Asymmetric synthesis of (+)-1-epiaustraline and attempted synthesis of australine

Article abstract of DOI:10.1016/j.tet.2004.05.010

A diastereoselective synthesis of the pyrrolizidine alkaloid, (+)-1-epiaustraline has been achieved via a diastereoselective syn-dihydroxylation of a pyrrolo[1,2-c]oxazol-3-one precursor that was readily prepared by a RCM reaction. Attempts to extend this

Full text of DOI:10.1016/j.tet.2004.05.010

Tetrahedron 60 (2004) 5759–5767
Asymmetric synthesis of (1)-1-epiaustraline and attempted
synthesis of australine
*
Minyan Tang and Stephen G. Pyne
Department of Chemistry, University of Wollongong, Wollongong, Northfields Ave, New South Wales 2522, Australia
Received 7 March 2004; revised 14 April 2004; accepted 6 May 2004
Abstract—A diastereoselective synthesis of the pyrrolizidine alkaloid, (þ)-1-epiaustraline has been achieved via a diastereoselective syn-
dihydroxylation of a pyrrolo[1,2-c]oxazol-3-one precursor that was readily prepared by a RCM reaction. Attempts to extend this
methodology to the synthesis of australine were not successful since the final pyrrolidine ring closure to produce the desired pyrrolizidine of
the target molecule was not productive.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Alexine (1) was the first alkaloid to be isolated with the
3-hydroxymethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine-
1,2,7-triol structure in 1988.1 In the same year its 7a-epimer,
australine (2), was isolated from the seeds of
Castanospermum australe.2 Later reports described the
isolation of other epimers of 2 from these seeds, including
1-epiaustraline 3.3,4 These alkaloids have been shown to
have glycosidase inhibitory activities2,3c,4 and other bio-
logical studies have revealed the potential of these and
related polyhydroxylated pyrrolizidines as antiviral and
anti-retroviral agents.5 These interesting biological proper-
ties coupled with the polyfunctional and stereochemically
rich nature of these compounds have attracted the attention
of synthetic chemists resulting in the total synthesis of
alexine,6 and its epimers,6,7 australine,8 and its epimers,7–11
and casuarine (Fig. 1).12
Figure 1. Structures of 3-hydroxymethyl pyrrolizidine.
as an extension of this work, the synthesis of (þ)-1-epi-
australine and our attempts to prepare australine. These
target molecules required that the starting vinyl epoxide 4
had the cis-[(3R, 4S)] stereochemistry rather than the trans-
[(3R,4R)] stereochemistry used by us previously and it was
of interest to examine the effect of this stereochemical
difference on the diastereoselectivities of the reactions
leading to our target molecules.
In 2003 we reported a new and potentially general synthetic
methodology for the synthesis of austaline and its epimers
using aminolysis of a chiral vinyl epoxide and RCM as key
reactions.11 We demonstrated the viability of this synthestic
methodology with the asymmetric synthesis of (2)-7-
epiaustaline and (þ)-1,7-diepiaustraline.11 We report here,
The starting vinyl epoxide (2)-(3R,4S)-4 was prepared from
the corresponding Sharpless epoxy alcohol (82% ee from 1H
NMR analysis of its Mosher ester, see experimental section)
via Swern oxidation followed by a Wittig-olefination
reaction.11,13 A solution of the vinyl epoxide (2)-4 and
the (S)-allylamine 514 (1.4 equiv., ca 99% ee) in acetonitrile
was heated at 120 8C in a sealed tube using LiOTf
(1.5 equiv.) as a catalyst for 3 days. This gave a mixture
Keywords: Pyrrolizidine alkaloid; (þ)-1-Epiaustraline; RCM.
Abbreviations: ArH, aromatic protons of PMB; ArpH, aromatic protons of
Bn or Ph; BzH, aromatic protons of Bz; ArCH2, CH2 of PMB; ArpCH2, CH2
of Bn; ArC, quaternary aromatic carbons of PMB; ArpC, quaternary
aromatic carbons of Bn; ArCH, aromatic CH carbons of PMB; ArpCH,
aromatic CH carbons of Bn; BzCH, aromatic CH carbons of Bz.
*
Corresponding author. Tel.: þ612-4221-3511; fax: þ612-4221-4287;
e-mail address: spyne@uow.edu.au
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.010

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M. Tang, S. G. Pyne / Tetrahedron 60 (2004) 5759–5767
of two diastereomeric products. Separation by PTLC gave
the desired amino alcohol (þ)-6 in 62% yield and its
diastereomer (structure not shown but referred to as
compound 60 in the experimental section) in 17% yield
that arises from the reaction of ent-4 with 5. The
amino-alcohol (þ)-6 was converted to the diastereomeri-
cally pure 2-oxazolidinone derivative (þ)-7 in 94% yield
using triphosgene under basic conditions.11,15 The minor
diastereomeric amino-alcohol was converted to its corre-
sponding 2-oxazolidinone derivative in 69% yield. In their
1H NMR specta, J4,5 for both 2-oxazolidinones was 7.5 Hz,
while the NOESY spectra of these compounds showed
strong cross peaks between H-4 and the exo-cyclic
methylenes at C-5 (see Scheme 1 for details). This was
consistent with both 2-oxazolidinones having the C-4, C-5
trans-stereochemistry which would arise from an SN2 ring
opening of 4 or ent-4 with 5.
The RCM of 7 using standard conditions, 5–10 mol%
of Grubbs I catalyst (benzylidenebis(tricyclohexyl-
phosphine)ruthenium dichloride) in refluxing CH2Cl2 at
high dilution (,4 mM) for 20 h, gave low conversion to
the desired 2,5-dihydropyrrole (2)-8. However, by
initiating the reaction using 22 mol% Grubbs I catalyst
and then adding a further 9 mol% catalyst after 25 h, (2)-
8 could be isolated in 97% yield after a total of 42 h of
heating at reflux.16,17 Compound (2)-8 was treated with
5 mol% K2OsO4·2H2O and NMO (2.1 equiv.),11,13 to
effect syn-dihydroxylation (DH) of the double bond,
giving diol (2)-9 in good yield (85%). A small amount
(,5%) of the C-6, C-7 di-epimeric diol was also formed
but was readily separated by column chromatography. The
stereochemistry of diol 9 was that expected from our
previous studies with osmylation occurring from the
concave face of the 2-oxazolidinone 8.11,17 This stereo-
chemistry was evident from NOESY studies on its acetate
10 that showed significant cross peaks between H-6 and
the exo-cyclic methylene at C-5 and between H-6 and
H-7a. The absolute stereochemistry assigned to 9 was
unequivocally confirmed by its conversion to (þ)-1-
epiaustraline (3).
Attempts to deprotect the primary PMB ether in 9 under
oxidative conditions with DDQ18 gave a poor yield of the
desired primary alcohol due to the formation of several
other products that could not be structurally identified.
The diacetate derivative 10 however was smoothly
converted to the primary alcohol 11 in 63% yield.
Compound 11 was then converted to the pyrrolizidine-
tetraacetate 15 in three synthetic steps. Base hydrolysis of
11 followed by ion-exchange chromatography gave 12
which was cyclized to the desired pyrrolizidine ring
system under Mitsunobu conditions12,19 in pyridine at
0 8C. The crude reaction mixture was then treated under
hydrogenolysis conditions12,13,20 and then peracetylation
gave the pyrrolizidine-tetraacetate 15 in 23% over yield
from 11. Finally, methoxide catalysed removal of the
acetates of 15 gave (þ)-1-epiaustraline (3) in quantitative
yield. This sample had identical spectral characteristics to
those reported in the literature for (þ)-3,7c,10 and its
specific rotation ([a]2D5¼þ14.3 (c 1.1, H2O)) closely
matched that previously reported (lit.10a ([a]D25¼þ13.695
(c 1.72, H2O)).
Scheme 2 outlines our attempted synthesis of australine (2).
This synthesis required inversion of the stereochemistry at
C-7 in the pyrrolo[1,2-c]oxazol-3-one 9. Thus 9 was
converted to its cyclic-sulfate 16 using thionyl chloride
followed by oxidation of the resulting cyclic sulfite with
catalytic ruthenium tetraoxide (88% yield for the two-step
conversion).11,21 Nucleophilic ring opening of the S,S-
dioxo-dioxathiole ring of 16 with cesium benzoate,11,21,22
followed by an acidic work up gave a 73:27 mixture of
regioisomeric benzoates in 88% yield. The regioisomers
were readily separated by column chromatography as their
acetate derivatives. In this way the acetate 18 of the major
regioisomer could be obtained in 66% yield while the
acetate of the minor regioisomer was isolated in 25% yield.
The structure of the major regioisomer 18 was established
by NOESY experiments which showed significant cross
peaks between H-6 the exo-cyclic methylene at C-5 and
Scheme 1. Reagents and conditions: (a) LiOTf, CH3CN, 120 8C, sealed
tube, 72 h; (b) triphosgene, Et3N, DCM, 0 8C, 2.5 h; (c) Grubbs’ catalyst I,
DCM, reflux, 3 days; (d) K2OsO4·2H2O, NMO, acetone, H2O, RT, 21 h;
(e) Ac2O, pyridine, RT, 23 h; (f) DDQ, DCM, H2O, RT, 5.5 h; (g) NaOH,
EtOH, 70 8C, sealed tube, 37 h; (h) DIAD, PPh3, pyridine, 0 8C, 4 h then RT
3 h; (i) PdCl2, H2, MeOH, RT, 1.5 h; (j) Ac2O, pyridine, RT, 22 h;
(k) Amberlyst A-26 (OH-form) resin, MeOH, RT, 2 h.

M. Tang, S. G. Pyne / Tetrahedron 60 (2004) 5759–5767
5761
2. Experimental
2.1. General methods
All reactions were carried out under an atmosphere of
nitrogen. All NMR spectra were obtained as a CDCl3
solution at 300 MHz (1H NMR) or 75 MHz (13C NMR)
unless otherwise stated and were referenced to the relevant
solvent peak. 13C NMR assignments were made from DEPT
experiments. Silica gel chromatography was performed
using Merck GF 254 flash silica gel packed by the slurry
method. Small-scale separations (,2.0 g) were performed
using either a 10 or 20 mm diameter column, and large-scale
separations (.2.0 g) were performed using either a 30 or
50 mm diameter column, each with the stated solvent
system. Specific rotations were measured using a 10 or a
50 mm cell, and the values quoted were an average of 5–10
measurements. They are reported by the following conven-
tion: optical rotation [1021 deg cm3 g21] (concentration,
solvent). Acidic ion-exchange chromatography was per-
formed using DOWEX 50WX8-50 acidic cation exchange
resin, packed by the slurry method in 10 mm diameter
column. In all cases the compounds were applied as their
HCl salts dissolved in distilled water. The column was first
eluted with water (100 mL) and then eluted with 14%
ammonia solution (w/w). In all cases, HRMS (exact masses)
Scheme 2. Reagents and conditions: (a) (i) SOCl2, Et3N, DCM, 0 8C,
30 min; (ii) RuCl3·3H2O, NaIO4, CCl4:CH3CN:H2O¼2:2:3, RT, 2 h; (b) (i)
PhCOOH, Cs2CO3, DMF, 40 8C, 23 h; (ii) H2SO4 (conc.), THF, H2O, RT,
18 h; (c) Ac2O, pyridine, RT, 23 h; (d) DDQ, DCM, H2O, RT, 2 h;
(e) NaOH, EtOH, 70 8C, 19 h; (f) DIAD, PPh3, THF, 0 8C, 3 h then RT, 3 h;
(g) PdCl2, H2, MeOH, RT, 1 h; (h) Ac2O, pyridine, RT, 15 h.
were obtained on lieu of elemental analysis, and 1H and 13
NMR spectroscopy were used as criteria for purity.
C
2.1.1. Synthesis of (2)-6-(4-methoxyphenyl)methoxy-
3R,4S-epoxy-1-hexene (4). Step 1. 5-(4-Methoxyphenyl)-
methoxy-2Z-penten-1-ol. To the solution of 1-(40-methoxy)-
benzyloxy-3-butyne (431 mg, 1.96 mmol) and quinoline
(329 mg, 2.55 mmol) was added Pd/CaCO3 (35.8 mg). The
mixture was stirred at RT under a nitrogen atmosphere for
1.5 h. The mixture was then filtered through celite before the
filtrate was washed with 1 M HCl (3£). The organic portion
was dried with MgSO4, filtered and evaporated to dryness in
vacuo. Chromatography of the residue eluting with EtOAc/
petrol (0–50%) gave the title compound (396 mg, 91%). 1H
NMR d 7.22 (d, 2H, J¼8.4 Hz, ArH), 6.85 (d, 2H,
J¼8.7 Hz, ArH), 5.73 (dt, 1H, J¼10.8, 7.2 Hz, H-2), 5.53
(dt, 1H, J¼10.8, 8.1 Hz, H-3), 4.41 (s, 2H, ArCH2), 4.06 (d,
2H, J¼6.9 Hz, H-1), 3.75 (s, 3H, OMe), 3.43 (t, 2H,
J¼6.0 Hz, H-5), 3.08 (bs, 1H, OH), 2.35 (td, 2H, J¼7.2,
6.6 Hz, H-4); 13C NMR d 158.9 (ArC), 130.7 (CH-2), 129.7
(ArC), 129.1 (ArCH), 128.7 (CH-3), 113.5 (ArCH), 72.4
(ArCH2), 68.6 (CH2-5), 57.4 (CH2-1), 54.9 (OMe), 27.7
(CH2-4); MS (CIþve) m/z 222 (Mþ); HRMS (CIþve) Calcd
for C13H18NO3 (Mþ) 222.1256, found: 222.1253.
between H-6 and H-7a (see Scheme 2 for proton number-
ing). The modest regioselectivity found in the ring opening
of 16 is in stark contrast to that of 1-epi-16 which gave less
than 5% of the other regioisomer resulting from attack of
benzoate anion at C-6.11 While, nucleophilic attack on 16
would be expected to occur preferentially at C-7, since
backside attack at C-6 would be more sterically demanding
due to the b-C-5 benzyloxymethyl substituent, the con-
figuration at C-1 also clearly influences the regiochemistry
of ring-opening. Thus the b-orientation of the C-1
substituent in 16 must be responsible for the reduced
regioselectivity found in the ring opening of 16. Oxidative
removal of the primary PMB ether in 18 using DDQ gave
the corresponding primary alcohol 19 in 67% yield. Base
hydrolysis of the esters and the oxazolidinone ring of 19
gave the amino tetrol 20 in 76% yield. Attempted
cyclization of 20 under Mitsunobu conditions proved
problematic and hydrogenolysis of the crude reaction
mixture and then peracetylation gave a mixture from
which only the hexaacetate 21 could be isolated in low
yield [12%, MS (ESþve) m/z 460 (MþHþ, 27%)]. None of
the desired peracetylated pyrrolizidine product could be
detected. While we have always had poor yields for this type
of cyclization reaction,11,16 this is the first time it has not
been successful.
Step 2. (2)-5-(4-Methoxyphenyl)methoxy-2R,3S-epoxy-1-
pentanol. To a mixture of titanium tetra-isopropoxide
˚
(1.6 mL, 5.35 mmol), 4 A molecular sieves (1.93 g) in dry
DCM (100 mL) were added D-(2)-diisopropyltartrate
(1.4 mL, 6.42 mmol) and anhydrous tert-butyl hydro-
peroxide (5.3 mL, 26.2 mmol, 5.0 M) under N2 at 240 8C.
After 10 min, a solution of 1 (2.37 g, 10.7 mmol) in dry
DCM (10 mL) was added. The resulting yellow mixture was
stirred at 220 8C for 18 h. After this time, 10% aqueous
tartaric acid (50 mL) was added dropwise and the mixture
was allowed to warm to RT over 1 h until the solution was
transparent. Then the organic layer was separated, washed
In summary, we have developed diastereoselective syn-
thesis of the pyrrolizidine alkaloid, (þ)-1-epi-australine via
a diastereoselective syn-dihydroxylation of a pyrrolo[1,2-
c]oxazol-3-one precursor that was readily prepared by a
RCM reaction. Attempts to extend this methodology to the
synthesis of australine were not successful since the final
pyrrolidine ring closure to produce the desired pyrrolizidine
of the target molecule was not productive.

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M. Tang, S. G. Pyne / Tetrahedron 60 (2004) 5759–5767
with brine and dried (MgSO4). The solvent was evaporated
in vacuo and the residue was chromatographed on silica gel.
Eluation with 30–100% EtOAc/petrol afforded the title
compound (2.41 g, 95%) as a yellow oil. [a]2D4¼210.5
water, aqueous Na2CO3 (sat.), water and dried (MgSO4).
The filtered solution was evaporated to give a yellow oil.
The crude aldehyde product was used in the next step
without further purification. A solution of potassium
bis(trimethylsilyl)amide (22.1 mL, 11.1 mmol, 0.5 M in
toluene) was cooled to 210 8C and transferred via cannula
to a stirred suspension of methyltriphenylphosphonium
bromide (4.09 g, 11.4 mmol) in dry THF (25 mL) at 210 8C
under N2. The bright yellow suspension was stirred at RT
for 20 min, re-cooled to 210 8C and the above crude
aldehyde in THF (8 mL) was added via cannula. TLC
analysis (30% EtOAc/petrol) indicated complete disappear-
ance of the crude 5-(4-methoxy)benzyloxy-2S,3S-epoxy-
pentanal after 2.5 h. The reaction mixture was poured into
brine and extracted with diethyl ether (3£). The combined
organic extract was dried (MgSO4). The solvent was
evaporated under reduced pressure to give a semi-solid
which was purified by column chromatography (10–35%
EtOAc/petrol) to give the title compound 5 as a pale
yellow oil (685 mg, 77% overall for 2 steps). [a]2D3¼214.2
1
(c2.3, CHCl3); H NMR d 7.25 (d, 2H, J¼8.7 Hz, ArH),
6.89 (d, 2H, J¼8.7 Hz, ArH), 4.47 (s, 2H, ArCH2), 3.86
(ddd, 1H, J¼12.0, 10.2, 5.1 Hz, H-1a), 3.80 (s, 3H, OMe),
3.68–3.54 (m, 2H, H-5), 3.46 (ddd, 1H, J¼12.3, 8.7, 3.6 Hz,
H-1b), 3.17 (dt, 1H, J¼9.0, 4.5 Hz, H-2), 3.10 (dd, 1H,
J¼10.5, 3.3 Hz, OH), 3.02 (dt, 1H, J¼9.6, 4.2 Hz, H-3),
2.09 (ddd, 1H, J¼14.7, 3.9, 2.7 Hz, H-4a), 1.74 (dddd, 1H,
J¼14.4, 10.8, 9.3, 4.8 Hz, H-4b); 13C NMR d 159.4 (ArC),
129.6 (ArCH), 129.0 (ArC), 113.8 (ArCH), 73.1 (ArCH2),
66.3 (CH2-5), 59.8 (CH2-1), 55.2 (CH-2), 55.1 (OMe), 54.8
(CH-3), 27.9 (CH2-4); MS (CIþve) m/z 238 (Mþ); HRMS
(CIþve) Calcd for C13H18NO4 (Mþ) 238.1205, found:
238.1197.
Mosher ester analysis. (2)-5-(4-Methoxyphenyl)methoxy-
2S,3S-epoxy-1-pentyl-(R)-a-methoxy-a(trifluoromethly)-
phenyl acetate. 5-(4-Methoxy)benzyloxy-2R,3S-epoxy-1-
pentanol (25 mg, 0.103 mmol) was dissolved in dry DCM
(0.9 mL), then triethylamine (90 mL), 4-dimethylamino-
pyridine (13 mg, 0.108 mmol) and R-(2)-a-methoxy-a-
(trifluoromethyl)phenylacetyl chloride (21 mL, 0.113
mmol) were added. The mixture was stirred at RT for
15 min. All the volatiles were removed in vacuo to give a
dark semi-solid which was purified by column chromato-
graphy (15–30% EtOAc/petrol) to give a pale yellow oil
(42 mg, 90, 82% ee). [a]2D4¼231.0 (c 2.1, CHCl3); 1H NMR
(major diastereomer) d 7.55–7.51 (m, 2H, ArpH), 7.43–
7.39 (m, 3H, ArpH), 7.25 (d, 2H, J¼8.4 Hz, ArH), 6.88 (d,
2H, J¼8.7 Hz, ArH), 4.48 (dd, 1H, J¼12.0, 3.9 Hz, H-1a),
4.44 (s, 2H, ArCH2), 4.36 (dd, 1H, J¼12.0, 7.2 Hz, H-1b),
3.79 (s, 3H, MeOAr), 3.60–3.56 (m, 2H, H-5), 3.57 (s, 3H,
MeOC), 3.26–3.15 (m, 2H, H-2, H-3), 1.84 (apparent q, 2H,
1
(c2.1, CHCl3); H NMR d 7.26 (dt, 2H, J¼8.7, 2.7 Hz,
ArH), 6.88 (dt, 2H, J¼8.7, 3.0 Hz, ArH), 5.71 (ddd, 1H,
J¼17.4, 10.5, 6.9 Hz, H-2), 5.47 (ddd, 1H, J¼17.4, 1.8,
0.6 Hz, H-1a), 5.35 (ddd, 1H, J¼10.8, 1.8, 0.6 Hz, H-1b),
4.46 (s, 2H, ArCH2), 3.80 (s, 3H, OMe), 3.60 (td, 2H, J¼6.3,
0.9 Hz, H-6), 3.43 (dd, 1H, J¼7.2, 4.5 Hz, H-3), 3.24
(ddd, 1H, J¼6.9, 5.7, 4.5 Hz, H-4), 1.92–1.75 (m, 2H, H-
5); 13C NMR d 159.1 (ArC), 132.3 (CH-2), 130.3 (ArC),
129.2 (ArCH), 120.5 (CH2-1), 113.7 (ArCH), 72.7 (ArCH2),
67.0 (CH2-6), 56.9 (CH-3), 56.3 (CH-4), 55.2 (OMe),
28.4 (CH2-5); MS (CIþve) m/z 234 (Mþ); HRMS
(CIþve) Calcd for C14H18NO3 (Mþ) 234.1256, found:
234.1254.
2.1.2. (1)-1-(4-Methoxyphenyl)methoxy-4S-[(1S-phenyl-
methoxymethyl)-2-propenyl]amino-5-hepten-3S-ol (6)
and its diastereomer (2)-1-(4-methoxyphenyl)methoxy-
4R-[(1S-phenylmethoxymethyl)-2-propenyl]amino-5-
hepten-3R-ol (60). To a mixture of 4 (860 mg, 3.68 mmol)
1
J¼6.0 Hz, H-4); H NMR (minor diastereomer, in part) d
4.54 (dd, 1H, J¼12.0, 3.9 Hz, H-1a), 4.31 (dd, 1H, J¼12.3,
7.2 Hz, H-1b); 13C NMR d 166.4 (CO), 159.2 (ArC), 132.0
(ArpC), 130.1 (ArC), 129.7 (ArpCH), 129.2 (ArCH),
128.4 (ArpCH), 127.2 (ArpCH), 123.1 (q, JC,F¼287.1 Hz,
CF3), 113.7 (ArCH), 84.6 (q, JC,F¼27.6 Hz, CCF3), 72.8
(ArCH2), 66.5 (CH2-5), 64.77 (CH2-1), 55.5 (q,
JC,F¼1.5 Hz, COMe), 55.2 (MeOPh), 54.3 (CH-3), 53.0
(CH-2), 28.7 (CH2-4); MS (CIþve) m/z 453 (M21þ);
HRMS (CIþve) Calcd for C23H25O6F3 (Mþ) 454.1603,
found: 454.1596.
and (2S)-1-(phenylmethoxymethyl)but-3-enyl amine
5
(761 mg, 4.30 mmol) in dry acetonitrile (2 mL), in a thick
walled glass tube, was added lithium triflate (860 mg,
5.51 mmol). The vessel was flushed with nitrogen and
sealed and then stirred and heated at 120 8C for 3 days. The
mixture was then cooled to RT and all volatiles were
removed in vacuo to give a dark sticky oil which was
purified by column chromatography (0–10% methanol/
DCM) and semi-preparative TLC (6% MeOH/DCM) to give
compound 6 (943 mg, 62%) and the diastereomer 60
(262 mg, 17%) as yellow oils. Spectral data for 6:
Steps 4 and 5. 5-(4-Methoxyphenyl)methoxy-2S,3S-epoxy-
pentanal and (2)-6-(4-methoxyphenyl)methoxy-3R,4S-
epoxy-1-hexene (4). To a stirred solution oxalyl chloride
(0.5 mL, 5.72 mmol) in dry DCM (7 mL) was added slowly
dimethyl sulfoxide (0.68 mL, 9.53 mmol) at 250 to 260 8C
under N2. The mixture was stirred for 5 min and 5-(4-
methoxy)benzyloxy-2R,3S-epoxy-1-pentanol (907 mg,
3.81 mmol) in DCM (3 mL) was added within 5 min via
cannula. Stirring was continued for an additional 40 min.
Triethylamine (2.7 mL, 19.1 mmol) was then added and the
mixture was stirred for 5 min and then allowed to warm to
RT. After 20 min, the reaction was quenched by water
(25 mL). The aqueous layer was re-extracted with
additional DCM (3£). The combined organic portions
were washed with saturated NaCl solution, HCl (1 M),
1
[a]2D4¼þ3.4 (c3.2, CHCl3); H NMR d 7.38–7.28 (m, 5H,
ArpH), 7.25 (d, 2H, J¼8.7 Hz, ArH), 6.86 (d, 2H, J¼8.7 Hz,
ArH), 5.56–5.42 (m, 2H, H-5, H-20), 5.21 (dd, 1H, J¼10.5,
2.1 Hz, x¼CH2(Z)), 5.19 (dd, 1H, J¼17.4, 2.1 Hz,¼
CH2(E)), 5.16 (dd, 1H, J¼9.9, 2.1 Hz,¼CH2(Z)), 5.10 (dd,
1H, J¼17.4, 1.8 Hz,¼CH2(E)), 4.53 (d, 1H, J¼12.0 Hz,
ArpCHaCHb), 4.48 (d, 1H, J¼12.0 Hz, ArpCHaCHb), 4.44
(s, 2H, ArCH2), 3.79 (s, 3H, OMe), 3.63 (dd, 2H, J¼6.6,
6.0 Hz, H-1), 3.50–3.35 (m, 4H, H-3, H-10, CH2OBn), 2.88
(t, 1H, J¼8.4 Hz, H-4), 1.86 (dddd, 1H, J¼14.1, 7.2, 6.9,
2.7 Hz, H-2a), 1.62 (dddd, 1H, J¼14.4, 9.3, 6.3, 6.0 Hz,
H-2b); 13C NMR d 159.0 (ArC), 137.9 (ArpC), 137.4, 136.8
(CH-5, CH-20), 130.4 (ArC), 129.2 (ArCH), 128.3, 127.6,

M. Tang, S. G. Pyne / Tetrahedron 60 (2004) 5759–5767
5763
127.5 (3£ArpCH), 118.3, 118.3 (CH2-6, CH2-30), 113.6
(ArCH), 73.2 (CH2OBn), 72.8 (ArpCH2), 72.6 (ArCH2),
70.7 (CH-3), 67.5 (CH2-1), 63.5 (CH-4), 57.3 (CH-10), 55.1
(OMe), 33.4 (CH2-2); MS (CIþve) m/z 412 (Mþ1þ, 100%);
HRMS (CIþve) Calcd for C25H34NO4 (MHþ) 412.2488,
found: 412.2505. Spectral data for 60: [a]D25¼25.6 (c2.3,
CHCl3); 1H NMR d 7.34–7.27 (m, 5H, ArpH), 7.24 (d, 2H,
J¼8.7 Hz, ArH), 6.86 (d, 2H, J¼8.4 Hz, ArH), 5.80 (ddd,
1H, J¼17.4, 10.2, 6.6 Hz, H-20), 5.61 (ddd, 1H, J¼17.1,
10.5, 8.1 Hz, H-5), 5.22–5.08 (m, 4H, H-6, H-30), 4.52 (s,
2H, ArCH2 or ArpCH2), 4.43 (s, 2H, ArCH2 or ArpCH2),
3.79 (s, 3H, OMe), 3.67–3.60 (m, 2H,, H-1), 3.56–3.36 (m,
4H, H-2, H-10, CH2OBn), 2.99 (t, 1H, J¼8.1 Hz, H-4), 1.86
(dtd, 1H, J¼14.1, 6.3, 2.7 Hz, H-2a), 1.63 (ddt, 1H, J¼14.01,
9.3, 6.3 Hz, H-2b); 13C NMR d 159.1 (ArC), 138.8 (CH-2 ),
138.2 (ArpC), 137.9 (CH-5), 130.3 (ArC), 129.2 (ArCH),
128.3, 127.6, 127.5 (3£ArpCH), 117.8 (CH2-6), 116.1 (CH2-
30), 113.7 (ArCH), 73.1, 72.7 (ArpCH2 and ArCH2), 72.9
(CH2OBn), 71.6 (CH-3), 67.9 (CH2-1), 65.0 (CH-4), 58.4
(CH-10), 55.2 (OMe), 33.3 (CH2-2); MS (CIþve) m/z 412
(Mþ1þ, 100%); HRMS (CIþve) Calcd for C25H34NO4
(MHþ) 412.2488, found: 412.2474.
ethyl-3-(1S-phenylmethoxymethyl-2-propenyl)-1,3-oxa-
zolidin-2-one (70).
The same procedure described above for the preparation of 7
was used starting with 60 (49 mg, 0.118 mmol) in dry DCM
(5 mL), triethylamine (92 mL, 0.66 mmol) and triphosgene
(18 mg, 0.059 mmol) in dry DCM (1 mL). Compound 70
(36 mg, 69%) was obtained as a pale yellow oil. [a]2D7¼þ12.7
(c1.8, CHCl3); 1H NMR d 7.36–7.29 (m, 5H, ArpH), 7.23 (d,
2H, J¼8.7 Hz, ArH), 6.87 (d, 2H, J¼8.7 Hz, ArH), 5.95 (ddd,
1H, J¼17.7, 9.9, 6.6 Hz, H-20), 5.69 (ddd, 1H, J¼17.4, 9.6,
8.7 Hz, H-100), 5.29–5.20 (m, 4H, H-30, H-200), 4.54 (d, 1H,
J¼12.6 Hz, ArpCHaCHb), 4.50 (d, 1H, J¼12.3 Hz, ArpCHa-
CHb), 4.42 (d, 1H, J¼11.4 Hz, ArCHaCHb), 4.37 (d, 1H,
J¼11.1 Hz, ArCHaCHb), 4.27 (ddd, 1H, J¼7.8, 7.5, 4.8 Hz,
H-5), 4.25–4.17 (m, 1H, H-10), 3.98 (dd, 1H, J¼8.7, 7.5 Hz,
H-4), 3.91 (t, 1H, J¼9.0 Hz, CHaCHbOBn), 3.80 (s, 3H,
OMe), 3.59–3.53 (m, 3H, CHaCHbOBn, CH2CH2O), 1.98–
1.81 (m, 2H, CH2CH2O); 13C NMR (one ArpCH could not be
observed) d 159.2 (ArC), 156.9 (CO), 137.9 (ArpC), 135.7
(CH-100), 132.6 (CH-20), 130.1 (A0r0C), 129.3 (ArCH), 128.3,
127.6 (2£ArpCH), 120.5 (CH2-2 ), 118.8 (CH2-30), 113.7
(ArCH), 76.5 (CH-5), 73.0 (ArpCH2), 72.8 (ArCH2), 69.8
(CH2OBn), 66.2 (CH-4), 65.3 (CH2CH2O), 56.1 (CH-10), 55.2
(OMe), 33.8 (CH2CH2O); MS (CIþve) m/z 438 (Mþ1þ);
HRMS (EIþve) Calcd for C26H31NO5 (Mþ) 437.2202, found:
437.2202.
2.1.3. (1)-4S-Ethenyl-5S-[2-(4-methoxyphenyl)methoxy]-
ethyl-3-(1S-phenylmethoxymethyl-2-propenyl)-1,3-oxa-
zolidin-2-one (7). A solution of 6 (226 mg, 0.549 mmol) in
dry DCM (15 mL) was cooled to 0 8C and triethylamine
(311 mg, 0.43 mL, 3.075 mmol) was added. A solution of
triphosgene (82 mg, 0.275 mmol) in dry DCM (1 mL) was
cooled to 0 8C and was then added to the above amine
solution at 0 8C. TLC analysis (34% EtOAc/petrol)
indicated complete disappearance of the compound 6 after
2.5 h. The reaction was quenched with water (30 mL). The
aqueous portion was extracted with DCM (4£). The
combined organic portions were dried (MgSO4) and filtered
and the solvent was evaporated to give a yellow semi-solid.
Chromatography of the residue eluting with (15–40%)
EtOAc/petrol gave diastereomerically pure compound 7
(226 mg, 94%) as a pale yellow oil. [a]2D8¼þ29.1 (c3.6,
2.1.5. (2)-(1S,5S,7aS)-1-[2-(4-Methoxyphenyl)methoxy]-
ethyl-5-(phenylmethoxy)methyl-5,7a-dihydro-1H,3H-
pyrrolo[1,2-c]oxazol-3-one (8). Grubbs’ catalyst
I
(212 mg, 0.258 mmol) was added to a solution of 7
(520 mg, 1.19 mmol) in dry DCM (200 mL) under nitrogen.
The mixture was heated at reflux under nitrogen for 25 h.
TLC analysis (35% EtOAc/petrol) indicated incomplete
conversion of compound 7. Additional Grubbs’ catalyst I
(85.0 mg, 0.103 mmol) was added and the reaction was
continued under the same conditions for another 17 h. The
reaction mixture was cooled and then the solvent was
removed in vacuo to give a brown oil which was purified by
column chromatography (25–85% EtOAc/petrol) to give 8
(204 mg, 97%) as a light brown oil. [a]2D6¼2134.9 (c2.1,
1
CHCl3); H NMR (500 MHz) d 7.35–7.26 (m, 5H, ArpH),
7.22 (d, 2H, J¼8.5 Hz, ArH), 6.86 (d, 2H,0 J¼8.5 Hz, ArH),
5.81 (ddd, 1H, J¼17.5, 10.5, 7.5 Hz, H-2 ), 5.69 (ddd, 1H,
J¼17.0, 10.0, 9.0 Hz, H-100), 5.22 (dt, 1H, J¼17.5, 1.0 Hz,
H-30a (E)), 5.19 (dt, 1H, 0J¼10.5, 1.0 Hz, H-200a), 5.18 (dt,
1H,00J¼10.5, 1.0 Hz, H-3 b), 5.11 (dt, 1H, J¼17.0, 1.0 Hz,
H-2 b), 4.59 (d, 1H, J¼12.0 Hz, ArpCHaCHb), 4.44 (d, 1H,
J¼12.0 Hz, ArpCHaCHb), 4.40 (d, 1H, J¼11.0 Hz, ArCHa-
CHb), 4.36 (d, 1H, J¼11.5 Hz, ArCHaCHb), 4.36–4.32 (m,
1H, H-10), 4.24 (td, 1H, J¼7.5, 4.5 Hz, H-5), 3.90 (dd, 1H,
J¼9.0 7.5 Hz, H-4), 3.81 (dd, 1H, J¼10.5, 9.5 Hz, CHa-
CHbOBn), 3.77 (s, 3H, OMe), 3.61 (dd, 1H, J¼10.0, 5.5 Hz,
CHaCHbOBn), 3.57–3.54 (m, 2H, CH2CH2O), 1.95–1.84
(m, 2H, CH2CH2O); 13C NMR0 d 159.0 (ArC), 157.3
(CO), 137.6 (ArpC), 135.9 (CH-2 ), 133.3 (CH-100), 123.0
(ArC), 129.2 (ArCH), 128.2, 127.8, 127.6 (3£ArpCH),
120.3 (CH2-200), 118.4 (CH2-30), 113.6 (ArCH), 76.2
(CH-5), 72.7 (ArpCH2 and ArCH2), 68.3 (CH2OBn), 65.2
(CH2CH2O), 64.3 (CH-4), 56.0 (CH-10), 55.1 (OMe), 33.4
(CH2CH2O); MS (CIþve) m/z 438 (Mþ1þ); HRMS
(CIþve) Calcd for C26H32NO5 (MHþ) 438.2280, found:
438.2262.
1
CHCl3); H NMR (500 MHz) d 7.34–7.26 (m, 5H, ArpH),
7.23 (d, 2H, J¼8.5 Hz, ArH), 6.87 (d, 2H, J¼8.5 Hz, ArH),
5.96 (dt, 1H, J¼5.5, 2.0 Hz, H-7), 5.87 (bd, 1H, J¼6.0 Hz,
H-6), 4.74–4.72 (m, 1H, H-5), 4.56 (d, 1H, J¼12.0 Hz,
ArpCHaCHb), 4.53 (d, 1H, J¼12.0 Hz, ArpCHaCHb), 4.54–
4.52 (m, 1H, H-1), 4.44 (d, 1H, J¼11.5 Hz, ArCHaCHb),
4.44–4.43 (m, 1H, H-7a), 4.40 (d, 1H, J¼11.5 Hz, ArCHa-
CHb), 3.77 (s, 3H, OMe), 3.61 (apparent dd, 2H, J¼7.0,
5.0 Hz, CH2CH2O), 3.53 (dd, 1H, J¼10.0, 5.0 Hz, CHa-
CHbOBn), 3.50 (dd, 1H, J¼10.0, 5.5 Hz, CHaCHbOBn),
2.14–2.02 (m, 2H, CH2CH2O); 13C NMR one ArC could
not be observed d 161.7 (CO), 158.8 (ArC), 137.5 (ArpC),
131.4 (CH-7), 129.5 (CH-6), 128.9 (ArCH), 127.9, 127.2,
127.1 (3£ArpCH), 113.3 (ArCH), 79.4 (CH-1), 72.8
2.1.4. (1)-4R-Ethenyl-5R-[2-(4-methoxyphenyl)methoxy]-

5764
M. Tang, S. G. Pyne / Tetrahedron 60 (2004) 5759–5767
(ArpCH2), 72.5 (ArCH2), 70.9 (CH2OBn), 70.0 (CH-7a),
66.0 (CH-5), 65.2 (CH2CH2O), 54.8 (OMe), 35.1
(CH2CH2O); MS (CIþve) m/z 410 (Mþ1þ); HRMS
(CIþve) Calcd for C24H28NO5 (Mþ) 410.1967, found:
410.1929.
113.7 (ArCH), 74.3 (CH-6), 73.3 (ArpCH2), 72.9 (CH-1),
72.8 (ArCH2), 72.1 (CH-7), 68.9 (CH2OBn), 65.1
(OCH2CH2), 64.7 (CH-7a), 59.9 (CH-5), 55.1 (OMe), 35.0
(OCH2CH2), 20.5 (CH3, Ac), 20.3 (CH3, Ac); MS (CIþve)
m/z 528 (Mþ1þ); HRMS (CIþve) Calcd for C28H34NO9
(MHþ) 528.2234, found: 528.2257.
2.1.6. (2)-(1S,5S,6R,7S,7aS)-1-[2-(4-Methoxyphenyl)-
methoxy]ethyl-5-(phenylmethoxy)methyl-5,6,7,7a-tetra-
hydro-6,7-dihydroxy-1H,3H-pyrrolo[1,2-c]oxazol-3-one
(9). To a solution of 8 (170 mg, 0.416 mmol) in acetone
(3 mL) were added water (2 mL), 4-morpholine N-oxide
(107 mg, 0.916 mmol) and potassium osmate dihydrate
(15 mg, 0.042 mmol). The mixture was stirred at RT for
21 h. Then all volatiles were removed in vacuo. The residue
was dissolved in toluene and evaporated to dryness in vacuo
to give a dark, semi-solid which was chromatographed on
silica gel (eluting with 0–7.5% methanol/DCM) to afford
compound 9 as a brown oil (156 mg, 85%). [a]2D4¼284.0
ArpH), 7.14 (d, 2H, J¼8.0 Hz, ArH), 6.78 (d, 2H, J¼9.0 Hz,
ArH), 4.79 (ddd, 1H, J¼7.5, 5.5, 2.5 Hz, H-1), 4.48 (d, 1H,
J¼12.0 Hz, ArpCHaCHb), 4.45 (d, 1H, J¼12.0 Hz, Arp-
CHaCHb), 4.34 (d, 1H, J¼11.5 Hz, ArCHaCHb), 4.30 (d,
1H, J¼11.5 Hz, ArCHaCHb), 4.26 (dd, 1H, J¼5.0, 4.0 Hz,
H-6), 3.82 (bs, 1H, H-7), 3.70 (s, 3H, OMe), 3.64–3.62 (m,
2H, H-5, CHaCHbOBn), 3.57–3.54 (m, 2H, H-7a, CHa-
CHbOBn), 3.52–3.49 (m, 2H, CH2CH2O), 1.99–1.92 (m,
1H, CHaCHbCH2O), 1.91–1.84 (m, 1H, CHaCHbCH2O);
13C NMR d 161.8 (CO), 159.2 (ArC), 137.8 (ArpC), 129.9
(ArC), 129.4 (ArCH), 128.4, 127.8, 127.6 (3£ArpCH),
113.8 (ArCH), 76.9 (CH-6), 73.5 (ArpCH2), 73.1 (CH-1),
73.0 (ArCH2), 71.5 (CH-7), 70.2 (CH2OBn), 66.6 (CH-7a),
65.7 (CH2CH2O), 62.0 (CH-5), 55.3 (OMe), 35.3
(CH2CH2O); MS (CIþve) m/z 444 (Mþ1þ); HRMS
(EIþve) Calcd for C24H29NO7 (Mþ) 443.1944, found:
443.1943.
2.1.8. (2)-(1S,5R,6R,7S,7aS)-6,7-Diacetoxy-1-(2-hydro-
xy)ethyl-5-(phenylmethoxy) methyl-5,6,7,7a-tetrahydro-
1H,3H-pyrrolo[1,2-c]oxazol-3-one (11). To a solution of
10 (227 mg, 0.432 mmol) in dichloromethane (30 mL) and
water (2.5 mL) was added 2,3-dichloro-5,6-dicyanobenzo-
quinone (DDQ) (137 mg, 0.604 mmol). After the mixture
was stirred at RT for 2.5 h, TLC analysis (70% EtOAc/
petrol) indicated the presence of compound 10. Additional
DDQ (59 mg, 0.259 mmol) was then added to the mixture.
The reaction was continued for another 3 h. The mixture
was diluted with water (25 mL) and extracted with DCM
(4£). The combined organics were dried (MgSO4) and
filtered and the solvent was removed under reduced pressure
to give a red, semi-solid that was purified by column
chromatography (40–90% EtOAc/petrol) to give the
1
(c1.3, CHCl3); H NMR (500 MHz) d 7.26–7.17 (m, 5H,
product 11 as
a pale yellow oil (114 mg, 65%).
1
[a]2D5¼24.6 (c2.0, CHCl3); H NMR d 7.36–7.24 (m, 5H,
ArpH), 5.56 (dd, 1H, J¼6.6, 3.6 Hz, H-6), 5.41 (t, 1H,
J¼3.6 Hz, H-7), 4.62 (ddd, 1H, J¼7.8, 5.7, 3.6 Hz, H-1),
4.58 (d, 1H, J¼12.0 Hz, ArpCHaCHb), 4.52 (d, 1H,
J¼12.3 Hz, ArpCHaCHb), 3.96–3.91 (m, 2H, H-7a, H-5),
3.78 (bt, 2H, J¼5.7 Hz, CH2CH2OH), 3.71 (dd, 1H, J¼10.2,
3.6 Hz, CHaCHbOBn), 3.62 (dd, 1H, J¼10.2, 3.0 Hz,
CHaCHbOBn), 2.22 (bs, 1H, OH), 2.13–1.85 (m, 2H,
CH2CH2OH), 2.11 (s, 3H, Ac), 1.99 (s, 3H, Ac); 13C NMR d
170. 1, 169.8 (2£CO, Ac), 160.7 (CO-3), 137.6 (ArpC),
128.4, 127.7, 127.5 (3£ArpCH), 74.3 (CH-6), 73.4
(ArpCH2), 73.0 (CH-1), 72.2 (CH-7), 68.9 (CH2OBn),
64.9 (CH-7a), 59.9 (CH-5), 58.2 (CH2CH2OH), 37.3
(CH2CH2OH), 20.6, 20.4 (2£CH3, Ac); MS (CIþve) m/z
408 (Mþ1þ, 100%); HRMS (CIþve) Calcd for C20H26NO8
(MHþ) 408.1658, found: 408.1666.
2.1.7. (2)-(1S,5R,6R,7S,7aS)-6,7-Diacetoxy-1-[2-(4-
methoxyphenyl)methoxy]ethyl-5-(phenylmethoxy)-
methyl-5,6,7,7a-tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-
3-one (10). Compound 9 (174 mg, 0.394 mmol) was
dissolved in anhydrous pyridine (2.0 mL) and then Ac2O
(2.0 mL) was added. The mixture was stirred at RT for 23 h,
then diluted with DCM (30 mL) and washed with saturated
aqueous NaHCO3 solution at 0 8C. The aqueous portion was
extracted with DCM (4£). The combined organic portions
were dried (MgSO4), filtered and evaporated in vacuo to
give an oil which was purified by column chromatography
(30–50% EtOAc/petrol) to give product 10 as a pale yellow
oil (174 mg, 84%). [a]2D6¼213.9 (c2.3, CHCl3); 1H NMR d
7.33–7.27 (m, 5H, ArpH), 7.21 (d, 2H, J¼8.7 Hz, ArH),
6.87 (d, 2H, J¼8.4 Hz, ArH), 5.56 (dd, 1H, J¼6.6, 3.6 Hz,
H-6), 5.37 (t, 1H, J¼3.6 Hz, H-7), 4.60 (ddd, 1H, J¼7.5,
6.0, 3.9 Hz, H-1), 4.58 (d, 1H, J¼11.7 Hz, ArpCHaCHb),
4.52 (d, 1H, J¼12.0 Hz, ArpCHaCHb), 4.43 (d, 1H,
J¼11.4 Hz, ArCHaCHb), 4.38 (d, 1H, J¼11.7 Hz, ArCHa-
CHb), 3.96–3.91 (m, 2H, H-5, H-7a), 3.79 (s, 3H, OMe),
3.70 (dd, 1H, J¼10.2, 3.6 Hz, CHaCHbOBn), 3.63 (dd, 1H,
J¼10.2, 3.0 Hz, CHaCHbOBn), 3.56 (dd, 2H, J¼6.6, 5.4 Hz,
OCH2CH2), 2.15–1.94 (m, 2H, OCH2CH2), 2.10 (s, 3H,
Ac), 1.99 (s, 3H, Ac); 13C NMR d 169.8 (CO, Ac), 169.6
(CO, Ac), 160.7 (CO-3), 159.2 (ArC), 137.6 (ArpC), 129.8
(ArC), 129.2 (ArCH), 128.3, 127.6, 127.4 (3£ArpCH),
2.1.9. Four step synthesis of (2)-(1S,2R,3R,7S,7aR)-
1,2,7-triacetoxy-3-(acetoxymethyl)hexahydro-1H-pyrro-
lizine (15) from 13. (þ)-(2S,3R,4S,5R)-5-[(1S)-1,3-Di-
hydroxypropyl]-2-[(phenylmethoxy)methyl]
pyrrolizine-
3,4-diol (13). To a solution of 12 (174 mg, 0.429 mmol)
in ethanol (6 mL) was added sodium hydroxide (171 mg,
4.285 mmol). The reaction was heated at 70 8C in a sealed
tube for 37 h. The volatiles were then removed in vacuo to
give a yellow solid, and the residue was treated with 1 M
hydrochloric acid (6 mL). The volatiles were removed in
vacuo to give a yellow solid that was purified by acidic ion-
exchange chromatography to give the desired compound 12
(ca 168 mg) as a yellow solid. This compound appeared
pure by NMR analysis but from the mass recovery (.100%)
this material was believed to contain salts. Spectral data for
12: 1H NMR (CD3OD) d 7.42–7.26 (m, 5H, ArpH), 4.66 (d,
1H, J¼11.7 Hz, ArpCHaCHb), 4.60 (d, 1H, J¼11.7 Hz,
ArpCHaCHb), 4.24 (dd, 1H, J¼8.7, 3.9 Hz, H-3), 4.22–4.16
(m, 2H, H-4, CHOH), 3.86 (dd, 1H, J¼10.5, 3.3 Hz,
CHaCHbOBn), 3.82–3.76 (m, 3H, CHaCHbOBn, CH2CH2-
OH), 3.69 (ddd, 1H, J¼8.7, 6.0, 3.0 Hz, H-2), 3.53 (dd, 1H,
J¼9.0, 3.0 Hz, H-5), 1.92 (dtd, 1H, J¼14.1, 7.2, 3.0 Hz,
CHaCHbCH2OH), 1.67 (ddt, 1H, J¼14.4, 9.0, 5.7 Hz,

M. Tang, S. G. Pyne / Tetrahedron 60 (2004) 5759–5767
5765
CHaCHbCH2OH); 13C NMR (CD3OD) d 138.9 (ArpC),
129.4, 129.0, 128.9 (3£ArpCH), 74.3 (ArpCH2), 73.5 (CH-
3), 71.6 (CH-4), 67.9 (CH2OBn), 67.6 (CH-5), 66.8
(CHOH), 61.7 (CH-2), 59.1 (CH2CH2OH), 37.5 (CH2CH2-
OH); MS (CIþve) m/z 298 (Mþ1þ, 100%); HRMS (CIþve)
Calcd for C15H24NO5 (MHþ) 298.1654, found: 298.1658.
3.80 (dd, 1H, J¼11.5, 4.0 Hz, CHaCHbOH), 3.63 (dd, 1H,
J¼11.5, 7.0 Hz, CHaCHbOH), 3.46 (t, 1H, J¼5.0 Hz, H-7a),
3.17 (ddd, 1H, J¼10.5, 7.0, 4.0 Hz, H-5a), 3.02 (ddd, 1H,
J¼9.0, 6.5, 4.0 Hz, H-3), 2.93 (ddd, 1H, J¼10.5, 9.5,
6.5 Hz, H-5b), 2.04 (ddt, 1H, J¼13.5, 6.5, 4.0 Hz, H-6a),
1.96 (dddd, 1H, J¼13.5, 9.5, 7.0, 5.0 Hz, H-6b); 13C NMR
(D2O) d 75.2 (CH-2), 73.7 (CH-7), 72.7 (CH-1), 70.6 (CH-
3), 66.6 (CH-7a), 63.6 (CH2OH), 52.7 (CH2-5), 35.9 (CH2-
6); MS (CIþve) m/z 190 (Mþ1þ, 100%); HRMS (EIþve)
Calcd for C8H15NO4 (Mþ) 189.1001, found: 189.0995.
2.1.10. (2)-(1S,2R,3R,7S,7aR)-1,2,7-Triacetoxy-3-(acet-
oxymethyl)hexahydro-1H-pyrrolizine (15). To a stirred
mixture of 12 obtained above, triphenylphosphine (157 mg,
0.600 mmol) and anhydrous pyridine (5 mL) at 0 8C was
added dropwise diisopropyl azodicarboxylate (0.12 mL,
0.60 mmol) under nitrogen. The mixture was stirred at 0 8C
for 4 h and then warm up to RT for 3 h. The volatiles were
removed in vacuo then 1 M hydrochloric acid (15 mL) and
DCM (15 mL) were added. The aqueous layer was washed
with DCM (15 mL) and then concentrated in vacuo to give a
yellow solid, which was purified by acidic ion-exchange
chromatography to give 13. This material was dissolved in
methanol (2 mL) and palladium chloride (21 mg,
0.118 mmol) was added. The mixture was stirred under
one atmosphere of hydrogen (H2 balloon) at RT for 1.5 h.
The mixture was then filtered through a plug of cotton wool
and the solvent was removed under reduced pressure to give
14 as a pale yellow oil. This oil was then dissolved in
anhydrous pyridine (1 mL) and Ac2O (1 mL) was added to
the solution. The mixture was stirred at RT for 22 h, then
diluted with DCM (20 mL) and washed with saturated
NaHCO3 solution at 0 8C. The aqueous portion was
extracted with DCM (3£). The combined organic portions
were dried (MgSO4), filtered and evaporated in vacuo to
give a solid which was purified by column chromatography
(35–90% EtOAc/petrol) to give 15 as a pale yellow oil
(21 mg, 23% overall for 4 steps). [a]2D6¼219.0 (c2.1,
2.1.12. (2)-(3aS,3bR,4S,8R,8aR)-4-[2-(4-Methoxy-
phenyl)methoxy]ethyl-8-phenylmethoxylmethyltetra-
hydro-3aH-[1,3,2]dioxathiolo[40,50:3,4]pyrrolo[1,2-
c][1,3]oxazol-6-one 2,2-dioxide (16). To a solution of 9
(190 mg, 0.430 mmol) in DCM (5 mL) was added Et3N
(0.14 mL, 0.988 mmol) followed by thionyl chloride
(39.2 mL, 0.537 mmol) at 0 8C. The mixture was stirred
for 30 min at 0 8C and water (15 mL) was added to the
mixture. The aqueous layer was extracted with DCM (4£).
The combined organic phases were dried (MgSO4), filtered
and evaporated under reduced pressure to give a brown oil.
The crude cyclic sulfite was used in the next step without
further purification. The crude cyclic sulfite obtained above
was dissolved in 7 mL of a solution of CCl4: CH3CN: H2O
(2: 2: 3, v/v/v) and RuCl3.3H2O (6 mg, 0.024 mmol) was
added followed by NaIO4 (175 mg, 0.816 mmol). The
mixture was stirred at RT for 2.5 h and then diluted with
diethyl ether (20 mL) and water (20 ml). The organic layer
was washed with saturated aqueous sodium bicarbonate
solution followed by brine and then dried (MgSO4). The
solvent was evaporated and then purification of the residue
by column chromatography (35–50% EtOAc/petrol) gave
compound 16 (191 mg, 88%) as a pale yellow oil.
[a]2D4¼252.9 (c2.0, CHCl3); 1H NMR d 7.37–7.34 (m,
5H, ArpH), 7.22–7.19 (m, 2H, ArpH), 7.20 (d, 2H,
J¼8.7 Hz, ArH), 6.86 (d, 2H, J¼8.7 Hz, ArH), 5.35 (dd,
1H, J¼5.4, 0.9 Hz, H-8a), 5.04 (t, 1H, J¼5.4 Hz, H-3a),
4.78 (td, 1H, J¼6.6, 3.9 Hz, H-4), 4.49 (d, 1H, J¼12.0 Hz,
ArCHaCHb or ArpCHaCHb), 4.43–4.39 (m, 2H, ArCHaCHb
or ArpCHaCHb and H-8), 4.39 (s, 2H, ArCH2 or ArpCH2),
4.25 (dd, 1H, J¼4.8, 3.9 Hz, H-3b), 3.78 (s, 3H, OMe),
3.73–3.57 (m, 4H, CH2OBn and CH2CH2O), 2.14–2.07 (m,
2H, CH2CH2O); 13C NMR d 159.3 (ArC), 158. 7 (CO-6),
136.6 (ArpC), 129.7 (ArC), 129.4, 128.7, 128.3, 127.7
(3£ArpCH and 1£ArCH), 113.8 (ArCH), 87.6 (CH-8a),
84.4 (CH-3a), 73.8 (ArCH2 or ArpCH2), 73.7 (CH-4), 73.1
(ArpCH2 or ArCH2), 70.9 (CH2OBn), 67.1 (CH-3b), 65.7
(CH2CH2O), 62.3 (CH-8), 55.2 (OMe), 34.9 (CH2CH2O);
MS (CIþve) m/z 506 (Mþ1þ); HRMS (EIþve) Calcd for
C24H27NO9S (Mþ) 505.1407, found: 505.1426.
1
CHCl3); H NMR d 5.44 (t, 1H, J¼3.9 Hz, H-1), 5.31 (dd,
1H, J¼15.3, 7.8 Hz, H-7), 5.10 (dd, 1H, J¼9.3, 4.2 Hz,
H-2), 4.20 (dd, 1H, J¼11.4, 4.2 Hz, CHaCHbOAc), 4.04
(dd, 1H, J¼11.4, 5.4 Hz, CHaCHbOAc), 3.87 (dd, 1H,
J¼7.5, 3.9 Hz, H-7a), 3.32 (ddd, 1H, J¼9.6, 5.7, 4.2 Hz,
H-3), 3.18 (dt, 1H, J¼11.1, 7.8 Hz, H-5a), 2.95 (ddd, 1H,
J¼11.1, 7.2, 5.4 Hz, H-5b), 2.14–1.92 (m, 2H, H-6), 2.11
(s. 3H, Ac), 2.09 (s, 3H, Ac), 2.03 (s, 3H, Ac), 2.01 (s, 3H,
Ac); 13C NMR d 170.8, 170.4, 169.6, 169.4 (4£CO), 74.4
(CH-7), 73.7 (CH-2), 71.7 (CH-1), 66.7 (CH-3), 65.0
(CH2OAc), 64.7 (CH-7a), 52.3 (CH2-5), 30.9 (CH2-6), 21.0,
20.8, 20.7, 20.4 (4£CH3, Ac); MS (CIþve) m/z 358 (Mþ1þ,
100%); HRMS (CIþve) Calcd for C16H24NO8 (MHþ)
358.1502, found: 358.1485.
2.1.11. (1)-(1S,2R,3R,7S,7aR)-Hexahydro-3-hydroxy-
methyl-1H-pyrrolizine-1,2,7-triol, [(1)-1-epiaustraline]
(1). To a solution of 15 (21 mg, 0.109 mmol) in methanol
(2 mL) was added Amberlyst A-26 resin (50 mg). The
reaction mixture was stirred for 2 h at RT. The TLC analysis
indicated the complete conversion. The mixture was then
filtered through a sintered glass frit and rinsed with
methanol. The filtrate was concentrated to give the title
compound (11 mg) as a colorless oil. [a]2D5¼þ14.3 (c1.1,
2.1.13. (2)-(1S,5S,6R,7R,7aS)-6-Hydroxyl-1-[2-(4-
methoxyphenyl)methoxy]ethyl-7-phenylcarbonyloxy-5-
phenylmethoxymethyltetrahydro-1H-pyrrolo[1,2-
c][1,3]oxazol-3-one (17). To a solution of 16 (192 mg,
0.381 mmol) in DMF (8 mL) was added benzoic acid
(79 mg, 0.65 mmol) followed by cesium carbonate (186 mg,
0.572 mmol). The mixture was stirred under nitrogen at
40 8C for 3 h. DMF was removed under reduced pressure
and the residue was suspended in THF (8 mL). Water (20
drops) followed by concentrated sulfuric acid (4 drops) was
added and the suspension became a clear solution. The
H2O) [lit.10a [a]2D5¼þ13.695 (c1.72, H2O)]; The 1H and 13
C
NMR spectral data for this compound were essentially
identical to that reported in the literature.10 1H NMR
(500 MHz, D2O) d 4.57 (dt, 1H, J¼5.0, 4.5 Hz, H-7), 4.40
(t, 1H, J¼5.0 Hz, H-1), 3.91 (dd, 1H, J¼9.0, 4.5 Hz, H-2),

5766
M. Tang, S. G. Pyne / Tetrahedron 60 (2004) 5759–5767
solution was stirred at RT for 9.5 h. The volatiles were
removed in vacuo to give a semi-solid which was purified by
column chromatography (20–60% EtOAc/petrol) to give 18
(184 mg, 88%) as a mixture (73:27) of regioisomers as a
colourless oil. Spectral data for the major isomer: 1H NMR
d 7.96 (d, 2H, J¼7.8 Hz, BzH), 7.60 (td, 1H, J¼7.5, 0.6 Hz,
BzH), 7.43 (t, 2H, J¼7.8 Hz, BzH), 7.32–7.26 (m, 5H,
ArpH), 7.18 (d, 2H, J¼8.4 Hz, ArH), 6.81 (d, 2H, J¼7.8 Hz,
ArH), 5.01 (dd, 1H, J¼6.3, 4.2 Hz, H-7), 4.97 (dt, 1H,
J¼7.2, 5.1 Hz, H-1), 4.61 (t, 1H, J¼3.6 Hz, H-6), 4.58 (s,
2H, ArpCH2), 4.36 (s, 2H, ArCH2), 4.10 (bdd, 1H, J¼9.0,
5.1 Hz, H-5), 3.88 (dd, 1H, J¼6.3, 5.1 Hz, H-7a), 3.76 (s,
3H, OMe), 3.75–3.58 (m, 4H, CH2OBn, CH2CH2O), 2.11–
2.00 (m, 2H, CH2CH2O); 13C NMR d 166.6 (CO, Bz), 160.6
(CO-3), 159.0 (ArC), 137.7 (ArpC), 133.6 (CH, Bz), 123.0
(ArC), 129.7, 129.2, 128.5, 128.4, 127.7, 127.5 (1£ArCH,
3£ArpCH and 2£BzCH), 128.7 (C, Bz), 113.7 (ArCH), 84.3
(CH-7), 79.0 (CH-6), 78.3 (CH-1), 73.3 (ArpCH2), 72.7
(ArCH2), 69.6 (CH2OBn), 67.7 (CH-7a), 65.4 (CH2CH2O),
64.4 (CH-5), 55.2 (OMe), 35.2 (CH2CH2O), 20.8 (CH3,
Ac); MS (ESþve) m/z 548 (Mþ1þ, 25%), 570 (MþNaþ,
100%); HRMS (ESþve) Calcd for C31H34NO8 (MHþ)
548.2284, found: 548.2284.
Ac); MS (ESþve) m/z 590 (Mþ1þ, 12%), 612 (MþNaþ,
100%); HRMS (ESþve) Calcd for C33H36NO9 (MHþ)
590.2390, found: 590.2379. HRMS (EIþve) Calcd for
C33H35NO9 (Mþ) 589.2312, found: 589.2300. Spectral data
for 180: 1H NMR (500 MHz) d 7.91 (dd, 2H, J¼8.0, 1.5 Hz,
BzH), 7.60 (tt, 1H, J¼7.5, 1.5 Hz, BzH), 7.43 (t, 2H,
J¼8.5 Hz, BzH), 7.20–7.13 (m, 7H, 2£ArH, 5£ArpH), 6.76
(d, 2H, J¼9.0 Hz, ArH), 5.74 (dd, 1H, J¼6.0, 2.0 Hz, H-6),
5.26 (dd, 1H, J¼4.0, 2.0 Hz, H-7), 4.53 (td, 1H, J¼6.5,
4.0 Hz, H-1), 4.45–4.35 (m, 5H, ArCH2, ArpCH2, H-5),
4.19 (t, 1H, J¼4.0 Hz, H-7a), 3.71 (s, 3H, OMe), 3.80–3.57
(m, 4H, CH2OBn, CH2CH2O), 2.11 (s, 3H, Ac), 2.17–2.04
(m, 2H, CH2CH2O); 13C NMR (125 MHz) d 169.6 (CO,
Ac), 164.5 (CO, Bz), 160.9 (CO-3), 159.2 (ArC), 137.4
(ArpC), 133.5 (CH, Bz), 131.5 (ArC), 129.7 (CH, Bz),
129.2, 128.5, 128.3, 127.6, 127.6 (1£ArCH, 3£ArpCH,
1£BzCH), 129.0 (C, Bz), 113.7 (ArCH), 76.9 (CH-6), 75.8
(CH-7), 73.5, 73.0 (ArCH2, ArpCH2), 73.5 (CH-1), 67.3
(CH2OBn), 65.6 (CH2CH2O), 65.5 (CH-7a), 59.2 (CH-5),
55.1 (OMe), 35.2 (CH2CH2O), 20.7 (CH3, Ac); MS
(ESþve) m/z 590 (Mþ1þ, 13%), 612 (MþNaþ, 100%);
HRMS (ESþve) Calcd for C33H36NO9 (MHþ) 590.2390,
found: 590.2374.
2.1.14. (2)-(1S,5R,6R,7R,7aS)-6-Acetoxy-1-[2-(4-
methoxyphenyl)methoxy]ethyl-7-phenylcarbonyloxy-5-
phenylmethoxymethyltetrahydro-1H-pyrrolo[1,2-c]-
[1,3]oxazol-3-one (18) and (1S,5R,6S,7S,7aS)-7-acetoxy-
1-[2-(4-methoxyphenyl)methoxy]ethyl-6-phenyl-
carbonyloxy-5-phenylmethoxymethyltetrahydro-1H-
pyrrolo[1,2-c][1,3]oxazol-3-one (180).
2.1.15. (2)-(1S,5R,6R,7R,7aS)-6-Acetoxy-1-(2-hydro-
xy)ethyl-7-phenylcarbonyloxy-5-(phenylmethoxy)-
methyl-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one
(19). The same procedure described above for the
preparation of 11 was used starting with 18 (61 mg,
0.104 mmol) and DDQ (33 mg, 0.146 mmol) in a solution
of DCM (10 mL) containing water (0.5 mL). After the
mixture had stirred at RT for 3 h, TLC analysis (60%
EtOAc/petrol) indicated the presence of compound 18.
Additional DDQ (14 mg, 0.062 mmol) was then added to
the mixture. The reaction was continued for another 1 h.
Compound 19 (33 mg, 67%) was obtained as a pale yellow
1
oil. [a]2D4¼254.7 (c1.6, CHCl3); H NMR d 7.96 (dt, 2H,
J¼8.4, 1.5 Hz, BzH), 7.62 (tt, 1H, J¼7.5, 1.5 Hz, BzH),
7.45 (t, 2H, J¼7.8 Hz, BzH), 7.33–7.29 (m, 2H, ArpH),
7.27–7.21 (m, 3H, ArpH), 5.63 (dd, 1H, J¼3.0, 2.4 Hz,
H-6), 5.15–5.09 (m, 2H, H-1, H-7), 4.61 (s, 2H, ArpCH2),
4.16 (td, 1H, J¼3.9, 2.4 Hz, H-5), 3.90–3.85 (m, 2H, H-7a,
CHaCHbOBn), 3.82–3.80 (m, 2H, CH2CH2OH), 3.74 (dd,
1H, J¼9.6, 4.2 Hz, CHaCHbOBn), 2.16–1.95 (m, 2H,
CH2CH2OH), 2.09 (s, 3H, Ac); 13C NMR d 170.3 (CO,
Ac), 166.5 (CO, Bz), 159.8 (CO-3), 137.6 (ArpC), 133.8,
129.8 (2£CH, Bz), 128.4 (C, Bz), 128.6, 128.4, 127.7, 127.3
(3£ArpCH, 1£BzCH), 83.3 (CH-7), 81.1 (CH-6), 78.5
(CH-1), 73.4 (ArpCH2), 70.4 (CH2OBn), 69.2 (CH-7a), 63.4
(CH-5), 58.5 (CH2CH2OH), 37.8 (CH2CH2OH), 20.8 (CH3,
Ac); MS (ESþve) m/z 470 (Mþ1þ, 8%), 492 (MþNaþ,
100%); HRMS (ESþve) Calcd for C25H28NO8 (MHþ)
470.1815, found: 470.1797.
The same procedure described above for the preparation of
10 was used starting with 17 (224 mg, 0.409 mmol), Ac2O
(2.0 mL) in anhydrous pyridine (2 mL). Compounds 18
(160 mg, 66%) and its regioisomer 180 (61 mg, 25%) were
obtained respectively, as pale yellow oils. Spectral data for
1
18: [a]2D3¼230.1 (c1.1, CHCl3); H NMR d 7.94 (dt, 2H,
J¼8.4, 1.2 Hz, BzH), 7.60 (tt, 1H, J¼7.8, 1.2 Hz, BzH),
7.43 (t, 2H, J¼8.1 Hz, BzH), 7.33–7.28 (m, 2H, ArpH),
7.26–7.23 (m, 3H, ArpH), 7.18 (d, 2H, J¼9.0 Hz, ArH),
6.81 (d, 2H, J¼9.0 Hz, ArH), 5.60 (t, 1H, J¼3.6 Hz, H-6),
5.15 (dd, 1H, J¼6.0, 3.3 Hz, H-7), 5.06 (ddd, 1H, J¼7.8,
4.8, 3.9 Hz, H-1), 4.59 (s, 2H, ArpCH2), 4.36 (s, 2H,
ArCH2), 4.15 (dd, 1H, J¼6.6, 3.9 Hz, H-5), 3.93 (dd, 1H,
J¼6.3, 4.2 Hz, H-7a), 3.86 (dd, 1H, J¼9.6, 3.6 Hz,
CHaCHbOBn), 3.78 (s, 3H, OMe), 3.72 (dd, 1H, J¼9.6,
4.2 Hz, CHaCHbOBn), 3.64–3.57 (m, 2H, CH2CH2O),
2.19–1.98 (m, 2H, CH2CH2O), 2.09 (s, 3H, Ac); 13C
NMR d 170.3 (CO, Ac), 166.0 (CO, Bz), 160.0 (CO-3),
159.1 (ArC), 137.7 (ArpC), 133.6 (CH, Bz), 130.1 (ArC),
129.7, 129.2, 128.5, 128.4, 127.7, 127.3 (1£ArCH,
3£ArpCH and 2£BzCH), 128.6 (C, Bz), 113.7 (ArCH),
82.7 (CH-7), 81.0 (CH-6), 78.3 (CH-1), 73.4 (ArpCH2), 72.7
(ArCH2), 70.4 (CH2OBn), 69.0 (CH-7a), 65.4 (CH2CH2O),
63.4 (CH-5), 55.2 (OMe), 35.3 (CH2CH2O), 20.8 (CH3,
2.1.16. (1)-(2S,3R,4R,5R)-5-[(1S)-1,3-Dihydroxypropyl]-
2-(phenylmethoxy)methyl pyrrolizine-3,4-diol (20). The
same procedure described above for the preparation of 12
was used starting with 19 (32 mg, 0.067 mmol) and sodium
hydroxide (427 mg, 0.674 mmol) in a solution of ethanol
(1 mL). Compound 20 (15 mg, 76%) was obtained as a pale
yellow oil. [a]2D5¼þ21.4 (c1.5, MeOH); 1H NMR (CD3OD)
d 7.38–7.23 (m, 5H, ArpH), 4.55 (s, 2H, ArpCH2),
3.84–3.69 (m, 5H, H-3, H-4, CHOH, CH2CH2OH), 3.64

M. Tang, S. G. Pyne / Tetrahedron 60 (2004) 5759–5767
5767
8264–8268. (b) Pearson, W. H.; Hines, J. V. J. Org. Chem.
2000, 65, 5785–5793. (c) Ikota, N.; Nakagawa, H.; Ohno, S.;
Noguchi, K.; Okuyama, K. Tetrahedron 1998, 54, 8985–8998.
(d) Pearson, W. H.; Hines, J. V. Tetrahedron Lett. 1991, 32,
5513–5516.
(dd, 1H, J¼9.6, 3.9 Hz, CHaCHbOBn), 3.51 (dd, 1H, J¼9.6,
6.9 Hz, CHaCHbOBn), 3.10 (dt, 1H, J¼6.9, 3.6 Hz, H-2),
2.80 (dd, 1H, J¼6.9, 5.4 Hz, H-5), 1.78 (dtd, 1H, J¼14.1,
6.9, 3.6 Hz, CHaCHbCH2OH), 1.65 (ddt, 1H, J¼14.7, 9.0,
5.7 Hz, CHaCHbCH2OH); 13C NMR (CD3OD) d 139.6
(ArpC), 129.4, 128.9, 128.7 (3£ArpCH), 80.1, 80.0 (CH-3,
CH-4), 74.3 (ArpCH2), 72.5 (CH2OBn), 69.7 (CHOH), 67.1
(CH-5), 62.3 (CH-2), 60.0 (CH2CH2OH), 38.0 (CH2CH2-
OH); MS (ESþve) m/z 298 (Mþ1þ, 100%); HRMS
(ESþve) Calcd for C15H24NO5 (MHþ) 298.1654, found:
298.1654.
8. (a) Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc.
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Acknowledgements
We thank the Australian Research Council and the
University of Wollongong for supporting this research.
11. Tang, M.; Pyne, S. G. J. Org. Chem. 2003, 68, 7818–7828.
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