Synthesis of calystegine A3 from glucose by the use of ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.200900310

A synthesis of the nortropane alkaloid calystegine A₃ is described from D-glucose. The key step employs a zinc-mediated tandem reaction where a benzyl-protected methyl 6iodo glucoside is fragmented to give an unsaturated aldehyde, which is then transformed into the corresponding benzylimine and allylated in the same pot. The functionalized nona-l,8-diene, thus obtained, is converted into the sevenmembered carbon skeleton in calystegine A₃ by ring-closing olefin metathesis. Subsequent deoxygenation by the BartonMcCombie protocol, hydroboration and oxidative workup followed by hydrogenolysis affords calystegine A₃. The synthesis uses a total of 13 steps from glucose and confirms the absolute configuration of the natural product.

Full text of DOI:10.1002/ejoc.200900310

FULL PAPER
DOI: 10.1002/ejoc.200900310
Synthesis of Calystegine A3 from Glucose by the Use of Ring-Closing
Metathesis
Rune Nygaard Monrad,[a] Charlotte Bressen Pipper,[a] and Robert Madsen*[a]
Keywords: Allylation / Carbohydrates / Metathesis / Natural products / Total synthesis
A synthesis of the nortropane alkaloid calystegine A3 is de-
scribed from -glucose. The key step employs a zinc-medi-
ated tandem reaction where a benzyl-protected methyl 6-
olefin metathesis. Subsequent deoxygenation by the Barton–
McCombie protocol, hydroboration and oxidative workup
followed by hydrogenolysis affords calystegine A3. The syn-
D
iodo glucoside is fragmented to give an unsaturated alde- thesis uses a total of 13 steps from glucose and confirms the
hyde, which is then transformed into the corresponding ben-
zylimine and allylated in the same pot. The functionalized
nona-1,8-diene, thus obtained, is converted into the seven-
membered carbon skeleton in calystegine A3 by ring-closing
absolute configuration of the natural product.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The calystegines are a class of naturally occurring imino
sugar mimetics containing a nortropane ring system.[1]
More than 10 different calystegines have been identified in
a number of edible vegetables such as tomatoes, potatoes
and cabbage (Scheme 1). They are divided into three cat-
egories depending on the number of hydroxy groups: calys-
tegine A (three hydroxy groups), calystegine B (four hy-
droxy groups) and calystegine C (five hydroxy groups). As
a common feature, they all contain a tertiary hydroxy group
as part of a hemiaminal functionality. In addition, deriva-
tives of the calystegines containing a glycosidic linkage, an
N-methyl group, or an amino group, where the latter has
replaced the tertiary hydroxy group, have also been iso-
lated.[1] Several calystegines show significant inhibition of
glycosidases in particular calystegine A3, B1, B2, B4, and
C1, which are all inhibitors of β-glucosidase.[2] Recently, the
binding of calystegine B2 to β-glucosidase from Thermotoga
maritima was investigated by X-ray crystallography.[3] Be-
cause all the hydroxy groups are equatorial, the natural
product could either bind with the ethylene bridge below or
above the plane of the ring as compared to the natural sub-
strate glucose (Scheme 1). The studies showed that calysteg-
ine B2 binds with the ethylene bridge above the plane, i.e.
with the amino group at the position of the anomeric car-
bon in the corresponding glucose structure.[3]
Scheme 1. The calystegines.
The most abundant calystegines in plants are A3, B1, and
B2.[1] Calystegine A3 was first isolated from Calystegia sep-
ium in 1988[4] and the relative configuration established in
1990.[5] There have only been two syntheses of calystegine
A3: a racemic synthesis in 8 steps from 4-aminocyclohexa-
nol[6] and an asymmetric synthesis in 18 steps from cyclo-
heptatriene.[7] Unfortunately, the optical rotation of the fi-
nal product in the latter synthesis could not be measured
and as a result the absolute configuration of calystegine A3
has not yet been unambiguously established. Naturally oc-
curring calystegine A7, B2, B3 and B4 have all been prepared
by synthesis starting from either a hexose[8] or from a cyclo-
heptadiene derivative.[9] The most efficient route to the caly-
stegine alkaloids employs a zinc-mediated tandem reaction
for converting hexoses into acyclic dienes which are then
[a] Department of Chemistry, Building 201, Technical University
of Denmark,
2800 Lyngby, Denmark
Fax: +45-4593-3968
E-mail: rm@kemi.dtu.dk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900310.
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R. N. Monrad, C. B. Pipper, R. Madsen
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cyclized by ring-closing olefin metathesis to furnish the
seven-membered carbocycle.[8a–8d] In this transformation,
methyl 6-iodohexopyranosides are treated with zinc metal,
benzylamine and allyl bromide (Scheme 2).[10,11] First, a re-
ductive fragmentation of the iodopyranoside takes place to
produce an unsaturated aldehyde B which is then converted
into the corresponding imine and allylated. Zinc serves a
dual role in this tandem reaction by promoting both the
reductive fragmentation and the allylation reaction. The re-
sulting diene C is subsequently cyclized by olefin metathesis
to generate the seven-membered carbon skeleton in the ca-
lystegines. Recently, we have also used this sequence for
preparation of other carbocyclic natural products from
carbohydrates including cyclophellitol,[12] 7-deoxypancratis-
tatin[13] and gabosine A and N.[14]
Scheme 3. Reagents and conditions: (a) TrCl, pyridine, 90 °C. (b)
PMBCl, Bu2SnO, Bu4NI, MeCN, 4-Å MS, 82 °C. (c) BnBr, NaH,
Bu4NI, DMF, room temp. (d) DDQ, H2O, CH2Cl2, room temp. (e)
CS2, imidazole, NaH, THF, room temp., then MeI, room temp. (f)
Bu3SnH, AIBN, toluene, 110 °C. (g) H2SO4, MeOH, room temp.
(h) I2, PPh3, imidazole, THF, 67 °C. (i) Zn, TMSCl, THF, 40 °C,
sonication, then BnNH2, then CH2=CHCH2Br, 40 °C, sonication.
ether 3 in 67% yield. Attempts to form the tin acetal in
refluxing toluene in a separate step followed by alkylation
with p-methoxybenzyl chloride only gave 3 in low yield due
to poor conversion and decomposition. Diol 3 was then
protected with benzyl groups followed by cleavage of the p-
methoxybenzyl ether to furnish 2-hydroxy glycoside 5. The
hydroxy group at C-2 was removed by a Barton–McCombie
radical deoxygenation[17] to afford 2-deoxy glycoside 7 in
good yield. Deprotection of the trityl ether and treatment
of the resulting alcohol 8 with iodine, triphenylphosphane
and imidazole[18] then gave iodo glycoside 9.
Scheme 2. Calystegine retrosynthesis.
Herein, we describe a concise synthesis of calystegine A3
from -glucose by the use of ring-closing metathesis and
confirm the absolute configuration of the natural product.
Results and Discussion
Calystegine A3 contains two secondary hydroxy groups
With this substrate in hand the zinc-mediated tandem
with the same stereochemical relationship as the hydroxy reaction was then investigated under various conditions. In
groups at C-3 and C-4 in -glucose. On the other hand, the all previous applications of this reaction the imines have
hydroxy group at C-2 in the starting material must be re- contained an ether protecting group at C-2 to secure a good
moved at some point during the synthesis. The strategy em- 1,2-stereochemical induction in the allylation.[8a–8d,10,19] Al-
ploys the zinc-mediated tandem reaction with iodoglycoside though good 1,3-induction can be achieved for certain ad-
A followed by ring-closing metathesis into cycloheptene D dition reactions to β-alkoxy aldehydes[20] there was no pre-
(Scheme 2). The deoxygenation can either be carried out cedence for the addition to imines derived from 9. Thus, 2-
before the tandem reaction or after the metathesis reaction. deoxy glycoside 9 was fragmented with zinc in THF and
The most straightforward approach is to remove the C-2 the intermediate aldehyde converted into the imine and al-
hydroxy group early in the synthesis. As a result, it was lylated with allyl bromide (Scheme 3). This gave a good
decided to prepare a 2-deoxy-6-iodo glycoside from glucose yield of the desired aminodiene 10, but unfortunately the
and investigate the tandem reaction with this substrate ratio between the desired diastereomer 10R and the unde-
(Scheme 3).
sired isomer 10S was only 7:8. The stereochemistry at the
The synthesis began with the introduction of temporary new stereocenter in 10R and 10S was established after the
protecting groups in the 6- and the 2-position in methyl α- ring-closing metathesis reaction (see Supporting Infor-
-glucopyranoside (1). A trityl ether was chosen for regiose- mation for details). We have previously observed that sugar-
lective protection of the 6-position because it can be intro- derived imines could be allylated in excellent selectivity with
duced in high yield and the product isolated by crystalli- magnesium and indium metal.[8b] However, when the 2-de-
zation from toluene. A p-methoxybenzyl ether was selected oxy imine derived from 9 was subjected to allyl bromide in
for protection of the 2-position and installed by a tin-medi- the presence of magnesium or indium, the result was a 3:4
ated alkylation.[15] The best result was obtained by generat- ratio between 10R and 10S in both cases. Changing the sol-
ing the tin acetal in situ in the presence of the alkylating vent to the more apolar toluene/dichloromethane (4:1) mix-
agent,[16] which afforded the desired 2-p-methoxybenzyl ture had no influence on the diastereoselectivity. As a re-
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Synthesis of Calystegine A3 from Glucose
sult, it was clear that 2-deoxy glycosides cannot be used for AIBN, which ensures a high concentration of tributyltin hy-
synthesis of the calystegines by this route and that the ether dride compared to the thiocarbonyl derivative and in this
group in the 2-position is necessary as a stereochemical way a rapid capture of the generated alkyl radical. The best
control element in the allylation. A revised strategy was result, however, was obtained by slow addition of 17 and
therefore devised where the deoxygenation was postponed AIBN to a toluene solution of tributyltin hydride which
until after the metathesis reaction.
furnished 18 in 74% yield.
For this purpose diol 3 was benzyl-protected and the
trityl ether removed in the workup to afford alcohol 11
(Scheme 4). The hydroxy group was replaced with iodine to
give 12 which was then submitted to the tandem reaction
with zinc, benzylamine and allyl bromide. Again, the amin-
odienes were obtained in good yield, but the ratio had now
changed to 5.3:1 in favor of the desired diastereomer 13R
in line with our earlier observations.[8b]
Scheme 5. Reagents and conditions: (a) CbzCl, KHCO3, H2O,
CH2Cl2, 0 °C
Ǟ room temp. (b) 5% (PCy3)(C3H4N2Mes2)-
Scheme 4. Reagents and conditions: (a) BnBr, NaH, Bu4NI, DMF,
room temp., then H2SO4, MeOH, room temp. (b) I2, PPh3, imid-
azole, THF, 67 °C. (c) Zn, TMSCl, THF, 40 °C, sonication, then
BnNH2, then CH2=CHCH2Br, 40 °C, sonication.
Cl2Ru=CHPh, CH2Cl2, room temp. (c) DDQ, H2O, CH2Cl2, room
temp. (d) imidazole, NaH, CS2, THF, room temp., then MeI, room
temp. (e) Bu3SnH, AIBN, toluene, 110 °C. (f) BH3·THF, THF
–40 °C, then H2O2, NaOH, H2O, room temp., then Dess–Martin
periodinane, CH2Cl2, room temp. (g) Pd(OH)2/C, H2, H2O, diox-
ane, room temp.
Amino dienes 13R and 13S were separated by silica gel
chromatography and the amino group in 13R was protected
with a Cbz group (Scheme 5). The fully protected diene 14
To complete the synthesis of calystegine A3 olefin 18 was
was cyclized by olefin metathesis to afford the seven-mem- subjected to hydroboration followed by oxidative workup
bered carbocycle 15 in high yield. Subsequent cleavage of to give a mixture of four isomeric alcohols. These were not
the p-methoxybenzyl ether with DDQ gave alcohol 16 in purified, but submitted directly to oxidation with the Dess–
near quantitative yield while the same reaction with ceric Martin periodinane[21] to furnish a 2:1 mixture of the two
ammonium nitrate afforded 68% yield. Alcohol 16 was then regioisomeric ketones 19 and 20. The major isomer 19 was
ready for the ensuing deoxygenation reaction which proved deprotected by hydrogenolysis with Pearlman’s catalyst to
to be more troublesome than with monosaccharide 5. furnish calystegine A3. In the earlier synthesis isolation of
Again, the Barton-McCombie protocol was selected and it the target molecule failed due to decomposition under basic
was attempted to form xanthate 17 by the same procedure conditions.[7] Therefore, hydrochloric acid was added during
as used above for compound 6. However, the basic condi- the deprotection to secure ring-closure into the nortropane
tions resulted in cleavage of the neighboring Cbz group and ring system. Workup with basic ion-exchange resin and pu-
the formation of a cyclic carbamate as the major product. rification on a Sephadex column afforded the natural prod-
Eventually, by using carbon disulfide as a co-solvent it was uct with optical rotation and spectroscopic data in agree-
possible to diminish this side reaction and obtain xanthate ment with literature data[2b,5] which confirms the absolute
17 in a satisfying 78% yield. The following reaction with configuration of the target molecule.
tributyltin hydride also required significant optimization.
Previously, there have been speculations whether calyste-
The first experiment was performed by mixing 17, AIBN gine A6 is derived from calystegine A3 by an isomerization
and tributyltin hydride in toluene and heating the solution reaction (Scheme 6).[1] Calystegine A6 has only been found
to reflux. This afforded deoxy compound 18 in 29% yield in a few cases and always together with calystegine A3.[1] If
together with several byproducts which were not further this isomerization is in fact occurring, the correct structure
identified. A better result was obtained by adding 17 slowly of calystegine A6 would be the enantiomer of the originally
to a refluxing toluene solution of tributyltin hydride and proposed structure. To investigate this possibility we treated
Eur. J. Org. Chem. 2009, 3387–3395
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R. N. Monrad, C. B. Pipper, R. Madsen
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Scheme 6.
= 67.19 ppm) served as the internal standards in 13C NMR spec-
troscopy. Only the major rotamer is reported in the 13C NMR of
Cbz-protected amines. High resolution mass spectra were recorded
at the Department of Physics and Chemistry, University of Sou-
thern Denmark.
synthetic calystegine A3 with base under different condi-
tions. In pyridine at 100 °C no reaction was observed after
1 d. In 1  aqueous calcium hydroxide at room temperature
the natural product underwent slow degradation into a
complex mixture during two weeks. At 100 °C the degrada-
tion was almost complete within 4 h and at no time did we
observe any formation of calystegine A6. Hence, it appears
that calystegine A3 is moderately stable to base and that
calystegine A6 is not derived from calystegine A3 by a sim-
ple base-mediated isomerization.
Methyl 6-O-Trityl-α-D-glucopyranoside (2): A solution of methyl α-
-glucopyranoside (23.2 g, 120 mmol) and TrCl (36.6 g, 131 mmol)
in pyridine (350 mL) was stirred at 90 °C for 3 h. The mixture was
concentrated in vacuo and co-concentrated with toluene
(2ϫ100 mL). The residue was dissolved in CH2Cl2 (600 mL) and
washed with H2O (600 mL). The organic phase was dried (MgSO4),
filtered and concentrated. The crude product was crystallized from
toluene to afford 2 (47.9 g, 92%) as white crystals. Rf = 0.21
(EtOAc). [α]2D5 = +62.0 (c = 2.0, CHCl3) [lit.[22] [α]D = +59.4 (c =
0.7, CHCl3)]. M.p. 143–145 °C (toluene) [lit.[23] 151–152 °C
Conclusions
In summary, we have developed a 13-step synthesis of
calystegine A3 from -glucose in an overall yield of 5.5%.
The cycloheptane skeleton of the natural product is created
(EtOH)]. IR (KBr): ν = 3424, 3058, 2930, 1490, 1449, 1147, 1049,
˜
901, 760, 740, 703, 630 cm–1. 1H NMR [300 MHz, (CD3)2CO]: δ =
7.57–7.48 (m, 6 H), 7.36–7.20 (m, 9 H), 4.73 (d, J = 3.7 Hz, 1 H),
by a zinc-mediated tandem reaction followed by ring-clos- 4.21 (d, J = 3.8 Hz, OH), 4.06 (d, J = 4.6 Hz, OH), 3.78 (ddd, J =
1.7, 6.8, 9.7 Hz, 1 H), 3.71 (d, J = 7.9 Hz, 1 H), 3.62 (td, J = 3.9,
9.2 Hz, 1 H), 3.48 (s, 3 H), 3.45–3.37 (m, 2 H), 3.30 (ddd, J = 4.2,
8.2, 9.5 Hz, 1 H), 3.24 (dd, J = 6.7, 9.6 Hz, 1 H) ppm. 13C NMR
[75 MHz, (CD3)2CO]: δ = 145.3, 129.5, 128.5, 127.7, 100.8, 87.0,
75.5, 73.4, 72.1, 71.9, 64.7, 55.1 ppm. HRMS: calcd. for
C26H28NaO6 [M + Na]+ m/z 459.1778; found m/z 459.1805.
ing olefin metathesis. In the zinc reaction an ether substitu-
ent was necessary in the 2-position of the carbohydrate in
order to secure a good diastereoselectivity. The results con-
firm the absolute configuration of calystegine A3 and em-
phasize the utility of the two organometallic reactions for
developing short syntheses of carbocyclic natural products
from carbohydrates.
Methyl 2-O-(p-Methoxybenzyl)-6-O-trityl-α-
D-glucopyranoside (3):
A
suspension of triol (2.0 g, 4.6 mmol), Bu2SnO (1.31 g,
2
5.3 mmol), Bu4NI (1.7 g, 4.6 mmol) and freshly made PMBCl
(0.68 mL, 5.0 mmol) in anhydrous MeCN (120 mL) was heated to
reflux for 16 h via a soxhlet containing 4 Å molecular sieves. The
reaction mixture was allowed to reach room temperature and the
solvent was removed under reduced pressure. The residue was dis-
solved in Et2O (100 mL) and stirred with saturated aqueous
NaHCO3 (40 mL) for 1 h. The mixture was filtered through a plug
of Celite and the phases were separated. The organic layer was
dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (EtOAc/heptane/
Et3N, 1:3:0.01 Ǟ EtOAc) to give 3 (1.71 g, 67%) as a white foam.
Experimental Section
General: CH2Cl2 was dried by distillation from CaH2 while MeOH
and DMF were dried with 4-Å molecular sieves. THF and toluene
were dried by distillation from sodium while pyridine was dried
with KOH and distilled prior to use. Zinc dust (Ͻ 10 micron) was
activated immediately before use: zinc (5 g) in 1  HCl (50 mL) was
stirred at room temperature for 20 min and then filtered, rinsed
with water and Et2O and finally dried at high vacuum with a heat
gun. Sonications were performed in a Branson 1210 sonic bath.
PMBCl was prepared by vigorous stirring of PMBOH with 6 
aqueous HCl followed by phase separation and drying over K2CO3.
All other reagents were obtained from commercial sources and
used without further purification. Reactions were monitored by
TLC using aluminium plates precoated with silica gel 60. Com-
pounds were visualized by dipping in a solution of (NH4)6-
Mo7O24·4H2O (25 g/L) and Ce(SO4)2 (10 g/L) 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). Optical rotations were measured with a Perkin–Elmer
241 polarimeter while IR spectra were recorded with a Bruker Al-
pha FT-IR spectrometer. NMR spectra were recorded with a Var-
ian Mercury 300 instrument. Residual solvent peaks were used as
Rf = 0.53 (EtOAc). [α]2D5 = +31.4 (c = 1.0, CHCl ). IR (KBr): ν =
˜
3
3443, 3057, 2930, 2834, 1612, 1513, 1490, 1449, 1250, 1151, 1053,
903, 765, 747, 707, 632 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.48–7.42 (m, 6 H), 7.33–7.19 (m, 11 H), 6.91–6.85 (m, 2 H), 4.64
(d, J = 11.9 Hz, 1 H), 4.60 (d, J = 3.4 Hz, 1 H), 4.59 (d, J =
11.9 Hz, 1 H), 3.86 (td, J = 2.0, 9.2 Hz, 1 H), 3.79 (s, 3 H), 3.71–
3.63 (m, 1 H), 3.49 (td, J = 2.6, 9.2 Hz, 1 H), 3.40–3.29 (m, 3 H),
3.36 (s, 3 H), 2.68 (d, J = 2.1 Hz, OH), 2.62 (d, J = 2.7 Hz, OH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 156.4, 143.6, 130.0, 129.7,
128.6, 127.8, 127.1, 113.9, 97.5, 86.9, 78.8, 72.9, 72.6, 71.7, 69.4,
66.9, 55.2, 55.1 ppm. HRMS: calcd. for C34H36NaO7 [M + Na]+
m/z 579.2353; found m/z 579.2386.
Methyl 3,4-Di-O-benzyl-2-O-(p-methoxybenzyl)-6-O-trityl-α-
copyranoside (4): Bu4NI (2.1 g, 5.7 mmol) was added to a suspen-
2.50 ppm, sion of diol 3 (31.5 g, 56.6 mmol) and NaH (8.25 g, 50%,
δ(HDO) = 4.79 ppm] while CDCl3 (δ = 77.16 ppm), (CD3)2CO (δ 171.9 mmol, washed with heptane) in anhydrous DMF (600 mL)
= 29.84 ppm), (CD3)2SO (δ = 39.52 ppm) and dioxane in D2O (δ at 0 °C followed by dropwise addition of BnBr (21.7 mL,
D-glu-
internal reference in 1H NMR [δ(CHCl3)
δ(CD2HCOCD3) 2.05 ppm, δ(CD2HSOCD3)
=
=
7.26 ppm,
=
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Synthesis of Calystegine A3 from Glucose
183 mmol). The mixture was left at ambient temperature overnight
while it warmed to room temperature. The reaction mixture was
quenched with MeOH (60 mL), diluted with Et2O (600 mL) and
washed with H2O (700 mL). The aqueous phase was extracted with
Et2O (2ϫ500 mL), and the combined organic phases were dried
(MgSO4), filtered and concentrated on Celite. Dry column vacuum
chromatography[24] (EtOAc/heptane, 1:5) afforded 4 (34.4 g, 82%)
as a white foam. Rf = 0.47 (EtOAc/heptane, 1:2). [α]2D5 = +10.9 (c
3.90–3.83 (m, 1 H), 3.76 (dd, J = 8.7, 10.1 Hz, 1 H), 3.53 (dd, J =
1.5, 9.9 Hz, 1 H), 3.43 (s, 3 H), 3.24 (dd, J = 4.5, 10.1 Hz, 1 H),
2.60 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 216.1, 144.0,
138.2, 137.8, 128.9, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8,
127.1, 96.2, 86.5, 81.6, 80.4, 78.2, 75.8, 75.2, 70.4, 62.5, 55.1,
19.6 ppm. HRMS: calcd. for C42H42NaO6S2 [M + Na]+ m/z
729.2315; found m/z 729.2330.
Methyl 3,4-Di-O-benzyl-2-deoxy-6-O-trityl-α-D-glucopyranoside (7):
= 1.0, CHCl ). IR (KBr): ν = 3061, 3030, 2926, 1612, 1513, 1449,
˜
3
The methyl xanthate 6 (10.3 g, 14.6 mmol) was dissolved in anhy-
drous toluene (190 mL) under nitrogen and heated to reflux. A
solution of AIBN (239 mg, 1.46 mmol) and Bu3SnH (8.9 mL,
33.6 mmol) in anhydrous toluene (60 mL) was added dropwise to
the reaction mixture over a period of 1 h. The solution was stirred
at reflux for 6 h, cooled to room temperature and concentrated on
Celite. The product was purified by dry column vacuum
chromatography[24] (heptane Ǟ EtOAc/heptane, 1:19) to afford 7
1249, 1159, 1072, 1036, 1028, 755, 703 cm–1. H NMR (300 MHz,
1
CDCl3): δ = 7.41–7.35 (m, 6 H), 7.30–7.06 (m, 19 H), 6.83–6.74
(m, 4 H), 4.86 (d, J = 10.7 Hz, 1 H), 4.71 (d, J = 10.7 Hz, 1 H),
4.69 (d, J = 11.8 Hz, 1 H), 4.62 (d, J = 3.7 Hz, 1 H), 4.57 (d, J =
11.1 Hz, 1 H), 4.61 (d, J = 9.0 Hz, 1 H), 4.20 (d, J = 10.4 Hz, 1
H), 3.86 (t, J = 8.8 Hz, 1 H), 3.76–3.68 (m, 1 H), 3.73 (s, 3 H),
3.57–3.49 (m, 2 H), 3.41 (d, J = 10.0 Hz, 1 H), 3.36 (s, 3 H), 3.10
(dd, J = 4.7, 9.9 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
159.5, 144.1, 138.8, 138.0, 130.5, 129.8, 128.9, 128.6, 128.3, 128.3,
128.2, 127.9, 127.8, 127.7, 127.0, 114.0, 98.1, 86.4, 82.4, 79.9, 78.2,
76.1, 75.1, 73.1, 70.3, 62.7, 55.4, 55.1 ppm. HRMS: calcd. for
C48H48NaO7 [M + Na]+ m/z 759.3292; found m/z 759.3257.
1
(7.53 g, 86%) as a white solid. Rf = 0.55 (EtOAc/heptane, 1:2). H
NMR (300 MHz, CDCl3): δ = 7.49–7.37 (m, 6 H), 7.39–7.07 (m,
17 H), 6.83 (dd, J = 2.0, 7.2 Hz, 2 H), 4.84 (d, J = 2.5 Hz, 1 H),
4.67 (d, J = 10.5 Hz, 1 H), 4.59–4.56 (m, 2 H), 4.26 (d, J = 10.5 Hz,
1 H), 3.92–3.81 (m, 1 H), 3.71 (dd, J = 3.3, 9.8 Hz, 1 H), 3.57–3.48
(m, 1 H), 3.47–3.41 (m, 1 H), 3.30 (s, 3 H), 3.17 (dd, J = 4.8,
9.9 Hz, 1 H), 2.25 (dd, J = 5.0, 12.9 Hz, 1 H), 1.70 (ddd, J = 3.6,
11.7, 13.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.2,
138.8, 138.3, 129.0, 128.5, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6,
127.0, 98.4, 86.4, 78.8, 77.9, 75.0, 72.2, 70.9, 63.1, 54.5, 35.8 ppm.
HRMS: calcd. for C40H40NaO5 [M + Na]+ m/z 623.2768; found
m/z 623.2764.
Methyl 3,4-Di-O-benzyl-6-O-trityl-α-D-glucopyranoside (5): DDQ
(6.84 g, 30.1 mmol) was added to a solution of fully protected 4
(14.8 g, 20.1 mmol) in CH2Cl2/H2O (19:1, 350 mL). The atmo-
sphere was exchanged with argon and the mixture was stirred at
room temperature for 2.5 h. The solution was diluted with CH2Cl2
(700 mL) and quenched by stirring with saturated aqueous
NaHCO3 (500 mL) for 1.5 h. The aqueous phase was extracted
with CH2Cl2 (2ϫ500 mL) and the combined organic phases were
washed with brine (200 mL), dried (Na2SO4), filtered and concen-
trated on Celite. Purification by dry column vacuum chromatog-
raphy[24] (EtOAc/heptane, 2:1) gave 5 (12.0 g, 97%) as a colorless
oil. Rf = 0.49 (EtOAc/heptane, 1:1). [α]2D5 = +71.5 (c = 1.0, CHCl3).
Methyl 3,4-Di-O-benzyl-2-deoxy-α-D-glucopyranoside (8): A sus-
pension of trityl ether 7 (7.5 g, 12.5 mmol) in 1% H2SO4 in MeOH
(550 mL) was stirred at room temperature under argon for 2.5 h.
The mixture was neutralized by stirring with Na2CO3 (10 g), fil-
tered and concentrated on Celite. Purification by dry column vac-
uum chromatography[24] (EtOAc/heptane, 1:9 Ǟ 1:4) gave 8 (4.15 g,
IR (KBr): ν = 3448, 3060, 3029, 2929, 1490, 1449, 1156, 1125, 1047,
˜
1
745, 698 cm–1. H NMR (300 MHz, CDCl3): δ = 7.51–7.45 (m, 6
1
93%) as a colorless oil. Rf = 0.38 (EtOAc/heptane, 1:1). H NMR
H), 7.41–7.15 (m, 17 H), 6.87 (dd, J = 1.8, 7.7 Hz, 2 H), 4.91–4.81
(m, 3 H), 4.67 (d, J = 10.4 Hz, 1 H), 4.29 (d, J = 10.4 Hz, 1 H),
3.84–3.62 (m, 4 H), 3.53 (dd, J = 1.8, 10.1 Hz, 1 H), 3.47 (s, 3 H),
3.22 (dd, J = 4.6, 10.0 Hz, 1 H), 2.17 (d, J = 7.4 Hz, OH) ppm.
13C NMR (75 MHz, CDCl3): δ = 144.1, 138.7, 137.9, 128.9, 128.6,
128.3, 128.2, 128.1, 127.9, 127.7, 127.1, 99.3, 86.5, 83.6, 78.0, 75.7,
75.0, 73.2, 70.7, 62.6, 55.1 ppm. HRMS: calcd. for C40H40NaO6
[M + Na]+ m/z 639.2717; found m/z 639.2734.
(300 MHz, CDCl3): δ = 7.39–7.24 (m, 10 H), 4.95 (d, J = 11.1 Hz,
1 H), 4.80 (d, J = 3.2 Hz, 1 H), 4.72–4.60 (m, 3 H), 4.05–3.94 (m,
1 H), 3.85–3.72 (m, 2 H), 3.68–3.60 (m, 1 H), 3.55–3.47 (m, 1 H),
3.30 (s, 3 H), 2.29 (dd, J = 5.0, 13.1 Hz, 1 H), 1.95 (s, OH), 1.66
(ddd, J = 3.6, 11.5, 13.0 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 138.7, 138.5, 128.5, 128.5, 128.1, 127.9, 127.7, 127.7,
98.6, 78.2, 77.6, 75.0, 71.9, 71.2, 62.3, 54.7, 35.6 ppm. 1H NMR
spectroscopic data are in accordance with literature values.[25]
HRMS: calcd. for C21H26NaO5 [M + Na]+ m/z 381.1672; found
m/z 381.1693.
Methyl 3,4-Di-O-benzyl-2-O-(methylsulfanylthiocarbonyl)-6-O-tri-
tyl-α-D-glucopyranoside (6): A solution of alcohol 5 (7.06 g,
11.4 mmol) in CS2 (13.8 mL, 22.8 mmol) and THF (140 mL) were
added to NaH (1.65 g, 50%, 34.4 mmol, washed with heptane) and
imidazole (374 mg, 5.5 mmol) under nitrogen. The reaction was
stirred at room temperature for 3.5 h after which time MeI (3.6 mL,
57.8 mmol) was added. After an additional 1.5 h at room tempera-
ture, the mixture was concentrated. The residue was dissolved in
CH2Cl2 (300 mL) and washed with H2O (2ϫ100 mL). The aque-
ous phase was extracted with CH2Cl2 (50 mL) and the combined
organic phases were dried (Na2SO4), filtered, concentrated on Ce-
lite followed by dry column vacuum chromatography[24] (heptane
Ǟ EtOAc/heptane, 1:19) to afford 6 (7.2 g, 89%) as a yellow solid.
Rf = 0.71 (EtOAc/heptane, 1:1). [α]2D5 = +52.9 (c = 1.0, CHCl3). IR
Methyl
3,4-Di-O-benzyl-2,6-dideoxy-6-iodo-α-D-glucopyranoside
(9): Alcohol 8 (4.4 g, 12.2 mmol), PPh3 (5.1 g, 19.4 mmol) and
imidazole (2.0 g, 29.4 mmol) were co-concentrated with toluene
(2ϫ125 mL) and then dissolved in THF (250 mL) under argon.
The solution was heated to reflux and a solution of I2 in THF
(0.17 mmol/mL) was added dropwise to the reaction mixture until
a permanent color change was achieved (79.4 mL, 13.3 mmol). Full
conversion was confirmed by TLC analysis, and the mixture was
cooled to room temperature, filtered, and concentrated on Celite.
The product was purified by dry column vacuum chromatog-
raphy[24] (EtOAc/heptane, 1:49 Ǟ 1:9) to afford 9 (5.33 g, 93%) as
(KBr): ν = 3058, 3030, 2926, 1491, 1449, 1359, 1207, 1171, 1046, a colorless oil. R = 0.53 (EtOAc/heptane, 1:2). IR (film): ν = 3030,
˜
˜
f
740, 688, 630 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.51–7.46 2933, 2901, 1496, 1453, 1366, 1213, 1130, 1100, 1047, 955, 741, 699
1
(m, 6 H), 7.32–7.16 (m, 17 H), 6.87 (dd, J = 1.7, 7.7 Hz, 2 H), 5.80
cm–1. H NMR (300 MHz, CDCl3): δ = 7.32–7.15 (m, 10 H), 4.93
(dd, J = 3.7, 9.9 Hz, 1 H), 5.17 (d, J = 3.7 Hz, 1 H), 4.78 (d, J = (d, J = 11.0 Hz, 1 H), 4.75 (d, J = 3.0 Hz, 1 H), 4.64 (d, J =
10.7 Hz, 1 H), 4.72 (d, J = 10.7 Hz, 1 H), 4.68 (d, J = 10.4 Hz, 1
H), 4.30 (d, J = 10.4 Hz, 1 H), 4.16 (dd, J = 8.7, 9.9 Hz, 1 H),
11.0 Hz, 1 H), 4.58 (d, J = 11.5 Hz, 1 H), 4.51 (d, J = 11.5 Hz, 1
H), 3.93 (ddd, J = 5.1, 8.3, 11.5 Hz, 1 H), 3.52–3.20 (m, 4 H), 3.28
Eur. J. Org. Chem. 2009, 3387–3395
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3391

R. N. Monrad, C. B. Pipper, R. Madsen
(s, 3 H), 2.23 (dd, J = 5.1, 13.1 Hz, 1 H), 1.62 (ddd, J = 3.6, 11.6, vacuo. The residue was stirred in 1% H2SO4 in MeOH (800 mL)
FULL PAPER
13.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.5, 138.4,
128.6, 128.5, 128.1, 127.9, 127.8, 98.6, 82.2, 77.3, 75.4, 71.8, 69.9,
55.1, 35.5, 8.7 ppm. 1H NMR spectroscopic data are in accordance
with literature values.[25] HRMS: calcd. for C21H25INaO4 [M +
Na]+ m/z 491.0690; found m/z 491.0698.
and when TLC revealed no further conversion (3 h and 15 min),
Na2CO3 (30 g) was added followed by stirring at room temperature
until pH Ͼ 7. The mixture was filtered and concentrated under
reduced pressure to give a residue which was dissolved in CH2Cl2
(500 mL) and washed with H2O (500 mL). The aqueous phase was
extracted with CH2Cl2 (2ϫ500 mL) and the combined organic
phases were dried (MgSO4), filtered and concentrated. The residue
was purified by flash column chromatography (EtOAc/heptane,
3:2) to afford 11 (10.5 g, 83%) as a sticky white solid. Rf = 0.30
(3R,4R,6R)- and (3R,4R,6S)-6-(Benzylamino)-3,4-bis(benzyloxy)-
nona-1,8-diene (10R and 10S): A suspension of activated Zn
(140 mg, 2.14 mmol) and iodide 9 (100 mg, 0.214 mmol) in THF
(4 mL) was sonicated at 40 °C under argon in a conical flask.
TMSCl (13.5 µL, 0.107 mmol) was added in two portions, after 15
and 25 min of sonication. When NMR revealed full conversion to
the aldehyde (1 h and 15 min), BnNH2 (117 µL, 1.07 mmol) was
added dropwise to the solution. When NMR revealed full conver-
sion of the aldehyde to the imine (45 min), allyl bromide (55.4 µL,
0.64 mmol) was added dropwise to the solution. After an ad-
ditional 2 h of sonication, the solution was cooled to room tem-
perature, diluted with Et2O (60 mL) and H2O (20 mL) and filtered
through a plug of Celite. The layers were separated and the organic
phase was washed with H2O (3ϫ20 mL) and brine (20 mL), dried
(K2CO3), filtered, and concentrated in vacuo to give a colorless
oil, which was purified by flash column chromatography (EtOAc/
heptane, 1:4) to afford a separable 7:8 diastereomeric mixture of
10R and 10S (89 mg, 94%) as colorless oils.
(EtOAc/heptane, 1:1). [α]2D5 = +20.3 (c = 2.2, CHCl ). IR (film): ν
˜
3
= 3475, 3063, 3030, 2925, 1700, 1612, 1586, 1512, 1496, 1456, 1359,
1303, 1251, 1093, 913, 822, 735, 701 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.41–7.25 (m, 12 H), 6.87 (d, J = 8.3 Hz, 2 H), 4.99
(d, J = 10.8 Hz, 1 H), 4.89 (d, J = 10.9 Hz, 1 H), 4.83 (d, J =
10.9 Hz, 1 H), 4.75 (d, J = 11.8 Hz, 1 H), 4.64 (d, J = 11.8 Hz, 1
H), 4.60 (d, J = 11.7 Hz, 1 H), 4.52 (d, J = 3.5 Hz, 1 H), 4.00 (t, J
= 9.2 Hz, 1 H), 3.81 (s, 3 H), 3.79–3.62 (m, 3 H), 3.57–3.46 (m, 2
H), 3.37 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.5,
138.9, 138.2, 130.3, 129.9, 128.6, 128.5, 128.2, 128.1, 128.0, 127.7,
114.0, 98.4, 82.1, 79.7, 77.5, 75.9, 75.2, 73.2, 70.7, 62.0, 55.4,
55.3 ppm. HRMS: calcd. for C29H34NaO7 [M + Na]+ m/z 517.2197;
found m/z 517.2198.
Methyl 3,4-Di-O-benzyl-6-deoxy-6-iodo-2-O-(p-methoxybenzyl)-α-
D-glucopyranoside (12): A mixture of alcohol 11 (9.62 g,
10R: Rf = 0.20 (EtOAc/heptane, 1:2). [α]2D3 = +10.9 (c = 1.6,
19.5 mmol), PPh3 (7.67 g, 29.2 mmol) and imidazole (2.67 g,
39.2 mmol) was co-concentrated with toluene (2ϫ500 mL) and
then dissolved in THF (350 mL) and heated to reflux. A solution of
I2 in THF (0.49 mmol/mL) was added dropwise until the reaction
permanently retained an iodine color (53.0 mL, 26.0 mmol). The
completion of the reaction was verified by TLC analysis. The mix-
ture was cooled to room temperature, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography
(EtOAc/heptane, 1:2) to afford 12 (11.1 g, 94%) as a white glass,
which slowly crystallized upon standing. Rf = 0.68 (EtOAc/hep-
CHCl ). IR (film): ν = 3064, 3029, 2925, 2861, 1496, 1454, 1353,
˜
3
1206, 1092, 1069, 1027, 995, 918, 735, 697 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.28–7.09 (m, 15 H), 5.74 (ddd, J = 7.5,
10.6, 17.1 Hz, 1 H), 5.68–5.53 (m, 1 H), 5.27–5.17 (m, 2 H), 5.01–
4.92 (m, 2 H), 4.66 (d, J = 11.5 Hz, 1 H), 4.55 (d, J = 12.0 Hz, 1
H), 4.41 (d, J = 11.5 Hz, 1 H), 4.29 (d, J = 12.0 Hz, 1 H), 3.83 (dd,
J = 5.6, 7.4 Hz, 1 H), 3.61 (s, 2 H), 3.58–3.50 (m, 1 H), 2.62 (p, J
= 6.3 Hz, 1 H), 2.18–2.06 (m, 1 H), 2.04–1.93 (m, 1 H), 1.62–1.54
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.8, 138.7,
138.6, 135.5, 135.3, 128.4, 128.3, 128.1, 127.9, 127.6, 127.6, 126.8,
119.0, 117.5, 82.2, 79.0, 72.9, 70.6, 53.8, 51.1, 38.3, 35.3 ppm.
HRMS: calcd. for C30H36NO2 [M + H]+ m/z 442.2741; found m/z
442.2733.
tane, 1:1). [α]2D5 = +27.2 (c = 2.1, CHCl ). IR (KBr): ν = 3030,
˜
3
2916, 2906, 2838, 1613, 1514, 1453, 1358, 1300, 1245, 1171, 1112,
1
1088, 1073, 1047, 1030, 1012, 735, 695 cm–1. H NMR (300 MHz,
CDCl3): δ = 7.39–7.25 (m, 12 H), 6.86 (d, J = 8.7 Hz, 2 H), 4.99
(d, J = 10.8 Hz, 1 H), 4.94 (d, J = 11.0 Hz, 1 H), 4.79 (d, J =
10.8 Hz, 1 H), 4.74 (d, J = 11.8 Hz, 1 H), 4.68 (d, J = 10.9 Hz, 1
H), 4.59 (d, J = 11.8 Hz, 1 H), 4.55 (d, J = 3.6 Hz, 1 H), 4.00 (dd,
J = 8.8, 9.5 Hz, 1 H), 3.81 (s, 3 H), 3.54–3.42 (m, 3 H), 3.41 (s, 3
H), 3.37–3.25 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
159.4, 138.5, 137.9, 130.0, 129.7, 128.5, 128.4, 127.9, 127.8, 127.6,
113.8, 98.1, 81.5, 81.4, 79.6, 75.7, 75.3, 73.0, 69.2, 55.5, 55.2,
7.7 ppm. HRMS: calcd. for C29H33INaO6 [M + Na]+ m/z 627.1214;
found m/z 627.1191.
10S: Rf = 0.27 (EtOAc/heptane, 1:2). [α]2D3 = +32.5 (c = 1.0,
CDCl ). IR (film): ν = 3064, 3028, 2918, 2859, 1495, 1453, 1355,
˜
3
1261, 1207, 1089, 1065, 1027, 993, 913, 733, 696 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.44–7.27 (m, 15 H), 5.94–5.75 (m, 2 H),
5.41–5.31 (m, 2 H), 5.19–5.10 (m, 2 H), 4.82–4.64 (m, 2 H), 4.49
(d, J = 11.4 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 3.96 (t, J =
6.6 Hz, 1 H), 3.90–3.80 (m, 2 H), 3.65 (d, J = 12.9 Hz, 1 H), 2.96–
2.86 (m, 1 H), 2.32 (dd, J = 6.9, 14.5 Hz, 2 H), 2.04 (br. s, NH),
1.70–1.62 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.8,
138.8, 138.6, 135.4, 135.3, 128.5, 128.4, 128.3, 128.2, 128.1, 127.8,
127.5, 127.4, 126.9, 118.9, 117.4, 82.6, 78.6, 73.4, 70.6, 52.9, 50.5,
38.7, 35.6 ppm. HRMS: calcd. for C30H36NO2 [M + H]+ m/z
442.2741; found m/z 442.2728.
(3R,4S,5S,6R)-6-(Benzylamino)-3,4-bis(benzyloxy)-5-(p-methoxy-
benzyloxy)nona-1,8-diene (13R): Activated Zn (639 mg, 9.77 mmol)
was added to a solution of iodide 12 (567 mg, 0.94 mmol) in THF
(15 mL). The solution was degassed for 20 min and then placed in
a sonic bath at 40 °C. After 10 min and after 20 min of sonication
two portions of TMSCl (0.06 mL, 0.47 mmol) were added to the
mixture. When NMR revealed full conversion of the starting mate-
Methyl 3,4-Di-O-benzyl-2-O-(p-methoxybenzyl)-α-D-glucopyrano-
side (11): NaH (3.70 g, 50%, 77.1 mmol, washed with heptane) was
added to a solution of diol 3 (14.2 g, 25.5 mmol) in anhydrous
DMF (350 mL) and the mixture was stirred at room temperature rial (2 h), BnNH2 (0.31 mL, 2.82 mmol) was added dropwise. When
for 25 min. The reaction was cooled to 0 °C followed by addition
of Bu4NI (660 mg, 1.80 mmol) and dropwise addition of BnBr
(9.10 mL, 76.6 mmol). After stirring at ambient temperature over-
night, the mixture was quenched with MeOH (20 mL), diluted with
Et2O (600 mL) and washed with H2O (600 mL). The aqueous
phase was extracted with Et2O (2ϫ600 mL) and the combined or-
ganic phases were dried (MgSO4), filtered, and concentrated in
NMR revealed full conversion of the aldehyde to the imine (1 h),
allyl bromide (0.24 mL, 2.82 mmol) was added dropwise and after
sonicating for an additional 1 h and 25 min, the mixture was al-
lowed to reach room temperature. H2O (10 mL) and Et2O (40 mL)
were added and the suspension was filtered through a plug of Ce-
lite. The organic phase was washed with H2O (2ϫ15 mL) and brine
(15 mL), dried (K2CO3), filtered, and concentrated in vacuo. The
3392
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3387–3395

Synthesis of Calystegine A3 from Glucose
residue was purified by flash column chromatography (EtOAc/hep-
2 H), 5.73–5.54 (m, 2 H), 5.25–5.06 (m, 2 H), 4.98–4.56 (m, 6 H),
tane/Et3N, 1:2:0.01) to afford a 5.3:1 diastereomeric mixture of 13R 4.42–4.00 (m, 5 H), 3.76 (s, 1 H), 3.73 (s, 2 H), 3.62–3.52 (m, 1 H),
and 13S (487 mg, 90%) as a colorless oil. Additional purification
by chromatography gave the major diastereomer 13R as a colorless
oil.
3.31 (t, J = 10.1 Hz, 0.3 H), 2.94–2.78 (m, 0.7 H), 2.58 (t, J =
12.9 Hz, 0.3 H), 2.02–1.82 (m, 0.7 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.1, 156.8, 139.0, 138.5, 138.2, 136.7, 132.8, 130.9,
129.7, 129.1, 128.5, 128.3, 128.1, 127.7, 127.7, 127.5, 127.3, 113.7,
84.7, 83.3, 77.9, 75.3, 75.0, 72.7, 66.9, 61.9, 55.3, 53.8, 30.0 ppm.
HRMS: calcd. for C44H46NO6 [M + H]+ m/z 684.3320; found m/z
684.3325.
13R: Rf = 0.42 (EtOAc/heptane, 1:2). 1H NMR (400 MHz, CDCl3):
δ = 7.35–7.17 (m, 17 H), 6.85–6.79 (m, 2 H), 5.92 (ddd, J = 7.6,
10.5, 17.4 Hz, 1 H), 5.68–5.54 (m, 1 H), 5.25 (dd, J = 1.8, 10.5 Hz,
1 H), 5.20 (dd, J = 1.8, 17.4 Hz, 1 H), 5.05–4.96 (m, 2 H), 4.78 (d,
J = 10.9 Hz, 1 H), 4.76 (d, J = 11.2 Hz, 1 H), 4.65 (d, J = 11.2 Hz,
1 H), 4.51 (d, J = 11.9 Hz, 1 H), 4.50 (d, J = 10.8 Hz, 1 H), 4.08
(d, J = 11.9 Hz, 1 H), 3.93 (dd, J = 3.2, 7.6 Hz, 1 H), 3.82 (d, J =
13.0 Hz, 1 H), 3.79–3.75 (m, 2 H), 3.78 (s, 3 H), 3.69 (dd, J = 3.0,
7.7 Hz, 1 H), 3.43 (d, J = 13.1 Hz, 1 H), 2.45–2.35 (m, 2 H), 2.30–
2.15 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 141.0,
138.8, 138.1, 136.3, 136.3, 131.5, 129.2, 128.7, 128.6, 128.4, 128.3,
128.2, 127.6, 127.4, 126.8, 118.3, 116.8, 113.6, 83.4, 80.5, 79.6, 75.3,
74.4, 70.1, 56.5, 55.3, 50.8, 35.1 ppm. HRMS: calcd. for
C38H43NNaO4 [M + Na]+ m/z 600.3084; found m/z 600.3112.
(3R,4R,5S,6R)-6-[(Benzyl)(benzyloxycarbonyl)amino]-3,4-bis(ben-
zyloxy)-5-hydroxycycloheptene (16): DDQ (265 mg, 1.17 mmol) was
added to a solution of PMB ether 15 (526 mg, 0.77 mmol) in
CH2Cl2/H2O (19:1, 15 mL) and the reaction was stirred at room
temperature for 2.5 h. The mixture was diluted with CH2Cl2
(40 mL) and washed with saturated aqueous NaHCO3 (40 mL).
The aqueous phase was extracted with CH2Cl2 (2ϫ20 mL) and the
combined organic phases were washed with brine (20 mL), dried
(Na2SO4), filtered and concentrated. Purification by flash column
chromatography (EtOAc/heptane, 1:4) afforded 16 (431 mg, 99%)
as a colorless oil. Rf = 0.39 (EtOAc/heptane, 1:2). [α]2D5 = –13.1 (c
13S: Rf = 0.36 (EtOAc/heptane, 1:2). 13C NMR (75 MHz, CDCl3):
δ = 159.1, 141.4, 138.7, 138.2, 136.5, 135.6, 131.2, 129.5, 128.7,
128.6, 128.4, 128.3, 128.2, 127.5, 127.5, 126.7, 118.7, 116.7, 113.8,
82.5, 81.0, 78.8, 74.9, 73.4, 70.6, 57.8, 54.4, 51.5, 35.0 ppm.
= 1.1, CHCl ). IR (film): ν = 3545, 3483, 3063, 3031, 2889, 1695,
˜
3
1496, 1453, 1416, 1248, 1031, 734, 701 cm–1. H NMR (300 MHz,
1
CDCl3): δ = 7.32–7.06 (m, 20 H), 5.76–5.51 (m, 2 H), 5.16–4.99
(m, 2 H), 4.97–4.22 (m, 5 H), 4.14–3.67 (m, 4 H), 3.42 (t, J =
7.7 Hz, 1 H), 2.52–2.18 (m, 1 H), 2.01–1.80 (m, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 156.4 138.9, 138.2, 136.7, 132.6,
130.6, 129.5, 128.7, 128.6, 128.5, 128.4, 128.1, 127.9, 127.8, 127.4,
127.2, 84.0, 78.3, 75.3, 75.0, 72.3, 67.3, 60.0, 50.1, 30.2 ppm.
HRMS: calcd. for C36H38NO5 [M + H]+ m/z 564.2744; found m/z
564.2773.
(3R,4S,5S,6R)-6-[(Benzyl)(benzyloxycarbonyl)amino]-3,4-bis(ben-
zyloxy)-5-(p-methoxybenzyloxy)nona-1,8-diene (14): KHCO3
(2.98 g, 29.7 mmol) was added to a solution of amine 13R (2.86 g,
4.96 mmol) in CH2Cl2/H2O (1:1, 140 mL) at 0 °C followed by drop-
wise addition of CbzCl (0.77 mL, 5.45 mmol) under vigorous stir-
ring. The mixture was slowly allowed to reach room temperature
and when TLC revealed full conversion of the starting material
(2 h), the phases were separated, and the organic phase was washed
with H2O (30 mL), dried (K2CO3), filtered and concentrated. The
residue was purified by flash column chromatography (EtOAc/hep-
tane, 1:3) to afford 14 (3.40 g, 96%) as a colorless oil. Rf = 0.49
(3R,4S,5S,6R)-6-[(Benzyl)(benzyloxycarbonyl)amino]-3,4-bis(ben-
zyloxy)-5-[(methylsulfanyl)thiocarbonyloxy]cycloheptene (17): A
solution of imidazole (47 mg, 0.69 mmol) in CS2 (42 mL, 0.69 mol)
was added to NaH (267 mg, 50%, 5.56 mmol, washed with hep-
tane) under nitrogen. A solution of alcohol 16 (773 mg, 1.37 mmol)
in CS2 (42 mL, 0.69 mol) and THF (35 mL) was added dropwise
to the reaction mixture under vigorous stirring over a period of 1 h
and 15 min. After 3 h, MeI (432 µL, 3.82 mmol) was added drop-
wise and the solution was stirred at room temperature overnight.
The mixture was concentrated on Celite and purified by flash col-
umn chromatography (EtOAc/heptane, 1:6) to afford 17 (700 mg,
78%) as a yellow oil. Rf = 0.50 (EtOAc/heptane, 1:2). [α]2D3 = –29.0
(EtOAc/heptane, 1:2). [α]2D5 = –4.9 (c = 2.0, CHCl ). IR (film): ν =
˜
3
3062, 3031, 2923, 1696, 1641, 1612, 1585, 1514, 1497, 1453, 1407,
1321, 1300, 1248, 1173, 1078, 924, 915, 823, 735, 700 cm–1. 1H
NMR (300 MHz, [D6]DMSO, 60 °C): δ = 7.36–7.16 (m, 20 H), 7.12
(d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 5.85 (ddd, J = 7.6,
10.3, 17.5 Hz, 1 H), 5.35–5.03 (m, 5 H), 4.88–4.75 (m, 2 H), 4.70–
4.60 (m, 1 H), 4.58–4.02 (m, 9 H), 3.93–3.83 (m, 1 H), 3.75 (s, 2.7
H), 3.73 (s, 0.3 H), 3.52–3.43 (m, 1 H), 2.44–2.29 (m, 1 H), 2.27–
2.13 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.1, 157.4,
138.6, 136.5, 135.9, 135.1, 134.8, 131.0, 129.7, 129.4, 129.2, 128.5,
128.4, 128.3, 128.1, 127.9, 127.6, 127.5, 126.7, 118.5, 117.5, 113.7,
83.1, 80.8, 79.9, 75.4, 75.2, 70.8, 67.2, 56.5, 55.4, 53.6, 35.2 ppm.
HRMS: calcd. for C46H50NO6 [M + H]+ m/z 712.3633; found m/z
712.3614. C46H49NO6 (711.9): calcd. C 77.61, H 6.94; found C
77.56, H 7.18.
(c = 2.4, CHCl ). IR (film): ν = 3087, 3063, 3029, 2923, 2865, 1697,
˜
3
1496, 1453, 1229, 1202, 1118, 1055, 734, 697 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 7.28–7.01 (m, 20 H), 5.79–5.48 (m, 2 H),
5.16–4.98 (m, 2 H), 4.70 (q, J = 11.3 Hz, 1 H), 4.57–3.91 (m, 8 H),
3.82–3.65 (m, 1 H), 2.83–2.52 (m, 1 H), 2.38 (s, 1.5 H), 2.32 (s, 1.5
H), 2.09–1.84 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
215.0, 156.5, 138.5, 138.4, 138.2, 138.1, 130.7, 130.2, 128.8, 128.6,
128.5, 128.4, 128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 127.2,
84.6, 79.9, 76.2, 74.2, 72.4, 67.3, 58.9, 54.5, 30.0, 19.2 ppm. HRMS:
calcd. for C38H39NNaO5S2 [M + Na]+ m/z 676.2162; found m/z
676.2182.
(3R,4S,5S,6R)-6-[(Benzyl)(benzyloxycarbonyl)amino]-3,4-bis(ben-
zyloxy)-5-(p-methoxybenzyloxy)cycloheptene (15): A solution of
diene 14 (21.77 g, 30.6 mmol) in CH2Cl2 (1.2 L) was degassed by
bubbling nitrogen through the mixture for 15 min. Grubbs’ 2nd gen-
eration catalyst (1.3 g, 1.5 mmol) was added to the solution under
nitrogen, and the reaction was protected from sunlight and left stir-
ring at room temperature for 48 h. The reaction mixture was con-
centrated on Celite and purified by dry column vacuum chromatog-
raphy[24] (heptane Ǟ EtOAc/heptane, 1:3) to give 15 (20.4 g, 98%)
as a colorless syrup. Rf = 0.45 (EtOAc/heptane, 1:2). [α]2D5 = –19.1
(3R,4R,6R)-6-[(Benzyl)(benzyloxycarbonyl)amino]-3,4-bis(benzyl-
oxy)cycloheptene (18): A solution of freshly distilled Bu3SnH
(243 µL, 0.92 mmol) in toluene (6 mL) was evacuated for 15 min,
purged with nitrogen and heated to reflux. To this solution were
added methyl xanthate 17 (200 mg, 0.31 mmol) and AIBN (10 mg,
0.061 mmol) in toluene (4 mL) dropwise under nitrogen over a
(c = 2.1, CHCl ). IR (film): ν = 3064, 3031, 2921, 1700, 1612, 1586, period of 20 min. Additional toluene (1.5 mL) was used to transfer
˜
3
1514, 1496, 1456, 1355, 1246, 1174, 1073, 824, 734, 701 cm–1. H
the material. Full conversion was achieved after 50 min and the
mixture was cooled to room temperature and concentrated in
1
NMR (300 MHz, CDCl3): δ = 7.42–7.03 (m, 22 H), 6.86–6.74 (m,
Eur. J. Org. Chem. 2009, 3387–3395
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3393

R. N. Monrad, C. B. Pipper, R. Madsen
FULL PAPER
vacuo. The residue was purified by flash column chromatography
(CH2Cl2/heptane, 4:1) to give 18 (124 mg, 74%) as a colorless oil.
Rf = 0.45 (EtOAc/heptane, 1:2). [α]2D5 = –10.6 (c = 2.0, CDCl3). IR
TLC analysis revealed disappearance of the protected cyclohep-
tanone, and 1  aqueous HCl (0.7 mL) was added to the solution,
which was stirred at room temperature under 1 atmosphere of H2
for an additional 32 h. The mixture was neutralized by addition
(film): ν = 3087, 3063, 3029, 2961, 2927, 2857, 1693, 1496, 1453,
˜
1413, 1357, 1305, 1259, 1233, 1090, 1070, 1027, 801, 733, 695 cm–1. of Amberlite IRA-400 OH–, filtered through a plug of Celite and
1H NMR (300 MHz, CDCl3): δ = 7.32–7.00 (m, 20 H), 5.64–5.51 thoroughly washed with H2O (15ϫ10 mL). The filtrate was con-
(m, 2 H), 5.18–4.97 (m, 2 H), 4.66–4.19 (m, 6 H), 4.00–3.80 (m, 2
centrated, co-concentrated with EtOH and purified by Sephadex
LH-20 column chromatography (EtOAc/EtOH, 4:1) to give calyste-
H), 3.43–3.18 (m, 1 H), 2.35–1.83 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 155.7, 138.9, 138.7, 136.6, 133.0, 128.5, gine A3 (9.2 mg, 84%). Rf = 0.42 (1-propanol/AcOH/H2O, 4:1:1).
128.3, 127.9, 127.8, 127.6, 127.5, 127.4, 127.1, 81.9, 79.2, 73.0, 72.6,
67.2, 53.9, 47.9, 39.6, 33.0 ppm. HRMS: calcd. for C36H37NNaO4
[M + Na]+ m/z 570.2615; found m/z 570.2633.
[α]2D3 = –14.0 (c = 0.1, H2O) [lit.[2b] [α]D = –17.3 (c = 0.47, H2O)].
IR (film): ν = 3382, 2954, 2929, 2857, 1635, 1399, 1387, 1259, 1088,
˜
1056, 1026, 934 cm–1. 1H NMR (800 MHz, D2O): δ = 3.62 (ddd, J
= 6.9, 8.4, 10.5 Hz, 1 H), 3.46–3.42 (m, 1 H), 3.35 (d, J = 8.5 Hz,
1 H), 2.04–1.93 (m, 2 H), 1.92 (ddd, J = 2.1, 6.5, 13.2 Hz, 1 H),
1.51–1.43 (m, 3 H) ppm. 13C NMR (125 MHz, D2O): δ = 93.4,
82.5, 72.7, 54.2, 42.6, 31.8, 29.3 ppm. C-1 at δ = 93.4 ppm was
assigned by HSQC. NMR spectroscopic data are in accordance
with literature values.[2b,5] HRMS: calcd. for C7H13NNaO3 [M +
Na]+ m/z 182.0788; found m/z 182.0793.
(2S,3R,5R)-5-[(Benzyl)(benzyloxycarbonyl)amino]-2,3-bis(benzyl-
oxy)cycloheptanone (19) and (3R,4R,6S)-6-[(benzyl)(benzyloxycar-
bonyl)amino]-3,4-bis(benzyloxy)cycloheptanone (20): Cycloheptene
18 (600 mg, 1.1 mmol) was dissolved in THF (30 mL) under argon
and cooled to –40 °C. BH3·THF (1  in THF, 2.30 mL, 2.3 mmol)
was added dropwise to the solution over a period of 20 min. After
3 h at –40 °C, the mixture was allowed to reach room temperature,
and after 4 h 2  aqueous NaOH (2 mL) and 35% aqueous H2O2
(4 mL) were added to the reaction. The solution was stirred at am-
bient temperature for 1 h, diluted with Et2O (70 mL) and washed
with H2O (3ϫ10 mL) and brine (10 mL). The organic phase was
dried (K2CO3), filtered, and concentrated in vacuo to give a mix-
ture of alcohols, which was used directly in the next step. The crude
alcohols were dissolved in CH2Cl2 (19 mL) and added to a solution
of the Dess–Martin periodinane[21] (929 mg, 2.2 mmol) in CH2Cl2
(15 mL). The mixture was stirred at room temperature for 1 h, after
which time Et2O (100 mL) was added. The resulting white suspen-
sion was stirred for 30 min and then filtered. The filtrate was
washed with saturated aqueous Na2S2O3 (2ϫ20 mL) and brine
(30 mL), and the organic phase was dried (K2CO3), filtered and
concentrated. Flash column chromatography (EtOAc/heptane, 1:9)
of the residue gave a separable 2:1 mixture of the isomeric cyclo-
heptanones (468 mg, 76% combined yield) as colorless oils; 19
(308 mg, 50%) and 20 (160 mg, 26%).
Supporting Information (see also the footnote on the first page of
1
this article): Structural proof for 10R and 10S, H and 13C NMR
spectra for compounds 3–20 and calystegine A3.
Acknowledgments
We thank Associate Professor C. H. Gotfredsen for assistance with
NMR spectroscopy. The spectra at 800 MHz were recorded with a
Bruker Avance 800 MHz spectrometer at the Danish Instrument
Center for NMR Spectroscopy of Biological Macromolecules. The
Danish National Research Foundation is gratefully acknowledged
for financial support.
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7, 738–742.
1
1357, 1238, 1096, 1072, 1028, 736, 698 cm–1. H NMR (300 MHz,
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CDCl3): δ = 7.37–7.00 (m, 20 H), 5.21–5.02 (m, 2 H), 4.59–4.15
(m, 6 H), 4.07–3.38 (m, 3 H), 2.69–2.41 (m, 1 H), 2.26–2.12 (m, 1
H), 2.01–1.75 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
209.2, 155.7, 138.6, 138.0, 137.2, 136.4, 128.6, 128.5, 128.4, 128.0,
127.9, 127.8, 127.7, 127.3, 126.9, 88.7, 79.4, 72.5, 72.2, 67.3, 55.4,
48.3, 37.3, 36.6, 30.5 ppm. HRMS: calcd. for C36H37NNaO5 [M +
Na]+ m/z 586.2564; found m/z 586.2549.
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IR (film): ν = 3087, 3063, 3030, 2930, 2871, 1695, 1496, 1454, 1415,
˜
1
1352, 1246, 1095, 1071, 1028, 736, 698 cm–1. H NMR (300 MHz,
CDCl3): δ = 7.30–7.04 (m, 20 H), 5.18–5.00 (m, 2 H), 4.62–3.95
(m, 7 H), 3.57–3.28 (m, 2 H), 2.86–2.31 (m, 4 H), 2.14–1.74 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 207.2, 155.8, 138.4,
138.2, 138.0, 136.5, 128.9, 128.8, 128.7, 128.62, 128.4, 128.3, 128.2,
128.1, 128.0, 127.9, 127.7, 127.3, 81.2, 79.3, 72.3, 72.3, 67.6, 50.6,
48.3, 44.9, 36.9, 29.9 ppm. HRMS: calcd. for C36H37NNaO5 [M +
Na]+ m/z 586.2564; found m/z 586.2582.
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Calystegine A3:
A solution of cycloheptanone 19 (39 mg,
0.069 mmol) in dioxane/H2O (9:1, 3.3 mL) was degassed by bub-
bling nitrogen through the mixture for 10 min. Pearlman’s catalyst
(8 mg, 7.5 µmol) was added to the solution and H2 was bubbled
through the solution for 10 min after which time the reaction was
stirred at room temperature under 1 atmosphere of H2 for 15 h.
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3394
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3387–3395

Synthesis of Calystegine A3 from Glucose
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Received: March 23, 2009
Published Online: May 27, 2009
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Eur. J. Org. Chem. 2009, 3387–3395
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3395