Total synthesis of 3-O-benzyl-1,3,5-tri-epi-calystegine B2 from L-sorbose

Article abstract of DOI:10.1002/ejoc.200801232

The well known 2,3:4,6-di-O-isopropylidene-α-L-sorbofuranose (12) was chosen as starting material for the synthesis of (1S,4R,5S,6S,7S)-4-amino-6- benzyloxy-1,7-isopropylidenedioxY-8-oxabicyclo[3.2.1]octane (33) and (1S,4S,5S,6S,7S)-4- amino-6-benzYloxY-1

Full text of DOI:10.1002/ejoc.200801232

FULL PAPER
DOI: 10.1002/ejoc.200801232
Total Synthesis of 3-O-Benzyl-1,3,5-tri-epi-calystegine B2 from -Sorbose
L
Daniele Lo Re,[a] Francisco Franco,[a] Fernando Sánchez-Cantalejo,[a] and
Juan A. Tamayo*[a]
Dedicated to Professor Isidoro Izquierdo Cubero on the occasion of his retirement
Keywords: Total synthesis / Calystegines / Alkaloids / Alkylation / Metathesis / Azasugars
The well known 2,3:4,6-di-O-isopropylidene-α-
anose (12) was chosen as starting material for the synthesis
L
-sorbofur-
methodology, respectively, followed by ring-closing olefin
metathesis (RCM). These promising oxabicyclic compounds
of (1S,4R,5S,6S,7S)-4-amino-6-benzyloxy-1,7-isopropylidene- were key intermediates for the preparation of the polyhy-
dioxy-8-oxabicyclo[3.2.1]octane (33) and (1S,4S,5S,6S,7S)-4- droxylated nor-tropane alkaloid 1,3,5-tri-epi-calystegine B2
amino-6-benzyloxy-1,7-isopropylidenedioxy-8-oxabicyclo- (10) as its 3-O-benzyl derivative 35.
[3.2.1]octane (34) through carbon chain-lengthening at C-1
and C-6 by Wittig and magnesium-mediated alkylation
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The nor-tropane alkaloids are bicyclic amines each com-
bining a piperidine (six carbons) and a pyrrolidine (five car-
bons) ring. They were first isolated from the roots of Calys-
tegia sepium (Convolvulaceae)[1] and since then many others
have been found from a variety of vascular plants, their only
natural source.[2] Structurally, these naturally occurring imi-
nosugars have been traditionally classified (Figure 1) into
three groups on the basis of their hydroxylation patterns:
the A series (with three OH groups), the B series (with four
OH groups), and the C series (with five OH groups). A
fourth group of calystegines, the N series, presenting an
amino group instead of a hydroxy moiety in the aminoketal
functionality at the bicyclic ring bridgehead, has also been
isolated,[3] from Hyoscyamus niger (Solanaceae).
A number of calystegines have been discovered to
date,[3,4] but the most abundant among them is calysteg-
ine B2, found in all the plants so far tested for the presence
of these types of alkaloids. Despite their natural occurrence,
the biological activities of nor-tropane alkaloids have not
been extensively studied as is the case with other related
sugar mimics.[5] Calystegines do, however, show remarkable
inhibitory activities against several glycosidase enzymes, in
comparison with other alkaloidal glycosidase inhibitors.[4a]
Calystegine B2 inhibits almond β-glucosidase and green
Figure 1. Examples of some naturally occurring calystegines and
the unnatural analogues 10 and 11.
coffee α-galactosidase with Ki values of 1.2 and 0.86 µ,
respectively,[6] and human lysosomal α-galactosidase with
an IC50 value of 30 µ.[2b]
Their inhibitory mechanism is not yet well understood.
It has been proposed[6,7] that their mode of action resembles
those of other glycosidase inhibitors that have been studied.
However, despite their close structural similarities with well
known α-glucosidase inhibitors such as 1-deoxynojirimycin
and castanospermine, calystegines in general show signifi-
[a] Department of Medicinal and Organic Chemistry, Faculty of
Pharmacy, University of Granada,
Campus de Cartuja, s/n, 18071 Granada, Spain
Fax: +34-958-243845
E-mail: jtamayo@ugr.es
1984
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Eur. J. Org. Chem. 2009, 1984–1993

Total Synthesis of 3-O-Benzyl-1,3,5-tri-epi-Calystegine B2
cant inhibitory activity against β-glucosidases but little or scribed[10] -sorbose derivative. Firstly, we carried out the
no inhibition of α-glucosidases. This notwithstanding, caly- chain-lengthening at C-1 of 12; this step was achieved
stegine B2 has also demonstrated a potent inhibition against through a methylenation reaction by Wittig’s methodology
α-galactosidases,[2b] a fact that suggest a different recogni- (Scheme 2) and afforded 1,2-dideoxy-3,4:5,7-di-O-isoprop-
tion pattern depending on the type of enzyme been in- ylidene-α--xylo-hept-1-en-3-ulofuranose (13). We next
hibited.[7]
approached the nitrone insertion at C-6; consequently, com-
For these reasons, methods for the enantioselective syn- pound 13 was subjected to acid-catalysed deacetonation of
thesis of new calystegines are strongly desired. In the litera- its 5,7-O-isopropylidene protecting group to provide diol 14
ture,[8] all the procedures described involve the obtention of exclusively. Accordingly, we proceeded to protect both OH
an amino polyhydroxycycloheptane derivative that un- groups in 14 orthogonally. We first regioselectively pro-
dergoes cyclization – either spontaneous or base-catalysed – tected the primary OH in 14 by treatment with tert-butyl-
to the corresponding calystegine, depending on the instabil- chlorodiphenylsilane as the silylating agent to provide
ity of the aminoketal function. It is in the creation of these alcohol 15. Next came the protection of the secondary OH
polyhydroxycycloheptane derivatives that these syntheses at C-5 in 15. A benzyl ether was the protecting group of
differ. Routes that involve the use of enantiopure carbo- choice here because of its stability and the simplicity of its
hydrates as starting materials[8a–8j,8l,8o–8s] predominate in removal. Alcohol 15 was thus treated with NaH and BnBr
the literature, with methodologies that vary from intramo- in anhydrous DMF, the classical Williamson reaction, but
lecular nitrone–alkene cycloaddition (INAC)[8c] to ring- an unexpected low yield (20%) of the desired benzyl ether
closing metathesis (RCM)[8g] or anionic cyclization of epox- 16 was obtained. Changing the solvent to DMSO afforded
ide dithioacetal derivatives.[8a] Other routes not based on a complex mixture of products not further analysed. In
sugars but taking advantages of nitroso–alkene cycloaddi- view of these results, we decided to modify the benzylation
tion[8d,8k,8n] as the way to obtain the amino polyhydroxycy- conditions and instead employed an acidic medium.
cloheptane derivative have also been employed.
Alcohol 15 was thus treated with benzyl trichloroacetimid-
In continuation of our efforts[9] in the use of common ate in the presence of triflic acid, but a complex mixture of
hexuloses (-fructose and -sorbose) as sources of function- products was again obtained. These negative results, both
alization and chirality in the asymmetric synthesis of biolo- in basic and in acidic media, moved us to try the reaction
gically active azasugars, in the course of our studies toward under neutral conditions. Dudley et al. recently pub-
the synthesis of calystegine B2 we describe here for the first lished[11] a paper describing the conversion of alcohols into
time the total synthesis of unnatural 1,3,5-tri-epi-calysteg- benzyl ethers in neutral media,[12] and under these condi-
ine B2 (10) as its 3-O-benzyl derivative 35 from -sorbose.
tions alcohol 15 was easily converted into benzyl ether 16
According to our retrosynthetic analysis for calysteg- in good yield (72%, Scheme 2). Compound 16 was sub-
ine B2 (1, Scheme 1), the already described -sorbose deriv- sequently subjected to desilylation, affording 5-O-benzyl-
ative 12 should be an appropriate substrate for the prepara- 1,2-dideoxy-3,4-O-isopropylidene-α--xylo-hept-1-en-3-ulo-
tion of intermediate C through chain-lengthening at C-1 furanose (17), a suitable substrate for introduction of the
and nitrone formation at C-6. Nitrone C could then be al- nitrone functional group at the C-6 position.
kylated to provide 1,8-nonadiene B, a suitable substrate for
a RCM reaction to achieve the tricyclic key intermediate A,
which should then be easily transformable into the desired
calystegine B2.
Scheme 2. Synthesis of benzyl ether 17 from “diacetone hexulose
aldehyde” 12: a) Ph3PMeBr, THF, tBuOK, 5 h, room temp. (59%);
b) aqueous AcOH (50 %), 30 min, 50 °C (93 %); c) TBDPSCl,
DCM, TEA, DMAP (cat.), 2 h, room temp. (84%); d) BnBr, NaH,
anh. DMF, 25 h, 0 °C (20%); e) BnBr, NaH, anh. DMSO, 25 h,
room temp.; f) benzyl 2,2,2-trichloroacetimidate, TfOH, Et2O, 2 h,
0 °C; g) 2-benzyloxy-1-methylpyridinium triflate, MgO, CF3Ph,
24 h, 90 °C (72%); h) TBAF·3H2O, THF, 7 h, room temp. (73%).
Scheme 1. Retrosynthetic analysis of calystegine B2 (1).
Results and Discussion
To achieve our next step, nitrone formation at C-6,
Our synthetic route starts with 2,3:4,6-di-O-isopropylid- alcohol 17 was subjected to Dess–Martin oxidation to af-
ene-α--xylo-hexos-2-ulofuranose (12), a previously de- ford aldehyde 18 (Scheme 3), which was not fully charac-
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1985

D. Lo Re, F. Franco, F. Sánchez-Cantalejo, J. A. Tamayo
FULL PAPER
terized but immediately treated with benzylhydroxylamine
This unsuccessful result made us think that the configu-
hydrochloride to give nitrone 19 in excellent yield (90%). ration at C-5 was playing an important role in the failure
The configuration of the new C–N double bond was estab- of the RCM, so a different approach, in which the same
lished as Z from the chemical shift of its azomethinic pro- reaction sequence was attempted on the C-5 epimer of 17,
ton, which appeared at δ = 6.95 ppm, outside the expected was designed. This change in the configuration of C-5
resonance range (8.0–8.5 ppm) for the E configuration.[13] would led us to the synthesis not of calystegine B2 (1) as
Because of the highly polarised state of the nitrone func- initially planned, but of 1,3,5-triepi-calystegine B2 (10) and
tionality, addition of several nucleophiles has been exten- 3-epi-calystegine B2 (11). Alcohol 15 was therefore oxidized
sively studied.[14] With this in mind, treatment of nitrone to diulose D (not isolated) and then immediately reduced
19 with vinylmagnesium bromide yielded a 2:1 mixture (1H with NaBH4 to afford 7-O-tert-butyldiphenylsilyl-1,2-dide-
NMR evidence) of hydroxylamines 20a and 20b, which oxy-3,4-O-isopropylidene-α--ribo-hept-1-en-3-ulofuranose
could be separated by column chromatography; their con- (24, Scheme 4), obtained as a single diastereoisomer. It is
figurations at C-7 were not established at this point. Re- worth mentioning that the high stereoselectivity of the re-
duction of 20a and 20b to the corresponding amines 21a duction reaction was due to the steric hindrance resulting
and 21b was carried out under mild conditions because of from the isopropylidene group in D directing the hydride
the presence of two reactive vinyl groups in the molecule. approach through the re face. Benzyl protection of 24 was
We thus took advantages of the methodology described by this time accomplished with BnBr/NaH in a good yield
Goti et al.,[15] which employs In0 as reducing agent in a (70%), affording benzyl derivative 25. Silyl deprotection of
mildly acidic medium. Cbz protection of amines 21a and 25 yielded alcohol 26, which was straightforwardly trans-
21b with benzyl chloroformate finally afforded dienes 22a formed into nitrone 28 through condensation of aldehyde
and 22b in excellent yield (92%).
27 (not isolated) with benzylhydroxylamine hydrochloride.
Nitrone 28 was subjected to alkylation with vinylmagne-
sium bromide as described earlier. We were only able to
isolate hydroxylamine 29, which was reduced to amine 30
as before. The absolute configuration of the new stereogenic
centre at C-7 in 29 could not be determined at this point
because of the free rotation of the C(6)–C(7) bond, al-
though after completion of the cyclization it was shown to
be the R diastereoisomer. N-Protection of 30 as carbamate
31, followed by RCM with the second-generation Grubbs
catalyst (23), to our delight afforded (1S,4R,5S,6S,7S)-6-
benzyloxy-4-[(benzyl)(benzyloxy-carbonyl)amino]-1,7-iso-
propylidenedioxy-8-oxabicyclo[3.2.1]oct-2-ene (32, Scheme 4)
in good yield (79%).
Scheme 3. Synthesis of amine 22 from alcohol 17 and initial ap-
proach to RCM. a) Dess–Martin, DCM, 24 h, room temp. (98%);
b) BnNHOH·HCl, AcONa, MS (3 Å), MeOH, 18 h, room temp.
(71%); c) CH2=CHMgBr, THF, 3 h, –78 °C, 20a (60%) and 20b
(30 %); d) In, EtOH, NH4Cl, 48 h, 120 °C, 21a (96 %) and 21b
(94%); e) CbzCl, K2CO3, acetone, 3 h, room temp., 22a (92%) and
22b (94%); f) 23, microwave irradiation, DCM, 60 min, 100 °C.
Scheme 4. a) TPAP, NMO, MS (4 Å), DCM, 2 h, room temp.;
b) NaBH4, MeOH, 30 min, room temp. (76 %); c) NaH, BnBr,
DMF, 24 h, room temp. (70%); d) TBAF·3H2O, THF, 5 h, room
temp. (95 %); e) Dess–Martin, DCM, 18 h, room temp. (97%);
f) BnNHOH·HCl, AcONa, MS (3 Å), MeOH, 18 h, room temp.
(79%); g) CH2=CHMgBr, THF, 2 h, –78 °C (90%); h) In, EtOH,
NH4Cl, 24 h, 120 °C (92%); i) CbzCl, K2CO3, acetone, 2.5 h, room
temp. (97%); j) 23, microwave irradiation, DCM, 60 min, 100 °C
(79%).
Next in the reaction sequence was the olefin RCM of
22a and 22b. The second-generation Grubbs catalyst[16] (23,
Scheme 3) was employed but did not provide the RCM ad-
ducts, even not under microwave conditions. Other authors
have described similar difficulties in the preparation of sim-
ilar or even less sterically demanding polycyclic com-
pounds.[17]
1986
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Total Synthesis of 3-O-Benzyl-1,3,5-tri-epi-Calystegine B2
Full characterisation of tricycle 32 probed difficult,
though, because of the occurrence of two rotamers in its
NMR spectra due to the presence of the carbamate protect-
ing group in the molecule.[18] However, when 32 was sub-
jected to catalytic hydrogenation, removal of the N-protect-
ing groups and reduction of the C=C bond took place to
yield amine 33, which could be fully characterized
(Scheme 5). 1H NMR studies on 33 confirmed the R config-
uration at C-4 by the coupling constant of H-4,5 (J4,5
=
5.5 Hz). Previous studies done by us[19] have shown that in
similar tricyclic rings, values of J4,5 = 3.2–6.9 Hz are associ-
ated with 4R configurations whereas values of J4,5 = 0–
1.6 Hz correspond with the 4S stereochemistry. Moreover,
when catalytic hydrogenation of 32 was repeated on a 3 g
scale, compound 34, the C-4 epimer of 33, could also be
isolated. This compound, as predicted by our studies, has a
J4,5 coupling constant of 0 Hz, and NOE experiments show
a positive H(4)–H(7) coupling, thus confirming a 4S stereo-
chemistry (Scheme 5).
Scheme 6. Synthesis of 3-O-benzyl-1,3,5-tri-epi-calystegine B2 (35).
NOE dif. couplings of 35. a) HCl (1 ), 10 h, room temp., 35
(53%).
presumably due to the axial dispositions of its OH groups at
C-2 and C-4. In addition, no natural nor-tropanic alkaloid
presenting such a hydroxylation pattern has to date been
described, possibly because of low stability. In the same
way, attempts to obtain 3-epi-calystegine B2 (11) yielded a
complex mixture of compounds, presumably those corre-
sponding to the bicyclic and monocyclic rings of 3-epi-caly-
stegine B2 (11, Figure 2). Similar results have been de-
scribed by Madsen[8f] in the synthesis of three different iso-
mers of 11 presenting the same axial disposition of the OH
group at C-3 and are probably due to a destabilizing 1,3-
diaxial interaction between the OH group at C-3 and the
methylene groups.
Scheme 5. Synthesis of tricycles 33 and 34 and NOE dif. couplings
of 34. a) H2, Pd–C (10%), MeOH, 7 h, room temp., 33 (85%) and
34 (14%).
Once the absolute configurations of both amines 33 and
34 had been correctly established, we proceeded to ac-
complish the synthesis of 1,3,5-tri-epi-calystegine B2 (10)
and 3-epi-calystegine B2 (11) by removing the remaining
protecting groups in 33 and 34, respectively. Treatment of
amine 34 with HCl (1 ) for 10 h thus yielded compound
35 as a single compound (Scheme 6). Its analytical and
spectroscopic data confirmed the nor-tropanic ring struc-
ture with a cis disposition for H(2), H(3) and H(4), and
NOE dif. couplings between H(3)–H(6)endo, H(3)–H(7)
endo, and H(4)–H(6)endo, corroborating once again the
configurations assigned to C-4 in 33 and 34 (see Scheme 6).
To the best of our knowledge, this is the first synthesis
of a nor-tropanic ring with two of its piperidinic OH groups
in an axial disposition. Unfortunately, final debenzylation
of 35 afforded a mixture of compounds that appeared as
single spot by TLC. NMR studies showed a complex mix-
ture of compounds, presumably the bicyclic and monocyclic
rings of the 1,3,5-tri-epi-calystegine B2 (10). Other deprotec-
tion methods were also tried with the same results. We sup-
pose that final product 10 could not be properly isolated
Figure 2. Proposed destabilizing interaction in 3-epi-calysteg-
ine (11).
Conclusions
We describe a total synthesis of 1,3,5-tri-epi-calysteg-
ine B2 (10) as its 3-O-benzyl derivative 35, starting from the
common sugar -sorbose. The synthetic route includes a
stereoselective nitrone alkylation combined with RCM to
afford a tricyclic intermediate easily transformed into the
desired calystegine. This is a rare example of a polyhy-
droxylated nor-tropanic ring with two of its piperidic OH
groups in an axial disposition.
Experimental Section
General: Solutions were dried with MgSO4 before concentration
under reduced pressure. The 1H and 13C NMR spectra were re-
corded with Variant INOVA UNITY 300 MHz, Variant DIRECT
because of the instability of the nor-tropanic bicyclic ring, DRIVE 400 MHz and 500 MHz spectrometers. Chemical shifts are
Eur. J. Org. Chem. 2009, 1984–1993
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1987

D. Lo Re, F. Franco, F. Sánchez-Cantalejo, J. A. Tamayo
FULL PAPER
quoted in ppm and are referenced to residual H in the deuterated
solvent as the internal standard. Splitting patterns are designated
as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet;
m, multiplet and br, broad. IR spectra were recorded with a Perkin–
Elmer FT-IR Spectrum One instrument and mass spectra were re-
corded with Hewlett–Packard HP-5988-A and Fisons mod. Plat-
form II and VG Autospec-Q mass spectrometers. Optical rotations
were measured, unless otherwise stated, for solutions in CHCl3
(1 dm tube) with a Jasco DIP-370 polarimeter. TLC was performed
on precoated silica gel (60 F254) aluminium sheets and compounds
were detected with a mixture of ammonium molybdate (10% w/v)
in aqueous sulfuric acid (10%) containing cerium sulfate (0.8% w/
v) and heating. Rf values refer to these TLC plates developed in
the solvents indicated. Column chromatography was performed on
silica gel (Merck, 7734). Non-crystalline compounds were shown
to be homogeneous by chromatographic methods and charac-
terized by NMR and HRMS (LSIMS).
at room temp. for 2 h, and TLC (diethyl ether) revealed the pres-
ence of a new compound of higher mobility. MeOH (1 mL) was
added and the reaction mixture was stirred for 20 min, DCM
(15 mL) was then added, and the mixture was washed successively
with aqueous HCl (10%), H2O, aqueous NaHCO3 (10%) and H2O.
The organic phase was concentrated to a residue and column chro-
matographed (diethyl ether/hexane, 1:5 Ǟ diethyl ether) to yield 15
(1.2 g, 84%) as a colourless syrup. Rf = 0.6 (diethyl ether/hexane,
1:1). [α]2D5 = –10 (c = 1.6, CHCl3). H NMR (300 MHz, CDCl3): δ
1
= 7.75–7.36 (m, 10 H, 2ϫPh), 6.09 (dd, J1trans,2 = 17.1, J1cis,2
=
10.5 Hz, 1 H, 2-H), 5.70 (dd, Jgem = 1.6 Hz, 1 H, 1trans-H), 5.18
(dd, 1 H, 1cis-H), 4.38 (brt, J5,6 = J5,HO = 2.4 Hz, 1 H, 5-H), 4.35
(s, 1 H, 4-H), 4.25 (d, 1 H, HO), 4.23–4.08 (m, 3 H, 6,7,7Ј-H), 1.49
and 1.46 (2ϫs, 6 H, CMe2) and 1.04 (s, 9 H, CMe3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 136.5 (C-2), 135.8, 135.6, 132.4,
132.0, 130.2 and 128.0 (Ph), 116.9 (C-1), 112.7 and 111.4 (C-
3,CMe2), 88.5 (C-4), 79.1 and 77.7 (C-5,6), 63.1 (C-7), 27.2 and
26.2 (CMe ), 26.8 (CMe ) and 19.1 (CMe ) ppm. IR: ν = 3460
˜
max
2
3
3
1,2-Dideoxy-3,4:5,7-di-O-isopropylidene-α-L-xylo-hept-1-en-3-ulo-
(OH) and 1373 (CMe2) cm–1. HRMS (LSIMS): calcd. for
furanose (13): A solution of tBuOK (5.5 g, 46 mmol) in anhydrous
THF (30 mL) was added under Ar to a stirred suspension of meth-
yltriphenylphosphonium bromide (16.8 g, 46 mmol) in a solution
of 12[10] (7.9 g, 30 mmol) in anhydrous THF (30 mL). After 5 h the
reaction mixture was diluted with diethyl ether, washed with aque-
ous KHSO4 (10%) and brine and then concentrated to a residue.
Column chromatography (diethyl ether/hexane, 1:2) gave 13 (4.14 g,
60%) as a colourless syrup. Rf = 0.7 (diethyl ether). [α]2D5 = +20 (c
= 1.6, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 6.05 (dd, J1trans,2
= 17.1, J1cis,2 = 10.4 Hz, 1 H, 2-H), 5.70 (dd, Jgem = 1.7 Hz, 1 H,
1trans-H), 5.29 (dd, 1 H, 1cis-H), 4.30 (d, J5,6 = 2.1 Hz, 1 H, 5-H),
4.28 (s, 1 H, 4-H), 4.09–4.07 (m, 3 H, 6,7,7Ј-H), 1.52, 1.43, 1.36 and
1.35 (4ϫs, 12 H, 2ϫCMe2) ppm. 13C NMR (75 MHz, CDCl3): δ
= 136.1 (C-2), 117.2 (C-1), 112.9 (C-3), 111.5 (1,3-dioxolane,
CMe2), 97.2 (CMe2, 1,3-dioxane), 87.7 (C-4), 73.6 (C-6), 72.4 (C-
5), 60.2 (C-7), 28.8 and 18.6 (CMe2, 1,3-dioxane), 27.0 and 26.0
C
26H34NaO5Si [M + Na]+ 477.2074; found 477.2073 (deviation
–0.1 ppm).
5-O-Benzyl-7-O-tert-butyldiphenylsilyl-1,2-dideoxy-3,4-O-isopropyl-
idene-α-L-xylo-hept-1-en-3-ulofuranose (16): 2-Benzyloxy-1-methyl-
pyridinium triflate (1.6 g, 4.6 mmol) and magnesium oxide
(180 mg, 4.46 mmol) were added to a solution of 15 (421 mg,
0.93 mmol) in α,α,α-trifluorotoluene (7 mL) and the mixture was
heated at 90 °C for 24 h. TLC (diethyl ether/hexane, 1:3) revealed
the presence of 16 and a new product with higher Rf. The reaction
mixture was filtered and washed with DCM. The filtrate was con-
centrated to a residue that was dissolved in DCM and washed with
brine, and the solvents were evaporated. Chromatography (diethyl
ether/hexane, 1:20) of the residue yielded 16 (364 mg, 72%) as a
colourless syrup together with 15 (570 mg). Rf 0.7 (diethyl ether/
hexane, 1:1). [α]2D5 = +20 (c = 1.9, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.71–7.30 (m, 15 H, 3ϫPh), 6.01 (dd, J1cis,2 = 10.5,
J1trans,2 = 17.1 Hz, 1 H, 2-H), 5.61 (dd, Jgem = 1.5 Hz, 1 H, 1trans-
H), 5.26 (dd, 1 H, 1cis-H), 4.72 and 4.63 (2ϫd, J = 11.9 Hz, 2 H,
(CMe , 1,3-dioxolane) ppm. IR: ν
= 1383 and 1375
˜
2
m a x
(CMe2) cm–1. HRMS (LSIMS): calcd. for C13H20NaO5 [M +
Na]+ 279.1208; found 279.1208 (deviation +0.2 ppm).
CH2Ph), 4.47 (m, 1 H, 6-H), 4.43 (s, 1 H, 4-H), 4.13 (d, J5,6
=
1,2-Dideoxy-3,4-O-isopropylidene-α-L-xylo-hept-1-en-3-ulofuranose
3.1 Hz, 1 H, 5-H), 4.10 (dd, J6,7 = 8.4 Hz, 1 H, 7-H), 3.97 (dd, J6,7Ј
= 5.2, J7,7Ј = 9.8 Hz, 1 H, 7Ј-H), 1.58 and 1.39 (2ϫs, 6 H, CMe2)
and 1.10 (s, 9 H, CMe3) ppm. 13C NMR (100 MHz, CDCl3): δ =
138.0, 133.5 and 133.4 (3 ϫ Ph ipso), 136.3 (C-2), 135.7, 129.8,
129.7, 128.4, 121.7 and 121.3 (Ph), 117.0 (C-1), 112.8 and 111.7
(C-3,CMe2), 85.5, 81.9 and 81.4 (C-4,5,6), 72.1 (CH2Ph), 60.5 (C-
7), 27.2 and 26.3 (CMe2), 26.9 (CMe3) and 19.3 (CMe3) ppm. IR:
(14): A solution of 13 (16.34 g, 63.37 mmol) in aqueous AcOH
(50%, 100 mL) was heated at 50 °C for 2 h. TLC (diethyl ether)
showed the absence of 13 and the presence of a new compound of
lower Rf. The solvent was removed, the obtained residue was dis-
solved in EtOAc and neutralized with K2CO3, and the solvent was
removed again. Column chromatography of the residue (diethyl
ether/hexane, 3:2 Ǟ diethyl ether/MeOH, 20:1) yielded 14 (12.24 g,
93%) as a colourless syrup. Rf = 0.3 (diethyl ether). [α]2D6 = +30 (c
= 1.2, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 6.04 (dd, J1trans,2
= 17.1, J1cis,2 = 10.6 Hz, 1 H, 2-H), 5.64 (dd, Jgem = 1.4 Hz, 1 H,
1trans-H), 5.28 (dd, 1 H, 1cis-H), 4.31 (d, J5,6 = 3.0 Hz, 1 H, 5-H),
4.30 (s, 1 H, 4-H), 4.22 (q, J6,7 = J6,7Ј = 3.0 Hz, 1 H, 6-H), 4.11
(dd, J7,7Ј = 12.5 Hz, 1 H, 7-H), 4.03 (dd, 1 H, 7Ј-H), 1.50 and 1.32
(2ϫs, 6 H, CMe2) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.2
(C-2), 117.1 (C-1), 112.6 (C-3), 111.7 (CMe2), 88.6 (C-4), 79.5 and
ν
= 3071 (arom.) and 1373 (CMe2) cm–1. C33H40O5Si (544.75):
˜
max
calcd. C 72.76, H 7.40; found C 71.37, H 6.92.
5-O-Benzyl-1,2-dideoxy-3,4-O-isopropylidene-α-L-xylo-hept-1-en-3-
ulofuranose (17): TBAF·3H2O (694 mg, 2.20 mmol) was added to
a stirred solution of 16 (1.04 g, 1.84 mmol) in THF (8 mL). The
mixture was stirred at room temp., and after 18 h the TLC (diethyl
ether/hexane, 3:1) revealed the absence of the starting material and
the presence of a new compound of lower Rf. The mixture was
concentrated to a residue that was dissolved in DCM and washed
with H2O, and the organic layer was then concentrated to a new
residue that was chromatographed (diethyl ether/hexane, 1:1) to
give 17 (412 mg, 73%) as a colourless syrup. Rf = 0.2 (diethyl ether/
hexane, 3:2). [α]2D5 = +58 (c = 1.1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.32 (m, 5 H, Ph), 6.06 (dd, J1cis,2 = 10.5, J1trans,2
= 17.1 Hz, 1 H, 2-H), 5.69 (dd, Jgem = 1.6 Hz, 1 H, 1trans-H), 5.32
(dd, 1 H, 1cis-H), 4.74 and 4.51 (2ϫd, J = 12.0 Hz, 2 H, CH2Ph),
4.47 (s, 1 H, 4-H), 4.41 (m, 1 H, 6-H), 4.05 (d, J5,6 = 3.3 Hz, 1 H,
5-H), 4.00 (dd, J7,7Ј = 11.9, J6,7 = 5.7 Hz, 1 H, 7-H), 3.90 (dd, J6,7Ј
77.6 (C-5,6), 61.4 (C-7), 27.1 and 26.1 (CMe ) ppm. IR: ν
=
˜
2
max
3444 (OH), 1381 and 1373 (CMe2) cm–1. HRMS (LSIMS): calcd.
for C10H16NaO5 [M + Na]+ 239.0898; found 239.0895 (deviation
–1.1 ppm).
7-O-tert-Butyldiphenylsilyl-1,2-dideoxy-3,4-O-isopropylidene-α-L-
xylo-hept-1-en-3-ulofuranose (15): Et3N (0.9 mL, 6.3 mmol),
DMAP (6 mg) and tert-butylchlorodiphenylsilane (1.2 mL,
4.7 mmol) were added under Ar to a stirred solution of 14 (680 mg,
3.15 mmol) in anhydrous DCM (15 mL). The mixture was stirred
1988
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1984–1993

Total Synthesis of 3-O-Benzyl-1,3,5-tri-epi-Calystegine B2
= 4.9 Hz, 1 H, 7Ј-H), 1.56 and 1.40 (2ϫs, 6 H, CMe2) ppm. 13C
NMR (100 MHz, CDCl3): δ = 137.5 (Ph ipso), 136.4 (C-2), 128.9,
128.4 and 127.9 (Ph), 117.5 (C-1), 113.0 and 112.1 (C-3, CMe2),
NCH2Ph), 4.14 (d, 1 H, 5-H), 3.78 (t, 1 H, 7-H), 1.50 and 1.34
(2ϫs, 6 H, CMe2) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.3
and 138.2 (2 ϫ Ph ipso), 138.2 (C-2), 132.5 (C-8), 129.6, 128.6,
85.7, 83.2 and 81.2 (C-4,5,6), 72.0 (CH2Ph), 61.4 (C-7), 27.4 and 128.5, 127.9, 127.5 and 127.4 (CH2Ph), 121.4 (C-9), 117.1 (C-1),
26.6 (CMe ) ppm. IR: ν
= 3469 (OH), 3031 (arom.) and 1374
112.7 and 111.7 (C-3, CMe2), 85.4 (C-4), 82.7 (C-5), 81.3 (C-6),
72.5 (OCH2Ph), 67.3 (C-7), 62.1 (NCH2Ph), 27.4 and 26.5
˜
2
max
(CMe2) cm–1. HRMS (LSIMS): calcd. for C17H22NaO5 [M +
Na]+ 329.1367; found 329.1365 (deviation –0.7 ppm).
(CMe ) ppm. IR: ν
= 3467 (OH), 3030 (arom.) and 1374
˜
2
max
(CMe2) cm–1. HRMS (LSIMS): calcd. for C26H31NNaO5 [M +
Synthesis of Nitrone 19: A solution of Dess–Martin periodinane in
DCM (15%, 4.4 mL, 2.1 mmol) was added under Ar at 0 °C to a
solution of 17 (536 mg, 1.75 mmol) in anhydrous DCM (7 mL) and
the mixture was stirred at room temp. for 18 h. The solvent was
evaporated to afford a residue that was dissolved in ether, cooled
to 5 °C and filtered. The filtrate was washed with aqueous
NaHCO3 (10%) and the organic layer was concentrated to afford a
residue. This residue was percolated with ether to yield presumably
aldehyde 18 (522 mg, 98%), which was immediately used in the
Na]+ 460.5181; found 460.5178 (deviation –0.6 ppm).
This was followed by 20b (297 mg, 30%). Rf = 0.5 (diethyl ether/
hexane, 2:1). [α]2D4 = +48 (c = 1.2, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.23 (m, 10 H, 2ϫPh), 6.03 (dd, J1cis,2 = 10.6,
J1trans,2 = 17.0 Hz, 1 H, 2-H), 5.97 (dt, 1 H, 8-H), 5.63 (dd, Jgem
=
1.5 Hz, 1 H, 1trans-H), 5.35 (dd, Jgem = 1.9, J8,9cis = 10.6 Hz, 1 H,
9cis-H), 5.27 (dd, 1 H, 1cis-H), 5.23 (dd, J8,9trans = 17.4 Hz, 1 H,
9trans-H), 5.04 (brs, 1 H, OH), 4.63 (dd, J5.6 = 2.7, J6,7 = 9.6 Hz,
1 H, 6-H), 4.58 and 4.39 (2ϫd, J = 11.4 Hz, 2 H, OCH2Ph), 4.37
(s, 1 H, 4-H), 3.98 and 3.82 (2ϫd, J = 13.5 Hz, 2 H, NCH2Ph),
3.83 (d, 1 H, 5-H), 3.80 (t, J7,8 = 10.0 Hz, 7-H), 1.55 and 1.36
(2ϫs, 6 H, CMe2) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.4
and 137.9 (2 ϫ Ph ipso), 138.3 (C-2), 132.1 (C-8), 129.5, 128.6,
128.3, 127.9, 127.6 and 127.5 (CH2Ph), 121.1 (C-9), 117.2 (C-1),
113.2 and 111.9 (C-3, CMe2), 84.6 (C-4), 83.1 (C-5), 80.7 (C-6),
72.0 (OCH2Ph), 68.0 (C-7), 61.5 (NCH2Ph), 27.4 and 26.6
next step. R = 0.7 (diethyl ether). IR: ν
= 3031 (arom.), 1740
˜
f
max
(CO) and 1374 (CMe2) cm–1.
MS (3 Å, 1.3 g) and a solution of 18 (1.95 g, 6.40 mmol) in MeOH
(10 mL) were added under Ar to a solution of BnNHOH·HCl
(1.22 g, 7.68 mmol) and AcONa (637 mg, 7.68 mmol) in anhydrous
MeOH (35 mL). The mixture was stirred at room temp. for 18 h,
and TLC (diethyl ether) revealed the absence of the starting mate-
rial and the presence of a new compound of lower Rf. The solvent
was evaporated and the obtained residue was chromatographed (di-
ethyl ether/hexane, 3:1) to give 19 (1.87 g, 71%). Rf = 0.4 (diethyl
ether). [α]2D6 = +137 (c = 1.4, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 7.38–7.32 (m, 10 H, 2ϫPh), 6.94 (d, J6,7 = 4.5 Hz, 1 H, 7-H),
6.05 (dd, J1cis,2 = 10.5, J1trans,2 = 17.1 Hz, 1 H, 2-H), 5.65 (dd, Jgem
= 1.5 Hz, 1 H, 1trans-H), 5.39 (brdd, 1 H, 6-H), 5.31 (dd, 1 H,
1cis-H), 4.92 and 4.85 (2ϫd, J = 13.6 Hz, 2 H, OCH2Ph), 4.59 (d,
J5,6 = 3.1 Hz, 1 H, 5-H), 4.54 and 4.44 (2ϫd, J = 11.8 Hz, 2 H,
(CMe ) ppm. IR: ν
= 3436 (OH), 3030 (arom.) and 1374
˜
2
max
(CMe2) cm–1. HRMS (LSIMS): calcd. for m/z 460.5183 [M +
Na]+; found C26H31NNaO5 460.5178 (deviation –1.0 ppm).
5-O-Benzyl-7-benzylamino-1,2,7,8,9-pentadeoxy-3,4-O-isopropyl-
idene-β-D-ido- and α-L-gluco-nona-1,8-dien-3-ulofuranose (21a and
21b): In (488 mg, 4.25 mmol) was added to a stirred solution of
20a (747 mg, 1.7 mmol) in EtOH/NH4Cl (2:1, 30 mL) and the mix-
ture was heated to 120 °C for 48 h. TLC (diethyl ether/hexane, 3:1)
NCH2Ph), 4.43 (s, 1 H, 4-H), 1.56 and 1.37 (2ϫs, 6 H, CMe2) ppm. revealed the presence of a new compound of lower Rf. The reaction
13C NMR (100 MHz, CDCl3): δ = 138.0 and 132.5 (2ϫPh ipso),
136.4 (C-2), 136.0 (C-7), 129.7, 129.3, 129.2, 128.1, 127.9 and 127.3
(CH2Ph), 117.4 (C-1), 112.9 and 112.3 (C-3, CMe2), 86.0, 82.9 and
78.9 (C-4,5,6), 72.6 (OCH2Ph), 69.5 (NCH2Ph), 27.4 and 26.4
mixture was filtered under celite, diluted with AcOEt and washed
with a sat. solution of Na2CO3. The organic layer was concentrated
to give a residue that was column chromatographed (diethyl ether)
to yield 21a (690 mg, 96%). Rf = 0.4 (diethyl ether/hexane, 2:1).
[α]2D6 = +30 (c = 1.8, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
(CMe ) ppm. IR: ν
= 3031 (arom.) and 1374 (CMe2) cm–1
.
˜
2
max
HRMS (LSIMS): calcd. for C24H27NNaO5 [M + Na]+ 432.1780; 7.36–7.24 (m, 10 H, 2 ϫ Ph), 6.05 (dd, J1cis,2 = 10.5, J1trans,2
=
=
found 432.1784 (deviation +0.9 ppm). 17.1 Hz, 1 H, 2-H), 5.85 (ddd, J7.8 = 7.9, J8,9cis = 9.6, J8,9trans
17.6 Hz, 1 H, 8-H), 5.66 (dd, Jgem = 1.4 Hz, 1 H, 1trans-H), 5.34–
5.27 (m, 3 H, 1cis,9cis,9trans-H), 4.73 and 4.55 (2ϫd, J = 11.8 Hz,
2 H, OCH2Ph), 4.45 (s, 1 H, 4-H), 4.16 (dd, J5,6 = 2.9, J6,7 = 8.1 Hz,
1 H, 6-H), 4.14 (d, 1 H, 5-H), 3.88 and 3.65 (2ϫd, J = 13.0 Hz, 2
H, NCH2Ph), 3.64 (t, 1 H, 7-H), 1.55 and 1.38 (2 ϫ s, 6 H,
CMe2) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.8 and 137.9
(2ϫPh ipso), 138.1 and 136.7 (C-2,8), 128.7, 128.5, 128.4, 128.0,
127.8 and 127.0 (CH2Ph), 117.7 and 117.2 (C-1,9), 112.8 and 111.7
(C-3, CMe2), 85.2, 83.9 and 82.2 (C-4,5,6), 72.1 (OCH2Ph), 59.3
5-O-Benzyl-7-[(benzyl)(hydroxy)amino]-1,2,7,8,9-pentadeoxy-3,4-O-
isopropylidene-β- -ido- and -α- -gluco-nona-1,8-dien-3-ulofuranose
D
L
(20a and 20b): Vinylmagnesium bromide (4.7 mL, 3.3 mmol) was
added at –78 °C under Ar to a stirred solution of 19 (935 mg,
2.3 mmol) in anhydrous THF (11 mL). After 2 h, TLC (diethyl
ether) revealed the absence of the starting material, whereas TLC
(diethyl ether/hexane, 2:1) showed the presence of two new com-
pounds of lower Rf. MeOH (3 mL) was added, and the reaction
mixture was stirred for a further 1 h. Solvent evaporation gave a
residue that was column chromatographed (diethyl ether/hexane,
1:2) to give a mixture of compounds 20a and 20b (900 mg, 90%)
in a 2:1 ratio (by 1H NMR). Fresh column chromatography (diethyl
ether/hexane, 1:4) of this mixture allowed us first to obtain com-
pound 20a (603 mg, 60%). Rf = 0.6 (diethyl ether/hexane, 2:1).
[α]2D6 = +15 (c = 0.1, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
7.35–7.24 (m, 10 H, 2ϫPh), 6.16 (ddd, J7,8 = 9.2, J8,9cis = 10.2,
(C-7), 51.4 (NCH Ph), 27.4 and 26.6 (CMe ) ppm. IR: νmax = 3028
˜
2
2
(arom.) and 1373 (CMe2) cm–1. HRMS (LSIMS): calcd. for
C26H31NNaO4 [M + Na]+ 444.5186; found 444.5184 (deviation
–0.4 ppm).
Compound 20b (1.33 g, 3.03 mmol) was treated with EtOH/NH4Cl
(3:1, 50 mL) and In (596 mg, 5.29 mmol) as in the case of 20a to
give 21b (1.2 g, 94%). Rf = 0.3 (diethyl ether/hexane, 2:1) [α]2D6
+3 (c = 1.1, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.41–7.25
=
1
J8,9trans = 17.4 Hz, 1 H, 8-H), 6.00 (dd, J1cis,2 = 10.4, J1trans,2
=
17.0 Hz, 1 H, 2-H), 5.61 (dd, Jgem = 1.6 Hz, 1 H, 1trans-H), 5.47 (m, 10 H, 2ϫPh), 6.03 (dd, J1cis,2 = 10.5, J1trans,2 = 17.1 Hz, 1 H,
(dd, Jgem = 1.6 Hz, 1 H, 9cis-H), 5.35 (dd, 1 H, 9trans-H), 5.24 (dd, 2-H), 5.72 (ddd, J7.8 = 8.1, J8,9cis = 10.1, J8,9trans = 17.9 Hz, 1 H,
1 H, 1cis-H), 4.70 and 4.62 (2ϫd, J = 11.9 Hz, 2 H, OCH2Ph),
4.59 (dd, J5.6 = 2.7, J6,7 = 9.4 Hz, 1 H, 6-H), 4.43 (brs, 1 H, OH),
4.39 (s, 1 H, 4-H), 3.95 and 3.70 (2 ϫ d, J = 13.5 Hz, 2 H,
8-H), 5.62 (dd, Jgem = 1.5 Hz, 1 H, 1trans-H), 5.35 (dd, Jgem =
1.8 Hz, 1 H, 9trans-H), 5.29 (dd, 1 H, 1cis-H), 5.26 (dd, 1 H, 9cis-
H), 4.62 and 4.44 (2ϫd, J = 11.5 Hz, 2 H, OCH2Ph), 4.40 (s, 1 H,
Eur. J. Org. Chem. 2009, 1984–1993
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1989

D. Lo Re, F. Franco, F. Sánchez-Cantalejo, J. A. Tamayo
FULL PAPER
4-H), 4.26 (dd, J5,6 = 2.9, J6,7 = 9.4 Hz, 1 H, 6-H), 3.89 (d, 1 H, 5-
H), 3.86 and 3.68 (2ϫd, J = 13.2 Hz, 2 H, NCH2Ph), 3.73 (t, 1 H,
7-H), 1.56 and 1.37 (2ϫs, 6 H, CMe2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 140.7 and 137.9 (2ϫPh ipso), 136.7 and 136.6 (C-2,8),
128.6, 128.5, 128.5, 128.0, 127.7 and 127.0 (CH2Ph), 119.4 and
117.2 (C-1,9), 113.0 and 112.0 (C-3, CMe2), 85.1, 83.7 and 82.6 (C-
4,5,6), 72.0 (OCH2Ph), 60.4 (C-7), 52.0 (NCH2Ph), 27.3 and 26.6
graphed under column (diethyl ether/hexane, 1:4) to yield 24
(3.64 g, 76%). Rf = 0.2 (diethyl ether/hexane, 1:2). [α]2D5 = –33 (c =
1, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.72–7.34 (m, 10 H,
2ϫPh), 5.96 (dd, J1trans,2 = 17.0, J1cis,2 = 11.4 Hz, 1 H, 2-H), 5.69
(dd, Jgem = 1.6 Hz, 1 H, 1trans-H), 5.29 (dd, 1 H, 1cis-H), 4.39 (d,
J4,5 = 4.7 Hz, 1 H, 4-H), 4.23 (brdt, J5,6 = J5,OH = 9.0 Hz, 1 H, 5-
H), 4.02 (dd, J7,7Ј = 11.3, J6,7 = 2.4 Hz, 7-H), 3.94–3.89 (m, 1 H,
6-H), 3.86 (dd, J6,7Ј = 3.0 Hz, 7Ј-H), 2.19 (brd, 1 H, OH), 1.58 and
1
(CMe ) ppm. IR: ν
= 3028 (arom.) and 1373 (CMe2) cm–1
.
˜
2
max
HRMS (LSIMS): calcd. for C26H31NNaO4 [M + Na]+ 444.5188; 1.42 (2ϫs, 6 H, CMe2) and 1.04 (s, 9 H, CMe3) ppm. 13C NMR
found 444.5184 (deviation –0.8 ppm).
(75 MHz, CDCl3): δ = 135.8 (C-2), 133.3, 133.2, 129.8, 129.7 and
127.8 (Ph), 117.9 (C-1), 112.8 (CMe2), 111.1 (C-3), 82.6 (C-4), 81.6
(C-6), 71.0 (C-5), 62.0 (C-7), 27.1 and 26.8 (CMe2), 26.9 (CMe3)
5-O-Benzyl-7-[(benzyl)(benzyloxycarbonyl)amino]-1,2,7,8,9-penta-
deoxy-3,4-O-isopropylidene-β-D-ido- and -α-L-gluco-nona-1,8-dien-
and 19.3 (CMe ) ppm. IR: ν
= 3470 (OH) and 1373
˜
3
m a x
3-ulofuranose (22a and 22b): CbzCl (0.87 mL, 6.06 mmol) was
added to a stirred suspension of 21a (2.13 g, 5.05 mmol) and
K2CO3 (4.88 g, 35.35 mmol) in anhydrous acetone (25 mL) and the
mixture was stirred at room temp. for 4.5 h. TLC (diethyl ether/
hexane, 3:1) showed a new product of lower Rf. MeOH (3 mL) was
added to the reaction mixture, which was stirred for 15 min and
then filtered and concentrated to afford a residue that was column
chromatographed (AcOEt/hexane, 1:6) to give 22a (2.6 g, 92%). Rf
(CMe2) cm–1. HRMS (LSIMS): calcd. for C26H34NaO5Si [M +
Na]+ 477.2071; found 477.2073 (deviation +0.4 ppm).
5-O-Benzyl-7-O-tert-butyldiphenylsilyl-1,2-dideoxy-3,4-O-isopropyl-
idene-α-L-ribo-hept-1-en-3-ulofuranose (25): Alcohol 24 (2.95 g,
6.50 mmol) was added to a stirred suspension of NaH (60% oil
dispersion, 310 mg, 7.79 mmol) in anhydrous DMF (20 mL), and
the reaction was allowed to proceed at room temp. for 15 min. The
mixture was then cooled to 0 °C and BrBn (0.85 mL, 7.14 mmol)
was added dropwise. The reaction mixture was allowed to reach
room temp. and stirred for 24 h. TLC (diethyl ether/hexane, 1:2)
revealed the presence of a new compound of lower Rf. MeOH
(10 mL) was added, and the mixture was stirred for 15 min. Con-
centration of the mixture gave a residue that was dissolved in ether
and washed with brine. The organic layer was evaporated and the
obtained residue was chromatographed on a column (diethyl ether/
hexane, 1:4) to yield 25 (2.47 g, 70%). Rf = 0.5 (diethyl ether/hex-
ane, 1:2). [α]2D5 = –37 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3):
= 0.6 (diethyl ether/hexane, 2:1). [α]2D6 = +32 (c = 1.8, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 7.34–7.21 (m, 15 H, 3ϫPh), 6.01–
5.94, 5.61–5.57, 5.26–4.56 and 4.39–3.57 (4 ϫ m, 16 H,
OCH2Ph,NCH2Ph, Cbz, 1cis,1trans,2,4,5,6,7,8,9cis,9trans-H), 1.29
and 1.26 (2ϫs, 6 H, CMe2) ppm. 13C NMR (75 MHz, CDCl3): δ
= 156.7 (Cbz), 138.8, 138.1 and 133.1 (Ph ipso), 137.8 and 136.6
(C-2,8), 128.7, 128.6, 128.3, 128.2 and 128.1 (Ph), 117.3 (C-1,9),
112.9 and 111.8 (C-3,CMe2), 84.8, 82.6 and 80.9 (C-4,5,6), 71.8
(OCH2Ph), 67.8 (Cbz), 54.1 (C-7), 51.4 (NCH2Ph), 27.3 and 26.5
(CMe ) ppm. IR: ν
= 3031 (arom.), 1699 (Cbz) and 1373
˜
2
max
(CMe2) cm–1. HRMS (LSIMS): calcd. for C34H37NNaO6 [M +
δ = 7.73–7.28 (m, 15 H, 3ϫPh), 5.92 (dd, J1cis,2 = 10.4, J1trans,2
=
Na]+ 578.2520; found 578.2519 (deviation –0.1 ppm).
17.1 Hz, 1 H, 2-H), 5.71 (dd, Jgem = 1.7 Hz, 1 H, 1trans-H), 5.25
(dd, 1 H, 1cis-H), 4.74 and 4.59 (2ϫd, J = 11.9 Hz, 2 H, CH2Ph),
Compound 21b (1.23 g, 2.9 mmol) was treated as in the case of 21a
with K2CO3 (2.8 g, 20.3 mmol) in anhydrous acetone (22 mL) and
CbzCl (0.5 mL, 3.5 mmol) to give 22b (2.72 g, 94%). Rf = 0.4 (di-
ethyl ether/hexane, 2:1). [α]2D7 = +31 (c = 1.1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.32–7.23 (m, 15 H, 3ϫPh), 6.01–5.99,
5 . 6 6 – 5 . 5 3 , 5 . 2 9 – 4 . 8 7 a n d 4 . 7 3 – 3 . 7 4 ( 4 ϫ m , 1 6 H ,
OCH2Ph,NCH2Ph, Cbz, 1cis,1trans,2,4,5,6,7,8,9cis,9trans-H, 2 rot-
amers), 1.66, 1.53, 1.37 and 1.33 (4 ϫ s, 6 H, CMe2, 2 rota-
mers) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.8 (Cbz), 138.7,
138.5 and 133.5 (Ph ipso), 136.7 and 136.4 (C-2,8), 128.3, 128.2,
127.7, 127.3, 127.2, 127.0 and 126.9 (Ph), 118.9 and 117.0 (C-1,9),
112.7 and 111.8 (C-3, CMe2), 85.0, 82.2 and 79.6 (C-4,5,6), 71.7
(OCH2Ph), 66.8 (Cbz), 60.3 (C-7), 51.6 (NCH2Ph), 27.2 and 26.5
4.40 (d, J4,5 = 3.8 Hz, 1 H, 4-H), 4.23 (dt, J6,7 = J6,7Ј = 1.9, J5,6
9.1 Hz, 1 H, 1 H, 6-H), 4.15 (dd, 1 H, 5-H), 4.06 (dd, J7,7Ј
=
=
11.9 Hz, 1 H, 7-H), 3.82 (dd, 1 H, 7Ј-H), 1.60 and 1.42 (2ϫs, 6 H,
CMe2) and 1.01 (s, 9 H, CMe3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 137.8, 133.4 and 133.2 (Ph ipso), 136.1, 134.9, 129.7, 128.5,
127.9 and 127.8 (Ph), 135.7 (C-2), 117.9 (C-1), 112.9 and 111.0 (C-
3, CMe2), 81.1, 80.0 and 76.5 (C-4,5,6), 72.5 (CH2Ph), 61.5 (C-7),
27.3 and 26.6 (CMe ), 26.9 (CMe ) and 19.3 (CMe ) ppm. IR: ν
˜
max
2
3
3
= 1373 (CMe2) cm–1. HRMS (LSIMS): calcd. for C33H40NaO5Si
[M + Na]+ 567.2543; found 567.2548 (deviation +0.8 ppm).
5-O-Benzyl-1,2-dideoxy-3,4-O-isopropylidene-α-L-ribo-hept-1-en-3-
ulofuranose (26): TBAF·3 H2O (2 g, 6.3 mmol) was added to a
stirred solution of 25 (2.47 g, 4.54 mmol) in THF (30 mL) and the
mixture was stirred for 5 h at room temp. TLC (diethyl ether/hex-
ane, 3:2) revealed the presence of a new compound of lower Rf.
The mixture was concentrated, the obtained residue was dissolved
in DCM and washed with H2O, and the organic layer was concen-
trated again. Column chromatography (diethyl ether/hexane, 1:1)
of the residue gave 26 (1.3 g, 94%). Rf = 0.2 (diethyl ether/hexane,
(CMe ) ppm. IR: ν
= 3030 (arom.), 1699 (Cbz) and 1373
˜
2
max
(CMe2) cm–1. HRMS (LSIMS): calcd. for C34H37NNaO6 [M +
Na]+ 578.2515; found 578.2519 (deviation +0.6 ppm).
7-O-tert-Butyldiphenylsilyl-1,2-dideoxy-3,4-O-isopropylidene-α-L-
ribo-hept-1-en-3-ulofuranose (24): MS (4 Å, 2 g), N-methylmorph-
oline N-oxide (1.85 g, 15.8 mmol) and tetrapropylammonium per-
ruthenate (70 mg) were added to a stirred solution of 15 (4.79 g,
10.55 mmol) in anhydrous DCM (30 mL) and the mixture was
stirred for 2 h at room temp. TLC (diethyl ether/hexane, 2:3) re-
vealed the presence of a new compound of lower Rf. The mixture
was diluted with diethyl ether and filtered through silica gel. The
filtrate was concentrated to a residue that was dissolved in anhy-
drous MeOH (35 mL) and cooled to 0 °C, and NaBH4 (800 mg,
21.03 mmol) was added. The reaction was complete after 30 min.
TLC (diethyl ether/hexane, 1:2) showed the presence of a new com-
pound of lower Rf. The crude product was neutralized with glacial
AcOH and concentrated to give a residue that was chromato-
1
3:2). [α]2D5 = –102 (c = 1, CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.38–7.29 (m, 5 H, Ph), 5.88 (dd, J1trans,2 = 17.1, J1cis,2 = 10.5 Hz,
1 H, 2-H), 5.50 (dd, Jgem = 1.4 Hz, 1 H, 1trans-H), 5.25 (dd, 1 H,
1cis-H), 4.74 and 4.57 (2ϫd, J = 11.9 Hz, 2 H, CH2Ph), 4.37 (d,
J4,5 = 4.1 Hz, 1 H, 4-H), 4.21 (dt, J5,6 = 9.2, J6,7 = J6,7Ј = 2.9 Hz,
1 H, 6-H), 3.93 (dd, J7,7Ј = 12.5 Hz, 1 H, 7-H), 3.84 (dd, 1 H, 5-
H), 3.65 (dd, 1 H, 7Ј-H), 1.61 and 1.39 (2ϫs, 6 H, CMe2) ppm.
13C NMR (75 MHz, CDCl3): δ = 137.6 (Ph ipso), 135.8 (C-2),
128.6, 128.1, 128.0 (Ph), 117.5 (C-1), 113.1 and 111.1 (C-3, CMe2),
81.1, 79.5 and 76.7 (C-4,5,6), 72.5 (CH2Ph), 61.0 (C-7), 27.1 and
26.5 (CMe ) ppm. IR: ν
= 3487 (OH) and 1373 (CMe2) cm–1.
max
˜
2
1990
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1984–1993

Total Synthesis of 3-O-Benzyl-1,3,5-tri-epi-Calystegine B2
HRMS (LSIMS): calcd. for C17H22NaO5 [M + Na]+ 329.1365;
found 329.1363 (deviation –0.6 ppm).
heated at 120 °C for 24 h. TLC (diethyl ether/hexane, 3:1) revealed
the presence of a new compound of lower Rf. The reaction mixture
was filtered through celite and diluted with AcOEt, and was then
washed with a saturated solution of Na2CO3 and concentrated. The
residue was column chromatographed (diethyl ether) to yield 30
(550 mg, 92%). Rf = 0.5 (diethyl ether/hexane, 2:1). [α]2D6 = –67 (c
Synthesis of Nitrone 28: A solution of the Dess–Martin periodinane
in DCM (15%, 10 mL, 4.8 mmol) was added at 0 °C under Ar to
a stirred solution of 26 (1.23 g, 4.02 mmol) in anhydrous DCM
(15 mL) and the mixture was stirred at room temp. for 18 h. The
reaction mixture was processed as described for compound 18, to
1
= 1.1, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.31–7.29 (m, 10
H, 2ϫPh), 5.86 (dd, J1cis,2 = 10.4, J1trans,2 = 17.0 Hz, 1 H, 2-H),
5.80 (ddd, J7,8 = 8.4, J8,9cis = 10.2, J8,9trans = 17.2 Hz, 1 H, 8-H),
5.49 (dd, Jgem = 1.4 Hz, 1 H, 1trans-H), 5.23 (dd, Jgem = 1.6 Hz, 1
H, 9cis-H), 5.21 (dd, 1 H, 1cis-H), 5.15 (dd, 1 H, 9trans-H), 4.63
and 4.48 (2ϫd, J = 11.9 Hz, 2 H, OCH2Ph), 4.31 (d, J4,5 = 4.1 Hz,
2 H, 4-H), 4.19 (dd, J5,6 = 8.8, J6,7 = 3.7 Hz, 1 H, 6-H), 4.04 (dd,
1 H, 5-H), 3.87 and 3.56 (2ϫd, J = 13.3 Hz, 2 H, NCH2Ph), 3.15
(dd, 1 H, 7-H), 1.60 and 1.39 (2ϫs, 6 H, CMe2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 140.9 and 138.1 (Ph, ipso), 137.7 and 136.2
(C-2,8), 128.6, 128.5, 128.4, 128.4, 128.2 and 127.0 (Ph), 117.4 and
117.4 (C1,9), 113.1 and 111.2 (C-3, CMe2), 82.2, 81.4, 78.3 and
61.0 (C-4,5,6,7), 72.5 (OCH2Ph), 50.7 (NCH2Ph), 27.4 and 26.8
give 27 (1.18 g, 97%). R = 0.7 (diethyl ether). IR: ν
= 1738
˜
f
max
(CO) cm–1.
Molecular sieves (3 Å, 700 mg) and a solution of 27 (600 mg,
1.98 mmol) in anhydrous MeOH (5 mL) were added under Ar to a
solution of BnNHOH·HCl (410 mg, 2.57 mmol) and AcONa
(210 mg, 2.57 mmol) in anhydrous MeOH (5 mL). The reaction
mixture was stirred for 18 h, and TLC (diethyl ether) revealed the
presence of a new compound of lower Rf. The solvent was removed,
and the obtained residue was chromatographed on a column (di-
ethyl ether/hexane, 3:1) to give 28 (640 mg, 79%). Rf = 0.4 (diethyl
1
ether). [α]2D6 = –21 (c = 0.4, CHCl3). H NMR (400 MHz, CDCl3):
(CMe ) ppm. IR: ν
= 3030 (arom.) and 1372 (CMe2) cm–1
.
δ = 7.46–7.38 (m, 10 H, 2ϫPh), 6.61 (d, J6,7 = 6.6 Hz, 1 H, 7-H),
5.86 (dd, J1trans,2 = 17.0, J1cis,2 = 10.8 Hz, 1 H, 2-H), 5.52 (dd, Jgem
= 1.5 Hz, 1 H, 1trans-H), 5.39 (dd, J5,6 = 8.9 Hz, 1 H, 6-H), 5.24
(dd, 1 H, 1cis-H), 4.92 (s, 2 H, OCH2Ph), 4.59 and 4.47 (2ϫd, J
= 12.5 Hz, 2 H, NCH2Ph), 4.38 (d, J4,5 = 4.1 Hz, 1 H, 4-H), 3.78
(dd, 1 H, 5-H), 1.64 and 1.39 (2ϫs, 6 H, CMe2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 137.7 and 132.6 (Ph ipso), 135.6 (C-2),
134.6 (C-7), 129.6, 129.4, 129.2, 128.7, 128.1 and 128.0 (Ph), 118.1
(C-1), 113.8 and 111.1 (C-3, CMe2), 82.0, 79.8 and 73.6 (C-4,5,6),
72.3 (OCH2Ph), 70.8 (NCH2Ph), 27.3 and 26.7 (CMe2) ppm. IR:
˜
2
max
HRMS (LSIMS): calcd. for C26H31NO4 [M]+ 421.2253; found
421.2243 (deviation –2.4 ppm).
5-O-Benzyl-7-[(benzyl)(benzyloxycarbonyl)amino]-1,2,7,8,9-penta-
deoxy-3,4-O-isopropylidene-β-D-talo-nona-1,8-dien-3-ulofuranose
(31): CbzCl (0.38 mL, 2.7 mmol) was added to a stirred suspension
of 30 (810 mg, 1.9 mmol) and K2CO3 (1.8 g, 13.6 mmol) in anhy-
drous acetone (15 mL) and the mixture was stirred at room temp.
for 2.5 h. TLC (diethyl ether/hexane, 3:1) revealed the presence of
a new compound of lower Rf. MeOH (1 mL) was added to the
reaction mixture, which was then filtered, and the filtrate was con-
centrated to afford a residue that was chromatographed on a col-
umn (AcOEt/hexane, 1:6) to give 31 (1.04 g, 97%). Rf = 0.6 (diethyl
ether/hexane, 2:1). [α]2D6 = –32 (c = 2.4, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.35–7.19 (m, 15 H, 3ϫPh), 6.03–5.94 (m,
1 H), 5.70–5.63 (m, 1 H), 5.25–5.12 (m, 5 H), 4.65–4.52 (m, 5 H),
4.42 (dd, 1 H), 4.21 (d, 1 H), 3.53 (dd, 1 H), 1.56 and 1.37 (2ϫs,
6 H, CMe2) ppm. 13C NMR (100 MHz, CDCl3, inter alia): δ =
157.0 (Cbz), 136.8 and 136.0 (C-2,8), 119.5 and 117.6 (C-1,9), 113.1
and 111.3 (C-3, CMe2), 80.9, 79.9 and 72.7 (C-4,5,6,OCH2Ph), 67.5
(Cbz), 60.6 (C-7), 49.2 (NCH2Ph), 27.3 and 26.9 (CMe2) ppm. IR:
ν
= 3031 (arom.) and 1374 (CMe2) cm–1. HRMS (LSIMS):
˜
max
calcd. for C24H27NNaO5 [M + Na]+ 432.1774; found 432.1784 (de-
viation +0.2 ppm).
5-O-Benzyl-7-[(benzyl)(hydroxy)amino]-1,2,7,8,9-pentadeoxy-3,4-O-
isopropylidene-β-D-talo-nona-1,8-dien-3-ulofuranose (29): A solution
of vinylmagnesium bromide in anhydrous THF (0.7 , 12 mL,
8.4 mmol) was added at –78 °C under Ar to a solution of 28 (1.9 g,
4.6 mmol) in anhydrous THF (22 mL). After 2 h, TLC (diethyl
ether) showed the absence of the starting material, whereas TLC
(diethyl ether/hexane, 2:1) showed a new compound of higher Rf.
MeOH (5 mL) was added, and the mixture was stirred for a further
1 h. The crude mixture was concentrated, and the residue was chro-
matographed on a column (diethyl ether/hexane, 1:1) to give 29
(1.8 g, 90%). Rf = 0.8 (diethyl ether). [α]2D6 = –62 (c = 2, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.32 (m, 10 H, 2ϫPh), 6.17
(ddd, J7,8 = 8.6, J8,9cis = 10.6, J8,9trans = 17.6 Hz, 1 H, 8-H), 5.88
ν
= 3031 (arom.), 1699 (CO) and 1372 (CMe2) cm–1. HRMS
˜
max
(LSIMS): calcd. for C34H37NNaO6 [M + Na]+ 578.2523; found
578.2519 (deviation –0.6 ppm).
(1S,4R,5S,6S,7S)-6-Benzyloxy-4-[(benzyl)(benzyloxycarbonyl)-
amino]-1,7-isopropylidenedioxy-8-oxabicyclo[3.2.1]oct-2-ene (32): A
mixture of 31 (618 mg, 1.11 mmol) and the Grubbs catalyst 23
(94 mg, 110 µmol) in anhydrous DCM (5 mL) was heated in a mi-
crowave under Ar in a sealed tube at 100 °C. After 2 h, TLC (di-
ethyl ether/hexane, 2:1) revealed the presence of a new compound
of lower Rf. The reaction mixture was supported on silica gel and
chromatographed on a column (diethyl ether/hexane, 1:2) to give
32 (386 mg, 79%). Rf = 0.5 (diethyl ether/hexane, 2:1). [α]2D6 = –56
(dd, J1cis,2 = 10.6, J1trans,2 = 17.0 Hz, 1 H, 2-H), 5.57 (dd, Jgem
=
1.6 Hz, 1 H, 1trans-H), 5.42 (dd, Jgem = 1.9 Hz, 1 H, 9cis-H), 5.29
(dd, 1 H, 9trans-H), 5.23 (dd, 1 H, 1cis-H), 4.67 and 4.48 (2ϫd, J
= 11.5 Hz, 2 H, OCH2Ph), 4.48 (dd, J5,6 = 9.0, J6,7 = 3.9 Hz, 1 H,
6-H), 4.36 (d, J4,5 = 4.3 Hz, 1 H, 4-H), 4.06 and 3.70 (2ϫd, J =
13.2 Hz, 2 H, NCH2Ph), 3.95 (dd, 1 H, 5-H), 3.50 (dd, 1 H, 7-H),
1.61 and 1.40 (2 ϫ s, 6 H, CMe2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 138.3 and 137.5 (Ph, ipso), 136.1 (C-2), 132.5 (C-8),
129.5, 129.4, 128.7, 128.6, 128.5, 128.4 (Ph), 121.0 (C-9), 117.8 (C-
1), 113.3 and 111.3 (C-3,CMe2), 81.1, 80.9, 78.1 and 68.6 (C-
4,5,6,7), 72.6 (OCH2Ph), 61.3 (NCH2Ph), 27.4 and 26.9
1
(c = 0.8, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.30–7.09 (m,
15 H, 3ϫPh), 6.10 (brs, 1 H), 5.55 (brs, 1 H), 4.82–3.98 (brm, 10
H), 1.66 and 1.44 (2ϫs, 6 H, CMe2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 155.9, 139.7, 136.3, 138.4, 133.4, 129.8, 129.0, 128.7,
128.6, 128.5, 127.9, 127.6, 126.8, 118.2, 110.2, 109.7, 85.4, 83.9,
(CMe ) ppm. IR: ν
= 3030 (arom.) and 1372 (CMe2) cm–1
.
˜
2
max
HRMS (LSIMS): calcd. for C26H31NO5 437.2202 [M]+; found
78.3, 72.1, 67.7, 56.6, 55.9, 50.9, 28.3 and 27.5 ppm. IR: ν
=
˜
max
3032 (arom.), 1699 (CO) and 1372 (CMe2) cm–1. HRMS (LSIMS):
calcd. for C32H33NNaO6 [M + Na]+ 550.5970; found 550.5973 (de-
viation +0.5 ppm).
437.2192 (deviation –2.3 ppm).
5-O-Benzyl-7-benzylamino-1,2,7,8,9-pentadeoxy-3,4-O-isopropylid-
ene-β-
D-talo-nona-1,8-dien-3-ulofuranose (30): In (608 mg,
5.3 mmol) was added to a stirred solution of 29 (620 mg,
(1S,4R,5S,6S,7S)-4-Amino-6-benzyloxy-1,7-isopropylidenedioxy-8-
1.42 mmol) in EtOH/NH4Cl (2:1, 24 mL), and the mixture was oxabicyclo[3.2.1]octane (33) and (1S,4S,5S,6S,7S)-4-Amino-6-ben-
Eur. J. Org. Chem. 2009, 1984–1993
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1991

D. Lo Re, F. Franco, F. Sánchez-Cantalejo, J. A. Tamayo
FULL PAPER
zyloxy-1,7-isopropylidenedioxy-8-oxabicyclo[3.2.1]octane (34): A
solution of 32 (1.06 g, 2.01 mmol) in MeOH (55 mL) was hydroge-
nated at atmospheric pressure over Pd-C (10%, 200 mg) at room
temp. After 7 h, TLC (diethyl ether/hexane, 2:1) revealed the pres-
ence of a new compound of lower Rf. The reaction mixture was
this project was provided by the Ministerio de Educación y Ciencia
of Spain (MEC) (Project Ref. No. CTQ2006-14043). Additional
support was provided by the Junta de Andalucía (Group CVI-250).
We also acknowledge the University of Granada (Spain) for a grant
(to D. L. R.) and the Fundación Ramón Areces for a grant (to
filtered, the catalyst was washed with MeOH, and the filtrate was F. S.-C.).
concentrated and chromatographed on a column (DCM/MeOH
20:1) to give 33 (550 mg, 85%) as a colourless syrup. Rf = 0.5 (Ac-
OEt/MeOH, 1:1). [α]2D6 = –56 (c = 0.4, in MeOH). 1H NMR
(400 MHz, [D4]MeOH): δ = 7.41–7.26 (m, 5 H, Ph), 4.82 and 4.52
(2ϫd, J = 11.7 Hz, 2 H, CH2Ph), 4.37 (dd, J5,6 = 0.7, J6,7 = 5.5 Hz,
[1] D. Tepfer, A. Goldmann, N. Pamboukdjian, M. Maille, A. Le-
pingle, D. Chevalier, J. Denarie, C. Rosenberg, J. Bacteriol.
1988, 170, 1153–1161.
[2] a) A. A. Watson, D. R. Davies, N. Asano, B. Winchester, A.
Kato, R. J. Molyneux, B. L. Stegelmeier, R. J. Nash in ACS
Symposium Series 745: Natural and Selected Synthetic Toxins-
Biological Implications (Eds.: A. T. Tu, W. Gaffield), American
Chemical Society, Washington DC, 2000, p. 129; b) N. Asano,
R. J. Nash, R. J. Molyneux, G. W. J. Fleet, Tetrahedron: Asym-
metry 2000, 11, 1645–1680; c) Iminosugars as Glycosidase Inhib-
itors-Nojirimycin and Beyond (Eds.: A. E. Stütz), Wiley-VCH,
Weinheim, Germany, 1999; d) Iminosugars: from synthesis to
therapeutic applications (Eds.: P. Compain, O. R. Martin)
Wiley-VCH, Weinheim, 2007.
[3] N. Asano, A. Kato, Y. Yokoyama, M. Miyauchi, M. Yamam-
oto, H. Kizu, K. Matsui, Carbohydr. Res. 1996, 284, 169–178.
[4] a) B. Dräger, Nat. Prod. Rep. 2004, 21, 211–223; b) S. Biastoff,
B. Dräger, Alkaloids 2007, 64, 49–102.
[5] a) N. Asano, Curr. Top. Med. Chem. 2003, 3, 471–484; b) N.
Asano, Glycobiology 2003, 13, 93–104; c) V. H. Lillelund, H. H.
Jensen, X. Liang, M. Bols, Chem. Rev. 2002, 102, 515–535; d)
P. Compain et al. in Iminosugars: from synthesis to therapeutic
applications (Eds.: P. Compain, O. R. Martin) Wiley-VCH,
Weinheim, 2007, pp. 327–455.
1 H, 6-H), 4.16 (brd, 1 H, 5-H), 4.09 (d, 1 H, 7-H), 3.02 (dt, J3,4
=
J4,5 = 5.5, J3Ј,4 = 11.3 Hz, 1 H, 4-H), 2.09 (dt, J = 5.5, J = 12.9 Hz,
1 H, 2-H), 1.96 (m, 1 H, 3-H), 1.71 (m, 1 H, 2Ј-H), 1.67 and 1.45
(2ϫs, 6 H, CMe2) and 1.05 (dq, J = 5.5, J = 12.9 Hz, 3Ј-H) ppm.
13C NMR (100 MHz, [D4]MeOH): δ = 139.5, 129.3, 129.0 and
128.7 (CH2Ph), 118.5 and 115.2 (C-1, CMe2), 84.5 (C-5), 84.0 (C-
6), 78.6 (C-7), 73.6 (CH2Ph), 48.5 (C-4), 30.0 (C-3), 25.7 (C-2), 28.3
and 28.0 (CMe ) ppm. IR: ν
= 3030 (arom.) and 1372
˜
2
max
(CMe2) cm–1. HRMS (LSIMS): calcd. for C17H23NNaO4 [M +
Na]+ 328.3580; found 328.3586 (deviation +1.8 ppm).
When the reaction was scaled up (3.04 g, 5.76 mmol of 32), 33
(1.41 g, 80%) was isolated first, followed by (1S,4S,5S,6S,7S)-4-
amino-6-benzyloxy-1,7-isopropylidenedioxy-8-oxabicyclo[3.2.1]oc-
tane (34, 246 mg, 14%). Rf = 0.2 (AcOEt/MeOH, 1:1). [α]2D6 = –59
1
(c = 0.5, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.30–7.27 (m,
5 H, Ph), 4.77 and 4.47 (2ϫd, J = 11.6 Hz, 2 H, CH2Ph), 4.41 (d,
J6,7 = 5.2 Hz, 1 H, 6-H), 4.25 (s, 1 H, 5-H), 3.83 (d, 1 H, 7-H),
2.70 (brs, 1 H, 4-H), 2.26–2.19 (m, 1 H, 2-H), 1.75–1.72 (m, 1
H, 3-H), 1.65–1.58 (m, 2 H, 2Ј,3Ј-H), 1.66 and 1.45 (2ϫs, 6 H,
CMe2) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.2, 128.6, 128.2
and 128.1 (CH2Ph), 117.0 and 114.0 (C-1, CMe2), 88.2 (C-5), 82.1
(C-6), 79.7 (C-7), 72.3 (CH2Ph), 46.9 (C-4), 28.4 (C-3), 27.1 (C-
[6] N. Asano, A. Kato, K. Oseki, H. Kizu, K. Matsui, Eur. J. Bio-
chem. 1995, 229, 369–376.
[7] a) D. Varrot, C. A. Tarling, J. M. Macdonald, R. V. Stick, D. L.
Zechel, S. G. Withers, G. J. Davies, J. Am. Chem. Soc. 2003,
125, 7496–7497; b) H. H. Jensen, L. Lyngbye, M. Bols, Angew.
Chem. 2001, 113, 3555–3557; Angew. Chem. Int. Ed. 2001, 40,
3447–3449; c) C. S. Rye, S. G. Withers, Curr. Opin. Chem. Biol.
2000, 4, 573–580; d) G. Legler, Glycosidase Inhibition by Basic
Sugar Analogs and the Transition State of Enzymatic Glycoside
Hydrolysis, in Iminosugars as Glycosidase Inhibitors (Eds.: A.
Stütz), Wiley-VCH, Weinheim, Germany, 1999, p. 31.
2), 28.1 and 28.0 (CMe ) ppm. IR: ν
= 3030 (arom.) and 1371
˜
2
max
(CMe2) cm–1. HRMS (LSIMS): calcd. for C17H23NNaO4 [M +
Na]+ 328.3582; found 328.3586 (deviation +1.2 ppm).
(1S,2S,3S,4S,5S)-3-O-Benzyl-8-azabicyclo[3.2.1]octane-1,2,3,4-tet-
raol (3-O-Benzyl-1,3,5-tri-epi-calystegine B2, 35): A solution of 34
(99 mg, 0.31 mmol) in HCl (1 , 6.25 mL) was stirred at room
temp. for 10 h. TLC (AcOEt/MeOH, 1:1) revealed the presence of
a new compound of lower Rf. The mixture was neutralized with
AMBERLITA® IRA 400 (OH– form) and then concentrated to a
residue that was column chromatographed with DOWEX 50 WX8
resin as the stationary phase and MeOH (15 mL), H2O (20 mL)
and NH4OH in MeOH (7%, 40 mL) as the mobile phase. Com-
pound 35 (44 mg, 53%) was obtained as an amorphous white solid.
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Rf = 0.8 (AcOEt/MeOH, 2:1). [α]2D8 = –13 (c = 2.2, in MeOH). H
NMR (400 MHz, [D4]MeOH): δ = 7.44–7.33 (m, 5 H, Ph), 4.71 (s,
2 H, CH2Ph), 3.89 (d, J2,3 = 3.4 Hz, 1 H, 2-H), 3.72 (brs, 1 H, 4-
H), 3.51 (t, J3,4 = 3.7 Hz, 1 H, 3-H), 3.38 (m, 1 H, 5-H), 1.99 (m,
1 H, 6exo-H), 1.70 (dt, J = 4.3, J = 13.1 Hz, 1 H, 7exo-H), 1.61
(m, 1 H, 7endo-H) and 1.32 (m, 1 H, 6endo-H) ppm. 13C NMR
(100 MHz, [D4]MeOH): δ = 138.2, 128.3, 128.1 and 127.8 (CH2Ph),
89.6 (C-1), 73.7 (C-2), 72.8 (C-3), 70.0 (CH2Ph), 69.0 (C-4), 57.2
(C-5), 30.8 (C-7) and 22.3 (C-6) ppm. HRMS (LSIMS): calcd. for
C14H19NNaO4 [M + Na]+ 288.1219; found 288.1212 (deviation
–2.4 ppm).
Acknowledgments
We would like especially to thank Prof. Andrea Goti for his helpful
suggestions in the development of this work. Major support for
1992
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1984–1993

Total Synthesis of 3-O-Benzyl-1,3,5-tri-epi-Calystegine B2
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Received: December 12, 2008
Published Online: March 6, 2009
Eur. J. Org. Chem. 2009, 1984–1993
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1993