Synthesis of naturally occurring iminosugars from d-fructose by the use of a zinc-mediated fragmentation reaction

Article abstract of DOI:10.1039/b605818c

A short synthesis of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) and a formal synthesis of australine are described. In both cases, d-fructose is employed as the starting material and converted into a protected methyl 6-deoxy-6-iodo- furanoside. Zinc-mediate

Full text of DOI:10.1039/b605818c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of naturally occurring iminosugars from D-fructose by the use of a
zinc-mediated fragmentation reaction†
Anne Lauritsen and Robert Madsen*
Received 24th April 2006, Accepted 13th June 2006
First published as an Advance Article on the web 27th June 2006
DOI: 10.1039/b605818c
A short synthesis of 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and a formal synthesis of australine are
described. In both cases, D-fructose is employed as the starting material and converted into a protected
methyl 6-deoxy-6-iodo-furanoside. Zinc-mediated fragmentation produces an unsaturated ketone
which serves as a key building block for both syntheses. Ozonolysis, reductive amination with
benzylamine and deprotection affords 1,4-dideoxy-1,4-imino-D-arabinitol in only 7 steps and 11%
overall yield from D-fructose. Alternatively, reductive amination with homoallylamine, ring-closing
metathesis and protecting group manipulations give rise to an intermediate which can be converted into
australine in 3 steps. The intermediate is prepared by two different strategies both of which use a total
of 9 steps. The first strategy utilizes benzyl ethers for protection of fructose while the second and more
effective strategy employs an isopropylidene acetal.
could offer new ways of using D-fructose as a synthetic starting
Introduction
material and lead to short syntheses of other iminosugars.
Iminosugars are a class of polyhydroxylated alkaloids that have
Fructose is one of the most inexpensive carbohydrates and has
been found in a number of plants and microorganisms.1 They can
structural similarity with several naturally occurring iminosugars.
be regarded as analogues of monosaccharides in which the ring
In connection with this, we were particularly interested in the
oxygen has been replaced by nitrogen. Many of these natural prod-
pyrrolidine alkaloid 1,4-dideoxy-1,4-imino-D-arabinitol (DAB)
ucts are potent inhibitors of glycosidases due to their resemblance
and the corresponding pyrrolizidine alkaloid australine (Fig. 1).
with the pyranosyl cation of the natural substrates.2 Furthermore,
numerous non-natural analogues have been prepared and inves-
tigated as glycosidase inhibitors.3 As a consequence, iminosugars
have been used as important lead compounds for the treatment
of viral infections, cancer, diabetes and other metabolic disorders.
Several iminosugars are currently in clinical development4 and two
N-alkylated derivatives of deoxynojirimycin have been approved as
drugs for the treatment of Gauchers disease and type II diabetes.5
Iminosugars are divided into five sub-classes based on the ring
system: pyrrolidines, piperidines, pyrrolizidines, indolizidines, and
nortropanes. The synthesis of these molecules is often performed
from a carbohydrate starting material.6 However, it is still a
challenge to introduce the amino group and to form the ring
system in few steps.7 We have recently developed a short synthetic
route to the nortropane alkaloids (calystegines) from cheap
aldohexoses.8 Three of these alkaloids were prepared in 7 steps
from the corresponding methyl glycopyranosides of D-glucose,
D-galactose, and D-mannose.8 One of the steps involved a zinc-
mediated fragmentation of the benzyl-protected methyl 6-iodo-
glycopyranosides.9 This reaction has been widely used in car-
bohydrate chemistry for converting aldohexoses into unsaturated
aldehydes, but has to the best of our knowledge never been applied
to ketohexoses. We speculated that this fragmentation reaction
DAB is a strong inhibitor of yeast a-glucosidase10 and several
mammalian a-glucosidases.11 It is also a powerful inhibitor
of glycogen phosphorylase12 and is a promising candidate for
treatment of type II diabetes.13 DAB was first isolated in 1985
from Arachniodes standishii14 and Angylocalyx boutiqueanus.15 It
has also been found in a number of other plants and seems to
be a fairly widespread secondary metabolite.1 Several chemical
syntheses of DAB have appeared which all employ a total of 10–
12 steps starting from either a carbohydrate,16 an amino acid,17 or
2-butene-1,4-diol.18 In addition, three enzyme-catalysed syntheses
with an aldolase have also been described.19
Fig. 1 Structure of D-fructofuranose, 1,4-dideoxy-1,4-imino-D-arabini-
tol, and australine.
Australine is a potent inhibitor of amyloglucosidase20 and
was first isolated in 1988 from the legume Castanospermum
australe.21 Only three de novo chemical syntheses of australine
have been reported. White and Hrnciar developed a 16 step
synthesis from D-mannitol by using a transannular cyclisation
as the key step to form the pyrrrolizidine ring system (vide
infra).22 Denmark and Martinborough utilized two asymmetric
cycloaddition reactions to afford the natural product in only 9
steps from 2,5-dihydrofuran23 while Pearson and Hines obtained
australine in 11 steps from L-xylose by using a reductive cyclisation
Center for Sustainable and Green Chemistry, Department of Chemistry,
Building 201, Technical University of Denmark, DK-2800, Lyngby, Den-
mark. E-mail: rm@kemi.dtu.dk
† Electronic supplementary information (ESI) available: Experimental
procedures for synthesis of 8–13 and copies of NMR spectra. See DOI:
10.1039/b605818c
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of an azido epoxy tosylate.24 In addition, australine has also been
prepared from the indolizidine alkaloid castanospermine by a ring
contraction reaction25 and from 1,4-pentadien-3-ol by a chemo-
enzymatic procedure with an aldolase.26
Herein, we describe a concise synthetic route to DAB and a
formal synthesis of australine. Both syntheses have been achieved
from fructose by the use of a zinc-mediated fragmentation
reaction.
into the furanose form by a Fischer glycosylation with methanol
under kinetic conditions27 (Scheme 1). The product consisting of
a 1 : 1 mixture of the a- and the b-furanoside was treated with
1.5 equivalents of iodine and triphenylphosphine.28 Under these
conditions only the primary hydroxyl group in the 6-position
was replaced by iodine while the primary hydroxyl group at
position 1 did not react. The obtained methyl 6-iodo-furanoside 2
was separated from triphenylphosphine oxide on a reverse-phase
column and isolated in 67% yield. The hydroxyl groups at positions
1, 3, and 4 were protected as benzyl ethers by reaction with
benzyl trichloroacetimidate under acidic conditions. The resulting
tribenzyl ether 3 was isolated in 73% yield and then subjected to
sonication with zinc in a THF–water mixture. This fragmentation
reaction proceeded smoothly and afforded unsaturated ketone
4 in 74% yield after purification by silica gel chromatography.
Ketone 4 is a useful chiral building block which has previously
been prepared from D-arabinose in 5 steps by the use of a Wittig
reaction and a chromium-mediated oxidation.29 The current route
from fructose utilizes 4 steps and avoids the use of a toxic metal.
Results and discussion
Retrosynthesis
The structural resemblance between the two alkaloids and D-
fructose is noteworthy (Fig. 1). The absolute configuration of
the two hydroxyl groups in the pyrrolidine ring is the same as
for the hydroxyl groups at position 3 and 4 in D-fructose. The
hydroxymethyl group in DAB and australine is found in fructose
at position 1. The amino group can be introduced by reductive
amination from the ketone at position 2 in fructose. Thus, we
envisaged that DAB and australine could both be derived from
a common building block A (Fig. 2). Ozonolysis of the olefin in
A followed by reductive amination would afford the pyrrolidine
ring in DAB. On the other hand, reductive amination with ho-
moallylamine followed by ring-closing metathesis and epoxidation
would yield aminoepoxide B. The pyrrolizidine ring in australine
can then be formed by a transannular cyclisation as demonstrated
by White and Hrnciar in their synthesis of the natural product.22
The key building block A can be prepared from fructose by a
zinc-mediated fragmentation of the corresponding methyl 6-iodo-
furanoside. This approach from fructose should be able to generate
the two natural products in relatively few synthetic steps.
Scheme 1 Reagents and conditions: (a) MeOH, H2SO4, rt;27 (b) I2, PPh3,
imidazole, THF, 65 ◦C; (c) BnOC(NH)CCl3, TfOH, dioxane, 0 ◦C; (d) Zn,
THF, H2O, ultrasound, 40 ◦C.
1,4-Dideoxy-1,4-imino-D-arabinitol (DAB)
With the key building block 4 in hand, our attention then turned
to the reductive amination. For the synthesis of DAB the C–C
double bond in 4 was first cleaved by ozonolysis to afford the
corresponding aldehyde (Scheme 2). This dicarbonyl compound
existed as a mixture of hydrates and was not further purified or
characterized. Instead, the crude product was submitted directly
to a double reductive amination30 with benzylamine, sodium
cyanoborohydride and acetic acid in THF. This afforded a 5 :
2 mixture of benzyl-protected DAB 5 and the corresponding L-
xylo compound 6, which could be separated by column chro-
matography. The two isomers were isolated in 62% overall yield
from olefin 4. The yield and diastereoselectivity were lower when
the more sterically demanding benzhydrylamine was used in the
reductive amination. Attempts to use ammonium acetate as the
amine source gave none of the desired product. Lower yield and
diastereoselectivity were also observed when the reducing agent
was changed to sodium triacetoxyborohydride or the acid was
changed to a Lewis acid. The desired isomer 5 was isolated in 44%
yield over two steps from olefin 4. Finally, hydrogenolysis over pal-
ladium on carbon gave 1,4-dideoxy-1,4-imino-D-arabinitol, which
crystallised as the hydrochloride salt in 74% yield. The spectral
data and physical properties of synthetic DAB hydrochloride were
in excellent accordance with those reported in the literature.16 This
Fig.
australine.
2
Retrosynthesis for 1,4-dideoxy-1,4-imino-D-arabinitol and
Zinc-mediated fragmentation of fructose
The iodofuranoside for the reductive fragmentation was prepared
in three steps from fructose. First, the ketose was converted
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gave the two diastereomers in a 1 : 1 ratio. The two amines
could be separated by column chromatography and were isolated
in 67% yield. Attempts to use other reducing agents like sodium
triacetoxyborohydride or L-selectride did not improve the reaction,
but mainly led to reduction of the ketone. The reductive amination
and the zinc-mediated fragmentation of iodide 3 could, however,
be combined and performed as a tandem reaction.32 When a
mixture of iodide 3, homoallylamine, acetic acid, zinc, and s◦odium
cyanoborohydride was sonicated in a THF solution at 40 C the
two amines were isolated in 55% yield as a 1 : 1 mixture. Some
reduction of the ketone also took place under these conditions
which may be due to the higher temperature during the reductive
amination. In order to improve the selectivity we decided to replace
acetic acid by other additives. Therefore, ketone 4 was reacted with
homoallylamine and sodium cyanoborohydride in the presence of
lithium chloride, magnesium dibromide, and indium trichloride.
The first two additives led to a similar yield and selectivity as
obtained with acetic acid. Indium trichloride, on the other hand,
gave a slightly improved 3 : 2 ratio of the two amines in favour of
the (R)-isomer. In this case, the yield of the two amines was 64%
and it was decided to continue the synthesis with this result.
The next step involved protection of the amine functionality
since the ensuing metathesis reaction is severely hampered by
the presence of a secondary amine. The amine protecting group
should be labile to base in order to be removed under the alkaline
conditions for the transannular cyclisation. The trifluoroacetyl
group was chosen for this purpose and installed by reaction
with trifluoroacetic anhydride to afford trifluoroacetamide 8. The
subsequent ring-closing metathesis reaction proceeded well with
Grubbs 2nd generation catalyst33 to form the eight-membered ring
in 71% yield.
Scheme 2 Reagents and conditions: (a) O3, MeOH, CH2Cl2, −78 ◦C, then
˚
Me2S, rt; (b) BnNH2, NaCNBH3, AcOH, 3 A MS, THF, rt; (c) H2, HCl,
MeOH, Pd/C, rt.
completes the synthesis of DAB from D-fructose in only 7 steps
and gives rise to the natural product in 11% overall yield.
First generation approach to australine
With the successful preparation of DAB, the synthesis of the
related pyrrolizidine alkaloid australine might also be realized
from olefin 4. In this case, the reductive amination will be per-
formed with homoallylamine and the diastereoselectivity should
be controlled to afford the (R)-isomer as the major product. Sinay¨
and co-workers have previously reacted 4 with allylamine, sodium
cyanoborohydride and acetic acid to give a 3 : 2 ratio between the
(R)- and the (S)-amine.31 Hence, as the first experiment we treated
olefin 4 with homoallylamine under these conditions at room
temperature (Scheme 3). To our disappointment, this reaction
The following step called for a diastereoselective epoxidation of
the C–C double bond. Unfortunately, treatment of olefin 9 with
m-CPBA afforded a 1 : 1 mixture of the two epoxides in 56% yield.
Changing the epoxidising agent to a dioxirane derived from either
trifluoroacetone34 or a fructose-derived ketone35 gave the same 1 :
1 mixture in a slightly lower yield. The two epoxides could not
be separated by column chromatography and were treated directly
with aqueous lithium hydroxide. Notably, only the desired isomer
underwent the transannular cyclisation while the other isomer was
recovered unchanged.
The complete lack of selectivity in the epoxidation came as
a surprise since White and Hrnciar performed an m-CPBA
epoxidation on a very similar compound in 75% yield with
complete stereocontrol.22 The only difference is the nitrogen
protecting group which in their case was an oxazolidinone ring
with the hydroxymethyl group. Apparently, this additional ring
changes the conformation of the eight-membered ring and the
steric bias around the double bond. At this point, we decided to
change the synthesis in order to introduce this oxazolidinone ring
since a bicyclic ring system seems to be the best way to control
the selectivity in the epoxidation. The synthesis of australine will
then be a formal synthesis, but the route from fructose will still be
shorter than the route from mannitol.
The bicyclic ring system was formed in four steps from amine
7R. First, the amine was protected with the Cbz group to afford
carbamate 11 (Scheme 4). Ring-closing olefin metathesis then
generated the medium-sized ring in 78% yield. Finally, the cyclic
carbamate was installed in two steps by selective acetolysis of the
Scheme 3 Reagents and conditions: (a) homoallylamine, NaCNBH3,
˚
InCl3,
3
A
MS, THF, rt; (b) TFAA, Et3N, CH2Cl2, rt; (c)
=
(PCy3)(C3H4N2Mes2)Cl2Ru CHPh, CH2Cl2, rt; (d) m-CPBA, CH2Cl2, rt;
(e) LiOH·H2O, EtOH, H2O, 100 ◦C.
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Scheme 4 Reagents and conditions: (a) CbzCl, KHCO3, CH2Cl2, H2O, rt;
=
(b) (PCy3)(C3H4N2Mes2)Cl2Ru CHPh, CH2Cl2, rt; (c) Ac2O, TMSOTf,
CH2Cl2, 0 ◦C, then NaOMe, MeOH, rt.
benzyl group on the primary alcohol followed by treatment with
sodium methoxide. Oxazolidinone 13 was isolated in 43% yield
over the last two steps with spectral data and optical rotation in
complete agreement with those reported previously.22 The overall
yield of 13 from fructose is 3.4% over 9 steps. White and Hrnciar
described the synthesis of australine from 13 in 3 steps and 75%
overall yield.22 Although, the route from fructose gives rise to
a shorter synthesis of australine we were still not pleased with
the diastereoselectivity in the reductive amination and the overall
yield. As a result, we decided to investigate an alternative synthesis
from fructose.
Second generation approach to australine
In this case, fructose will be protected with an isopropylidene
group instead of benzyl ethers. The acetal protecting group will
generate a cyclic ketone which may induce a better selectivity in
the reductive amination. Initially, the 1,3-isopropylidene group
was installed from methyl fructofuranoside 1 by reaction with 2,2-
dimethoxypropane, acetone, and camphorsulfonic acid. However,
since furanoside 1 is a 1 : 1 a–b mixture and only the a-anomer
reacted with the acetal, the yield of methyl 1,3-O-isopropylidene-
a-D-fructofuranoside (14) was only 35%. Instead, we turned our
attention to a report by Richardson and co-workers where 14 was
prepared from sucrose by cleavage of the glycosidic linkage.36 In
their work, sucrose was reacted with 2,2-dimethoxypropane and
p-toluenesulfonic acid in dimethylformamide followed by work-up
with basic ion-exchange resin and acetylation to afford acetylated
14 in 36% yield.36 Although a moderate yield, it was noted that
14 was formed as the major product according to TLC. Thus, we
envisioned that this procedure could be further optimized. In fact,
by leaving out the ion-exchange resin, which often binds organic
compounds, and by increasing the amount of acid, we were able to
isolate 14 in 59% yield after purification by flash chromatography
(Scheme 5).
Scheme 5 Reagents and conditions: (a) Me2C(OMe)2, TsOH·H2O, DMF,
rt; (b) I2, PPh3, imidazole, THF, 65 ◦C; (c) Zn, THF, H2O, ultrasound,
◦
˚
40 C; (d) homoallylamine, NaCNBH3, AcOH, 3 A MS, THF, rt; (e)
=
CbzCl, KHCO3, CH2Cl2, H2O, rt; (f) (PCy3)(C3H4N2Mes2)Cl2Ru CHPh,
CH2Cl2, rt; (g) AcOH, H2O, rt; (h) NaOMe, MeOH, rt; (i) BnBr, NaH,
THF, rt.22
could be separated after protection with the Cbz group. The
major isomer 18R was submitted to ring-closing metathesis to
afford the eight-membered ring in 90% yield. Hydrolysis of the
isopropylidene group then gave triol 20, which upon treatment
with base furnished oxazolidinone 21. The spectroscopic data for
21 were in agreement with those reported by White and Hrnciar
who described the following benzylation to give 13 in 84% yield.22
This alternative synthesis of 13 requires 9 steps from sucrose and
gives rise to the target molecule in 4.0% overall yield.
Conclusion
With acetal 14 in hand, the next step required a substitution
of the primary hydroxyl group with iodide. This reaction was
conducted under the same conditions as described above to afford
iodofuranoside 15 in 84% yield. Subsequent fragmentation with
zinc proceeded uneventfully to give cyclic ketone 16 in 70%
yield. Treatment of this compound with homoallylamine, sodium
cyanoborohydride and acetic acid in THF gave a 2 : 1 mixture
of the (R)- and the (S)-amine in 64% yield. This is only a slight
improvement compared to the result with ketone 4. Unfortunately,
it was not possible in this case to enhance the selectivity by adding
indium trichloride which mainly led to reduction of the ketone
16. The two amines co-eluted by column chromatography, but
We have described a new synthesis of 1,4-dideoxy-1,4-imino-D-
arabinitol and a formal synthesis of australine where the latter
has been achieved by two different protecting group strategies.
The synthesis of 1,4-dideoxy-1,4-imino-D-arabinitol requires 7
steps from D-fructose and occurs in 11% overall yield. This
constitutes the shortest chemical synthesis of 1,4-dideoxy-1,4-
imino-D-arabinitol reported to date. The formal synthesis of
australine with benzyl protection gives rise to the key intermediate
13 in 9 steps from fructose and 3.4% overall yield. The alternative
synthesis with isopropylidene protection affords 13 in 9 steps from
sucrose and 4.0% overall yield. In their synthesis of australine
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White and Hrnciar prepared the key intermediate 13 in 13 steps
from D-mannitol and 4.2% overall yield.
For methyl 6-deoxy-6-iodo-b-D-fructofuranoside: Rf 0.57
(CHCl3–MeOH, 5 : 1); [a]D −21.2 (c 2.1, MeOH); mmax(KBr)/cm−1:
3426, 2941, 1371, 1139, 1093, 1060, 1011; dH (300 MHz, D2O):
4.20 (d, J = 8.1 Hz, 1H), 4.13 (t, J = 6.9 Hz, 1H), 3.89–3.83
(m, 1H), 3.74 (d, J = 12.3 Hz, 1H), 3.66 (d, J = 12.3 Hz, 1H),
3.50 (dd, J = 10.8, 5.1 Hz, 1H), 3.42–3.36 (m, 1H), 3.36 (s, 3H);
dC (75 MHz, D2O): 104.6, 81.0, 79.5, 77.9, 60.3, 50.2, 7.7; Anal.
calcd. for C7H13IO5: C, 27.65; H, 4.31. Found: C, 27.91; H, 4.23%.
The syntheses highlight the use of D-fructose as a synthetic
starting material by exploiting the zinc-mediated fragmentation
of the methyl 6-iodo-furanoside. Benzyl-protected ketone 4 is
prepared from fructose in 4 steps while the isopropylidene-
protected ketone 16 is obtained from sucrose in only 3 steps.
Unsaturated ketones 4 and 16 are valuable building blocks for
further synthesis.
Methyl 1,3,4-tri-O-benzyl-6-deoxy-6-iodo-D-fructofuranoside
(3). A solution of 2 (1.49 g, 4.90 mmol) in freshly distilled
dioxane (30 mL) was cooled to 0 ◦C followed by addition of
freshly distilled benzyl trichloroacetimidate (3.3 mL, 17.7 mmol).
Triflic acid was added (30 drops) to ensure that the mixture
was strongly acidic and the solution was stirred for 12 min. The
reaction was quenched with saturated aqueous NaHCO3 (50 mL)
and extracted with Et2O (50 mL). The organic phase was dried
(K2CO3) and concentrated. The residue was purified by flash
chromatography (hexane–Et2O, 7 : 1) to give the title compound
(2.06 g, 73%) as a mixture of two diastereomers which could not
be separated. Pure samples of both epimers were prepared from
anomerically pure samples of 2.
For methyl 1,3,4-tri-O-benzyl-6-deoxy-6-iodo-a-D-fructo-
furanoside: Rf 0.58 (hexane–EtOAc, 3 : 1); [a]D +25.0 (c 2,
CHCl3); mmax(neat)/cm−1: 3029, 2868, 1496, 1454, 1113, 736, 699;
dH (300 MHz, CDCl3): 7.37–7.27 (m, 15H), 4.70–4.42 (m, 6H),
4.10 (d, J = 2.7 Hz, 1H), 3.97 (q, J = 5.3 Hz, 1H), 3.76 (dd,
J = 5.5, 2.3 Hz, 1H), 3.66 (s, 2H), 3.31 (s, 3H), 3.29 (dd, J =
10.6, 5.7 Hz, 1H), 3.20 (dd, J = 10.7, 6.6 Hz, 1H); dC (75 MHz,
CDCl3): 138.0, 137.8, 137.7, 128.6, 128.5 (2C), 128.2, 128.1, 128.0,
127.9 (3C), 108.4, 87.6 (2C), 80.7, 73.7, 72.8, 72.2, 65.8, 48.8, 6.4;
HRMS calcd. for C28H31IO5Na [M + Na]+ m/z 597.1114, found
m/z 597.1111.
For methyl 1,3,4-tri-O-benzyl-6-deoxy-6-iodo-b-D-fructo-
furanoside: Rf 0.58 (hexane–EtOAc, 3 : 1); [a]D +21.6 (c 2.1,
CHCl3); mmax(neat)/cm−1: 2925, 1454, 1114, 1106, 736, 700; dH
(300 MHz, CDCl3): 7.36–7.25 (m, 15H), 4.74 (d, J = 11.8 Hz,
1H), 4.65–4.54 (m, 4H), 4.50 (d, J = 12.0 Hz, 1H), 4.32 (d,
J = 6.8 Hz, 1H), 4.07 (t, J = 6.2 Hz, 1H), 3.99–3.93 (m, 1H),
3.59–3.57 (m, 2H), 3.41 (s, 3H), 3.31–3.26 (m, 2H); dC (75 MHz,
CDCl3): 138.1, 137.9, 137.8, 128.6 (2C), 128.5, 128.3, 128.0 (3C),
127.9 (2C), 104.7, 86.8, 85.4, 79.7, 73.7, 73.0, 72.8, 69.9, 50.3, 7.9;
Anal. calcd. for C28H31IO5: C, 58.54; H, 5.44. Found: C, 58.14; H,
5.40%.
Experimental
General
Reactions were conducted under an atmosphere of nitrogen when
anhydrous solvents were used. CH2Cl2 was dried over activated
˚
4 A molecular sieves, while THF was distilled from sodium-
benzophenone. Sonications were carried out in a Branson 1210
sonic bath. Zinc (Aldrich, particle size <0.01 mm) was activated
and dried immediately before use: zinc dust (5 g) in 1 M HCl
(50 mL) was stirred at room temperature for 15 min, and then
filtered, washed with water (2 × 50 mL) and Et2O (2 × 50 mL),
and finally dried under high vacuum with a heatgun. All reactions
were monitored with thin-layer chromatography using aluminium
plates precoated with silica gel 60. Compounds were visualized by
dipping in a solution of Ce(SO4)2 (10 g L−1) and (NH4)6Mo7O24
(25 g L−1) in 10% aqueous H2SO4 followed by heating. Flash
column chromatography was performed with E. Merck silica
gel 60 (particle size 0.040–0.063 mm) while reverse phase flash
chromatography was conducted with Macherey-Nagel silica gel
60 C18 (particle size 0.040–0.063 mm). Optical rotations were
measured on a Perkin Elmer 241 polarimeter while IR spectra
were recorded on a Perkin Elmer 1720 Infrared Fourier Transform
spectrometer. NMR spectra were recorded on a Varian Unity
Inova 500 or a Varian Mercury 300 instrument. Chemical shifts are
reported in parts per million (ppm) with the residual undeuterated
solvent as internal reference for 1H NMR and the deuterated
solvent as reference for 13C NMR.37 Microanalyses and high
resolution mass spectra were obtained at the Department of
Chemistry, University of Copenhagen.
Methyl 6-deoxy-6-iodo-D-fructofuranoside (2). To a solution
of 127 (5.23 g, 26.9 mmol) in dry THF (200 mL) were added PPh3
(10.6 g, 40.4 mmol) and imidazole (3.65 g, 53.6 mmol). The mixture
was heated to reflux and a solution of I2 (10.35 g, 40.8 mmol) in dry
THF (80 mL) was added over 2 h. The reaction mixture was cooled
to room temperature, filtered and concentrated. The residue was
purified by reverse phase flash chromatography (H2O–MeOH, 9 :
1). The appropriate fractions were concentrated and purified by
silica gel flash chromatography (CH2Cl2–MeOH, 50 : 1 → 50 : 3)
to give a mixture of the two epimers as a white solid (5.46 g, 67%).
For methyl 6-deoxy-6-iodo-a-D-fructofuranoside: Rf 0.67
(CHCl3–MeOH, 5 : 1); [a]D +78.8 (c 2.0, MeOH); mmax(KBr)/cm−1:
3347, 2926, 2876, 1451, 1041, 1024; dH (500 MHz, D2O): 4.11 (d,
J = 3.4 Hz, 1H), 3.89–3.83 (m, 2H), 3.75 (d, J = 12.2 Hz, 1H),
3.63 (d, J = 12.4 Hz, 1H), 3.47–3.42 (m, 1H), 3.36–3.30 (m, 1H),
3.27 (s, 3H); dC (75 MHz, D2O): 108.9, 82.5, 81.5, 81.0, 58.3, 48.9,
5.9; Anal. calcd. for C7H13IO5: C, 27.65; H, 4.31. Found: C, 27.90;
H, 4.23%.
(3S,4R)-1,3,4-Tris(benzyloxy)-hex-5-en-2-one (4). To a solu-
tion of 3 (2.42 g, 4.21 mmol) in THF (30 mL) and H2O (8 mL)
was added pre-activated zinc (2.7 g, 41.3 mmol) and the mixture
was sonicated for 2 h at 40 ◦C. The mixture was then filtered
through a short column of Celite, which was rinsed with CH2Cl2.
The filtrate was washed with saturated aqueous NaHCO3 (2 ×
25 mL), dried and concentrated. The residue was purified by
flash chromatography (hexane–EtOAc, 6 : 1) to afford ketone 4
(1.29 g, 74%). Rf 0.56 (hexane–EtOAc, 3 : 1); [a]D −45.7 (c 1.7,
CHCl3); mmax(neat)/cm−1: 3032, 2864, 1733, 1496, 1455, 1104, 735;
dH (300 MHz, CDCl3): 7.29–7.14 (m, 15H), 5.90–5.78 (m, 1H),
5.27 (d, J = 17.2 Hz, 1H), 5.26 (d, J = 10.7 Hz, 1H), 4.54–4.34 (m,
5H), 4.29–4.27 (m, 2H), 4.22 (d, J = 11.8 Hz, 1H), 4.12 (dd, J =
7.9, 3.4 Hz, 1H), 3.94 (d, J = 3.2 Hz, 1H); dC (75 MHz, CDCl3):
207.7, 137.6, 137.4, 136.9, 134.2, 128.6, 128.5 (2C), 128.4, 128.3,
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128.2, 128.1, 128.0, 127.9, 119.9, 85.9, 80.9, 74.6, 74.4, 73.3, 70.9;
Anal. calcd. for C27H28O4: C, 77.86; H, 6.78. Found: C, 77.83; H,
6.67%.
for 3 h and then filtered. The filtrate was diluted with Et2O
(10 mL) and washed with saturated aqueous NaHCO3 (10 mL).
The aqueous phase was extracted with Et2O (3 × 5 mL) and the
combined organic phases were dried (K2CO3) and concentrated.
The residue was purified by flash chromatography (heptane–Et2O–
Et3N, 66 : 33 : 1) to give 7 (0.060 g, 64%) as a 2 : 3 mixture of 7S
and 7R.
For 7S. Rf 0.35 (hexane–EtOAc, 3 : 1); [a]D +9.5 (c 2, CHCl3);
mmax(neat)/cm−1: 2860, 1714, 1454, 1095, 734; dH (300 MHz,
CDCl3): 7.38–7.24 (m, 15H), 5.91–5.69 (m, 2H), 5.37–5.29 (m,
2H), 5.07–4.95 (m, 2H), 4.87 (d, J = 11.2 Hz, 1H), 4.60 (d, J =
11.5 Hz, 1H), 4.55 (d, J = 11.4 Hz, 1H), 4.37 (m, 3H), 4.17 (t, J =
6.8 Hz, 1H), 3.70 (dd, J = 6.6, 3.5 Hz, 1H), 3.45–3.43 (m, 2H),
2.93–2.88 (m, 1H), 2.76 (dt, J = 11.2, 7.1 Hz, 1H), 2.53 (dt, J =
11.1, 7.3 Hz, 1H), 2.18–2.11 (m, 2H); dC (75 MHz, CDCl3): 139.2,
138.8, 138.5, 136.9, 136.0, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9,
127.7, 127.6, 127.5, 118.8, 116.0, 82.8, 81.7, 75.3, 73.2, 70.8, 69.7,
57.8, 47.4, 35.1; Anal. calcd. for C31H37NO3: C, 78.95; H, 7.91; N,
2.97. Found: C, 78.62; H, 8.04; N, 2.96%.
2,3,5-Tri-O-benzyl-1,4-benzylimino-1,4-dideoxy-D-arabinitol (5)
and -L-xylitol (6). A solution of ketone 4 (0.920 g, 2.21 mmol)
in MeOH–CH2Cl2 (80 mL, 2 : 1) was cooled to −78 ◦C. N2
was bubbled through the solution for 15 min followed by ozone
for 30 min and then N2 for 15 min. Me2S (0.9 mL) was added
and the reaction was warmed to room temperature. The mixture
was concentrated and the residue dissolved in dry THF (70 mL).
˚
Molecular sieves (3 A) were added followed by benzylamine (2 mL,
18.3 mmol) and then AcOH until pH ∼ 6–7. NaCNBH3 (0.7 g,
11.1 mmol) was added at 0 ◦C and the reaction was stirred
overnight at room temperature. The mixture was quenched with
saturated aqueous NaHCO3 (100 mL), filtered and extracted with
EtOAc (3 × 50 mL). The combined organic layers were dried
(Na2SO4), concentrated and purified by flash chromatography
(heptane–EtOAc, 8 : 1) to give a 5 : 2 mixture of 5 and 6 (0.674 g,
62%).
For 7R. Rf 0.19 (hexane–EtOAc, 3 : 1); [a]D −7.3 (c 1, CHCl3);
mmax(neat)/cm−1: 2862, 1454, 1095, 734, 699; dH (300 MHz, CDCl3):
7.33–7.28 (m, 15H), 5.95–5.84 (m, 1H), 5.79–5.66 (m, 1H), 5.32–
5.26 (m, 2H), 5.06–4.95 (m, 2H), 4.74 (d, J = 11.5 Hz, 1H), 4.64–
4.59 (m, 2H), 4.52 (d, J = 12.3 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H),
4.35 (d, J = 12.0 Hz, 1H), 4.16 (dd, J = 7.7, 4.7 Hz, 1H), 3.67–3.56
(m, 3H), 2.95–2.91 (m, 1H), 2.61 (dt, J = 11.3, 7.0 Hz, 1H), 2.47
(dt, J = 11.3, 7.0 Hz, 1H), 2.10 (q, J = 7.2 Hz, 2H); dC (75 MHz,
CDCl3): 139.0, 138.7, 138.6, 136.9, 136.3, 128.4 (2C), 128.3, 128.2
(2C), 127.9, 127.6 (2C), 127.5, 118.4, 116.0, 81.6, 81.2, 74.9, 73.2,
70.7, 68.7, 58.3, 47.0, 34.9; Anal. calcd. for C31H37NO3: C, 78.95;
H, 7.91; N, 2.97. Found: C, 78.62; H, 8.04; N, 2.96%.
For 5. Rf 0.35 (heptane–EtOAc, 3 : 1); [a]D +25.8 (c 2, CHCl3);
dH (300 MHz, CDCl3): 7.35–7.23 (m, 20H), 4.44 (s, 2H), 4.43 (s,
2H), 4.38 (d, J = 12.4 Hz, 1H), 4.30 (d, J = 12.2 Hz, 1H), 4.07 (d,
J = 13.1 Hz, 1H), 3.84–3.82 (m, 2H), 3.54–3.52 (m, 2H), 3.41 (d,
J = 13.0 Hz, 1H), 2.97 (d, J = 10.5 Hz, 1H), 2.79 (q, J = 5.1 Hz,
1H), 2.48 (dd, J = 10.5, 5.5 Hz, 1H); dC (75 MHz, CDCl3): 139.0,
138.7, 138.5 (2C), 129.2, 128.6, 128.4, 128.0, 127.9, 127.8, 127.1,
86.1, 81.7, 73.5, 71.6, 71.5, 71.1, 68.7, 59.4, 57.2; HRMS calcd. for
C33H36NO3 [M + H]+ m/z 494.2695, found m/z 494.2703.
For 6. Rf 0.27 (heptane–EtOAc, 3 : 1); [a]D +28.7 (c 2, CHCl3)
(lit.38 [a]22 +30.5 (c 0.95, CHCl3)); dH (300 MHz, CDCl3): 7.32–
D
7.26 (m, 20H), 4.64 (d, J = 12.3 Hz, 1H), 4.57 (d, J = 12.3 Hz,
1H), 4.53 (s, 2H), 4.42 (s, 2H), 4.15–4.00 (m, 3H), 3.87 (dd, J = 9.6,
6.2 Hz, 1H), 3.67–3.64 (m, 1H), 3.48 (d, J = 13.0 Hz, 1H), 3.30–
3.25 (m, 1H), 3.15–3.13 (m, 1H), 2.35–2.31 (m, 1H); dC (75 MHz,
CDCl3): 139.1, 138.5 (2C), 138.2, 129.1, 128.5 (2C), 128.4, 128.3,
127.9, 127.8 (2C), 127.7 (2C), 127.6, 127.0, 83.6, 82.1, 73.6, 72.2,
71.5, 69.6, 65.4, 59.5, 57.3; HRMS calcd. for C33H36NO3 [M + H]+
m/z 494.2695, found m/z 494.2728.
Methyl 1,3-O-isopropylidene-a-D-fructofuranoside (14).
A
mixture of sucrose (2.00 g, 5.84 mmol) and TsOH·H2O (0.50 g,
2.63 mmol) in DMF (30 mL) was stirred at room temperature
for 30 min. 2,2-Dimethoxypropane (8.0 mL, 66 mmol) was added
and the resulting solution stirred for 48 h. The reaction was
quenched with Na2CO3 (4.0 g) and stirred for an additional 1 h.
The mixture was filtered and the filtrate concentrated at high
vacuum. The residue was purified twice by flash chromatography
(CH2Cl2–MeOH, 14 : 1 and then EtOAc–heptane, 2 : 1) to give
14 (0.804 g, 59%) as a syrup. Rf 0.40 (CH2Cl2–MeOH, 10 :
1); [a]D +38.6 (c 2, CHCl3) (lit.36 [a]D +42.5 (c 1, MeOH));
mmax(neat)/cm−1: 3416, 2989, 2944, 1378, 1219, 1096; dH (CDCl3,
300 MHz): 4.08–4.05 (m, 1H), 4.00 (s, 1H), 3.95–3.85 (m, 3H),
3.77–3.75 (m, 2H), 3.27 (s, 3H), 3.08 (br s, 2H), 1.42 (s, 3H), 1.33
(s, 3H); dC (75 MHz, CDCl3): 101.4, 98.8, 87.3, 79.9, 77.6, 62.8,
61.9, 48.7, 27.8, 19.5; dC (75 MHz, CD3OD): 104.1, 100.4, 86.2,
83.4, 78.7, 63.4, 62.8, 48.6, 27.1, 21.3; HRMS calcd. for C10H19O6
[M + H]+ m/z 235.1182, found m/z 235.1179.
Methyl 6-deoxy-6-iodo-1,3-O-isopropylidene-a-D-fructofurano-
side (15). To a solution of 14 (0.420 g, 1.79 mmol) in dry THF
(16 mL) were added PPh3 (0.71 g, 2.7 mmol) and imidazole (0.25 g,
3.7 mmol) and the mixture was heated to reflux. A solution of I2
(0.7 g, 2.8 mmol) in dry THF (7 mL) was added quickly, and the
reaction had gone to completion within a few minutes according
to TLC. The mixture was cooled to room temperature, filtered
and concentrated. The residue was purified by flash chromato-
graphy (hexane–EtOAc, 3 : 1) to afford 15 (0.520 g, 84%). Rf 0.19
1,4-Dideoxy-1,4-imino-D-arabinitol hydrochloride. Amine
5
(0.340 g, 0.689 mmol) was dissolved in 1.25 M HCl in MeOH
(30 mL) and Pd/C (186 mg) was added. The reaction was stirred
under 10 bar of H2 for 4 days. The mixture was filtered through a
short column of Celite, which was rinsed with MeOH. The filtrate
was concentrated and co-concentrated with toluene to give a solid
residue which was recrystallised from Et2O–MeOH. This gave
DAB hydrochloride as a ◦white solid (0.086 g, 74%). Mp 110–
112 ◦C (lit.16a mp 113–114 C); [a]D +31.1 (c 0.2, H2O) (lit.16a [a]20
D
+34.7 (c 0.78, H2O)); dH (300 MHz, D2O): 4.30–4.27 (m, 1H), 4.04
(t, J = 2.8 Hz, 1H), 3.91 (dd, J = 12.2, 4.6 Hz, 1H), 3.78 (dd, J =
12.0, 8.5 Hz, 1H), 3.57–3.48 (m, 2H), 3.29 (dd, J = 12.7, 2.8 Hz,
1H); dC (75 MHz, D2O): 76.4, 75.1, 67.3, 59.7, 50.7. NMR data
are in accordance with literature values.16
(3R,4R)-1,3,4-Tris(benzyloxy)-2-(but-3-enylamino)-hex-5-ene
(7). To a solution of ketone 4 (0.083 g, 0.199 mmol) in THF
˚
(8 mL) were added activated molecular sieves (3 A), InCl3 (0.226 g,
1.02 mmol), homoallylamine (0.145 g, 2.04 mmol) and NaCNBH3
(0.024 g, 0.38 mmol). The mixture was stirred at room temperature
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(hexane–EtOAc, 4 : 1); [a]D +26.1 (c 2, CH2Cl2); mmax(neat)/cm−1:
3445 (br), 2990, 2939, 1376, 1093; dH (300 MHz, CDCl3): 4.19 (m,
1H), 4.02 (s, 1H), 3.97 (dd, J = 9.9, 1.7 Hz, 1H), 3.88 (d, J = 1.2 Hz,
1H), 3.36–3.29 (m, 2H), 3.28 (s, 3H), 2.87 (d, J = 10.4 Hz, 1H),
1.42 (s, 3H), 1.34 (s, 3H); dC (75 MHz, CDCl3): 102.5, 98.8, 87.5,
80.2, 79.7, 61.9, 48.9, 27.9, 19.6, 5.6; Anal. calcd. for C10H17IO5:
C, 34.90; H, 4.98. Found: C, 35.24; H, 4.95%.
(Na2SO4) and concentrated. The residue was purified by flash
chromatography (heptane–EtOAc, 3 : 1) to give 18R (0.123 g,
54%) and 18S (0.062 g, 27%).
For 18R: Rf 0.35 (hexane–EtOAc, 3 : 1); [a]D −20.9 (c 2, CHCl3);
mmax(neat)/cm−1: 3459, 2990, 1679, 1429, 1227, 944; dH (300 MHz,
CDCl3): 7.39–7.26 (m, 5H), 5.94–5.63 (m, 2H), 5.32–5.00 (m, 6H),
4.55–4.39 (m, 1H), 4.17–4.04 (m, 2H), 3.80–3.47 (m, 3H), 3.20 (q,
J = 7.4 Hz, 1H), 2.47–2.20 (m, 2H), 1.54, 1.38, 1.31, 1.16 (4s,
6H); dC (75 MHz, CDCl3): 155.6, 137.8, 136.5, 135.1, 134.9, 128.9,
128.8, 128.7, 128.4, 128.2, 127.8, 117.3, 116.3, 116.2, 99.1, 72.0,
71.1, 70.8, 68.0, 67.2, 61.1, 60.2, 52.5, 49.1, 34.1, 33.4, 28.4, 20.3,
19.8; HRMS calcd. for C21H30NO5 [M + H]+ m/z 376.2124, found
m/z 376.2114.
For 18S: Rf 0.18 (hexane–EtOAc, 3 : 1); [a]D +10.6 (c 2.1,
CHCl3); mmax(neat)/cm−1: 3450 (br), 2990, 1696, 1422, 1384, 1288,
1228, 1200, 1148, 1011; dH (300 MHz, CDCl3): 7.35–7.26 (m, 5H),
5.95–5.67 (m, 2H), 5.30–4.98 (m, 6H), 4.24–3.52 (m, 6H), 3.17 (d,
J = 5.0 Hz, 1H), 2.43 (q, J = 7.6 Hz, 2H), 1.49 (s, 3H), 1.44 (s,
3H); dC (75 MHz, CDCl3): 157.4, 136.5, 135.7, 135.1, 128.6, 128.2,
128.0, 116.5, 116.1, 99.6, 75.0, 71.7, 67.7, 64.6, 47.1, 45.8, 34.2,
29.5, 18.7; HRMS calcd. for C21H30NO5 [M + H]+ m/z 376.2124,
found m/z 376.2112.
(1ꢀR,4S)-2,2-Dimethyl-4-(1ꢀ -hydroxyallyl)-1,3-dioxan-5-one
(16). To a solution of 15 (3.02 g, 8.78 mmol) in THF (50 mL)
and H2O (15 mL) was added pre-activated zinc (4.9 g, 75 mmol)
followed by sonication for 1.5 h at 40 ◦C. The mixture was filtered
through a short column of Celite and the column was rinsed with
CH2Cl2. The filtrate was washed with saturated aqueous NaHCO3
(100 mL). The aqueous layer was extracted with CH2Cl2 (100 mL)
and the combined organic phases were dried (Na2SO4) and
concentrated. The residue was purified by flash chromatography
(CH2Cl2–MeOH, 49 : 1) to give 16 (1.14 g, 70%). Rf 0.19 (hexane–
EtOAc, 4 : 1); [a]D −164.9 (c 2, CHCl3); mmax(neat)/cm−1: 3484 (br),
2988, 1750, 1377, 1227; dH (300 MHz, CDCl3): 6.01–5.90 (m, 1H),
5.37 (dt, J = 17.3, 1.5 Hz, 1H), 5.22 (dt, J = 10.5, 1.5 Hz, 1H), 4.56
(br s, 1H), 4.27–4.21 (m, 2H), 3.99 (dd, J = 17.1, 1.2 Hz, 1H), 2.58
(br s, 1H), 1.45 (s, 3H), 1.44 (s, 3H); dC (75 MHz, CDCl3): 208.2,
136.3, 116.8, 101.0, 77.2, 70.6, 67.2, 24.3, 23.5; HRMS calcd. for
C9H14O4 [M]+ m/z 186.0892, found m/z 186.0903.
(1R,7R,8R)-N -Benzyloxycarbonyl-7-hydroxy-10,10-dimethyl-
9,11-dioxo-2-azabicyclo[6.4.0]dodec-5-ene (19). A solution of di-
ene 18R (0.240 g, 0.639 mmol) in CH2Cl2 (30 mL) was degassed
under argon. Grubbs 2nd generation catalyst (0.025 g, 0.029 mmol)
was added and the reaction was stirred at room temperature
overnight. The mixture was concentrated and the residue purified
by flash chromatography (heptane–EtOAc, 2 : 1) to give 19
(0.200 g, 90%), which showed 2 rotamers by NMR. Rf 0.24
(heptane–EtOAc, 2 : 1); [a]D +38.5 (c 2, CHCl3); mmax(neat)/cm−1:
3476 (br), 2936, 1697, 1424, 1130; dH (300 MHz, CDCl3): 7.37–
7.31 (m, 5H), 5.65–5.46 (m, 2H), 5.12–4.92 (m, 2H), 4.74, 4.59 (2t,
J = 10.8 Hz, J = 9.4 Hz, 1H), 4.34–3.78 (m, 3H), 3.67–3.57 (m,
1H), 2.93–2.81 (m, 2H), 2.32–2.10 (m, 2H), 1.64, 1.41, 1.31, 1.08
(4s, 6H); dC (75 MHz, CDCl3): 156.1, 155.6, 136.3, 135.5, 134.4,
133.2, 129.2, 128.7 (2C), 128.5, 128.2, 128.1, 126.4, 125.9, 99.2,
99.0, 72.1, 72.0, 71.4, 69.6, 68.2, 66.9, 60.5, 59.5, 54.8, 54.0, 46.4,
46.1, 29.1, 28.9, 27.0, 26.8, 19.9, 19.4; HRMS calcd. for C19H26NO5
[M + H]+ m/z 348.1811, found m/z 348.1790.
(1ꢀR,4R)-5-(But-3-enylamino)-2,2-dimethyl-4-(1ꢀ-hydroxyallyl)-
1,3-dioxane (17). To a solution of ketone 16 (0.058 g, 0.31 mmol)
˚
in dry THF (5 mL) were added activated molecular sieves (3 A)
and homoallylamine (0.24 g, 3.4 mmol). The mixture was cooled
to 0 ◦C and AcOH was added until pH 6–7. NaCNBH3 (0.095 g,
1.5 mmol) was then added and the reaction was stirred at room
temperature for 1 h. The mixture was filtered and the filtrate
was diluted with CH2Cl2 (10 mL) and washed with saturated
aqueous NaHCO3 (15 mL). The aqueous layer was extracted
with EtOAc (2 × 5 mL) and the combined organic phases were
dried (K2CO3) and concentrated. The residue was purified by flash
chromatography (CH2Cl2–MeOH, 19 : 1) to give 17 (0.048 g, 64%)
as a 2 : 1 mixture of diastereomers which could not be separated.
Rf 0.53 (CH2Cl2–MeOH, 9 : 1); mmax(neat)/cm−1: 3282, 2995, 2935,
1378, 1201, 1103; dH (300 MHz, CDCl3): 6.05–5.64 (m, 4H), 5.43–
5.00 (m, 8H), 4.36–4.34 (m, 1H), 4.24–4.21 (m, 1H), 3.93 (dd, J =
11.5, 5.3 Hz, 1H), 3.85–3.83 (m, 2H), 3.70 (t, J = 2.2 Hz, 1H), 3.66
(dd, J = 9.9, 3.8 Hz, 1H), 3.45 (t, J = 10.0 Hz, 1H), 2.94–2.74 (m,
4H), 2.60–2.50 (m, 2H), 2.30–2.15 (m, 4H), 1.40 (s, 6H), 1.39 (s,
3H), 1.33 (s, 3H); dC (75 MHz, CDCl3): 138.0, 137.3, 135.8 (2C),
117.0, 116.8, 115.8, 115.2, 99.3, 98.7, 75.6, 73.4, 73.2, 72.6, 63.6,
61.4, 55.1, 52.4, 46.0, 45.9, 34.6, 34.5, 29.6, 28.7, 19.3, 18.4; HRMS
calcd. for C13H23NO3 [M]+ m/z 241.1678, found m/z 241.1672.
(2R,3R,4R)-N-Benzyloxycarbonyl-5,6-didehydro-3,4-dihydroxy-
2-hydroxymethyl-azocane (20). Cycloheptene 19 (0.171 g,
0.492 mmol) was dissolved in 80% AcOH (3 mL) and stirred at
room temperature for 4 h. The mixture was concentrated and the
residue was purified by flash chromatography (CH2Cl2–MeOH,
9 : 1) to afford 20 (0.117 g, 77%). Rf 0.48 (CHCl3–MeOH, 9 : 1);
[a]D +69.6 (c 2, CHCl3); mmax(neat)/cm−1: 3416 (br), 2948, 1678,
1436, 1235, 1058; dH (300 MHz, CDCl3): 7.39–7.26 (m, 5H), 5.60
(dd, J = 10.7, 6.0 Hz, 1H), 5.51–5.44 (m, 1H), 5.14–4.98 (m,
2H), 4.27–3.76 (m, 5H), 2.94–2.87 (m, 2H), 2.32–2.14 (m, 2H);
dC (75 MHz, CDCl3): 157.6, 136.1, 134.7, 128.6, 128.4, 128.1,
125.6, 72.3, 69.3, 67.6, 65.4, 62.1, 46.2, 26.7; HRMS calcd. for
C16H22NO5 [M + H]+ m/z 308.1498, found m/z 308.1491.
(1ꢀR,4R,5R)-N -Benzyloxycarbonyl-5-(but-3-enylamino)-2,2-
dimethyl-4-(1ꢀ-hydroxyallyl)-1,3-dioxane (18R) and (1ꢀR,4R,5S)-
N -benzyloxycarbonyl-5-(but-3-enylamino)-2,2-dimethyl-4-(1ꢀ-hy-
droxyallyl)-1,3-dioxane (18S). To a solution of aminodiene 17
(0.147 g, 0.609 mmol) in CH2Cl2 (20 mL) and H2O (15 mL) was
added KHCO3 (0.49 g, 4.9 mmol) and the mixture was cooled
to 0 ◦C. CbzCl (0.17 mL, 1.2 mmol) was added dropwise, and
the stirring was continued for 45 min at room temperature. The
organic phase was isolated and the aqueous phase extracted with
CH2Cl2 (2 × 10 mL). The combined organic phases were dried
(9R,10R,10aR)-9,10-Dihydroxy-1,5,6,9,10,10a-hexahydro[1,3]-
oxazolo[3,4-a]azocin-3-one (21). To a solution of the triol 20
(0.070 g, 0.228 mmol) in MeOH (2 mL) was added a 1 M solution
of NaOMe in MeOH (0.1 mL). The mixture was stirred at room
2904 | Org. Biomol. Chem., 2006, 4, 2898–2905
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temperature for 7.5 h and then concentrated. The residue was
partitioned between CH3CN (3 ml) and H2O (5 mL) and the
phases were separated. The aqueous phase was extracted with
CH3CN (2 × 3 mL) and the combined organic phases were dried
(Na2SO4) and concentrated. The residue was purified by flash
chromatography (CH2Cl2–MeOH, 9 : 1) to give 21 (0.026 mg,
57%). Rf 0.38 (CH2Cl2–MeOH, 9 : 1); mmax(neat)/cm−1: 3378 (br),
1746, 1423, 1215, 1065; dH (300 MHz, CD3CN): 5.61–5.55 (m,
2H), 4.38 (dd, J = 8.9, 2.2 Hz, 1H), 4.28 (dd, J = 9.0, 7.8 Hz,
1H), 4.20 (dd, J = 9.7, 3.9 Hz, 1H), 3.75 (br s, 1H), 3.57–3.45 (m,
3H), 3.20–3.20 (m, 2H), 2.39–2.23 (m, 2H); dC (75 MHz, CD3CN):
160.8, 135.6, 126.5, 75.4, 71.0, 68.8, 58.9, 44.6, 27.1; HRMS calcd.
for C9H14NO4 [M + H]+ m/z 200.0923, found m/z 200.0956.
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Acknowledgements
Financial support from the Lundbeck Foundation is gratefully
acknowledged. The Center for Sustainable and Green Chemistry
is sponsored by the Danish National Research Foundation.
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