Asymmetric synthesis of ( - )-7-epiaustraline and (+)-1,7-diepiaustraline

Article abstract of DOI:10.1021/jo034914q

A diastereoselective and modular approach to the synthesis of the 3-hydroxymethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine-1,2,7-triol structure, characteristic of several natural pyrrolizidine natural products, has been developed. This approach culminated i

Full text of DOI:10.1021/jo034914q

Asym m etr ic Syn th esis of (-)-7-Ep ia u str a lin e a n d
(+)-1,7-Diep ia u str a lin e†
Minyan Tang and Stephen G. Pyne*
Department of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia
spyne@uow.edu.au
Received J une 27, 2003
A diastereoselective and modular approach to the synthesis of the 3-hydroxymethyl-2,3,5,6,7,7a-
hexahydro-1H-pyrrolizine-1,2,7-triol structure, characteristic of several natural pyrrolizidine natural
products, has been developed. This approach culminated in the synthesis of (-)-7-epiaustraline
and (+)-1,7-diepiaustraline. The oxazolidinone group has been found to be a useful protecting group
in the RCM reaction and, as part of a pyrrolo[1,2-c]oxazol-3-one ring system, has functioned as a
stereo- and regio-directing group in a key diastereoselective cis-dihydroxylation reaction and a
regioselective nucleophilic ring-opening of a S,S-dioxo-dioxathiole.
Alexine (1) was the first alkaloid to be isolated, in 1988,
with the 3-hydroxymethyl-2,3,5,6,7,7a-hexahydro-1H-
pyrrolizine-1,2,7-triol structure.1 In the same year its 7a-
epimer, australine (2), was isolated from the seeds of the
Australian legume Castanospermum australe.2 Later
reports described the isolation of other epimers of 2 from
these seeds.3 A recent reinvestigation of these seed
extracts confirmed the presence of the alkaloids 2-4 and
revealed the isolation of three new alkaloids, the 2-O-â-
D-glucopyranosyl derivative of 3 and the compounds 5
and 6.4 The latter two alkaloids were epimeric at C-7,
with 6 having the same C-7, C-7a stereochemistry as
casuarine 7.5 Compound 6 is the first 7-epiaustraline
alkaloid to be isolated. Although this honor was originally
claimed for 7-epiaustraline itself,3c synthetic studies by
Denmark6 established that 7-epiaustraline was not a
natural product and that the original investigators had
isolated australine. These alkaloids have been tested for
their glycosidase inhibitory activities2,3c and recently on
several R- and â-glucosidase enzymes and R-L-fucosidase.4
Compounds 2, 5, and 7 and the 2-O-â-D-glucopyranosyl
derivative of 3 and the 6-O-R-D-glucopyranosyl derivative
of 7 were the most potent and specific enzyme inhibitors.
Other biological studies7 have revealed the potential of
these and related polyhydroxylated pyrrolizidines as
antiviral and antiretroviral agents.7b,c These interesting
biological properties coupled with the polyfunctional and
stereochemically rich nature of these compounds have
attracted the attention of synthetic chemists, resulting
in the total synthesis of alexine8 and its epimers,8,9
australine10 and its epimers,6,9-11 and casuarine.12
We report here a new synthetic strategy for the
preparation of these natural products, and their various
stereoisomers, as shown in Figure 1. This modular
approach, which in principle allows access to all stereo-
isomers of 3-hydroxymethyl-2,3,5,6,7,7a-hexahydro-1H-
pyrrolizine-1,2,7-triol (A), is shown in Figure 2.
Aminolysis13-15 of the enantiomerically enriched cis-
or trans-vinyl epoxide E, which is readily available in all
(7) (a) Tropea, J . E.; Molyneux, R. J .; Kaushal, G. P.; Pan, Y. T.;
Mitchell, M.; Elbein, A. D. Biochemistry 1989, 28, 2027-2034. (b)
Fellows, L.; Nash, R. PCT Int. Appl. WO GB 89/7951; Chem Abstr.
1990, 114, 143777f. (c) Elbein, A. D.; Tropea, J . E.; Molyneux, R. J .
U.S. Pat. Appl. 289,907; Chem Abstr. 1990, 113, P91444p.
(8) (a) Fleet, G. W. J .; Haraldsson, M.; Nash, R. J .; Fellows, L. E.
Tetrahedron Lett. 1988, 29, 5441-5444. (b) Yoda, H.; Katoh, H.;
Takabe, K. Tetrahedron Lett. 2000, 41, 7661-7665.
(9) (a) Romero, A.; Wong, C.-H. J . Org. Chem. 2000, 65, 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. (c) Pearson, W. H.; Hines, J . V.
Tetrahedron Lett. 1991, 32, 5513-5516.
* Corresponding author.
† Dedicated to Prof. J ohn Bremner on the occasion of his 60th
birthday.
(1) Nash, R. J .; Fellows, L. E.; Dring, J . V.; Fleet, G. W. J .; Derome,
A. E.; Hamor, T. A.; Scofield, A. M.; Watkin, D. J . Tetrahedron Lett.
1988, 29, 2487-2490.
(2) Molyneux, R. J .; Benson, M.; Wong, R. Y.; Tropea, J . E.; Elbein,
A. D. J . Nat. Prod. 1988, 51, 1198-1206.
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Derome, A. E.; Baird, P. D.; Hegarty, M. P.; Scofield, A. M. Tetrahedron
1988, 44, 5959-5964. (b) Harris, C. M.; Harris, T. M.; Molyneux, R.
J .; Tropea, J . E.; Elbein, A. D. Tetrahedron Lett. 1989, 30, 5685-5688.
(c) Nash, R. J .; Fellows, L. E.; Dring, J . V.; Fleet, G. W. J .; Girdhar,
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10.1021/jo034914q CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/06/2003
7818
J . Org. Chem. 2003, 68, 7818-7824

(-)-7-Epiaustraline and (+)-1,7-Diepiaustraline
F IGURE 3. Target molecules.
9 as our target molecules (Figure 3). These compounds
have the 1,2-cis and 1,2-trans diol stereochemistry,
respectively. It was anticipated that by employing a
oxozolidinone protecting group the conformationally rigid
pyrrolo[1,2-c]oxazol-3-one structure (F , Figure 3) ob-
tained would allow for the introduction of these func-
tionalities in a diastereoselective manner.
F IGURE 1. Structures of 3-hydroxymethyl pyrrolizidine.
The starting vinyl epoxide (+)-(2R,3R)-10 was prepared
from the corresponding Sharpless epoxy alcohol (94% ee
from 1H NMR analysis of its Mosher ester) via Swern
oxidation followed by a Wittig-olefination reaction.13,15,22
A solution of the vinyl epoxide (+)-10 and the (S)-
allylamine 1117 (1.4 equiv) in acetonitrile was heated at
120 °C in a sealed tube using LiOTf (1.5 equiv) as a
catalyst for 72 h. This gave the amino alcohol (+)-12,
along with no more than 2-3% of another diastereomer,
in 98% yield via an SN2 ring opening. The amino-alcohol
(+)-12 was converted to the diastereomerically pure
2-oxazolidinone derivative (+)-13 in 79% yield using
triphosgene under basic conditions.23 We were then ready
to try the ring-closing metathesis (RCM) of 13. While
F IGURE 2. Retrosynthetic analysis.
18g,19a,20a-d,24
2-oxazolo[3,4-a]pyridin-3-ones
and their sev-
en- and eight-membered18d,19b,e ring analogues have been
successfully prepared via RCM, the RCM of 3-allyl-4-
configurational forms using the Sharpless epoxida-
tion,15,16 with either R or S chiral allylic amine D,17 could
regio- and diastereoselectively provide the corresponding
1,2-amino alcohol with any stereochemistry desired.
Protection of the amino alcohol functionality as the
2-oxazolidinone C followed by a ring-closing metathesis
reaction13,15,18-20 should provide the conformationally
rigid pyrrolo[1,2-c]oxazol-3-one structure B. The bicyclic
nature of B should allow for a stereochemically controlled
cis-dihydroxylation of the 3,4-double bond of B, a problem
that we15 and others18j,21 experienced in the synthesis of
(-)-swainsonine. To test the feasibility of this approach
we chose (+)-1,7-diepiaustraline 8 and (-)-7-epiaustaline
(19) For the application of the ring-closing metathesis reaction to
the synthesis of 2,5-dihydropyrroles from dienes, see: (a) Huwe, C.
M.; Velder, J .; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35,
2376-2378. (b) Furstner, A.; Fursterner, A.; Picquet, M.; Bruneau, C.;
Dixneuf, P. H. Chem. Commun. 1998, 1315-1316. (c) Cerezo, S.;
Cortes, J .; Moreno-Manas, M.; Pleixats, R.; Roglans, A. Tetrahedron
1998, 54, 14869-14884. (d) Furstner, A.; Ackermann, L. Chem.
Commun. 1999, 95-96. (e) Bujard, M.; Briot, A.; Gouverneur, V.;
Mioskowski, C. Tetrahedron Lett. 1999, 40, 8795-8788. (f) Furstner,
A.; Liebl, M.; Hill, A. F.; Wilton-Ely, J . D. E. T. Chem. Commun. 1999,
601-602. (g) Ackermann, L.; Furstner, A.; Weskamp, T.; Kohl, F. J .;
Hermann, W. A. Tetrahedron Lett. 1999, 40, 4787-4790. (h) Ahmed,
M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.; Procopiou, P. A.
Tetrahedron Lett. 1999, 40, 8657-8662. (i) Evans, P. A.; Robinson, J .
E. Org. Lett. 1999, 1, 1929-1931. (j) Hunt, J . C. A.; Laurent, P.; Moody,
C. J . Chem. Commun. 2000, 1771-1772.
(20) For RCM reactions on related acyclic N-protected dienes, see:
(a) Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 67-68. (b)
Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett. 2000, 41, 4113-
4116. (c) Mart´ın, R.; Moyano, A.; Perica`s, M. A.; Riera, A. Org. Lett.
2000, 2, 93-95. (d) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron
2001, 57, 5393-5401. (e) Fustero, S.; Navarro, A.; Pina, B.; Soler, J uan
G.; Bartolome, A.; Asensio, A.; Simon, A.; Bravo, P.; Fronza, G.;
Volonterio, A.; Zanda, M. Org. Lett. 2001, 3, 2621-2624.
(16) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780.
(17) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J . Am.
Chem. Soc. 2000, 122, 5968-5976.
(18) For the application of the ring-closing metathesis reaction to
the synthesis of aza-sugars, see ref 15 and (a) Huwe, C. M.; Blechert,
S. Tetrahedron Lett. 1995, 36, 1621-1624. (b) Overkleeft, H. S.; Pandit,
U. K. Tetrahedron Lett. 1996, 37, 547-550. (c) Huwe, C. M.; Blechert,
S. Synthesis 1997, 61-67. (d) White, J . D.; Hrnciar, P.; Yokochi, A. F.
T. J . Am. Chem. Soc. 1998, 120, 7359-7360. (e) Lindstrom, U. M.;
Somfai, P. Tetrahedron Lett. 1998, 39, 7173-7176. (f) Ovaa, H.;
Stragies, R.; van der Marcel, G. A.; van Boom, J . H.; Blechert, S. Chem.
Commun. 2000, 1501-1502. (g) Subramanian, T.; Lin, C.-C.; Lin, C.-
C. Tetrahedron Lett. 2001, 42, 4079-4082. (h) Klitze, C. F.; Pilli, R.
A. Tetrahedron Lett. 2001, 42, 5605-5608. (i) Chandra, K. L.; Chan-
drasekhar, M.; Singh, V. K. J . Org. Chem. 2002, 67, 4630-4633. (j)
Buschmann, N.; Ru¨ckert, A.; Blechert, S. J . Org. Chem. 2002, 67,
4325-4329.
(21) Oishi, T.; Iwakuma, T.; Hirama, M.; Itoˆ, S. Synlett 1995, 404-
406. Mukai, C.; Sugimoto, Y.-i.; Miyazawa, K.; Yamaguchi, S.; Ha-
naoka, M. J . Org. Chem. 1998, 63, 6281-6287. de Vicente, J .; Arrayas,
R. G.; Canada, J .; Carretero, J . C. Synlett 2000, 53-56.
(22) For the synthesis of the corresponding O-benzyl analogue, see:
Diez-Martin, D.; Kotecha, N. R.; Ley, S. L.; Mantegani, S.; Menendez,
J . C.; Organ, H. M.; White, A. D.; Banks, J . B. Tetrahedron 1992, 48,
7899-7938.
J . Org. Chem, Vol. 68, No. 20, 2003 7819

Tang and Pyne
SCHEME 1a
F IGURE 4. Molecular Model (PC Spartan Pro, AM1) of 14
(PMB group not shown).
product was isolated, which was expected to arise from
delivery of the two hydroxyl groups to the least hindered
face of the 6,7-double bond in (-)-14. Figure 4 shows a
molecular model (PC Spartan Pro, AM1) of 14. The â-face
is more sterically demanding because of the pseudoaxial
proton H7a and the â-C-5 benzyloxymethyl substituent,
which hinder the â-face (convex face) to attack by the
osmium reagent (Figure 4). A similar argument has been
proposed for the facial selectivity of DH reactions on
related indolizines.15,18j,21 The absolute stereochemistry
assigned to 15 was unequivocally confirmed by its
conversion to (+)-1,7-di-epiaustraline (8).
Attempts to deprotect the primary PMB ether in 15
under oxidative conditions with DDQ25 gave a poor yield
of the desired primary alcohol as a result of the formation
of several other products that could not be structurally
identified. The diacetate derivative 16, however, was
smoothly converted to the primary alcohol 17 in 88%
yield. Compound 17 was then converted to the pyrrolizi-
dine-triacetate 20 in three synthetic steps. Base hydroly-
sis of 17 followed by ion-exchange chromatography gave
18, which was cyclized to the desired pyrrolizidine ring
system under Mitsunobu conditions26 in pyridine at 0 °C.
This reaction resulted in a mixture of 19 and starting
tetrol 18, which were readily separated as their peracetyl-
ated derivatives. In this way the pyrrolizidine-triacetate
20 was obtained in 20% overall yield from 17, over the
three synthetic steps. The use of longer reaction times
or other cyclization methods (e.g., CBr4, Ph3P)15,27 did not
result in improved yields of 20. Compound 20 was then
smoothly converted to the triacetate of (+)-1,7-diepiaus-
traline (22) by first hydrogenolysis of the primary benzyl
ether group15,28 and then acetylation in 84% overall yield.
Finally, methoxide-catalyzed removal of the acetates in
22 gave (+)-1,7-diepiaustraline (8) in 92% yield. This
sample had spectral characteristics identical to those
reported in the literature for (+)-8,9c and its specific
rotation ([R]24 +6.4 (c 0.7, MeOH), [R]24 +8.6 (c 0.7,
a
Reagents and conditions: (a) LiOTf, CH3CN, 120 °C, sealed
tube, 72 h; (b) triphosgene, Et3N, DCM, rt, 2 h; (c) Grubbs’ catalyst
I, DCM, reflux, 44 h; (d) K2OsO4‚H2O, NMO, acetone, H2O, rt, 24
h; (e) Ac2O, pyridine, rt, 24 h; (f) DDQ, DCM, H2O, rt, 2 h; (g)
NaOH, EtOH, 70 °C, sealed tube, 24 h; (h) DIAD, PPh3, pyridine,
0 °C, 2.5 h; (i) Ac2O, pyridine, rt, 24 h; (j) PdCl2, H2, MeOH, rt,
1.5 h; (k) Ac2O, pyridine, rt, 24 h; (l) NaOMe, MeOH, rt, 15 h.
vinyl-2-oxazolidinone to give pyrrolo[1,2-c]oxazol-3-one
has been reported not to proceed at room temperature.18a
We found that the RCM of 13 using standard conditions,
5-10 mol % of Grubbs I catalyst (benzylidenebis(tricy-
clohexylphosphine)ruthenium dichloride) in refluxing
CH2Cl2 at high dilution (∼4 mM)13,15 for 20 h, gave low
conversion to the desired 2,5-dihydropyrrole 14. However,
by initiating the reaction using 25 mol % Grubbs I
catalyst and then adding a further 25 mol % catalyst after
24 h, 14 could be isolated in 73% yield after a total of 48
h of heating at reflux. Compound (-)-14 was treated with
5 mol % K2OsO4‚2H2O and NMO (2.1 equiv),15 to effect
cis-dihydroxylation (DH) of the double bond, giving diol
(-)-15 in good yield (82%). Only one diastereomeric
D
D
H2O)) closely matched that previously reported (lit.9c
[R]20 + 4.7 (c 0.5, H2O)).
D
Scheme 2 outlines the synthesis of (-)-7-epiaustraline
(9). This synthesis required inversion of the stereochem-
(25) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 855-888.
(26) Bernotas, R. C.; Cube, R. V. Tetrahedron Lett. 1991, 32, 161-
164. Chen, Y.; Vogel, P. J . Org. Chem. 1994, 59, 2487-2496.
(27) Mulzer, J .; Dehmlow, H. J . Org. Chem. 1992, 57, 3194-3202.
Casiraghi, G.; Ulgheri, F.; Spanu, P.; Rassu, G.; Pinna, L.; Gasparri
F., G.; Belicchi F., M.; Pelosi, G. J . Chem. Soc., Perkin Trans. 1 1993,
2991-2997.
(23) Colson, P.-J .; Hegedus, L. S. J . Org. Chem. 1993, 58, 5918-
5924.
(24) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett. 2001, 42,
4633-4635.
(28) Zhao, H.; Hans, S.; Chemg, X.; Mootoo, D. R. J . Org. Chem.
2001, 66, 1761-1767. Zhou, W.-S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.-F.
Tetrahedron Lett. 1995, 36, 1291-1294.
7820 J . Org. Chem., Vol. 68, No. 20, 2003

(-)-7-Epiaustraline and (+)-1,7-Diepiaustraline
SCHEME 2a
-14.1 (c 0.22, H2O)) almost identical to that reported in
the literature (lit.6 [R]20 -13.04 (c 0.55, H2O, pH 8.37)).
D
In summary, we have developed a diastereoselective
and modular approach to the synthesis of the 3-hy-
droxymethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine-1,2,7-
triol structure, characteristic of several pyrrolizidine
natural products. The oxazolidinone group has been
found to be a useful protecting group in the RCM reaction
and, as part of a pyrrolo[1,2-c]oxazol-3-one ring system,
has functioned as a stereo- and regio-directing group, in
a key diastereoselective cis-dihydroxylation reaction and
a regioselective nucleophilic ring-opening of a S,S-dioxo-
dioxathiole. The application of this strategy to the
synthesis of the alkaloids in the australine family (2-6)
is currently in progress.
Exp er im en ta l Section
(+)-6-(4-Me t h ox yp h e n yl)m e t h o xy-3R -[(1S -p h e n y l-
m eth oxym eth yl)-2-p r op en yl]a m in o-1-h ep ten -4-ol (12). To
a mixture of 10 (195 mg, 0.833 mmol) and 1117 (202 mg, 1.144
mmol) in dry acetonitrile (1 mL), in a thick-walled glass tube,
was added lithium triflate (195 mg, 1.249 mmol). The vessel
was flushed with nitrogen and sealed and then stirred and
heated at 120 °C for 3 days. The mixture was then cooled to
room temperature, and all volatiles were removed in vacuo to
give a dark sticky oil, which was purified by column chroma-
a
Reagents and conditions: (a) (i) SOCl2, Et3N, DCM, 0 °C, 30
min, (ii) RuCl3‚3H2O, NaIO4, CCl4/CH3CN/H2O ) 2:2:3, rt, 2 h;
(b) (i) PhCOOH, Cs2CO3, DMF, 40 °C, 23 h, (ii) H2SO4 (conc), THF,
H2O, rt, 18 h; (c) DDQ, DCM, H2O, rt, 2 h; (d) NaOH, EtOH, 70
°C, 19 h; (e) DIAD, PPh3, THF, 0 °C, 3 h; (f) Ac2O, pyridine, rt, 21
h; (g) PdCl2, H2, MeOH, rt, 1 h; (h) Ac2O, pyridine, rt, 15 h; (i)
K2CO3, MeOH, rt, 24 h.
tography (0-10% methanol/DCM) to give compound 12 (334
1
mg, 98%) as a yellow oil: [R]22 +3.8 (c 2.7, CHCl3); H NMR
D
δ 7.34-7.27 (m, 5H), 7.23 (d, 2H, J 8.7 Hz), 6.86 (d, 2H, J 8.7
Hz), 5.66 (ddd, 1H, J 8.4, 10.2, 17.1 Hz), 5.54 (dddd, 1H, J
1.8, 6.0, 9.9, 15.9 Hz), 5.25-5.09 (m, 4H, 2× dCH2), 4.51 (s,
2H), 4.43 (s, 2H), 3.79 (s, 3H), 3.79 (m, 1H), 3.66-3.59 (m, 2H),
3.47-3.39 (m, 3H), 3.12 (dd, 1H, J 4.2, 8.1 Hz), 1.77-1.59 (m,
2H); 13C NMR δ 159.0 (C, Ar), 137.9 (C, Ar), 137.4 (CH), 136.0
(CH), 130.1 (C, Ar), 129.2 (CH, Ar), 128.3 (CH, Ar), 127.5 (CH,
Ar), 127.5 (CH, Ar), 118.1 (CH2), 118.0 (CH2), 113.7 (CH, Ar),
73.2 (CH2), 73.0 (CH2), 72.8 (CH2), 72.0 (CH), 68.3 (CH2), 62.4
(CH), 57.9 (CH), 55.3 (CH3), 33.0 (CH2); MS (CI +ve) m/z 412
(M + 1+, 100%); HRMS (CI +ve) calcd for C25H34NO4 (MH+)
412.2488, found 412.2478.
istry at C-7 in the pyrrolo[1,2-c]oxazol-3-one 15. Thus 15
was converted to its cyclic-sulfate 23 using thionyl
chloride followed by oxidation of the resulting cyclic
sulfite with catalytic ruthenium tetroxide (80% yield for
the two-step conversion).29 Regioselective nucleophilic
ring opening of the S,S-dioxo-dioxathiole ring of 23 with
cesium benzoate,29,30 followed by an acid catalyzed hy-
drolysis, gave the benzoate 24 in 56% yield. A small
amount (ca. 5%) of the other regioisomer could be
detected from 1H NMR analysis of the crude reaction
mixture; however, this minor compound could not be
isolated pure. Nucleophilic attack on 23 would be ex-
pected to occur preferentially at C-7 since backside attack
at C-6 would be more sterically demanding because of
the â-C-5 benzyloxymethyl substituent. Oxidative re-
moval of the primary PMB ether in 24 using DDQ gave
the corresponding primary alcohol 25 in 75% yield,
without the need to protect the C-6 hydroxyl group. Base
hydrolysis of the oxazolidinone ring gave the amino tetrol
26 in 61% yield. Cyclization of 26 under Mitsunobu
conditions again proved problematic, and after acetyla-
tion of the crude cyclization mixture, the desired triac-
etate 28 was isolated in 22% overall yield from 26. This
compound was readily converted to the known tetraac-
etate of (-)-7-epiaustraline (30) according to Scheme 2.
This sample had spectral characteristics identical to
those reported in the literature for (-)-30.3b,7a Base-
catalyzed hydrolysis of 30 gave (-)-7-epiaustaline (9),
(+)-4S-Eth en yl-5R-[2-(4-m eth oxyph en yl)m eth oxy]eth yl-
3-(1S-p h en ylm eth oxym eth yl-2-p r op en yl)-1,3-oxa zolid in -
2-on e (13). A solution of 12 (618 mg, 1.503 mmol) in dry DCM
(50 mL) was cooled to 0 °C, and triethylamine (852 mg, 1.2
mL, 8.416 mmol) was added. A solution of triphosgene (268
mg, 0.902 mmol) in dry DCM (3 mL) was cooled to 0 °C and
was then added to the above amine solution at 0 °C. TLC
analysis (40% EtOAc/petrol) indicated complete disappearance
of the compound 12 after 2 h. The reaction was quenched with
water (50 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
semisolid. Chromatography of the residue eluting with (20-
40%) EtOAc/petrol gave compound 13 (520 mg, 79%) as a pale
1
yellow oil: [R]25 +18.3 (c 2.5, CHCl3); H NMR δ 7.34-7.30
D
(m, 5H), 7.24 (d, 2H, J 8.7 Hz), 6.87 (d, 2H, J 8.7 Hz), 5.87-
5.66 (m, 2H), 5.24 (dt, 1H, J 17.1, 1.2 Hz), 5.24 (dd, 1H, J 1.2,
10.8 Hz), 5.18 (dt, 1H, J 10.2, 1.2 Hz), 5.13 (dt, 1H, J 17.7, 1.2
Hz), 4.70 (ddd, 1H, J 3.9, 8.1, 9.3 Hz), 4.59 (d, 1H, J 12.0 Hz),
4.47 (d, 1H, J 11.7 Hz), 4.44 (d, 1H, J 11.4 Hz), 4.39 (d, 1H, J
11.4 Hz), 4.32 (dtt, 1H, J 5.4, 1.2, 9.0 Hz), 4.21 (t, 1H, J 8.7
Hz), 3.81 (dd, 1H, J 8.7, 10.2 Hz), 3.71 (s, 3H), 3.63 (dd, 1H, J
5.7, 10.2 Hz), 3.60-3.56 (m, 2H), 1.91-1.71 (m, 2H); 13C NMR
δ 159.2 (C, Ar), 157.3 (CO), 137.8 (C, Ar), 133.9 (CH), 133.5
(CH), 130.2 (C, Ar), 129.3 (CH, Ar), 128.4 (CH, Ar), 127.8 (CH,
Ar), 127.7 (CH, Ar), 120.9 (CH2), 118.5 (CH2), 113.8 (CH, Ar),
74.4 (CH), 72.9 (CH2), 72.9 (CH2), 68.8 (CH2), 65.8 (CH2), 61.5
(CH), 56.2 (CH), 55.2 (CH3), 31.0 (CH2); MS (CI +ve) m/z 438
(M + 1+); HRMS (EI +ve) calcd for C26H31NO5 (M+) 437.2202,
found 437.2184.
which had spectral data and a specific rotation ([R]24
D
(29) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538-
7539.
(30) For related reactions of six-membered rings, see: Trost, B. M.;
Pulley, S. R. J . Am. Chem. Soc. 1995, 117, 10143-10144. Pettit, G.
R.; Melody, N.; Herald, D. L. J . Org. Chem. 2001, 66, 2583-2587.
J . Org. Chem, Vol. 68, No. 20, 2003 7821

Tang and Pyne
(-)-(1R,5R,6R,7S,7aR)-1-[2-(4-Meth oxyph en yl)m eth oxy]-
eth yl-5-(p h en ylm eth oxy)m eth yl-5,7a -dih ydr o-1H,3H-p yr -
r olo[1,2-c]oxa zol-3-on e (14). Grubbs’ catalyst I (245 mg,
0.298 mmol) was added to a solution of 13 (520 mg, 1.190
mmol) in dry DCM (600 mL) under nitrogen. The mixture was
heated at reflux under nitrogen for 24 h. TLC analysis (35%
EtOAc/petrol) indicated incomplete conversion of compound
13. Additional Grubbs’ catalyst I (245 mg, 0.298 mmol) was
added, and the reaction was continued under the same
conditions for another 24 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 (20-70%
EtOAc/petrol) to give 14 (358 mg, 73%) as a pale brown oil:
[R]24D -90.3 (c 2.4, CHCl3); 1H NMR δ 7.36-7.21 (m, 7H), 6.87
(d, 1H, J 8.7 Hz), 6.02 (ddd, 1H, J 1.8, 1.8, 6.0 Hz), 5.91 (ddd,
1H, J 1.8, 1.8, 6.0 Hz), 4.92 (ddd, 1H, J 4.2, 8.4, 8.7 Hz), 4.83-
4.78 (m, 2H), 4.56 (s, 2H), 4.45 (d, 1H, J 11.4 Hz), 4.41 (d, 1H,
J 11.4 Hz), 3.79 (s, 3H), 3.62-3.53 (m, 4H), 1.92 (dddd, 1H, J
4.5, 6.9, 8.1, 14.4 Hz), 1.78 (dddd, 1H, J 4.5, 4.8, 8.7, 14.4 Hz);
13C NMR δ 162.2 (CO), 159.2 (C, Ar), 137.9 (C, Ar), 132.9 (CH),
130.0 (C, Ar), 129.3 (CH, Ar), 128.3 (CH, Ar), 128.1 (CH), 127.6
(CH, Ar), 127.5 (CH, Ar), 113.8 (CH, Ar), 76.4 (CH), 73.2 (CH2),
73.0 (CH2), 71.1 (CH2), 68.2 (CH), 66.8 (CH), 65.8 (CH2), 55.2
(CH3), 32.5 (CH2); MS (CI +ve) m/z 410 (M + 1+); HRMS (CI
+ve) calcd for C24H28NO5 (MH+) 410.1967, found 410.1958.
(CH2), 63.2 (CH), 59.7 (CH), 55.1 (CH3), 29.6 (CH2), 20.7 (CH3),
20.2 (CH3); MS (CI +ve) m/z 528 (M + 1+); HRMS (ES +ve)
calcd for C28H34NO9 (MH+) 528.2234, found 528.2238.
(+)-(1R,5R,6R,7S,7aR)-6,7-Diacetoxy-1-(2-h ydr oxy)eth yl-
5-(ph en ylm eth oxy)m eth yl-5,6,7,7a-tetr ah ydr o-1H,3H-pyr -
r olo[1,2-c]oxa zol-3-on e (17). To a solution of 16 (150 mg,
0.285 mmol) in dichloromethane (25 mL) and water (2 mL)
was added 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (90.5
mg, 0.399 mmol). After the mixture had stirred at room
temperature for 3 h, TLC analysis (70% EtOAc/petrol) indi-
cated the presence of compound 16. Additional DDQ (38.8 mg,
0.171 mmol) was then added to the mixture. The reaction was
continued for another 2 h. The mixture was diluted with water
(50 mL) and extracted with DCM (3×). The combined organics
were dried (MgSO4) and filtered, and the solvent was removed
under reduced pressure to give a red semisolid that was
purified by column chromatography (30-80% EtOAc/petrol)
to give the product 17 as a colorless oil (102 mg, 88%): [R]25
D
1
+15.9 (c 1.4, CHCl3); H NMR δ 7.38-7.26 (m, 5H), 5.57 (dd,
1H, J 3.6, 7.5 Hz), 5.52-5.50 (m, 1H), 4.86 (ddd, 1H, J 6.0,
7.8, 7.8 Hz), 4.61 (d, 1H, J 12.0 Hz), 4.55 (d, 1H, J 12.0 Hz),
4.04 (dd, 1H, J 2.1, 7.5 Hz), 3.98 (dt, 1H, J 7.2, 3.3 Hz), 3.86-
3.77 (m, 2H), 3.73 (dd, 1H, J 3.3, 10.2 Hz), 3.63 (dd, 1H, J 3.3,
10.2 Hz), 2.12 (s, 3H), 2.08-1.98 (m, 1H), 1.98 (s, 3H), 1.93-
1.82 (m, 1H); 13C NMR δ 169.9 (CO), 169.7 (CO), 161.4 (CO),
137.7 (C, Ar), 128.4 (CH, Ar), 127.7 (CH, Ar), 127.5 (CH, Ar),
73.9 (CH), 73.8 (CH), 73.4 (CH2), 72.7 (CH), 69.0 (CH2), 63.4
(CH), 59.9 (CH), 59.1 (CH2), 31.8 (CH2), 20.8 (CH3), 20.4 (CH3);
MS (CI +ve) m/z 408 (M + 1+, 100%); HRMS (ES +ve) calcd
for C20H26NO8 (MH+) 408.1658, found 408.1657.
(-)-(1R,5R,6R,7S,7aR)-1-[2-(4-Meth oxyph en yl)m eth oxy]-
eth yl-5-(p h en ylm eth oxy)m eth yl-5,6,7,7a -tetr a h yd r o-6,7-
d ih yd r oxy-1H,3H-p yr r olo[1,2-c]oxa zol-3-on e (15). To a
solution of 14 (327 mg, 0.800 mmol) in acetone (6 mL) were
added water (4 mL), 4-morpholine N-oxide (206 mg, 1.759
mmol), and potassium osmate dihydrate (14.7 mg, 0.040
mmol). The mixture was stirred at room temperature for 24
h, and then all volatiles were removed in vacuo. The residue
was dissolved in toluene and evaporated to dryness in vacuo
to give a dark semisolid, which was chromatographed on silica
gel eluating with 2.5-7.5% methanol/DCM affording com-
Th r ee-Step Syn th esis of (-)-(1S,2R,3R,7R,7a R)-1,2,7-
Tr ia cetoxy-3-(ph en ylm eth oxy)m eth ylh exa h yd r o-1H-p yr -
r olizin e (20) fr om 17. To a solution of 17 (101 mg, 0.248
mmol) in ethanol (4 mL) was added sodium hydroxide (99.3
mg, 2.482 mmol). The reaction was heated at 70 °C in a sealed
tube for 24 h. The volatiles were then removed in vacuo to
give a yellow-green solid, and the residue was treated with 2
M hydrochloric acid (3 mL). All volatiles were removed in vacuo
to give a yellow solid that was purified by acidic ion-exchange
chromatography to give the desired compound 18 (ca. 100 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 18: 1H NMR
(CD3OD) δ 7.43-7.26 (m, 5H), 5.07 (bs, 1H, OH), 4.67 (d, 1H,
J 11.7 Hz), 4.62 (d, 1H, J 11.7 Hz), 4.38 (t, 1H, J 3.3 Hz), 4.25
(dd, 1H, J 3.3, 8.7 Hz), 4.22-4.17 (m, 1H), 3.88 (dd, 1H, J 3.3,
10.8 Hz), 3.84-3.71 (m, 4H), 3.55 (dd, 1H, J 2.7, 7.5 Hz), 1.96-
1.75 (m, 2H); 13C NMR (CD3OD) δ 138.8 (C, Ar), 129.4 (CH,
Ar), 129.0 (CH, Ar), 128.9 (CH, Ar), 74.3 (CH), 73.1 (CH), 71.9
(CH), 67.9 (CH2), 66.0 (CH), 65.5 (CH), 62.6 (CH), 59.1 (CH2),
pound 15 as a brown oil (191 mg, 82%): [R]24 -43.9 (c 2.2,
D
CHCl3); 1H NMR δ 7.35-7.28 (m, 5H), 7.22 (d, 2H, J 8.4 Hz),
6.86 (d, 2H, J 8.7 Hz), 4.80 (dt, 1H, J 5.4, 7.8 Hz), 4.59 (d, 1H,
J 12.0 Hz), 4.54 (d, 1H, J 12.0 Hz), 4.44 (d, 1H, J 12.3 Hz),
4.40 (d, 1H, J 12.0 Hz), 4.31 (dd, 1H, J 3.3, 6.3 Hz), 4.00 (t,
1H, J 2.7 Hz), 3.80-3.53 (m, 6H), 3.79 (s, 3H), 2.48-2.38 (m,
1H), 2.26-2.15 (m, 1H); 13C NMR (one Ar C could not be
observed) δ 162.6 (CO), 137.8 (C, Ar), 130.1 (C, Ar), 129.3 (CH,
Ar), 128.5 (CH, Ar), 127.8 (CH, Ar), 127.6 (CH, Ar), 113.8 (CH,
Ar), 76.4 (CH), 74.1 (CH), 73.5 (CH2), 72.9 (CH2), 72.3 (CH),
70.4 (CH2), 66.4 (CH2), 65.0 (CH), 62.3 (CH), 55.2 (CH3), 30.8
(CH2); MS (CI +ve) m/z 444 (M + 1+); HRMS (EI +ve) calcd
for C24H29NO7 (M+) 443.1944, found 443.1926.
(-)-(1R,5R,6R,7S,7a R)-6,7-Dia cetoxy-1-[2-(4-m eth oxy-
p h en yl)m eth oxy]eth yl-5-(p h en ylm eth oxy)m eth yl-5,6,7,-
7a-tetr ah ydr o-1H,3H-pyr r olo[1,2-c]oxazol-3-on e (16). Com-
pound 15 (170 mg, 0.384 mmol) was dissolved in pyridine (2.0
mL), and then Ac2O (2.0 mL) was added. The mixture was
stirred at room temperature for 20 h, then diluted with DCM
(40 mL), and washed with saturated NaHCO3 solution at 0
°C. The aqueous portion was extracted with DCM (3×). The
combined organic portions were dried (MgSO4), filtered, and
evaporated in vacuo to give an oil, which was purified by
column chromatography (30-70% EtOAc/petrol) to give prod-
37.5 (CH2); [R]26 +18.1 (c 1.8, MeOH); MS (CI +ve) m/z 298
D
(M + 1+, 100%); HRMS (ES +ve) calcd for C15H24NO5 (MH+)
298.1654, found 298.1645. To a stirred mixture of 18 obtained
above, triphenylphosphine (111 mg, 0.424 mmol) and anhy-
drous pyridine (4 mL) at 0 °C was added dropwise diisopropyl
azodicarboxylate (83.5 µL, 0.424 mmol) under nitrogen. The
mixture was stirred at 0 °C for 2.5 h. The volatiles were
removed in vacuo, and then 1 M hydrochloric acid (15 mL)
was added. The solution was concentrated in vacuo to give a
yellow solid, which was purified by acidic ion-exchange chro-
matography to give compound 19. This material was dissolved
in pyridine (2.0 mL), and then Ac2O (2.0 mL) was added. The
mixture was stirred at room temperature for 24 h, diluted with
DCM (25 mL), and washed with saturated NaHCO3 solution.
The aqueous portion was extracted with DCM (3×), and the
combined organic extracts were dried (MgSO4), filtered, and
evaporated in vacuo to give a solid. Purification by column
chromatography (30-70% EtOAc/petrol) gave product 20 (19.4
uct 16 as a colorless oil (154 mg, 76%): [R]26 -4.3 (c 2.0,
D
CHCl3); 1H NMR (500 MHz) δ 7.35-7.26 (m, 5H), 7.22 (d, 2H,
J 8.5 Hz), 6.87 (d, 2H, J 8.5 Hz), 5.53 (dd, 1H, J 3.0, 7.5 Hz),
5.46-5.45 (m, 1H), 4.82 (ddd, 1H, J 7.0, 7.0, 14.0 Hz), 4.60 (d,
1H, J 12.0 Hz), 4.54 (d, 1H, J 12.0 Hz), 4.42 (s, 2H), 3.96 (dt,
1H, J 7.0, 3.5 Hz), 3.92 (dd, 1H, J 2.0, 7.5 Hz), 3.71 (dd, 1H,
J 3.5, 10.5 Hz), 3.61 (dd, 1H, J 3.0, 10.5 Hz), 3.58-3.51 (m,
2H), 2.10 (s, 3H), 2.07-2.01 (m, 1H), 1.99-1.89 (m, 1H), 1.97
(s, 3H); 13C NMR δ 169.6 (CO), 169.4 (CO), 161.2 (CO), 159.2
(C, Ar), 137.6 (C, Ar), 129.7 (C, Ar), 129.2 (CH, Ar), 128.3 (CH,
Ar), 127.6 (CH, Ar), 127.4 (CH, Ar), 113.7 (CH, Ar), 73.8 (CH),
73.4 (CH), 73.3 (CH2), 72.8 (CH2), 72.6 (CH), 69.0 (CH2), 65.6
mg, 20% overall for 3 steps) as a colorless oil: [R]27 -5.1 (c
D
1
1.0, CHCl3); H NMR δ 7.36-7.27 (m, 5H), 5.48 (t, 1H, J 4.5
Hz), 5.20-5.15 (m, 2H), 4.58 (d, 1H, J 12.0 Hz), 4.51 (d, 1H, J
12.0 Hz), 3.66 (dd, 1H, J 3.6, 4.5 Hz), 3.55 (dd, 1H, J 4.2, 9.6
7822 J . Org. Chem., Vol. 68, No. 20, 2003

(-)-7-Epiaustraline and (+)-1,7-Diepiaustraline
Hz), 3.47 (dd, 1H, J 5.7, 9.9 Hz), 3.29 (ddd, 1H, J 6.6, 6.9, 10.8
Hz), 3.04 (ddd, 1H, J 4.2, 5.7, 9.6 Hz), 2.89 (ddd, 1H, J 6.3,
6.6, 10.8 Hz), 2.26-1.88 (m, 2H), 2.10 (s, 3H), 2.02 (s, 3H),
1.95 (s, 3H); 13C NMR δ 170.6 (CO), 169.7 (CO), 169.5 (CO),
138.1 (C, Ar), 128.3 (CH, Ar), 127.6 (CH, Ar), 127.5 (CH, Ar),
74.0 (CH), 73.9 (CH), 73.4 (CH2), 71.5 (CH), 71.4 (CH2), 69.5
(CH), 65.8 (CH), 53.2 (CH2), 32.3 (CH2), 21.0 (CH3), 20.8 (CH3),
20.5 (CH3); MS (CI +ve) m/z 406 (M + 1+, 100%); HRMS (ES
+ve) calcd for C21H28NO9 (MH+) 406.1866, found 406.1860.
Hz), 3.69-3.55 (m, 3H), 2.42-2.24 (m, 2H); 13C NMR (CO could
not be observed) δ 159.3 (C, Ar), 137.1 (C, Ar), 129.8 (C, Ar),
129.4 (CH, Ar), 128.7 (CH, Ar), 128.2 (CH, Ar), 127.7 (CH, Ar),
113.9 (CH, Ar), 88.4 (CH), 85.2 (CH), 74.6 (CH), 73.7 (CH2),
73.1 (CH2), 71.1 (CH2), 66.2 (CH2), 65.5 (CH), 63.7 (CH), 55.3
(CH3), 29.5 (CH2); MS (CI +ve) m/z 370 (M - PMB + 2+);
HRMS (ES +ve) calcd for C24H28NO8 (MH+) 490.1536, found
490.1531. The crude cyclic sulfite obtained above was dissolved
in 1.75 mL of a solution of CCl4/CH3CN/H2O (2:2:3, v/v/v), and
RuCl3‚3H2O (1.1 mg, 0.0042 mmol) was added followed by
NaIO4 (31.4 mg, 0.1467 mmol). The mixture was stirred at
room temperature for 1.5 h and then diluted with ethyl ether
(5 mL). The organic layer was filtered through a pad of Celite.
The filtrate was washed with water and saturated sodium
bicarbonate solution followed by brine and then dried (MgSO4).
The solvent was evaporated, and then chromatography of the
residue, eluting with EtOAc/petrol (40-70%), gave compound
(+)-(1S,2R,3R,7R,7a R)-1,2,7-Tr ia cetoxy-3-(a cetoxym e-
th yl)h exa h yd r o-1H-p yr r olizin e (22). To a solution of 20
(19.4 mg, 0.048 mmol) in methanol (1 mL) was added pal-
ladium chloride (7.3 mg, 0.041 mmol). The mixture was stirred
under an atmosphere of hydrogen at room temperature for 1
h. The mixture was then filtered through a plug of cotton wool,
and the solvent was removed under reduced pressure to give
the title product 21 as a pale yellow oil. This oil was then
dissolved in pyridine (0.5 mL), and Ac2O (0.5 mL) was added
to the solution. The mixture was stirred at room temperature
for 18 h, diluted with DCM (25 mL), and washed with
saturated NaHCO3 solution. The aqueous portion was ex-
tracted 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 (30-70%
23 (31.1 mg, 80%) as a pale yellow oil: [R]26 -14.6 (c 1.5,
D
CHCl3); 1H NMR δ 7.40-7.33 (m, 3H), 7.24 (dd, 2H, J 1.5, 8.1
Hz), 7.17 (d, 2H, J 8.4 Hz), 6.84 (d, 2H, J 8.7 Hz), 5.36 (dd,
1H, J 1.8, 5.4 Hz), 5.21 (dd, 1H, J 3.0, 5.1 Hz), 4.88 (dt, 1H, J
6.6, 7.8 Hz), 4.56 (d, 1H, J 11.7 Hz), 4.46 (d, 1H, J 11.7 Hz),
4.45-4.40 (m, 3H), 4.19 (dd, 1H, J 3.0, 7.2 Hz), 3.78 (s, 3H),
3.74 (dd, 1H, J 3.0, 9.9 Hz), 3.67 (dd, 1H, J 3.0, 9.9 Hz), 3.70-
3.64 (m, 1H), 3.57 (dt, 1H, J 3.3, 10.2 Hz), 2.40-2.17 (m, 2H);
13C NMR (CO could not be observed) δ 159.4 (C, Ar), 136.8 (C,
Ar), 129.6 (C, Ar), 129.5 (CH, Ar), 128.7 (CH, Ar), 128.3 (CH,
Ar), 127.7 (CH, Ar), 113.9 (CH, Ar), 87.3 (CH), 85.4 (CH), 74.8
(CH), 73.8 (CH2), 73.2 (CH2), 70.8 (CH2), 66.1 (CH2), 65.8 (CH),
62.7 (CH), 55.2 (CH3), 29.3 (CH2); MS (CI +ve) m/z 386 (M -
PMB + 2+); HRMS (ES +ve) calcd for C24H28NO9S (MH+)
506.1485, found 506.1505; calcd for C24H27NO9NaS (M + Na+)
528.1304, found 528.1318.
EtOAc/petrol) to give compound 22 as a pale yellow oil (14.4
1
mg, 84% overall for 2 steps): [R]25 +10.5 (c 1.4, CHCl3); H
D
NMR δ 5.48 (dd, 1H, J 3.9, 4.2 Hz), 5.18 (ddd, 1H, J 3.9, 5.4,
9.6 Hz), 5.12 (dd, 1H, J 3.9, 9.3 Hz), 4.18 (dd, 1H, J 4.2, 11.4
Hz), 4.03 (dd, 1H, J 5.7, 11.4 Hz), 3.64 (dd, 1H, J 3.9, 4.2 Hz),
3.26 (ddd, 1H, J 6.6, 6.6, 10.5 Hz), 3.08 (ddd, 1H, J 4.2, 5.4,
9.3 Hz), 2.83 (ddd, 1H, J 6.6, 6.9, 10.5 Hz), 2.28-1.92 (m, 2H),
2.12 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H); 13C NMR
δ 170.7 (CO), 170.6 (CO), 169.6 (CO), 169.4 (CO), 73.9 (CH),
73.7 (CH), 71.3 (CH), 69.5 (CH), 64.9 (CH2), 64.6 (CH), 53.0
(CH2), 32.4 (CH2), 20.9 (CH3), 20.80 (CH3), 20.7 (CH3), 20.4
(CH3); MS (CI +ve) m/z 358 (M + 1+, 100%); HRMS (ES +ve)
calcd for C16H24NO8 (MH+) 358.1502, found 358.1507.
(+)-(1R,5R,6R,7R,7aR)-6-Hydr oxyl-1-[2-(4-m eth oxyph en -
y l)m e t h o x y ]e t h y l-7-p h e n y lc a r b o n y lo x y -5-p h e n y l-
m eth oxym eth yltetr a h yd r o-1H-p yr r olo[1,2-c][1,3]oxa zol-
3-on e (24). To a solution of 23 (158 mg, 0.312 mmol) in DMF
(5 mL) was added benzoic acid (64.7 mg, 0.530 mmol) followed
by cesium carbonate (152 mg, 0.468 mmol). The mixture was
stirred under nitrogen at 40 °C for 4 h. DMF was removed
under reduced pressure, and the residue was suspended in
THF (6 mL). Water (6 drops) followed by concentrated sulfuric
acid (3 drops) was added, and the suspension became a clear
solution. The solution was stirred at room temperature for 22
h. The volatiles were removed in vacuo to give a semisolid,
which was purified by column chromatography (20-60%
(+)-(1S,2R,3R,7R,7a R)-H exa h yd r o-3-h yd r oxym et h yl-
1H-p yr r olizin e-1,2,7-tr iol [(+)-1,7-Diep ia u str a lin e] (8). To
a solution of 22 (14.4 mg, 0.040 mmol) in dry methanol (1 mL)
was added the solution of sodium methoxide (0.087M, 46 µL,
0.004 mmol). The mixture was stirred under nitrogen at room
temperature for 20 h, and all volatiles were removed in vacuo
to give compound 8 as a colorless oil (7.0 mg, 92%): [R]24D +6.4
(c 0.7, MeOH), [R]24 +8.6 (c 0.7, H2O) [lit9c [R]20 +4.7 (c 0.5,
D
D
1
H2O)]; H NMR (500 MHz, CD3OD) δ 4.55 (dt, 1H, J 3.5, 5.5
Hz), 4.02 (t, 1H, J 4.0 Hz), 3.80 (dd, 1H, J 4.0, 9.5 Hz), 3.76
(dd, 1H, J 3.5, 11.0 Hz), 3.56 (dd, 1H, J 6.5, 11.5 Hz), 3.26 (t,
1H, J 4.0 Hz), 3.18 (ddd, 1H, J 6.5, 6.5, 11.0 Hz), 2.79-2.71-
(m, 2H), 2.12-2.06 (m, 1H), 1.79-1.73(m, 1H); 13C NMR (CD3-
OD) δ 76.1 (CH), 74.7 (CH), 71.9 (CH), 71.8 (CH), 70.7 (CH),
64.2 (CH2), 54.2 (CH2), 36.1 (CH2); MS (CI +ve) m/z 190 (M +
1+, 100%); HRMS (ES +ve) calcd for C8H16NO4 (MH+) 190.1079,
found 190.1099.
EtOAc/petrol) to give 24 (95.3 mg, 56%) as a colorless oil: [R]25
D
1
+40.0 (c 1.8, CHCl3); H NMR δ 7.95 (dd, 2H, J 1.2, 8.4 Hz),
7.63-7.56 (m, 1H), 7.48-7.41 (m, 2H), 7.35-7.25 (m, 5H), 7.21
(d, 2H, J 8.7 Hz), 6.84 (d, 2H, J 8.7 Hz), 5.16 (dd, 1H, J 4.8,
7.8 Hz), 4.98 (ddd, 1H, J 3.9, 7.8, 11.7 Hz), 4.63-4.52 (m, 1H),
4.61 (d, 1H, J 12.0 Hz), 4.54 (d, 1H, J 12.6 Hz), 4.42 (d, 1H, J
11.4 Hz), 4.37 (d, 1H, J 11.4 Hz), 4.26 (t, 1H, J 7.8 Hz), 4.14
(apparent q, 1H, J 4.2 Hz), 3.79-3.74 (m, 1H), 3.77 (s, 3H),
3.71 (dd, 1H, J 2.4, 4.2 Hz), 3.62-3.58 (m, 2H), 2.10-1.88 (m,
2H); 13C NMR (one Ar C could not be observed) δ 166.8 (CO),
160.5 (CO), 159.2 (C, Ar), 137.7 (C, Ar), 133.8 (CH, Ar), 129.9
(C, Ar), 129.7 (CH, Ar), 129.4 (CH, Ar), 128.6 (CH, Ar), 128.3
(CH, Ar), 127.7 (CH, Ar), 127.5 (CH, Ar), 113.8 (CH, Ar), 79.8
(CH), 79.3 (CH), 73.3 (CH2), 72.9 (CH2), 70.0 (CH2), 65.6 (CH2),
64.6 (CH), 64.5 (CH), 55.2 (CH3), 30.8 (CH2); MS (ES +ve) m/z
570 (M + Na+, 100%); HRMS (ES +ve) calcd for C31H34NO8
(MH+) 548.2284, found 548.2350; calcd for C31H33NO8Na (M
+ Na+) 570.2104, found 570.2164.
(-)-(3a S ,3b R ,4R ,8R ,8a R )-4-[2-(4-Me t h o x y p h e n y l)-
m eth oxy]eth yl-8-ph en ylm eth oxylm eth yltetr ah ydr o-3aH-
[1,3,2]d ioxa t h iolo[4′,5′:3,4]p yr r olo[1,2-c][1,3]oxa zol-6-
on e 2,2-d ioxid e (23). To a solution of 22 (34.2 mg, 0.077
mmol) in DCM (1 mL) was added Et3N (24.8 µL, 0.178 mmol)
followed by thionyl chloride (7.1 µL, 0.097 mmol) at 0 °C. The
mixture was stirred for 20 min at 0 °C, and water (2 mL) was
added to the mixture. The aqueous layer was extracted with
DCM (3×). 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
(+)-(1R,5R,6R,7R,7a R)-6-Hyd r oxyl-1-(2-h yd r oxy)eth yl-
7-p h en ylca r bon yloxy-5-(ph en ylm eth oxy)m eth yl-tetr a h y-
d r o-1H-p yr r olo[1,2-c][1,3]oxa zol-3-on e (25). The same pro-
cedure described above for the preparation of 17 was used
starting with 24 (30.6 mg, 0.056 mmol) and DDQ (15.2 mg,
0.067 mmol) in a solution of DCM (5 mL) containing water
without further purification. A purified sample had: [R]25
D
1
-21.3 (c 0.3, CHCl3); H NMR δ 7.40-7.32 (m, 3H), 7.26 (dd,
2H, J 2.1, 8.1 Hz), 7.20 (d, 2H, J 8.7 Hz), 6.85 (d, 2H, J 9.0
Hz), 5.50 (dd, 1H, J 2.1, 5.1 Hz), 5.38 (dd, 1H, J 3.3, 5.1 Hz),
4.90 (dd, 1H, J 7.2, 14.1 Hz), 4.58 (d, 1H, J 12.0 Hz), 4.48 (d,
1H, J 12.0 Hz), 4.43 (s, 2H), 4.28 (dd, 1H, J 3.0, 6.9 Hz), 4.19
(bdd, 1H, J 3.0, 5.1 Hz), 3.79 (s, 3H), 3.73 (dd, 1H, J 2.7, 9.6
(0.5 mL). Compound 25 (17.9 mg, 75%) was obtained as a pale
1
yellow oil: [R]28 +56.9 (c 1.5, CHCl3); H NMR δ 7.98 (ddd,
D
J . Org. Chem, Vol. 68, No. 20, 2003 7823

Tang and Pyne
2H, J 0.6, 1.2, 7.8 Hz), 7.62 (tt, 1H, J 1.5, 7.5 Hz), 7.46 (t, 2H,
J 7.8 Hz), 7.32-7.29 (m, 5H), 5.14 (dd, 1H, J 4.8, 7.8 Hz), 4.97
(bdd, 1H, J 7.5, 13.8 Hz), 4.62 (d, 1H, J 11.7 Hz), 4.56 (d, 1H,
J 12.0 Hz), 4.64-4.54 (m, 1H), 4.29 (t, 1H, J 8.1 Hz), 4.13 (bdd,
1H, J 4.2, 8.1 Hz), 3.87-3.78 (m, 2H), 3.74 (dd, 1H, J 4.2, 9.9
Hz), 3.69 (dd, 1H, J 4.5, 9.9 Hz), 2.04-1.96 (m, 2H); 13C NMR
δ 167.1 (CO), 160.4 (CO), 137.7 (C, Ar), 134.0 (CH, Ar), 129.8
(CH, Ar), 128.7 (CH, Ar), 128.6 (C, Ar), 128.4 (CH, Ar), 127.8
(CH, Ar), 127.6 (CH, Ar), 80.1 (CH), 79.4 (CH), 73.4 (CH2),
73.3 (CH), 70.1 (CH2), 64.8 (CH), 64.7 (CH), 59.0 (CH2), 33.0
(CH2); MS (CI +ve) m/z 428 (M + 1+, 100%); HRMS (EI +ve)
calcd for C23H25NO7 (M - 1+) 426.1553, found 426.1514.
(+)-(2R,3R,4R,5R)-5-[(1R)-1,3-Dih ydr oxypr opyl]-2-(ph en -
ylm eth oxy)m eth yl p yr r olizin e-3,4-d iol (26). The same
procedure described above for the preparation of 18 was used
starting with 25 (48.6 mg, 0.114 mmol) and sodium hydroxide
(45.5 mg, 1.138 mmol) in a solution of ethanol (1 mL).
(5.2 mg, 0.013 mmol) in MeOH (0.5 mL) was treated with
palladium chloride (2.0 mg, 0.011 mmol) as described above
for the preparation of 20. The product 29 was acetylated using
pyridine (0.5 mL) and Ac2O (0.5 mL) as described above for
the synthesis of 21. Compound 30 (4.3 mg, 94% overall for 2
steps) was obtained as a pale yellow oil: 1H NMR δ 5.22 (t,
1H, J 5.4 Hz), 5.22-5.19 (m, 1H), 5.16 (t, 1H, J 5.4 Hz), 4.11
(bd, 1H, J 1.2 Hz), 4.09 (bd, 1H, J 1.2 Hz), 3.39 (dd, 1H, J 3.0,
5.7 Hz), 3.20 (ddd, 1H, J 6.3, 9.0, 11.4 Hz), 3.03 (dd, 1H, J 5.4,
11.7 Hz), 2.91 (ddd, 1H, J 4.2, 7.5, 11.4 Hz), 2.17-2.09 (m,
1H), 2.09 (s, 6H), 2.06 (s, 3H), 2.04 (s, 3H), 1.91-1.84 (m, 1H);
13C NMR δ 170.8 (CO), 170.6 (CO), 170.3 (CO), 169.8 (CO),
77.8 (CH), 77.5 (CH), 77.1 (CH), 73.1 (CH), 66.7 (CH), 64.9
(CH2), 52.7 (CH2), 30.3 (CH2), 21.0 (CH3), 20.9 (CH3), 20.8
(CH3); MS (CI +ve) m/z 358 (M + 1+, 100%); HRMS (EI +ve)
calcd for C16H24NO8 (MH+) 358.1502, found 358.1505.
(-)-(1R,2R,3R,7R,7a R)-H exa h yd r o-3-h yd r oxym et h yl-
1H-p yr r olizin e-1,2,7-tr iol [(-)-7-Ep ia u str a lin e] (9). To a
solution of 30 (4.3 mg, 0.012 mmol) in methanol (0.5 mL) was
added potassium carbonate (2.0 mg). The mixture was stirred
at room temperature for 24 h and then concentrated under
reduced pressure. The residue was dissolved in CHCl3/MeOH
(5:1, 6 mL) and filtered though a small pad of Celite to give
Compound 26 (20.5 mg, 61%) was obtained as a pale yellow
1
oil: [R]29 +14.0 (c 2.1, MeOH); H NMR (D2O) δ 7.57-7.44
D
(m, 5H), 4.66 (bs, 2H), 4.13 (t, 1H, J 6.9 Hz), 3.98-3.93 (m,
2H), 3.81-3.66 (m, 4H), 3.34 (bs, 1H), 3.12 (bs, 1H), 1.87-
1.75 (m, 2H); 13C NMR (CD3OD) δ 139.1 (C, Ar), 129.5 (CH,
Ar), 129.0 (CH, Ar), 128.9 (CH, Ar), 78.5 (CH), 76.9 (CH), 74.4
(CH2), 69.3 (CH2), 69.0 (CH), 66.5 (CH), 63.1 (CH), 59.5 (CH2),
37.1 (CH2); MS (CI +ve) m/z 298 (M + 1+, 100%); HRMS (ES
+ve) calcd for C15H24NO5 (MH+) 298.1654, found 298.1661.
(+)-(1R ,2R ,3R ,7R ,7a R )-1,2,7-Tr ia ce t oxy-3-(p h e n yl-
m eth oxy)m eth ylh exah ydr o-1H-pyr r olizin e (28). The same
procedure described above for the preparation of 19 was
followed using DIAD (16.3 µL, 0.083 mmol), Ph3P (21.7 mg,
0.083 mmol), and 26 (20.5 mg, 0.069 mmol) in dry THF (1 mL).
Compound 27 was obtained as a pale yellow oil. Acetylation
of 27, using the same procedure described above for the
preparation of 20, gave the title compound 28 (6.3 mg, 22%
the title product 9 (2.2 mg, 97%) as a pale yellow oil: [R]24
D
-14.1 (c 0.22, H2O) [lit.6 [R]23D -13.04 (c 0.55, H2O, pH 8.37)];
1H NMR (500 MHz, D2O) δ 4.18 (dt, 1H, J 5.0, 2.5 Hz), 3.62
(dd, 1H, J 4.0, 11.5 Hz), 3.55 (t, 1H, J 8.0 Hz), 3.52 (t, 1H, J
8.0 Hz), 3.47 (dd, 1H, J 6.5, 11.5 Hz), 2.92 (ddd, 1H, J 6.0,
10.0, 11.5 Hz), 2.82 (dd, 1H, J 2.0, 7.5 Hz), 2.70 (ddd, 1H, J
4.0, 7.5, 11.5 Hz), 2.49 (ddd, 1H, J 4.0, 6.5, 10.0 Hz), 1.91 (dddd,
1H, J 5.5, 7.5, 10.5, 13.0 Hz), 1.63-1.58 (m, 1 H); 13C NMR
(D2O) δ 77.5 (CH), 76.0 (CH), 74.4 (CH), 73.3 (CH), 67.7 (CH),
62.2 (CH2), 50.9 (CH2), 30.7 (CH2); MS (CI +ve) m/z 190 (M +
1+); HRMS (ES +ve) calcd for C8H16NO4 (MH+) 190.1079,
found 190.1073.
overall for 2 steps) as a pale yellow oil: [R]29 +18.5 (c 0.6,
D
CHCl3); 1H NMR δ 7.36-7.27 (m, 5H), 5.29 (dd, 1H, J 6.3, 6.9
Hz), 5.21 (dt, 1H, J 6.0, 3.0 Hz), 5.11 (dd, 1H, J 6.0, 6.3 Hz),
3.56-3.47 (m, 2H), 3.38 (dd, 1H, J 3.0, 6.0 Hz), 3.19 (ddd, 1H,
J 6.0, 9.3, 11.7 Hz), 3.01-2.94 (m, 2H), 2.19-2.04 (m, 1H),
Ack n ow led gm en t. We thank the Australian Re-
search Council and the University of Wollongong for
supporting this research.
2.05 (s, 3H), 2.02 (s, 3H), 1.99 (s, 3H), 1.89-1.80 (m, 2H); 13
C
NMR (one Ar C could not be observed) δ 170.2 (CO), 170.1
(CO), 169.6 (CO), 127.9 (CH, Ar), 127.2 (CH, Ar), 127.2 (CH,
Ar), 77.3 (CH), 76.8 (CH), 76.1 (CH), 73.0 (CH2), 72.5 (CH),
71.4 (CH2), 66.7 (CH), 52.2 (CH2), 29.7 (CH2), 20.6 (CH3), 20.5
(CH3), 20.4 (CH3); MS (CI +ve) m/z 406 (M + 1+, 100%); HRMS
(ES +ve) calcd for C21H28NO7 (MH+) 406.1866, found 406.1858.
(1R,2R,3R,7R,7a R)-1,2,7-Tr ia cetoxy-3-a cetoxym eth yl-
h exa h yd r o-1H-p yr r olizin e (30). A solution of compound 28
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details and characterization data for the synthesis of 10 from
3-butyn-1-ol; copies of the 1H and 13C NMR spectra of com-
pounds 8-23 and 25-29; 1H NMR spectrum of 30 and 13C
NMR spectrum of 24. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O034914Q
7824 J . Org. Chem., Vol. 68, No. 20, 2003