A short synthetic route to the calystegine alkaloids

Article abstract of DOI:10.1021/jo020645c

An efficient strategy is described for the synthesis of enantiopure calystegine alkaloids. The key step employs a zinc-mediated fragmentation of benzyl-protected methyl 6-iodo-glycosides followed by in situ formation of the benzyl imine and Barbier-type allylation with zinc, magnesium, or indium metal. Stereochemistry in the pivotal allylation is controlled by the choice of the metal. The functionalized 1,8-nonadienes, thus formed, are converted into cycloheptenes by ring-closing olefin metathesis. Regioselective hydroboration and oxidation give the corresponding cycloheptanones, which are deprotected to afford the desired calystegines. Hereby, calystegine B₂, B₃, and B₄ are prepared from D-glucose, D-galactose, and D-mannose, respectively. This route constitutes the shortest synthesis of calystegine B₂ and gives rise to the first total syntheses of calystegine B₃ and B₄.

Full text of DOI:10.1021/jo020645c

A Sh or t Syn th etic Rou te to th e Ca lystegin e Alk a loid s
Philip R. Skaanderup and Robert Madsen*
Department of Chemistry, Building 201, Technical University of Denmark, DK-2800 Lyngby, Denmark
rm@kemi.dtu.dk
Received October 10, 2002
An efficient strategy is described for the synthesis of enantiopure calystegine alkaloids. The key
step employs a zinc-mediated fragmentation of benzyl-protected methyl 6-iodo-glycosides followed
by in situ formation of the benzyl imine and Barbier-type allylation with zinc, magnesium, or indium
metal. Stereochemistry in the pivotal allylation is controlled by the choice of the metal. The
functionalized 1,8-nonadienes, thus formed, are converted into cycloheptenes by ring-closing olefin
metathesis. Regioselective hydroboration and oxidation give the corresponding cycloheptanones,
which are deprotected to afford the desired calystegines. Hereby, calystegine B2, B3, and B4 are
prepared from D-glucose, D-galactose, and D-mannose, respectively. This route constitutes the
shortest synthesis of calystegine B2 and gives rise to the first total syntheses of calystegine B3 and
B4.
In tr od u ction
The calystegines are a family of polyhydroxylated
nortropane alkaloids, which were first isolated in 1988
from Calystegia sepium.1 More than 10 different calys-
tegines have since then been found in a variety of fruits
and vegetables.2,3 They are subdivided into three groups
on the basis of the number of hydroxy groups present:
calystegine A (with three hydroxy groups), calystegine
B (with four hydroxy groups), and calystegine C (with
five hydroxy groups). In all cases, a tertiary hydroxy
group is part of an aminoketal functionality at the bicyclic
ring bridgehead. Several derivatives of the calystegines
have also been isolated containing a glycoside, an N-
methyl group, or an amino group, the latter instead of
the tertiary hydroxy group.2 Due to their structural
resemblance to monosaccharides, many calystegines
show potent glycosidase inhibitory activity particularly
of glucosidases and galactosidases and are interesting
lead compounds for pharmaceutical research.2,3 However,
the calystegines have been significantly less explored
than the other classes of sugar mimics with nitrogen in
the ring, e.g. polyhydroxylated pyrrolidines, piperidines,
pyrrolizidines, and indolizidines.3
F IGURE 1. Structures of common calystegines and hexoses.
are both potent inhibitors of almond â-glucosidase with
Ki values of 1.2 and 0.45 µM, respectively.6 In addition,
calystegine B2 is also a strong inhibitor of green coffee
bean R-galactosidase (Ki ) 0.86 µM).6 For all compounds,
the structural similarity to D-glucose, D-galactose, and
D-mannose is noteworthy, although the absolute config-
uration has only been established for calystegine B2. The
configuration of the remaining calystegines has been
determined by NMR spectroscopy studies and based on
biosynthetic arguments they are also believed to be
derived from D-sugars. Indeed, these cheap monosaccha-
rides are obvious starting materials for chemical synthe-
sis of the calystegines. However, creating the seven-
membered carbocycle with the nitrogen bridge from these
Some of the most abundant calystegines in plants are
calystegine A3, A5, B2, B3, B4, and C1 (Figure 1).2,4
Calystegine A3, B2, B3, and B4 are all inhibitors of
trehalases from various origins.5 Calystegine B2 and C1
(1) Tepfer, D.; Goldmann, A.; Pamboukdjian, N.; Maille, M.; Lepi-
ngle, A.; Chevalier, D.; De´narie´, J .; Rosenberg, C. J . Bacteriol. 1988,
170, 1153.
(2) Watson, A. A.; Davies, D. R.; Asano, N.; Winchester, B.; Kato,
A.; Molyneux, R. J .; Stegelmeier, B. L.; Nash, R. J . In ACS Symposium
Series 745: Natural and Selected Synthetic Toxins-Biological Implica-
tions; Tu, A. T., Gaffield, W., Eds.; American Chemical Society:
Washington, DC, 2000; p 129.
(3) Asano, N.; Nash, R. J .; Molyneux, R. J .; Fleet, G. W. J .
Tetrahedron: Asymmetry 2000, 11, 1645. Stu¨tz, A. E., Ed. Iminosugars
as Glycosidase Inhibitors-Nojirimycin and Beyond; Wiley-VCH: Wein-
heim, Germany, 1999.
(4) Rothe, G.; Garske, U.; Dra¨ger, B. Plant Sci. 2001, 160, 1043.
Bekkouche, K.; Daali, Y.; Cherkaoui, S.; Veuthey, J .-L.; Christen, P.
Phytochemistry 2001, 58, 455. Keiner, R.; Dra¨ger, B. Plant Sci. 2000,
150, 171.
(5) Asano, N.; Kato, A.; Kizu, H.; Matsui, K.; Watson, A. A.; Nash,
R. J . Carbohydr. Res. 1996, 293, 195.
(6) Asano, N.; Kato, A.; Oseki, K.; Kizu, H.; Matsui, K. Eur. J .
Biochem. 1995, 229, 369.
10.1021/jo020645c CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/15/2003
J . Org. Chem. 2003, 68, 2115-2122
2115

Skaanderup and Madsen
sugars is not an easy task. Previously, several syntheses
of enantiopure calystegine B2 have been achieved from
D-glucose.7,8 A number of calystegine analogues have also
been prepared from D-glucose and tested for glycosidase
inhibition.9
In recent years ring-closing olefin metathesis has been
introduced for converting sugars into carbocycles.10 In
this context, we have developed a zinc-mediated tandem
reaction for preparation of the diene precursors, which
employs a reductive ring-opening of methyl ω-iodo-
glycosides followed by an alkylation (e.g. allylation) in
the same pot.11 The obtained R,ω-dienes are subjected to
metathesis to form the carbocyclic ring and all ring-sizes
from five- to eight-membered rings have been prepared
by the combination of these two reactions.11,12
Herein, we report a full account on a concise synthetic
strategy to the calystegine alkaloids starting from hex-
oses using a zinc-mediated tandem reaction, ring-closing
metathesis, and a regioselective olefin oxidation as the
crucial transformations.13 This strategy has led to the
preparation of calystegine B2, B3, and B4.
F IGURE 2. Retrosynthesis for the calystegines.
fragmentation of the iodoglycoside and the allylation of
the intermediate imine.11,14 Controlling stereochemistry
in this allylation reaction is crucial because the (R)-amine
is the required isomer for further synthesis regardless
of the sugar starting material.
Resu lts a n d Discu ssion
Ca lystegin e B2. We decided to probe the synthetic
strategy starting from D-glucose, which would lead to
calystegine B2. For the first experiments, triethylsilylated
glucopyranoside 2 was chosen as the iodoglycoside be-
cause this compound has previously been used in a
tandem reaction for synthesis of conduritols.11,15 In fact,
treating 2 with zinc and benzylamine under sonication
while slowly adding allyl bromide gave rise to aminodiene
3 in very good yield (Scheme 1). The two diastereomers
were obtained in a 5:1 ratio and could be separated by
flash chromatography. At this point, the absolute ster-
eochemistry of these two diastereomers was not known.
Nevertheless, the synthesis continued with the major
diastereomer, which was shown to be the desired dias-
tereomer 3R after completing the synthesis (vide infra).
The next step involved ring-closing metathesis to form
the seven-membered carbocycle. However, in our previous
metathesis reactions with sugar substrates and catalyst
1 we have been unable to achieve good conversion with
dienes containing a free amino group.11,14 A solution to
this problem has been to convert the amino group into
an amide or a carbamate. Hence, 3R was protected with
a Cbz group to afford 4R. Unfortunately, this compound
turned out to be a very poor substrate for olefin metath-
esis with catalyst 1. Presumably, the triethylsilyl groups
are too sterically demanding for the ring-closure to take
place. Accordingly, 4R was deprotected with TBAF in
acetic acid to give trihydroxy diene 5R. This could be
metathesized with 1 to afford cycloheptene 6, although
in a moderate yield. At this point, the metathesis reaction
was not further optimized. In the next step, the double
bond has to be regioselectively oxidized and the Wacker
oxidation16 was chosen for this purpose. Although the
Wacker oxidation is very selective for monosubstituted
double bonds, internal olefins may also be oxidized by
this procedure.16,17 In some cases, this oxidation of
internal olefins appears to be aided by an additional
Retr osyn th esis. Assembling the bicyclic skeleton of
the calystegines in a few steps from sugars represents a
very interesting challenge. A key feature in the synthetic
planning will be to introduce and manipulate carbon-
carbon double bonds to create the seven-membered
carbocycle by olefin metathesis. Neither the product
calystegines nor the starting monosaccharides contain
any double bonds that can take part in a metathesis
7
reaction. As in the previous syntheses of calystigine B2
we envisioned preparing the nortropane ring structure
by deprotection of aminoketone A (Figure 2). The ketone
could emerge from a regioselective oxidation of cyclohep-
tene B, which on the other hand can be prepared by ring-
closing metathesis from diene C. This diene can be
disconnected into an allyl group, an amino group, and
an enal D, where the latter would derive from fragmen-
tation of a methyl 6-iodo-glycoside. Hereby, diene C
would be assembled by a zinc-mediated tandem reaction
where zinc serves a dual purpose by mediating both the
(7) (a) Marco-Contelles, J .; de Opazo, E. J . Org. Chem. 2002, 67,
3705. (b) Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2001, 42, 1275. (c)
Boyer, F.-D.; Lallemand, J .-Y. Tetrahedron 1994, 50, 10443. (d) Duclos,
O.; Mondange, M.; Dure´ault, A.; Depezay, J . C. Tetrahedron Lett. 1992,
33, 8061.
(8) Calystegine B2 and A3 have also been prepared by asymmetric
reactions from cycloheptadiene derivatives: Faitg, T.; Soulie´, J .;
Lallemand, J .-Y.; Ricard, L. Tetrahedron: Asymmetry 1999, 10, 2165.
J ohnson, C. R.; Bis, S. J . J . Org. Chem. 1995, 60, 615.
(9) Garc´ıa-Moreno, M. I.; Benito, J . M.; Ortiz Mellet, C.; Garc´ıa
Ferna´ndez, J . M. J . Org. Chem. 2001, 66, 7604. van Hooft, P. A. V.;
Litjens, R. E. J . N.; van der Marel, G. A.; van Boeckel, C. A. A.; van
Boom, J . H. Org. Lett. 2001, 3, 731. Duclos, O.; Dure´ault, A.; Depezay,
J . C. Tetrahedron Lett. 1992, 33, 1059.
(10) J ørgensen, M.; Hadwiger, P.; Madsen, R.; Stu¨tz, A. E.; Wrod-
nigg, T. M. Curr. Org. Chem. 2000, 4, 565. Roy, R.; Das, S. K. Chem.
Commun. 2000, 519. For general reviews on ring-closing olefin
metathesis, see: Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
34, 18. Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(11) (a) Hyldtoft, L.; Madsen, R. J . Am. Chem. Soc. 2000, 122, 8444.
(b) Hyldtoft, L.; Poulsen, C. S.; Madsen, R. Chem. Commun. 1999, 2101.
(12) Boyer, F.-D.; Hanna, I.; Nolan, S. P. J . Org. Chem. 2001, 66,
4094. Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651. Marco-Contelles,
J .; de Opazo, E. J . Org. Chem. 2000, 65, 5416.
(14) Poulsen, C. S.; Madsen, R. J . Org. Chem. 2002, 67, 4441.
(15) Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; J ørgensen, M.
R.; Madsen, R. Synthesis 2002, 1721.
(13) Preliminary communication: Skaanderup, P. R.; Madsen, R.
Chem. Commun. 2001, 1106.
(16) Tsuji, J . Synthesis 1984, 369.
2116 J . Org. Chem., Vol. 68, No. 6, 2003

A Short Synthetic Route to the Calystegine Alkaloids
SCHEME 1 a
SCHEME 2 a
a
Reagents and conditions: (a) Zn, BnNH2, CH2dCHCH2Br,
THF, ultrasound, 40 °C. (b) CbzCl, KHCO3, EtOAc, H2O. (c) 2%
1, CH2Cl2, rt. (d) BH3‚THF, THF, -40 f 0 °C, then H2O2, NaOH,
H2O, 0 °C, then Dess-Martin periodinane, CH2Cl2, rt. (e) H2,
Pd(OH)2/C, THF, H2O.
a
Reagents and conditions: (a) Zn, BnNH2, CH2dCHCH2Br,
THF, ultrasound, 40 °C. (b) CbzCl, KHCO3, EtOAc, H2O. (c) TBAF,
THF. (d) 10% 1, CH2Cl2, rt. (e) 10% PdCl2, CuCl, O2, H2O, DMF,
50 °C. (f) H2, Pd(OH)2/C, THF, H2O.
benzyl ethers compared to the triethylsilyl groups and
the free hydroxy groups in previous dienes 4R and 5R.
The benzyl ether protecting groups in cycloheptene 12
also give new opportunities for the next oxidation to
ketone. Initially, the Wacker oxidation was also at-
tempted, but conversion was low and only gave the
unwanted regioisomer 13. Therefore, another method
was investigated and particular attention was given to
hydroboration-oxidation, which has shown promising
selectivity in a similar system.19 Treatment of 12 with
borane followed by alkaline hydrogen peroxide solution
gave a mixture of all four possible alcohols that was not
further characterized. Without purification this mixture
was oxidized to the corresponding ketones with the
Dess-Martin periodinane.20 Hereby, ketones 13 and 14
were obtained in an overall yield of 81% as a 1:3 mixture,
which could be separated by chromatography. Interest-
ingly, the hydroboration favors the opposite ketone
regioisomer as compared to the Wacker oxidation. Hy-
drogenolysis of 13 gave the same aminotriol 8 as pre-
pared in Scheme 1. Hydrogenolysis of 14 afforded calys-
tegine B2 with spectral data and optical rotation in
accordance with those reported for the natural product.6
The deprotection was carried out in THF:H2O mixture
followed by purification on a Sephadex LH-20 column
eluting with ethanol.21 If the hydrogenolysis was
performed in ethanol the N-methylated derivative of
calystegine B2 was obtained as the main product.22
N-Methyl calystegine B2 has been isolated from the same
coordination between palladium and a heteroatom in the
substrate. Interestingly, when cycloheptene 6 was sub-
jected to the standard Wacker conditions at elevated
temperature only one ketone regioisomer was obtained.
Unfortunately, it was the unwanted regioisomer 7, which
on deprotection furnished aminotriol 8. NMR analysis
revealed that these compounds close into an 8-oxabicyclo-
[3.2.1]octane ring system that still resembles the calys-
tegine structure. Compound 8 was tested as an inhibitor
of yeast R-glucosidase, almond â-glucosidase, green coffee
bean R-galactosidase, E. coli â-galactosidase, and J ack
bean R-mannosidase.18 However, it showed no inhibition
of these enzymes. At this point, no further oxidation
experiments were carried out with cycloheptene 6. Due
to the difficulties with the metathesis reaction another
starting material was tried and it was decided to change
the triethylsilyl groups in 2 to benzyl groups.
Benzyl-protected iodoglycoside 9 is available in 2 steps
from methyl R-D-glucopyranoside.15 Treating 9 under the
same conditions as employed for 2 gave aminodiene 10
in 85% yield (Scheme 2). Again, a 5:1 mixture of two
diastereomers was formed and the major diastereomer
was shown to be 10R after completion of the synthesis.
After separating 10R and 10S by chromatography,
aminodiene 10R was Cbz-protected and transformed into
cycloheptene 12 by ring-closing metathesis. In this case,
a very good yield was obtained with relatively low
catalyst loading, which illustrates the importance of the
(19) Wang, W.; Zhang, Y.; Zhou, H.; Ble´riot, Y.; Sinay¨, P. Eur. J .
Org. Chem. 2001, 1053.
(20) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(21) Henke, H. Preparative Gel Chromatography on Sephadex LH-
20; Hu¨thig Verlag: Heidelberg, Germany, 1995.
(22) Partial N-methylation of amino groups in amino acids has
previously been observed during hydrogenations in methanol: Maza-
leyrat, J .-P.; Xie, J .; Wakselman, M. Tetrahedron Lett. 1992, 33,
4301.
(17) For recent examples, see: Kishi, A.; Higashino, T.; Sakaguchi,
S.; Ishii, Y. Tetrahedron Lett. 2000, 41, 99. Kang, S.-K.; J ung, K.-Y.;
Chung, J .-U.; Namkoong, E.-Y.; Kim, T.-H. J . Org. Chem. 1995, 60,
4678.
(18) For details of the enzymatic assays, see: Andersen, S. M.;
Ekhart, C.; Lundt, I.; Stu¨tz, A. E. Carbohydr. Res. 2000, 326, 22.
J . Org. Chem, Vol. 68, No. 6, 2003 2117

Skaanderup and Madsen
SCHEME 3 a
reoselectivity was only 2:1. The two diastereomers could
be separated and the major diastereomer was shown to
be 16R after finishing the synthesis of calystegine B3.
Cbz-protection and ring-closing metathesis proceeded
very well to afford cycloheptene 18. Applying the same
hydroboration-oxidation procedure as described above
gave a 3:1 mixture of the two ketones with the desired
regioisomer 19 as the main component. Deprotection of
the benzyl groups then furnished calystegine B3 with
spectral and physical data in accordance with those
reported for the natural substance.6
Following the same strategy benzyl-protected methyl
6-iodo-mannopyranoside 2015 was also subjected to the
tandem reaction (Scheme 3). Aminodiene 21 was isolated
in 80% yield as an 8:1 mixture of diastereomers. Gratify-
ingly, the major diastereomer was again the desired (R)-
isomer, which was verified after completing the synthesis
of calystegine B4. Cbz-protection and metathesis occurred
in good yield although the ring-closing metathesis reac-
tion of 22R was slower than with the previous dienes
11R and 17R. Hydroboration and oxidation of cyclohep-
tene 23 gave a 3:1 mixture of the two ketone regioiso-
mers, which could be separated. The major isomer 24 was
subjected to hydrogenolysis to afford calystegine B4 with
analytical data in accordance with literature values.5
These syntheses confirm the absolute configuration of
calystegine B3 and B4.
Im in e Allyla tion s. The stereochemical outcome of the
three tandem reactions is noteworthy. In all three cases
the (R)-isomer is formed as the major product regardless
of the sugar stereochemistry although the diastereose-
lectivity varies from 2:1 to 8:1. In our previous zinc-
mediated alkylations of protected sugar aldehydes we
have observed that sugars with 2,3-erythro configuration
give very good selectivity for the 1,2,3-ribo product while
the outcome with 2,3-threo sugar aldehydes is less certain
and in some cases the 1,2,3-xylo product dominates.11,14
These observations are in accordance with the imine
allylations in Schemes 1-3, but a systematic model
explaining these additions to 2,3-alkoxy aldehydes and
imines has not yet been developed.24,25
The poor diastereoselectivity with galacto substrate 15
prompted us to analyze the allylation with other metals.
We have recently investigated the fragmentation of
benzyl-protected methyl 6-iodo-glycopyranosides with a
variety of metals and found that only zinc would frag-
ment these pyranosides efficiently.26 This afforded enals
25-27 in high yields from glycosides 9, 15, and 20.26
Therefore, we decided to treat these enals with benzy-
lamine, allyl bromide, and different metals under soni-
cation conditions (Table 1). Notably, when glucose-
derived enal 25 was reacted under these Barbier
conditions with magnesium metal, an improved 16:1 ratio
was obtained between 10R and 10S as compared to the
5:1 ratio with zinc metal in Scheme 2. This ratio could
be even further improved with indium metal (entry 2),27
where the (S)-isomer could not be detected at all. A
number of other metals did not give any imine allylation
a
Reagents and conditions: (a) Zn, BnNH2, CH2dCHCH2Br,
THF, ultrasound, 40°C. (b) CbzCl, KHCO3, EtOAc, H2O. (c) 2% 1,
CH2Cl2, rt. (d) BH3‚THF, THF, -40 f 0 °C, then H2O2, NaOH,
H2O, 0 °C, then Dess-Martin periodinane, CH2Cl2, rt. (e) H2,
Pd(OH)2/C, THF, H2O.
sources as the parent compound and is a very selective
inhibitor of green coffee bean R-galactosidase.23
Ca lystegin e B3 a n d B4. Having successfully com-
pleted the synthesis of calystegine B2, attention was then
shifted toward calystegine B3 and B4 to investigate the
general applicability of the synthetic strategy. Due to the
configuration of the secondary hydroxy groups these two
alkaloids will require D-galactose and D-mannose as
starting materials. For the synthesis of calystegine B3
benzyl-protected methyl 6-iodo-galactopyranoside 1515
was treated with zinc, benzylamine, and allyl bromide
(Scheme 3). Thereby, aminodiene 16 was obtained in a
satisfying 88% yield. To our disappointment, the diaste-
(24) For a review on 1,2- and 1,3-induction in carbonyl addition
reactions, see: Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.
(25) For a review on addition of organometallic reagents to imines,
see: Bolch, R. Chem. Rev. 1998, 98, 1407.
(26) Skaanderup, P. R.; Hyldtoft, L.; Madsen, R. Monatsh. Chem.
2002, 133, 467.
(23) Asano, N.; Kato, A.; Miyauchi, M.; Kizu, H.; Tomimori, T.;
Matsui, K.; Nash, R. J .; Molyneux, R. J . Eur. J . Biochem. 1997, 248,
296.
2118 J . Org. Chem., Vol. 68, No. 6, 2003

A Short Synthetic Route to the Calystegine Alkaloids
TABLE 1. Allyla tion of Im in es Der ived fr om Ald eh yd es
25-27a
F IGUR E 3. Epimeric compounds 28-30 derived from (S)-
amines.
cycloheptanones 28, 29, and 30 were prepared (Figure
3), which can be considered as epimers of calystegine B2,
B3, and B4, respectively. Unfortunately, the structures
of these epimers were not well defined. Compounds 28-
30 were isolated by Sephadex LH-20 gel chromatography.
They had similar retention times as the parent calyste-
1
gines and showed only one spot by TLC. The H NMR
spectra of 28-30 were complex and only showed broad
signals in the 3.9-3.3 and 2.0-1.4 ppm range. The
protons in the parent calystegines are observed in the
same areas. It was impossible to obtain useful 13C NMR
spectra of 28-30. Apparently, compounds 28-30 are not
able to form stable bicyclic ring systems, but exist as
mixtures of monomers and oligomers. The same has been
observed with other calystegine analogues.7c,28 Additional
work will be necessary to characterize these three
epimers.
Con clu sion . We have described here an effective
synthetic route to calystegine B2, B3, and B4 starting from
D-glucose, D-galactose, and D-mannose, respectively. The
strategy highlights the utility of our previously developed
zinc-mediated tandem reaction, which combined with
ring-closing metathesis converts iodo-sugars into car-
bocycles in just two steps. Other calystegines containing
a different number of hydroxy groups can potentially be
prepared by the same route. With this strategy in hand,
analogue preparation and screening have also been
greatly accelerated.
a
All reactions were carried out in THF by sonication at 40 °C.
under these conditions, including iron, tin, antimony,
bismuth, copper, and aluminum. When the imine of
galactose-derived enal 26 was allylated with magnesium
a 8:1 ratio was obtained between 16R and 16S (entry 3),
which is a significant improvement over the 2:1 ratio
produced with zinc in Scheme 3. With indium the (R)-
isomer was again formed exclusively (entry 4). This
reaction was slower than that with glucose-derived
substrate 25 and was accompanied by some decomposi-
tion. On the other hand, allylating the imine from
mannose-derived enal 27 gave the (S)-isomer of 21
(entries 5 and 6). In this case, magnesium and indium
completely reversed the facial selectivity as compared to
zinc in Scheme 3. These results strongly implicate that
the magnesium- and indium-mediated allylations occur
with chelation to the R-benzyloxy group.
By varying the metal in the allylation reaction the
necessary (R)-amines for the calystegine syntheses can
all be prepared in high yields. The corresponding (S)-
amines can also be isolated from these reactions. Amines
10S and 16S are best isolated as the minor diastereomers
from the zinc-mediated allylations in Schemes 2 and 3,
while 21S is obtained as the major product with mag-
nesium and indium in Table 1. We decided to subject
these (S)-amines to the same synthetic sequence as
employed for the (R)-amines. The reactions were carried
out under the same conditions as in Schemes 2 and 3
and gave rise to similar results and selectivities. Hereby,
Exp er im en ta l Section
Gen er a l P r oced u r es. Thin-layer chromatography was
performed on aluminum plates precoated with silica gel 60.
Compounds were visualized by heating after dipping in a
solution of Ce(SO4)2 (2.5 g) and (NH4)6Mo7O24 (6.25 g) in 10%
aqueous H2SO4 (250 mL) or in a solution of 0.3% ninhydrin
and 3% AcOH in n-BuOH. Flash chromatography was per-
formed with silica gel 60. Lipophilic Sephadex LH-20 (bead
size 25-100 µm) was used for gel chromatography. Mi-
croanalyses were conducted by the Department of Chemistry
at the University of Copenhagen.
Gen er a l P r oced u r e for th e Zin c-Med ia ted Ta n d em
Rea ction . To a solution of the benzyl-protected methyl 6-iodo-
glycoside (3.0 g, 5.2 mmol) in THF (40 mL) was added
preactivated zinc dust11,14 (3.4 g, 52 mmol). The mixture was
sonicated at 40 °C with use of a Branson 1210 sonic bath.
TMSCl (0.33 mL, 2.6 mmol) was added in two portions after
10 and 20 min. When TLC or NMR revealed full consumption
of the iodo-sugar (8-10 h) benzylamine (2.8 mL, 26 mmol) was
added and the sonication was continued for an additional hour
(27) For recent examples on indium-mediated allylations of imines,
see: Hilt, G.; Smolko, K. I.; Waloch, C. Tetrahedron Lett. 2002, 43,
1437. Vilaivan, T.; Winotapan, C.; Shinada, T.; Ohfune, Y. Tetrahedron
Lett. 2001, 42, 9073. Lu, W.; Chan, T. H. J . Org. Chem. 2000, 65, 8589.
Choucair, B.; Le´on, H.; Mire´, M.-A.; Lebreton, C.; Mosset, P. Org. Lett.
2000, 2, 1851. Choudhury, P. K.; Foubelo, F.; Yus, M. J . Org. Chem.
1999, 64, 3376.
(28) Boyer, F.-D.; Ducrot, P.-H.; Henryon, V.; Soulie´, J .; Lallemand,
J .-Y. Synlett 1992, 357.
J . Org. Chem, Vol. 68, No. 6, 2003 2119

Skaanderup and Madsen
at 40 °C. Allyl bromide (1.3 mL, 16 mmol) was then added
carefully in small portions over a period of 20 min during
which time the sonication was maintained at 40 °C. The
reaction was worked up by cooling to room temperature
followed by addition of Et2O (100 mL) and water (20 mL).
Filtration of the resulting suspension through a pad of Celite
removed all precipitated zinc salts. The layers were separated
and the organic phase was washed with water (3 × 20 mL)
and brine (10 mL) and dried (K2CO3), followed by removal of
the solvent in vacuo. Purification by silica gel flash chroma-
tography (hexane:Et2O ) 3:1 f 1:1) yielded the desired
diastereomeric aminodienes.
Gen er a l P r oced u r e for Cbz-P r otection . To an ice-cooled
suspension of the aminodiene (347 mg, 0.60 mmol) and KHCO3
(362 mg, 3.6 mmol) in CH2Cl2 (20 mL) and water (20 mL) was
added benzyl chloro formate (94 µL, 0.66 mmol) dropwise over
2 min with vigorous stirring. The reaction mixture was stirred
for 1 h, during which time the mixture warmed to room temp-
erature. The layers were separated and the organic phase was
washed with water (10 mL) and dried (K2CO3), and the solvent
was removed in vacuo to give a colorless syrup, which was pur-
ified by silica gel flash chromatography (hexane:Et2O ) 4:1).
Gen er a l P r oced u r e for Rin g-Closin g Olefin Meta th e-
sis. The protected aminodiene (408 mg, 0.60 mmol) was
dissolved in CH2Cl2 (30 mL). The solution was degassed under
reduced pressure for 5 min followed by addition of 1 (10 mg,
0.012 mmol, 2 mol %). The reaction mixture was stirred at
room temperature until TLC showed complete consumption
of the starting diene (10-20 h). The solvent was removed in
vacuo and the residue purified by silica gel flash chromatog-
raphy (hexane:Et2O ) 4:1).
Gen er a l P r oced u r e for Hyd r obor a tion -Oxid a tion . To
a stirred solution of the cycloheptene (368 mg, 0.56 mmol) in
THF (15 mL) at -40 °C under nitrogen was added BH3‚THF
complex (1.1 mL of a 1 M solution in THF, 1.1 mmol) dropwise.
The mixture was stirred for 4 h, during which time it warmed
to 0 °C. Then 2 M aqueous NaOH (1 mL) and 35% aqueous
H2O2 (2 mL) were added. The reaction turned cloudy instantly
and the slurry was stirred for an additional hour at ambient
temperature. The mixture was then diluted with Et2O (30 mL)
and the organic layer was washed with water (3 × 5 mL) and
brine (5 mL). Removal of the solvent in vacuo gave the crude
alcohols, which were used immediately in the next step. To a
stirred solution of Dess-Martin periodinane (382 mg, 0.90
mmol) in CH2Cl2 (20 mL) at room temperature was added the
crude alcohols in CH2Cl2 (1 mL). The resultant milky white
suspension was stirred at room temperature for 30 min. The
mixture was then diluted with Et2O (50 mL) and stirred for
an additional 30 min. The solution was filtered and washed
with saturated aqueous Na2S2O3 (2 × 10 mL) and brine (10
mL). The organic phase was then dried (K2CO3) and concen-
trated to give a pale white residue that was purified by flash
chromatography (hexane:Et2O ) 3:1).
6.8, 4.3 Hz, 1H), 3.86-3.81 (m, 1H), 3.76 (dd, J ) 9.8, 4.3 Hz,
1H), 2.34 (dd, J ) 12.8, 6.0 Hz, 1H), 2.24 (dd, J ) 14.1, 11.1
Hz, 1H), 1.92 (dd, J ) 14.1, 3.8 Hz, 1H), 1.86 (br d, J ) 12.8
Hz, 1H). 13C NMR (125 MHz, D2O:CD3COOD ) 99:1): δ 103.9,
75.8, 71.9, 70.9, 50.5, 43.2, 39.7. ESI HRMS calcd for C7H14
-
NO4 [M + H]+ m/z 176.0923, found m/z 176.0918.
(3R,4S,5S,6R)-6-[(N-Ben zyl)am in o]-3,4,5-tr is(ben zyloxy)-
1,8-n on a d ien e (10R). Colorless syrup, Rf 0.51 (hexane:EtOAc
1
) 3:1). [R]D -20.0 (c 2.0, CHCl3). H NMR (500 MHz, CDCl3):
δ 7.34-7.28 (m, 20H), 5.98 (ddd, J ) 17.5, 10.2, 7.7 Hz, 1H),
5.67 (dddd, J ) 17.1, 10.2, 7.7, 6.4 Hz, 1H), 5.30 (dd, J ) 10.2,
1.7 Hz, 1H), 5.26 (dd, J ) 17.5, 1.7 Hz, 1H), 5.04 (dd, J ) 17.1,
1.8 Hz, 1H), 5.03 (dd, J ) 10.2, 1.8 Hz, 1H), 4.90 (d, J ) 11.5
Hz, 1H), 4.78 (d, J ) 11.1 Hz, 1H), 4.70 (d, J ) 11.1 Hz, 1H),
4.62 (d, J ) 11.5 Hz, 1H), 4.56 (d, J ) 11.9 Hz, 1H), 4.15 (d,
J ) 11.9 Hz, 1H), 4.00 (dd, J ) 7.3, 3.4 Hz, 1H), 3.88 (d, J )
13.2 Hz, 1H), 3.83 (dd, J ) 7.3, 2.6 Hz, 1H), 3.78 (dd, J ) 7.7,
3.4 Hz, 1H), 3.52 (d, J ) 13.2 Hz, 1H), 2.51 (ddd, J ) 8.1, 5.1,
2.6 Hz, 1H), 2.46 (m, 1H), 2.28 (ddd, J ) 13.7, 8.1, 7.7 Hz,
1H). 13C NMR (75 MHz, CDCl3): δ 140.9, 139.2, 138.7, 138.0,
136.2, 136.1, 128.8, 128.4, 128.1, 127.4, 127.2, 127.1, 126.7,
118.1, 116.6, 83.3, 80.7, 79.6, 75.2, 74.5, 70.0, 56.4, 50.8, 35.1.
Anal. Calcd for C37H41NO3: C, 81.13; H, 7.54; N, 2.56. Found:
C, 81.10; H, 7.53; N, 2.50.
(3R,4S,5S,6S)-6-[(N-Ben zyl)am in o]-3,4,5-tr is(ben zyloxy)-
1,8-n on a d ien e (10S). Colorless syrup, Rf 0.40 (hexane:EtOAc
1
) 3:1). [R]D -31.5 (c 2.0, CHCl3). H NMR (500 MHz, CDCl3):
δ 7.34-7.20 (m, 20H), 5.88 (ddd, J ) 17.1, 10.7, 7.5 Hz, 1H),
5.79 (dddd, J ) 17.1, 10.1, 7.3, 6.8 Hz, 1H), 5.28 (br dd, J )
10.7, 0.9 Hz, 1H), 5.25 (br dd, J ) 17.1, 0.9 Hz, 1H), 5.06 (br
dd, J ) 10.7, 1.3 Hz, 1H), 5.05 (br dd, J ) 17.1, 1.3 Hz, 1H),
4.76 (d, J ) 11.1 Hz, 1H), 4.74 (d, J ) 11.1 Hz, 1H), 4.73 (d,
J ) 12.0 Hz, 1H), 4.71 (d, J ) 12.0 Hz, 1H), 4.61 (d, J ) 11.7
Hz, 1H), 4.35 (d, J ) 11.7 Hz, 1H), 4.02 (dd, J ) 7.5, 5.1 Hz,
1H), 3.81 (dd, J ) 5.5, 4.3 Hz, 1H), 3.75 (dd, J ) 5.5, 5.1 Hz,
1H), 3.55 (d, J ) 13.7 Hz, 1H), 3.35 (d, J ) 13.7 Hz, 1H), 2.86
(dt, J ) 7.7, 4.3 Hz, 1H), 2.36 (m, 1H), 2.29 (br dd, J ) 14.5,
7.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 140.8, 139.0, 138.6,
138.1, 136.3, 135.5, 128.4, 128.2, 128.1, 128.0, 127.8, 127.6,
127.4, 127.3 (2C), 126.6, 118.5, 116.6, 82.3, 81.0, 79.3, 74.8,
73.7, 70.5, 57.6, 51.4, 34.8. Anal. Calcd for C37H41NO3: C,
81.13; H, 7.54; N, 2.56. Found: C, 81.25; H, 7.51; N, 2.53.
(3R,4S,5S,6R)-6-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-3,4,5-tr is(ben zyloxy)-1,8-n on a d ien e (11R). Color-
less syrup, Rf 0.64 (hexane:EtOAc ) 3:1). [R]D -8.2 (c 2.0,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.44-7.21 (m, 25H),
5.85 (m, 1H), 5.46 (m, 1H), 5.23-5.19 (m, 3H), 5.11 (d, J )
11.9 Hz, 1H), 4.90-4.75 (m, 5H), 4.64 (m, 1H), 4.51-4.44 (m,
3H), 4.40 (m, 1H), 4.22 (m, 1H), 4.02 (m, 1H), 3.91 (m, 1H),
3.37 (m, 1H), 2.42 (m, 1H), 2.19 (m, 1H). 13C NMR (125 MHz,
CDCl3): δ 158.2, 139.0, 138.7 (2C), 136.7, 136.1, 135.2 (2C),
128.6, 128.4 (2C), 128.3, 128.1, 127.8, 127.7, 127.6, 126.8,
118.5, 117.3, 83.2, 81.0 (2C), 75.4 (2C), 70.9, 67.4, 56.8, 47.7,
35.0. Anal. Calcd for C45H47NO5: C, 79.27; H, 6.95; N, 2.05.
Found: C, 79.10; H, 6.89; N, 2.01.
(3R,4S,5S,6R)-6-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-3,4,5-tr is(ben zyloxy)cycloh ep ten e (12). Colorless
syrup, Rf 0.54 (hexane:EtOAc ) 3:1). [R]D -23.4 (c 2.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ 7.38-7.18 (m, 25H), 5.72-5.58
(m, 2H), 5.22-5.16 (m, 3H), 5.09 (d, J ) 12.2 Hz, 1H), 4.89 (d,
J ) 11.1 Hz, 1H), 4.85 (d, J ) 10.7 Hz, 1H), 4.74 (d, J ) 11.1
Hz, 1H), 4.67 (d, J ) 11.9 Hz, 1H), 4.64 (d, J ) 11.9 Hz, 1H),
4.44 (d, J ) 10.7 Hz, 1H), 4.36 (m, 1H), 4.21 (m, 1H), 4.16-
4.04 (m, 1H), 3.64-3.56 (m, 1H), 2.86 (m, 1H), 1.98-1.88 (m,
1H). 13C NMR (125 MHz, CDCl3): δ 155.5, 139.0, 138.9, 138.7,
138.3, 136.8, 132.6, 129.3, 128.6, 128.4, 128.2, 128.1, 128.0
(2C), 127.9, 127.8, 127.6, 127.5 (3C), 127.3, 84.7, 83.6, 78.0,
Gen er a l P r oced u r e for Ca ta lytic Hyd r ogen olysis. The
cycloheptanone (141 mg, 0.21 mmol) was dissolved in THF (4.5
mL) and water (0.5 mL) and H2 was bobbled through the
solution for 10 min. Pearlman’s catalyst (22 mg, 0.021 mmol)
was added and the reaction mixture was stirred at room
temperature under 1 atm of H2 for 12 h. TLC indicated
complete disappearance of the fully protected cycloheptanone
and the mixture was acidified by addition of 1 M aqueous HCl
(1 mL). The reaction was stirred for an additional 36 h at room
temperature and 1 atm of H2. The mixture was then neutral-
ized by addition of Amberlite IRA-400 OH- and the resulting
suspension was filtered through a glass frit. The resin was
washed thoroughly with water (15 × 10 mL). The filtrate was
concentrated in vacuo to give a colorless residue that was
purified on Sephadex LH-20 eluting with EtOH.
75.6, 75.1, 72.7, 67.0, 62.0, 53.8, 30.2. Anal. Calcd for C43H43
-
NO5: C, 78.99; H, 6.63; N, 2.14. Found: C, 78.84; H, 6.57; N,
2.14.
(3S,4R,5S,6R)-6-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-3,4,5-tr is(ben zyloxy)cycloh ep ta n on e (13). Color-
(3R ,4S ,5S ,6R )-6-Am in o -3,4,5-t r ih y d r o x y c y c lo h e p -
ta n on e (8). Clear glass, Rf 0.49 (n-PrOH:AcOH:H2O ) 4:1:1).
[R]D -28.3 (c 2.0, H2O). 1H NMR (500 MHz, D2O:CD3COOD )
99:1): δ 4.75 (ddd, J ) 11.1, 6.8, 3.8 Hz, 1H), 4.26 (dd, J )
2120 J . Org. Chem., Vol. 68, No. 6, 2003

A Short Synthetic Route to the Calystegine Alkaloids
less syrup, Rf 0.36 (hexane:EtOAc ) 3:1). [R]D -41.7 (c 2.0,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.35-7.12 (m, 25H),
5.21-4.96 (m, 3H), 4.85-4.66 (m, 2H), 4.56-4.32 (m, 5H),
4.14-4.09 (m, 2H), 3.94-3.90 (m, 2H), 3.34-3.05 (m, 1H),
(3S,4S,5S,6R)-6-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-3,4,5-tr is(ben zyloxy)cycloh ep ten e (18). Colorless
syrup, Rf 0.43 (hexane:EtOAc ) 5:1). [R]D +27.2 (c 2.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ 7.34-7.14 (m, 25H), 5.77-5.50
(m, 2H), 5.12 (d, J ) 12.4 Hz, 1H), 5.10 (d, J ) 12.4 Hz, 1H),
4.72 (d, J ) 11.9 Hz, 1H), 4.60-3.88 (m, 11H), 3.07 (m, 1H),
1.96 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 156.4, 138.8,
138.5, 138.3, 138.1, 136.7, 133.4, 129.8, 129.0, 128.8, 128.7,
128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 127.5,
80.8, 79.2, 79.1, 76.2, 72.2, 71.2, 67.4, 65.2, 52.6, 31.1. Anal.
Calcd for C43H43NO5: C, 78.99; H, 6.63; N, 2.14. Found: C,
78.92; H, 6.61; N, 2.12.
2.97-2.79 (m, 1H), 2.73-2.59 (m, 1H), 2.47-2.32 (m, 1H). 13
C
NMR (125 MHz, CDCl3): δ 155.5, 138.6, 138.1, 137.8, 137.7,
136.7, 128.7, 128.6, 128.5, 128.1, 128.0, 127.8 (2C), 127.6, 82.7,
81.0, 75.5, 74.3, 73.1, 71.6, 67.1, 57.4, 46.7, 44.2. ESI HRMS
calcd for C43H44NO6 [M + H]+ m/z 670.3168, found m/z
670.3143.
(2S,3R,4S,5R)-5-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-2,3,4-tr is(ben zyloxy)cycloh ep ta n on e (14). Color-
less syrup, Rf 0.47 (hexane:EtOAc ) 3:1). [R]D -8.1 (c 1.2,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.32-7.07 (m, 25H),
5.15 (s, 2H), 4.68 (d, J ) 11.1 Hz, 1H), 4.67 (d, J ) 11.1 Hz,
1H), 4.62 (d, J ) 11.5 Hz, 1H), 4.57 (d, J ) 11.5 Hz, 1H), 4.51
(d, J ) 11.5 Hz, 1H), 4.49 (d, J ) 11.9 Hz, 1H), 4.45 (d, J )
11.9 Hz, 1H), 4.39 (d, J ) 11.5 Hz, 1H), 4.32-4.27 (m, 1H),
4.22-4.18 (m, 1H), 4.01-3.86 (m, 1H), 3.82 (t, J ) 5.8 Hz, 1H),
2.42-2.14 (m, 2H), 1.68-1.51 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ 193.6, 156.3, 146.3, 145.1, 141.4, 139.2, 139.0, 129.8,
129.2, 129.0, 128.7, 128.6, 128.2, 127.9, 85.8, 82.3, 82.0, 74.3,
74.2, 73.2 (3C), 67.7, 40.0, 26.3. Anal. Calcd for C43H43NO6:
C, 77.11; H, 6.47; N, 2.09. Found: C, 76.93; H, 6.26; N, 2.02.
(2R,3R,4S,5R)-5-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-2,3,4-tr is(ben zyloxy)cycloh ep ta n on e (19). Color-
less syrup, Rf 0.36 (hexane:EtOAc ) 3:1). [R]D -3.3 (c 0.46,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.33-7.14 (m, 25H),
5.19-5.11 (m, 2H), 4.77-3.88 (m, 11H), 2.53 (br d, J ) 14.5
Hz, 1H), 2.44 (m, 1H), 2.21 (m, 1H), 1.55 (br d, J ) 12.8 Hz,
1H), 1.41 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 206.6, 156.6,
138.4, 137.6 (3C), 136.3, 128.3, 128.2, 128.1, 127.9, 127.8,
127.5, 127.0, 84.1, 80.5, 78.9, 72.8, 72.5, 72.3 (2C), 67.2, 62.2,
42.0, 25.8. Anal. Calcd for C43H43NO6: C, 77.11; H, 6.47; N,
2.09. Found: C, 76.76; H, 6.44; N, 2.08.
(3R,4S,5R,6R)-6-[(N-Ben zyl)am in o]-3,4,5-tr is(ben zyloxy)-
1,8-n on a d ien e (21R). Colorless syrup, Rf 0.61 (hexane:EtOAc
(3S,4S,5S,6R)-6-[(N-Ben zyl)am in o]-3,4,5-tr is(ben zyloxy)-
1,8-n on a d ien e (16R). Colorless syrup, Rf 0.35 (hexane:EtOAc
1
) 3:1). [R]D +4.9 (c 2.0, CHCl3). H NMR (500 MHz, CDCl3):
1
) 5:1). [R]D +1.2 (c 2.0, CHCl3). H NMR (500 MHz, CDCl3):
δ 7.46-7.23 (m, 20H), 6.00 (ddd, J ) 17.5, 10.2, 6.8 Hz, 1H),
5.79 (dddd, J ) 17.9, 9.8, 7.3, 2.6 Hz, 1H), 5.39 (br d, J ) 17.5
Hz, 1H), 5.33 (dd, J ) 10.2, 0.9 Hz, 1H), 5.10 (d, J ) 9.8 Hz,
1H), 5.09 (d, J ) 17.9 Hz, 1H), 4.83 (d, J ) 11.5 Hz, 1H), 4.75
(d, J ) 11.5 Hz, 1H), 4.74 (d, J ) 11.1 Hz, 1H), 4.71 (d, J )
11.9 Hz, 1H), 4.58 (d, J ) 11.1 Hz, 1H), 4.44 (d, J ) 11.9 Hz,
1H), 4.29 (dd, J ) 6.8, 5.3 Hz, 1H), 3.88 (dd, J ) 4.7, 4.0 Hz,
1H), 3.83 (d, J ) 12.6 Hz, 1H), 3.82 (dd, J ) 5.3, 4.7 Hz, 1H),
3.77 (d, J ) 12.6 Hz, 1H), 3.08 (dt, J ) 8.1, 4.0 Hz, 1H), 2.51
(br d, J ) 14.1 Hz, 1H), 2.36 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 140.6, 138.8, 138.6, 138.5, 136.4, 136.3, 128.8, 128.7,
128.1, 127.8 (2C), 127.5, 127.3, 126.6, 126.2, 125.9, 118.1,
117.0, 82.3, 81.1, 79.4, 74.4, 73.1, 70.5, 57.1, 51.7, 34.6. Anal.
Calcd for C37H41NO3: C, 81.13; H, 7.54; N, 2.56. Found: C,
81.08; H, 7.54; N, 2.61.
δ 7.36-7.23 (m, 20H), 5.99 (ddd, J ) 17.5, 10.2, 8.1 Hz, 1H),
5.66 (dddd, J ) 17.1, 10.2, 7.7, 6.4 Hz, 1H), 5.32 (dd, J ) 10.2,
2.1 Hz, 1H), 5.16 (dd, J ) 17.5, 2.1 Hz, 1H), 5.01 (br dd, J )
10.2, 1.7 Hz, 1H), 5.00 (br dd, J ) 17.1, 1.7 Hz, 1H), 4.93 (d,
J ) 11.1 Hz, 1H), 4.86 (d, J ) 11.3 Hz, 1H), 4.73 (d, J ) 11.1
Hz, 1H), 4.57 (d, J ) 12.2 Hz, 1H), 4.54 (d, J ) 11.3 Hz, 1H),
4.30 (d, J ) 12.2 Hz, 1H), 4.20 (dd, J ) 7.3, 3.6 Hz, 1H), 3.90
(d, J ) 13.2 Hz, 1H), 3.84 (dd, J ) 8.1, 3.6 Hz, 1H), 3.67 (d, J
) 13.2 Hz, 1H), 3.54 (dd, J ) 7.3, 3.0 Hz, 1H), 2.67 (ddd, J )
8.1, 4.7, 3.0 Hz, 1H), 2.45 (m, 1H), 2.29 (ddd, J ) 14.1, 8.1, 7.7
Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 140.7, 139.2 (2C),
138.8, 135.9, 135.2, 128.4, 128.1 (3C), 128.0, 127.9, 127.6,
127.2, 127.1, 126.7, 119.1, 116.8, 82.6, 81.7, 80.3, 74.8, 74.6,
69.9, 56.9, 50.9, 34.7. Anal. Calcd for C37H41NO3: C, 81.13; H,
7.54; N, 2.56. Found: C, 81.15; H, 7.52; N, 2.49.
(3R,4S,5R,6S)-6-[(N-Ben zyl)am in o]-3,4,5-tr is(ben zyloxy)-
1,8-n on a d ien e (21S). Colorless syrup, Rf 0.42 (hexane:EtOAc
(3S,4S,5S,6S)-6-[(N-Ben zyl)am in o]-3,4,5-tr is(ben zyloxy)-
1,8-n on a d ien e (16S). Colorless syrup, Rf 0.29 (hexane:EtOAc
1
) 1:1). [R]D -12.6 (c 2.0, CHCl3). H NMR (500 MHz, CDCl3):
1
) 5:1). [R]D -5.2 (c 2.0, CHCl3). H NMR (500 MHz, CDCl3):
δ 7.24-7.09 (m, 20H), 5.76 (ddd, J ) 17.7, 10.2, 7.7 Hz, 1H),
5.64 (dddd, J ) 17.1, 10.2, 8.1, 6.0 Hz, 1H), 5.16 (dd, J ) 17.7,
2.1 Hz, 1H), 5.14 (dd, J ) 10.2, 2.1 Hz, 1H), 4.92 (br d, J )
10.2 Hz, 1H), 4.89 (br d, J ) 17.1 Hz, 1H), 4.60 (d, J ) 11.3
Hz, 1H), 4.52 (d, J ) 11.3 Hz, 1H), 4.50 (d, J ) 11.7 Hz, 1H),
4.37 (s, 2H), 4.20 (d, J ) 11.7 Hz, 1H), 3.85 (dd, J ) 7.7, 4.3
Hz, 1H), 3.82 (d, J ) 13.0 Hz, 1H), 3.79 (dd, J ) 6.6, 4.3 Hz,
1H), 3.63 (dd, J ) 6.6, 2.1 Hz, 1H), 3.53 (d, J ) 13.0 Hz, 1H),
2.83 (m, 1H), 2.41 (m, 1H), 2.17 (ddd, J ) 15.4, 8.1, 7.3 Hz,
1H). 13C NMR (75 MHz, CDCl3): δ 140.8, 138.6, 138.5, 138.4,
136.2, 136.1, 128.3, 128.0, 127.7, 127.4, 127.2, 126.5, 118.4,
116.6, 81.9, 81.0, 78.6, 74.8, 73.1, 70.0, 56.6, 51.0, 35.5. Anal.
Calcd for C37H41NO3: C, 81.13; H, 7.54; N, 2.56. Found: C,
81.02; H, 7.60; N, 2.56.
δ 7.32-7.18 (m, 20H), 5.96 (ddd, J ) 17.5, 10.2, 8.1 Hz, 1H),
5.80 (dddd, J ) 17.9, 11.1, 7.3, 5.1 Hz, 1H), 5.34 (dd, J ) 10.2,
1.7 Hz, 1H), 5.25 (dd, J ) 17.5, 1.7 Hz, 1H), 5.03 (dd, J ) 17.9,
1.7 Hz, 1H), 5.02 (dd, J ) 11.1, 1.7 Hz, 1H), 4.77 (d, J ) 10.9
Hz, 1H), 4.71 (d, J ) 11.7 Hz, 1H), 4.70 (d, J ) 10.9 Hz, 1H),
4.61 (d, J ) 11.7 Hz, 1H), 4.58 (d, J ) 11.7 Hz, 1H), 4.22 (d,
J ) 11.7 Hz, 1H), 3.91 (dd, J ) 8.1, 5.1 Hz, 1H), 3.86 (t, J )
5.1 Hz, 1H), 3.73 (dd, J ) 5.1, 4.7 Hz, 1H), 3.65 (d, J ) 13.2
Hz, 1H), 3.62 (d, J ) 13.2 Hz, 1H), 2.80 (dt, J ) 7.3, 4.7 Hz,
1H), 2.33-2.28 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 141.0,
139.3, 139.0, 138.7, 136.5, 135.7, 128.4 (3C), 128.3 (2C), 128.2,
127.9, 127.8, 127.6, 127.5 (2C), 126.9, 119.6, 116.9, 82.5, 81.2,
79.5, 74.6, 74.4, 70.1, 57.7, 51.4, 34.8. Anal. Calcd for C37H41
-
NO3: C, 81.13; H, 7.54; N, 2.56. Found: C, 81.05; H, 7.50; N,
2.51.
(3R,4S,5R,6R)-6-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-3,4,5-tr is(ben zyloxy)-1,8-n on a d ien e (22R). Color-
less syrup, Rf 0.56 (hexane:EtOAc ) 4:1). [R]D +3.6 (c 2.0,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.41-7.02 (m, 25H),
5.81 (m, 1H), 5.66 (m, 1H), 5.37 (br d, J ) 17.1 Hz, 1H), 5.31
(br d, J ) 9.8 Hz, 1H), 5.30-5.09 (m, 4H), 4.84-4.20 (m, 8H),
4.05 (m, 1H), 3.93 (m, 1H), 3.77-3.70 (m, 1H), 2.69 (m, 1H),
2.59 (m, 1H), 2.40 (m, 1H). 13C NMR (125 MHz, CDCl3): δ
157.6, 139.1, 139.0, 138.8, 138.5, 136.9, 136.4, 135.5, 129.0,
128.7, 128.5, 128.4 (2C), 128.1, 128.0, 127.9, 127.5, 127.0,
119.4, 116.3, 82.1, 81.8, 81.5, 75.0, 70.9, 67.7, 67.1, 58.0, 49.3,
33.6. Anal. Calcd for C45H47NO5: C, 79.27; H, 6.95; N, 2.05.
Found: C, 79.04; H, 7.14; N, 2.02.
(3S,4S,5S,6R)-6-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-3,4,5-tr is(ben zyloxy)-1,8-n on a d ien e (17R). Color-
less syrup, Rf 0.62 (hexane:EtOAc ) 5:1). [R]D +2.1 (c 2.0,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.34-6.97 (m, 25H),
6.15 (m, 1H), 5.97 (m, 1H), 5.50-5.35 (m, 2H), 5.18-5.02 (m,
2H), 4.92-4.66 (m, 4H), 4.58 (br d, J ) 12.0 Hz, 1H), 4.50-
4.26 (m, 3H), 4.15 (br s, 2H), 4.02-3.60 (m, 3H), 2.55-2.32
(m, 2H), 2.22 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 156.7,
138.8 (2C), 138.5, 136.3, 135.2, 134.8 (2C), 128.2, 128.0, 127.8,
127.2, 126.7, 119.7, 117.1, 82.4, 81.3, 80.6, 75.3, 74.5, 69.8, 67.1,
57.3, 48.7, 34.6. Anal. Calcd for C45H47NO5: C, 79.27; H, 6.95;
N, 2.05. Found: C, 79.31; H, 6.96; N, 2.01.
J . Org. Chem, Vol. 68, No. 6, 2003 2121

Skaanderup and Madsen
(3R,4S,5R,6R)-6-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-3,4,5-tr is(ben zyloxy)cycloh ep ten e (23). Colorless
syrup, Rf 0.41 (hexane:EtOAc ) 4:1). [R]D +59.5 (c 2.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ 7.37-7.03 (m, 25H), 5.71 (m,
1H), 5.60 (m, 1H), 5.25-5.13 (m, 1H), 5.09 (d, J ) 11.1 Hz,
1H), 4.93 (d, J ) 11.1 Hz, 1H), 4.80-4.76 (m, 1H), 4.73 (d, J
) 11.9 Hz, 1H), 4.68 (d, J ) 11.9 Hz, 1H), 4.65-3.96 (m, 7H),
3.67-3.47 (m, 1H), 2.69 (br t, J ) 13.2 Hz, 1H), 1.84 (br dd, J
) 13.2, 9.4 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 156.5,
140.0 (2C), 139.1, 138.8 (2C), 136.6, 134.0, 129.0 (2C), 128.4
(2C), 128.1, 127.9, 127.8, 127.6, 127.5, 126.6, 126.1, 85.0, 82.9,
77.0, 74.6, 74.2, 73.2, 67.4, 56.7, 47.5, 25.8. Anal. Calcd for
(+)-Ca lystegin e B2. Colorless glass. [R]D +28.1 (c 0.27,
1
H2O) (lit.6 [R]D +27.2 (c 0.5, H2O)). H NMR (500 MHz, D2O):
δ 3.64 (dd, J ) 8.5, 3.8 Hz, 1H), 3.48 (dd, J ) 8.5, 2.1 Hz, 1H),
3.41 (t, J ) 8.5 Hz, 1H), 3.38 (dd, J ) 6.8, 3.8 Hz, 1H), 2.09-
1.98 (m, 2H), 1.86-1.80 (m, 1H), 1.63-1.57 (m, 1H). 13C NMR
(125 MHz, D2O): δ 93.3, 80.4, 77.7, 77.6, 58.6, 31.5, 24.5. NMR
data are in accordance with literature values.6
(+)-Ca lystegin e B3. White powder. [R]D +76.8 (c 0.88, H2O)
(lit.6 [R]D +82.8 (c 0.50, H2O)). 1H NMR (500 MHz, D2O): δ
3.89 (d, J ) 3.8 Hz, 1H), 3.70 (dd, J ) 9.4, 3.8 Hz, 1H), 3.67
(dd, J ) 9.4, 3.8 Hz, 1H), 3.33 (dd, J ) 6.8, 3.8 Hz, 1H), 2.02-
1.96 (m, 1H), 1.88-1.78 (m, 3H). 13C NMR (125 MHz, D2O): δ
93.0, 77.3, 75.3, 73.1, 58.3, 34.1, 23.0. NMR data are in
accordance with literature data.6
C
43H43NO5: C, 78.99; H, 6.63; N, 2.14. Found: C, 78.72; H,
6.67; N, 2.14.
(2S,3R,4R,5R)-5-[(N-Ben zyl-N-(b en zyloxyca r b on yl))-
a m in o]-2,3,4-tr is(ben zyloxy)cycloh ep ta n on e (24). Color-
less syrup, Rf 0.50 (hexane:EtOAc ) 3:1). [R]D +21.9 (c 2.0,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.36-6.98 (m, 25H),
5.14 (d, J ) 11.5 Hz, 1H), 5.08 (d, J ) 11.9 Hz, 1H), 4.91 (d,
J ) 11.5 Hz, 1H), 4.76 (s, 2H), 4.59 (d, J ) 11.5 Hz, 1H), 4.57
(d, J ) 11.5 Hz, 1H), 4.49 (d, J ) 11.9 Hz, 1H), 4.44-4.15 (m,
3H), 4.03-3.97 (m, 1H), 3.94 (dd, J ) 7.3, 0.9 Hz, 1H), 3.91-
3.81 (m, 1H), 2.71 (br t, J ) 11.9 Hz, 1H), 2.29 (ddd, J ) 11.9,
5.6, 1.7 Hz, 1H), 2.19-2.09 (m, 1H), 1.69 (m, 1H). 13C NMR
(125 MHz, CDCl3): δ 192.2, 157.5, 139.7, 138.3, 137.9, 137.6,
136.5, 129.1, 128.9, 128.5, 128.4, 128.2, 128.0, 127.8, 126.7,
126.1, 86.0, 85.4, 83.0, 73.6 (2C), 72.6, 67.5, 58.5, 47.1 37.0,
26.0. Anal. Calcd for C43H43NO6: C, 77.11; H, 6.47; N, 2.09.
Found: C, 76.91; H, 6.77; N, 2.02.
(-)-Ca lystegin e B4. Colorless glass. [R]D -46.4 (c 0.18,
H2O) (lit.5 [R]D -63.0 (c 0.65, H2O)). 1H NMR (500 MHz, D2O):
δ 3.70 (dt, J ) 3.0, 1.2 Hz, 1H), 3.54-3.49 (m, 2H), 3.32 (dd,
J ) 7.7, 3.0 Hz, 1H), 2.04-1.89 (m, 2H), 1.46-1.36 (m, 2H).
13C NMR (125 MHz, D2O): δ 92.5, 79.6, 74.9, 73.8, 59.2, 29.8,
25.1. NMR data are in accordance with literature data.5
Ack n ow led gm en t. Financial support from the Dan-
ish Natural Science Research Council is gratefully
acknowledged. We thank Dr. J ørn Smedsgaard, Bio-
Centrum, Technical University of Denmark for conduct-
ing analyses by electrospray mass spectrometry.
J O020645C
2122 J . Org. Chem., Vol. 68, No. 6, 2003