D-Glucosamine trimethylene dithioacetal derivatives: Formation of six- and seven-membered ring amino carbasugars. Synthesis of (-)-calystegine B 3

Article abstract of DOI:10.1039/b711112f

By virtue of carefully chosen protecting groups, d-glucosamine trimethylene dithioacetal derivatives were successfully oxidized to the corresponding 6-aldehydes. This methodology reverses the donor and acceptor position on a normal open chain sugar and changes the relative position of the N-substituent. From the 6-aldehydes, heptose epoxide derivatives were prepared by a Corey-Chaykovsky reaction, and cyclized by the Corey-Seebach method. Depending on the designed protecting groups, the orthogonally protected six- and seven-membered ring amino carbasugars can be produced selectively and efficiently. (-)-Calystegine B₃ was synthesized from one of those products with high yield. This is the first anionic cyclization pathway to calystegine type structures. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b711112f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
D-Glucosamine trimethylene dithioacetal derivatives: formation of six- and
seven-membered ring amino carbasugars. Synthesis of (−)-calystegine B3†,‡
Yue-Lei Chen,a,b Hartmut Redlich,*a Klaus Bergandera and Roland Fro¨hlicha
Received 19th July 2007, Accepted 21st August 2007
First published as an Advance Article on the web 6th September 2007
DOI: 10.1039/b711112f
By virtue of carefully chosen protecting groups, D-glucosamine trimethylene dithioacetal derivatives
were successfully oxidized to the corresponding 6-aldehydes. This methodology reverses the donor and
acceptor position on a normal open chain sugar and changes the relative position of the N-substituent.
From the 6-aldehydes, heptose epoxide derivatives were prepared by a Corey–Chaykovsky reaction, and
cyclized by the Corey–Seebach method. Depending on the designed protecting groups, the
orthogonally protected six- and seven-membered ring amino carbasugars can be produced selectively
and efficiently. (−)-Calystegine B3 was synthesized from one of those products with high yield. This is
the first anionic cyclization pathway to calystegine type structures.
Introduction
Iminosugars (also known as azasugars) and amino carbasugars
as selective and efficient glycosidase inhibitors are presently the
two most attractive categories1 in the field of N-containing car-
bohydrates. The compounds are mainly five- or six-membered (or
fused) ring systems. Some of them are used as chemotherapeutic
agents against diabetes or viral infections. The interest in larger
rings (seven or even eight-membered) has recently increased
significantly. Despite the difficulties, syntheses of iminosugars,1a,b,2
as well as amino carbasugars,2a,3 have been investigated and
Fig. 1 Some calystegines discovered in nature.
reviewed extensively. Versatile, low cost, and concise synthetic
methodologies are of high interest.
A representative example is the calystegine family isolated
stabilized dilithiated dithiane-imidate intermediate without 1,2-
from Solanaceae and other plants4 (Fig. 1). These compounds,
elimination) by use of 6-O-Ts derivatives.10b Another attractive
typically constructed by a seven-membered carbocycle with a
step of conceptual importance would be oxidizing the 6-OH
nitrogen bridge, are considered as conformationally restricted
derivative to the corresponding aldehyde. It reverses the donor
6-membered ring iminosugars; this explains their selective and
and acceptor position of a normal open chain sugar, switches
strong activities. Since they are regarded as lead compounds for
the relative stereochemistry from D-gluco to L-gulo according to
new bioactive structures and even drugs, calystegine ( )-A3,5
the established concept,11 and changes the relative substituting
( )-B2,6 (+)-B3,7 (+)-B4 and their analogues8 have been synthe-
7
position of the nitrogen. In general, this allows for many further
sized. More calystegine type structures, especially their homo-
interesting conversions, for example, elongating the chain at the
morphous analogues,9 which are believed to possess biological
side rather than the dithiane end.
activities, too, are still requested.
In the work reported here, we have synthesized such aldehydes.
In contrast to most of the traditional synthetic methodologies
From the aldehydes bearing carefully designed protecting groups
where the nitrogen has to be introduced into the molecules
of different types, the corresponding epoxides are produced
at a later synthesis stage, we recently demonstrated10 that the
by one carbon elongation via an anionic cyclization10b of the
trimethylene dithioacetal derivatives, which are readily prepared
epoxides according to the Corey–Seebach method;12 depending on
from D-glucosamine as an abundant natural source, serve as
the protecting groups,13 divergent syntheses of seven-membered
cheap and versatile starting materials for N-containing carbo-
ring amino carbasugars as well as a six-membered ring fully
hydrates, especially iminosugars and amino carbasugars (via a
functionalized amino carbasugar bearing orthogonal protections
can be conducted efficiently. All products are valuable precursors
aOrganisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t
for iminosugar and amino carbasugar synthesis. Subsequently,
the power of this synthetic methodology is demonstrated by the
first synthesis of (−)-calystegine B3 from one of the cyclization
products, which is also the first anionic pathway to the calystegine
family, while the ring expansions,5a,6b,c the enzymatical resolution,5b
the cycloadditions,6a,d,e the ring closure metathesis,6f ,g,7 and the
radical cyclization6g have been explored.
Mu¨nster, Corrensstraße 40, D-48149, Mu¨nster, Germany. E-mail: redlich@
uni-muenster.de; Fax: (+49)/251-839772
bNRW Graduate School of Chemistry, Corrensstraße 36, D-48149, Mu¨nster,
Germany
† Dedicated to Prof. Dr Hans Paulsen on the occasion of his 85th birthday.
‡ This article is part 8 of a series of work on carbohydrate trimethylene
dithioacetals. We thank Dr Klaus Bergander for NMR studies and Dr
Roland Fro¨hlich for X-ray analysis.
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aldehyde 2e with the Dess–Martin reagent in 63% isolated yield
(Scheme 2).
Results and discussion
For the success of the entire plan, it was essential to be able to
oxidize efficiently the non-reducing ends of properly protected D-
glucosamine trimethylene dithioacetals to aldehydes. However, an
oxidation reaction on densely functionalized compounds, espe-
cially those with sulfur and amide functional groups, is generally
a difficult task. Various known typical oxidation methods14 (e.g.
most of the DMSO based oxidations, chromium based oxidations,
hypervalent iodine based oxidations, manganese based oxidations,
TEMPO based oxidations, Ley oxidation, Oppenauer oxidation
and some other reported oxidation methods) were applied to the
N-acetyl (Ac) protected model compounds 1a and 1b. However,
the results were either no reaction or decomposition of the starting
material. Modification of these oxidation conditions did not
give any improvement. Similarly, the N-tert-butoxycarbonyl (Boc)
protected compound 1c failed to give the desired aldehydo group,
too (Scheme 1).
Scheme 2 The preparation of the aldehydes. Reaction conditions and
yields: (a) reported procedures;10a,b (b) 3 steps,10b 25%; (c) Dess–Martin
reagent, 83%; (d) TrCl, Py, DMAP, 95%; (e) BnCl, NaH, n-Bu4NI, THF,
99%; (f) MeOH, EtOAc, p-TsOH hydrate, 78%; (g) Dess–Martin reagent,
63%.
Scheme 1 The preliminary exploration of the oxidation.
Surprisingly, we found that when the free amino group was
protected by an N-trifluoroacetyl (Tfa) group, the oxidations
worked excellently even with different protection patterns for
the secondary hydroxyls in the molecule. When the N-Tfa
protection was used, the corresponding alcohols could be oxidized
smoothly to the desired aldehydes with typical methods, i.e., Dess–
Martin reagent (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-
(1H)-one)15 or Parikh–Doering oxidation (SO3·Py, triethylamine
and DMSO).16 According to the experimental results, the dom-
inant factor for the successful oxidation of the hydroxyl in the
presence of the dithiane functional group is the N-protection. It
can be deduced from the results that an N-protection of strong
electron withdrawing capability enables the desired oxidation.
In another aspect, hydroxyl protections are crucial for further
reactions, though they do not strongly affect the oxidation as
observed in this particular case. We designed two series of
compounds with different types of O-protecting groups suitable
for the later cyclization reactions. One of the two types has the O-
acetal (an O-MOM and a cyclic formaldehyde acetal) protections,
while the other one has non-cyclic O-Bn protecting groups.
They are expected to induce diverse stereochemistry outcomes
in different stages.
Experimentally, from N-trifluoroacetyl D-glucosamine dithiane,
which was prepared readily10a,b by protecting D-glucosamine, O-
acetal-N-Tfa derivative 1d was produced in three steps and in 25%
yield.10b The subsequent oxidation of compound 1d with Dess–
Martin reagent gave the corresponding aldehyde 2d in a satisfying
83% yield after isolation. Also, starting from N-trifluoroacetyl
D-glucosamine dithiane, via regioselective 6-O tritylation, per-
O-benzylation, and de-O-tritylation, the O-Bn-N-Tfa derivative
1e was prepared in a high yield. Compound 1e was oxidized to
By oxidating the 6-hydroxy to an a-synthon, along with the
established dithiane group, the donor and the acceptor position
in a normal open chain sugar is reversed. The relative position of
the N-substituent is also changed. In the extensively investigated
field of the so-called dithiane route, this is the first time that such a
manipulation is realized on a nitrogen containing sugar dithiane.
It is of great conceptual importance because a full utilization
of carbohydrate type intermediates in many natural product or
bioactive structure syntheses is enabled by this methodology.
The following epoxidation on compounds 2d and 2e could be re-
alized by the Corey–Chaykovsky method17 (using the ylide formed
from trimethyl sulfoxonium iodide and sodium hydride). As a
comparison, the halomethyllithium methods18 led to significant
decomposition of the aldehyde due to its strong basicity, which
probably interferes with the dithiane functional group or induces
side reactions on the aldehydo group.
In this epoxidation, the two different O-protecting patterns
gave distinct stereochemical outcomes. The tri-O-acetal protected
compound 2d gave a 1 : 1 mixture (by NMR) of the two
diastereoisomers 5a and 5b, which are inseparable by silica
gel chromatography. As an interesting comparison, the tri-O-
Bn derivative 2e gave only one diastereoisomer 6 (by NMR)
with the D-gluco-D-glycero configuration out of the two possible
diastereoisomers (Scheme 3). This absolute configuration was
decided by its cyclized derivatives, as the following describes.
The results can be understood by conformational analysis. The
rigid cyclic protection on compound 2d separates the main chain
as two substituents above and below the dioxolane ring. Therefore,
the epoxidation was performed without being strongly affected by
the chiral substituents. The nucleophilic reagent can attack the
carbonyl group of compound 2d from both the Re and Si face
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A crystal structure of compound 7b is also available for further
confirmation of the stereochemistry (Fig. 2).21
Scheme 3 Corey–Chaykovsky epoxidation.
to produce the 1 : 1 diastereomeric mixture. On the contrary, the
epoxidation on compound 2e took place on a molecule with the
natural sickle conformation.19 The Si face of the carbonyl group
of compound 2e is shielded most probably by the 3,4-hydroxyl
protections, while the Re face is left open to nucleophilic attack.
As a result, perfect diastereoselectivity is observed. Computer
modeling supported this idea, too.20
Fig. 2 Crystal structure of compound 7b.
The tri-O-Bn counterpart 6 was cyclized under similar condi-
tions using 2.5 eq. of n-BuLi as the base and THF as the solvent.
Contrary to the last cyclization, a carba-analogue of 1-amino-
1-deoxy-b-L-galacto-pyranose derivative (8) was obtained as the
main product, accompanied by a certain amount of the carba-
analogue of a 1-amino-1-deoxy-a-D-altro-septanose derivative (9).
As illustrated in Scheme 5, in the last cyclization, under standard
Corey–Seebach conditions (at −10 ◦C due to the slow cyclization
rate), compounds 8 and 9 were obtained in 54% and 23% yield
respectively (ca. 2.4 : 1, 78% in total). However, when LiBr was
added, the cyclization was speeded up (therefore the reaction was
started from −90 ◦C and quenched at −50 ◦C) and the ratio of the
six-membered ring product to seven-membered ring product was
increased significantly, probably via a Li-chelated intermediate,
to give 62% yield for compound 8 and 8% yield for compound
9 (ca. 7.8 : 1, 70% in total). Clearly, the latter LiBr condition is
ideal for selective preparation of a fully functionalized branched
six-membered ring amino carbasugar 8.
Scheme 4 illustrates the intramolecular anionic cyclization
according to the Corey–Seebach method.12 When the above-
produced tri-O-acetal protected epoxides 5a and 5b as a 1 : 1
mixture were deprotonated with n-BuLi at −90 ◦C, the stabilized
dilithiated dithiane-imidate intermediate was formed according to
our former report.10b,c An anionic cyclization from◦this intermedi-
ate took place immediately. Warming up to −70 C in one hour
completed the reaction, and gave the carba-analogue of a 1-
amino-1-deoxy-a-D-altro-septanose derivative (7a) and the carba-
analogue of a 1-amino-1-deoxy-b-L-galacto-septanose derivative
(7b), which are readily separated by silica gel chromatography, with
yields of 50% and 33% respectively (ca. 1.5 : 1, 83% in total). No
six-membered ring was obtained under such conditions. The high
cyclization yield to seven-membered rings could be expected for
compounds with trans-3,4-O-cyclic acetal protection, again due
to the separated reaction centers. The ratio of products 7a and 7b
indicates that the anionic cyclization is accompanied by a slight
kinetic resolution process for the adducts 5a and 5b as a 1 : 1
diastereoisomeric pair, though the adduct related to the low yield
product 5b was not recovered. The kinetic resolution process can
be understood, for the dithiane anion of compound 7b attacks
the epoxide ring from a more hindered face than that of com-
pound 7a.
Scheme 5 Anionic cyclization of the O-Bn epoxide 6. Reaction conditions
and yields: (a) n-BuLi, THF, −10 ◦C; (b) n-BuLi, THF, 1 eq. LiBr, −90 ◦C
to −50 ◦C.
Furthermore, in various optimization experiments, it was
found22 that with the Corey–Seebach method, a preference of
cyclization to a six-membered ring over a seven-membered ring
is a strong intrinsic nature of the epoxide 6, independent of
the conditions tested, because the six-membered ring formation
benefits from both geometrical and energetical factors, while the
formation of the seven-membered ring results only from the more
reactive C-7 of the epoxide.
Scheme 4 Anionic cyclization of the O-acetal epoxides 5a,b.
The stereochemistry at C-6 and the conformations of both
diastereomers 7a (in CDCl3) and 7b (in C6D6) have been assigned
unambiguously by the corresponding coupling constants and the
NOE (see experimental section for detail).
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The stereochemistry at C-6 and conformations of six-membered
ring 8 and seven-membered ring 9 have been assigned unambigu-
ously by the corresponding coupling constants and the NOE. Both
the stereochemistry at C-6 on compound 8 and compound 9 match
each other and the configuration of C-6 on the epoxide 6 was
deduced readily (see experimental section for detail).
Several points from the above described cyclizations are worth
discussing here. Side reactions, such as deprotonation of the O-
Bn protecting group and the subsequent Wittig rearrangement23
did not occur when epoxide 6 was treated with n-BuLi. Besides,
it has been well known conceptually that the cyclization can
depend strongly on the protecting groups. However, the successful
application of such a concept is rare.13 As described above,
by generating a proper conformation with different protecting
groups, the fast reaction and strong preference for 7-endo-
cyclization of the tri-O-acetal epoxides 5a,b, as well as the rare
preference13a,b of the 6-exo-cyclization of the tri-O-Bn epoxide
6, were achieved divergently. This demonstrates a successful
application of a protection controlled cyclization concept.
In a practical aspect, the resulting orthogonally protected seven-
membered ring amino carbasugars 7a,b from the epoxides 5a,b as
well as the fully functionalized six-membered ring amino carba-
sugar 8 from epoxide 6 are useful precursors for many bioactive
structures. For example, from compound 8, the carba-analogue of
1-amino-1-deoxy-b-L-galacto-pyranose is readily available. From
compounds 7a,b and 9, calystegine type structures could be pro-
duced as well. Experimentally, the deprotections for compounds
7a, b, 8 and 9 are possible by our previously reported methods10b
or standard conditions.24 As an example, we decided to apply
the resulting seven-membered ring product in the synthesis of
an enantiomer of naturally discovered (+)-calystegine B3. For
simplicity of deprotection and purification, compound 9 was used
as the starting material.
The dithiane ring of compound 9 was cleaved by hydrogenol-
ysis with Raney-Ni. Without significant deprotection of O-Bn,
compound 10 was obtained in 71% isolated yield. The N-Tfa
protection25 of the resulting compound 10 was then removed by
heating with Ba(OH)2 octahydrate in a water–methanol mixture.
NaHCO3 and CbzCl were added to the above reaction mixture
to achieve an interesting one-pot protection group switching
reaction and produced the crude compound 11 (indicated by
HRMS-ESI+) mixed with inseparable impurities introduced by
CbzCl.26 The crude compound 11 was directly oxidized with
Dess–Martin reagent15 to the corresponding ketone 12, which
is readily purified by silica gel chromatography. The isolated
yield based on compound 10 is 58%. Hydrogenolysis of ketone
12 with 10% Pd-C in a THF–water mixture cleaved N-Cbz
completely without significant deprotection of O-Bn (according to
the HRMS-ESI+). The following hydrogenolytic de-O-benzylation
under acidic conditions led to (−)-calystegine B3 (81% isolated
yield), which shows a correct HRMS(ESI+) peak, a reversed
specific rotation signal and parallel NMR data as those from the
reported (+)-calystegine B3 (Scheme 6).27
Scheme 6 The synthesis of (−)-calystegine B3. Reaction conditions and
yields: (a) R-Ni, EtOH, reflux, 71%; (b) i. Ba(OH)2 octahydrate, MeOH,
water, 80 ◦C; ii. CbzCl, NaHCO3; (c) Dess–Martin reagent, 58% for steps
b and c; (d) 1 atm H2, 10% Pd/C, THF, water, RT, overnight, followed by
addition of excessive 1 N HCl, 3 more days, 81%.
reaction center from head to tail as well as the relative position
of the N-substituent to yield valuable N-containing carbohydrate
dithiane synthetic intermediates. By virtue of carefully selected
protecting groups, the aldehydes 2d and 2e as very useful N-
containing carbohydrate building blocks were produced. The
following Corey–Chaykovsky method yielded the N-containing
heptose epoxide derivatives 5a, b and 6. The stereochemistry of
this epoxidation can be controlled to a certain extent by the
hydroxy protecting groups. Depending on the protecting groups,
via the stabilized dilithiate dithiane-imidate intermediate, the
anionic cyclizations of those epoxides according to the Corey–
Seebach method achieved either highly functionalized seven-
membered ring amino carbasugars 7a,b and 9 or six-membered
ring amino carbasugar 8 with defined stereochemistry and high
yields. From compound 9, we accomplished the first synthesis
of (−)-calystegine B3 as an interesting enantiomer, also a possible
homomorphous analogue of the naturally discovered calystegines.
As the first realization of an anionic cyclization pathway to
calystegine type structures, the strategy described above has a
high potential for the syntheses of various structural analogues
of calystegines. The bioactivity of (−)-calystegine B3 will be tested
in due course.
Experimental
Thin layer chromatography (TLC) was conducted on silica gel
aluminium sheets (Kieselgel 60 F254, Merck). The spots were vi-
sualized by UV light or heating after being dipped into a mixture of
two solutions (500 mg 1,3-dihydroxy naphthalin in 250 mL ethanol
and 250 mL 2 N H2SO4) or a mixture of 25 g phosphomolybdic
acid, 10 g Ce(SO4)2, 60 mL conc. H2SO4 and 940 mL water. All
solvents used were dried as a standard method or as indicated
in the procedures when an anhydrous condition was required. All
reagents are commercially available and were used without further
purification. Air or moisture sensitive reactions were performed
under an argon atmosphere (Argon 4.8 of Messer Griesheim,
without further drying) with standard Schlenk techniques. The
specific rotation was measured on a polarimeter 341 (Perkin-
Elmer) with 1 dm cuvettes. Nuclear magnetic resonance spectra
were recorded on a Bruker AMX 400 spectrometer, a Varian
500 INOVA, or a Varian Unity Plus 600. The chemical shift is
specified as d in ppm and the signal of the solvent was used as the
internal standard. Electrospray ionisation mass spectra (MS-ESI)
Conclusions
In summary, we used D-glucosamine trimethylene dithioacetal
as a cheap and versatile starting material and established a
methodology for the first time that switches the sugar carbonyl
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were recorded on a Quattro LCZ or a MicroTof. Medium pressure
chromatography (MPLC) was performed on silica gel 60 (230–400
mesh, Merck). Melting points were measured on an uncorrected
Buchi B-540 apparatus. Elementary analysis was performed on
CHN-O-RAPID (Heraeus) and refers to the stoichiometric mass.
The elementary analysis results for most compounds were not
presented due to the large data deviation caused by the several
additional hetero elements in the system.
3.73 (brd, J 4.1 Hz, 1H, H-5), 3.56 (brs, 1H, H-4), 3.33 (dd, J
4.4 Hz, J 9.8 Hz, 1H, H-6a), 3.25 (dd, J 3.3 Hz, J 9.8 Hz, 1H,
H-6b), 2.89–2.49 (m, 6H, dithiane and 3 × OH), 1.95–1.85 (m,
2H, dithiane); dC (CDCl3, 100 MHz): 157.3 (q, J 36.4 Hz, 1C,
COCF3), 146.8 (Cq,aryl-Tr), 128.5–127.1 (m, 15C, CHaryl-Ph), 116.1
(q, J 288.0 Hz, 1C, COCF3), 87.4 (Cq,alkyl-Tr), 72.8 (C-4), 71.5 (C-5),
69.3 (C-3), 64.3 (C-6), 53.5 (C-2), 46.1 (C-1), 27.6 (dithiane), 27.3
(dithiane), 25.2 (dithiane); HRMS-ESI+: m/z [M + Na]+ 630.1549,
C30H32F3NNaO5S2 requires 630.1566.
2-Deoxy-3,4-O-methylene-5-O-methoxymethyl-2-
trifluoracetamido-D-gluco-hexodialdose-1,1-trimethylene
dithioacetal, 2d
2-Deoxy-3,4,5-tri-O-benzyl-2-trifluoracetamido-6-O-trityl-D-
glucose-1,1-trimethylene dithioacetal, 4
Under argon, alcohol 1d10b (4.0 g, 9.5 mmol, dried by coevapora-
tion with toluene) was dissolved in dichloromethane (40 mL). To
this solution at RT, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-
3-(1H)-one (Dess–Martin periodinane, 15% wt., from Acros,
28 mL, 9.9 mmol, 1.04 eq.) in dichloromethane was added. The
mixture was stirred at RT for 2 h (monitored by TLC). Then
triethylamine (1.5 mL) was added and the resulting mixture was
stirred for another 10 min at RT. All the volatile components were
removed under vacuum (bath temperature should be lower than
40 ◦C) and the residue was purified by MPLC (cyclohexane–ethyl
acetate 5 : 1) to yield product 2d (3.3 g, 83%) as a light yellow
oil; [a]D −1.7 (c 1.00, MeOH); dH (CD2Cl2, 400 MHz): 9.74 (d, J
1.6 Hz, 1H, H-6), 6.79 (m, 1H, NH), 5.14 (s, 1H, 3,4-O-methylene-
Ha), 5.01 (s, 1H, 3,4-O-methylene-Hb), 4.82 (dd, 1H, J 1.5 Hz, J
6.2 Hz, H-3), 4.81 (s, 2H, CH2-MOM), 4.60 (dt, J 1.5 Hz, J 9.7 Hz,
1H, H-2), 4.23 (dd, J 1.6 Hz, J 6.1 Hz, 1H, H-5), 4.02 (pseudo-t,
J 6.1 Hz, 1H, H-4), 3.95 (d, J 9.7 Hz, 1H, H-1), 3.47 (s, 3H, CH3-
MOM), 3.06–2.95 (m, 2H, dithiane), 2.75–2.66 (m, 2H, dithiane),
2.05–2.03 (m, 2H, dithiane); dC (CD2Cl2, 100 MHz): 200.4 (C-6),
157.9 (q, J 37.4, 1C, CO-Tfa), 116.2 (q, J 287.9, 1 C, CF3-Tfa), 97.8
(CH2-MOM), 96.6 (3,4-O-methylene), 81.7 (C-5), 76.8 (C-3), 76.7
(C-4), 56.6 (CH3-MOM), 52.2 (C-2), 46.2 (C-1), 27.6 (dithiane),
27.1 (dithiane), 25.5 (dithiane); HRMS-ESI+: m/z [M + MeOH +
Na]+ 474.0837, C15H24F3NNaO7S2 requires 474.0838.
Purified starting material 3 (30.0 g, 0.049 mol, crude product from
last step can be used too) was dissolved in THF (500 mL) and
immersed in an ice-water bath. To this solution, NaH (17.0 g, 60%
in oil, 0.71 mol) was added portion-wise followed by BnCl (80 mL,
0.7 mol) and n-Bu4NI (1.0 g). The resulting suspension was then
stirred at RT for 2 days and poured into a mixture of ethyl acetate
(1 L), ice cold water (1 L), and the necessary amount of HOAc
for keeping the mixture neutral. The two phases were separated
and the water phase was washed with ethyl acetate several times.
Combined organic layers were washed with HCl (1 N, 100 mL), sat.
aqueous NaHCO3 (100 mL), and brine (100 mL) in turn. Finally
the solvent was evaporated and the residue was coevaporated
with toluene several times to dryness. The resulting crude product
can be used directly for the next reaction or purified by MPLC
(cyclohexane–ethyl acetate 10 : 1) to yield compound 4 (42.5 g,
99%) as a colorless syrup; [a]D −4.0 (c 1.00, benzene); dH (C6D6,
600 MHz): 7.57–6.94 (m, 15H, Haryl-Bn), 6.86 (d, J 9.8 Hz, 1H,
NH), 4.85 (t, J 9.8 Hz, 1H, H-2), 4.76 (d, J 11.0 Hz, 1H, Halkyl
-
Bn), 4.65 (d, J 12.0 Hz, 1H, Halkyl-Bn), 4.61 (d, J 11.0 Hz, 1H,
Halkyl-Bn), 4.51–4.47 (m, 3H, H-3 and 2 × Halkyl-Bn), 4.43 (d, J
12.0 Hz, 1H, Halkyl-Bn), 3.99 (dd, J 5.1 Hz, J 8.1 Hz, 1H, H-4),
3.74 (dd, J 4.3 Hz, J 8.1 Hz, 1H, H-5), 3.60 (br-d, J 3.6 Hz, 2H,
H-6a,b), 3.53 (d, J 9.6 Hz, 1H, H-1), 2.77–2.72 (m, 1H, dithiane),
2.26–2.21 (m, 1H, dithiane), 2.00–1.96 (m, 1H, dithiane), 1.71–
1.67 (m, 1H, dithiane), 1.45–1.39 (m, 1H, dithiane), 1.22–1.17
(m, 1H, dithiane); dC (C6D6, 150 MHz): d 157.4 (q, J 36.7 Hz,
2-Deoxy-2-trifluoracetamido-6-O-trityl-D-glucose-1,1-
trimethylene dithioacetal, 3
1C, COCF3), 144.47 (3C, Cq,aryl-Tr), 138.7 (Cq,aryl-Bn), 138.6 (Cq,aryl
-
Bn), 138.2 (Cq,aryl-Bn), 129.2–127.2 (30 C, CHaryl-Bn and CHaryl-Tr),
116.7 (q, J 288.3 Hz, 1C, COCF3), 87.3 (3C, Calkyl-Tr), 80.8 (C-
5), 79.6 (C-4), 77.6 (C-3), 75.4 (Calkyl-Bn), 74.6 (Calkyl-Bn), 72.0
(Calkyl-Bn), 62.8 (C-6), 53.2 (C-2), 45.8 (C-1), 26.5 (dithiane), 25.2
(dithiane), 23.3 (dithiane); HRMS-ESI+: m/z [M + Na]+ 900.2978,
C51H50F3NNaO5S2 requires 900.2975.
˚
In dry pyridine (400 mL, over MS 4 A), N-trifluoroacetamido-
D-glucose-1,1-trimethylene dithioacetal10b (20.0 g, 0.055 mol) was
dissolved. To this solution at RT, TrCl (28.0 g, 0.1 mmol) and
DMAP (0.5 g) were added. The clear solution was then stirred
at RT for 2 days. For quenching the reaction, MeOH (20 mL)
was added. Then all volatile components were removed under
vacuum. The residue was distributed in ethyl acetate (1 L) and
HCl (1 N, 500 mL). The organic phase was separated and washed
with saturated aqueous NaHCO3 (100 mL) and brine (100 mL)
in turn. The resulting solution was then evaporated to yield a
syrup, which was triturated with cyclohexane several times and
coevaporated to dryness with toluene. The resulting crude syrup
can be used directly for the next step of the reaction. Otherwise
it can be purified by MPLC (n-pentane–ethyl acetate 5 : 1) to
2-Deoxy-3,4,5-tri-O-benzyl-2-trifluoracetamido-D-glucose-1,1-
trimethylene dithioacetal, 1e
In a flask, purified starting material 4 (39.0 g, 0.044 mol, crude
product from last step can be used too) was dissolved in ethyl
acetate (400 mL) and MeOH (400 mL) followed by addition of
p-TsOH monohydrate (45.0 g, 0.237 mol). The reaction mixture
was stirred at RT for 2 days and poured into a mixture of water
(1 L) and ethyl acetate (1 L) with excessive NaHCO3 for keeping
the mixture slightly basic. The biphasic mixture was separated
and the water phase was washed several times with ethyl acetate.
Combined organic phases were washed with brine and evaporated
◦
yield compound 3 (31.8 g, 95%) as a white solid; mp: 96–98 C;
[a]D −12.7 (c 1.00, MeOH); dH (CDCl3, 400 MHz): 7.36–7.17 (m,
15H, Haryl-Tr), 6.87 (d, J 9.4 Hz, 1H, NH), 4.46 (m, 1H, H-2),
4.27 (brd, J 2.4 Hz, 1H, H-3), 3.97 (d, J 8.4 Hz, 1H, H-1),
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to dryness. The residue was purified by MPLC (cyclohexane–ethyl
acetate 4 : 1) to yield compound 1e (21.8 g, 78%) as a light yellow
solid; mp: 150–151 ◦C; [a]D −19.6 (c 1.00, MeOH); dH (CDCl3,
500 MHz): d 7.42–7.27 (m, 15H, Haryl-Bn), 6.84 (d, J 9.8 Hz, 1H,
NH), 4.96–4.64 (m, 3H, Halkyl-Bn), 4.58 (t, J 9.8 Hz, 1H, H-2),
4.45 (d, J 8.6 Hz, 1H, H-3), 3.89 (d, J 4.7 Hz, 2H, H-6), 3.85–3.82
(m, 1H, H-4), 3.72–3.69 (m, 1H, H-5), 3.63 (d, J 9.6 Hz, 1H, H-1),
3.01–2.95 (m, 1H, dithiane), 2.75–2.70 (m, 1H, dithiane), 2.57–
2.52 (m, 1H, dithiane), 2.44–2.39 (m, 1H, dithiane), 2.21–2.08
(brs, OH), 1.98–1.86 (m, 2H, dithiane); dC (CDCl3, 125 MHz):
157.4 (q, J 37.1 Hz, 1C, COCF3), 137.7 (2C, Cq,aryl-Bn), 138.5
(Cq,aryl-Bn), 128.6–127.7 (15C, CHaryl-Bn), 115.8 (q, J 288.0 Hz,
1C, COCF3), 80.2 (C-5), 80.1 (C-4), 77.2 (C-3), 75.3 (Calkyl-Bn),
75.0 (Calkyl-Bn), 71.7 (Calkyl-Bn), 60.8 (C-6), 52.3 (C-2), 45.6 (C-1),
26.9 (dithiane), 26.2 (dithiane), 25.0 (dithiane); HRMS-ESI+: m/z
[M + Na]+ 658.1871, C32H36F3NNaO5S2 requires 658.1879.
and the resulting mixture was stirred for 1 h at RT. The reaction
mixture was then poured into ice-cold water (20 mL) and extracted
with ethyl acetate several times. Combined organic phases were
evaporated and purified by MPLC (cyclohexane–ethyl acetate 5 :
1) to yield inseparable diastereomeric epoxides 5a,b (28 mg, 68%)
as a colorless oil; [a]D −16.2 (c 1.00, MeOH). The NMR spectra
are listed as separated compounds: diastereomer 1, dH (CD2Cl2,
600 MHz): 6.80 (m, 1H, NH), 5.07 (s, 1H, 3,4-O-methylene-Ha),
4.96 (s, 1H, 3,4-O-methylene-Hb), 4.84 (dd, J 1.1 Hz, J 6.3 Hz,
1H, H-3), 4.75 (s, 1H, CH2-MOM-Ha), 4.66 (s, 1H, CH2-MOM-
Hb), 4.60–4.56 (m, 1H, H-2), 3.96 (d, J 9.6 Hz, 1H, H-1), 3.85 (t, J
4.6Hz, 1H, H-5), 3.77–3.73(m, 1H, H-4), 3.40(s, 3H, CH3-MOM),
3.10–3.08 (m, 1H, H-6), 3.02–2.95 (m, 2H, dithiane), 2.83–2.78 (m,
2H, H-7), 2.72–2.61 (m, 2H, dithiane), 2.02–1.95 (m, 2H, dithiane);
dC (CD2Cl2, 150 MHz): 157.86 (q, J 37.3, 1C, CO-Tfa), 116.2 (q, J
287.8, 1C, CF3-Tfa), 97.0 (CH2-MOM), 96.4 (3,4-O-methylene),
78.4 (C-4), 75.9 (C-3), 75.7 (C-5), 56.4 (CH3-MOM), 52.3 (C-2),
51.3 (C-6), 46.4 (C-1), 44.8 (C-7), 27.7 (dithiane), 27.3 (dithiane),
25.5 (dithiane); diastereomer 2, dH (CD2Cl2, 600 MHz): 6.80 (m,
1H, NH), 5.05 (s, 1H, 3,4-O-methylene-Ha), 4.90 (s, 1H, 3,4-O-
methylene-Hb), 4.88 (s, 1H, CH2-MOM-Ha), 4.79 (dd, J 1.1 Hz,
J 6.5 Hz, 1H, H-3), 4.71 (s, 1H, CH2-MOM-Hb), 4.68–4.66 (m,
1H, H-2), 3.92 (d, J 9.8 Hz, 1H, H-1), 3.77–3.73 (m, 1H, H-4),
3.59 (t, J 6.3 Hz, 1H, H-5), 3.37 (s, 3H, CH3-MOM), 3.06–3.02
(m, 1H, H-6), 2.82 (t, J 4.6 Hz, 1H, H-7a), 3.02–2.95 (m, 2H,
dithiane), 2.72–2.61 (m, 1H, H-7b), 2.72–2.61 (m, 2H, dithiane),
2.02–1.95 (m, 2H, dithiane); dC (CD2Cl2, 150 MHz): 157.89 (q, J
37.3, 1C, CO-Tfa), 116.2 (q, J 288.0, 1C, CF3-Tfa), 96.2 (3,4-O-
methylene), 96.0 (CH2-MOM), 78.0 (C-4), 76.8 (C-5), 76.7 (C-3),
56.4 (CH3-MOM), 52.5 (C-6), 52.3 (C-2), 46.2 (C-1), 43.8 (C-7),
27.4 (dithiane), 27.0 (dithiane), 25.5 (dithiane); HRMS-ESI+: m/z
[M + Na]+ 456.0725, C15H22F3NNaO6S2 requires 456.0733.
2-Deoxy-3,4,5-tri-O-benzyl-2-trifluoracetamido-D-gluco-
hexodialdose-1,1-trimethylene dithioacetal, 2e
Alcohol 1e (16.0 g, 25.2 mmol, dried by coevaporation with
toluene) was dissolved in dichloromethane (80 mL). To this
solution, Dess–Martin periodinane (75.0 mL, 15% wt, from Acros,
26.5 mmol, 1.05 eq.) was added via syringe at RT. The mixture was
then stirred at RT for 1 h followed by addition of TEA (6.0 mL).
The dark mixture was stirred for 10 min and quenched by addition
of saturated aqueous Na2S2O3 (100 mL) and saturated aqueous
NaHCO3 (100 mL). The biphasic mixture was separated and
the water phase was washed with dichloromethane several times.
Combined organic phases were then evaporated and purified by
MPLC (cyclohexane–ethyl acetate 50 : 1–20 : 1) to yield aldehyde
2e (10.1 g, 63%) as a light yellow oil; [a]D −16.3 (c 1.00, benzene); dH
(C6D6, 600 MHz): 9.60 (s, 1H, H-6), 7.19–6.97 (m, 15H, Haryl-Bn),
6.91 (d, J 9.7 Hz, 1H, NH), 4.87 (t, J 9.2 Hz, 1H, H-2), 4.60–4.58
(m, 2H, H-3 and Halkyl-Bn), 4.49–4.34 (m, 5H, Halkyl-Bn), 3.95–
3.92 (m, 2H, H-4 and H-5), 3.63 (d, J 8.8 Hz, 1H, H-1), 2.73–
2.70 (m, 1H, dithiane), 2.56–2.52 (m, 1H, dithiane), 2.04–2.00
(m, 1H, dithiane), 1.94–1.90 (m, 1H, dithiane), 1.44–1.40 (m, 1H,
dithiane), 1.33–1.28 (m, 1H, dithiane); dC (C6D6, 150 MHz): 202.0
(C-6), 157.1 (q, J 36.7 Hz, 1C, COCF3), 137.7 (Cq,aryl-Bn), 137.4
(Cq,aryl -Bn), 136.9 (Cq,aryl-Bn), 128.4–127.5 (15C, CHaryl-Bn), 116.3
(q, J 288.3 Hz, 1C, COCF3), 83.3 (C-5), 81.6 (C-4), 76.4 (C-3),
74.4 (Calkyl-Bn), 73.7 (Calkyl-Bn), 72.9 (Calkyl-Bn), 51.1 (C-2), 46.4 (C-
1), 26.7 (dithiane), 26.0 (dithiane), 24.9 (dithiane); HRMS-ESI+:
m/z [M + MeOH + Na]+ 688.1978, C33H38F3NNaO6S2 requires
688.1985.
6,7-Anhydro-2-deoxy-3,4,5-tri-O-benzyl-2-trifluoracetamido-D-
gluco-D-glycero-heptose-1,1-trimethylene dithioacetal, 6
To a suspension of NaH (1.69 g, 60% in oil, 42.2 mmol) in
˚
dry DMSO (20.0 mL, dried over MS 4 A), a solution of
trimethylsulfoxonium iodide (9.21 g, 41.9 mmol) in dry DMSO
(100 mL) was added at RT. The mixture was stirred for 1 h at
RT, to which a solution of aldehyde 2e (8.0 g, 12.6 mmol, dried
by coevaporation with toluene) in dry DMSO (80 mL, dried over
˚
MS 4 A) was added via syringe. The resulting dark red solution
was stirred at RT for 1 h and poured into ice-cold saturated
aqueous ammonium chloride solution (200 mL). The water phase
was then extracted with ethyl acetate several times. Combined
organic phases were washed with brine and evaporated. The crude
product was purified by MPLC (cyclohexane–ethyl acetate 20 : 1)
to yield epoxide 6 (5.0 g, 61%) as a light yellow oil; [a]D −14.3 (c
1.00, MeOH); dH (C6D6, 600 MHz): 7.28–7.01 (m, 15H, Haryl-Bn),
6.78 (d, J 10.1 Hz, 1H, NH), 4.94 (d, J 11.0 Hz, 1H, Halkyl-Bn),
4.84 (d, J 11.0 Hz, 1H, Halkyl-Bn), 4.82 (t, J 10.1 Hz, 1H, H-2),
4.78 (dd, J 1.5 Hz, J 8.6 Hz, 1H, H-4), 4.66 (d, J 11.1 Hz, 1H,
6,7-Anhydro-2-deoxy-3,4-O-methylene-5-O-methoxymethyl-2-tri-
fluoracetamido-D-gluco-D-glycero-heptose-1,1-trimethylene
dithioacetal and 6,7-anhydro-2-deoxy-3,4-O-methylene-5-O-
methoxy-methyl-2-tri-fluoracetamido-D-gluco-L-glycero-heptose-
1,1-trimethylene dithioacetal, 5a,b
A solution of trimethylsulfoxonium iodide (97 mg, 0.4 mmol)
in DMSO (1.0 mL) was added to a suspension of NaH (60%
dispersion in oil, 18 mg, 0.4 mmol) in DMSO (1 mL) at RT. The
suspension was stirred at room temperature for 30 min. A solution
of aldehyde 2d (40 mg, 0.1 mmol, dried by coevaporation with
toluene) in DMSO (1 mL) was added to the above suspension,
Halkyl-Bn), 4.62 (d, J 11.1 Hz, 1H, Halkyl-Bn), 4.44 (s, 2H, Halkyl-
Bn), 3.94 (dd, J 1.9 Hz, J 8.6 Hz, 1H, H-5), 3.65 (d, J 10.1 Hz,
1H, H-1), 3.49 (dd, J 1.5 Hz, J 8.6 Hz, 1H, H-3), 3.32–3.29 (m,
1H, H-6), 2.82–2.75 (m, 2H, dithiane), 2.33–2.20 (m, 1H, H-7),
2.33–1.96 (m, 2H, dithiane), 1.52–1.48 (m, 1H, dithiane), 1.35–
1.32 (m, 1H, dithiane); dC (C6D6, 150 MHz): 157.7 (q, J 36.7 Hz,
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1C, COCF3), 138.9 (Cq,aryl-Bn), 138.6 (Cq,aryl-Bn), 138.5 (Cq,aryl-Bn),
128.7–127.8 (15C, CHaryl-Bn), 117.0 (q, J 288.3 Hz, 1C, COCF3),
84.2 (C-5), 81.1 (C-3), 77.9 (C-4), 76.1 (Calkyl-Bn), 75.3 (Calkyl-Bn),
72.7 (Calkyl-Bn), 52.4 (C-2), 48.9 (C-6), 46.1 (C-7), 45.4 (C-1), 26.6
(dithiane), 25.9 (dithiane), 25.3 (dithiane); HRMS-ESI+: m/z [M +
Na]+ 670.1886, C33H36F3NNaO5S2 requires 670.1879.
25.8 (dithiane), 24.9 (dithiane), 24.1 (dithiane); HRMS-ESI+: m/z
[M + Na]+ 456.0728, C15H22F3NNaO6S2 requires 456.0733.
Fig. 3 shows selected NOE effects on compounds 7a,b, which
confirmed their absolute stereochemistry along with the single
crystal structure21 of compound 7b.§
(2R,3R,4S,5R,6R)-6-Hydroxy-3,4-methylenedioxy-5-
methoxymethoxy-2-trifluoracetamido-cycloheptanone trimethylene
dithioacetal, 7a and (2R,3R,4S,5R,6S)-6-hydroxy-3,4-
methylenedioxy-5-methoxymethoxy-2-trifluoracetamido-
cycloheptanone trimethylene dithioacetal, 7b
Under argon, epoxides 5a,b as a 1 : 1 mixture (1.2 g, 2.8 mmol,
dried by coevaporation with toluene) were dissolved in THF
(12 mL) and cooled down to −90 ◦C. n-BuLi (6.5 mL, 1.6 M
in hexane, 10.4 mmol, 3.7 eq.) was added to the stirred solution.
The reaction mixture was then warmed up to −70 ◦C in 2 h and
saturated aqueous ammonium chloride was added to quench the
reaction. The resulting mixture was extracted by ethyl acetate.
The organic layer was then evaporated and purified by MPLC
(cyclohexane–ethyl acetate 3 : 1–2 : 1) to yield the faster moving
component as compound 7a (0.6 g, 50%) and the slower moving
component as compound 7b (0.4 g, 33%). Compound 7a as an
amorphous solid can be crystallized from a cyclohexane and ethyl
acetate mixture. Compound 7b was initially a light yellow oil that
turned into a solid after storage.
Fig. 3 The NOE observed from the protons on the seven-membered ring
skeletons of compounds 7a,b.
(2R,3R,4R,5R,6S)-3,4,5-Tris(benzyloxy)-6-hydroxymethyl-2-
trifluoracetamido-cyclohexanone trimethylene dithioacetal, 8 and
(2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-hydroxy-2-
trifluoracetamido-cycloheptanone trimethylene dithioacetal, 9
The salt free procedure:
Epoxide 6 (250 mg, 0.467 mmol, dried by coevaporation with
toluene) was dissolved in THF (10.0 mL) and cooled to −90 ◦C. To
this solution, n-BuLi (0.73 mL, 1.6 M in hexane, 2.5 eq.) was added
and the mixture was then warmed up to −10 ◦C immediately.
The reaction mixture was stirred at this temperature for 3 h
followed by addition of 3 mL saturated aqueous ammonium
chloride. The resulting mixture was then warmed to RT and
extracted by ethyl acetate (50 mL). The organic layer was washed
with brine, evaporated and purified by MPLC (cyclohexane–ethyl
acetate 10 : 1) to yield the faster moving component as the seven-
membered ring 9 (57 mg, 23%, colorless oil) and the slower moving
component as the six-membered ring 8 (135 mg, 54%, colorless oil,
but can be crystallized from ethanol).
◦
Compound 7a (the faster moving component), mp: 61–63 C;
[a]D −48.8 (c 1.00, MeOH); dH (CDCl3, 600 MHz): 7.28–7.19 (brs,
1H, NH), 5.01 (d, J 8.7 Hz, 1H, 3,4-O-methylene-Ha), 4.96 (d,
J 8.7 Hz, 1H, 3,4-O-methylene-Hb), 4.82 (d, J 6.4 Hz, 1H, CH2-
MOM-Ha), 4.76 (d, J 6.4 Hz, 1H, CH2-MOM-Hb), 4.49 (t, J
9.8 Hz, J 9.8 Hz, 1H, H-2), 4.25 (s, 1H, H-5), 4.14–4.10 (m, 2H,
H-6 and H-3), 4.02 (m, 1H, H-4), 3.65–3.62 (m, 1H, OH), 3.46
(s, 3H, H-CH3-MOM), 2.96–2.90 (m, 1H, dithiane), 2.85–2.77 (m,
3H, dithiane), 2.53 (dd, J 15.1 Hz, J 10.5 Hz, 1H, H-7ax), 2.36
(d, J 15.1 Hz, 1H, H-7eq), 2.04–1.95 (m, 2H, dithiane); dC (CDCl3,
150 MHz): 156.7 (q, J 37.3 Hz, 1C, COCF3), 115.9 (q, J 288.2 Hz,
1C, COCF3), 98.5 (C-8), 95.2 (C-10), 78.3 (C-5), 78.1 (C-4), 74.0
(C-3), 66.3 (C-6), 58.1 (C-2), 56.1 (C-9), 53.3 (C-1), 40.4 (C-7),
27.3 (dithiane), 26.0 (dithiane), 23.7 (dithiane); HRMS-ESI+: m/z
[M + Na]+ 456.0733, C15H22F3NNaO6S2 requires 456.0733; Anal.
Calcd. for C15H22F3NO6S2: C 41.56, H 5.12, N 3.23%. Found: C
42.18, H 5.35, N, 3.13%.
Compound 7b (the slower moving component), mp: 128–
129 ◦C; [a]D +25.2◦ (c 1.00, MeOH); dH (C6D6, 600 MHz): 7.19 (d,
J 9.8 Hz, 1H, NH), 4.74 (s, 1H, 3,4-O-methylene-Ha), 4.72 (s, 1H,
3,4-O-methylene-Hb), 4.57 (d, J 6.6 Hz, 1H, CH2-MOM-Ha), 4.46
(d, J 6.6 Hz, 1H, CH2-MOM-Hb), 4.30 (t, J 10.2 Hz, J 10.2 Hz,
1H, H-2), 4.18 (dd, J 10.6 Hz, J 5.4 Hz, 1H, H-6), 3.94 (dd, J
10.2 Hz, J 8.6 Hz, 1H, H-3), 3.73 (t, J 5.4 Hz, J 5.1 Hz, 1H, H-5),
3.29 (dd, J 8.6 Hz, J 5.1 Hz, 1H, H-4), 3.21 (brs, 1H, OH), 3.04
(s, 3H, H-CH3-MOM), 2.58 (d, J 15.8 Hz, 1H, H-7eq), 2.43–2.38
(m, 1H, dithiane), 2.34–2.29 (m, 1H, dithiane), 2.00–1.90 (m, 3H,
2 × dithiane and H-7ax), 1.20–1.07 (m, 2H, dithiane); dC (C6D6,
150 MHz): 157.3 (q, J 37.1 Hz, 1C, COCF3), 116.9 (q, J 288.5 Hz,
1C, COCF3), 98.1 (C-8), 95.4 (C-10), 81.5 (C-5), 79.1 (C-4), 73.3
(C-3), 73.1 (C-6), 60.8 (C-2), 55.7 (C-1), 55.3 (C-9), 40.3 (C-7),
The procedure with LiBr:
Epoxide 6 (50 mg, 0.094 mmol, dried by coevaporation with
toluene) and anhydrous LiBr (8 mg, 0.09 mmol, 1 eq.) were
dissolved in THF (1.0 mL) and cooled to −90 ◦C. At this
temperature, n-BuLi (0.13 mL, 1.6 M in hexane, 2.2 eq.) was
added to the resulting solution. The reaction mixture was then
warmed up to −50 ◦C in 2 h followed by addition of saturated
aqueous ammonium chloride (3 mL). The resulting mixture was
then warmed to RT and extracted by ethyl acetate (30 mL). The
organic layer was washed with brine, evaporated and purified
by MPLC to yield seven-membered ring 9 (4 mg, 8%) and six-
membered ring 8 (31 mg, 62%).
Compound 8, mp: 128–129 ◦C; [a]D +19.0 (c 1.00, MeOH);
dH (C6D6, 600 MHz): 7.36–7.01 (m, 15H, Haryl-Bn), 7.18 (d, J
2.7 Hz, 1H, NH), 5.03 (dd, J 9.0 Hz, J 2.7 Hz, 1H, H-2), 4.80 (d, J
11.9 Hz, 1H, Halkyl-Bn), 4.59–4.58 (m, 1H, H-5), 4.52 (d, J 11.9 Hz,
1H, Halkyl-Bn), 4.31–4.16 (m, 4H, Halkyl-Bn), 4.12 (dd, J 10.3 Hz,
J 2.0 Hz, 1H, H-7a), 3.98–3.91 (m, 2H, H-3 and H-7b), 3.71 (m,
1H, H-4), 2.43–2.40 (brs, 1H, H-6), 2.36–2.29 (m, 2H, dithiane),
§ CCDC reference number 648111. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b711112f
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2.24–2.20 (m, 1H, dithiane), 2.04–2.00 (m, 1H, dithiane), 1.39–
1.34 (m, 2H, dithiane); dC (C6D6, 150 MHz): 156.3 (q, J 37.0 Hz,
1C, COCF3), 138.3 (Cq,aryl-Bn), 137.9 (Cq,aryl-Bn), 136.5 (Cq,aryl-Bn),
128.4–127.4 (15C, CHaryl-Bn), 116.7 (q, J 288.0 Hz, 1C, COCF3),
77.8 (C-3), 77.7 (C-4), 73.1 (Calkyl-Bn), 72.7 (C-5), 72.4 (Calkyl-Bn),
71.8 (Calkyl-Bn), 57.0 (C-7), 54.2 (C-1), 51.8 (C-2), 47.7 (C-6), 27.0
(dithiane), 25.6 (dithiane), 23.8 (dithiane); HRMS-ESI+: m/z [M +
Na]+ 670.1879, C33H36F3NNaO5S2 requires 670.1879.
Compound 9, [a]D −72.4 (c 1.00, MeOH); dH (C6D6, 600 MHz):
8.32 (d, J 10.6 Hz, 1H, NH), 7.28–7.03 (m, 15H, Haryl-Bn), 5.33 (d,
J 10.6 Hz, 1H, H-2), 4.76 (d, J 11.4 Hz, 1H, Halkyl-Bn), 4.68 (d, J
11.4 Hz, 1H, Halkyl-Bn), 4.57 (d, J 11.4 Hz, 1H, Halkyl-Bn), 4.47 (d,
J 11.4 Hz, 1H, Halkyl-Bn), 4.40 (d, J 11.4 Hz, 1H, Halkyl-Bn), 4.31
(d, J 7.7 Hz, 1H, H-4), 4.25 (d, J 11.4 Hz, 1H, Halkyl-Bn), 3.95 (m,
1H, H-5), 3.94–3.87 (m, 1H, H-6), 3.88 (m, 1H, H-3), 3.27–3.23
(m, 1H, dithiane), 2.93–2.88 (m, 1H, dithiane), 2.16–1.93 (m, 4H,
H-7ax, H-7eq and 2 × dithiane), 1.48–1.41 (m, 1H, dithiane), 1.31–
1.28 (m, 1H, dithiane); dC (C6D6, 150 MHz): 156.2 (q, J 36.5 Hz,
1C, COCF3), 138.6 (Cq,aryl-Bn), 137.8 (Cq,aryl-Bn), 136.9 (Cq,aryl-Bn),
128.6–127.4 (15C, CHaryl-Bn), 116.4 (q, J 288.5 Hz, 1C, COCF3),
86.8 (C-3), 83.7 (C-5), 82.9 (C-4), 75.7 (Calkyl-Bn), 73.1 (Calkyl-Bn),
73.0 (Calkyl-Bn), 68.2 (C-6), 51.1 (C-2), 51.0 (C-1), 38.9 (C-7), 27.4
(dithiane), 26.0 (dithiane), 24.3 (dithiane); HRMS-ESI+: m/z [M +
Na]+ 670.1890, C33H36F3NNaO5S2 requires 670.1879.
Bn), 71.9 (C-5), 48.5 (C-1), 26.2 (C-6), 22.3 (C-7); HRMS-ESI+:
m/z [M + Na]+ 566.2131, C30H32F3NNaO5 requires 566.2125.
(1S,2R,3S,4R,5R)-1-(N-Benzyloxycarbonyl)-amino-5-hydroxy-
2,3,4-tris(benzyloxy)-cycloheptane, 11
In a sealed tube, starting material 10 (200 mg, 0.368 mmol) was
dissolved in MeOH (15.0 mL) and water (2.0 mL) followed by
addition of Ba(OH)2 octahydrate (1.5 g, 4.7 mmol). The mixture
was stirred at 80 ◦C for 1 h, cooled to RT, to which NaHCO3
(3.0 g) and CbzCl (1.0 mL) were added in turn. The resulting
mixture was stirred at RT for 2 h with the addition of two batches
of CbzCl (1.0 mL) at an interval of 1 h. Then the reaction mixture
R
was stirred overnight, to which Celiteꢀ 512 medium (Fluka) was
R
added followed by filtration through a Celiteꢀ 512 medium (Fluka)
pad. The clear filtrate was evaporated and purified by MPLC
(cyclohexane–ethyl acetate 5 : 1) to yield crude product 11 (which
was mixed with an inseparable impurity introduced by CbzCl) as
a colorless oil. In HRMS, the desired peak accompanied by other
impurity peaks can be observed: HRMS-ESI+: m/z [M + Na]+
604.2663, C36H39NNaO6 requires 604.2670.
(2S,3S,4R,5S)-5-(N-Benzyloxycarbonyl)-amino-2,3,4-
tris(benzyloxy)-cycloheptanone, 12
Fig. 4 shows selected NOE effects on compounds 8 and 9, which
confirmed their absolute stereochemistry
Under argon, the crude product 11 from the last step (dried by
coevaporation with toluene) was dissolved in dichloromethane
(5.0 mL) followed by addition of Dess–Martin periodinane
(1.5 mL, 15% wt., from Acros, 0.53 mmol). The mixture was stirred
at RT for 1 h, to which TEA (1 mL) was then added. The resulting
mixture was stirred for 10 min, and quenched by addition of
saturated aqueous Na2S2O3 (20 mL), saturated aqueous NaHCO3
(20 mL) and ethyl acetate (30 mL). The biphasic mixture was
separated and the water phase was washed with ethyl acetate
several times. The combined organic phases were then evaporated
and the residue was purified by MPLC (cyclohexane–ethyl acetate
10 : 1) to yield ketone 12 (149 mg) as a colorless syrup. The total
yield of the 2 steps is 58%; [a]D −3.5 (c 1.00, CHCl3); dH (C6D6,
600 MHz): 7.34–7.02 (m, 20H, Haryl-Bn), 6.13 (d, J 9.0 Hz, 1H,
NH), 5.15–4.78 (m, 4H, Halkyl-Bn), 4.75 (s, 1H, H-2), 4.51–4.48 (m,
1H, H-5), 4.36–4.05 (m, 4H, Halkyl-Bn), 4.04 (s, 1H, H-3), 3.56–3.54
(m, 1H, H-4), 2.51–2.05 (m, 1H, H-7a), 2.02–1.98 (m, 1H, H-
7b), 1.98–1.75 (m, 2H, H-6a and 6b); dC (C6D6, 150 MHz): 205.5
(COketone), 155.7 (NCOOBn), 138.7 (Cq,aryl-Bn), 138.1 (Cq,aryl-Bn),
137.8 (Cq,aryl-Bn), 137.4 (Cq,aryl-Bn), 128.6–127.6 (20C, CHaryl-Bn),
83.4 (C-2), 82.4 (C-3), 76.7 (C-4), 73.8 (Calkyl-Bn), 72.6 (Calkyl-Bn),
71.8 (Calkyl-Bn), 66.6 (Calkyl-Bn), 50.7 (C-5), 34.6 (C-7), 30.2 (C-6);
HRMS-ESI+: m/z [M + Na]+ 602.2511, C36H37NNaO6 requires
602.2513.
Fig. 4 The NOE observed from the protons on the six-membered ring
(compound 8) and seven-membered ring (compound 9) skeletons.
(1S,2R,3S,4R,5R)-2,3,4-Tris(benzyloxy)-5-hydroxy-1-
trifluoracetamido-cycloheptane, 10
Under air, compound 9 (200 mg, 0.309 mmol) was dissolved in
EtOH (10.0 mL) followed by addition of Raney-Ni suspension
in EtOH (4 mL, containing ca. 3 g W-2 Raney-Ni, purchased
from Aldrich as a water slurry). The mixture was then refluxed
R
for 1 h, cooled to RT, and filtered through a Celiteꢀ 512 medium
(Fluka) pad. The filtrate was evaporated to dryness and purified by
MPLC (cyclohexane–ethyl acetate 10 : 1–5 : 1) to yield compound
10 (119 mg, 71%) as a colorless oil; [a]D −43.0 (c 1.00, MeOH); dH
(−)-Calystegine B3
(C6D6, 600 MHz): 8.06 (brs, 1H, NH), 7.22–7.07 (m, 15H, Haryl
-
In THF (4.5 mL) and water (0.5 mL), ketone 12 (98 mg,
0.169 mmol) was dissolved. Then 10% Pd-C (20 mg) was added
to the solution. This suspension was hydrogenated at RT by a
balloon charged with hydrogen overnight. HRMS-ESI+ showed a
complete deprotection of N-Cbz, but no deprotection of O-Bn was
observed. Therefore HCl (1 N, 1.0 mL) was added and the mixture
was hydrogenated under the same conditions for 3 more days.
The resulting suspension was neutralized with Amberlite 400 OH−
Bn), 4.63–4.53 (m, 3H, 2 × Halkyl-Bn and H-1), 4.50–4.25 (m, 4H,
Halkyl-Bn), 3.89 (brs, 1H, H-4), 3.57 (d, J 6.7 Hz, 1H, H-2), 3.43 (d, J
6.7 Hz, 1H, H-3), 3.66 (s, 1H, H-5), 1.66–1.29 (m, 4H, H-6a,b and
H-7a,b); dC (C6D6, 150 MHz): 156.1 (q, J 36.5 Hz, 1C, COCF3),
138.6 (Cq,aryl-Bn), 138.2 (Cq,aryl-Bn), 137.6 (Cq,aryl-Bn), 128.8–127.8
(m, 15C, CHaryl-Bn), 116.7 (q, J 288.4 Hz, 1C, COCF3), 83.9 (C-2),
83.7 (C-3), 83.0 (C-4), 74.8 (Calkyl-Bn), 73.5 (Calkyl-Bn), 72.2 (Calkyl
-
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(Fluka), and filtered over a pad of silica gel. The filter cake was
washed with distilled water (10 × 15 mL). Combined filtrates
were washed with dichloromethane (5 × 20 mL), evaporated, and
coevaporated with toluene to dryness. This resulting white solid is
relatively pure according to NMR. But it can be further purified
by MPLC (ca. 25 × 2 cm) filled with Sephadex LH-20 (Sigma-
Aldrich) using ethanol as an eluent (ca. 2 mL for each fraction)
to yield (24 mg, 81%) (−)-calystegine B3 as an amorphous white
solid; [a]D −59.1 (c 1.00, water) {as a reference: for (+)-calystegine
B3, [a]D +76.8 (c 0.88, water),7b or [a]D +82.8 (c 0.50, water)27}; dH
(D2O, 600 MHz): 3.70 (d, J 4.0 Hz, 1H, H-2), 3.54 (dd, J 3.9 Hz, J
9.4 Hz, 1H, H-4), 3.47 (dd, J 4.0 Hz, J 9.4 Hz, 1H, H-3), 3.21 (dd, J
3.9 Hz, J 6.4 Hz, 1H, H-5), 1.85–1.75 (m, 1H, H-6a), 1.74–1.63 (m,
3H, H-6b and H-7a,b); dC (D2O, 150 MHz): 95.7 (C-1), 79.0 (C-2),
76.5 (C-4), 74.9 (C-3), 60.3 (C-5), 35.7 (C-7), 24.9 (C-6). The NMR
data are in full accordance with those reported for (+)-calystegine
B3;7b,27 HRMS-ESI+: m/z [M + H]+ 176.0924, C7H14NO4 requires
176.0917.
9 See for example: J. F. Stoddart, Stereochemistry of Carbohydrates, John
Wiley & Sons Inc., New York, 1971, pp. 37–38.
10 (a) Y.-L. Chen, R. Leguijt and H. Redlich, J. Carbohydr. Chem., 2007,
26, 279; (b) Y.-L. Chen, R. Leguijt and H. Redlich, Synthesis, 2006, 13,
2242; (c) Y.-L. Chen, R. Leguijt, H. Redlich and R. Fro¨hlich, Synthesis,
2006, 24, 4212.
11 H. Redlich, W. Bruns, W. Francke, V. Schurig, T. L. Payne and J. P. Vite´,
Tetrahedron, 1987, 43, 2029.
12 (a) E. J. Corey and D. Seebach, Angew. Chem., 1965, 77, 1134; E. J.
Corey and D. Seebach, Angew. Chem., Int. Ed. Engl., 1965, 4, 1075;
(b) D. Seebach, N. R. Jones and E. J. Corey, J. Org. Chem., 1968, 33,
300.
13 For the effect of protecting groups in cyclizations, see for example: (a) K.
Krohn and G. Bo¨rner, J. Org. Chem., 1994, 59, 6063; (b) K. Krohn, G.
Bo¨rner and S. Gringard, in ref. 1a, pp. 107–122; (c) P. Balbuena, E. M.
Rubio, C. O. Mellet and J. M. G. Ferna´ndez, Chem. Commun., 2006,
2610.
14 See for example: M. B. Smith and J. March, March’s Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure, John Wiley & Sons,
Inc., New York, 5th edn, 2001.
15 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
16 J. R. Parikh and W. von E. Doering, J. Am. Chem. Soc., 1967, 89,
5505.
17 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87,
1353.
18 See for example: T. J. Michnick and D. S. Matteson, Synlett, 1991,
631.
Acknowledgements
19 D. Horton and J. D. Wander, J. Org. Chem., 1974, 39, 1859.
20 Models were generated by the Spartanꢀ04 program at Hartree–Fock
3-21G* level.
Y.-L. C. would like to thank the NRW International Graduate
School of Chemistry for a PhD scholarship. We thank the research
students: Mr Wei Kang, Mr Armin Babrowski and Mr Christian
Roesener for their work on this project.
21 X-Ray crystal structure analysis for compound 7b: formula
C15H22F3NO6S2, M = 433.46, colorless crystal 0.35 × 0.30 × 0.15 mm,
3
a = 9.905(1), c = 39.488(1) A, V = 3874.1(6) A , qcalc = 1.486 g cm−3, l =
˚
˚
3.055 mm−1, empirical absorption correction (0.414 ≤ T ≤ 0.657), Z =
˚
8, tetragonal, space group P41212 (no. 92), k = 1.54178 A, T = 293 K,
References
x and u scans, 24194 reflections collected ( h, k, l), [(sinh)/k] =
0.59 A−1, 2937 independent (Rint = 0.047) and 2803 observed reflections
˚
1 (a) See for example: Carbohydrate Mimics, Concepts and Methods,
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parameter 0.02(3), max. residual electron density 0.93 (−0.28) e A
,
hydrogen atoms calculated and refined as riding atoms. Data set
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22 The reaction was started from −90 ◦C, and it was found that the
reaction is rather slow, and the 6-exo-cyclization of the epoxide was
preferred at this temperature. A prolonged reaction time (more than
8 h) at −90 ◦C to −50 ◦C did not increase the cyclization yield
significantly, while more side products were observed. Increasing the
reaction temperature to −10 ◦C immediately after adding the n-BuLi
improved the cyclization yield significantly. Also, at this temperature,
the ratio of the 6-exo- vs. 7-endo-cyclization of the epoxide was
decreased and compounds 8 and 9 were obtained with yields of 54%
and 23% respectively (ca. 2.4 : 1, 78% in total). Changing the solvent to
diethyl ether led to slower cyclization, while using toluene as the solvent
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cyclization of the epoxide is also favored in such cases probably due to
a Li-chelated intermediate. As a typical example, with a stoichiometric
amount of LiBr, the six-membered ring 8 was obtained in 62% yield
and the yield of seven-membered ring 9 decreased to 8% (ca. 7.8 : 1,
70% in total) accompanied by slight decomposition.
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24 Y.-L. Chen and H. Redlich, unpublished work.
have to be removed under very mild conditions, which is not compatible
with the vigorous basic conditions for deprotecting N-Tfa. Therefore
N-Tfa protection has to be removed and reprotected with N-Cbz before
the free hydroxy is oxidized. Also leaving the hydrogenolysis as the last
step for cleveage of all protections offers further benefit in purifiction.
27 N. Asano, A. Kato, K. Oseki, H. Kizu and K. Matsui, Eur. J. Biochem.,
1995, 229, 369.
25 Generally, the N-Tfa protection is readily removed under very mild
conditions. However, in this special case, it was unusually stable. See,
for example: T. W. Green, P. G. M. Wuts, Protective Groups in Organic
Synthesis, John Wiley & Sons, London, 3rd edn, 1999.
26 Fully protected ketone compound 8 can be sensitive to acid or base
treatment. Hence, once the ketone is produced the O- and N-protections
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 3330–3339 | 3339
©