Synthesis of 8-epi-castanospermine and 6,7,8-tri-epi-castanospermine

Article abstract of DOI:10.1139/v00-043

8-epi-Castanospermine (11) and 6,7,8-tri-epi-castanospermine (12) were synthesized from the hydroxyproline precursor 13 which was obtained enantioselectively via an enzymatic process.

Full text of DOI:10.1139/v00-043

776
Synthesis of 8-epi-castanospermine and 6,7,8-tri-
epi-castanospermine
Yves St-Denis and Tak Hang Chan
Abstract: 8-epi-Castanospermine (11) and 6,7,8-tri-epi-castanospermine (12) were synthesized from the hydroxyproline
precursor 13 which was obtained enantioselectively via an enzymatic process.
Key words: castanospermine, synthesis of, enzymatic reduction, enzymatic resolution, asymmetric synthesis.
Résumé : On a synthétisé les 8-épi-castanospermine (11) et 6,7,8-tri-épi-castanospermine (12) à partir du précurseur
hydroxyproline (13) obtenu de façon énantiosélective par le biais d’un processus enzymatique.
Mots clés : castanospermine, synthèse, réduction enzymatique, résolution enzymatique, synthèse asymétrique. St-
Denis and Chan 783
Introduction
Structure 1.
Castanospermine (1) is a polyhydroxylated indolizidine
alkaloid which has elicited much biological and chemical in-
terest (1). It was isolated from the Australian legume
Castanospermum australe (Moreton Bay chestnut) and has
been shown to be a potent inhibitor of various glycosidases
(2). It also inhibits the processing of N-linked glycoproteins
(3). Castanospermine and its analogs have been examined as
potential therapeutic agents (4) in the treatment of cancer (5)
and HIV-I (6). Epimers of castanospermine, including 6-epi-
castanospermine (2) (7) and 6,7-di-epi-castanospermine (3)
(8), have been isolated as well. Comparison of their inhibi-
tory activities toward different glycosidases showed that the
change of stereochemistry at a single hydroxy group could
alter the inhibitory properties.
Structure 2.
Many syntheses of 1 and its modifications have been re-
ported (9). A commonly used synthetic approach is to start
with the appropriate carbohydrate precursor. Depending on
the carbohydrate precursor used, epimers of castanospermine
have also been synthesized. Thus, the syntheses of 6-epi-
(2), 1,6-di-epi- (4), 1-epi- (5), 1,6,8-tri-epi- (6), 1,7,8-tri-epi-
(7), and 1,6,7,8-tetra-epi-castanospermine (8) have all been
reported (10). We recently reported on the use of the amino
acid derivative (S)-prolinol (9) as the precursor for the syn-
thesis of various isomers of 1-deoxycastanospermine (10)
(11, 12, footnote 2). We have now extended the approach by
starting with an amino acid precursor with the incorporation
of the 1-hydroxy function. The results gave rise to a synthe-
sis of 8-epi- (11) and 6,7,8-tri-epi-castanospermine (12) (13).
Structure 3.
Structure 4.
Received August 30, 1999. Published on the NRC Research Press website on June 9, 2000.
Dedicated to Professor Stephen Hanessian on the occasion of his 65th birthday in recognition of his significant contributions to the
art of organic synthesis.
Y. St-Denis and T.H. Chan.1 Department of Chemistry, McGill University, Montreal, QC H3A 2K6, Canada.
1Author to whom correspondence may be addressed. e-mail: thchan@chemistry.mcgill.ca
2Recent work by Martin et al. (12) has led to reassignment of the stereochemistry of the compounds reported by us in reference 11.
The revised stereochemistries should be: compound 22aa: 6R, 7S, 8R, 8aS; 22ab: 6S, 7R, 8R, 8aS; 22ba: 6S, 7R, 8S, 8aS; 22bb:
Can. J. Chem. 78: 776–783 (2000)
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St-Denis and Chan
777
Structure 5.
Structure 9.
Structure 6.
Structure 7.
Structure 8.
Structure 10.
Structure 11.
Structure 12.
of 18 gave the (2R,3S)-β-hydroxyester 19 in good enantio-
selectivity (>99% ee). For comparison purpose, sodium
borohydride reduction of 18 in ethanol gave the racemic 19
as the sole diastereomer, spectroscopically identical to the
enantiomerically pure compound. Many of the subsequent
reactions could therefore be explored with the racemic com-
pound first. Protection of the secondary alcohol of (+)-19
with the MOM protecting group gave compound 20. Reduc-
tion of 20 with lithium borohydride in ether gave a good
yield of the primary alcohol 21, which was oxidized by the
Swern oxidation to the aldehyde 13 in quantitative yield.
Results and discussion
Preparation of (2R,3S)-N-benzyloxycarbonyl-3-
methoxymethyloxypyrrolidine-2-carboxaldehyde (13)
Since the stereochemistry of the 8a position of castano-
spermine itself corresponds to the unnatural R-configuration
of proline, the requisite 3-hydroxylated proline precursor 13
cannot be prepared from the natural amino acids. In the liter-
ature, Sih and coworkers have used microbial enzymatic re-
duction or hydrolysis to prepare (2R,3S)-3-hydroxyproline
derivatives (3b). Alternatively, Sibi and Christensen im-
proved an already known baker’s yeast reduction method to
give the (2R,3S)-Boc-protected proline ester in good chemi-
cal and optical yields (14). Since the baker’s yeast reduction
is easy to perform, we adopted this method with modifica-
tion (15) to prepare the Cbz protected compound 13 accord-
ing to Scheme 1. Thus, condensation of ethyl 3-
bromopropionate (14) with freshly prepared ethyl glycinate
was accomplished in refluxing benzene to give a good yield
of the N,N-disubstituted aminodiester 15. Protection of the
free amine with the Cbz group was performed to provide the
carbamate 16 in good yield (16). Dieckmann cyclization of
16 using potassium t-butoxide in toluene afforded a 1.3:1
mixture of regioisomers 17 and 18 which could be separated
by distillation and chromatography. Even though the re-
quired 18 was the minor isomer, the sequence for its prepa-
ration was nevertheless quite short and utilized cheap and
readily available starting materials. Baker’s yeast reduction
Synthesis of 8-epi- (11) and 6,7,8-tri-epi-castanospermine
(12) (Scheme 2)
Coupling of 13 with the titanium reagent derived from the
anion of allyl phenyl sulfide gave only one stereoisomer, 22
(17). It is interesting to compare the stereoselectivity in the
present coupling with our previously reported coupling of N-
Cbz-pyrrolidine-2-carboxaldehyde where the 3-MOM
substituent was missing (11). The stereoselectivity is much
higher in the present case, presumably due to the influence
of the MOM group. Since it was established by Yamamoto
and co-workers that the coupling reaction gave excellent
erythro selectivity (17), the two newly created stereogenic
centers could have either the 1′S, 2′S or the 1′R, 2′R configu-
rations. Definitive assignment could not be made at this
point. Furthermore, the stereochemistry at the carbon 2 posi-
tion is of no real interest to us since it will be destroyed in
the subsequent reactions. In any case, oxidation of the
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Scheme 1.
Scheme 2.
pyrrolidinecarboxaldehyde 13, the stereochemistries of car-
bons 1 and 8a (corresponding to carbons 2 and 3 of 13) are
secured as 1S and 8aR in the final products 11 and 12. Since
the dihydroxylation of double bond with osmium tetroxide
has been well established to give the cis diol (20), the rela-
tive stereochemistry of carbons 6 and 7 in compounds 11
and 12 must be trans. There were two reactions in Scheme 2
which could give rise to uncertain stereochemical outcomes.
The first was the conversion of 13 to 22, which created the
stereogenic carbon 8 in the final products. The stereochem-
istry could be either 8S or 8R. The second was that, in the
hydroxylation step, the relative stereochemistry of the cis
diol with respect to the existing stereogenic carbon 8 could
be syn or anti (21). Consequently, there could be four stereo-
chemical outcomes from Scheme 2. If, in the conversion of
13 to 22 the stereochemistry was 8R, then the final two
products must have either 1S, 6S, 7R, 8R, 8aR (castano-
spermine 1) or 1S, 6R, 7S, 8R, 8aR (6,7-di-epi-castanospermine 3)
stereochemistry. These two possibilities can be ruled out be-
cause the NMR spectra of neither 11 nor 12 correspond to
the known 1 (9f) and 3 (8). If, on the other hand, in the con-
version of 13 to 22 the stereochemistry was 8S, then the fi-
nal two products must have either 1S, 6S, 7R, 8S, 8aR (8-
epi-castanospermine) or 1S, 6R, 7S, 8S, 8aR (6,7,8-tri-epi-
castanospermine) stereochemistry. We were able to assign
compound 11 to the 8-epi-castanospermine structure based
sulfide 22 to the corresponding sulfoxide 23 followed by
trimethyl phosphite treatment (18) gave the rearranged diol
24. In conformity with similar rearrangements observed pre-
viously (11), the double bond in 24 was expected to have the
trans stereochemistry. This was confirmed through the cou-
pling constants of the olefinic protons in the bicyclic com-
pound 25 prepared by intramolecular cyclization of 24 under
basic conditions. The primary allylic alcohol function in 25
was transformed to the chloride 26 with triphenylphosphine
in carbon tetrachloride (19). Hydroxylation of the double
bond of 26 with osmium tetroxide and N-methylmorpholine
N-oxide (20) led to an inseparable mixture of diols 27a and
27b. Conversion of the diols to the corresponding acetonides
allowed separation into individual compounds 28a and 28b
in a ratio of about 5:3. Base hydrolysis of compound 28a,
the major isomer, followed by spontaneous intramolecular
cyclization gave the protected indolizidine 29a. Removal of
the MOM and the isopropylidene protecting groups of 29a
under aqueous acidic conditions gave in quantitative yield
the product 11 which we subsequently assigned the structure
as (+)-8-epi-castanospermine (vide infra). Base hydrolysis of
28b, the minor isomer, led not only to cyclization but
deprotection as well to give product 12 to which the struc-
ture 6,7,8-tri-epi-castanospermine was assigned.
1
on comparison of the coupling constants in the H NMR
spectrum of 11 with those reported for the various
stereoisomers of castanospermine (Table 1). In particular,
the H6 proton has a trans-diaxial coupling with H7 (J =
9.5 Hz), which has a gauche coupling with H8 (J = 3.0 Hz),
fully compatible with the 6S, 7R, 8S relative configurations
of trans-diaxial/gauche relationship between the three pro-
tons. Martin et al. recently reported on the synthesis of 1-
deoxy-8-epi-castanospermine (30) (22). The three protons
Assignment of stereochemistry
Castanospermine (1) itself has the 1S, 6S, 7R, 8R, and 8aR
configurations. From the 1H and 13C NMR spectra of
compounds 11 and 12, it is clear that they are not identical
to that of castanospermine (9f ). In starting from the known
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St-Denis and Chan
779
1
Table 1. Partial H NMR spectra of castanospermine and epimers.
Castanospermine (1)a
6,7-epi- (3)b
Compound 11c
1-Deoxy-8-epi- (30)d
H6 3.41–3.47 (m) for H6 and H8 3.98 (dd, J = 1.5, 2) for H6 and H7 3.43 (ddd, J = 5.5, 9.5, 11.2) 3.72 (ddd, J = 5.2, 9.6, 10.7)
H7 3.15 (t, J = 9.0)
H8 see H6
see H6
4.08 (dd, J = 2, 10)
2.96 (dd, J = 3.0, 9.5)
3.89 (dd, J = 1.0, 3.0)
3.34 (dd, J = 3.5, 9.6)
3.84 (dd, J = 1.4, 3.5)
aReference 9f.
bReference 3.
cThis work.
dReference 12.
H6, H7, and H8 in compound 30 have the same relative con-
figurations of 6S, 7R, and 8S and similar coupling constants
of JH6–H7 = 9.6 Hz and JH7–H8 = 3.5 Hz.
extracts were washed with 5% HCl, water, brine, and dried
(MgSO4). Evaporation of the solvents was followed by dis-
tillation (198°C, 0.25 mm Hg) to afford 16 as a colorless oil
(5.4 g, 80%). IR (neat): 2978, 1722, and 1693 cm–1. 1H NMR
(CDCl3): 7.40–7.18 (m, 5H), 5.13 + 5.07 (2s, 2H), 4.14 +
4.11 (2q, 2H, J = 7.1), 4.06 (2q, 2H, J = 7.1), 3.59 + 3.58
(2t, 2H, J = 6.4), 2.64 + 2.58 (2t, 2H, J = 6.4), 1.22 + 1.15
(2t, 3H, J = 7.1), 1.21 + 1.20 (2t, 3H, J = 7.1). 13C NMR
(CDCl3): 172.7 + 172.4, 170.4 + 170.3, 156.7 + 156.2,
136.8, 129.0 + 128.9, 128.5 + 128.4, 128.3 + 128.2, 68.0 +
67.8, 61.6, 61.1 + 61.0, 50.9, 45.8 + 45.0, 34.6 + 34.0, 14.6.
MS: 337 (4), 229 (2), 264 (2), 220 (12), 202 (28), 91 (100).
Experimental3
1
The assignment of the peaks for some H and 13C NMR
spectra were complicated because of the geometric isomers
produced by the Cbz group in compounds 16, 18, 19, 20, 21,
13, 22, and 24.
Ethyl N-(2-ethoxycarbonylethyl)-glycinate (15)
To a solution of freshly prepared ethyl glycinate (10.2 g,
98.4 mmol: from ethyl glycinate hydrochloride neutralized
with 10 M NaOH: pH 9.5 and extracted with chloroform) in
dry benzene (10 mL) was added ethyl 3-bromopropionate
(14. 6.3 mL, 0.5 equiv.) in benzene (5 mL). A white solid
formed immediately upon addition. The suspension was
heated at 60°C for 5 h and poured into saturated aqueous so-
dium carbonate solution. The aqueous phase was extracted
with chloroform (3×) and the combined organic extracts
were dried (MgSO4) and evaporated. The residue was dis-
tilled (95°C, 0.25 mm Hg) to yield 15 as a colorless oil
(6.3 g, 63%). IR (neat): 3348, 2985, 1721, and 1121 cm–1.
1H NMR (CDCl3): 4.05 (q, 2H, J = 7.2), 4.01 (q, 2H, J =
7.2), 3.27 (s, 2H), 2.76 (t, 2H, J = 6.6), 2.36 (t, 2H, J = 6.6),
1.72 (s, 1H), 1.14 (t, 3H, J = 7.2), 1.12 (t, 3H, J = 7.2). 13C
NMR (CDCl3): 172.8, 172.6, 61.1, 60.8, 51.2, 45.1, 35.2,
14.6. MS: 204 (5), 203 (7), 174 (2), 158 (4), 130 (100), 116
(49), 84 (76), 56 (14), 42 (38).
Ethyl N-benzoxycarbonyl-3-oxopyrrolidine-2-carboxylate
(18)
To a suspension of potassium t-butoxide (2.52 g, 1.4 eq)
in dry toluene (54 mL) at 0°C, under argon, was added 16
(5.41 g, 16.0 mmol) in toluene (10 mL) over a period of
10 min. The suspension was stirred at 0°C for 30 min after
which 2 mL of glacial acetic acid were added, immediately
followed by a solution of sodium dihydrogen phosphate hy-
drate (9.1 g) in water (91 mL). The heterogeneous mixture
was extracted with chloroform (3×), and the combined or-
ganic extracts were dried (MgSO4) and concentrated. The
residue was dissolved in cold toluene (100 mL) and washed
with cold, pH 9.5 carbonate buffer (3×). The toluene solu-
tion was washed with water, dried (MgSO4), and concen-
trated. The residue was distilled (Kugelrohr: oven
temperature 160°C, 0.03 mm Hg) and the distillate was puri-
fied by flash chromatography over silica gel with hex-
anes:ethyl acetate (2:1) as eluent. Compound 18 was
obtained as a colorless oil (slightly contaminated with com-
Ethyl N-benzoxycarbonyl-N-(2-ethoxycarbonylethyl)-
glycinate (16)
1
pound 17). IR (neat): 2978, 1741, 1712, and 1695 cm–1. H
To a solution of 15 (3.88 g, 20.2 mmol) in dry acetonitrile
(40 mL) at 0°C, under argon, was added slowly benzyl
chloroformate (3.17 mL, 1.1 equiv.). The solution was stirred
at 0°C for 1 h after which it was poured into water (50 mL).
The phases were separated and the aqueous layer was ex-
tracted with methylene chloride (3×). The combined organic
NMR (CDCl3): 7.41–7.23 (m, 5H), 5.22 + 5.15 and 5.20 +
5.07 (2 AB, 2H, J = 8.2), 4.58 + 4.54 (2s, 1H), 4.24 (q, 2H,
J = 4.7), 4.08 (m, 1H), 3.96 (m, 1H), 3.85 (m, 1H), 2.67 (t,
2H, J = 4.9), 1.28 + 1.14 (2t, 3H, J = 4.7). 13C NMR
(CDCl3): 204.6, 166.4, 154.9, 136.6 + 136.4, 128.9, 128.7,
3 For general experimental conditions, see reference 11.
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Can. J. Chem. Vol. 78, 2000
128.5 + 128.4, 68.03, 65.9 + 65.8, 62.8, 42.6, 37.3 + 36.7,
14.5 + 14.4. MS: 292 (100), 248 (80), 176 (32), 158 (23).
(2q, 2H, J = 7.1), 3.70 (m, 1H), 3.49 (m. 1H), 3.34 + 3.33
(2s, 3H), 2.10 (m, 2H), 1.25 + 1.14 (2t, 3H, J = 7.1). 13C
NMR (CDCl3): 170.0 + 169.9, 155.2 + 154.8, 136.9, 128.9 +
128.8, 128.5 + 128.4, 128.2, 96.1, 76.7 + 76.0, 67.6, 62.6 +
62.3, 61.5 + 61.4, 56.2, 44.8 + 44.6, 31.0 + 30.2, 14.7 +
14.6. Exact mass calcd. for C17H23NO6 (M·+ + H): 338.1605,
found: 338.1604.
Ethyl (2R,3S)-N-benzoxycarbonyl-3-hydroxypyrrolidine-
2-carboxylate (19)
To a solution of sucrose (300 mg) in distilled water
(4.1 mL) was added baker’s yeast (200 mg). The flask was
equipped with a bubble counter and the suspension was
heated at 32°C for 1 h. The content of the flask was then
poured into a 15 mL flask containing the keto ester 18
(0.12 g, 0.42 mmol). Stirring was continued for 24 h after
which additional sucrose (300 mg) in warm (40°C) distilled
water (1 mL) was added. After 48 h, celite (500 mg) was
added to the mixture and the suspension was filtered through
a sintered glass funnel (medium porosity). After the filtrate
was washed with water, the aqueous layer was extracted
with ether (3×) and the combined organic extracts were
dried (MgSO4). After filtration, the solvent was evaporated
and the residue was purified by flash chromatography (silica
gel, 3:7 hexanes:ethyl acetate) to give the optically active
compound 19 (55 mg, 45%). [α]2D0 = +22.8° (c: 2.7 in
CH2Cl2); lit. [α]2D0 = +21.9° (c: 2.0 in CH2Cl2)(15). IR
(neat): 3378, 2978, 1741, 1701 cm–1. 1H NMR (CDCl3):
7.40–7.22 (m, 5H), (5.13 + 5.00) + 5.11 (1 AB and 1s, 2H,
JAB = 12.5), 4.56 (q, 1H, J = 6.4), 4.39 (t, 1H, J = 6.4),
4.19–4.06 (m, 2H), 3.66 (m, 1H), 3.49 (m, 1H), 2.02
(m, 1H), 1.23 + 1.11 (2t, 3H, J = 7.1). 13C NMR (CDCl3):
170.7 + 170.5, 155.4 + 154.9, 136.9 + 136.8, 128.9 + 128.8,
128.5, 128.4 + 128.2, 72.7 + 71.8, 67.6, 64.4 + 64.1, 61.8 +
61.7, 44.9 + 44.7, 33.2 + 32.4, 14.6 + 14.5. Exact mass
calcd. for C15H19NO5 (M·+ + H): 294.1342, found: 284.1341.
Racemic 19 was prepared by the reduction of 18 with so-
dium borohydride. To a solution of 18 (0.29 g, 0.72 mmol)
in absolute ethanol (3.6 mL) at 0°C, under argon, was added
sodium borohydride (29.8 mg, 1.1 equiv.). The solution was
stirred at 0°C for 60 min after which a few drops of acetic
acid were added. The solution was poured in saturated aque-
ous sodium bicarbonate and the aqueous layer was extracted
with ether (3×). The combined organic extracts were washed
with brine and dried (MgSO4). After fitration, the solvents
were evaporated and the residue was purified by flash chro-
matography to give racemic 19 (0.14 g, 66%), identical in all
spectroscopic aspects with those of (+)-19.
(2S,3S)-N-Benzoxycarbonyl-2-hydroxymethyl-3-methoxy-
methyloxypyrrolidine (21)
To a solution of the ester 20 (0.84 g, 2.48 mmol) in ether
(25 mL) at 0°C, under argon, was added lithium borohydride
(0.12 g, 2.2 eq) and the suspension was stirred at 0° for 4 h.
Acetic acid (1 mL) was then added to destroy the excess hy-
dride and the solution was poured in saturated aqueous so-
dium bicarbonate solution. The phases were separated and
the aqueous phase was extracted with ether (2×). The com-
bined organic phase was washed with brine and dried
(MgSO4). Filtration and evaporation of the solvent was fol-
lowed by flash chromatography (silica gel, 4:6 hexanes:ethyl
acetate) of the residue to give alcohol 21 as a colorless oil
(0.53 g, 72%). [α]2D0 = +44.7° (c: 1.1 in CHCl3). IR (neat):
1
3450, 2948, 2888, 1704 cm–1. H NMR (CDCl3): 7.40–7.22
(m, 5H), 5.12 (s, 2H), 4.71–4.58 (m, 2H), 4.32 (q, 1H, J =
5.3), 3.96 (m. 1H), 3.89–3.75 (m, 2H), 3.51 (t, 2H, J = 6.8),
3.36 (s, 3H), 3.27 (bs, 1H), 1.98 (t, 2H, J = 6.8). 13C NMR
(CDCl3): 156.9, 136.9, 129.0, 128.6, 128.4, 96.2, 77.8, 67.7,
63.4, 63.2, 56.3, 45.1, 30.6. Exact mass calcd. for
C15H21NO5 (M·+ + H): 296.1499, found: 296.1498.
(2R,3S)-N-Benzoxycarbonyl-3-methoxymethyloxypyrroli-
dine-2-carboxaldehyde (13)
Dimethyl sulfoxide (49.3 µl, 2.84 equiv.) was slowly
added to a solution of oxalyl chloride (30.1 µl, 1.41 equiv.)
in methylene chloride (2 mL) under argon at –78°C. The
colorless solution was stirred for 15 min after which a solu-
tion of the alcohol 21 (72.2 mg, 0.24 mmol) in methylene
chloride (1 mL) was added dropwise over a period of 5 min.
A white precipitate was formed and the suspension was
stirred for 1 h. Triethylamine (0.17 mL, 5 equiv.) in methy-
lene chloride was added and the solution was allowed to
slowly warm to room temperature. The mixture was diluted
with methylene chloride (10 mL) and washed successively
with 5% HCl, water, brine, and dried (MgSO4). Evaporation
of the solvent under vacuum gave a pale brown oil which
was purified by flash chromatography (silica gel, 1:1 hex-
anes:ethyl acetate) to give the aldehyde 13 as a pale yellow
oil (70.0 mg, 98%). [α]2D0 = +70.4° (c: 1.1 in CHCl3). IR
(neat): 2958, 2888, 1736, 1701 cm–1. 1H NMR (CDCl3):
9.53 + 9.44 (2d, 1H, J = 2.5), 7.42–7.21 (m, 5H), 5.14 +
5.09 (2s, 2H), 4.72–4.51 (m, 3H), 4.27 + 4.21 (2dd, 1H, J =
2.5, 5.7), 2.75–3.60 (m, 2H), 3.29 (s, 3H), 2.16–1.80 (m, 2H).
13C NMR (CDCl3): 200.2 + 200.1, 155.7 + 154.8, 136.8 +
136.6, 129.0, 128.6, 128.5 + 128.4, 95.8, 79.4 + 78.3, 68.4 +
68.0, 67.8, 56.3, 45.7 + 45.1, 31.5 + 30.9. Exact mass calcd.
for C15H19NO5 (M·+ + H): 294.1342, found: 294.1341.
Ethyl (2R,3S)-N-benzoxycarbonyl-3-methoxymethyloxy-
pyrrolidine-2-carboxylate (20)
To a solution of the alcohol (+)-19 (0.14 g, 0.48 mmol) in
methylene chloride (4.8 mL) at 0°C, under argon, was suc-
cessively added diisopropylethylamine (0.25 mL, 3 equiv.)
and chloromethyl methyl ether (0.11 mL, 3 equiv.). The so-
lution was stirred at rt for 24 h after which it was poured
into 5% HCl. The aqueous phase was extracted with methy-
lene chloride (3×) and the combined organic extracts were
washed with saturated aqueous sodium bicarbonate and
dried (MgSO4). After evaporation of the solvent, the residue
was purified by flash chromatography on silica gel with 1:1
hexanes:ethyl acetate as eluent to give compound 20 as a
colorless oil (0.15 g, 92%). [α]2D0 = –18.4° (c: 1.1 in CHCl3).
(2R,3S,1 S,2 S)-N-Benzoxycarbonyl-2-(1 -hydroxy-2 thio-
′
′
′
′
1
IR (neat) : 2957, 1746, 1701 cm–1. H NMR (CDCl3): 7.42–
phenyl-3 -butenyl)-3-methoxymethyloxypyrrolidine (22)
′
7.20 (m, 5H), (5.14 + 5.02) + 5.11 (AB + s, 2H, JAB = 12.2),
(4.68 + 4.60) + (4.66 + 4.58) (2 AB, 2H, J = 6.9), 4.21–4.07
To a solution of allyl phenyl sulfide (0.35 g, 15 equiv.)
in dry THF (10.5 mL) at –78°C, under argon, was added
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St-Denis and Chan
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n-butyllithium (2.0 M in pentane, 1.16 mL, 1.5 equiv.) and
the solution was stirred at 0°C for 30 min. It was then
brought back to –78°C and titanium (IV) isopropoxide
(0.69 mL, 1.5 equiv.) was added slowly. After 10 min, alde-
hyde 13 (0.45 g, 1.55 mmol) in THF (5 mL) was added over
a period of 10 min. The solution was stirred for 10 min and
warmed up at 0°C for 30 min. It was then poured into 5%
HCl and extracted with ether (3×). The combined organic
extracts were washed with brine, dried (MgSO4), and fil-
tered. Evaporation of the solvent followed by flash chroma-
tography (silica gel, 1:1 hexanes:ethyl acetate) gave the
product 22 as a colorless oil (0.49 g, 72%). [α]2D0 = +50.2°
(c: 1.1 in CHCl3). IR (neat): 3424, 2948, 2893, 1693 cm–1.
1H NMR (CDCl3): 7.54–7.09 (m, 10H), 6.06 (m, 1H), 5.12
(s, 2H), 5.06 (d, 1H, J = 10.7), 4.90 (d, 1H, J = 17.2), 4.63
(s, 2H), 4.60 (m, 1H), 4.26 (q, 1H, J = 6.0), 4.14 (bs, 1H),
3.95 (d, 1H, J = 9.6), 3.66–3.42 (m, 2H), 3.33 (s, 3H), 2.15–
1.84 (m, 2H). 13C NMR (CDCl3): 158.2, 136.7, 134.9,
133.4, 129.1, 128.7, 128.6, 127.6, 126.0, 118.5, 96.4, 77.1,
72.8, 68.0, 63.1, 56.8, 56.5, 45.3, 30.8. Exact mass calcd. for
C24H29NO5S (M·+ + H): 444.1846, found: 444.1845.
14.1), 1.92 (dddd, 1H, J = 3.6, 9.5, 9.6, 14.1). 13C NMR
(CDCl3): 162.2, 134.5, 127.6, 95.5, 75.5, 75.4, 69.4, 62.3,
56.3, 44.2, 32.6. Exact mass calcd. for C11H17NO5 (M·+ + H):
244.1186, found: 244.1185.
(2R,3S,1′R)-1,1′-N,O-Carbonyl-2-(1′hydroxy-4′-chloro-2′-
butenyl)-3-methoxymethyloxypyrrolidine (26)
To a solution of the allylic alcohol 25 (0.11 g, 0.47 mmol)
in a mixture of carbon tetrachloride:methylene chloride (4:1,
6.0 mL) were added successively finely powdered potassium
carbonate (0.13 g, 2 equiv.) and triphenylphosphine (0.31 g,
2.5 equiv.) and the solution was stirred at 60°C for 8 h. The
solvent was evaporated and the residue was purified by flash
chromatography (silica gel, 2:8 hexanes:ethyl acetate) af-
fording the chloride 26 (83.9 mg, 70%) as a pale yellow oil.
[α]2D0 = +87.7° (c: 1.5 in CHCl3). IR (neat): 2965, 2895,
1
1751 cm–1. H NMR (CDCl3): 6.06–5.84 (m, 2H), 5.06 (dd,
1H, J = 3.6, 5.1), 4.65 (AB, 2H, J = 7.0), 4.11 (td, 1H, J =
1.1, 3.6), 4.05 (d, 2H, J = 6.2), 3.62 (t, 1H, J = 3.6), 3.58
(ddd, 1H, J = 7.9, 9.5, 11.0), 3.33 (s, 3H), 3.22 (ddd, 1H, J =
2.2, 9.7, 11.0), 2.28 (dddd, 1H, J = 1.1, 2.2, 7.9, 14.1), 1.93
(dddd, 1H, J = 3.6, 9.5, 9.7, 14.1). 13C NMR (CDCl3):
161.8, 131.7, 129.9, 95.5, 75.6, 74.4, 69.1, 56.4, 44.3, 43.9,
32.5. Exact mass calcd. for C11H16NO4Cl (M·+ + H):
262.0847, found: 262.0846.
(2R,3S,1′R)-N-Benzoxycarbonyl-2-(1′,4′-dihydroxy-2′-
butenyl)-3-methoxymethyloxypyrrolidine (24)
To
a solution of the hydroxysulfide 22 (0.49 g,
1.11 mmol) in methylene chloride (11.1 mL) at 0°C under
argon was added m-chloroperoxybenzoic acid (0.27 g, 1.4
equiv.) and the solution was stirred for 60 min. It was then
dissolved in ether, washed with saturated aqueous sodium
bicarbonate solution (2×), dried (MgSO4), filtered, and the
solvent was evaporated. The residue was dissolved in dry
methanol (11.1 mL) and trimethyl phosphite (0.65 mL, 5
equiv.) was added slowly. After 2 h of stirring at 60°C, the
methanol was evaporated and the thick residual oil was puri-
fied by flash chromatography (silica gel, 2:8 hexanes:ethyl
acetate, then ethyl acetate as eluents) to give the allylic alco-
hol 24 (0.28 g, 71%). [α]2D0 = +31.2° (c: 1.5 in CHCl3). IR
(neat): 3450, 2948, 2888, 1704, 1671 cm–1. 1H NMR
(CDCl3): 7.42–7.21 (m, 5H), 5.96–5.70 (m, 2H), 5.12 (s,
2H), 4.67 (s, 2H), 4.51 (m, 1H), 4.29 (m, 1H), 4.21–3.88 (m.
3H), 3.62–3.43 (m, 2H), 3.37 (s, 3H), 3.29 (m, 1H), 3.16
(bs, 1H), 2.20–1.91 (m, 2H). 13C NMR (CDCl3): 157.3,
136.9, 131.8, 131.0, 129.0, 128.6, 128.4, 97.0, 78.2, 72.1,
67.8, 63.2, 56.4, 45.5, 30.9. Exact mass calcd. for
C18H25NO6 (M·+ + H): 352.1761, found: 352.1760.
(2R,3S,1′S,2′S,3′R)- and (2R,3S,1′S,2′R,3′R)-1,1′-N,O-
Carbonyl-2-(1′,2′,3′-trihydroxy-4′-chlorobutanyl)-
3methoxymethyloxypyrrolidine (27a and 27b)
To a solution of the chloride 26 (83.9 mg, 0.32 mmol) in a
mixture of acetone:water:t-butanol (6:3:1, 2.0 mL) were
added successively N-methylmorpholine-N-oxide (45.1 mg,
1.2 equiv.) and osmium tetroxide (15.0 mg, 0.05 equiv.). The
orange solution was stirred at room temperature for 3 h, af-
ter which 2 mL of a solution-suspension of magnesium sili-
cate and sodium hydrosulfite (1.2 g and 0.1 g respectively in
8 mL of water) was added. The slurry was filtered through
celite and the cake was rinsed with acetone. The solvents
were evaporated and the dark residual oil was purified by
flash chromatography (silica gel, ethyl acetate) to provide a
mixture of the products 27a and 27b (2:1 by NMR, 94.8 mg,
1
99%). IR (neat): 3335, 2952, 1751 cm–1. H NMR (CDCl3):
4.83–4.59 (m, 3H), 4.09 (m, 2H), 3.95 (m, 1H), 3.86 (m,
1H), 3.77–3.46 (m, 5H), 3.32 (s, 3H), 3.27 (m, 1H), 2.29 (m,
1H), 2.01 (m, 1H). 13C NMR (CDCl3): 27a: 162.1, 95.7,
76.1, 75.5, 71.1, 70.8, 66.1, 56.3, 45.8, 44.0, 33.0; 27b:
162.0, 95.5, 76.4, 75.3, 72.1, 71.6, 66.0, 56.3, 45.8, 44.0,
32.8. Exact mass calcd. for C11H18NO6Cl (M·+ + H):
296.0902, found: 296.0901.
(2R,3S,1′R)-1,1′-N,O-Carbonyl-2-(1′,4′-dihydroxy-2′-
butenyl)-3-methoxymethyloxypyrridine (25)
To a solution of the allylic diol 24 (0.21 g, 0.61 mmol) in
2-propanol:water (2:1, 6.1 mL) was added finely powdered
potassium carbonate (0.17 g, 2 equiv.) and the solution was
heated at 65°C for 15 h. The solvent was evaporated and the
residue purified by flash chromatography (silica gel, ethyl
acetate) to give the product 25 as a colorless oil (0.11 g,
77%). [α]2D0 = +99.6° (c: 1.1 in CHCl3). IR (neat): 3436,
(2R,3S,1 S,2 S,3 R)- and (2R,3S,1 S,2 R,3 S)-1,1 -N,O-
′
′
′
′
′
′
′
′
′ ′
Carbonyl-2-(1 hydroxy-2 ,3 -O-isopropylidene-4 -chloro-
′
butanyl)-3-methoxymethyloxypyrrolidine (28a and 28b)
To a solution of the diol mixture 27a and 27b (94.8 mg,
0.32 mmol) in dry acetone (3.2 mL) at room temperature un-
der argon were added 2,2-dimethoxypropane (0.20 mL, 5
equiv.) and camphorsulfonic acid (5.2 mg, 0.05 equiv.). The
solution was stirred for 15 h at room temperature and heated
at 40°C for 1 h after which a few drops of conc. ammonium
hydroxide were added. The solvent was evaporated and the
residue was taken up in ethyl acetate. The organic solution
1
2946, 2895, 1751, 1674 cm–1. H NMR (CDCl3): 5.96 (dt,
1H, J = 4.0, 15.5), 5.83 (dd, 1H, J = 6.5, 15.5), 5.04 (dd, 1H,
J = 3.6, 6.5), 4.63 (AB, 2H, J = 7.0), 4.13 (d, 2H, J = 4.0),
4.08 (td, 1H, J = 0.9, 3.6), 3.62 (t, 1H, J = 3.6), 3.54 (ddd,
1H, J = 7.8, 9.5, 10.8), 3.32 (s, 3H), 3.19 (ddd, 1H, J = 2.1,
9.6, 10.8), 2.83 (bs, 1H), 2.25 (dddd, 1H, J = 0.9, 2.1, 7.8,
© 2000 NRC Canada

782
Can. J. Chem. Vol. 78, 2000
was washed with brine and dried (MgSO4). Evaporation of
the solvent followed by flash chromatography (silica gel, 6:4
hexanes:ethyl acetate) purification gave 28a (51.0 mg, 48%)
and 28b (31.7 mg, 29%) separately, for a combined yield of
melting point of 190–192°C. [α]2D0 = +44.4° (c: 1.3 in H2O).
1
IR (KBr): 3450 cm–1. H NMR (D2O): 4.07 (ddd, 1H, J =
2.1, 4.5, 6.5), 3.89 (dd, 1H, J = 1.2, 3.0), 3.43 (ddd, 1H, J =
5.5, 9.5, 11.2), 3.09 (ddd, 1H, J = 4.4, 9.0, 10.0), 3.07 (dd,
1H, J = 5.5, 11.2), 2.96 (dd, 1H, J = 3.0, 9.5), 2.70 (d, 1H,
J = 4.5), 2.45 (ddd, 1H, J = 7.9, 10.0, 10.1), 2.23 (t, 1H, J =
11.2), 1.87 (dddd, 1H, J = 4.4, 6.5, 10.1, 14.3), 1.31 (dddd,
1H, J = 2.1, 7.9, 9.0, 14.3). 13C NMR (D2O): 76.2, 73.1,
71.8, 69.8, 67.9, 56.0, 53.8, 35.4. Exact mass calcd. for
C8H15NO4 (M·+ + H): 190.1080, found: 190.1079.
77%. Compound 28a (white solids): mp 74–76°C. [α]D201
=
+50.8° (c: 1.0 in CHCl3). IR (CHCl3): 2980, 1751 cm–1. H
NMR (CDCl3): 4.70 + 4.62 (AB, 2H, J = 7.0), 4.60 (dd, 1H,
J = 3.2, 8.3), 4.21 (ddd, 1H, J = 3.8, 5.2, 7.0), 4.13 (td, 1H,
J = 0.9, 3.2), 4.05 (dd, 1H, J = 7.0, 8.3), 3.88 (t, 1H, J =
3.2), 3.80 (dd, 1H, J = 3.8, 11.8), 3.65 (dd, 1H, J = 5.2,
11.8), 3.59 (ddd, 1H, J = 7.8, 9.5, 10.8), 3.34 (s, 3H), 3.26
(ddd, 1H, J = 2.1, 9.8, 10.8), 2.32 (dddd, 1H, J = 0.9, 2.1,
7.8, 14.1), 1.98 (dddd, 1H, J = 3.2, 9.5, 9.8, 14.1), 1.44 (s,
3H), 1.40 (s, 3H). 13C NMR (CDCl3): 162.0, 112.1, 96.3,
80.8, 79.4, 76.5, 76.4, 67.7, 57.2, 45.7, 45.1, 33.5, 28.6,
28.4. Exact mass calcd. for C14H22NO6Cl (M·+ + H):
336.1215, found: 336.1214.
(1S,6R,7S,8R,8aR)-1,5,7,8-Tetrahydroxyindolizidine
(6,7,8-tri-epi-castanospermine, 12)
The same experimental procedures for the conversion of
compound 28a to 29a were followed by starting with com-
pound 28b. The deprotection of the MOM ether group as
well as the isopropylidene occurred during the cyclization.
The reaction time was 36 h. The purification procedures for
11 were followed but with 70:24:3:3 chloroform:metha-
nol:water:NH4OH as eluent for the flash chromatography
Compound 28b (white solids): mp 153–155°C. [α]D20
=
+66.1° (c: 1.6 in CHCl3). IR (CHCl3): 2997, 1751 cm–1. H
NMR (CDCl3): 4.77 (dd, 1H, J = 1.8, 3.4), 4.71 + 4.63 (AB,
2H, J = 7.0), 4.40 (ddd, 1H, J = 4.4, 6.6, 7.5), 4.11 (td, 1H,
J = 0.9, 3.4), 4.08 (dd, 1H, J = 1.8, 7.5), 3.91 (t, 1H, J =
3.4), 3.73 (dd, 1H, J = 4.4, 11.4), 3.62 (dd, 1H, J = 6.6,
11.4), 3.40 (ddd, 1H, J = 8.0, 9.5, 10.9), 3.34 (s, 3H), 3.31
(ddd, 1H, J = 2.1, 9.8, 10.9), 2.32 (dddd, 1H, J = 0.9, 2.1,
8.0, 14.3), 1.97 (dddd, 1H, J = 3.4, 9.5, 9.8, 14.3), 1.43 (s,
6H). 13C NMR (CDCl3): 171.1, 112.1, 96.4, 81.8, 76.7, 76.5,
74.1, 67.1, 57.3, 45.4, 45.3, 33.5, 28.6, 27.9. Exact mass
calcd. for C14H22NO6Cl (M·+ + H): 336.1215, found:
336.1214.
1
(silica gel) to give compound 12 in 65% yield. [α]D20
=
–7.3° (c: 1.0 in H2O). IR (KBr): 3500 cm–1. 1H NMR (D2O):
4.00 (ddd, 1H, J = 2.4, 4.8, 7.1), 3.55 (t, 1H, J = 4.3), 3.27
(t, 1H, J = 4.8), 3.14 (q, 1H, J = 4.2), 2.79–2.59 (m, 2H),
2.46–2.31 (m, 2H), 2.17 (m, 1H), 1.71 (dddd, 1H, J = 3.8,
7.1, 9.5, 14.0), 1.21 (dddd, 1H, J = 2.4, 8.8, 8.8, 14.0). 13C
NMR (D2O): 74.5, 72.7, 72.6, 71.2, 68.07, 56.9, 55.0, 34.7.
Exact mass calcd. for C8H15NO4 (M·+ + H): 190.1080,
found: 190.1079.
Acknowledgements
(1S,6S,7R,8S,8aR)-1-Methoxymethyloxy-6,7-O-isopropy-
lidene-8-hydroxyindolizidine (29a)
We thank NSERC of Canada for financial support of this
research. THC acknowledges the Department of Applied Bi-
ology and Chemical Technology, Hong Kong Polytechnic
University for their hospitality during his sabbatic leave.
To a solution of the chloride 28a (51.0 mg, 0.15 mmol) in
a mixture of methanol:water (1:1, 2 mL) was added sodium
hydroxide (18.3 mg, 3 equiv.) and the solution was stirred at
85°C for 18 h. The solvents were evaporated and the solid
residue was extracted with chloroform. The chloroform solu-
tion was evaporated to give the aminoalcohol 29a as a waxy
solid (41.0 mg, 98%). [α]2D0 = +50.6° (c: 0.83 in CHCl3). IR
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© 2000 NRC Canada