Asymmetric syntheses of (-)-lentiginosine and an original pyrrolizidinic analogue thereof from a versatile epoxyamine intermediate

Article abstract of DOI:10.1039/b505303j

Ready access to natural (-)-lentiginosine and its pyrrolizidinic analogue from a chiral vinylic epoxyamine in a straightforward five-step sequence is presented. Careful use of the RCM reaction on aminotriols 5 and 6 constitutes the key feature of the synt

Full text of DOI:10.1039/b505303j

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A R T I C L E
Asymmetric syntheses of (−)-lentiginosine and an original
pyrrolizidinic analogue thereof from a versatile epoxyamine
intermediate
Tahar Ayad, Yves Ge´nisson* and Michel Baltas
LSPCMIB,UMR 5068, Universite´ Paul Sabatier, 118 route de Narbonne, 31062, Toulouse,
France. E-mail: genisson@chimie.ups-tlse.fr; Fax: +33 (0)5 61 55 82 45;
Tel: +33 (0)5 61 55 62 99
Received 15th April 2005, Accepted 17th May 2005
First published as an Advance Article on the web 13th June 2005
Ready access to natural (−)-lentiginosine and its pyrrolizidinic analogue from a chiral vinylic epoxyamine in a
straightforward five-step sequence is presented. Careful use of the RCM reaction on aminotriols 5 and 6 constitutes
the key feature of the synthetic pathway. The a-amyloglucosidase inhibitory activities of the target compounds were
evaluated and showed that the more easily accessible pyrrolizidinic analogue possesses an inhibitory activity quite
similar to that of (−)-lentiginosine.
Introduction
Naturally occurring and synthetic polyhydroxylated alkaloids
with glycosidase inhibitory properties have been the subject of
an intense research effort during the past two decades.1 Such in-
hibitors are not only useful as potential drugs2 for the treatment
of viral infections, cancer, autoimmune pathologies, diabetes and
other metabolic disorders but can also provide new insight into
the widespread and important glycoside cleavage/formation
process. Iminosugars such as polyhydroxylated pyrrolidines,
piperidines, and their bicyclic congeners, indolizidines and
pyrrolizidines represent by far, the broadest and most studied
class of glycosidase inhibitors.3 Their pronounced biological
activity has been ascribed to their ability to mimic the transition
state involved in enzymatic glycoside hydrolysis.4
As part of a continuing program directed towards the total
Scheme 1 Retrosynthetic scheme for synthesis of (−)-lentiginosine (1)
synthesis of iminosugars, we have recently reported a flexible ap-
proach for the construction of five-membered ring iminosugars
based on the use of a chiral cis a,b-epoxyamine and demon-
strated its effectiveness through the preparation of 1,4-dideoxy-
1,4-imino-D-glucitol, 1,4-dideoxy-1,4-imino-D-arabinitol, 1,4-
dideoxy-1,4-imino-L-galactitol and novel 2-deoxy-2-fluoro
analogues.5 We now wish to report a detailed account of the
extension of our approach to polyhydroxylated indolizidines and
pyrrolizidines.6
and its pyrrolozidinic analogue 2.
Our general retrosynthetic analysis for the synthesis of these
classes of alkaloids is outlined in Scheme 1. We envisioned a
highly convergent route in which the last annulation process
should be an Appel cyclisation reaction.7 The six- or five-
membered ring of the indolizidine and pyrrolizidine cores
respectively, would be constructed from dienic derivatives 5, 6 by
a ring closing metathesis reaction (RCM).8 In turn, these dienes
would arise from the key intermediate 7 by regioselective epoxide
ring-opening followed by N-alkylation with the appropriate
alkenyl moiety. On the basis of the above simple retrosynthetic
analysis, (−)-lentiginosine (1)9 as well as its original pyrrolizi-
dinic analogue 2 were chosen as our first targets.
Scheme 2 Reagents and conditions: a) n-BuLi, TBDPSCl, THF, −78 ◦C,
˚
then reflux, 91%; b) i) Ti(Oi-Pr4), (−)-DET, t-BuOOH, CH2Cl2, 4 A MS,
−23 ◦C, 93%; ii) IBX, DMSO, 92%; c) BnNH2, 4 A MS, Et2O, rt, then
˚
Et2OBF3, CH2CHMgBr, −78 ◦C, 67%.
bromide to an imine derived from the readily accessible aldehyde
10 (Scheme 2).
With this efficient route to 7, highly regio- and stereoselective
conversion of the 2,3-epoxy alcohol moiety into amino triol 11
possessing the three stereogenic centers related to our target
molecules was readily achieved using aqueous acidic conditions.
Thus, treatment of epoxyamine 7 with 3 M H2SO4 in refluxing p-
dioxane gave exclusively the desired (2R,3R,4R)-amino triol as a
result of the electron withdrawing ammonium group-directed C-
2 hydrolysis.11 As expected, under such conditions, concomitant
cleavage of the silyl ether protecting-group occurred. Unambigu-
ous assignment of the configuration of 7 was first confirmed
Results and discussion
Chemistry
According to our previous work,10 the required cis a,b-
epoxyamine 7 was conveniently prepared from commercially
available cis-2-butene-1,4-diol through a reaction sequence
based on the stereocontrolled addition of vinylmagnesium
2 6 2 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 2 6 – 2 6 3 1
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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by the total synthesis of the known 1,4-dideoxy-1,4-imino-D-
arabinitol5c and by its transformation into the targeted (−)-
lentiginosine (1) (vide infra).
Our next objective was to construct the required tetrahy-
dropyridine 16 by ruthenium-catalysed RCM. Unfortunately,
treatment of 13 with 5–10% mol of either Grubbs I or Grubbs
II catalyst in refluxing CH2Cl2 completely failed to provide
the cyclised product.13 Pleasingly, when the second generation
catalyst was used intoluene at 70 ◦C, instead of refluxing CH2Cl2,
tetrahydropyridine 16 was rapidly (over ca. 50 min) obtained in
72% yield after purification.
With the advanced intermediate 11 in hand, we embarked
on the synthesis of (−)-lentiginosine according the sequence
depicted in Scheme 3. In order to secure our plan, prelim-
inary studies were first conducted on the partially protected
derivative 12. Thus, exposure of 11 to 2,2-dimethoxypropane
in the presence of a catalytic amount of camphorsulfonic
acid (CSA), cleanly proceeded to give the corresponding (1,2)-
acetonide in 80% isolated yield. At this stage, introduction of
the butenyl moiety as the second olefinic partner necessary for
tetrahydropyridine ring construction, via the key RCM step,
turned out to be particularly reluctant. Indeed, initial attempts
to alkylate the secondary amine 12 with 1-bromobutene under
standard reaction conditions (Et3N, NaI, THF, reflux or K2CO3,
NaI, DMF, 100 ◦C) were unsuccessful and led at the best,
to the recovery of the starting material. Similar results were
obtained when the reaction was conducted with the tosylate
derivative instead of the bromide. In view of these unsuccessful
results, we turned our attention to the use of the much
more reactive but-3-en-1-yl trifluoromethanesulfonate (15) as a
potential electrophilic reagent. Although preparation of 15 from
thecorresponding alcoholhad been mentionedto proceedwell,12
in our hands the use of such standard conditions (i-Pr2EtN, triflic
anhydride, CH2Cl2) invariably resulted in low yield (ca. 20%).
We reasoned that the presence of salts in the raw material might
be detrimental to the distillation. Filtering the crude product
on heat-activated silica prior to distillation, thus affording 15
in 70% yield, indeed solved the problem. Then we were very
pleased to find that exposure of compound 12 to 1.2 eq. of
but-3-en-1-yl trifluoromethanesulfonate (15) in presence of 1.2
eq. of the hindered 2,6-di-tert-butyl-4-methylpyridine in CH2Cl2
proceeded smoothly (over 24 h) to afford the expected diene 13,
albeit in a low yield (25%), along with 70% yield of the recovered
starting material. Somewhat surprising was that completion of
the reaction could not be achieved, even under forced conditions.
In each attempt, and despite a relatively clean transformation
as judged by TLC monitoring, compound 13 was isolated in
typically low yield 25–30% with only 30–50% of conversion.
With the above pilot experiment completed, we concentrated
our efforts to its application to the free triol 11, according to
our synthetic plan. Thus, treatment of N-benzyl derivative 11
with 1.2 eq. of but-3-en-1-yl trifluoromethanesulfonate (15) in
R
the presence of proton spongeꢀ gave the diolefin 14, which was
then cyclised under the RCM conditions described above to
provide 17 in 67% yield after purification. It should be noted
that, to the best of our knowledge, although ruthenium-based
RCM catalysts are known to be tolerant to a wide variety of
functionalities, no previous reports have dealt with a dienic
substrate bearing three non-protected hydroxyl groups such as
14. Compound 17 represents an attractive platform for further
oxidative functionalisation on the remaining olefin, thereby
offering a potential access to a variety of polyhydroxylated
indolizidines.14
Completion of the synthesis required three further transfor-
mations. One-pot N-debenzylation and reduction of the olefin
by catalytic hydrogenation provided after simple filtration on
R
Celiteꢀ the corresponding piperidine 18, in nearly quantitative
yield. The latter was then directly submitted to Appel cyclisation
conditions, which smoothly delivered (−)-lentiginosine (1) in
67% isolated yield through a remarkably selective activation of
the primary hydroxyl group. The 1H NMR, 13C NMR and mass
spectra of our synthetic sample were in agreement with those
reported in the literature.9
With the preparation of (−)-lentiginosine successfully ac-
complished, attention was then focused on the synthesis of
the original target compound 2 (Scheme 4) via a parallel
synthetic route. Allylation of amino triol 11 under standard
conditions proceeded cleanly to afford, in 85% yield, the dienic
precursor 19 required for the RCM. However, unsatisfactory
results were obtained under the conditions previously used
for the preparation of (−)-lentiginosine precursor 17. In fact,
although a fast reaction ensued, the expected dihydropyrrole 20
was isolated in moderate yield (50%) accompanied by oligomeric
products. Extended reaction times resulted in decomposition of
both starting material and product.
Scheme 3 Reagents and conditions: a) 3 M H2SO4, p-dioxane, reflux,
70%; b) dimethoxypropane, CSA, rt, 80%; c) but-3-en-1-yl trifluo-
romethanesulfonate (15), proton-spongeꢀR , CH2Cl2, rt, 67%; d) Grubbs
II catalyst, toluene, 70 ◦C, 66%; e) 12 bars H2, 10% Pd/C, MeOH, 12 M
HCl (cat.), 90%; f) PPh3, CCl4, Et3N, DMF, rt, 68%.
Scheme
4
Reagents and conditions: a) allyl bromide, NaHCO3,
THF–H2O, rt 85%; b) Grubbs I catalyst, CH2Cl2, reflux, 70%; c) 12
bars H2, 10% Pd/C, MeOH, 12 M HCl (cat.), 90%; d) PPh3, CCl4, Et3N,
DMF, rt, 68%.
These observations led us to assume that aminoalcohols 12
and/or 13 could be converted into non-nucleophilic ammonium
salts through competitive quenching of the trifluoromethane
sulfonic acid generated in the course of the reaction, thus
preventing its completion. We therefore thought that the use of
a strongly sequestering base would lead to a more favourable is-
It was clear that in this case, the greater reactivity of the
second-generation Grubbs’ catalyst was detrimental to the
success of the reaction. Much to our delight, the dihydropyrrole
derivative 20 was obtained in a 70% yield when the reaction was
carried out using the less reactive Grubbs I catalyst in refluxing
CH2Cl2. Finally, sequential catalytic hydrogenation–Appel cycli-
sation was again used to convert 20 into dihydroxypyrrolizidine
2 via pyrrolidine intermediate 21 (61% overall yield).
R
sue. The proton-spongeꢀ (1,8-bis(dimethylamino)naphthalene)
turned out to be an excellent base for this purpose, yielding diene
13 in 72% isolated yield.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 2 6 – 2 6 3 1
2 6 2 7

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Biological evaluation
95 XL spectrometer (DCI). Optical rotations were measured on
a Perkin-Elmer model 141 polarimeter and are given in units of
10−1 deg cm2 g−1.
This synthetic work was complemented by enzymatic inhibi-
tion experiments with respect to the amyloglucosidase from
Aspergillus niger. The enzymatic assay was performed in the
presence of 0.01 to 0.5 u ml−1 of 1,4-a-D-glucanglucohydrolase
from Aspergillus niger. After preincubation with the inhibitor,
5 mM of an aqueous solution of p-nitrophenyl glucoside used
as substrate was added and the mixture was allowed to react at
(1R,2R)-2-(Benzylamino)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-
yl]but-3-en-1-ol (12)
To aminotriol 11 (200 mg, 0.84 mmol) dissolved in 10 mL of
freshly distilled 2,2-dimethoxypropane, camphorsulfonic acid
(46 mg, 0.93 mmol) was added. After stirring for 48 h in an
inert atmosphere at room temperature, the reaction mixture
was neutralised by addition of saturated aq. NaHCO3 (5 mL).
The 2,2-dimethoxypropane was then evaporated under reduced
pressure and the resulting aqueous solution extracted with Et2O
(3 × 50 mL). The combined organic layers were successively
washed with water and brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography on silica gel eluting
with petroleum ether–EtOAc (70 : 30) to afford acetonide 12
(186 mg, 0.82 mmol, 80% yield). Rf = 0.25 (petroleum ether–
EtOAc, 70 : 30). [a]D25 −3.0 (c 1.30 in CHCl3). mmax (film)/cm−1:
◦
45 C for 20 min. After quenching, the inhibitory activity was
determined spectrophotometrically (k = 410 nm) by measuring
the quantity of p-nitrophenate released. An IC50 of 25.5 lg
mL−1 was measured for our sample of (−)-lentiginosine (1).
This is in agreement with the IC50 value (17 lg mL−1) that
Brandi et al. found for the laevorotatory isomer, proposed
to be the unnatural enantiomer of lentiginosine.15 The novel
dihydroxylated pyrrolizidine 2 was found to display an IC50 of
27.3 lg mL−1, comparable with that of (−)-lentiginosine, and to
behave as a competitive inhibitor (Ki = 121 lM).
Conclusion
=
3256 (O–H), 1499 (C C); dH (250 MHz, CDCl3) 1.32 (s, 6H,
3
3
In conclusion, we achieved the total synthesis of (−)-
lentiginosine (1) and of its pyrrolizidinic analogue 2 through
a common straightforward five-step sequence in 19 and 26%
overall yield respectively, from the versatile chiral cis a,b-
epoxyamine 7. Interestingly, the activity of the more easily
accessible pyrrolizidinic analogue 2 is quite similar to that of
(−)-lentiginosine.
2 × Me), 3.02 (pseudot, JH4H5 = JH4H3 = 7.8 Hz, 1H, H-4),
3.20–3.47 (m, 1H, O-H), 3.50–3.60 (m, 3H, H-1ꢀ, H-3 and 1 ×
NCH2Ph), 3.70–3.90 (m, 3H, H-1, H-2 and 1 × NCH2Ph), 5.19
(dd, 2Jgem = 1.1 Hz and 3JH6 H5 = 17.2 Hz, 1H, H-6ꢀ), 5.33 (dd,
ꢀ
2Jgem = 1.1 Hz and 3JH6H5 = 10.2 Hz, 1H, H-6), 5.62–5.77 (m, 1H,
H-5), 7.20–7.28 (m, 5H, H-Ph); dC (63 MHz, CDCl3) 26.9, 26.8
(2 × Me), 50.8 (NCH2Ph), 62.3 (C-4), 62.8 (C-1), 80.5 (C-2), 82.3
(C-3), 108.7 (Cquat. acetonide), 118.5 (C-6), 127.4, 128.6 (CH
arom.), 136.2 (C-5), 138.8 (Cquat. arom.); HRMS (DCI/NH3)
m/z: Calc. for C16H24NO3 278.1756, found 278.1752.
A key feature of these syntheses is the RCM of highly
functionalised aminotriols 14 and 19. Tetrahydropyridine 17 and
dihydropyrrole 20 thus prepared constitute valuable intermedi-
ates for further late transformations, via oxidation of the olefin.
In addition, the starting epoxyamine being equally available
in both optical series and cis or trans isomeric structures, the
chemistry disclosed here opens an expeditious route to the
synthesis of a large number of indolizidines and pyrrolizidines
iminosugars of biological interest. Efforts toward this aim are
currently in progress in our laboratory and will be reported in
due course.
But-3-en-1-yl trifluoromethanesulfonate (15)
To a solution of but-3-en-1-ol (586 mg, 8.10 mmol) and
diisopropylethylamine (1.15 g, 8.90 mmol) dissolved in 35 mL of
freshly distilled CH2Cl2, triflic anhydride (1.50 mL, 8.90 mmol)
was added dropwise, at 0 ◦C in an inert atmosphere. After
stirring for 2 h at this temperature, the reaction mixture was
allowed to warm to room temperature for 30 min before being
rapidly filtered through a plug of activated silica (70–200 lm,
heated overnight at 110 ◦C in an oven), and rinsed with freshly
distilled CH2Cl2 (20 mL) to remove the salt. The solvent was
then evaporated in vacuo and the crude product was purified by
Experimental
General methods
◦
Reactions were performed in flame-dried glass, sealed with a
rubber septum, and stirred with a magnetic stirring bar, under
argon or nitrogen when required. Materials were obtained
from commercial suppliers and were used without purification,
unless otherwise stated. The following solvents were dried
prior to use: CH2Cl2 (freshly distilled from calcium hydride),
distillation under reduced pressure (65 C/10 mbar) to afford
pure 15 as an◦colorless liquid which can be stored for a few
weeks at −20 C (1.55 mg, 70% yield). mmax (film)/cm−1: 1425,
1355, 1220, 1150, 960; dH (250 MHz, CDCl3) 2.59 (pseudoq, 2H,
3
3JH2H1 = JH2H3 = 6.6 Hz, H-2), 4.56 (t, 2H, 3JH1H2 = 6.6 Hz, H-1),
5.18–5.30 (m, 2H, 2 × H-4), 5.67–5.82 (m, 1H, H-3); dC (63 MHz,
˚
DMF (from calcium hydride, stored over 4-A molecular sieves),
CDCl3) 33.5 (C-2), 76.1 (C-1), 119.5 (C-4), 131.1 (C-3).
Et2O and THF (distilled from sodium–benzophenone), toluene
(distilled from calcium hydride). Thin layer chromatography
(TLC) reaction monitoring was carried out with Macherey-
(1R,2R)-2-[Benzyl(but-3-en-1-yl)amino]-1-[(4R)-2,2-dimethyl-
1,3-dioxolan-4-yl]but-3-en-1-ol (13)
R
Nagel ALUGRAMꢀ SIL G/UV254 (0.2 mm) plates visualised
with 10% phosphomolybdic acid in ethanol or Dragendorff
reagent as dipping solutions. Standard column chromatography
was performed with SDS 70–200 lm silica gel. Flash column
chromatography was carried out with SDS 35–70 lm silica
gel. Medium-pressure liquid chromatography was performed
with a Jobin-Yvon apparatus using Merck 15–40 lm silica gel.
Deactivated silica gel was obtained by treatment with 2.5%
v/v Et3N. NMR spectroscopic data were obtained with Bruker
AC200, AC250, and AC400 instruments operating for 1H spectra
at 200, 250, and 400 MHz, and 13C spectra at 50, 63, and
100 MHz, respectively. Chemical shifts are quoted in parts per
million (ppm) downfield from tetramethylsilane and coupling
constants are in Hertz. Infrared (IR) spectra were recorded on a
Perkin-Elmer FT-IR 1725X spectrometer. High-resolution mass
spectra (HRMS) were performed on a ThermoFinnigan MAT
In an inert atmosphere at room temperature, 1,8-
bis(dimethylamino)naphthalene (289 mg, 1.35 mmol) and but-
3-en-1-yl trifluoromethanesulfonate (15) (110 mg, 0.54 mmol)
were successively added to a solution of acetonide 12 (250 mg,
0.90 mmol) dissolved in 10 mL of anhydrous CH2Cl2. After
stirring for 6 h at this temperature, but-3-en-1-yl trifluo-
romethanesulfonate (15) (110 mg, 0.54 mmol) was again added.
The reaction mixture was then stirred overnight before being
neutralised by addition of saturated aq. NaHCO3 (10 mL).
The resulting aqueous solution was extracted with CH2Cl2 (3 ×
40 mL). The combined organic phases were successively washed
with water and brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. Flash column chromatography
on silica gel eluting with petroleum ether–EtOAc (gradient 85 :
15 to 75 : 25) afforded pure 13 (214 mg, 0.64 mmol, 72% yield).
2 6 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 2 6 – 2 6 3 1

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Rf = 0.30 (solvent petroleum ether–AcOEt, 75 : 25). [a]2D5 −23.2
5H, H–Ph); dC (100 MHz, CDCl3) 18.9 (C-7), 26.9, 27.0 (2 ×
Me), 42.9 (C-8), 57.7 (NCH2Ph), 59.2 (C-4), 63.5 (C-1), 81.0
(C-2), 83.7 (C-3), 108.9 (Cquat. acetonide), 125.9 (C-5), 126.5
(C-6), 128.0, 128.7, 130.2 (CH arom.), 136.9 (Cquat. arom.);
HRMS (DCI/NH3) m/z: Calc. for C18H26NO3 304.1913, found
304.1912.
−1
=
(c 1.70 in CHCl3); mmax (film)/cm : 3256 (O–H), 1499 (C C); dH
(250 MHz, CDCl3) 1.26 (s, 3H, Me), 1.36 (s, 3H, Me), 2.27–2.34
(m, 2H, 2 × H-8), 2.36–2.47 (m, 1H, H-7ꢀ), 2.69–2.81 (m, 1H,
3
3
H-7), 3.07 (pseudot, 1H, JH4H3 = JH4H5 = 8.8 Hz, H-4), 3.63
2
(ABq, 2H, Jgem = 13.3 Hz, NCH2Ph) Dda − db = 140.2 Hz,
3
ꢀ
3.55–3.62 (m, 1H, H-2), 3.72 (AB of an ABX, 2H, JH1 H2
=
3
2
3.8 Hz, JH1H2 = 6.1 Hz and Jgem = 10.7 Hz, 2 × H-1), Dda −
(1R,2R)-1-[(2R)-1-Benzyl-1,2,5,6-tetrahydropyridin-
2-yl]propane-1,2,3-triol (17)
db = 28.0 Hz, 3.95 (pseudot, 1H, 3JH3H2 = JH3H4 = 7.9 Hz, H-3),
3
4.99–5.10 (m, 2H, 2 × H-10), 5.19 (dd, 1H, 2Jgem = 1.8 Hz and
Following the procedure described above for the preparation
of 16, starting aminotriol 14 (100 mg, 0.34 mmol) gave after
reaction and purification by flash preparative chromatography
(silica gel, eluent AcOEt–THF–MeOH (80 : 10 : 10 in a sat-
urated atmosphere of NH3), the tetrahydropyridine 17 (60 mg,
0.22 mmol, 66% yield). Rf = 0.20 (solvent AcOEt–THF–MeOH,
90 : 10 : 10 in a saturated atmosphere of NH3). [a]2D5 +35.0 (c
3.00 in CHCl3); mmax (film)/cm−1: 3365 (O–H); dH (250 MHz,
CDCl3–D2O) 2.00–2.10 (m, 2H, 2 × H-7), 2.34–2.45 (m, 1H,
JH6 H5 = 17.2 Hz, H-6ꢀ), 5.46 (dd, 1H, 2Jgem = 1.8 Hz and 3JH6H5
=
3
ꢀ
10.2 Hz, H-6), 5.68–5.95 (m, 2H, H-5 and H-9), 7.20–7.40 (m,
5H, H–Ph); dC (63 MHz, CDCl3) 26.8, 26.9 (2 × Me), 32.6 (C-8),
50.1 (C-7), 55.6 (NCH2Ph), 62.7 (C-1), 64.9 (C-4), 79.2 (C-3),
81.1 (C-2), 108.8 (Cquat. acetonide), 116.1 (C-10), 121.2 (C-6),
127.4, 128.5, 129.4 (CH arom.), 131.8 (C-9), 136.1 (C-5), 138.1
(Cquat. arom.); HRMS (DCI/NH3) m/z: Calc. for C20H30NO3
332.2226, found 332.2226.
3
H-8ꢀ), 2.94 (dpseudot, 1H, 3JH8H7 = JH8H7 = 5.2 Hz and 2Jgem
=
ꢀ
(2R,3R,4R)-4-[Benzyl(but-3-en-1-yl)amino]hex-5-ene-
1,2,3-triol (14)
12.1 Hz, H-8), 3.35–3.40 (m, 1H, H-4), 3.72 (AB of an ABX,
2H, 3JH1 H2 = 3.9 Hz, 3JH1H2 = 4.2 Hz and 2Jgem = 11.6 Hz, 2 ×
ꢀ
2
By applying to aminotriol 11 (200 mg, 0.84 mmol) the alkylation
procedure described above for compound 13, pure diene 14
(163 mg, 0.56 mmol, 67% yield) was obtained after purification
by flash column chromatography on deactivated silica gel eluting
with AcOEt–THF–MeOH (gradient from 83 : 17 : 0 to 78 : 17
: 5). Rf = 0.31 (solvent AcOEt–THF–MeOH, 80 : 17 : 3 in a
saturated atmosphere of NH3). [a]2D5 −15.8 (c 0.90 in CHCl3);
mmax (film)/cm−1: 3490, 1495; dH (250 MHz, CDCl3) 2.18–2.31
(m, 2H, 2 × H-8), 2.38–2.53 (m, 1H, H-7ꢀ), 2.59–2.74 (m, 1H,
H-7), 3.10–3.30 (m, 4H, H-4 and 3 × O-H), 3.48–3.62 (m, 2H,
H-1) Dda − db = 27.3 Hz, 3.92 (ABq, 2H, Jgem = 13.0 Hz,
NCH2Ph) Dda − db = 238 Hz, 3.85–3.93 (m, 2H, H-2 and H-3),
5.61–5.66 (m, 1H, H-5), 5.99–6.04 (m, 1H, H-6), 7.26–7.35 (m,
5H, H–Ph); dC (63 MHz, CDCl3–D2O) 23.1 (C-7), 46.6 (C-8),
60.3 (NCH2Ph), 62.2 (C-4), 65.1 (C-1), 71.0 (C-2), 74.5 (C-3),
125.8 (C-5), 127.4 (C-6), 128.4, 128.5, 129.3 (CH arom.), 138.2
(Cquat. arom.); HRMS (DCI/NH3) m/z: Calc. for C15H22NO3
264.1600, found 264.1599.
(1R,2R)-1-[(2R)-Piperidin-2-yl]propane-1,2,3-triol (18)
2
2 × H-1), 3.59 (ABq, 2H, Jgem = 13.5 Hz, NCH2Ph), Dda −
db = 118 Hz, 3.72 (dd, 1H, 3JH3H2 = 2.7 Hz and 3JH3H4 = 8.9 Hz,
To a solution of 17 (60 mg, 0.23 mmol) in MeOH (4 mL)
containing 12 M HCl (3 drops) was added 10% Pd/C (12 mg)
and the resulting suspension was stirred under 12 bars of H2.
H-3), 3.94–4.03 (m, 1H, H-2), 4.96–5.11 (m, 2H, 2 × H-10),
5.24 (dd, 1H, 2Jgem = 1.7 Hz and 3JH6 H5 = 17.0 Hz, H-6ꢀ), 5.45
ꢀ
R
After 4 days, the reaction mixture was filtered through Celiteꢀ
2
3
(dd, 1H, Jgem = 1.7 Hz and JH6H5 = 10.2 Hz, H-6), 5.68–5.87
(m, 2H, H-5 and H-9), 7.20–7.37 (m, 5H, H–Ph); dC (63 MHz,
CDCl3) 32.6 (C-8), 50.1 (C-7), 55.2 (NCH2Ph), 64.5 (C-4), 64.4
(C-1), 70.9 (C-2), 71.2 (C-3), 116.2 (C-10), 121.7 (C-6), 127.3,
128.5, 128.6, 129.1 (CH arom.), 132.6 (C-9), 136.6 (C-5), 139.2
(Cquat. arom.); HRMS (DCI/NH3) m/z: Calc. for C17H26NO3
292.1913, found 292.1911.
and concentrated to dryness under reduced pressure. The crude
product was then dissolved in H2O–MeOH (66 : 33) 10 mL,
acidic resin (Dowex 50 WX8, 100–200 mesh, 5 g) was added
and the suspension was stirred slowly for 1 h before being
filtered. The resin was successively rinsed with water (150 mL)
and MeOH (50 mL), taken up in 2.5 M aqueous NH4OH
(20 ml) and the mixture stirred slowly for 1 h. The suspension
was then filtered and the resin rinsed with 2.5 M aqueous
NH4OH (200 mL). The resulting solution was lyophilised to
give piperidine 18 (37 mg, 0.21 mmol, 92% yield). Rf = 0.30
(solvent AcOEt–petroleum ether: 25 : 75). [a]2D5 −6.8 (c 3.00 in
MeOH); mmax (film)/cm−1: 3335 (O–H); dH (400 MHz, CD3OD–
D2O) 1.28–1.55 (m, 3H, H-5ꢀ, H-6ꢀ and H-7ꢀ), 1.65–1.72 (m,
1H, H-7), 1.88–1.92 (m, 2H, H-5 and H-6), 2.68 (dpseudot, 1H,
(R)-[(2R)-1-Benzyl-1,2,5,6-tetrahydropyridin-2-yl][(4R)-2,2-
dimethyl-1,3-dioxolan-4-yl]methanol (16)
The RCM precursor 13 (100 mg, 0,34 mmol) was dissolved
in 10 mL of dry toluene and the solution degassed by
bubbling with argon over 30 min. Benzylidene[1,3-bis(2,4,6-
trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexyl-
phosphine)ruthenium (GrubbsII catalyst) (23 mg, 8% mol) was
then added and the mixture was stirred at 70 ◦C in an inert
atmosphere until TLC analysis showed no remaining starting
material (ca. 50 min). The reaction mixture was then allowed to
cool to room temperature and the solvent was removed under
reduced pressure. The residue thus obtained was purified by
flash column chromatography on deactivated silica gel eluting
with petroleum ether–EtOAc (gradient from 85 : 15 to 70 : 30)
to afford 16 (79 mg, 0.26 mmol, 77% yield). Rf = 0.24 (solvent
petroleum ether–AcOEt, 75 : 25 in a saturated atmosphere of
NH3). [a]2D5 +25.6 (c 0.40 in CHCl3); mmax (film)/cm−1: 3352
3
3
JH8 H7 = JH8 H7 = 2.6 Hz and 2Jgem = 12.3 Hz, H-8ꢀ), 2.82–2.88
ꢀ
ꢀ
ꢀ
(m, 1H, H-4), 3.15 (d, 1H, 2Jgem = 12.3 Hz, H-8), 3.53 (dd, 1H,
3JH3H2 = 3.2 Hz and 3JH3H4 = 5.5 Hz, H-3), 3.59–3.67 (m, 2H, 2 ×
H-1), 3.71–3.75 (m, 1H, H-2); dC (100 MHz, CD3OD–D2O) 23.8
(C-6), 25.2 (C-7), 27.1 (C-5), 46.2 (C-8), 59.2 (C-4), 63.3 (C-1),
71.8 (C-2), 72.9 (C-3); MS (DCI/NH3) m/z: 176 (MH+, 100%).
(−)-Lentiginosine (1)
To a solution of amino triol 18 (36.4 mg, 0.21 mmol) in
anhydrous DMF (4 mL) were successively added Ph3P (113 mg,
0.42 mmol), CCl4 (56 lL, 0.42 mmol) and Et3N (58.5 lL,
0.42 mmol). After stirring overnight at room temperature in
an inert atmosphere, MeOH (0.5 mL) was added. The reaction
mixture was then stirred for an additional 45 min before
being concentrated to dryness under reduce pressure. The crude
product was dissolved in H2O–MeOH (66 : 33) 10 mL, acidic
resin (Dowex 50 WX8, 100–200 mesh, 5 g) was added and the
suspension was stirred slowly for 1 h before being filtered. The
resin was successively rinsed with water (150 mL) and MeOH
=
(O–H), 1625 (C C); dH (400 MHz, CDCl3) 1.83 (dpseudot, 1H,
3
3
JH7 H8 = JH7 H8 = 4.8 Hz and 2Jgem = 18.3 Hz, H-7ꢀ), 2.32–2.42
ꢀ
ꢀ
ꢀ
3
3
ꢀ
(m, 1H, H-7), 2.88 (AB of an ABX, 2H, JH8 H7 = 4.7 Hz, J
2
ꢀ
= 5.0 Hz and Jgem = 14.2 Hz, 2 × H-8) Dda − db =
H8H7
3
2
55.0 Hz, 2.90 (dd, 1H, JH4H3 = 4.7 Hz and JH4H5 = 14.0 Hz,
H-4), 3.54–3.59 (m, 1H, H-2), 3.70 (AB of an ABX, 2H,
JH1H2 = 3.2 Hz, 3JH1 H2 = 9.1 Hz and 2Jgem = 9.7 Hz, 2 × H-1)
3
ꢀ
Dda − db = 150.0 Hz, 3.74–3.80 (m, 3H, H-3 and NCH2Ph),
5.87–5.92 (m, 2H, H-5), 6.02–6.06 (m, 2H, H-6), 7.28–7.38 (m,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 2 6 – 2 6 3 1
2 6 2 9

View Article Online
(50 mL), taken up in 2.5 M aqueous NH4OH (20 ml) and the
mixture stirred slowly for 1 h. The suspension was then filtered
and the resin rinsed with 2.5 M aqueous NH4OH (200 mL). The
resulting solution was lyophilised and the residue obtained was
purified by flash column chromatography on deactivated silica
gel eluting with CH2Cl2–MeOH–NH4OH (gradient from 95 : 4
: 1 to 89 : 10 : 1) to give (−)-lentiginosine (1) (22 mg, 0.14 mmol,
67% yield). Rf = 0.33 (solvent CH2Cl2–MeOH–NH4OH, 90 : 9
: 1). [a]2D5 −2.0 (c 1.01 in MeOH); mmax (film)/cm−1: 3285 (O–H);
dH (400 MHz, CD3OD) 1.19–1.35 (m, 4H, H-6ꢀ, H-7ꢀ and 2 ×
O-H), 1.48–1.70 (m, 2H, H-5ꢀ and H-8ꢀ), 1.79–1.88 (m, 2H, H-7
and H-8), 1.95–2.09 (m, 2H, H-5 and H-6), 2.70 (AB of an ABX,
75.4 (C-4), 127.4, 127.5 (C-6 and C-5), 128.8, 128.9, 129.0 (CH
arom.), 138.8 (Cquat. arom.); HRMS (DCI/NH3) m/z: Calc.
for C14H20NO3 250.1443, found 250.1447.
(1R,2R)-1-[(2R)-Pyrrolidin-2-yl]propane-1,2,3-triol (21)
Following the catalytic hydrogenation procedure described
above for 18, dihydropyrrole 20 (60 mg, 0.24 mmol) gave after
purification pyrrolidine 21 (35 mg, 0.22 mmol, 92% yield). Rf =
0.18 (EtOAc–Et2O–MeOH, 80 : 10 : 10 in a saturated atmosphere
of NH3). [a]2D5 +7.8 (c 1.80 in MeOH); mmax (film)/cm−1: 3378 (O–
H and N–H); dC (63 MHz, CD3OD) 26.3, 28.3 (C-5 and C-6),
47.1 (C-7), 62.3 (C-4), 64.6 (C-1), 73.2, 73.8 (C-3 and C-2); MS
(DCI/NH3) m/z: 162 (MH+, 100%).
2H, 3JH1H2 = 1.4 Hz, 3JH1 H2 = 7.2 Hz and 2Jgem = 10.8 Hz, 2 ×
ꢀ
H-1) Dda − db = 130.0 Hz, 2.96–3.02 (m, 1H, H-4), 3.63 (dd,
1H, 3JH3H2 = 3.4 Hz and 3JH3H4 = 8.4 Hz, H-3), 3.96 (ddd, 1H,
3
JH2H1 = 1.5 Hz, 3JH2H3 = 3.4 Hz and 3JH2H1 = 7.2 Hz and H-2);
(1R,2R,7aR)-Hexahydro-1H-pyrrolizine-1,2-diol (2)
ꢀ
dC (100 MHz, CD3OD) 25.8 (C-6), 26.6 (C-7), 30.3 (C-5), 55.4
(C-8), 63.8 (C-1), 72.0 (C-4), 78.5 (C-2), 86.0 (C-3); HRMS (EI)
m/z: Calc. for C8H15NO2 157.1102, found 157.1101.
Using the Appel cyclisation procedure described above for the
preparation of the compound 1, pyrrolizidine 2 was obtained
(18 mg, 0.90 mmol, 68% yield) from 21 after purification by
flash column chromatography on deactivated silica gel eluting
with CH2Cl2–MeOH–EtOH–NH4OH (gradient from 60 : 10 :
20 : 10 to 50 : 20 : 20 : 10). Rf = 0.27 (solvent CH2Cl2–MeOH–
EtOH–NH4OH, 50 : 20 : 20 : 10). [a]2D5 +7.6 (c 1.28 in MeOH);mmax
(film)/cm−1: 3465 (O–H); dH (400 MHz, CD3OD) 1.78–1.87 (m,
1H, H-6ꢀ), 1.93–2.09 (m, 2H, H-5ꢀ and H-6), 2.10–2.20 (m, 1H,
H-5), 2.90–3.23 (m, 1H, H-7ꢀ), 3.25–3.28 (m, 1H, H-7), 3.19
ꢀ
(2R,3R,4R)-4-[Allyl(benzyl)amino]hex-5-ene-1,2,3-triol (19)
To a solution of 11 (200 mg, 0,84 mmol) in THF–H2O (4 : 2)
were successively added allyl bromide (0.291 lL, 3.36 mmol)
and potassium carbonate (697 mg, 5,04 mmol). After stirring
for 48 h at room temperature, the aqueous phase was extracted
with CH2Cl2 (3 × 20 ml) and then with EtOAc (2 × 15 mL).
The combined organic layers were successively washed with
water and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography on deactivated silica gel eluting with
petroleum ether–Et2O–AcOEt (gradient from 60 : 10 : 30 to 30
: 10 : 60) to give 19 (197 mg, 0.71 mmol, 85% yield). Rf = 0,22
(AB of an ABX, 2H, 3JH1 H2 = 4.4 Hz, 3JH1H2 = 5.2 and 2Jgem
=
11.60 Hz, 2 × H-1) Dda − db = 230.0 Hz, 3.55–3.63 (m, 1H, H-4),
3.88–3.95 (m, 1H, H-3), 4.13–4.23 (m, 1H, H-2); dC (100 MHz,
CD3OD) 28.0 (C-6), 32.1 (C-5), 58.9 (C-7), 61.0 (C-1), 75.0 (C-
4), 80.0 (C-2), 82.8 (C-3); HRMS (EI) m/z: Calc. for C7H13NO2
143.0946, found 143.0950.
(solvent petroleum ether–Et2O–AcOEt, 30 : 10 : 60). [a]2D5 −2.8
−1
=
(c 1.00 in CHCl3); mmax (film)/cm : 3465 (O–H), 1489 (C C);
References
dH (250 MHz, CDCl3) 2.91 (dd, 1H, 3JH7 H8 = 8.2 Hz and 2Jgem
=
ꢀ
14.0 Hz, m, H-7ꢀ), 3.20–3.36 (m, 2H, H-4 and H-7), 3.48–3.60
1 T. Ayad, Y. Ge´nisson and M. Baltas, Curr. Org. Chem., 2004, 8,
1211–1233 and references cited therein.
2 M. Mammen, S.-K. Choi and G. M. Whitesides, Angew. Chem., Int.
Ed., 1998, 37, 2754–2794.
2
(m, 2H, 2 × H-1), 3.58 (ABq, 2H, Jgem = 13.4 Hz, NCH2Ph)
Dda − db = 137.5 Hz, 3.79 (dd, 1H, 3JH3H2 = 3.0 Hz and 2JH3H4
=
9.1 Hz, H-3), 4.03–3.98 (m, 1H, H-2), 4.71–4.85 (m, 3H, O–H),
5.17–5.32 (m, 3H, H-6ꢀ and 2 × H-9), 5.51 (dd, 1H, 2Jgem = 2.0 Hz
3 A. E. Stu¨tz, in Iminosugars as glycosidases inhibitors: Nojirimycin and
beyond, Wiley-VCH Verlag GmbH, 1998.
4 M. Bols, Acc. Chem. Res., 1998, 31, 1–8; T. D. Heightman and A. T.
Vasella, Angew. Chem., Int. Ed., 1999, 38, 750–770 and references
cited therein.; D. L. Zechel and S. G. Withers, Acc. Chem. Res., 2000,
33, 11–18.
5 (a) T. Ayad, Y. Ge´nisson, M. Baltas and L. Gorrichon, Synlett, 2001,
866–868; (b) K. Marotte, T. Ayad, Y. Genisson, G. S. Besra, M. Baltas
and J. Prandi, Eur. J. Org. Chem., 2003, 2557–2565; (c) T. Ayad,
Y. Genisson, S. Broussy, M. Baltas and L. Gorrichon, Eur. J. Org.
Chem., 2003, 2903–2910.
3
and JH6H5 = 10.2 Hz, H-6), 5.77–5.93 (m, 2H, H-5 and H-8),
7.20–7.37 (m, 5H, H-Ph); dC (63 MHz, CDCl3) 53.6 (C-7), 55.6
(NCH2Ph), 63.9 (C-4), 64.3 (C-1), 71.1 (C-2), 71.5 (C-3), 118.1,
121.6 (C-6 and C-9), 127.3, 128.5, 129.1 (CH arom.), 132.7 (C-
8), 136.0 (C-5), 139.0 (Cquat. arom.); HRMS (DCI/NH3) m/z:
Calc. for C16H24NO3 278.1756, found 278.1756.
(1R,2R)-1-[(2R)-1-Benzyl-2,5-dihydro-1H-pyrrol-2-yl]propane-
6 For a preliminary communication see: T. Ayad, Y. Genisson, M.
Baltas and L. Gorrichon, Chem. Commun., 2003, 582–583.
7 R. Appel and R. Kleinstu¨ck, Chem. Ber., 1974, 107, 5–12.
8 For a review of the use of RCM in synthesis of bicyclic azasugars
see: U. K. Pandit, H. S. Overkleeft, B. C. Borer and H. Biera¨ugel,
Eur. J. Org. Chem., 1999, 959–968.
1,2,3-triol (20)
To a solution of diene 19 (100 mg, 0,36 mmol) in freshly distilled
CH2Cl2 (10 mL) was added benzylidene-bis (tricyclohexylphos-
phine)dichlororuthenium (Grubbs I catalyst) (25 mg, 8% mol)
at room temperature. The resulting mixture was refluxed in an
inert atmosphere until no remaining starting material could be
detected by TLC (ca. 5 h). The reaction mixture was then allowed
to cool to room temperature and the solvent was removed under
reduced pressure. The residue thus obtained was purified by
flash column chromatography on deactivated silica gel eluting
with AcOEt–petroleum ether–MeOH (gradient from 60 : 30 :
10 to 80 : 10 : 10) to give 20 (63 mg, 0.25 mmol, 70% yield).
Rf = 0,23 (solvent AcOEt–petroleum ether–MeOH, 80 : 10 :
10). [a]2D5 +60.2 (c 2.80 in CHCl3); mmax (film)/cm−1: 3465 (O–H),
9 For isolation of (−)-lentiginosine see: I. Pastuszak, R. J. Molyneux,
L. F. James and A. D. Elbein, Biochemistry, 1990, 29, 1886–1891. For
chiral pool syntheses see: (a) H. Yoda, H. Kitayama, T. Katagiri and
K. Takabe, Tetrahedron: Asymmetry., 1993, 4, 1455–1456; (b) Mk
Gurjar, L. Ghosh, M. Syamala and V. Jayasree, Tetrahedron Lett.,
1994, 35, 8871–8872; (c) R. Giovannini, E. Marcantoni and M.
Petrini, J. Org. Chem., 1995, 60, 5706–5707; (d) A. Goti, F. Cardona
and A. Brandi, Synlett, 1996, 761–763; (e) H. Yoda, M. Kawauchi
and K. Takabe, Synlett, 1998, 137–138; (f) A. E. McCaig, K. P.
Meldrum and R. H. Wightman, Tetrahedron, 1998, 54, 9429–9446;
(g) D.-C. Ha, C.-S. Yun and Y. Lee, J. Org. Chem., 2000, 65, 621–
623; (h) H. Yoda, H. Katoh, Y. Ujihara and K. Takabe, Tetrahedron
Lett., 2001, 42, 2509–2512; (i) J. Rabiczko, Z. Urban´czyk-Lipkowska
and M. Chmielewski, Tetrahedron, 2002, 58, 1433–1441; (j) K. L.
Chandra, M. Chandrasekhar and V. K. Singh, J. Org. Chem., 2002,
67, 4630–4633; (k) Y. Ichikawa, T. Ito, T. Nishiyama and M. Isobe,
Synlett, 2003, 7, 1034–1036. For asymmetric syntheses see:; (l) S.
Nukui, M. Sodeoka, H. Sasai and M. Shibasaki, J. Org. Chem., 1995,
60, 398–404; (m) M. O. Rasmussen, P. Delair and A. E. Greene,
1489 (C C); dH (250 MHz, CD3OD) 3.20–3.31 (m, 1H, H-7ꢀ),
=
3.54–3.69 (m, 3H, 2 × H-1, H-7), 3.71 (dd, 1H, 3JH3H2 = 2.0 Hz,
3JH3H4 = 4.0 Hz, H-3), 3.84 (td, 1H, JH2H3 = 2.0 Hz, JH2H1
=
3
3
6.0 Hz, H-2), 3.98 (ABq, 2H, 2Jgem = 13.0 Hz, NCH2Ph), Dda −
db = 203.0 Hz, 4.05–4.13 (m, 1H, H-4), 5.75–5.87 (m, 2H, H-
5 and H-6), 7.24–7.39 (m, 5H, H–Ph); dC (63 MHz, CD3OD)
60.6 (C-7), 61.2 (NCH2Ph), 65.7 (C-1), 71.2 (C-2), 72.9 (C-3),
2 6 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 2 6 – 2 6 3 1

View Article Online
J. Org. Chem., 2001, 66, 5438–5443; (n) S. H. Lim, S. Ma and P.
Beak, J. Org. Chem., 2001, 66, 9056–9062; (o) Z.-X. Feng and W.-S.
Zhou, Tetrahedron Lett., 2003, 44, 497–498; (p) S. Raghavan and T.
Sreekanth, Tetrahedron: Asymmetry, 2004, 15, 565–570.
(b) G. H. P. Roos and K. A. Dastlik, Synth. Commun., 2003, 33,
2197–2208 (c) S. Hanessian, M. Tremblay and J. F. W. Petersen,
J. Am. Chem. Soc., 2004, 126, 6064–6071.
13 Grubbs
I catalyst refers to benzylidene-bis(tricyclohexylphos-
10 T. Ayad, V. Faugeroux, Y. Ge´nisson, C. Andre´, M. Baltas and L.
Gorrichon, J. Org. Chem., 2004, 69, 8775–8779.
11 For the sake of coherence, carbon numbering of the pivotal
aminotriol intermediate has been used throughout the article,
including for NMR peak assignments.
12 (a) A. P. Dobbs, K. Jones and K. T. Veal, Tetrahedron Lett., 1997,
38, 5383–5386. After completion of our work, two procedures for
the preparation of 15 have been described to work equally well:
phine)dichlororuthenium and Grubbs II catalyst refers to benzyl-
idene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-
(tricyclohexylphosphine)ruthenium.
14 For syntheses of related tetrahydroxyindolizidines see: A. T. Car-
mona, J. Fuentes, I. Robina, E. R. Garc´ıa, R. Demange, P. Vogel and
A. L. Winters, J. Org. Chem., 2003, 68, 3874–3883.
15 A. Brandi, S. Cicchi, F. M. Cordero, R. Frignoli, A. Goti, S. Picasso
and P. Vogel, J. Org. Chem., 1995, 60, 6806–681.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 2 6 – 2 6 3 1
2 6 3 1