2R,3R,6R,7aS)-1,2,6-Trihydroxy-3-(hydroxymethyl)-hexahydro-
1H-pyrrolizine (16): To a solution of 15 (67 mg, 0.15 mmol) in
MeOH (20 mL), 10 % Pd on carbon (35 mg) and 37 % HCl (2
drops) were added while stirring under nitrogen atmosphere, then
the mixture was stirred under hydrogen atmosphere at room temp.
for 3 d. After that a TLC analysis (CH2Cl2/MeOH, 3:1) showed the
disappearance of starting material (Rf = 0.76) and formation of a
new product (Rf = 0.17), the mixture was filtered through Celite®
and the solvent was removed under reduced pressure affording a
crude yellow oil (40 mg). The free amine was obtained by passing
the hydrochloride salt through a Dowex 50WX8 ion-exchange
resin. Elution with ammonia 6 % afforded free base 16 (29 mg,
0.15 mmol, 100% yield over two steps) as a pale yellow solid; m.p.
111–112 °C. [α]2D6 = +35.5 (c = 1.22, MeOH). 1H NMR (400 MHz,
CD3OD): δ = 4.25 (pseudo quint, J = 6.3 Hz, 1 H, 6-H), 4.02 (dd,
J = 8.3, 5.4 Hz, 1 H, 2-H), 3.88 (t, J = 5.4 Hz, 1 H, 1-H), 3.86 (dd,
J = 11.7, 3.9 Hz, 1 H, 8-Ha), 3.79 (dd, J = 12.2, 7.8 Hz, 1 H, 8-
Hb), 3.36 (td, J = 7.8, 3.4 Hz, 1 H, 7a-H), 3.16 (td, J = 8.3, 3.9 Hz,
1 H, 3-H), 3.00 (dd, J = 9.8, 5.4 Hz, 1 H, 5-Ha), 2.77 (dd, J = 9.8,
6.3 Hz, 1 H, 5-Hb), 2.32 (ddd, J = 13.2, 8.3, 6.3 Hz, 1 H, 7-Ha),
1.55 (dt, J = 13.2, 7.3 Hz, 1 H, 7-Hb) ppm. 13C NMR (50 MHz,
CD3OD): δ = 75.1 (d, C-1) 70.5 (d, C-2), 70.2 (d, C-6), 68.0 (d, C-
(1S,2R,3R,6S,7aS)-1,2-Bis(benzyloxy)-3-[(benzyloxy)methyl]-6-hy-
droxyhexahydro-5H-pyrrolizin-5-one (13): [α]2D4 = –62.0 (c = 0.80,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.34–7.19 (m, 15 H,
Ar), 4.63–4.39 (m, 7 H, Bn, 6-H), 4.09 (d, J = 4.4 Hz, 1 H, 2-H),
4.03 (dd, J = 9.8, 4.4 Hz, 1 H, 8-Ha), 3.98 (dd, J = 9.3, 4.9 Hz, 1
H, 7a-H), 3.87–3.85 (m, 1 H, 3-H), 3.74 (dd, J = 9.3, 4.4 Hz, 1 H,
1-H), 3.69 (dd, J = 9.8, 2.4 Hz, 1 H, 8-Hb), 2.68 (ddd, J = 11.7,
6.8, 4.9 Hz, 1 H, 7-Ha), 1.63 (dt, J = 11.2, 9.8 Hz, 1 H, 7-Hb) ppm.
13C NMR (50 MHz, CDCl3): δ = 173.4 (s, C=O), 137.7, 137.6,
137.5 (s, C-Ar), 128.4–127.7 (d, 15 C, C-Ar), 82.1 (d, C-2), 82.0 (d,
C-1), 73.7 (d, C-6) 73.5, 72.2, 72.1 (t, C-Bn), 65.8 (t, C-8), 61.0 (d,
1
7a), 65.2 (d, C-3), 58.9 (t, C-8), 52.9 (t, C-5) 36.9 (t, C-7) ppm. H
NMR (400 MHz, D2O): δ = 4.19 (dq, J = 7.8, 6.3 Hz, 1 H, 6-H),
3.99 (dd, J = 9.3, 5.4 Hz, 1 H, 2-H), 3.88 (dd, J = 5.4, 2.9 Hz, 1
H, 1-H), 3.78–3.69 (m, 2 H, 8-Ha, 8-Hb), 3.25 (td, J = 7.8, 2.9 Hz,
1 H, 7a-H), 3.03 (ddd, J = 9.3, 7.8, 5.4 Hz, 1 H, 3-H), 2.93 (dd, J
= 9.8, 5.9 Hz, 1 H, 5-Ha), 2.55 (dd, J = 9.8, 8.3 Hz, 1 H, 5-Hb),
2.32 (dt, J = 13.2, 7.3 Hz, 1 H, 7-Ha), 1.44 (dt, J = 13.2, 7.8 Hz, 1
H, 7-Hb) ppm. 13C NMR (50 MHz, D2O): δ = 75.7 (d, C-1), 70.9
(d, C-2), 70.6 (d, C-6), 67.9 (d, C-7a), 64.8 (d, C-3), 59.6 (t, C-8),
52.8 (t, C-5), 36.9 (t, C-7) ppm. MS (ESI): m/z (%) = 190.17 (100)
[M + H]+. C8H15NO4 (189.21): calcd. C 50.78, H 7.99, N 7.40;
found C 50.43, H 8.26, N 7.22.
C-3), 58.7 (d, C-7a), 37.0 (t, C-7) ppm. IR (CDCl ): ν = 3354, 3088,
˜
3
3066, 3031, 3009, 2926, 2867, 1690, 1454, 1261, 1116, 1027 cm–1.
MS (ESI): m/z (%) = 496.42 (61) [M + Na]+. C29H31NO5 (473.56):
calcd. C 73.55, H 6.60, N 2.96; found C 73.24, H 7.04, N 3.36.
(1S,2R,3R,6R,7aS)-1,2-Bis(benzyloxy)-3-[(benzyloxy)methyl]-6-hy-
droxyhexahydro-1H-pyrrolizine (15): A solution of 13 (145 mg,
0.31 mmol) in 10 mL of dry THF was stirred under nitrogen atmo-
sphere at 0 °C and LiAlH4 (1 m solution in THF, 1.22 mL,
1.22 mmol) was added drop wise. The mixture was raised to room
temp. and refluxed for 2 h, until TLC analysis (AcOEt/PE, 3:1)
showed the disappearance of the starting material (Rf = 0.33) and
the formation of a new product (Rf = 0.00). Reaction was then
quenched with 2 mL of a saturated aqueous solution of Na2SO4 at
0 °C, filtered through Celite® and the solvent was removed under
reduced pressure. The crude was purified by flash column
chromatography (CH2Cl2/MeOH, 10:1), affording pure 15 (Rf =
0.22, 116 mg, 0.25 mmol, 82% yield) as a white solid; m.p. 146–
(1S,2R,3R,6S,7aS)-1,2-Bis(benzyloxy)-3-[(benzyloxy)methyl]-6-
(methylsulfonyloxy)-hexahydro-1H-pyrrolizine (17): To a stirred
solution of 15 (56 mg, 0.12 mmol) in dry CH2Cl2 (10 mL), NEt3
(50 μL, 0.36 mmol) was added under nitrogen atmosphere, and, at
0 °C, MsCl (12 μL, 0.16 mmol) was added dropwise. The solution
was left stirring at room temp. for 2 h. TLC analysis (CH2Cl2/
MeOH, 3:1) showed disappearance of the starting material (Rf =
0.63) and formation of a new product (Rf = 0.75). Then 20 mL of
H2O were added, the mixture was extracted with CH2Cl2
(3 ϫ 15 mL) and the organic layers were dried on Na2SO4. Fil-
tration on cotton and evaporation under reduced pressure afforded
crude 17 that was purified by flash column chromatography (eluent
Eur. J. Org. Chem. 2011, 7155–7162
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7159

A. Goti, F. Cardona et al.
FULL PAPER
CH2Cl2/MeOH, 10:1) affording pure 17 as a yellow oil, (Rf = 0.37,
57 mg, 0.11 mmol, 88% yield). [α]2D6 = +23.7 (c = 1.04, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.35–7.25 (m, 15 H, Ar), 5.10 (ddd,
6-Hb), 1.71 (dtd, J = 12.9, 10.9, 6.6 Hz, 1 H, 7-Hb) ppm. 13C NMR
(50 MHz, CD3OD): δ = 72.3 (d, C-7a) 72.1 (d, C-1), 68.7 (d, C-2),
64.3 (d, C-3), 56.0 (t, C-8), 47.8 (t, C-5) 27.3 (t, C-7), 24.5 (t, C-
J = 12.2, 11.2, 5.9 Hz, 1 H, 6-H) 4.65–4.50 (AB system, J = 6) ppm. 1H NMR (400 MHz, D2O): δ = 4.17 (dd, J = 10.5, 4.3 Hz,
12.2 Hz, 2 H, Bn), 4.57–4.46 (AB system, J = 12.2 Hz, 2 H, Bn), 1 H, 2-H), 4.07 (d, J = 4.3 Hz, 1 H, 1-H), 4.02–3.98 (m, 1 H, 7a-
4.53–4.50 (AB system, J = 11.7 Hz, 2 H, Bn), 3.91 (dd, J = 6.3,
5.9 Hz, 1 H, 2-H), 3.72 (t, J = 5.4 Hz, 1 H, 1-H), 3.64 (dd, J =
10.2, 3.4 Hz, 1 H, 8-Ha), 3.56 (dd, J = 10.2, 6.3 Hz, 1 H, 8-Hb),
H), 3.93 (dd, J = 13.3, 3.5 Hz, 1 H, 8-Ha), 3.83 (dd, J = 13.3,
9.3 Hz, 1 H, 8-Hb), 3.70 (td, J = 9.7, 3.5 Hz, 1 H, 3-H), 3.46–3.42
(m, 1 H, 5-Ha), 3.18 (td, J = 11.7, 5.9 Hz, 1 H, 5-Hb), 2.33–2.25
3.51–3.49 (m, 1 H, 7a-H), 3.48 (dt, J = 3.9, 2.9 Hz, 1 H, 3-H), 3.12 (m, 1 H, 7-Ha), 2.09–2.00 (m, 1 H, 6-Ha), 1.76 (ddd, J = 12.9, 11.7,
(d, J = 5.4 Hz, 2 H, 5-H), 2.81 (s, 3 H, Ms), 2.43 (ddd, J = 13.7, 6.6 Hz, 1 H, 6-Hb), 1.60 (ddd, J = 12.8, 11.3, 6.6 Hz, 1 H, 7-
7.8, 6.8 Hz, 1 H, 7-Ha), 1.80 (dt, J = 13.7, 6.3 Hz, 1 H, 7-Hb) ppm. Hb) ppm. 13C NMR (50 MHz, D2O): δ = 72.1 (d, C-7a), 72.0 (d,
13C NMR (50 MHz, CDCl3): δ = 138.0, 137.9, 137.8 (s, 3 C, C-
C-1), 68.5 (d, C-2), 63.3 (d, C-3), 56.3 (t, C-8), 48.2 (t, C-5), 27.7
Ar), 128.7–127.7 (d, 15 C, C-Ar), 80.9 (d, C-6) 80.9 (d, C-1), 78.5
(t, C-7), 24.6 (t, C-6) ppm. MS-EI (70 eV): m/z (%) = 142 (99),
(d, C-2), 73.3, 72.2, 71.9 (t, C-Bn), 68.2 (t, C-8), 67.3 (d, C-7a), 96 (100), 70 (68). The free amine 7 was obtained by passing the
63.9 (d, C-3), 52.8 (t, C-5), 38.1 (q, Ms), 36.2 (t, C-7) ppm. IR hydrochloride salt through a Dowex 50WX8 ion-exchange resin,
(CDCl ): ν = 3087, 3065, 3031, 2867, 1495, 1453, 1362, 1177, 1118, eluting with 6% ammonia. C8H15NO3 (173.21): calcd. C 55.47, H
˜
3
1027 cm–1. MS (ESI): m/z (%) = 538.33 (100) [M + H]+.
C30H35NO6S (537.22): calcd. C 67.02, H 6.56, N 2.61; found C
67.03, H 6.51, N 2.68.
8.73, N 8.09; found C 55.36, H 8.71, N 7.96.
N–O Ring Cleavage of Cycloadduct 11: To a solution of 11 (224 mg,
0.41 mmol) in 4 mL of a 9:1 CH3COOH/H2O mixture, Zn dust
(107 mg, 1.64 mmol) was added. The suspension was heated at re-
flux and stirred for 24 h then a TLC analysis (AcOEt/PE, 3:1)
showed the disappearance of the starting material (Rf = 0.84) and
formation of two new products (Rf = 0.28 and 0.68). After cooling
to room temp. and filtration through cotton the mixture was con-
centrated at reduced pressure and then saturated aqueous solution
of NaHCO3 was added at 0 °C until basic pH. After extraction
with AcOEt (3ϫ25 mL), the organic layers were dried on Na2SO4
and concentrated at reduced pressure affording a crude brown oil
(1S,2R,3R,7aS)-1,2-Bis(benzyloxy)-3-[(benzyloxy)methyl]hexahy-
dro-1H-pyrrolizine (18): A solution of 17 (57 mg, 0.11 mmol) in
4 mL of dry toluene was stirred under nitrogen atmosphere at 0 °C
and DIBAL-H (1 m solution in CH2Cl2, 0.53 mL, 0.53 mmol) was
added dropwise. The mixture was raised to room temp. and re-
fluxed for 3 h, until TLC analysis (AcOEt) showed the disappear-
ance of the starting material (Rf = 0.32) and formation of a new
product (Rf = 0.00). Reaction was then quenched with 0.5 mL of
a saturated aqueous solution of Na2SO4 at 0 °C, filtered through
Celite® and the solvent was removed under reduced pressure. The
crude product was purified by flash column chromatography
(CH2Cl2/MeOH, 10:1), affording pure 18 (Rf = 0.41, 13 mg,
0.03 mmol, 27% yield) as a yellow oil. [α]2D6 = +49.1 (c = 0.87,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.28–7.19 (m, 15 H,
Ar), 4.56–4.39 (m, 6 H, Bn), 3.89 (dd, J = 8.3, 4.9 Hz, 1 H, 2-H),
3.86–3.80 (m, 1 H, 7a-H), 3.76 (dd, J = 11.2, 2.4 Hz, 1 H, 8-Ha),
3.74–3.71 (m, 1 H, 3-H), 3.61 (dd, J = 11.2, 5.9 Hz, 1 H, 8-Hb),
3.58 (dd, J = 4.9, 2.9 Hz, 1 H, 1-H), 3.16–3.06 (m, 1 H, 5-Ha),
2.92–2.82 (m, 1 H, 5-Hb), 2.09–2.02 (m, 1 H, 7-Ha), 1.84–1.78 (m,
2 H, Ha-6 and Hb-6), 1.35–1.25 (m, 1 H, 7-Hb) ppm. 13C NMR
(50 MHz, CDCl3): δ = 137.3 (s, Ar), 137.2 (s, 2 C, Ar), 128.1–127.4
(d, 15 C, C-Ar), 79.1 (d, C-1) 77.4 (d, C-2), 73.1 (d, C-Bn), 71.9 (t,
C-Bn), 71.3 (t, C-Bn), 68.4 (d, C-7a), 66.3 (t, C-8), 62.1 (d, C-3),
1
(194 mg) resulting, after H NMR 200 MHz spectra analysis, a
mixture of the desired product 19 and of its acetylated derivative.
This crude material was stirred at room temp. with Ambersep 900
OH (600 mg) in 20 mL of MeOH for 10 h, then a TLC analysis
(AcOEt/PE, 3:1) showed conversion of the two products (Rf = 0.38
and 0.60) in 19 (Rf = 0.38). The resin was filtered off and the sol-
vent removed under reduced pressure affording 19 (178 mg,
0.38 mmol, 92% yield over two steps) as a colourless oil sufficiently
pure to be used in subsequent steps. A small amount of the product
was purified by flash column chromatography (eluent AcOEt/PE,
2:1).
(1S,2R,3R,6R,7aR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-6-hy-
droxyhexahydro-5H-pyrrolizin-5-one (19): [α]2D5 = +19.7 (c = 1.15,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.28–7.12 (m, 15 H,
Ar), 4.71–4.54 (AB system, J = 12.2 Hz, 2 H, Bn), 4.51–4.29 (AB
system, J = 11.7 Hz, 2 H, Bn), 4.42–4.35 (AB system, J = 12.2 Hz,
2 H, Bn), 4.43–4.37 (m, 1 H, 6-H), 4.28 (dd, J = 9.3, 2.9 Hz, 1 H,
2-H), 3.88–3.80 (m, 2 H, 3-H, Ha-8), 3.82 (dd, J = 9.8, 2.9 Hz, 1
H, 1-H), 3.70–3.65 (m, 1 H, 7a-H), 3.51 (dd, J = 10.2, 2.0 Hz, 1
H, 8-Hb), 2.36–2.29 (m, 1 H, 7-Ha), 2.20–2.10 (m, 1 H, 7-Hb) ppm.
13C NMR (50 MHz, CDCl3): δ = 175.0 (s, C=O), 137.9, 137.8,
137.6 (s, C-Ar), 128.4–127.5 (d, 15 C, C-Ar), 82.0 (d, C-2), 74.9 (d,
C-1), 73.5, 73.4, 72.9 (t, C-Bn), 71.5 (d, C-6), 67.5 (t, C-8), 59.0 (d,
48.4 (t, C-5), 29.7 (t, C-7), 26.2 (t, C-6) ppm. IR (CDCl ): ν = 3153,
˜
3
3088, 3065, 3030, 2901, 2868, 1467, 1454, 1381, 1207, 1097 cm–1.
MS (ESI): m/z (%) = 444.50 (100) [M + H]+. C29H33NO3 (443.58):
calcd. C 78.52, H 7.50, N 3.16; found C 78.67, H 7.12, N 3.01.
(1S,2R,3R,7aS)-3-(Hydroxymethyl)hexahydro-1H-pyrrolizine-1,2-
diol (7): To a solution of 18 (26 mg, 0.06 mmol) in 20 mL of MeOH
13 mg of 10% Pd on carbon and 2 drops of 37% HCl were added
while stirring under a nitrogen atmosphere, then the mixture was
stirred under a hydrogen atmosphere at room temp. for 2 d. After
that a TLC analysis (CH2Cl2/MeOH, 5:1) showed the disappear-
ance of starting material (Rf = 0.71) and formation of a new prod-
uct (Rf = 0.00), the mixture was filtered through Celite® and the
solvent was removed under reduced pressure affording quantita-
tively the hydrochloride salt of 7 (13 mg, 0.06 mmol, 100% yield
over two steps) as a waxy yellow solid. [α]3D0 = +56.5 (c = 0.12,
H2O). 1H NMR (400 MHz, CD3OD): δ = 4.16 (dd, J = 10.2,
C-7a), 57.2 (d, C-3), 30.6 (t, C-7) ppm. IR (CDCl ): ν = 3373, 3088,
˜
3
3066, 3030, 2868, 1693, 1454, 1361, 1120, 1044 cm–1. MS (ESI):
m/z (%) = 496.36(12) [M + Na]+. C29H31NO5 (473.56): calcd. C
73.55, H 6.60, N 2.96; found C 73.28, H 6.89, N 2.73.
(1S,2R,3R,6S,7aR)-1,2-Bis(benzyloxy)-3-[(benzyloxy)methyl]-6-hy-
droxyhexahydro-1H-pyrrolizine (20): A solution of 19 (178 mg,
4.3 Hz, 1 H, 2-H), 4.04–3.96 (m, 2 H, 1-H, 7a-H), 3.97 (dd, J = 0.38 mmol) in 12 mL of dry THF was stirred under nitrogen atmo-
12.4, 3.1 Hz, 1 H, 8-Ha), 3.86 (dd, J = 12.4, 9.3 Hz, 1 H, 8-Hb),
3.75 (td, J = 10.1, 3.5 Hz, 1 H, 3-H), 3.49 (ddd, J = 11.7, 6.7,
sphere at 0 °C and LiAlH4 (1 m solution in THF, 1.52 mL,
1.52 mmol) was added dropwise. The mixture was raised to room
2.0 Hz, 1 H, 5-Ha), 3.38 (td, J = 11.3, 5.8 Hz, 1 H, 5-Hb), 2.39– temp. and refluxed for 2 h, until TLC analysis (AcOEt/PE, 3:1)
2.32 (m, 1 H, 7-Ha), 2.18–2.11 (m, 1 H, 6-Ha), 1.93–1.79 (m, 1 H, showed the disappearance of the starting material (Rf = 0.29) and
7160
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7155–7162

Total Synthesis of (+)-Hyacinthacine A1 and Related Congeners
formation of a new product (Rf = 0.00). The reaction was then
quenched with 2 mL of a saturated aqueous solution of Na2SO4 at
0 °C, filtered through Celite® and the solvent was removed under
reduced pressure. The crude material was purified by flash column
chromatography (CH2Cl2/MeOH, 10:1), affording pure 20 (Rf =
0.35, 138 mg, 0.30 mmol, 79% yield) as a white solid. mp: 98.5–
99 °C. [α]2D2 = +35.3 (c = 0.89, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.28–7.19 (m, 15 H, Ar), 4.86 (d, J = 12.2 Hz, 1 H,
tion was left stirring for 2 h at room temp. TLC analysis (CH2Cl2/
MeOH, 10:1) showed disappearance of the starting material (Rf =
0.13) and formation of a new product (Rf = 0.68). Then 20 mL of
H2O were added, the mixture was extracted with CH2Cl2
(3 ϫ 15 mL) and the organic layers were dried on Na2SO4. Fil-
tration on cotton and evaporation under reduce pressure afforded
crude 22 that was purified by flash column chromatography (eluent
AcOEt) affording pure 22 as a yellow oil, (Rf = 0.27, 183 mg,
Bn), 4.54 (d, J = 11.7 Hz, 2 H, Bn), 4.55–4.43 (AB system, J = 0.34 mmol, quantitative yield). [α]2D7 = +40.8 (c = 1.46, CHCl3). 1H
11.7 Hz, 2 H, Bn), 4.43 (d, J = 12.2 Hz, 1 H, Bn), 4.20 (d, J = NMR (400 MHz, CDCl3): δ = 7.36–7.25 (m, 15 H, Ar), 5.23 (dq,
9.8 Hz, 1 H, OH), 4.13–4.07 (m, 1 H, 6-H), 3.93 (dd, J = 9.3, J = 13.6, 7.3 Hz, 1 H, 6-H) 4.78–4.57 (AB system, J = 12.2 Hz, 2
3.4 Hz, 1 H, 2-H), 3.87 (t, J = 3.9 Hz, 1 H, 1-H), 3.66 (dt, J = 9.3, H, Bn), 4.58–4.47 (AB system, J = 12.2 Hz, 2 H, Bn), 4.58–4.44
3.4 Hz, 1 H, 7a-H), 3.56 (dd, J = 9.8, 3.4 Hz, 1 H, 8-Ha), 3.46 (dd, (AB system, J = 11.7 Hz, 2 H, Bn), 3.93–3.89 (m, 2 H, 1-H, 2-H),
J = 9.8, 4.9 Hz, 1 H, 8-Hb), 3.36 (ddd, J = 8.7, 4.9, 2.9 Hz, 1 H,
3-H), 2.99 (dd, J = 12.7, 3.9 Hz, 1 H, 5-Ha), 2.91 (d, J = 12.7 Hz,
3.59 (dd, J = 9.8, 3.4 Hz, 1 H, 8-Ha), 3.60–3.55 (m, 1 H, 7a-H),
3.45 (dd, J = 9.8, 5.9 Hz, 2 H, Hb-8, Ha-5), 3.24 (ddd, J = 7.8, 5.4,
1 H, 5-Hb), 1.99 (dt, J = 14.1, 1.5 Hz, 1 H, 7-Ha), 1.92 (ddd, J = 3.4 Hz, 1 H, 3-H), 3.12 (dd, J = 9.8, 6.8 Hz, 1 H, 5-Hb), 2.90 (s, 3
14.1, 9.3, 4.9 Hz, 1 H, 7-Hb) ppm. 13C NMR (50 MHz, CDCl3): δ
= 138.4, 137.7, 137.3 (s, C-Ar), 128.5–127.4 (d, 15 C, C-Ar), 82.4
(d, C-2) 77.5 (d, C-1), 74.0, 73.4, 73.3 (t, C-Bn), 73.2 (d, C-6), 71.2
(t, C-8), 67.8 (d, C-3), 65.2 (d, C-7a), 63.0 (t, C-5) 34.9 (t, C-7) ppm.
H, Ms), 2.45 (dt, J = 12.7, 7.8 Hz, 1 H, 7-Ha), 2.19 (ddd, J = 12.7,
8.8, 7.3 Hz, 1 H, 7-Hb) ppm. 13C NMR (50 MHz, CDCl3): δ =
138.0, 137.9, 137.5 (s, C-Ar), 128.1–127.2 (d, 15 C, C-Ar), 82.2 (d,
C-2), 80.7 (d, C-6), 76.1 (d, C-1), 73.1, 72.9, 72.4 (t, C-Bn), 70.7 (t,
IR (CDCl ): ν = 3423, 3088, 3065, 3031, 2939, 2862, 1496, 1453, C-8), 66.9 (d, C-3), 63.5 (d, C-7a), 58.7 (t, C-5), 37.9 (q, Ms), 30.7
˜
3
1362, 1208, 1136, 1066 cm–1. MS (ESI): m/z (%) = 460.39 (100) [M
(t, C-7) ppm. IR (CDCl ): ν = 3087, 3065, 3030, 2863, 1495, 1453,
˜
3
+ H]+, 482.38 (75) [M + Na]+. C29H33NO4 (459.24): calcd. C 75.79, 1360, 1331, 1176, 1134, 1027 cm–1. MS (ESI): m/z (%) = 538.42
H 7.24, N 3.05; found C 76.03, H 7.52, N 3.44.
(100) [M + H]+, 560.17 (76) [M + Na]+. C30H35NO6S (537.67):
calcd. C 67.02, H 6.56, N 2.61; found C 66.72, H 6.86, N 2.55.
(1S,2R,3R,6S,7aR)-1,2,6-Trihydroxy-3-(hydroxymethyl)-hexahydro-
1H-pyrrolizine (21): To a solution of 20 (107 mg, 0.23 mmol) in
20 mL of MeOH, 54 mg of 10% Pd on carbon and 2 drops of HCl
37% were added while stirring under nitrogen atmosphere, then the
mixture was stirred under hydrogen atmosphere at room temp. for
3 d. After that a TLC analysis (CH2Cl2/MeOH, 10:1) showed the
disappearance of starting material (Rf = 0.57) and formation of a
new product (Rf = 0.00), the mixture was filtered through Celite®
and the solvent was removed under reduced pressure affording a
crude yellow oil (72 mg). The free amine was obtained by passing
the hydrochloride salt through a Dowex 50WX8 ion-exchange
resin. Elution with ammonia 6 % afforded free base 21 (41 mg,
0.22 mmol, 96%) as a yellow oil. [α]2D6 = +50.5 (c = 1.03, MeOH).
(1S,2R,3R,7aR)-1,2-Bis(benzyloxy)-3-[(benzyloxy)methyl]-hexahy-
dro-1H-pyrrolizine (23): A solution of 22 (128 mg, 0.24 mmol) in
10 mL of dry toluene was stirred under nitrogen atmosphere at
0 °C and DIBAL-H (1 m solution in CH2Cl2, 2.40 mL, 2.40 mmol)
was added dropwise. The mixture was raised to room temp. and
refluxed for 3 h, until TLC analysis (AcOEt) showed the disappear-
ance of the starting material (Rf = 0.27) and formation of a new
product (Rf = 0.00). The reaction was then quenched with 0.5 mL
of a saturated aqueous solution of Na2SO4 at 0 °C, filtered through
Celite® and the solvent was removed under reduced pressure. The
crude product was purified by flash column chromatography
(CH2Cl2/MeOH, 15:1), affording pure 23 (Rf = 0.23, 59 mg,
1H NMR (400 MHz, CD3OD): δ = 4.28 (dq, J = 5.4, 4.9 Hz, 1 H, 0.13 mmol, 56% yield) as a yellow oil. [α]2D5 = +33.2 (c = 1.06,
6-H), 3.87 (dd, J = 7.8, 3.9 Hz, 1 H, 1-H), 3.84 (dd, J = 9.8, 3.9 Hz,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.36–7.25 (m, 15 H,
1 H, 2-H), 3.78 (dd, J = 11.2, 3.4 Hz, 1 H, 8-Ha), 3.64 (dt, J = 8.8, Ar), 4.76 (d, J = 11.7 Hz, 1 H, Bn), 4.62–4.54 (m, 4 H, Bn), 4.47
3.9 Hz, 1 H, 7a-H), 3.55 (dd, J = 11.2, 6.3 Hz, 1 H, 8-Hb), 3.08
(dd, J = 11.7, 4.4 Hz, 1 H, 5-Ha), 2.99 (ddd, J = 9.8, 6.3, 3.4 Hz,
1 H, 3-H), 2.83 (ddd, J = 11.7, 3.4, 1.5 Hz, 1 H, 5-Hb), 2.13 (dtd,
J = 13.7, 3.9, 1.5 Hz, 1 H, 7-Ha), 1.98 (ddd, J = 14.1, 9.3, 5.4 Hz,
(d, J = 11.7 Hz, 1 H, Bn), 3.98–3.92 (m, 2 H, 2-H, 1-H), 3.90–3.80
(m, 1 H, 7a-H), 3.75 (pq, J = 8.6 Hz, 1 H, 8-Ha), 3.70 (dd, J = 9.8,
3.3 Hz, 1 H, 8-Hb), 3.32 (dq, J = 5.5, 4.9 Hz, 1 H, 5-Ha), 3.25 (td,
J = 9.8, 3.5 Hz, 1 H, 3-H), 2.79–2.73 (m, 5-Hb), 2.11 (dq, J = 11.7,
1 H, 7-Hb) ppm. 13C NMR (50 MHz, CD3OD): δ = 74.5 (d, C-2) 7.2 Hz, 1 H, 7-Ha), 2.01–1.86 (m, 2 H, Ha-6, Hb-6), 1.77 (ddd, J
72.4 (d, C-6), 72.0 (d, C-1), 70.2 (d, C-3), 64.9 (d, C-7a), 63.0 (t,
= 11.9, 7.2, 5.9 Hz, 1 H, 7-Hb) ppm. 13C NMR (50 MHz, CDCl3):
δ = 137.9, 137.2 (s, 3 C, C-Ar), 128.1–127.2 (d, 15 C, C-Ar), 82.2
C-8), 61.7 (t, C-5) 32.5 (t, C-7) ppm. 1H NMR (400 MHz, D2O): δ
= 4.27 (dq, J = 5.4, 3.9 Hz, 1 H, 6-H), 3.90 (t, J = 3.9 Hz, 1 H, 1- (d, C-2) 75.9 (d, C-1), 73.2, 73.1, 72.6 (t, C-Bn), 70.0 (t, C-8), 66.8
H), 3.81 (dd, J = 9.8, 3.9 Hz, 1 H, 2-H), 3.70 (dd, J = 11.7, 3.4 Hz, (d, C-3), 65.9 (d, C-7a), 55.4 (t, C-5), 26.8 (t, C-6), 24.5 (t, C-
1 H, 8-Ha), 3.55–3.51 (m, 1 H, 7a-H), 3.49 (dd, J = 11.7, 6.8 Hz, 7) ppm. IR (CDCl ): ν = 3087, 3065, 3031, 2909, 2870, 1496, 1453,
˜
3
1 H, 8-Hb), 3.03 (dd, J = 11.2, 4.4 Hz, 1 H, 5-Ha), 2.87 (ddd, J =
10.2, 6.8, 3.4 Hz, 1 H, 3-H), 2.62 (dd, J = 11.2, 4.9 Hz, 1 H, 5-Hb),
1365, 1208, 1143, 1124, 1095, 1027 cm–1. MS (ESI): m/z (%) =
444.44 (100) [M + H]+. C29H33NO3 (443.58): calcd. C 78.52, H
1.99–1.89 (m, 2 H, Ha-7, Hb-7) ppm. 13C NMR (50 MHz, D2O): 7.50, N 3.16; found C 78.27, H 7.58, N 2.67.
δ = 74.5 (d, C-2), 72.4 (d, C-6), 71.6 (d, C-1), 69.4 (d, C-3), 64.2
Synthesis of (1S,2R,3R,7aR)-3-Hydroxymethylhexahydro-1H-pyr-
(d, C-7a), 63.4 (t, C-8), 61.1 (t, C-5) 31.9 (t, C-7) ppm. MS (ESI):
m/z (%) = 190.12 (100) [M + H]+, 212.10 (54) [M + Na]+.
C8H15NO4 (189.21): calcd. C 50.78, H 7.99, N 7.40; found C 50.74,
H 8.04, N 7.42.
rolizine-1,2-diol (+)-Hyacinthacine A1 (6): To a solution of 23
(50 mg, 0.11 mmol) in 20 mL of MeOH 25 mg of 10% Pd on car-
bon and 2 drops of HCl 37% were added while stirring under nitro-
gen atmosphere, then the mixture was stirred under hydrogen atmo-
sphere at room temp. for 2 d. After TLC analysis (CH2Cl2/MeOH,
10:1) showed the disappearance of starting material (Rf = 0.33) and
formation of a new product (Rf = 0.00), the mixture was filtered
through Celite® and the solvent was removed under reduced pres-
sure affording a crude yellow oil (60 mg). The free amine was ob-
(1S,2R,3R,6R,7aR)-1,2-Bis(benzyloxy)-3-[(benzyloxy)methyl]-6-
(methylsulfonyloxy)-hexahydro-1H-pyrrolizine (22): To a stirred
solution of 20 (157 mg, 0.34 mmol) in dry CH2Cl2 (10 mL), NEt3
(142 μL, 1.02 mmol) was added under nitrogen atmosphere, and,
at 0 °C, MsCl (34 μL, 0.44 mmol) was added dropwise. The solu-
Eur. J. Org. Chem. 2011, 7155–7162
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7161

A. Goti, F. Cardona et al.
FULL PAPER
chi, F. M. Cordero, A. Goti, Chem. Eur. J. 2009, 15, 7808–7821;
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tained by passing the hydrochloride salt through a Dowex 50WX8
ion-exchange resin. Elution with ammonia 6% afforded free base
6 (18 mg, 0.10 mmol, 95% yield over two steps) as a waxy yellow
solid. [α]2D4 = +35.6 (c = 0.32, H2O). 1H NMR (400 MHz, CD3OD):
δ = 3.90–3.87 (m, 2 H, 1-H, 2-H), 3.81 (dd, J = 11.2, 3.4 Hz, 1 H,
8-Ha), 3.59 (dd, J = 11.2, 6.3 Hz, 1 H, 8-Hb), 3.53–3.49 (m, 1 H,
7a-H), 3.11–3.06 (m, 1 H, 5-Ha), 2.83–2.77 (m, 1 H, 3-H), 2.68
(ddd, J = 10.2, 7.8, 6.3 Hz, 1 H, 5-Hb), 2.10 (dq, J = 11.7, 6.8 Hz,
1 H, 7-Ha), 1.96 (ddd, J = 10.7, 5.3, 4.3 Hz, 1 H, 6-Ha), 1.83–1.65
(m, 2 H, Hb-6, Hb-7) ppm. 13C NMR (50 MHz, CD3OD): δ = 74.1
(d, C-2) 70.4 (d, C-1), 68.7 (d, C-3), 65.0 (d, C-7a), 61.7 (t, C-8),
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1
54.5 (t, C-5), 25.7 (t, C-6) 22.9 (t, C-7) ppm. H NMR (400 MHz,
D2O): δ = 3.92 (t, J = 3.9 Hz, 1 H, 1-H), 3.86 (dd, J = 9.7, 3.9 Hz,
1 H, 2-H), 3.70 (dd, J = 11.7, 3.5 Hz, 1 H, 8-Ha), 3.53 (dd, J =
11.7, 6.9 Hz, 1 H, 8-Hb), 3.45–3.39 (m, 1 H, 7a-H), 3.02–2.94 (m,
1 H, 5-Ha), 2.73 (ddd, J = 9.7, 6.3, 3.4 Hz, 1 H, 3-H), 2.52–2.46
(m, 1 H, 5-Hb), 1.90–1.78 (m, 2 H, Ha-6, Ha-7), 1.70–1.60 (m, 2
H, Hb-6, Hb-7) ppm. 13C NMR (50 MHz, D2O): δ = 74.1 (d, C-2)
70.4 (d, C-1), 67.8 (d, C-3), 64.5 (d, C-7a), 61.9 (t, C-8), 54.6 (t, C-
5), 26.0 (t, C-6), 22.7 (t, C-7) ppm. MS-EI (70 eV): m/z (%) = 142
(100), 96 (44), 70 (40), 41 (30). C8H15NO3 (173.21): calcd. C 55.47,
H 8.73, N 8.09; found C 55.15, H 8.54, N 7.63.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization of compound 14, syntheses of compounds
24–26, 1H and 13C NMR spectra of compounds 6 and of the hydro-
chloride salt of 7, 10–11 and 13–26, and glycosidase inhibition as-
says.
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Acknowledgments
We thank Ministero dell’Università e della Ricerca (MIUR) (PRIN
2008) and Ente CRF for financial support. The Spanish Ministerio
de Educación y Ciencia (MEC) (CTQ2008-01565/BQU) and the
Junta de Andalucía (FQM-345) are also acknowledged for finan-
cial support.
[11] The ratio between the two diastereoisomers was evaluated by
1
analysis of the H NMR at 400 MHz using the crude reaction
mixture.
[12] Two other minor cycloadducts were formed in trace quantities
but could not be completely characterized.
[13] Among the acrylic acid derivatives tested, tert-butyl acrylate
gave the best yields of the exo-syn adduct, useful for the synthe-
sis of the natural product.
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Received: July 27, 2011
Published Online: October 24, 2011
7162
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7155–7162