Novel formal synthesis of stereospecifically C-6 deuterated d-glucose employing configurationally stable alkoxymethyllithiums

Article abstract of DOI:10.1016/j.tet.2009.11.084

The synthesis and testing of configurational stability of chirally monodeuterated PMB- and THP-substituted oxymethyllithiums are described. Macroscopically they are configurationally stable up to -35 °C, the limit of their chemical stability, and microscopically even up to 0 °C. Furthermore, THP-protected oxy-[D₁]methyllithium has been applied in the formal synthesis of (6R)-[6-D₁]-d-glucose (four steps, 40% yield), an example of its use as a homochiral hydroxymethyl synthon.

Full text of DOI:10.1016/j.tet.2009.11.084

Tetrahedron 66 (2010) 591–598
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel formal synthesis of stereospecifically C-6 deuterated
configurationally stable alkoxymethyllithiums
D-glucose employing
*
Dagmar C. Kapeller, Friedrich Hammerschmidt
Institute of Organic Chemistry, University of Vienna, Wa¨hringerstrasse 38, A-1090 Wien, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and testing of configurational stability of chirally monodeuterated PMB- and THP-
substituted oxymethyllithiums are described. Macroscopically they are configurationally stable up to
ꢀ35 ꢁC, the limit of their chemical stability, and microscopically even up to 0 ꢁC. Furthermore, THP-
Received 17 September 2009
Received in revised form 18 November 2009
Accepted 19 November 2009
Available online 23 November 2009
protected oxy-[D1]methyllithium has been applied in the formal synthesis of (6R)-[6-D1]-D-glucose (four
steps, 40% yield), an example of its use as a homochiral hydroxymethyl synthon.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Organolithiums
Configurational stability
Stereospecificity
Deuterium labelling
D
-Glucose
1. Introduction
O
H
O
H
D
D H
OBn
Chirally deuterated sugars have been widely used to elucidate
mechanisms of biosynthesis and chemical reactions. As such, ste-
reospecifically C-6 deuterated D-galacto- and D-glucopyranosides
RO
(R)-[D1]1
Li
Li
OR
O
O
(S)-[D1]1
2
facilitated studies concerning the preferred conformation of the C-
3 steps
5/C-6 bond of some simple sialosaccharides,1 and chirally deuter-
4 steps
4 steps
D
ated [6-D1]-D-glucose fed to Streptomyces ribosidificus shed light
onto the biosynthesis of the antibiotic ribostamycin.2 The latter was
also applied to investigate the stereochemical course of the Ferrier
reaction.3 Despite the usefulness of such substrates, only very few
regio- and stereospecific syntheses have been reported.
H
H
O
OBn
O
O
[6-D1]3
The first synthesis of (6S)-and (6R)-[6-D1]-D-glucose ([6-D1]4)
was achieved by Kakinuma in 1977.4 He started from aldehyde 2,
converting it to xylohexenofuranose [6-D1]3. (6R)-[6-D1]4 was then
prepared utilising a reaction sequence of epoxidation/chromato-
graphic separation/epoxide opening and (6S)-[6-D1]4 directly via
dihydroxylation (Scheme 1).
4 steps
3 steps
D
OH
O
D
OH
O
OH
OH
(6R)-[6-D1]4
OH
OH
(6S)-[6-D1]4
OH
OH
Ohrui et al. also synthesised both diastereomers employing
OH
OH
stereospecific photo-bromination.5 The latest synthesis of (6S)-[6-
D1]-D-glucose was performed by Xu and Price via stereospecific
reduction of both anomers of methyl 2,3,4-tri-O-benzyl D-gluco-[6-
Scheme 1. Synthesis of stereospecifically C-6 deuterated D-glucose [6-D1]4 according
to Kakinuma (blue) and our own strategy (red).
D1]hexodialdo-1,5-pyranoside with (R)-Alpine-BoraneÒ to give
protected (6S)-[6-D1]glucoses (almost 100% (S)).6
We have recently been successful in testing the configurational
stability of several chiral methyllithiums.7 These compounds are
chiral by virtue of the hydrogen isotopes protium and deuterium, as
* Corresponding author. Tel.: þ43 1 4277 52105; fax: þ43 1 4277 9521.
E-mail address: friedrich.hammerschmidt@univie.ac.at (F. Hammerschmidt).
well as
a heteroatom or heteroatom containing substituent
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.084

592
D.C. Kapeller, F. Hammerschmidt / Tetrahedron 66 (2010) 591–598
necessary for the carbanion to retain its configuration. Among
these compounds diisopropylcarbamoyloxy-,7a chloro-,7c 2,4,6-
triisopropylbenzoyloxy-7e and amino-substituted methyllithiums7d
displayed generally high up to complete configurational stability
depending on the reaction conditions.
We envisioned these methyllithiums to be versatile chiral methyl
synthons. To prove their usefulness we decided to prepare [6-D1]4
by employing configurationally stable chiral oxymethyllithiums
[D1]1. The key step in our approach was their addition to aldehyde 2,
trichloroacetimidate),14 gave low yields at best. Transformation
into the mesylate7b and subsequent SN2 reaction with the potas-
sium salt of para-methoxybenzyl alcohol gave the best result with
an overall yield of 64% (Scheme 2). When repeated with the la-
belled compound, inversion of configuration at the deuterated
carbon atom was assumed to occur.
R
R
X
Bu3Sn
OH
Bu3Sn
OPMB
which could be easily prepared from D-glucose (4) according to lit-
5: R = H
6: R = H
erature procedures8 and had already been used by Kakinuma.4
Depending on the stereochemistry of the newly formed asym-
metric centre, the former carbonyl group of the aldehyde, this
would lead to a protected glucofuranose, if the configuration was
(5R) (non-chelated Felkin–Ahn product). In case of C-5 turning out
to be (S)-configured (chelation of lithium with the aldehyde), one
(R)-[D1]5: R = D
(R)-[D1]6: R = D
1. LiTMP
2. MsCl
CH2OK
R
MeO
6
would get the L-ido isomer, respectively. Due to the conformational
Bu3Sn
7: R = H
(R)-[D1]7: R = D
OMs
(S)-[D1]6
flexibility of the furanose ring and various chelation possibilities,
the stereochemical outcome was difficult to predict. But the work of
Bonnaffe´ et al., who tested the addition of several organometallic
reagents to 2, showed that organolithiums, if not too bulky, favoured
2 steps:
66%
Scheme 2. Towards the preparation of
TMP¼2,2,6,6-tetramethylpiperidinyl.
6
and [D1]6. Ms¼methanesulfonyl;
the D
-gluco isomer, substantiating the success of our approach.9
In comparison, preparation of the PMB-ether proceeded
straightforward. Treatment of tributylstannylmethanol with DHP in
the presence of the cation exchange resin Amberlyst H-15 delivered
8 and later on labelled [D1]8 in 91% yield (Scheme 3).15
2. Results and discussion
2.1. Testing of the configurational stability of THP- and PMB-
substituted alkoxymethyllithiums
Amberlyst H-15
DHP, 91%
Bu3Sn
O
O
5 or
When comparing the carbamoyloxy- and aroyloxy-
methyllithiums tested,7a,e the choice for their application as deu-
terium-labelling synthons lay with the latter, as deprotection of the
ester moiety by reduction generally proceeded more readily. But
still the conditions therefore were harsh (refluxing with excess
LiAlH4 in THF), making the use of a differently protected oxy-
methyllithium desirable.
(S)-[D1]5
R
8: R = H
(S)-[D1]8: R = D
Scheme 3. Preparation of PMB-ethers 8 and [D1]8.
Before starting with the determination of the configurational
stability of the chiral alkoxymethyllithiums, we wanted to test their
chemical stability first. Therefore, unlabelled 6 and 8 were trans-
metalated with nBuLi and quenched with benzaldehyde in analogy
to the carbamoyloxy and aroyloxy series at various temperatures
with THF as solvent (Scheme 4, Table 1).7a,e
In their seminal report Still and Sreekumar managed to prove
that a-alkoxy-substituted organolithiums could be configuration-
ally stable.10 In their wake quite a number of alkoxymethyllithiums
have been examined towards their configurational stability, and
found not to racemise over a period of up to 30 min at ꢀ78 ꢁC.11 We
thought them very well suited for our purpose, plus their testing
would increase the still limited knowledge about the configura-
tional stability of methyllithiums.
R
R
PhCHO
nBuLi
6
Ph
OPMB
(S)-[D1]6
Li
OPMB
Initially, the para-methoxybenzyl group was used as protecting
group because it can be introduced and removed easily. It is also
one of the most significant protecting groups in organic chemistry,
as it can be selectively cleaved under hydrogenolytic, oxidative
(with DDQ or CAN), or Lewis acidic conditions.12 We also reasoned
that acetals would probably be more (chemically) stable due to an
additional complexation of lithium by the second oxygen atom. In
this case the THP protecting group was preferred, due to the exis-
tence of several very mild methods for its introduction. Further-
more, Hutchinson and Fuchs had already synthesised unlabelled
THP-protected oxymethyllithium 11, thus proving the feasibility of
this approach and outweighing the disadvantage of the additional
stereogenic centre.13 But we had to find a new way for its genera-
tion, as tributyl(iodomethyl)stannane was not a viable starting
material in our case.
OH
10: R = H
(1R)-[1-D1]10: R = D
9: R = H
(R)-[D1]9: R = D
TMSCl, SnCl2
anisol, 81%
R
Ph
OH
OH
13: R = H
(2R)-[2-D1]13: R = D
Amberlyst H-15
MeOH, quant.
According to previous work in our laboratory, enantiopure
tributylstannylmethanol ([D1]5) was used as a common precursor.7a
Tin–lithium exchange proceeding under retention of configuration
would thus deliver the deuterated alkoxymethyllithiums in
a stereospecific way, following prior protection of the alcohol.
Transformation of tributylstannylmethanol into the PMB-ether
proved tricky. Direct conversion, despite screening different bases
in combination with PMBCl and Bundle’s reagent (PMB
R
R
PhCHO
nBuLi
8
Ph
OTHP
(S)-[D1]8
Li
OTHP
OH
11: R = H
12: R = H
(1R)-[1-D1]12: R = D
(R)-[D1]11: R = D
Scheme 4. Testing of the chemical and configurational stability of alkoxy-
methyllithiums 9 and 11.

D.C. Kapeller, F. Hammerschmidt / Tetrahedron 66 (2010) 591–598
593
Table 1
Testing of the chemical stability of alkoxymethyllithiums 9 and 11
2.2. Synthesis of ido- and gluco-type reference compounds
Addition of an alkoxymethyllithium to aldehyde 2 can lead to
a substituted gluco or idofuranose, making a distinction between
these two necessary. As we decided to initially perform the reaction
with aroyloxymethyllithium 15, which had been intensively ex-
amined in our laboratory,7e we expected 16 and/or 17 as products
(Scheme 6).
Entry
Substrate
Temp (ꢁC)
Time (min)
Yield (%)
1
2
3
4
5a
6
7
8
6
6
6
8
8
8
8
8
ꢀ78
ꢀ50
ꢀ30
ꢀ78
ꢀ78
ꢀ78
ꢀ50
ꢀ30
3
3
3
10
10
60
1
84
66
d
70
24
59
51
21
0.75
O
a
OH
O
The reaction was performed in Et2O/TMEDA.
Ar
O
OBn
2
O
For both substrates the best yields were obtained at ꢀ78 ꢁC and
trapping after a few minutes (6: entry 1, 84%; 8: entry 4, 70%). In
case of the PMB-ether the time between transmetalation and
trapping was extended to 1 h, in which slight decomposition oc-
curred (entry 6). Also, when using Et2O/TMEDA instead of THF the
yield dropped to almost a third (entry 5). At ꢀ50 ꢁC decomposition
increased significantly for both organolithiums, an indication for
their chemical instability (entries 2 and 7). At ꢀ30 ꢁC only product
derivated from the THP-protected oxymethyllithium could be iso-
lated, but not from the PMB-protected one (entries 3 and 8).
With these results in hand testing of the configurational stability
could proceed (Scheme 4, Table 2). For PMB-protected oxy-
methyllithium [D1]9, this was done macroscopically at ꢀ78 and
ꢀ50 ꢁC and microscopically (with benzaldehyde present upon
transmetalation) at 0 ꢁC (entries 1–3). Determination of the con-
figuration at the deuterated centre was done after deprotection and
transformation into the known bis-(R)-Mosher ester.7a In all cases
complete retention of configuration was observed. The same
qualitative result was found for THP-substituted oxymethyllithium
[D1]11, which was completely configurationally stable at ꢀ78 and
ꢀ35 ꢁC (entries 4 and 5).
O
+
16
O
O
OH
O
OBn
Ar
O
Li
Ar
O
15
O
O
17
Scheme 6. Possible products of addition of aroyloxymethyllithium 15 to aldehyde 2.
Ar¼2,4,6-(i-Pr)3C6H2.
To be able to distinguish between these two, the independent
synthesis of reference compounds seemed prudent, especially with
respect to the determination of the ee at C-6 in the deuterated
series later on.
Therefore, one of the isopropylidene groups of 18, an in-
termediate in the synthesis of aldehyde 2, was selectively removed
to give diol 19,8a which could then be esterified with 2,4,6-triiso-
propylbenzoyl chloride at the primary hydroxyl group, yielding 65%
of the protected glucofuranose 16 and approximately 10% of the
dibenzoylated compound as side product (Scheme 7).
Table 2
O
OH
Testing of the configurational stability of alkoxymethyllithiums (R)-[D1]9 and
(R)-[D1]11
O
OH
O
O
CH3COOH
H2O, 99%
Entry
Substrate
Temp (ꢁC)
Time (min)
Yield (%)
ee (%)
OBn
OBn
1
2
3
4
5
(S)-[D1]6
(S)-[D1]6
(S)-[D1]6
(S)-[D1]8
(S)-[D1]8
ꢀ78
ꢀ50
0
30
10
d
87
99
99
99
99
98
O
O
61a
46b
50
O
O
18
19
ꢀ78
60
0.5
O
ꢀ35
62
Ar
Cl
Ph3P/DIAD
a
16
10% of (R)-[D1]14.
4% of (R)-[D1]14.
b
benzoic acid
29%
pyr, 65%
O
O
Remarkable was the formation of the side product [D1]14 result-
OC(O)Ph
LiBEt3H
75%
Ar
O
ing from [D1]9. It was isolated in a few percents when performing the
17
OBn
reaction at or above ꢀ50 ꢁC (see footnotes of Table 2) and probably
O
resulted from
a [2,3]-Wittig rearrangement (Scheme 5). Its
O
1
20
(R)-Mosher ester showed a broadened singlet in the H NMR spec-
trum at
d
¼5.29 ppm for the CHD group, indicating that the rear-
OH
ranged product had at least 95% ee. We tentatively assign
(S)-configuration to the chiral centre, assuming inversion7d of con-
figuration, which is the rule for Wittig rearrangements.
OH
O
OBn
LiAlH4
76%
O
O
21
Scheme 7. Synthesis of reference compounds. Ar¼2,4,6-(i-Pr)3C6H2.
1. rearr.
2. rearomat.
3. H+
O
OH
MeO
Li
R
MeO
Mitsunobu reaction with benzoic acid gave 20 in low yield
(29%). This was probably due to steric hindrance and difficulties at
purification, as the starting material had a very similar Rf value to
the product. Selective removal of the benzoyl group with Super-
R
(R)-[D1]9
(S)-[D1]14
Scheme 5. [2,3]-Wittig rearrangement as side reaction of PMB-protected oxy-
methyllithium 9.
hydride finally gave protected L-idofuranose 17. A sample of it was

594
D.C. Kapeller, F. Hammerschmidt / Tetrahedron 66 (2010) 591–598
further treated with LiAlH4 to cleave the second, more hindered
2,4,6-triisopropylbenzoyl ester to yield 21, which would work as
Comparison of the 1H NMR spectra with those of the unlabelled
compounds proved complete retention of configuration at C-6 (99%
ee) on addition of the chiral oxymethyllithium to the carbonyl
group, as only one signal for the CHDO group was visible in the 1H
NMR spectrum, apart from 2% of the unlabelled compound (Fig. 1).
a
general ido-reference for differently substituted oxy-
methyllithiums after deprotection, the same as 19, its gluco-
counterpart.
2.3. Towards the synthesis of stereospecifically C-6 deuterated
D-glucose
With these reference compounds in hand, aroyloxmethyllithium
15 was quenched with aldehyde 2 10 min after its generation from
the respective stannane by tin–lithium exchange (Scheme 6).7e
Under these conditions no racemisation had been detected in
previous experiments with benzaldehyde as electrophile. 1H NMR
spectroscopy of the crude product revealed that a mixture of gluco-
and ido-type in a ratio of 4:1 was formed, contaminated with a lot of
side products. In the end glucofuranose 16 could be isolated in
a yield of only 31%. Additionally, the side product methyl 2,4,6-
triisopropylbenzoate was found in a yield of 40%, probably due to
protonation of 15 by the enoliseable aldehyde 2.
Not satisfied with this result, we switched to the THP-protected
oxymethyllithium 11, which seemed superior to its PMB analogue
in terms of ease of introduction and lack of side reactions. Trans-
metalation was effected at ꢀ78 ꢁC and aldehyde 2 was added 5 min
after the addition of nBuLi. Unlabelled 11 again delivered the gluco-
to ido-type (22/23) in a ratio of 4:1 (Scheme 8). Isolation of the
products by flash chromatography was easier than before, when
the aroyloxy-substituted methyllithium was used, as there were
fewer side products formed. In the end homogenous 22 and 23
could be obtained in yields of 55% and 13%, respectively. The as-
signment of absolute configurations was secured by removal of the
THP groups, which worked in a yield of about 80%, and comparing
their spectra to those of the reference compounds.
Figure 1. Comparison of the relevant parts in the 1H NMR spectra (400 MHz, CDCl3) of
unlabelled 19 (bottom) and (6R)-[6-D1]19 (top).
3. Conclusions
In summary, we have proven PMB- and THP-protected oxy-
methyllithiums to be macroscopically configurationally stable up to
ꢀ35 ꢁC and microscopically up to 0 ꢁC. They were prepared by tin-
lithium exchange, aged and quenched with benzaldehyde. This
allowed direct comparison to other methyllithiums tested, which
they exceeded both in chemical, as well as configurational stability.
Furthermore, the use of THP-protected oxy-[D1]methyllithium as
a versatile chiral hydroxymethyl synthon was shown by its appli-
cation in the formal synthesis of (6R)-[6-D1]4 (four steps in
a combined yield of 40% starting from the known sugar aldehyde 2).
19
(6R)-[6-D1]19
Amberlyst H-15
MeOH, 80%
4. Experimental
R
OH
THPO
O
4.1. General information
OBn
O
1H/13C (J modulated) NMR spectra were measured, unless oth-
erwise specified, at 300 K on a Bruker Avance DPX 250, DRX 400 or
DRX 600 at 250.13/62.90 MHz, 400.13/100.61 MHz or 600.13/
150.92 MHz, respectively. 2D spectra were recorded on the DRX
O
22: R = H
(6R)-[6-D1]22: R = D
11 or
(R)-[D1]11
R
OH
THPO
O
400. All chemical shifts (
either to residual CHCl3
(OCHD: dH¼3.57) or CDCl3
d
) are given in ppm. They were referenced
dH¼7.24)/toluene (CHD2: dH¼2.09)/THF
dC¼77.00)/toluene-d8 (CHD2:
OBn
(
O
(
23: R = H
O
dC¼21.04)/THF-d8 (OCD2: dC¼67.20). IR spectra were run on a sili-
con disc on a Perkin–Elmer 1600 FT-IR spectrometer.16 Optical ro-
tations were measured at 20 ꢁC on a Perkin–Elmer 351 polarimeter
in a 1 dm cell. Melting points were determined on a Reichert
Thermovar instrument and are uncorrected. Flash chromatography
was performed with Merck silica gel 60 (230–400 mesh) and
monitored by TLC, carried out on 0.25 mm thick Merck plates, silica
gel 60F254. Spots were visualised by UV and/or dipping the plate
into a solution of (NH4)6Mo7O24$4H2O (23.0 g) and Ce(SO4)2$4H2O
(1.0 g) in 10% aqueous H2SO4 (500 mL), followed by heating with
a heat gun.
(6R)-[6-D1]23: R = D
Amberlyst H-15
MeOH, 83%
21
(6R)-[6-D1]21
Scheme 8. Formal synthesis of (6R)-[6-D1]-D-glucose and (6R)-[6-D1]-L-idose.
Finally, repeating the experiment with labelled (R)-[D1]11, 43%
of (6R)-[6-D1]22 and 12% of (6R)-[6-D1]23 could be isolated.
Cleavage of the PMB-ether gave (6R)-[6-D1]19 and (6R)-[6-D1]21,
TMEDA and pyridine were refluxed over powdered CaH2, tolu-
ene over sodium/benzophenone, then distilled and stored over
molecular sieves (4 Å). CH2Cl2 was dried by passing through alu-
minium oxide 90 active neutral (0.063–0.200 mm, activity I) and
stored over molecular sieves (3 Å). Et2O was refluxed over LiAlH4,
completing the formal synthesis of D-glucose and L-idose stereo-
specifically deuterated at C-6, as removal of the remaining pro-
tecting groups (benzyl and isopropylidene) had already been
performed by Kakinuma.4

D.C. Kapeller, F. Hammerschmidt / Tetrahedron 66 (2010) 591–598
595
THF over potassium and distilled prior to use. All other chemicals
were used as supplied in the highest available purity from Aldrich,
Fluka, or Merck.
was added and the reaction quenched with benzaldehyde (0.34 mL,
2 M solution in dry Et2O, 0.68 mmol) after several minutes. It was
stirred for further 30 min at low temperature, before 1 M HCl
(4 mL) was added. The organic phase was separated and the
aqueous one extracted with Et2O (3ꢂ4 mL). The combined organic
layers were dried (MgSO4), concentrated and purified by flash
chromatography (hexane/EtOAc 4:1, Rf 0.16) to yield 10. IR (Si): nmax
3449, 3031, 2858, 1612, 1514, 1249, 1174, 1103, 1034 cmꢀ1; 1H NMR
All glass-ware for moisture sensitive reactions was dried for
several hours at 100 ꢁC. Reactions at ꢀ78 ꢁC were performed in an
acetone/dry ice bath. Small quantities of reagents (mL) were mea-
sured with appropriate syringes (Hamilton). The experimental
procedures, when identical for the non-deuterated and deuterated
compounds, were generally given for the former. The deuterium
content of all compounds lay between 97 and 98%.
(400.13 MHz, CDCl3):
d 7.36–7.21 (m, 7Harom), 6.88–6.83 (m,
2Harom), 4.87 (br d [X-part of ABX-sys.], J¼7.8 Hz, 1H, CHOH), 4.50
(AB-sys., JAB¼11.4 Hz, 2H, OCH2Ph), 3.77 (s, 3H, OCH3), 3.51 (AB-part
of ABX-sys., J¼9.6, 9.6, 3.0 Hz, 2H, CH2O), 2.86 (d, J¼1.8 Hz, 1H, OH);
4.2. Synthesis
13C NMR (100.61 MHz, CDCl3):
d 159.3, 140.2, 129.8, 129.4 (2C),
4.2.1. Tributylstannylmethyl para-methoxybenzyl ether (6) and (S)-
[D1]6. To a solution of KOt-Bu (293 mg, 2.60 mmol) in dry THF
(15 mL) was added para-methoxybenzyl alcohol (468 mg,
3.40 mmol dissolved in 1 mL of THF) at 0 ꢁC under argon; 15 min
later tributylstannylmethyl mesylate7b (750 mg, 1.70 mmol dis-
solved in 1 mL of dry THF) was added and stirring was continued
for another 1.5 h. Afterwards, the reaction was quenched with 1 M
HCl (10 mL) and hexane (10 mL) was added. The organic phase was
separated, washed with brine, dried (MgSO4), and then concen-
trated under reduced pressure. The crude product was purified by
flash chromatography (hexane/Et2O 50:1, Rf 0.36) to yield 6 as
a colourless oil (611 mg, 81%). IR (Si): nmax 2955, 2927, 1512, 1457,
128.3 (2C), 127.8, 126.1 (2C), 113.9 (2C), 75.5, 73.0, 72.8, 55.2.
Compound (1R)-[1-D1]10: The spectroscopic data were identical to
those of 10, except for 1H NMR (400.13 MHz, CDCl3):
d 4.91–4.86 (m,
1H, CHOH), 3.58 (dt, J¼3.0, w1 Hz, 1H, CHD, dia. A), 3.44 (dt, J¼9.6,
w1 Hz, 1H, CHD, dia. B), 2.83 (s, 1H, OH); 13C NMR (100.61 MHz,
CDCl3):
d
75.1 (t, J¼21.1 Hz, CHD, dia. A), 75.1 (t, J¼21.1 Hz, CHD, dia.
B), 72.74 and 72.71 (CHOH, dias. A and B).
4.2.4. Deprotection of PMB-protected diol (1R)-[1-D1]10 to (2R)-[2-
D1]1312. PMB-ether 10 (56 mg, 0.22 mmol), TMSCl (72 mg,
0.66 mmol), anisol (36 mg, 0.33 mmol) and SnCl2 (4 mg,
0.22 mmol) were dissolved in dry CH2Cl2 (1 mL) and stirred for
1.5 h at rt. Afterwards, a saturated aqueous solution of NaHCO3
(2 mL) was added, the organic phase separated and the aqueous
one extracted with EtOAc (4ꢂ2 mL). The combined organic layers
were dried (MgSO4), concentrated under reduced pressure and the
residue was purified by flash chromatography (hexane/EtOAc 1:2)
to yield diol 13 (25 mg, 81%) as colourless crystals.
1247, 1041 cmꢀ1; 1H NMR (400.13 MHz, CDCl3):
d 7.21 (m, 2Harom),
6.85 (m, 2Harom), 4.33 (s, 2H, OCH2), 3.79 (s, 3H, OCH3), 3.70 (s, J(117/
119Sn)¼14.7 Hz, 2H, SnCH2O), 1.53–1.44 (m, 6H, 3SnCH2CH2), 1.28
(sext, J¼7.3 Hz, 6H, 3 Sn(CH2)2CH2), 0.92–0.84 (m, J(117/119Sn)¼51.0,
49.0 Hz, 6H, 3SnCH2), 0.87 (t, J¼7.3 Hz, 9H, 3Sn(CH2)3CH3); 13C NMR
(100.61 MHz, CDCl3): d 159.0, 131.0, 129.1 (2C), 113.6 (2C), 76.8, 61.1
(J(117/119Sn)¼366.4, 350.3 Hz), 55.2, 29.1 (3C, J(117/119Sn)¼20.6 Hz,),
27.3 (3C, J(117/119Sn)¼52.8 Hz), 13.7 (3C), 9.0 (3C, J(117/119Sn)¼320.5,
306.7 Hz). Compound (S)-[D1]6: The spectroscopic data were iden-
4.2.5. Transmetalation 8 and (S)-[D1]8, quenching of the respective
oxymethyllithiums 11 and (R)-[D1]11 with benzaldehyde, and de-
protection of 12 and (1R)-[1-D1]12. A solution of 8 (122 mg,
0.3 mmol) in dry solvent (2 mL) was cooled to the respective
temperature (see Tables 1 and 2) under argon. It was then trans-
tical to those of 6, except for 1H NMR (400.13 MHz, CDCl3):
d 3.68
(br s, J(117/119Sn)¼14.1 Hz, 1H, CHD) and 13C NMR (100.61 MHz,
CDCl3):
d
60.7 (t, J¼21.4 Hz, CHD).
metalated with nBuLi (144 mL, 2.5 M solution in hexane, 0.36 mmol)
4.2.2. Tributylstannylmethyl-tetrahydropyranyl ether (8) and (S)-
[D1]8. A mixture of (333 mg, 1.04 mmol), DHP (174 mg,
and quenched after various periods of time with benzaldehyde
(0.30 mL, 2 M solution in dry THF, 0.6 mmol). After stirring at bath
temperature for 30 min, a saturated solution of NaHCO3 (2 mL) was
added, the organic phase separated and the aqueous one extracted
with Et2O. The combined organic layers were dried (MgSO4), con-
centrated under reduced pressure and immediately deprotected.
Therefore, Amberlyst H-15 (100 mg) and MeOH (2 mL) were added
and the mixture stirred for 3 h at rt. Afterwards, the catalyst was
filtered off, the filtrate concentrated and the residue purified by
flash chromatography (hexane/EtOAc 1:2) to yield diol 13.
5
2.07 mmol) and Amberlyst H-15 (210 mg) in hexane (6 mL) was
stirred for 3.5 h at rt. Then the catalyst was removed via filtration.
The reaction mixture was concentrated under reduced pressure
and purified by flash chromatography (hexane/CH2Cl2 2:1, Rf 0.24)
to yield 8 as a colourless oil (382 mg, 91%). IR (Si): nmax 2955, 2925,
2871, 2852, 1465, 1052, 1021 cmꢀ1 1H NMR (400.13 MHz, CDCl3):
;
d
4.37 (t, J¼3.0 Hz, 1H, OCHO), 3.97 (d [AB-sys.], J¼10.6 Hz, J(117/
119Sn)¼15.2 Hz, 1H, OCH2Sn), 3.78 (ddd, J¼11.5, 8.8, 2.9 Hz, 1H,
OCH2), 3.57 (d [AB-sys.], J¼10.6 Hz, J(117/119Sn)¼15.2 Hz, 1H,
OCH2Sn), 3.51–3.44 (m, 1H, OCH2), 1.81–1.71 (m, 1H, CH2), 1.69–1.40
(m, 5H, 3CH2), 1.54–1.44 (m, 6H, 3SnCH2CH2), 1.29 (sext, J¼7.3 Hz,
6H, 3Sn(CH2)2CH2), 0.92–0.86 (m, 6H, 3SnCH2), 0.86 (t, J¼7.3 Hz,
In one instance the intermediate product 12 was purified by
flash chromatography (hexane/EtOAc 3:1, Rf 0.30) for analytical
purposes and to determine the yield of deprotection (quantitative).
NMR data revealed the existence of two diastereomers in a ratio of
2:1 (A/B). 12: IR (Si): nmax 3441, 3030, 2942, 2869, 1137, 1123,
9H, 3Sn(CH2)3CH3); 13C NMR (100.61 MHz, CDCl3):
d
101.4 (J(117/
119Sn)¼37.5 Hz), 61.6, 57.5 (J(117/119Sn)¼368.7, 351.8 Hz), 30.7, 29.1
(3C, J(117/119Sn)¼20.7 Hz), 27.3 (3C, J(117/119Sn)¼51.3 Hz), 25.6, 19.3,
13.7 (3C), 9.1 (3C, J(117/119Sn)¼322.8, 309.0 Hz). Compound (S)-
[D1]8: The spectroscopic data were identical to those of 8, except for
1031 cmꢀ1 1H NMR (400.13 MHz, CDCl3):
; d 7.40–7.23 (m, 5Harom),
4.91–4.85 (m [X-part of ABX-sys.], 1H, OCHPh), 4.605 (t, J¼4.8 Hz,
1H, OCHO, dia. A), 4.598 (t, J¼4.8 Hz, 1H, OCHO, dia. B), 3.95–3.80
(m, 2H, OCH2, OH dia. B), 3.89 (dd [AB-part of ABX-sys.], J¼10.4,
3.0 Hz, 1H, OCH2, dia. A), 3.81 (dd [AB-part of ABX-sys.], J¼11.4,
3.0 Hz, 1H, OCH2, dia. B), 3.64 (dd [AB-part of ABX-sys.], J¼11.4,
9.1 Hz, 1H, OCH2, dia. B), 3.55–3.47 (m, 1H, OCH2), 3.51 (dd [AB-part
of ABX-sys.], J¼10.4, 8.6 Hz, 1H, OCH2, dia. A), 3.05 (d, J¼2.5 Hz, 1H,
OH, dia. A), 1.89–1.72 (m, 2H, CH2), 1.66–1.49 (m, 4H, 2CH2);
1H NMR (400.13 MHz, CDCl3):
d
3.95 (br s, J(117/119Sn)¼14.9 Hz, 1H,
OCHD, dia. A), 3.55 (br s, J(117/119Sn)¼14.9 Hz, 1H, OCHD, dia. B) and
13C NMR (100.61 MHz, CDCl3):
d
57.2 (t, J¼21.4 Hz, OCHD).
4.2.3. 2-Hydroxy-2-phenylethyl para-methoxybenzyl ether (10) and
(1R)-[1-D1]10. Tributylstannylmethyl para-methoxybenzyl ether
(6) (150 mg, 0.34 mmol) dissolved in dry THF (2 mL) was cooled to
the respective bath temperature (see Tables 1 and 2) under argon
atmosphere. nBuLi (0.26 mL, 1.6 M solution in hexane, 0.41 mmol)
Diastereomer A: 13C NMR (100.61 MHz, CDCl3):
127.7, 126.2 (2C), 100.0, 73.8, 73.0, 63.0, 30.60, 25.3, 19.8;
Diastereomer B: 13C NMR (100.61 MHz, CDCl3):
140.3, 128.3 (2C),
127.6, 126.2 (2C), 100.3, 75.7, 73.8, 63.5, 30.8, 25.1, 20.1.
d 140.4, 128.3 (2C),
d

596
D.C. Kapeller, F. Hammerschmidt / Tetrahedron 66 (2010) 591–598
4.2.6. 2-Methyl-5-methoxyphenyl-[D1]methanol {(S)-[1-D1]14}. Com-
pound (S)-[1-D1]14 was isolated in less than 10% yield when
performing the transmetalation of (S)-[D1]8 and quenching of
(R)-[D1]11 at temperatures of ꢀ50 ꢁC or above. It could only be
partly separated from (1R)-[1-D1]10, as the two had virtually the
(dd, J¼11.6, 3.2 Hz, 1H, H-6a), 4.52 (d, [AB-sys.], J¼11.6 Hz, 2H,
OCH2Ph), 4.37 (dd, J¼11.6, 6.8 Hz, 1H, H-6b), 4.30–4.22 (m, 1H, H-5),
4.13 (dd, J¼7.8, 3.3 Hz, 1H, H-4), 4.09 (d, J¼3.3 Hz, 1H, H-3), 2.87
(sept, J¼6.8 Hz, 1H, CH(CH3)2), 2.84 (sept, J¼6.8 Hz, 2H, 2CH(CH3)2),
2.46 (d, J¼5.3 Hz, 1H, OH), 1.44 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.224
(d, J¼6.8 Hz, 6H, CH(CH3)2), 1.219 (d, J¼6.8 Hz, 6H, CH(CH3)2), 1.208
same Rf value. 1H NMR (250.13 MHz, CDCl3):
d
7.06 (d, J¼8.3 Hz,
1Harom), 6.94 (d, J¼2.8 Hz, 1Harom), 6.73 (dd, J¼8.3, 2.8 Hz, 1Harom),
4.64 (br s, 1H, CHD), 3.78 (s, 3H, OCH3), 2.25 (s, 3H, PhCH3); OH not
determined.
(d, J¼6.8 Hz, 6H, CH(CH3)2); 13C NMR (100.61 MHz, CDCl3):
d 171.0,
150.3, 144.7 (2C), 137.1, 130.2, 128.7 (2C), 128.2, 127.9 (2C), 120.9
(2C),111.9,105.3, 82.1, 82.0, 79.7, 72.3, 67.8, 67.1, 34.4, 31.5 (2C), 26.8,
26.2, 24.2 (4C), 23.9 (2C). Assignment was assisted by 2D spectra.
Anal. Calcd for C32H44O7: C, 71.08; H, 8.20. Found: C, 71.09; H, 8.07.
4.2.7. (R)-Mosher ester of (1R)-[1-D1]10 and (S)-[D1]14. A 1:1
mixture of (1R)-[1-D1]10 and (S)-[D1]14 (0.05þ0.05 mmol), dry
pyridine (0.25 mL) and (S)-MTPACl (300
mL, 0.5 M solution in dry
4.2.10. 5-O-Benzoyl-3-O-benzyl-1,2-O-isopropylidene-6-O-(2,4,6-tri-
CH2Cl2, 0.15 mmol) in dry CH2Cl2 (2 mL) were stirred over night at
rt. Afterwards, CH2Cl2 (10 mL) and 1 M HCl (10 mL) were added, the
organic layer was separated, washed with a saturated solution of
NaHCO3 and dried (MgSO4). The solvent was removed under re-
duced pressure. The residue was purified by flash chromatography
(hexane/EtOAc 10:1), giving the (R)-Mosher esters of (1R)-[1-D1]10
(Rf 0.15) in 74% and of (S)-[D1]14 (Rf 0.23) in 83% yield as oils.
Compound (1R)-[1-D1]10 MTPA-(R): 1H NMR (250.13 MHz, CDCl3):
isopropylbenzoyl)-a-L-idofuranose (20). A solution of 16 (243 mg,
0.45 mmol), Ph3P (152 mg, 0.58 mmol), benzoic acid (71 mg,
0.58 mmol) and DIAD (117 mg, 0.58 mmol) in dry toluene (4 mL)
was stirred over night under argon at 100 ꢁC. A drop of water was
added and the solvent removed under reduced pressure. The crude
mixture, which still contained some starting material, was then
flash chromatographed (hexane/EtOAc 7:1, Rf 0.37) to yield 20
(84 mg, 29%) as homogenous glassy product. This procedure was
not optimised. Furthermore some product was lost during chro-
matography, as it had almost the same Rf value as the starting
material. IR (Si): nmax 2963, 2931, 1728, 1269, 1248, 1106, 1073,
d
7.47 (d, J¼7.8 Hz, 2Harom), 7.33–7.03 (m, 10Harom), 6.83–6.78 (m,
2Harom), 6.25 (d, J¼3.3 Hz, 1H, OCHPh) and 6.19 (d, J¼9.3 Hz, 1H,
OCHPh), 4.49 and 4.40 (br s, 2H, OCH2Ph), 3.79 and 3.78 (s, 3H,
PhOCH3), 3.76 (br d, J¼9.3 Hz, 1H CHD) and 3.60 (br d, J¼3.3 Hz, 1H,
CHD), 3.55 (q, J¼1.0 Hz, 3H, OCH3) and 3.44 (q, J¼1.0 Hz, OCH3). Two
diastereomers, determination of ee impossible! Compound (S)-[1-
1026 cmꢀ1; 1H NMR (400.13 MHz, CDCl3):
d 8.02–7.97 (m, 2Harom),
7.53–7.48 (m, 1Harom), 7.40–7.30 (m, 7Harom), 6.95 (s, 2Harom), 5.96
(d, J¼3.8 Hz, 1H, H-1), 5.73 (ddd [X-part of ABX-sys.], J¼8.3, 4.3,
2.8 Hz, 1H, H-5), 4.66 (dd [AB-part of ABX-sys.], J¼12.5, 2.8 Hz, 1H,
H-6a), 4.65 (d, J¼3.8 Hz, 1H, H-2), 4.73 (d [AB-sys.], J¼11.6 Hz, 1H,
OCH2Ph), 4.54 (dd, J¼8.3, 3.5 Hz, 1H, 4-H), 4.50 (d [AB-sys.],
J¼11.6 Hz, 1H, OCH2Ph), 4.39 (dd [AB-part of ABX-sys.], J¼12.5,
4.3 Hz, 1H, H-6b), 4.01 (d, J¼3.5 Hz, 1H, H-3), 2.85 (sept, J¼6.8 Hz,
1H, CH(CH3)2), 2.70 (sept, J¼6.8 Hz, 2H, 2CH(CH3)2), 1.43 (s, 3H,
CH3), 1.29 (s, 3H, CH3), 1.21 (d, J¼6.8 Hz, 6H, CH(CH3)2), 1.14 (d,
J¼6.8 Hz, 6H, CH(CH3)2), 1.11 (d, J¼6.8 Hz, 6H, CH(CH3)2); 13C NMR
D1]14 MTPA-(R): 1H NMR (400.13 MHz, CDCl3):
d 7.43 (br d,
J¼6.8 Hz, 2Harom), 7.40–7.30 (m, 3Harom), 7.05 (d, J¼8.3 Hz, 1Harom),
6.85 (d, J¼2.5 Hz, 1Harom), 6.77 (dd, J¼2.5, 8.3 Hz, 1Harom), 5.29 (br s,
1H, CHD), 3.72 (s, 3H, PhOCH3), 3.51 (br s, 3H, OCH3), 2.18 (s, 3H,
ArCH3); ee at least 95%.
4.2.8. 3-O-Benzyl-1,2-O-isopropylidene-
solution of 3-O-benzyl-1,2:5,6-di-O-isopropylidene-
a
-
D
-glucofuranose (19). A
-glucofur-
a-D
anose8 (700 mg, 2.0 mmol) in 85% acetic acid was stirred for one
day at ambient temperature, before the solvent was removed on
a rotary evaporator. The crude product was purified by flash chro-
matography (hexane/EtOAc 1:2, Rf 0.30) to give diol 19 (629 mg,
99%) as a colourless syrup. IR (Si): nmax 3450, 3032, 2986,1375,1216,
(100.61 MHz, CDCl3): d 170.5, 165.7, 150.2, 144.8 (2C), 136.5, 133.0,
130.0 (2C), 129.9 (2C), 128.7 (2C), 128.3, 128.2 (2C), 128.2 (2C), 120.8
(2C), 111.8, 105.1, 81.8, 81.3, 78.5, 71.7, 71.1, 63.2, 34.4, 31.5 (2C), 26.8,
26.2, 24.14 (2C), 24.07 (2C), 23.9 (2C).
1077, 1020 cmꢀ1
;
1H NMR (400.13 MHz, CDCl3):
d
7.37–7.27 (m,
4.2.11. 3-O-Benzyl-1,2-O-isopropylidene-6-O-(2,4,6-triisopro-
5Harom), 5.91 (d, J¼3.8 Hz, 1H, H-1), 4.71 (d [AB-sys.], 11.6 Hz, 1H,
OCH2Ph), 4.60 (d, J¼3.8 Hz, 1H, H-2), 4.53 (d [AB-sys.], 11.6 Hz, 1H,
OCH2Ph), 4.10 (dd, J¼7.8, 3.3 Hz, 1H, H-4), 4.08 (d, J¼3.3 Hz, 1H, H-
3), 4.00 (ddd, J¼7.8, 5.6, 3.5 Hz,1H, H-5), 3.79 (dd, J¼11.6, 3.5 Hz,1H,
H-6a), 3.66 (dd, J¼11.6, 5.6 Hz, 1H, H-6b), 2.59 (br s, 1H, OH), 2.28
(br s, 1H, OH), 1.46 (s, 3H, CH3), 1.30 (s, 3H, CH3); 13C NMR
pylbenzoyl)-a-L-idofuranose (17). To a solution of 20 (80 mg,
0.124 mmol) in dry THF (2 mL) was added Superhydride (0.5 mL,
1 M solution in THF, 0.5 mmol) at ꢀ40 ꢁC under argon. After stirring
for 1 h and allowing the temperature in the cooling bath to rise
continuously to ꢀ20 ꢁC, the reaction was quenched with acetone
(0.5 mL) and water (3 mL). The organic phase was separated, and
the aqueous one extracted with Et2O (3ꢂ4 mL). The combined or-
ganic layers were washed with water, dried (MgSO4) and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography (hexane/EtOAc 5:1; TLC: hexane/EtOAc 2:1,
(100.61 MHz, CDCl3):
d 137.2, 128.7 (2C), 128.2, 127.8 (2C), 111.8,
105.1, 82.1, 82.0, 79.8, 72.1, 69.3, 64.4, 26.7, 26.2.
4.2.9. 3-O-Benzyl-1,2-O-isopropylidene-6-O-(2,4,6-triisopropyl-
benzoyl)-
a
-
D
-glucofuranose (16). A solution of diol 19 (250 mg,
Rf 0.44) to yield protected L-idofuranose 17 (50 mg, 75%) as col-
0.8 mmol) and 2,4,6-triisopropylbenzoyl chloride (235 mg,
0.88 mmol) in dry pyridine (2.5 mL) was stirred for 8 h at 90 ꢁC.
Pyridine was then removed under reduced pressure, the residue
dissolved in 1 M HCl (4 mL) and extracted with EtOAc (3ꢂ5 mL).
The combined organic layers were dried (MgSO4), concentrated
under reduced pressure and purified by flash chromatography
(hexane/EtOAc 7:1, Rf 0.26) to give 2,4,6-triisopropylbenzoate 16
(280 mg, 65%) as a colourless foam. Furthermore, the bis(2,4,6-
ourless crystals, which were recrystallised from hexane. Mp 111 ꢁC
20
(hexane); [
a]
ꢀ37.5 (c 0.97, acetone); IR (Si): nmax 3510, 2963,
D
2932, 2871, 1727, 1457, 1383, 1252, 1076 cmꢀ1
;
1H NMR
(400.13 MHz, CDCl3): 7.37–7.27 (m, 5Harom), 6.98 (s, 2Harom), 5.99
d
(d, J¼3.8 Hz, 1H, H-1), 4.72 (d [AB-sys.], J¼11.9 Hz, 1H, OCH2Ph),
4.64 (d, J¼3.8 Hz, 1H, H-2), 4.49 (d [AB-sys.], J¼11.9 Hz, 1H,
OCH2Ph), 4.38 (dd, J¼11.2, 3.9 Hz, 1H, H-6a), 4.31 (dd, J¼11.2, 5.7 Hz,
1H, H-6b), 4.27–4.21 (m, 1H, 5-H), 4.24 (d, J¼3.2 Hz, 1H, H-4), 4.00
(d, J¼3.2 Hz, 1H, H-3), 2.93 (d, J¼1.8 Hz, 1H, OH), 2.87 (sept,
J¼6.8 Hz, 2H, 2CH(CH3)2), 2.86 (sept, J¼6.8 Hz, 1H, CH(CH3)2), 1.43
(s, 3H, CH3), 1.31 (s, 3H, CH3), 1.22 (d, J¼6.8 Hz, 6H, CH(CH3)2), 1.21
(d, J¼6.8 Hz, 6H, CH(CH3)2), 1.20 (d, J¼6.8 Hz, 6H, CH(CH3)2); 13C
triisopropylbenzoylated) compound was isolated in 10% yield
(65 mg). This procedure was not optimised. Compound 16: [a]
D
20
ꢀ18.3 (c 1.38, acetone); IR (Si): nmax 3505, 2962, 2932, 1727, 1252,
1218, 1139, 1077 cmꢀ1 1H NMR (400.13 MHz, CDCl3):
;
d
7.36–7.25
(m, 5Harom), 6.99 (s, 2Harom), 5.93 (d, J¼3.8 Hz, 1H, H-1), 4.52 (d,
NMR (100.61 MHz, CDCl3):
d 170.7, 150.2, 144.9 (2C), 136.5, 130.2,
[AB-sys.], J¼11.6 Hz, 2H, OCH2Ph), 4.60 (d, J¼3.5 Hz, 1H, H-2), 4.55
128.7 (2C), 128.4, 128.0 (2C), 120.8 (2C), 112.0,105.0, 82.8, 82.3, 79.6,

D.C. Kapeller, F. Hammerschmidt / Tetrahedron 66 (2010) 591–598
597
72.0, 68.7, 65.5, 34.4, 31.5 (2C), 26.8, 26.3, 24.2 (2C), 24.1 (2C), 23.93
(2C). Anal. Calcd for C32H44O7: C, 71.08; H, 8.20. Found: C, 71.05; H,
8.16.
3.54–3.45 (m, 1H, OCH2-THP), 3.25 (br d, J¼3.0 Hz, 1H, OH, minor
dia.), 3.20 (br d, J¼3.0 Hz, 1H, OH, major dia.), 1.84–1.69 (m, 2H,
CH2-THP), 1.63–1.43 (m, 4H, 2CH2-THP),1.46 (s, 3H, CH3, major dia.),
1.45 (s, 3H, CH3, minor dia.), 1.29 (s, 3H, CH3, major dia.), 1.28 (s, 3H,
4.2.12. 3-O-Benzyl-1,2-O-isopropylidene-
a-L
-idofuranose (21). A so-
CH3, minor dia.); 13C NMR (100.61 MHz, CDCl3): Major Dia.:
d 137.6,
lution of 17 (37 mg, 0.068 mmol) and LiAlH4 (10 mg, 0.27 mmol) in
dry THF (1.5 mL) was stirred for 2 h at 70 ꢁC. The reaction was
quenched with acetone (1 mL) followed by water (2 mL). Tartaric
acid was added to dissolve the resulting precipitate, the organic
phase was separated and the aqueous one extracted with EtOAc
(3ꢂ3 mL). The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. The crude product was pu-
rified by flash chromatography (hexane/EtOAc 1:2, Rf 0.27) to give
diol 21 (16 mg, 76%) as a colourless syrup. IR (Si): nmax 3460, 2930,
128.4 (2C), 127.8, 127.7 (2C), 111.7, 105.1, 100.5, 82.4, 81.9, 79.8, 72.4,
70.8, 67.7, 63.4, 30.7, 26.8, 26.3, 25.2 (1C, CH2-THP), 20.14 (1C, CH2-
THP); Minor Dia.: 13C NMR (100.61 MHz, CDCl3):
d 137.6, 128.4 (2C),
127.8, 127.7 (2C), 111.6, 105.1, 99.6, 82.4, 81.9, 79.9, 72.4, 70.9, 67.9,
62.7, 30.6, 26.7, 26.3, 25.2, 19.7.
4.2.14.2. (6R)-[6-D1]22. Two inseparable diastereomers (1:1);
the spectroscopic data were identical to those of 22, except for 1H
NMR (400.13 MHz, CDCl3):
d
3.87 (d, J¼2.8 Hz, 1H, CHD) and 3.81
1374, 1218, 1166, 1072, 1028 cmꢀ1 1H NMR (400.13 MHz, CDCl3):
;
(br s, 1H, CHD), 3.22 (br s, 1H, OH) and 13C NMR (100.61 MHz,
d
7.38–7.26 (m, 5Harom), 5.97 (d, J¼3.8 Hz,1H, H-1), 4.71 (d [AB-sys.],
CDCl3):
CHD).
d
70.6 (t, J¼22.2 Hz, 1C, CHD) and 70.5 (t, J¼21.8 Hz, 1C,
J¼11.9 Hz,1H, OCH2Ph), 4.64 (d, J¼3.8 Hz,1H, H-2), 4.46 (d [AB-sys.],
J¼11.9 Hz, 1H, OCH2Ph), 4.19 (dd, J¼5.1, 3.5 Hz, 1H, H-4), 4.05 (dt,
J¼5.1, 4.6 Hz,1H, H-5), 4.00 (d, J¼3.5 Hz,1H, H-3), 3.68–3.54 (m, 2H,
H-6), 3.02 (br s, 1H, OH), 2.14 (br s, 1H, OH), 1.46 (s, 3H, CH3), 1.31 (s,
4.2.14.3. Compound 23. Two inseparable diastereomers (4:3);
IR (Si): nmax 3497, 2936, 2873, 1124, 1075, 1031 cmꢀ1 1H NMR
(400.13 MHz, CDCl3): 7.36–7.26 (m, 5Harom), 5.976 and 5.971 (d,
;
3H, CH3); 13C NMR (100.61 MHz, CDCl3):
d
136.6, 128.7 (2C), 128.4,
d
127.9 (2C), 112.0, 104.9, 82.9, 82.2, 79.7, 71.9, 70.4, 63.6, 26.8, 26.3.
Similarly, the gluco-type 16 (85 mg, 0.16 mmol) gave 19 in 83%
(41 mg) after flash chromatography (hexane/EtOAc 1:2, Rf 0.30).
J¼3.8 Hz, 1H, H-1), 4.698 and 4.693 (d [AB-sys.], J¼11.6 Hz, 1H,
OCH2Ph), 4.63 (d, J¼3.8 Hz, 1H, H-2), 4.57–4.52 (m, 1H, CHacetate),
4.48 (d [AB-sys.], J¼11.6 Hz,1H, OCH2Ph), 4.26 (dd, J¼5.3, 3.5 Hz,1H,
H-4, minor dia.) and 4.22 (dd, J¼5.3, 3.5 Hz, 1H, H-4, major dia.),
4.18–4.11 (m, 1H, H-5), 4.00 (br s, 1H, H-3), 3.88–3.70 (m, 2H, OCH2-
THP, H-6a), 3.56–3.40 (m, 2H, H-6b, OCH2-THP), 3.21 (br d,
J¼3.0 Hz, 1H, OH, major dia.), 3.08 (br d, J¼3.0 Hz, 1H, OH, minor
dia.), 1.83–1.38 (m, 6H, 3CH2-THP), 1.46 (s, 3H, CH3), 1.31 (s, 3H,
4.2.13. 3-O-Benzyl-1,2-O-isopropylidene-6-O-(2,4,6-triisopro-
pylbenzoyl)-a-D-glucofuranose (16). To a solution of tributyl-
stannylmethyl 2,4,6-triisopropylbenzoate7e (250 mg, 0.45 mmol) in
dry THF (2 mL) under argon was added nBuLi (0.34 mL, 1.6 M so-
lution in hexane, 0.54 mmol) at ꢀ78 ꢁC; 5 min later the reaction
was quenched with 2 (150 mg, 0.54 mmol, in 0.5 mL of THF) and
kept for further 30 min at bath temperature. Afterwards, a satu-
rated solution of NaHCO3 (2 mL) was added, the organic phase
separated and the aqueous one extracted with Et2O (3ꢂ3 mL). The
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (hexane/EtOAc 7:1) to yield the product as a col-
ourless syrup (75 mg, 31%). 1H NMR analysis of the crude product
revealed a ratio of 4:1 for 16/17.
CH3); 13C NMR (100.61 MHz, CDCl3): Major Dia.:
d 136.8, 128.6 (2C),
128.2, 127.8 (2C), 111.8, 104.9, 99.3, 83.2, 82.2, 79.8, 71.8, 69.4, 68.9,
62.3, 30.5, 26.8, 26.4, 25.3, 19.5; Minor Dia.: 136.9, 128.6 (2C), 128.2,
127.8 (2C), 111.8, 104.9, 99.4, 83.0, 82.3, 79.6, 71.9, 69.3, 68.5, 62.5,
30.5, 26.8, 26.4, 25.3, 19.6.
4.2.14.4. (6R)-[6-D1]23. Two inseparable diastereomers (3:2).
The spectroscopic data were identical to those of 23, except for 1H
NMR (400.13 MHz, CDCl3):
d
4.13 (t, J¼5.3 Hz 1H, H-5), 3.71 (d,
J¼5.3 Hz, 1H, CHD) and 3.48 (d, J¼5.8 Hz, 1H, CHD) and 13C NMR
(100.61 MHz, CDCl3):
d
68.5 (t, J¼22.2 Hz, 1C, CHD), 68.2 (t,
4.2.14. 3-O-Benzyl-1,2-O-isopropylidene-6-O-tetrahydropyranyl-
-glucofuranose (22) and (6R)-[6-D1]22 and 3-O-benzyl-1,2-O-iso-
propylidene-6-O-tetrahydropyranyl- -idofuranose (23) and
a
-
J¼21.4 Hz, 1C, CHD).
D
a-L
4.2.15. 3-O-Benzyl-1,2-O-isopropylidene-
a-
D-glucofuranose (19) and
(6R)-[6-D1]23. A solution of tributylstannylmethyl tetrahydro-
pyranyl ether (8, 122 mg, 0.30 mmol) in dry THF (1.5 mL) was
treated with nBuLi (0.23 mL, 1.6 M solution in hexane, 0.36 mmol)
at ꢀ78 ꢁC under argon; 5 min later the reaction was quenched with
aldehyde 2 (100 mg, 0.36 mmol) and stirred for further 30 min at
bath temperature. Afterwards, a saturated solution of NaHCO3
(2 mL) was added, the organic phase separated and the aqueous
one extracted with Et2O. The combined organic layers were dried
(MgSO4), concentrated under reduced pressure and purified by
flash chromatography (hexane/EtOAc 3:1; TLC: hexane/EtOAc 1:1,
(6R)-[6-D1]19dcleavage of the PMB ether. A solution of
D
-glucose
derivative 22 (65 mg, 0.16 mmol) in MeOH (1 mL) and Amberlyst H-
15 (50 mg) was stirred for 3 h at rt. The catalyst was filtered off, the
mixture concentrated under reduced pressure and purified by flash
chromatography (hexane/EtOAc 1:1, Rf 0.15) to give 80% (40 mg) of
diol 19. Compound (6R)-[6-D1]19: The spectroscopic data were
identical to those of 19, except for 1H NMR (400.13 MHz, CDCl3):
d
4.00 (dd, J¼7.6, 3.5 Hz, 1H, H-5), 3.77 (d, J¼3.5 Hz, 1H, CHD) and
13C NMR (100.61 MHz, CDCl3):
d
64.0 (t, J¼21.8 Hz, 1C, CHD).
Rf 0.64) to give the protected
D-glucose 22 (65 mg, 55%) and the
4.2.16. 3-O-Benzyl-1,2-O-isopropylidene-a-L-idofuranose (21) and
protected -idose 23 (15 mg, 13%, Rf 0.38) as colourless oils. Starting
L
(6R)-[6-D1]21dcleavage of the PMB ether. Idose derivative 23
L
from (S)-[D1]8, 43% of (6R)-[6-D1]22 and 12% of (6R)-[6-D1]23 were
isolated.
(15 mg, 0.04 mmol) was converted to 21 (10 mg, 83%, hexane/EtOAc
1:2, Rf 0.23) in analogy to 19 above. (6R)-[6-D1]21: The spectro-
scopic data were identical to those of 21, except for 1H NMR
4.2.14.1. Compound 22. Two inseparable diastereomers (11:9);
(400.13 MHz, CDCl3):
d
3.57 (d, J¼5.8 Hz, 1H, CHD) and 13C NMR
63.3 (t, J¼22.2 Hz, 1C, CHD).
IR (Si): nmax 3451, 3031, 2938, 2869, 1076, 1024 cmꢀ1
;
1H NMR
(100.61 MHz, CDCl3): d
(400.13 MHz, CDCl3):
d
7.35–7.24 (m, 5Harom), 5.89 (d, J¼3.5 Hz, 1H,
H-1), 4.66 (AB-sys., JAB¼11.6 Hz, 2H, OCH2Ph), 4.59–4.51 (m, 2H, H-
2, CHacetate), 4.18–4.02 (m, 3H, H-3, H-4, H-5), 3.95–3.81 (m, 1H,
OCH2-THP), 3.89 (dd [AB-part of ABX-sys.], J¼11.1, 3.0 Hz, 1H, H-6a,
major dia.), 3.83 (dd [AB-part of ABX-sys.], J¼11.1, 2.3 Hz, 1H, H-6a,
minor dia.), 3.75 (dd [AB-part of ABX-sys.], J¼11.1, 5.1 Hz, 1H, H-6b),
Acknowledgements
This work was supported by Grant No. P19869-N19 from the
FWF. We thank Dr. Lothar Brecker for his help with the NMR

598
D.C. Kapeller, F. Hammerschmidt / Tetrahedron 66 (2010) 591–598
15, 5729–5739; (e) Kapeller, D. C.; Hammerschmidt, F. J. Org. Chem. 2009, 74,
2380–2388.
measurements. D.K. is grateful to the Austrian Academy of Sciences
for a DOC-FFORTE scholarship.
8. (a) Mehltretter, C. L.; Alexander, B. H.; Mellies, R. L.; Rist, C. E. J. Am. Chem. Soc.
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