Synthesis of d-arabinose-derived polyhydroxylated pyrrolidine, indolizidine and pyrrolizidine alkaloids. Total synthesis of hyacinthacine A2

Article abstract of DOI:10.1016/j.tet.2009.12.030

Several new polyhydroxylated alkaloids including pyrrolidines with a long side chain and 3-(hydroxymethyl) indolizidines were prepared from a common nitrone easily obtained from d-arabinose. In addition, a total synthesis of hyacinthacine A₂ has been achieved in five steps and 67.7% overall yield starting from the same d-arabino-derived nitrone. All synthesized compounds have a common structural feature consisting of a pyrrolidine ring with d-arabino configuration.

Full text of DOI:10.1016/j.tet.2009.12.030

Tetrahedron 66 (2010) 1220–1227
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of
D-arabinose-derived polyhydroxylated pyrrolidine, indolizidine and
pyrrolizidine alkaloids. Total synthesis of hyacinthacine A2
a
a
b,
a,
*
*
´
Ignacio Delso , Tomas Tejero , Andrea Goti , Pedro Merino
a Laboratorio de Sintesis Asimetrica, Departamento de Quimica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza, CSIC, 50009 Zaragoza. Aragon, Spain
b
`
Dipartimento di Chimica Organica Ugo Schiff and HeteroBioLab, Universita di Firenze, associated with ICCOM-CNR, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Several new polyhydroxylated alkaloids including pyrrolidines with a long side chain and 3-(hydroxy-
Received 19 November 2009
Received in revised form 8 December 2009
Accepted 9 December 2009
Available online 16 December 2009
methyl) indolizidines were prepared from a common nitrone easily obtained from
dition, a total synthesis of hyacinthacine A2 has been achieved in five steps and 67.7% overall yield
starting from the same -arabino-derived nitrone. All synthesized compounds have a common structural
feature consisting of a pyrrolidine ring with -arabino configuration.
Ó 2009 Elsevier Ltd. All rights reserved.
D-arabinose. In ad-
D
D
Keywords:
Alkaloids
Pyrrolidines
Nitrones
1. Introduction
Polyhydroxylated nitrogen saturated heterocycles, such as
pyrrolidines, indolizidines, and pyrrolizidines constitute one of
the most extensively examined family of compounds that
have been shown to be potent inhibitors of a great variety of
glycosidases.1 This biological activity confers those compounds
a well-recognized chemotherapeutic potential as antibacterial,2
antidiabetic,3 antitumoral,4 and antiviral5 agents and, as a conse-
quence, they have been broadly studied subjects of synthetic
chemistry for many years.6 Among the pleyade of natural and
unnatural polyhydroxylated alkaloids of biological interest, those
found in Hyacinthaceae plants have received considerable atten-
tion from both biological7 and synthetic8 points of view. Most
derivatives isolated from the leaves of bluebells (Hyacinthoides
non-scripta) possess a common structural motif consisting of
a pyrrolidine having D-arabino substitution pattern, that is, three
contiguous centers bearing two hydroxyl groups and a hydroxy-
methyl group, all having R configuration. The simplest member of
this family is DAB-1 1. Other structural variations reside in the
side chain at C-1 of the pyrrolidine ring leading to DMDP 2 and
homo-DMDP 3 among others like 4–6 (Fig. 1).9 The same struc-
tural motif has also been found in radicamines A 7 and B 8, both
isolated from Lobelia chinensis.10 The side chain at C-1 can also be
linked to the nitrogen atom forming a bicyclic structure as in the
* Corresponding authors. Tel./fax: þ34 976 762075.
E-mail address: pmerino@unizar.es (P. Merino).
Figure 1. Alkaloids with D-arabino configuration.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.030

I. Delso et al. / Tetrahedron 66 (2010) 1220–1227
1221
case of hyacinthacines A2 9 and A3 1011 as well as in the well-
known pyrrolizidines alexine 11,12 australine 1213, casuarine 13,14
and uniflorine A 14.15
In all cases the reaction proceeded with no selectivity, lower
chemical yield and with the formation of a large number of by-
products. The benzyl and benzyloxycarbonyl protecting groups in
26 and 27 could be removed in the same reaction vessel by treat-
ment of those compounds with hydrogen at 3 bar under catalytic
conditions (10% Pearlman’s catalyst) in acidic methanol. Purifica-
tion of 28 and 29 by C-18 reverse-phase chromatography and fur-
ther liophylization afforded those target compounds in 98% and
97% yield, respectively (Scheme 2).
Among the various approaches reported in the literature, nu-
cleophilic additions to cyclic nitrones have demonstrated to be an
expeditious and efficient method for preparing a variety of poly-
hydroxylated pyrrolidines and derivatives.16 The main advantage of
this approach resides in the fact that a variety of cyclic nitrones can
be prepared from sugars having a different configuration in such
a way that most of stereocenters are incorporated in the starting
materials. Previous work in our laboratories17 illustrated this con-
cept and a variety of natural compounds including codonop-
sinine,18 lentiginosine,19 DAB-1,20 DMDP,21 and radicamine B22 have
been synthesized.
We describe herein the synthesis of the naturally occurring
hyacinthacine A2 9 and the non-natural polyhydroxylated alkaloids
15–18, compounds, which have the D-arabino configuration at the
pyrrolidine ring (Fig. 2). We envisaged preparing compounds 15–18
using nitrone 19 as a suitable starting material. Nitrone 19 can be
readily prepared from D
-arabinose as described by one of us22 in
four steps and 21% overall yield,23 and it has already been used in
our laboratories for preparing DAB-1,19 radicamine B,20 and hya-
cinthacine A2,21 in the last case through a dipolar cycloaddition
approach.
Scheme 1. Synthesis of pyrrolidines with a long side chain. (i) allylmagnesium bro-
mide, THF, 0 ꢀC. (ii) H2, 3 bar, Pd(OH)2–C, MeOH–HCl,. (iii) Zn, AcOH. (iv) Cbz2O, di-
oxane. (v) 9-BBN, then H2O2.
Figure 2. Target compounds from nitrone 19.
2. Results and discussion
2.1. Synthesis of pyrrolidines with a long side chain
Allylation of nitrone 19 took place with complete selectivity and
excellent chemical yield furnishing hydroxylamine 20 as the only
product of the reaction (Scheme 1).24 The configurational assign-
ment of 20 was unambiguously determined by 2D NMR techniques
(NOESY, COSY). Concomitant deoxygenation, reduction of the
double bond, and removal of the benzyl groups were achieved by
catalytic hydrogenation (Pearlman’s catalyst, 3 bar) in acidic
methanol. Purification of the resulting material afforded 21 (90%
from 19), which was characterized as the hydrochloride salt.
Selective deoxygenation of hydroxylamine 20 was achieved by
using Zn in aqueous acetic acid as reducing system. The resulting
pyrrolidine 22 was then protected at the nitrogen atom as the N-
Cbz derivative 23. The olefin 23 was then submitted to a typical
hydroboration with 9-BBN25 to afford primary alcohol 24 in 96%
yield after purification (Scheme 1). Compound 24 was subjected to
hydrogenolysis under 3 bar of hydrogen in acidic methanol to give
25 in 80.6% overall yield (six steps from 19).
Scheme 2. Synthesis of pyrrolidines with a long side chain. (i) OsO4, NMO, acetone–
H2O. (ii) H2, 3 bar, Pd(OH)2–C, MeOH–HCl.
The relative stereochemistry of the newly created stereogenic
center in 26 and 27 was determined by transforming the major
isomer 26 into the bicyclic 30 through a NaH-mediated intra-
molecular cyclization (Scheme 3). 2D NMR NOESY experiments
(C6D6, 500 MHz) indicated an NOE between H-1 and H-a and H-b of
the hydroxymethyl group, thereby confirming that in 26 the hy-
droxyl group at the side chain possessed the indicated
configuration.
Compound 23 was treated with catalytic osmium tetroxide and
N-methylmorpholine oxide (NMO) to give a 1.4:1 mixture of hy-
droxylated derivatives 26 and 27 in 87% combined yield. In seeking
a higher selectivity for the hydroxylation reaction we checked dif-
ferent conditions including the use of AD-MIX
a
and
b
complexes.26
Scheme 3. Determination of configuration for 26. (i) NaH, THF, rt.

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I. Delso et al. / Tetrahedron 66 (2010) 1220–1227
2.2. Synthesis of 3-(hydroxymethyl)indolizidines27
Again, any attempt of enhancing osmylation selectivity was
unsuccessful; use of AD-MIX reagents led to the production of
many polar products and lower yields without improving selec-
tivity. Hydrogenolysis of compounds 34 and 35 produced the target
3-(hydroxymethyl) indolizidines 36 and 37, respectively, as the
hydrochloride salts in excellent yields.
For the synthesis of the target analogs 18 we envisaged the
formation of the six-membered ring from 22 via a Ring-Closing
Metathesis (RCM), which had been successfully employed in the
preparation of several bicyclic polyhydroxylated alkaloids.28 The
introduction of the second alkene residue in 22 was achieved
through N-allylation under basic conditions (Scheme 4), which
gave the RCM precursor 31 in quantitative yield. This precursor was
then subjected to RCM using second generation Grubbs’ catalyst29
in toluene at 80 ꢀC and bicycle 32 was obtained in 91% isolated
yield.
30
2.3. Synthesis of hyacinthacine A2
Our approach to hyacinthacine A2 9 was based on the consec-
utive nucleophilic addition-RCM metathesis previously described
for the preparation of 3-(hydroxymethyl) indolizidines 33, 36, and
37. In the case of compound 9 the ring to be formed should have
one less carbon atom that in the case of compounds 33, 36, and 37
in order to produce the pursued pyrrolizidine skeleton. Therefore,
nucleophilic addition of vinylmangnesium bromide (VMB)31 to 19
in diethyl ether at 0 ꢀC was carried out to obtain hydroxylamine 38.
The reaction took place with quantitative yield and only one isomer
could be detected by NMR (400 MHz). The relative stereochemistry
between the vinyl group and the benzyloxy group at C-3 was de-
termined to be trans by 2D NMR NOESY experiments. As expected,
the nucleophile attacked by the less hindered Re face of the nitrone.
Deoxygenation (Zn, aq acetic acid) of 38 to 39 followed by N-ally-
lation as described for 22 furnished diallylamine 40 in 81% yield
(overall two steps) (Scheme 5).
Scheme 4. Synthesis of 3-(hydroxymethyl) indolizidines. (i) allyl bromide, DMF,
K2CO3, Bu4NI. (ii) Grubbs second generation catalyst, toluene, 80 ꢀC. (iii) H2, 3 bar,
Pd(OH)2–C, MeOH–HCl. (iv) OsO4, NMO, acetone–H2O.
Scheme 5. Synthesis of Hyacinthacine A2. (i), vinylmagnesium bromide, Et2O, 0 ꢀC. (ii)
Zn, AcOH. (iii) allyl bromide, DMF, K2CO3, Bu4NI. iv) Grubbs second generation catalyst,
toluene, 80 ꢀC. (v) H2, 3 bar, Pd(OH)2–C, MeOH–HCl, then Dowex 50WX8-200.
Hydrogenolysis of 32 afforded 3-(hydroxymethyl) indolizidine
33 in an excellent yield after purification. Treatment of 32 with
OsO4/NMO in acetone–water gave cis-hydroxylated compounds 34
and 35 in 1.2:1 ratio and 79% combined yield. After chromato-
graphic separation, 2D NMR NOESY on 34 and 35 confirmed both
Compound 40 was subjected to RCM in toluene at 80 ꢀC for 24 h
and bicycle 41 was obtained in 87% isolated yield. In contrast to that
reported for other chiral diallylamines32 the RCM reaction of the
basic nitrogen-containing substrate 40 took place smoothly with-
out the assistance of any additive. Finally, catalytic hydrogenation
of 41 under usual conditions gave hyacinthacine A2, which was
obtained as the free base after purification by ion-exchange chro-
matography. The overall yield for 9 was 67.7% (five steps from
nitrone 19).
the
a-cis configuration of the two newly introduced hydroxyl
groups and the relative configuration of those groups with respect
to the benzyloxy groups already present in the molecules (Fig. 3).
3. Conclusions
Several polyhydroxylated saturated nitrogen heterocycles hav-
ing a pyrrolidine ring with D-arabino configuration have been pre-
pared. Incorporation of the side chain was achieved by completely
stereoselective allylation of the starting nitrone. By introducing
a second allylic chain it has been possible to prepare the scarcely
Figure 3. interactions found (2D NOESY) for 34 and 35.

I. Delso et al. / Tetrahedron 66 (2010) 1220–1227
1223
21
studied 3-(hydroxymethyl) indolizidines via RCM. Following
a similar strategy a successful total synthesis of hyacinthacine A2
has also been achieved in five steps and 67.7% overall yield.
as a white solid; mp84–86 ꢀC. [
(400 MHz, D2O)
a
]
þ9 (c 0.28, H2O). 1H NMR
D
0
0
d
0.95 (t, J¼7.3 Hz, 3H, H3 ), 1.38–1.53 (m, 2H, H2 ),
0
0
1.69–1.80 (m, 1H, H1 a), 1.81–1.92 (m, 1H, H1 b), 3.44 (td, J¼8.4,
5.8 Hz,1H, H5), 3.56 (ddd, J¼7.7, 6.1, 3.9 Hz, 1H, H2), 3.86 (dd, J¼12.6,
6.0 Hz, 1H, CH2OH), 3.93 (dd, J¼12.6, 3.8 Hz, 1H, CH2OH), 3.96 (dd,
J¼7.9, 6.8 Hz, 1H, H4), 4.05 (dd, J¼7.7, 6.9 Hz, 1H, H3). 13C NMR
4. Experimental section
4.1. General
0 0 0
d 12.8 (C3 ), 18.6 (C2 ), 32.1 (C1 ), 57.9 (CH2OH), 61.2
(100 MHz, D2O)
(C5), 62.0 (C2), 74.2 (C3), 78.1 (C4). Anal. Calcd for C8H18ClNO3: C,
The reaction flasks and other glass equipment were heated in an
oven at 130 ꢀC overnight and assembled in a stream of Ar. All re-
actions were monitored by TLC on silica gel 60 F254; the position of
the spots was detected with 254 nm UV light or by spraying with 5%
ethanolic phosphomolybdic acid. Preparative centrifugally accel-
erated radial thin-layer chromatography (radial chromatography)
was performed with a ChromatotronÒ Model 7924 T (Harrison
Research, Palo Alto, CA, USA) and with solvents that were distilled
prior to use; the rotors (1 or 2 mm layer thickness) were coated
with silica gel Merck grade type 7749, TLC grade, with binder and
fluorescence indicator (Aldrich 34,644-6) and the eluting solvents
45.39; H, 8.57; N, 6.62. Found: C, 45.55; H, 8.70; N, 6.32.
4.1.3. (2R,3R,4R,5R)-2-Allyl-3,4-bis(benzyloxy)-5-(benzyloxy-meth-
yl)pyrrolidine (22). A solution of hydroxylamine 20 (0.92 g,
2 mmol) in acetic acid (10 mL) was treated with water (10 mL) and
Zn powder (2.6 g, 40 mmol). The resulting mixture was stirred at
ambient temperature for 40 min, diluted with water (50 mL) and
treated with Na2CO3 until bubbling of CO2 stopped. The reaction
mixture was extracted with dichloromethane (3ꢂ50 mL) and the
combined organic extracts were washed with NaOH 3 M (50 mL)
and brine, dried (MgSO4) and evaporated under reduced pressure
were delivered by the pump at a flow-rate of 0.5–1.5 mL minꢁ1
Column chromatography was carried out in a Buchi 800 MPLC
.
to give pure amine 22 (0.88 g, quant.), which did not need further
27
purification. [
d
a]
ꢁ24 (c 1.3, CHCl3). 1H NMR (400 MHz, CDCl3)
D
system using silica gel 60
m
. Melting points were uncorrected. 1H
2.20 (td, J¼14.3, 7.3 Hz, 1H, CH2CH]CH2), 2.30 (td, J¼13.1, 6.5 Hz,
and 13C NMR spectra were recorded on Bruker Avance 400 or 500
instruments in the stated solvent. Chemical shifts are reported in
1H, CH2CH]CH2), 3.11–3.17 (m, 1H, H2), 3.35 (dt, J¼6.0, 4.2 Hz, 1H,
H5), 3.42–3.48 (m, 2H, CH2OBn), 3.68 (dd, J¼3.1 Hz, J¼4.8 Hz, 1H,
H3), 3.82 (dd, J¼4.0, 3.2 Hz, 1H, H4), 4.40–4.50 (m, 6H, CH2Ph), 4.98–
5.05 (m, 2H, CH2CH]CH2), 5.72 (ddt, J¼17.2, 10.2, 7.1 Hz, 1H,
CH2CH]CH2), 7.15–7.35 (m, 15H, Ar). 13C NMR (100 MHz, CDCl3)
parts per million (
d
) relative to CHCl3
(
d
¼7.26) in CDCl3. Optical
rotations were taken on a Perkin–Elmer 241 polarimeter or on
a JASCO DIP-370 polarimeter. Elemental analyses were performed
on a Perkin–Elmer 240B microanalyzer or with a Perkin–Elmer
2400 instrument.
d
37.9 (CH2CH]CH2), 61.3 (C2), 61.7 (C5), 70.7 (CH2OBn), 71.8
(CH2Ph), 71.8 (CH2Ph), 73.2 (CH2Ph), 86.2 (C4), 88.4 (C3), 117.5
(CH2CH]CH2), 127.6 (Ar), 127.7 (Ar), 127.7 (Ar), 127.8 (Ar), 127.9
(Ar), 128.4 (Ar), 128.4 (Ar), 135.1 (CH2CH]CH2), 138.1 (Ar), 138.1
(Ar), 138.2 (Ar). Anal. Calcd for C29H33NO3: C, 78.52; H, 7.50; N, 3.16.
Found: C, 78.42; H, 7.92; N, 3.35.
4.1.1. (2R,3R,4R,5R)-2-Allyl-3,4-bis(benzyloxy)-5-(benzyloxy-meth-
yl)pyrrolidin-1-ol (20). To a cooled (0 ꢀC) solution of nitrone 19
(1.0 g, 2.4 mmol) in anhydrous THF (30 mL), allylmagnesium bro-
mide (7.2 mL of a 1 M solution in THF, 7.2 mmol) was added
dropwise. After stirring for 13 h at 0 ꢀC the reaction was quenched
with satd aq NH4Cl (20 mL). The reaction mixture was diluted with
diethyl ether (20 mL), the organic layer was separated and the
aqueous layer was extracted with diethyl ether (2ꢂ20 ml). The
combined organic extracts were washed with brine (20 mL), dried
over MgSO4, filtered, and the solvent was eliminated under reduced
pressure to afford the crude product, which was purified by radial
4.1.4. (2R,3R,4R,5R)-Benzyl
2-allyl-3,4-bis(benzyloxy)-5-(benzyl-
oxymethyl)pyrrolidine-1-carboxylate (23). A solution of amine 22
(0.6 g, 1.35 mmol) in dioxane (15 mL) was treated with dibenzyl
dicarbonate (0.57 g, 2 mmol) and sodium hydroxide (10 mg). After
stirring for 2.5 h, the solvent was evaporated and the residue pu-
rified by radial chromatography (hexane–EtOAc, 7:3) to afford pure
27
23 (0.715 g, 92%) as an oil. [
a]
ꢁ27 (c 1.075, CHCl3). 1H NMR
D
chromatography (Hexane–EtOAc, 7:3) to give pure 20 (1.15 g, 98%)
(500 MHz, CDCl3, mixture of conformers)
d
2.38 (ddd, J¼13.1, 11.6,
22
as an oil. Rf (Hexane–EtOAc, 7:3)¼0.55. [
a
]
D
ꢁ3 (c 0.815, CHCl3). 1H
9.1 Hz, 0.5H, CH2CH]CHA2), 2.47 (ddd, J¼13.4, 11.3, 8.7 Hz, 0.5H,
CH2CH]CHB2), 2.67–2.74 (m, 0.5H, CH2CH]CHB2), 2.99–3.07 (m,
0.5H, CH2CH]CHA2), 3.55–3.65 (m, 1H, CH2OBnA, CH2OBnB), 3.83
(dd, J¼8.9, 4.1 Hz, 0.5H, CH2OBnA), 3.94–4.02 (m, 1.5H, H2B, H4A, HB4),
4.05 (dd, J¼11.3, 3.3 Hz, 0.5H, HA2), 4.15 (dd, J¼4.2, 8.7 Hz, 0.5H,
CH2OBnB), 4.23–4.28 (m, 1.5H, H5A, H3A, HB3), 4.37 (dd, J¼10.5, 4.0 Hz,
0.5H, HB5), 4.41 (d, J¼13.2 Hz, 0.5H, CH2Ph), 4.43 (d, J¼11.5 Hz, 0.5H,
CH2Ph), 4.49 (d, J¼12.0 Hz, 0.5H, CH2Ph), 4.52 (d, J¼11.2 Hz, 0.5H,
CH2Ph), 4.53 (d, J¼12.0 Hz, 0.5H, CH2Ph), 4.54 (d, J¼11.2 Hz, 0.5H,
CH2Ph), 4.57 (d, J¼11.7 Hz, 0.5H, CH2Ph), 4.65 (d, J¼12.1 Hz, 0.5H,
CH2Ph), 4.69 (d, J¼12.2 Hz, 0.5H, CH2Ph), 4.72 (d, J¼12.0 Hz, 0.5H,
CH2Ph), 5.04 (d, J¼17.1 Hz, 0.5H, CH2CH]CHB2), 5.09 (d, J¼10.1 Hz,
0.5H, CH2CH]CHB2), 5.11–5.18 (m, 2H, CH2CH]CH2A, N(CO)OCH2Ph),
5.25 (d, J¼12.4 Hz, 0.5H, N(CO)OCH2Ph), 5.28 (d, J¼12.4 Hz, 0.5H,
N(CO)OCH2Ph), 5.74 (dddd, J¼14.5, 10.1, 8.3, 6.0 Hz, 0.5H,
CH2CH]CHB2), 5.84 (dddd, J¼14.6, 10.8, 8.8, 5.6 Hz, 0.5H,
CH2CH]CHA2), 7.24–7.41 (m, 20H, Ar). 13C NMR (125 MHz, CDCl3,
NMR (400 MHz, CDCl3)
d
2.27–2.37 (m, 1H, CH2CH]CH2), 2.66–
2.75 (m, 1H, CH2CH]CH2), 3.37 (dt, J¼8.5, 5.1 Hz, 1H, H2), 3.52–3.57
(m, 1H, H5), 3.65 (dd, J¼9.6, 6.5 Hz, 1H, CH2OH), 3.80 (dd, J¼9.6,
5.2 Hz, 1H, CH2OH), 3.86 (dd, J¼4.8, 2.5 Hz, 1H, H3), 3.97 (dd, J¼4.2,
2.5 Hz,1H, H4), 4.45 (d, J¼11.8 Hz, 1H, CH2Ph), 4.47 (d, J¼11.9 Hz,1H,
CH2Ph), 4.51 (d, J¼11.8 Hz, 1H, CH2Ph), 4.54 (d, J¼12.0 Hz, 1H,
CH2Ph), 4.54 (d, 1H, J¼12.0 Hz, 1H, CH2Ph), 4.59 (d, J¼12.0 Hz, 1H,
CH2Ph), 5.07–5.15 (m, 2H, CH2CH]CH2), 5.86 (dddd, J¼16.9, 10.2,
7.5, 6.7 Hz, 1H, CH2CH]CH2), 7.27–7.38 (m, 15H, Ar). 13C NMR
(100 MHz, CDCl3)
d 32.6 (CH2CH]CH2), 68.4 (CH2OBn), 69.5 (C2),
69.9 (C5), 71.7 (CH2Ph), 71.7 (CH2Ph), 73.4 (CH2Ph), 84.2 (C4), 85.3
(C3), 117.1 (CH2CH]CH2), 127.6 (Ar), 127.7 (Ar), 127.7 (Ar), 127.9 (Ar),
127.9 (Ar), 128.3 (Ar), 128.3 (Ar), 128.4 (Ar), 135.5 (CH2CH]CH2),
138.1 (Ar),138.2 (Ar),138.5 (Ar). Anal. Calcd for C26H27NO4: C, 74.80;
H, 6.52; N, 3.35. Found: C, 74.73; H, 6.41; N, 3.24.
4.1.2. (2R,3R,4R,5R)-2-(Hydroxymethyl)-5-propylpyrrolidine-3,4-diol
hydrochloride (21). A solution of hydroxylamine 20 (0.15 g,
0.32 mmol) in methanol (5 mL) was treated with HCl 1 M in
methanol (0.5 mL) and Pd(OH)2–C (50 mg). The resulting mixture
was stirred under 3 bar of hydrogen for 6 h. The catalyst was
eliminated by filtration through a pad of Celite, and the solvent was
eliminated under reduced pressure to afford pure 21 (65 mg, 97%)
mixture of conformers) d
34.8 (CH2CH]CHA2), 36.1 (CH2CH]CHB2),
63.0 (CA5), 63.3 (C5B), 64.0 (C2B), 64.1 (C2A), 67.0 (O(CO)OCH2Ph), 67.0
(O(CO)OCH2Ph), 67.8 (CH2OHB), 68.8 (CH2OHA), 71.0 (CH2Ph), 71.0
(CH2Ph), 71.1 (CH2Ph), 71.2 (CH2Ph), 73.1 (CH2Ph), 73.1 (CH2Ph),
82.0 (CB3), 82.7 (C4A), 83.1 (C3A), 83.8 (C4B), 117.9 (CH2CH]CHA2), 117.9
(CH2CH]CHB2), 127.6 (Ar), 127.6 (Ar), 127.7 (Ar), 127.7 (Ar), 127.7
(Ar), 127.8 (Ar), 127.8 (Ar), 128.0 (Ar), 128.1 (Ar), 128.1 (Ar), 128.2

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I. Delso et al. / Tetrahedron 66 (2010) 1220–1227
0
(Ar), 128.4 (Ar), 128.4 (Ar), 128.5 (Ar), 128.5 (Ar), 128.6 (Ar), 134.9
(CH2CH]CHB2), 135.1 (CH2CH]CHA2), 136.6 (Ar), 136.6 (Ar), 137.7
(Ar), 137.7 (Ar), 137.9 (Ar), 138.0 (Ar), 138.3 (Ar), 138.6 (Ar), 154.3
(C]O),154.7 (C]O). Anal. Calcd for C37H39NO5: C, 76.92; H, 6.80; N,
2.42. Found: C, 76.73; H, 6.99; N, 2.21.
2.04 (ddd, J¼13.9, 8.8, 3.5 Hz, 1H, H1 b), 3.48 (dd, J¼10.2, 6.9 Hz, 1H,
0
H3 a), 3.51 (dd, J¼10.5, 9.1 Hz, 1H, CH2OBn), 3.59 (dd, J¼11.2, 3.1 Hz,
0
0
1H, H3 b), 3.72 (tdd, J¼10.2, 6.8, 3.3 Hz, 1H, H2 ), 3.84 (dd, J¼8.8,
4.1 Hz, 1H, CH2OBn), 3.92 (s, 1H, H4), 4.16 (dd, J¼10.5, 3.6 Hz, 1H,
H2), 4.22 (s, 1H, H3), 4.26 (dd, J¼8.6, 5.2 Hz, 1H, H5), 4.36 (d,
J¼12.1 Hz, 1H, CH2Ph), 4.40 (d, J¼12.0 Hz, 1H, CH2Ph), 4.46 (d,
J¼12.0 Hz, 1H, CH2Ph), 4.47 (d, J¼12.1 Hz, 1H, CH2Ph), 4.51 (d,
J¼12.2 Hz, 1H, CH2Ph), 4.60 (d, J¼12.2 Hz, 1H, CH2Ph), 5.12 (d,
J¼12.2 Hz, 1H, CH2Ph), 5.19 (d, J¼12.2 Hz, 1H, CH2Ph),7.19–7.42 (m,
0
4.1.5. (2R,3R,4R,5R)-Benzyl 3,4-bis(benzyloxy)-2-(benzyloxy-methyl)
-5-(3-hydroxypropyl)-pyrrolidine-1-carboxylate (24). A solution of
23 (0.2 g, 0.346 mmol) in anhydrous THF (10 mL) was treated with
9-BBN (1.5 mL of a 0.5 M solution in THF, 0.75 mmol) under an ar-
gon atmosphere. The resulting mixture was stirred at ambient
temperature until complete disappearance of the starting material
(TLC), at which time 35% hydrogen peroxide (0.65 mL) and 3 M
NaOH (0.5 mL) were added. Saturated aqueous ammonium chlo-
ride (10 mL) was added and the resulting mixture was extracted
with diethyl ether (3ꢂ20 mL). The combined organic extracts were
washed with brine, dried (MgSO4) and evaporated under reduced
pressure to give a residue, which was purified by radial chroma-
20H, Ar). 13C NMR (125 MHz, CDCl3)
d
36.7 (C1 ), 61.2 (C5), 63.1 (C2),
0
0
66.3 (C3 ), 67.5 (N(CO)OCH2Ph), 68.4 (CH2OBn), 68.9 (C2 ), 71.0
(CH2Ph), 71.1 (CH2Ph), 73.0 (CH2Ph), 82.8 (C3), 84.9 (C4), 127.5 (Ar),
127.5 (Ar), 127.6 (Ar), 127.7 (Ar), 127.8 (Ar), 128.2 (Ar), 128.3 (Ar),
128.4 (Ar), 128.4 (Ar), 128.5 (Ar), 136.0 (Ar), 137.4 (Ar), 137.5 (Ar),
138.1 (Ar),155.9 (C]O). Anal. Calcd for C37H41NO7: C, 72.65; H, 6.76;
N, 2.29. Found: C, 72.78; H, 6.46; N, 2.41.
20
Compound 27: (0.133 g, 36 %); oil. [
a]
ꢁ52 (c 0.118, CHCl3). 1H
D
0
NMR (500 MHz, CDCl3)
d
1.93–2.01 (m, 2H, H1 ), 3.44 (dd, J¼11.2,
0
tography (hexane–EtOAc, 7:3) to afford alcohol 24 (0.195 g, 96%) as
6.9 Hz, 1H, CH2OBn), 3.52 (dd, J¼10.6, 9.0 Hz, 1H, H3 a), 3.58 (dd,
J¼11.2, 3.7 Hz, 1H, CH2OBn), 3.70 (ddd, J¼9.4, 6.8, 3.3 Hz, 1H, H2),
20
an oil. [
a
]
ꢁ43 (c 0.363, CHCl3). 1H NMR (300 MHz, DMSO-d6,
D
120 ꢀC)
d
1.46 (q, J¼6.7 Hz, 2H, H2 ), 1.61–1.73 (m, 1H, H1 a), 1.84–
3.75 (dd, J¼8.9, 4.2 Hz, 1H, H3 b), 3.96 (s, 1H, H4), 4.15 (c, J¼7.1 Hz,
0
0
0
0
0
0
1.94 (m, 1H, H1 b), 3.40 (t, J¼6.4 Hz, 2H, H3 ), 3.51 (t, J¼9.2 Hz, 1H,
H2), 3.78–3.86 (m, 2H, H5, CH2OBn), 3.96 (s, 1H, H4), 4.05 (dd, J¼9.7,
3.8 Hz, 1H, CH2OH), 4.17 (s, 1H, H3), 4.42 (d, J¼12.2 Hz, 1H, CH2Ph),
4.46–4.52 (m, 3H, CH2Ph), 4.54 (d, J¼12.1 Hz, 1H, CH2Ph), 4.58 (d,
J¼2.1 Hz, 1H, CH2Ph), 5.08 (d, J¼12.5 Hz, 1H, CH2Ph), 5.12 (d,
J¼12.5 Hz, 1H, CH2Ph), 7.23–7.39 (m, 20H, Ar). 13C NMR (75 MHz,
1H, H5), 4.19–4.22 (m, 2H, H3, H2 ), 4.38 (d, J¼12.1 Hz, 1H, CH2Ph),
4.40–4.49 (m, 3H, CH2Ph), 4.51 (d, J¼12.8 Hz, 1H, CH2Ph), 4.62 (d,
J¼12.2 Hz, 1H, CH2Ph), 5.07 (d, J¼12.3 Hz, 1H, CH2Ph), 5.19 (d,
J¼12.3 Hz, 1H, CH2Ph), 7.19–7.42 (m, 20H, Ar). 13C NMR (125 MHz,
0
0
CDCl3)
d
35.1 (C1 ), 61.5 (C2 ), 62.8 (C5), 66.9 (CH2OBn), 67.3
0
(N(CO)OCH2Ph), 68.5 (C3 ), 69.8 (C2), 71.1 (CH2Ph), 71.3 (CH2Ph),
73.1 (CH2Ph), 83.1 (C3), 85.1 (C4), 127.5 (Ar), 127.6 (Ar), 127.7 (Ar),
127.8 (Ar), 127.8 (Ar), 127.9 (Ar), 128.2 (Ar), 128.2 (Ar), 128.4 (Ar),
128.5 (Ar), 128.5 (Ar), 128.6 (Ar), 136.2 (Ar), 137.5 (Ar), 137.5 (Ar),
137.5 (Ar), 138.2 (Ar), 154.7 (C]O). Anal. Calcd for C37H41NO7: C,
72.65; H, 6.76; N, 2.29. Found: C, 72.51; H, 6.95; N, 2.34.
DMSO-d6, 90 ꢀC)
d 28.2 (C1 ), 29.9 (C2 ), 61.3 (C3 ), 63.7 (C5), 65.1 (C2),
0 0 0
66.6 (N(CO)OCH2Ph), 68.9 (CH2OBn), 69.0 (CH2Ph), 71.1 (CH2Ph),
71.2 (CH2Ph), 83.3 (C3), 84.5 (C4), 127.7 (Ar), 127.8 (Ar), 127.8 (Ar),
127.9 (Ar), 127.9 (Ar), 127.9 (Ar), 128.1 (Ar), 128.2 (Ar), 128.5 (Ar),
128.6 (Ar), 128.7 (Ar), 136.4 (Ar), 137.6 (Ar), 137.8 (Ar), 138.2 (Ar),
154.6 (C]O). Anal. Calcd for C37H41NO6: C, 74.60; H, 6.94; N, 2.35.
Found: C, 74.86; H, 7.12; N, 2.63.
4.1.8. (2R,3R,4R,5R)-2-((R)-2,3-Dihydroxypropyl)-5-(hydroxy-meth-
yl)pyrrolidine-3,4-diol hydrochloride (28). The hydrogenation of 26
4.1.6. (2R,3R,4R,5R)-2-(Hydroxymethyl)-5-(3-hydroxypropyl)-pyrro-
lidine-3,4-diol hydrochloride (25). The hydrogenation of 24
(0.190 g, 0.32 mmol), as described above for 20 to give 21, afforded
(0.150 g, 0.25 mmol), as described above for 20 to give 21, afforded
28
pure 28 (60 mg, 98%) as an oil. [
a
]
þ5 (c 0.05, H2O). 1H NMR
D
0
(500 MHz, D2O)
d
1.70–1.74 (m, 2H, H1 ), 3.27 (dd, J¼11.8, 6.3 Hz,
22
þ47 (c 0.27, H2O). 1H
1H, H3 a), 3.34–3.40 (m, 3H, H2, H5, H3 b), 3.62 (dd, J¼12.8, 5.8 Hz,
0
0
pure 25 (71 mg, 98%) as a yellow oil. [
a
]
D
0
0
NMR (400 MHz, D2O)
d
1.55 (dc, J¼8.7, 6.7 Hz, 2H, H2 ), 1.63–1.73
1H, CH2OH), 3.63–3.66 (m, 1H, H2 ), 3.69 (dd, J¼12.7, 3.6 Hz, 1H,
0
0
(m, 1H, H1 a), 1.83 (dtd, J¼9.1, 7.7, 6.1 Hz, 1H, H1 b), 3.31 (dt, J¼8.1,
CH2OH), 3.78 (dd, J¼8.5, 7.1 Hz, 1H, H4), 3.83 (t, J¼7.4 Hz, 1H, H3).
13C NMR (125 MHz, D2O)
d
32.2 (C1 ), 57.9 (CH2OH), 58.1 (C2 or C5),
0
6.3 Hz, 1H, H5), 3.44 (ddd, J¼7.5, 6.2, 3.8 Hz, 1H, H2), 3.50 (t,
0
0
0
J¼6.3 Hz, 2H, H3 ), 3.71 (dd, J¼12.6, 6.1 Hz, 1H, CH2OH), 3.79 (dd,
61.8 (C2 or C5), 65.0 (C3 ), 67.8 (C2 ), 73.7 (C3), 77.2 (C4). Anal. Calcd
for C8H18ClNO5: C, 39.43; H, 7.45; N, 5.75. Found: C, 39.51; H, 7.68;
N, 5.58.
J¼12.3, 3.8 Hz, 1H, CH2OH), 3.84 (dd, J¼7.8, 6.8 Hz, 1H, H4), 3.91
(dd, J¼7.6, 6.8 Hz, 1H, H3). 13C NMR (100 MHz, D2O)
d
26.7 (C1 ),
0
0
0
27.7 (C2 ), 57.9 (CH2OH), 60.8 (C3 ), 61.2 (C5), 62.1 (C2), 74.2 (C3),
78.0 (C4). Anal. Calcd for C8H18ClNO4: C, 42.20; H, 7.97; N, 6.15.
Found: C, 42.18; H, 8.14; N, 6.02.
4.1.9. (2R,3R,4R,5R)-2-((S)-2,3-Dihydroxypropyl)-5-(hydroxy-meth-
yl)pyrrolidine-3,4-diol hydrochloride (29). The hydrogenation of 27
(0.120 g, 0.20 mmol), as described above for 20 to give 21, afforded
21
4.1.7. (2R,3R,4R,5R)-Benzyl 3,4-bis(benzyloxy)-2-(benzyloxy-methyl)
-5-((R)-2,3-dihydroxypropyl)pyrrolidine-1-carboxylate (26) and
pure 29 (46 mg, 97%) as an oil. [
a
]
D
þ11 (c 0.285, H2O). 1H NMR
0
(400 MHz, D2O)
d
1.70 (dt, J¼14.7, 9.3 Hz,1H, H1 a), 1.92 (ddd, J¼14.7,
0
0
(2R,3R,4R,5R)-benzyl
3,4-bis(benzyl-oxy)-2-(benzyloxymethyl)-5-
5.1, 2.4 Hz,1H, H1 b), 3.35 (dd, J¼11.5, 5.8 Hz, 1H, H3 a), 3.39–3.49 (m,
0
((S)-2,3-dihydroxypropyl)-pyrrolidine-1-carboxylate (27). A cooled
(0 ꢀC) solution of N-methylmorpholine oxide (0.106 g, 0.9 mmol) in
10:1 acetone–water (10 mL) was treated with osmium tetroxide
(4.6 mg, 0.018 mmol) and a solution of 23 (0.35 g, 0.6 mmol) in
acetone (5 mL). The resulting mixture was stirred at ambient
temperature for 16 h at which time a 30% aqueous solution of
NaHSO3 (30 mL) was added. The solvent was partially evaporated
and the residue was extracted with dichloromethane (3ꢂ30 mL).
The combined organic extracts were washed with brine, dried
(MgSO4) and evaporated under reduced pressure. The crude mix-
ture of diols was purified by radial chromatography (hexane–
3H, H2, H5, H3 b), 3.69 (dd, J¼12.6, 6.0 Hz, 1H, CH2OH), 3.68–3.76 (m,
0
1H, H2 ), 3.77 (dd, J¼12.6, 3.3 Hz, 1H, CH2OH), 3.84 (t, J¼7.0 Hz, 1H,
H4), 3.89 (t, J¼6.9 Hz, 1H, H3). 13C NMR (100 MHz, D2O)
d
32.8 (C1 ),
0
0
0
57.9 (CH2OH), 60.0 (C2 or C5), 62.3 (C2 or C5), 65.2 (C3 ), 69.4 (C2 ),
74.0 (C3), 78.1 (C4). Anal. Calcd for C8H18ClNO5: C, 39.43; H, 7.45; N,
5.75. Found: C, 39.19; H, 7.26; N, 5.90.
4.1.10. (3R,4aR,5R,6R,7R)-5,6-Bis(benzyloxy)-7-(benzyloxy-methyl)-
3-(hydroxymethyl)hexahydro-1H-pyrrolo[1,2-c][1,3]oxazin-1-one
(30). To a solution of 26 (20 mg, 0.033 mmol) in anhydrous THF
(3 mL) under an argon atmosphere, sodium hydride (1.5 mg of
a 60% dispersion in mineral oil, 0.04 mmol) was added at ambient
temperature. The resulting mixture was stirred for 3 h at which
time saturated aqueous ammonium chloride (3 mL) was carefully
EtOAc, 1:1).
Compound 26: (0.186 g, 51%); Oil. [
NMR (500 MHz, CDCl3)
20
a
]
ꢁ31 (c 0.136, CHCl3). 1H
D
0
d
1.65 (ddd, J¼14.4, 10.0, 5.3 Hz, 1H, H1 a),

I. Delso et al. / Tetrahedron 66 (2010) 1220–1227
1225
added. The reaction mixture was extracted with diethyl ether
(3ꢂ5 mL) and the combined organic extracts were washed with
brine, dried (MgSO4) and evaporated under reduced pressure. The
(m, 15H, Ar). 13C NMR (100 MHz, CDCl3)
d
28.5 (C8), 45.8 (C5), 59.8
(C9), 65.0 (C3), 69.4 (CH2OBn), 71.6 (CH2Ph), 71.7 (CH2Ph), 73.4
(CH2Ph), 86.2 (C2), 88.9 (C1), 124.0 (C7), 125.2 (C6), 127.6 (Ar),
127.6 (Ar), 127.6 (Ar), 127.7 (Ar), 127.8 (Ar), 127.9 (Ar), 128.3 (Ar),
128.4 (Ar), 128.4 (Ar), 138.3 (Ar), 138.4 (Ar), 138.4 (Ar). Anal. Calcd
for C30H33NO3: C, 79.09; H, 7.30; N, 3.07. Found: C, 79.18; H, 7.46;
N, 3.21.
residue was purified by semipreparative HPLC (hexane–EtOAc,
22
1:1) to afford pure 30 (12 mg, 72%) as an oil. [
a
]
þ62 (c 0.11,
D
CHCl3). 1H NMR (500 MHz, C6D6)
d
1.28 (ddd, J¼13.7, 10.4, 5.3 Hz,
1H, H4a), 1.81 (ddd, J¼13.7, 5.1, 2.8 Hz, 1H, H4b), 3.41 (dd, J¼11.5,
5.1 Hz, 1H, CHOH), 3.47 (dd, J¼11.6, 5.9 Hz, 1H, CHOH), 3.66 (dd,
J¼8.3, 5.4 Hz, 1H, H6), 3.73 (dd, J¼9.5, 3.1 Hz, 1H, CHOBn), 3.82
(ddd, J¼10.2, 8.4, 5.2 Hz, 1H, H5), 3.94 (dd, J¼9.5, 5.7 Hz, 1H,
CHOBn), 4.01–4.06 (m, 1H, H3), 4.39 (d, J¼12.1 Hz, 1H, CH2Ph),
4.40–4.43 (m, 1H, H7), 4.46 (d, J¼11.9 Hz, 1H, CH2Ph), 4.48–4.55
(m, 3H, H8, CH2Ph), 4.60 (d, J¼11.9 Hz, 1H, CH2Ph), 4.62 (d,
J¼11.7 Hz, 1H, CH2Ph), 7.18–7.39 (m, 15H, Ar). 13C NMR (125 MHz,
4.1.13. (1R,2R,3R,8aR)-3-(Hydroxymethyl)octa-hydroindolizine-1,2-
diol hydrochloride (33). The hydrogenation of 32 (0.150 g,
0.25 mmol), as described above for 20 to give 21, afforded pure 33
28
(63 mg, 98%) as a white solid; mp 111–113 ꢀC. [
a
]
þ27 (c 0.05,
D
H2O). 1H NMR (500 MHz, D2O)
d 1.13–1.25 (m, 2H, H7a, H8a), 1.31–
1.44 (m, 1H, H6a), 1.47–1.55 (m, 1H, H6b), 1.64–1.72 (m, 1H, H7b),
1.72–1.80 (m, 1H, H8b), 2.51 (td, J¼11.5, 2.9 Hz, 1H, H5a), 2.54–2.59
(m, 1H, H9), 2.85 (dt, J¼11.5, 3.3 Hz, 1H, H5b), 2.90 (c, J¼4.9 Hz, H3),
3.61 (dd, J¼7.8, 5.4 Hz, 1H, H1), 3.67 (dd, J¼11.9, 5.2 Hz, 1H,
CH2OH), 3.77 (dd, J¼11.9, 5.2 Hz, 1H, CH2OH), 3.83 (t, J¼4.7 Hz, 1H,
C6D6) d 27.3 (C5), 56.0 (C4), 62.3 (C8), 63.4 (CH2OH), 69.3 (CH2OBn),
72.1 (CH2Ph), 72.2 (CH2Ph), 73.3 (CH2Ph), 76.3 (C3), 83.7 (C7), 88.6
(C6), 127.7 (Ar), 127.7 (Ar), 127.8 (Ar), 127.9 (Ar), 128.1 (Ar), 128.4
(Ar), 128.4 (Ar), 128.4 (Ar), 138.3 (Ar), 138.4 (Ar), 138.5 (Ar), 151.3
(C]O). Anal. Calcd for C30H31NO6: C, 71.84; H, 6.23; N, 2.79.
Found: C, 71.64; H, 6.38; N, 2.96.
H2). 13C NMR (125 MHz, D2O)
d 22.4 (C7), 23.3 (C6), 27.3 (C8), 46.6
(C5), 59.8 (CH2OH), 64.0 (C9), 67.4 (C3), 78.0 (C2), 81.1 (C1). Anal.
Calcd for C9H18ClNO3: C, 48.32; H, 8.11; N, 6.26. Found: C, 48.27; H,
8.36; N, 6.13.
4.1.11. (2R,3R,4R,5R)-1,2-Diallyl-3,4-bis(benzyloxy)-5-(benzyloxy-
methyl)pyrrolidine (31). A solution of amine 22 (555 mg,
1.25 mmol) in DMF (20 mL) was treated sequentially with potas-
sium carbonate (275 mg, 2 mmol), allyl bromide (1.1 mL, 1.5 g,
12.5 mmol) and tetrabutylammonium iodide (10 mg) at ambient
temperature under an argon atmosphere. The reaction mixture was
stirred for additional 12 h, diluted with water (30 mL) and extrac-
ted with hexane (3ꢂ30 mL). The combined organic extracts were
washed with brine, dried (MgSO4) and evaporated under reduced
4.1.14. (1R,2R,3R,6R,7S,8aR)-1,2-Bis(benzyloxy)-3-(benzyloxy-meth-
yl)octa-hydroindolizine-6,7-diol (34) and (1R,2R,3R,6S, 7R,8aR)-1,2-
bis(benzyloxy)-3-(benzyloxymethyl)octa-hydroindolizine-6,7-diol
(35). The osmylation of 32 (0.120 g, 0.20 mmol), as described above
for 23 to give 26 and 27, afforded pure 34 and 35 after purification
by radial chromatography (hexane–EtOAc, 1:1).
26
Compound 34: (151 mg, 43%). White solid; mp 108–110 ꢀC. [
a]
D
pressure to give pure 31 (0.595 mg, quant.) that did not need fur-
ꢁ4 (c 1.06, CHCl3). 1H NMR (500 MHz, CDCl3)
d
1.63 (ddd, J¼13.9,
25
ther purification. [
d
a]
ꢁ9 (c 0.59, CHCl3). 1H NMR (400 MHz, CDCl3)
11.5, 2.5 Hz, 1H, H8a), 2.06 (dt, J¼13.8, 3.5 Hz, 1H, H8b), 2.83 (t,
J¼10.8 Hz, 1H, H5a), 2.96 (dd, J¼11.2, 5.1 Hz, 1H, H5b), 3.22 (ddd,
J¼11.4, 5.8, 3.1 Hz, 1H, H9), 3.36 (ddd, J¼6.9, 5.3, 2.3 Hz, 1H, H3),
3.53 (dd, J¼9.4, 6.7 Hz, 1H, CH2OBn), 3.65 (dd, J¼5.9, 2.8 Hz, 1H,
H1), 3.68 (dd, J¼9.4, 5.2 Hz, 1H, CH2OBn), 3.81 (ddd, J¼10.3, 5.1,
3.0 Hz, 1H, H6), 3.90 (t, J¼2.6 Hz, 1H, H2), 4.01 (dd, J¼6.0, 3.0 Hz,
1H, H7), 4.47 (d, J¼12.0 Hz, 1H, CH2Ph), 4.49 (d, J¼11.8 Hz, 1H,
CH2Ph), 4.53 (d, J¼12.0 Hz, 1H, CH2Ph), 4.54 (d, J¼12.0 Hz, 1H,
CH2Ph), 4.57 (d, J¼12.0 Hz, 1H, CH2Ph), 4.60 (d, J¼12.0 Hz, 1H,
D
2.07 (dt, J¼13.9, 8.9 Hz, 1H, CH2CH]CH2), 2.30–2.39 (m, 1H,
CH2CH]CH2), 3.03–3.17 (m, 3H, H2, H5, NCH2CH]CH2), 3.38–3.44
(m, 2H, CH2OBn, CH2CH]CH2), 3.55 (dd, J¼9.4, 4.7 Hz,1H, CH2OBn),
3.68 (s, 1H, H3), 3.80 (s, 1H, H4), 4.29 (d, J¼12.0 Hz, CH2Ph), 4.35 (d,
J¼12.1 Hz, CH2Ph), 4.36 (d, J¼12.1 Hz, CH2Ph), 4.39 (d, J¼12.2 Hz,
CH2Ph), 4.43 (sist. AB, CH2Ph), 4.91 (dd, J¼8.7, 1.6 Hz, 1H,
CH2CH]CH2), 4.95 (s, 1H, CH2CH]CH2), 5.01 (d, J¼10.2 Hz, 1H,
NCH2CH]CH2), 5.12 (d, J¼17.2 Hz, 1H, NCH2CH]CH2), 5.76–5.89
(m, 1H, CH2CH]CH2), 5.96–6.07 (m, 1H, NCH2CH]CH2), 7.31–7.44
CH2Ph), 7.29–7.39 (m, 15H, Ar). 13C NMR (125 MHz, CDCl3)
d 34.1
(m, 15H, Ar). 13C NMR (100 MHz, CDCl3)
d
31.9 (CH2CH]CH2), 51.1
(C8), 47.7 (C5), 57.5 (C9), 65.1 (C3), 67.6 (C6), 68.0 (C7), 68.7
(CH2OBn), 71.6 (CH2Ph), 71.7 (CH2Ph), 73.4 (CH2Ph), 86.6 (C2), 88.3
(C1), 127.6 (Ar), 127.7 (Ar), 127.7 (Ar), 127.8 (Ar), 128.0 (Ar), 128.3
(Ar), 128.3 (Ar), 128.3 (Ar), 128.4 (Ar), 138.1 (Ar), 138.2 (Ar), 138.2
(Ar). Anal. Calcd for C30H35NO5: C, 73.59; H, 7.21; N, 2.86. Found: C,
(NCH2CH]CH2), 65.0 (C2), 65.6 (C5), 69.3 (CH2OBn), 71.3 (CH2Ph),
71.4 (CH2Ph), 73.3 (CH2Ph), 85.7 (C4), 85.7 (C3), 116.6
(NCH2CH]CH2), 117.1 (CH2CH]CH2), 127.6 (Ar), 127.7 (Ar), 127.8
(Ar), 127.9 (Ar), 128.3 (Ar), 128.3 (Ar), 128.3 (Ar), 135.5
(CH2CH]CH2), 136.5 (NCH2CH]CH2), 138.4 (Ar), 138.4 (Ar), 138.4
(Ar). Anal. Calcd for C32H37NO3: C, 79.47; H, 7.71; N, 2.90. Found: C,
79.61; H, 7.58; N, 3.04.
73.48; H, 7.01; N, 3.10.
25
Compound 35: (126 mg, 36%); Oil. [
NMR (500 MHz, CDCl3)
a
]
þ10 (c 0.10, CHCl3). 1H
D
d
1.47 (c, J¼11.7 Hz, 1H), 2.14 (dddd, J¼12.6,
5.2, 3.1, 0.6 Hz, 1H, H8a), 2.70 (dd, J¼12.1, 1.1 Hz, 1H, H8b), 2.83 (ddd,
J¼10.3, 7.0, 2.8 Hz,1H, H5a), 3.16 (dd, J¼12.1, 3.3 Hz, 1H, H9), 3.40 (dt,
J¼5.4, 2.1 Hz, 1H, H5b), 3.48–3.52 (m, 1H, H7), 3.52 (dd, J¼9.6, 5.7 Hz,
1H, CH2OBn), 3.60 (dd, J¼9.6, 5.3 Hz, 1H, CH2OBn), 3.74 (dd, J¼7.0,
3.4 Hz, 1H, H1), 3.79 (s, 1H, H6), 3.95 (dd, J¼3.5, 2.3 Hz, 1H, H2), 4.48
(d, J¼11.8 Hz, 1H, CH2Ph), 4.53 (s, 2H, CH2Ph), 4.56 (s, 2H, CH2Ph),
4.58 (d, J¼11.8 Hz, 1H, CH2Ph), 7.29–7.38 (m, 15H, Ar). 13C NMR
4.1.12. (1R,2R,3R,8aR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-
1,2,3,5,8,8a-hexahydroindolizine (32). To a solution of 31 (500 mg,
1.03 mmol) in anhydrous toluene (20 mL) the second generation
Grubbs’ catalyst (56 mg, 0.1 mmol) was added and the resulting
mixture was stirred at 80 ꢀC for 14 h. The solvent was evaporated
under reduced pressure without exceeding 30 ꢀC and the residue
was purified by radial chromatography (hexane–EtOAc, 4:1) to
(125 MHz, CDCl3) d 34.2 (C8), 51.0 (C5), 63.3 (C9), 65.1 (C3), 68.3 (C6),
25
give pure 32 (0.428 g, 91%) as an oil. [
NMR (400 MHz, CDCl3)
a
]
þ32 (c 1.05, CHCl3). 1H
68.4 (CH2OBn), 69.9 (C7), 71.8 (CH2Ph), 72.1 (CH2Ph), 73.4 (CH2Ph),
86.5 (C2), 89.0 (C1), 127.6 (Ar), 127.8 (Ar), 127.8 (Ar), 128.7 (Ar), 128.4
(Ar), 128.4 (Ar), 128.5 (Ar), 137.9 (Ar), 137.9 (Ar), 138.0 (Ar). Anal.
Calcd for C30H35NO5: C, 73.59; H, 7.21; N, 2.86. Found: C, 73.48; H,
7.40; N, 2.66.
D
d
2.18–2.23 (m, 2H, H8), 3.16 (td, J¼7.3,
4.7 Hz, 1H, H9), 3.38 (ddd, J¼17.2, 3.9, 1.9 Hz, 1H, H5a), 3.44 (td,
J¼5.3, 3.3 Hz, 1H, H3), 3.48–3.54 (m, 1H, H5b), 3.60 (dd, J¼9.7,
5.6 Hz, 1H, CH2OBn), 3.70 (dd, J¼9.7, 5.0 Hz, 1H, CH2OBn), 3.75
(dd, J¼4.5, 2.5 Hz, 1H, H1), 3.98 (t, J¼2.8 Hz, 1H, H2), 4.53 (d,
J¼12.1 Hz, 1H, CH2Ph), 4.56 (s, 2H, CH2Ph), 4.56 (d, J¼12.1 Hz, 1H,
CH2Ph), 4.60 (d, J¼12.0 Hz, 1H, CH2Ph), 4.61 (d, J¼12.1 Hz, 1H,
CH2Ph), 5.69–5.74 (m, 1H, H6), 5.75–5.80 (m, 1H, H7), 7.30–7.39
4.1.15. (1R,2R,3R,6S,7R,8aR)-3-(Hydroxymethyl)octahydro-in-
dolizine-1,2,6,7-tetraol hydrochloride (36). The hydrogenation of 34
(0.120 g, 0.251 mmol), as described above for 20 to give 21,

1226
I. Delso et al. / Tetrahedron 66 (2010) 1220–1227
28
afforded pure 36 (78 mg, 97%) as an oil. [
a
]
þ16 (c 0.12, H2O). 1H
138.2 (Ar), 138.2 (Ar), 138.8 (CH]CH2). Anal. Calcd for
C28H31NO3: C, 78.29; H, 7.27; N, 3.26. Found: C, 78.45; H, 7.16; N,
3.12.
D
NMR (300 MHz, D2O, 60 ꢀC)
d
2.46 (ddd, J¼13.5, 10.2, 2.5 Hz, 1H,
H8a), 2.60 (td, J¼15.2, 5.3 Hz, 1H, H8b), 3.83 (d, J¼6.4 Hz, 2H, H5),
4.01 (dd, J¼9.0, 4.6 Hz, 1H, H3), 4.18 (td, J¼9.9, 4.8 Hz, 1H, H9),
4.33 (dd, J¼13.0, 5.4 Hz, 1H, CH2OH), 4.42 (dd, J¼13.0, 4.0 Hz, 1H,
CH2OH), 4.47–4.56 (m, 4H, H1, H2, H6, H7). 13C NMR (75 MHz, D2O,
4.1.19. (2R,3R,4R,5R)-1-Allyl-3,4-bis(benzyloxy)-2-(benzyloxy-
methyl)-5-vinylpyrrolidine (40). Allylation of 39 (0.520 g,
1.2 mmol), as described above for 22 to give 31, afforded pure 40
60 ꢀC)
d
27.8 (C8), 48.2 (C5), 58.3 (CH2OH), 62.6 (C9), 64.5 (C6 or
26
C8), 64.6 (C6 or C8), 71.0 (C3), 77.2 (C1 or C2), 77.4 (C1 or C2). Anal.
Calcd for C9H18ClNO5: C, 42.28; H, 7.10; N, 5.48. Found: C, 42.44;
H, 7.03; N, 5.68.
(0.445 g, 81%) as an oil. [
a]
ꢁ14 (c 0.31, CHCl3). 1H NMR (400 MHz,
D
CDCl3)
d
3.16 (dd, J¼14.3, 7.8 Hz, 1H, NCH2CH]CH2), 3.31 (ddd,
J¼7.0, 4.1, 2.9 Hz, 1H, H5), 3.39 (tdd, J¼14.3, 4.5, 1.9 Hz, 1H,
NCH2CH]CH2), 3.54 (dd, J¼9.4, 6.9 Hz, 1H, CH2OBn), 3.59 (dd,
J¼9.4, 4.2 Hz, 1H, H2), 3.63 (dd, J¼9.5, 4.3 Hz, 1H, CH2OBn), 3.82 (dd,
J¼4.2, 2.4 Hz, 1H, H3), 4.00 (t, J¼2.7 Hz, 1H, H4), 4.48 (m, 6H, CH2Ph),
5.08 (dtd, J¼10.2, 1.8, 0.9 Hz, 1H, NCH2CH]CH2), 5.15 (dtd, J¼17.3,
1.8 ,1.0 Hz, 1H, NCH2CH]CH2), 5.20–5.29 (m, 2H, CH]CH2), 5.81–
4.1.16. (1R,2R,3R,6R,7S,8aR)-3-(Hydroxymethyl)octahydro-in-
dolizine-1,2,6,7-tetraol hydrochloride (37). The hydrogenation of 35
(0.060 g, 0.12 mmol), as described above for 20 to give 21, afforded
28
pure 37 (31 mg, 98%) as an oil. [
a
]
þ7 (c 0.08, H2O). 1H NMR
D
(300 MHz, D2O, 45 ꢀC)
d
2.22–2.51 (m, 2H, H8), 3.61 (dd, J¼13.7,
5.93 (m, 2H, NCH2CH]CH2, CH]CH2), 7.25–7.38 (m, 15H, Ar). 13
NMR (100 MHz, CDCl3) 50.8 (NCH2CH]CH2), 64.8 (C5), 68.8
C
1.9 Hz, 1H, H5a), 3.87 (dd, J¼13.7, 4.4 Hz, 1H, H5b), 3.91–3.96 (m, 1H,
d
H3), 4.10–4.41 (m, 6H, H1, H2, H6, H7, CH2OH). 13C NMR (75 MHz,
(CH2OBn), 70.4 (C2), 71.4 (CH2Ph), 71.6 (CH2Ph), 73.3 (CH2Ph), 85.7
(C4), 88.1 (C3), 116.4 (NCH2CH]CH2), 118.5 (CH]CH2), 127.5 (Ar),
127.5 (Ar), 127.7 (Ar), 127.7 (Ar), 127.8 (Ar), 127.8 (Ar), 128.3 (Ar),
128.3 (Ar), 136.4 (CH]CH2), 137.9 (NCH2CH]CH2), 138.3 (Ar), 138.4
(Ar), 138.4 (Ar). Anal. Calcd for C31H35NO3: C, 79.28; H, 7.51; N, 2.98.
Found: C, 79.19; H, 7.42; N, 2.68.
D2O, 45 ꢀC)
d 34.8 (C8), 39.9 (C5), 59.2 (C9), 59.23 (CH2OH), 63.1 (C6
or C8), 64.1 (C6 or C8), 75.8 (C3 or C1 or C2), 76.9 (C3or C1 or C2), 79.7
(C3 or C1 or C2). Anal. Calcd for C9H18ClNO5: C, 42.28; H, 7.10; N, 5.48.
Found: C, 42.50; H, 7.18; N, 5.38.
4.1.17. (2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-vi-
nylpyrrolidin-1-ol (38). To a cooled (0 ꢀC) solution of nitrone 19
(1.0 g, 2.4 mmol) in anhydrous diethyl ether (30 mL), vinyl-
magnesium bromide (7.2 mL of a 1 M solution in THF, 7.2 mmol)
was added dropwise. After stirring for 13 h at 0 ꢀC the reaction
was quenched with satd aq NH4Cl (20 mL). The reaction
mixture was diluted with diethyl ether (20 mL), the organic layer
was separated and the aqueous layer was extracted with diethyl
ether (2ꢂ20 ml). The combined organic extracts were washed
with brine (20 mL), dried over MgSO4, filtered and the solvent
was eliminated under reduced pressure to afford the crude
4.1.20. (1R,2R,3R,7aR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-
2,3,5,7a-tetrahydro-1H-pyrrolizine (41). Ring-closing metathesis of
40 (0.50 g, 1.05 mmol), as described above for 31 to give 32, affor-
ded pure 41 (0.405 g, 87%) as an oil. 1H NMR (400 MHz, CDCl3)
d
2.87 (ddd, J¼8.1, 5.9, 3.9 Hz, 1H, H3), 3.43–3.52 (m, 2H, H5a
,
CH2OBn), 3.55 (dd, J¼9.7, 3.9 Hz, 1H, CH2OBn), 3.75–3.83 (m, 2H, H1,
H5b), 3.96 (dd, J¼6.5, 8.1 Hz, 1H, H2), 4.05–4.10 (m, 1H, H7a), 4.23–
4.57 (m, 5H, CH2Ph), 4.65 (d, J¼11.6 Hz, 1H, CH2Ph), 5.63–5.69 (m,
2H, H6, H7), 7.14–7.30 (m, 15H, Ar). 13C NMR (100 MHz, CDCl3)
d 62.2
(C5), 68.8 (C3), 71.9 (CH2OBn), 72.2 (CH2Ph), 72.7 (CH2Ph), 73.4
(CH2Ph), 74.9 (C7a), 83.7 (C2), 87.6 (C1), 127.4 (Ar), 127.6 (Ar), 127.7
(Ar), 127.7 (Ar), 127.8 (Ar), 127.9 (C6 or C7), 128.3 (Ar), 128.3 (Ar),
128.5 (Ar), 129.2 (C6 or C7), 138.1 (Ar), 138.5 (Ar), 138.5 (Ar). Anal.
Calcd for C29H31NO3: C, 78.88; H, 7.08; N, 3.17. Found: C, 78.73; H,
7.35; N, 3.68.
product, which was purified by radial chromatography (Hexane–
27
EtOAc, 7:3) to give pure 20 (1.05 g, 98%) as an oil. [
a
]
ꢁ198 (c
D
0.48, CHCl3). 1H NMR (500 MHz, CDCl3)
d
3.56 (dt, J¼6.4, 4.7 Hz,
1H, H2), 3.68 (dd, J¼9.6, 6.4 Hz, 1H, CH2OBn), 3.80 (dd, J¼9.7,
4.9 Hz, 1H, CH2OBn), 3.84 (dd, J¼8.3, 5.4 Hz, 1H, H5), 3.94 (dd
J¼5.3, 3.0 Hz, 1H, H4), 4.01 (dd, J¼4.1, 3.2 Hz, 1H, H3), 4.50 (d,
J¼11.9 Hz, 2H, CH2Ph), 4.55 (d, J¼6.4 Hz, 1H, CH2Ph), 4.57 (d,
J¼6.4 Hz, 1H, CH2Ph), 4.59 (d, J¼11.4 Hz, 2H, CH2Ph), 5.31 (ddd,
JJ¼10.2, 1.5, 0.6 Hz, 1H, CH]CHHtrans), 5.36 (ddd, J¼17.2, 1.5,
1.0 Hz, 1H, CH]CHHcis), 6.07 (ddd, J¼17.2, 10.2, 8.3 Hz, 1H,
CH]CH2), 7.28–7.39 (m, 15H, Ar). 13C NMR (125 MHz, CDCl3)
4.1.21. Hyacinthacine A2 (9). The hydrogenation of 41 (0.060 g,
0.12 mmol), as described above for 20 to give 21, afforded pure 9
(40 mg, 96%) after purification by ion-exchange chromatography
(Dowex 50WX8-200; eluent: 3 M methanolic ammonia) as an oil.
26
20
[a
]
þ12 (c 0.4, H2O) [lit.30c
[a
]
þ11.2 (c 0.52, H2O)]. 1H NMR
D
d
67.9 (CH2OBn), 69.6 (C2), 71.7 (CH2Ph), 71.9 (CH2Ph), 72.9 (C5),
(400 MHz, CDCl3) d 1.65–1.94 (m, 4H, H6, H7), 2.61–2.72 (m, 2H, H3,
73.4 (CH2Ph), 83.8 (C3), 86.1 (C4), 119.3 (CH]CH2), 127.6 (Ar),
127.7 (Ar), 127.7 (Ar), 127.8 (Ar), 127.9 (Ar), 128.0 (Ar), 128.4 (Ar),
128.4 (Ar), 128.4 (Ar), 135.5 (CH]CH2), 137.9 (Ar), 138.0 (Ar),
138.2 (Ar). Anal. Calcd for C28H31NO4: C, 75.48; H, 7.01; N, 3.14.
Found: C, 74.29; H, 7.36; N, 3.29.
H5a), 2.84 (ddd, J¼11.0, 6.9, 5.9 Hz, 1H, H5b), 3.08 (dt, J¼7.5, 4.5 Hz,
1H, H7a), 3.59 (dd, J¼11.6, 6.6 Hz, 1H, CH2OH), 3.67 (t, J¼7.9 Hz, 1H,
H1), 3.70–3.76 (m, 2H, H2, CH2OH). 13C NMR (100 MHz, CDCl3)
d 27.5
(C6), 32.8 (C7), 57.8 (C5), 66.2 (CH2OH), 68.9 (C7a), 72.1 (C3), 80.3 (C2),
83.3 (C1). Anal. Calcd for C8H15NO3: C, 55.47; H, 8.73; N, 8.09.
Found: C, 55.60; H, 8.95; N, 7.75.
4.1.18. (2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-vi-
nylpyrrolidine (39). Deoxygenation of 38 (0.550 g, 1.2 mmol), as
described above for 20 to give 22, afforded pure 39 (0.52 g,
Acknowledgements
26
quant.) as an oil. [
CDCl3)
a
]
ꢁ101 (c 1.11, CHCl3). 1H NMR (500 MHz,
D
We thank for their support of our programs: the Spanish Min-
istry of Science and Education (MEC. Madrid, Spain. Project
CTQ2007-67532-C02-01), FEDER Program and the Government of
Aragon (Research group E-10, Zaragoza, Spain) and MiUR (Italy).
One of us (I.D.) also thanks Gobierno de Aragon for a pre-doctoral
grant.
d
3.46 (c, J¼5.7 Hz, 1H, H2), 3.53 (dd, J¼9.3, 6.5 Hz, 1H,
CH2OBn), 3.57 (dd, J¼9.3, 5.5 Hz, 1H, CH2OBn), 3.71 (dd, J¼6.9,
5.7 Hz, 1H, H5), 3.89 (dd, J¼5.4, 3.9 Hz, 1H, H4), 3.92 (t, J¼4.2 Hz,
1H, H3), 4.54–4.58 (m, 5H, CH2Ph), 4.63 (d, J¼11.7 Hz, 1H, CH2Ph),
5.16 (ddd, J¼10.2, 1.2, 1.0 Hz, 1H, CH]CHHtrans), 5.29 (ddd, J¼17.1,
1.3, 1.1 Hz, 1H, CH]CHHcis), 5.96 (ddd, J¼17.2, 10.2, 7.2 Hz, 1H,
CH]CH2), 7.29–7.41 (m, 15H, Ar). 13C NMR (125 MHz, CDCl3)
References and notes
d
61.4 (C2), 64.5 (C5), 70.9 (CH2OBn), 71.9 (CH2Ph), 72.1 (CH2Ph),
73.3 (CH2Ph), 85.9 (C3), 89.3 (C4), 116.1 (CH]CH2), 127.7 (Ar),
127.7 (Ar), 127.8 (Ar), 127.8 (Ar), 128.4 (Ar), 128.4 (Ar), 138.1 (Ar),
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