Acetonation of l-pentoses and 6-deoxy-l-hexoses under kinetic control using heterogeneous acid catalysts

Article abstract of DOI:10.1016/j.carres.2010.05.002

The fibrous polymer-supported sulfonic acid catalyst Smopex-101 H⁺ proved to be an efficient catalyst for the preparation of O-isopropylidene derivatives from a series of rare sugars. Acetonation of the reducing sugars l-arabinose, l-ribose, l-xylose, l-fucose, and l-rhamnose in N,N-dimethylformamide by 2,2-dimethoxypropane or 2-methoxypropene led to the formation of the kinetically favored di-O- and/or mono-O-isopropylidene derivatives in 46-88% yields. The method consists of a simple experimental procedure which does not require predried solvents or reagents. The catalyst is easily recovered and can be regenerated making the procedure economically viable even for large-scale synthesis.

Full text of DOI:10.1016/j.carres.2010.05.002

Carbohydrate Research 345 (2010) 1548–1554
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Acetonation of L-pentoses and 6-deoxy-L-hexoses under kinetic control
using heterogeneous acid catalysts
*
Jonas J. Forsman, Reko Leino
Laboratory of Organic Chemistry, Åbo Akademi University, FI-20500 Åbo, Finland
a r t i c l e i n f o
a b s t r a c t
The fibrous polymer-supported sulfonic acid catalyst Smopex-101 H+ proved to be an efficient catalyst for
the preparation of O-isopropylidene derivatives from a series of rare sugars. Acetonation of the reducing
sugars L-arabinose, L-ribose, L-xylose, L-fucose, and L-rhamnose in N,N-dimethylformamide by 2,2-dime-
thoxypropane or 2-methoxypropene led to the formation of the kinetically favored di-O- and/or mono-O-
isopropylidene derivatives in 46–88% yields. The method consists of a simple experimental procedure
which does not require predried solvents or reagents. The catalyst is easily recovered and can be regen-
erated making the procedure economically viable even for large-scale synthesis.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 28 April 2010
Accepted 6 May 2010
Available online 12 May 2010
Keywords:
L-Carbohydrates
Isopropylidene acetals
Heterogeneous catalysis
Kinetic control
Acetonation
1. Introduction
or 2-methoxypropene (MP) in combination with acid catalyst,
often p-toluenesulfonic acid. In general, a better kinetic control is
The condensation of acetone with aldoses, aldosides, and
ketoses to form the corresponding O-isopropylidene derivatives
is a widely employed reaction in carbohydrate chemistry.1 The
conventional method consists of the condensation of a 1,2- or
1,3-diol with acetone in the presence of a catalyst under anhydrous
reaction conditions. Several catalysts have been used for this pur-
pose, including mineral acids, anhydrous zinc chloride together
with phosphoric acid, anhydrous copper(II) sulfate, iodine, anhy-
drous ferric chloride, boron trifluoride etherate, and anhydrous
aluminum chloride.2 Recently, Khan and Khan reported on the
acetonation of carbohydrates using bromodimethylsulfonium bro-
mide, generating HBr in situ, as catalyst.3 The major products
formed in these reactions are generally the thermodynamically
more stable ones, except when anhydrous copper(II) sulfate is
used. In this case, some kinetic control is introduced. Thus, acetone
normally reacts with vicinal 1,2-hydroxyl groups which are
positioned in a cis-arrangement on the sugar ring to give five-
membered 1,3-dioxolanes. In the cases where two 1,2-acetonides
are possible, the thermodynamically more favored one usually pre-
vails. Secondary alcohols have a greater tendency to form cyclic
acetals than the primary ones, but an acetonide from a primary
alcohol is generally preferred over an acetonide from vicinal trans
secondary alcohols. Isopropylidene acetals are also commonly
formed under kinetic conditions by transacetalization reaction in
dimethyl formamide solution using 2,2-dimethoxypropane (DMP)
obtained using successively acetone, or DMP, or MP. Under kinetic
conditions, the initial bond is formed from the least hindered (pri-
mary) oxygen atom of the carbohydrate, if available. Among the
secondary hydroxyl groups, the 2-OH is often the most reactive
one if the anomeric hydroxyl group is overlooked. Generally, the
equatorial secondary hydroxyl groups are more reactive than the
axial ones.
Previously, some approaches to acetalization of alcohols in the
presence of heterogeneous acid catalysts have been described.
Lorette et al. prepared a series of ketone acetals from linear pri-
mary alcohols by use of acidic Dowex 50 ion exchange resin as a
catalyst.4 Meakins and co-workers have reported the acetalization
of steroidal compounds with ethylene glycol in the presence of
Amberlite IR 120-H ion exchange resin.5 Yet, in another report, eth-
ylene acetals of an unhindered steroid, triterpene, and other ke-
tones were prepared by running a mixture of the ketone and
ethylene glycol in a suitable solvent through an acidic Amberlyst
15 ion-exchange column.6 Roelofsen et al. have described a meth-
odology for the high yield preparation of acetals from the corre-
sponding aldehydes or ketones and alcohols by use of catalytic
dual-function proton-exchange molecular sieves of the Zeolon
500, AW 500, or mordenite types.7 Likewise, the acetonation of
L
-sorbose in the presence of various macroporous cationic ion
exchange resins of the Amberlyst and Indion types to form
2,3:4,6-di-O-isopropylidene
-sorbose has been reported.8 Only a
L
few examples related to the acetonation of carbohydrates by use
of solid-supported catalysts have been published. Cai and co-
workers reacted various carbohydrates with acetone in the
* Corresponding author. Tel.: +358 2 2154132; fax: +358 2 2154866.
E-mail address: reko.leino@abo.fi (R. Leino).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.05.002

J. J. Forsman, R. Leino / Carbohydrate Research 345 (2010) 1548–1554
1549
presence of molecular sieves.9 The catalyst employed was, how-
ever, conventional homogeneous p-toluenesulfonic acid and the
reaction proceeded in the liquid phase. The function of the solid
additive was limited to the adsorption of water formed in the ace-
tonation reaction. Nishida and Thiem observed the unexpected for-
of
L
-arabinose (1) with acetone and DMP in DMF. All three hetero-
-arabi-
geneous catalysts proved suitable for the acetonation of
L
nose on preparative scale (10 mmol). In all cases the starting
material was consumed by stirring the reaction mixture overnight.
1H NMR spectroscopic analysis of the crude products from the
reactions using DMP as acetonide-forming agent indicated the for-
mation of allyl 4,6-O-propylidene-D-galactopyranoside when
galactose was refluxed in allyl alcohol in the presence of Amberlyst
15 ion exchange resin.10 Under these conditions, allyl alcohol is
apparently isomerized to propanal which then reacts with the
4,6-hydroxyl groups of galactose to form the corresponding cyclic
acetal. Rauter et al. reported a method for the synthesis of various
O-isopropylidene carbohydrate derivatives by use of Zeolite HY as
a heterogeneous acid catalyst.11 Several monosaccharides, includ-
mation of 3,4-O-isopropylidene-L-arabinopyranose (2) in high
yields. The acid catalysts were regenerated by subsequent washing
with water, 1 M hydrochloric acid, methanol, and drying under
vacuum. For the Dowex catalyst, breakdown into a fine powder
was observed after the second reaction making further recycling
impossible. On the other hand, both the Amberlyst and Smopex
catalysts retained their morphology also after the second reaction
and subsequent filtration. Interestingly, the regenerated fibrous
Smopex-101 catalyst proved ‘faster’ than the off-the-shelve origi-
ing
D-galactose, D-glucose, D-xylose, D-ribose, L-arabinose, and
L-sorbose were reacted with acetone in the presence of zeolite to
form the corresponding mono and di-O-isopropylidene acetals.
As expected, the reactions proceeded under thermodynamic control.
nal fiber consuming all of the L-arabinose starting material within
4 h. Based on the preliminary results, the following conditions,
DMP and Smopex-101 H+ in DMF at ambient temperature, were
chosen for the present study which was expanded to also cover
For example, when
L
-arabinose was subjected to these experimen-
-arabinofuranose was
tal conditions, the 1,2-O-isopropylidene-b-
L
isolated in 37% yield, together with 24% of the corresponding
1,2:3,4-di-O-isopropylidenepyranose derivative. Another example
of acetonation of carbohydrates under heterogeneously catalyzed
reaction conditions has been reported by Asakura et al.12 They
the following sugars:
and -fucose (12). The results are summarized in Table 1.
In addition to the -sugars, presented in Table 1, the acetonation
procedure was tested on the common sugars -glucose, -galact-
ose, and -mannose for which acetonation under similar reaction
L-ribose (3), L-xylose (6), L-rhamnose (10),
L
L
D
D
treated various monosaccharides, including
D
-ribose,
L-rhamnose,
D
D
-xylose, -glucose, -mannose, and -galactose with acetone in
D
D
D
conditions using p-toluenesulfonic acid as catalyst have been re-
ported to yield the kinetically favored pyranoid 4,6-isopropylidene
acetals.22 However, in the case of these hexoses the kinetic control
was negligible, when using the solid-supported sulfonic acid cata-
lyst Smopex-101, producing complex and inseparable product
mixtures containing different mono-O- and di-O-isopropylidene
derivatives. The rate of the reaction appears considerably slower
when the heterogeneous catalyst is used as compared to the homo-
geneous catalyst, hence providing more time for subsequent
conversion of the kinetic products into the more stable thermody-
namic ones. In the present study, this problem was not encoun-
tered for the pentoses and 6-deoxyhexoses investigated, as for
these substrates the kinetic products do not contain the relatively
unstable 1,3-dioxane-type acetals and are thus not readily con-
verted to the corresponding thermodynamic products.
the presence of acidic clay catalysts such as montmorillonite K 10
to obtain the corresponding isopropylidene derivatives in good
yields. The products obtained were consistent with thermody-
namic control. Ning et al. have reported the synthesis of 1,2:5,6-
di-O-isopropylidene-a-D-galactofuranose from galactose and
acetone by use of a heterogeneous Dry Hydrogen Resin catalyst in
a solvent mixture of acetone and DMF.13 Mukhopadhyay and
co-worker recently reported the acetonation of a set of aldoses and
ketoses catalyzed by sulfuric acid immobilized on silica.14 In
addition, Isobe has reported the preparation of the 4,6-O-isopropyl-
idene derivative of methyl-a-D-glucoside by reaction of the parent
carbohydrate with DMP in DMF in the presence of Amberlyst
A-15E solid-supported acid catalyst.15 Further, Palumbo and co-
workers reported a new method for thermodynamic acetonation of
sugars using triphenylphosphine polymer-bound/iodine complex,
where the complex acts as both Lewis acid and dehydrating agent.16
Here, we describe the preparation of cyclic acetal derivatives of
some rare carbohydrates by use of the acetonating reagent DMP or
MP in DMF in the presence of the fibrous polymer-supported sul-
fonic acid catalyst Smopex-101 H+. The results are summarized
in Table 1. Such simple derivatives of rare sugars are valuable
building blocks, not only as glycosyl acceptors and donors in syn-
thetic carbohydrate chemistry but as key starting material for
enantioselective synthesis of biologically active substances includ-
ing solandelactone E17 and spicigerolide18 (Fig. 1). In comparison to
traditional polymer-supported catalysts on beads suffering from
low mechanical strength and restricted thermo-oxidative stability,
the use of a mechanically stable fibrous catalyst such as Smopex-
101 facilitates the handling during filtration and recycling of the
supported catalyst. Smopex-101 has been utilized earlier in various
heterogeneously catalyzed reactions including esterification,19
etherification,20 and acetalization.21 To our knowledge, earlier
applications of Smopex-101 in synthetic carbohydrate chemistry
have not been reported.
In a typical run, L-arabinose (1, 10 mmol) was treated with a
twofold molar excess of DMP in DMF in the presence of Smopex-
101 catalyst (200 mg, loading 2.6 mmol/g) at ambient temperature
without special precautions concerning predrying of solvents
(Scheme 1). The reaction was run overnight in order to elucidate
whether it was driven by kinetic or thermodynamic control. Simple
filtration and evaporation of the reaction mixture followed by a
quick chromatographic purification showed that the DMP was at-
tacked by the two cis-disposed secondary hydroxyl groups provid-
ing 3,4-O-isopropylidene-
very good yield (88%) as a 4:5
products were detected in the crude product mixture, consisting
of the thermodynamic product 1,2:3,4-di-O-isopropylidene-b-
arabinopyranose, typically obtained by conventional acetonation
of -arabinose with acetone/sulfuric acid, and some 1,2-O-isopro-
pylidene-b- -arabinopyranose, present as <4% contaminant in puri-
fied 2 (vide supra). Notably, we also carried out the Smopex-101-
catalyzed acetonation of -arabinose on large scale (100 g) without
L
-arabinopyranose (2) (>96% purity) in
a
/b-mixture. Only traces of side
L-
L
L
L
difficulties. The workup of the large-scale reaction was performed
using the procedure given above providing 127 g of crude product.
1H NMR spectroscopic analysis of the crude product indicated the
formation of 2 in high yield similar to the gram-scale reactions
with only trace amounts of side products. Earlier, Kiso and Hase-
gawa have shown that increasing the reaction temperature to
80 °C, in the presence of DMP and p-toluenesulfonic acid, will shift
the reaction toward formation of the thermodynamic product.23
2. Results and discussion
In our initial experiments, the commercially available solid-
supported sulfonic acid catalysts, Amberlyst 15 H+, Dowex
DR-2030 H+, and Smopex-101 H+, were screened for acetonation
They also treated D-ribose with DMP in dry DMF in the presence

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J. J. Forsman, R. Leino / Carbohydrate Research 345 (2010) 1548–1554
Table 1
Acetonation of different L-carbohydrates under kinetic control using Smopex-101 H+ as catalyst
Substrate
Product
Reaction time (h)
Reagenta
DMP
Yieldb (%)
88
O
O
23
L-Arabinose (1)
O
OH
2
OH
O
O
O
19
DMP
45
47
L-Ribose (3)
OH
HO
O
4
O
OH
OH
O
5
O
O
24.5
DMP
48
L-Xylose (6)
O
H
O
O
7
OH
O
HO
23
24
DMP
MP
82
L
-Rhamnose (10)
H3C
O
O
11
OH
OH
H3C
O
O
61 (36)c
L-Fucose (12)
O
13
O
O
O
26 (13)c
H
O
O
14
a
b
c
The reactions were carried out using 2 equiv of DMP (2,2-dimethoxypropane) or MP (2-methoxypropene) in DMF overnight.
Yield of isolated product after column chromatography.
Isolated yield from the reaction using DMP as the acetonating agent.
OH
O
DMP,
Smopex-101
O
O
H
HO
OH
OH
HO
DMF, RT, 23 h
O
O
OH
OH
O
1
2
H
OAc OAc
OH
Scheme 1.
O
O
Solandelactone E
OAc OAc
Spicigerolide
Kiso,23 together with the kinetically favored 3,4-O-isopropyli-
dene-
L
-ribopyranose (5) (Scheme 2).
-ribose favors the pyranose form in solution, it was not sur-
Figure 1. Examples of natural products, the synthesis of which utilizes isopropyl-
idene derivatives of -carbohydrates as starting material.
As
L
L
prising that DMP was initially attacked by a secondary hydroxyl
group.24 Since all three hydroxyl groups of
-ribose (C-2, C-3, and
L
of a trace of p-toluenesulfonic acid at room temperature affording
2,3-O-isopropylidene- -ribofuranose.
We next investigated the acetonation of
ditions similar to those utilized for -arabinose and catalyzed by
Smopex-101 providing a 1:1 mixture of the thermodynamically fa-
vored 2,3-O-isopropylidene- -ribofuranose (4), reported earlier by
C-4) are mutually cis, the likelihood of forming the 2,3- versus
the 3,4-acetal should be equal. However, the initially formed pyr-
anoid 2,3-acetal is expected to tautomerize to the furanose form
having the more stable bicyclo[3.3.0] ring system. The NMR spec-
troscopic analysis of pure 4, obtained by column chromatography
in 45% yield, showed that the furanoid 2,3-acetal almost
D
L
-ribose (3) under con-
L
L

J. J. Forsman, R. Leino / Carbohydrate Research 345 (2010) 1548–1554
1551
OH
O
OH
OH
DMP, DMF
OH
OH
OH
HO
O
O
HO
HO
O
3
Smopex-101
O
HO
6
O
O
+
OH
OH
OH
O
O
HO
O
O
O
O
O
O
5
O
H
HO
H
O
O
OH
O
7
Ac2O,
Pyridine
O
O
MeOD-d4
O
OH
HO
4
OAc
OAc
O
OH
O
Scheme 2. Acetonation of L-ribose with DMP and Smopex-101 in DMF.
O
O
OCD3
O
O
O
O
exclusively uptakes the b-form showing only traces of the a-fura-
8
9
noses. In the 3,4-acetal on the other hand such stabilization is ab-
sent and hence this compound retains the bicyclo[4.3.0] form. The
13C NMR chemical shifts of the acetal carbons, 110.8 ppm for com-
pound 5 and 113.1 ppm for 4, are in good agreement with those of
an acetal carbon cis-fused to a pyranoid and fused to a furanoid
ring, respectively.25 The 3,4-isopropylidene derivative 5 was iso-
lated in 47% yield being comparable to the yields reported by Gelas
and Horton (40–50%).26 However, in their study, 2-ethoxypropene
and p-toluenesulfonic acid in DMF were used requiring scrupu-
lously anhydrous conditions and temperatures below 5 °C to reach
maximum yields.
Scheme 3.
was the one initially formed in the reaction from which the methyl
hemiacetalinturn was formedduringthechromatographic purifica-
tion of the reaction mixture using benzene–methanol as eluent.
According to Horton and co-workers a threefold excess of MP is
required to obtain complete conversion of D
-xylose.27 Under these
conditions the initialattacktakesplace at themostreactive hydroxyl
group (O-2) of xylose that exclusively exists in the pyranose form in
solution containing equatorial hydroxyl groups only (Scheme 3).24
Since all hydroxyl groups in xylose are mutually trans, the
unstable pyranoid 2,3-acetal must form in order for the ring-clo-
sure to take place. The trans-fused acetal introduces strain into
the bicyclic system rendering the acyclic aldehydo form more
favorable. This in turn makes the primary hydroxyl at C-5 and
the hydroxyl at C-4 accessible for acetonation to yield the acyclic
diacetal 7. In our hands, however, increasing the excess of DMP
in the reaction improved only the conversion of the starting mate-
When L-xylose (6) was treated with 2 equiv of DMP in the pres-
ence of Smopex-101, a conversion of ꢀ70% was only observed after
24 h. The major compound formed was identified as di-acetal iso-
lated in 48% yield by column chromatography. At first glance, after
analyzing the product by 1H and 13C NMR spectroscopy in MeOD-
d4, it appeared to consist of an anomeric mixture. Further
assignment revealed, however, that all coupling constants of the
two isomers were nearly identical thus excluding this possibility.
An HMBC NMR experiment revealed a long-range coupling from
H-1 in the 1H NMR spectrum to a ‘missing’ carbon signal at
54 ppm (shown in the Supplementarydata). Further analytical data
showed that the compound formed in the reaction was the acyclic
rial
the side products 3,5-O-isopropylidene-
O-isopropylidene- -xylofuranose, and 1,2-O-isopropylidene-a-L-
L
-xylose but not the formation of 7, instead the formation of
L
-xylofuranose, 1,2:3,5-di-
a
-L
xylopyranose was enhanced. Nevertheless, the formation of these
compounds was marginal and their purification and isolation
was not pursued further. The acyclic aldehyde 7 turned out to be
rather unstable resulting in decomposition upon standing at room
temperature and in dimerization when dissolved in chloroform for
analysis.
2,3:4,5-di-O-isopropylidene-aldehydo-L-xylose (7) which, when
dissolved during the NMR-sample preparation, was attacked by
deuterated methanol to form the isomeric mixture of 2,3:4,5-di-
O-isopropylidene-L-xylose methyl-d3 hemiacetal (8) (Scheme 3).
The deuterated methoxy group was not detected in the 1H NMR
spectrum and the combined result of the splitting of the 13C
NMR signal by deuterium, the lack of the NOE enhancement, and
the prolonged relaxation time of the methyl carbon atom made it
nearly invisible in the 13C NMR spectrum as well (Supplementary
data). Simple evaporation of the MeOD-d4 from the sample and
redissolving into CDCl3 was sufficient to convert the hemiacetal 8
back to the parent aldehyde 7. For further verification of the struc-
ture of the isolated compound, acetylation by acetic anhydride in
pyridine was carried out providing the 1,1-di-O-acetyl-2,3:4,5-di-
Without
analogue -rhamnose (10) was investigated instead, expected to
provide comparable results. -Rhamnose possesses the manno con-
L-lyxose on the shelf, the acetonation of its 5-methyl
L
L
figuration existing almost exclusively in pyranose form in solution
with <1% contribution of the furanose form.28 The hydroxyl groups
of
as the preferred site for acetal formation, potentially forming 2,3-
O-isopropylidene- -rhamnopyranose. Instead, we observed the for-
mation of 2,3-O-isopropylidene- -rhamnofuranose (11) isolated in
L-rhamnose at C-3 and C-4 are trans, leaving the C-2/C-3 cis-diol
L
L
O-isopropylidene-
L
-xylose hydrate (9), thus proving that the iso-
82% yield after column chromatography. Again, analogous to the ri-
bose case, the product formation is due to tautomerization of the
pyranose form to furanose in order to gain stability by forming
the bicyclo[3.3.0] ring-system (Scheme 4). The 2,3-O-isopropyli-
lated compound indeed was the aldehyde 7 and not the methyl
hemiacetal 8. Kiso and Hasegawa earlier reported the formation
of the
our results at hand, it appears likely that the aldehydo compound
D
-analogues of 7 and 8 during acetonation with DMP.23 With
dene-L-rhamnofuranose thus formed is also formed via standard

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J. J. Forsman, R. Leino / Carbohydrate Research 345 (2010) 1548–1554
condensation with acetone,14 showing that a kinetic product can
be a thermodynamic product as well.
OH
OH
H3C
O
Compound 11 is exclusively formed as the pure a-anomer due
OH
12
OH
to the corresponding b-furanose potentially having all-cis arrange-
ment of substituents. Upon dissolving in CDCl3, 11 mutarotates to
form some of the b-anomer together with minor amounts of the
MP, DMF
-pyranose form. As noted by Angyal et al.,28 the manno configura-
Smopex-101
a
tion of L-rhamnose favors the pyranose form to such an extent that
OH
OH
fusion with the 1,3-dioxolane ring is not stabilizing enough in or-
der to retain the 2,3-O-isopropylidene derivative in pure furanose
OH
H3C
O
H3C
OH
O
+
O
form. The shifting from
a-furanose to a-pyranose is clearly ob-
O
O
served in the 13C NMR spectrum where the chemical shift of the
acetal carbon is moved upfield from 112.7 to 109.6 ppm.
O
13
Finally, the Smopex-101 H+-catalyzed acetonation of
L-fucose
(12) with DMP was investigated. In this case the conversion was
low, only around 60% after 22 h. Horton and co-workers have ear-
lier reported the acetonation of L-fucose under kinetic control
using MP as the acetonating agent.29 In the present work, upon
changing from DMP to MP the conversion improved remarkably
O
O
O
OH
O
O
and the favored 3,4-O-isopropylidene-
L-fucopyranose (13) was iso-
H
lated in 61% yield in 1:1 ratio of the - and b-anomers (Scheme 5).
a
H
O
O
The yield obtained is similar to that reported by Horton. In their
case, however, rigorously dry reaction conditions were required
to obtain satisfactory yields which otherwise dropped to the level
of 30–40%. In addition to compound 13, the acyclic diacetal
OH
O
14
Scheme 5.
2,3:4,5-di-O-isopropylidene-aldehydo-L-fucose (14) was here iso-
lated in 26% yield after column chromatography. Formation of
the acyclic compound 14 again nicely demonstrates the forcing
conditions introduced into the acetal exchange reaction when
DMP or MP is used enabling the introduction of the trans-fused
the solid-supported acid catalyst followed by evaporation of the
excess solvent and reagent. The acid catalyst is easily separated
and regenerated by subsequent washing and drying under vacuum.
The procedure is equally applicable to larger scale synthesis as
2,3-O-isopropylidene group.30 As in the
L-xylose case, when the
demonstrated here for 100 g scale with L-arabinose.
trans-fused acetal is formed, the strain in the bicyclic structure
makes ring opening favored which further enables the introduction
of the second isopropylidene acetal between O-4 and O-5 to form
the acyclic diacetal 14 (Scheme 5). A crystalline sample of 14
(mp 62–64 °C) was obtained by sublimation.
4. Experimental
4.1. General experimental details
The Smopex-101 H+ catalyst (loading 2.6 mmol/g) was obtained
from Johnson Mathey Finland. The DMF used was of analytical
grade (99%) and the acetonating agents were of reagent grade
(98%), all purchased from commercial sources and used with-
out further purification or drying. The NMR spectra were
recorded using a Bruker Avance 600 MHz spectrometer equipped
with a 5 mm inverse z-axis fg probe operating at 600.13 MHz for
1H and 150.92 MHz for 13C. All products were fully characterized
with 1D 1H and 13C NMR spectroscopy in combination with 2D
COSY, HMBC, and HSQC by using pulse sequences provided by
the instrument manufacturer. The NMR spectra were referenced
against TMS or the solvent signal. Signal multiplicities and cou-
pling constants are given in parentheses. HRMS were recorded
using either a Bruker micrOTOF-Q with ESI (electrospray ioniza-
tion) operated in the positive mode or a Fison ZABSpec-oaTOF with
EI (electron impact) ionization operated in the positive mode,
working at a resolution of 10,000 and 7000, respectively. Melting
points were determined in open-end glass capillaries and are
uncorrected. Optical rotations were measured with a Perkin–Elmer
241 polarimeter equipped with a Na lamp (589 nm) at 24 °C. TLC
analyses were performed on silica gel F254-precoated aluminum
sheets using CH2Cl2/MeOH 10:1 as eluent and visualized by char-
ring with 25% H2SO4 in methanol. Column chromatography was
performed using silica gel 60 Å (Merck, 230–400 mesh).
3. Summary and conclusions
In summary, the transacetalization of L-pentoses and 6-deoxy-L-
hexoses with 2,2-dimethoxypropane or 2-methoxypropene in DMF
catalyzed by the heterogeneous acid catalyst Smopex-101 H+ has
proven to be a straightforward method to produce the kinetically
favored cyclic acetals in good yields. The procedure described can
be performed at ambient reaction temperature and does not
require the use of rigorously predried solvents or reagents. The
reaction products can be isolated in good yield by filtration of
OH
OH
H3C
HO
O
DMP, DMF
H3C
HO
O
O
Smopex-101
O
HO
OH
10
OH
O
HO
H3C
O
O
4.2. 3,4-O-Isopropylidene-L-arabinopyranose (2)
11
To a solution of
L-arabinose (1.5 g, 10 mmol) in DMF (25 mL)
Scheme 4.
was added DMP (2.5 mL, 20 mmol). The reaction was initiated by

J. J. Forsman, R. Leino / Carbohydrate Research 345 (2010) 1548–1554
1553
the addition of Smopex-101 H+ (200 mg, 0.5 mmol) and the reac-
tion mixture was stirred at room temperature for 23 h. The reac-
tion was stopped by filtration and the solvent and excess of
reagents were removed by evaporation. The crude product was
purified by column chromatography (silica gel, petroleum ether/
EtOAc, gradient elution) to give pure 2 (1.67 g, 88%) as a colorless
9.79 (d, 1H, J1,2 = 1.6 Hz, H-1), 4.26 (ddd, 1H, J4,3 = 4.9, J4,5b = 6.6,
J4,5a = 6.7 Hz, H-4), 4.24 (dd, 1H, J2,1 = 1.6, J2,3 = 7.1 Hz, H-2), 4.14
(dd, 1H, J3,4 = 4.9, J3,2 = 7.1 Hz, H-3), 4.07 (dd, 1H, J5a,4 = 6.7,
J5a,5b = 8.6 Hz, H-5a), 3.88 (dd, 1H, J5b,4 = 6.6, J5b,5a = 8.6 Hz, H-5b),
1.52, 1.45, 1.42 and 1.39 (each s, each 3H, C(CH3)2); 13C NMR
(150 MHz, CDCl3): d 201.2 (C-1), 111.9 and 110.2 (C(CH3)2), 81.4
(C-2), 77.3 (C-3), 75.6 (C-4), 65.4 (C-5), 26.6, 26.3, 26.0 and 25.3
(C(CH3)2); HRMS: m/z [M+H] calcd for C11H19O5 231.1232; found:
231.1231.
oil in a 4:5
a
/b ratio: ½a 2D4
ꢁ
+110.6 (c 1.03, H2O), lit.23
½
a 2D0
ꢁ
ꢂ111.1
(c 0.5, H2O) for D
-isomer; 1H NMR (600 MHz, CD3OD): d 5.01 (d,
1H, J1,2 = 3.3 Hz, H-1b), 4.37 (d, 1H, J1,2 = 7.9 Hz, H-1
1H, J4,5b = 1.4, J4,5a = 2.9, J4,3 = 5.7 Hz, H-4b), 4.20 (ddd, 1H,
J4,5a = 1.9, J4,5b = 2.9, J4,3 = 5.8 Hz, H-4 ), 4.18 (dd, 1H, J3,4 = 5.7,
J3,2 = 7.2 Hz, H-3b), 4.17 (dd, 1H, J5a,4 = 2.9, J5a,5b = 13.2 Hz, H-5ab),
4.11 (dd, 1H, J5a,4 = 1.9, J5a,5b = 13.6 Hz, H-5a ), 4.00 (dd, 1H,
J3,4 = 5.8, J3,2 = 7.2 Hz, H-3 ), 3.81 (dd, 1H, J5b,4 = 2.9, J5b,5a = 13.6 Hz,
H-5b ), 3.80 (dd, 1H, J5b,4 = 1.4, J5b,5a = 13.2 Hz, H-5bb), 3.62 (dd,
1H, J2,1 = 3.3, J2,3 = 7.2 Hz, H-2b), 3.41 (dd, 1H, J2,3 = 7.2,
J2,1 = 7.9 Hz, H-2 ), 1.50 and 1.34 (each s, each 3H, C(CH3)2 ),
1.47 and 1.34 (each s, each 3H, C(CH3)2b); 13C NMR (150 MHz,
CD3OD): d 110.7 (C(CH3)2 ), 109.9 (C(CH3)2b), 97.7 (C-1 ), 93.7
(C-1b), 80.5 (C-3 ), 77.4 (C-3b), 75.6 (C-2 ), 75.0 (C-4 ), 74.6
(C-4b), 71.7 (C-2b), 64.0 (C-5 ), 59.9 (C-5b), 28.4 and 26.4
(C(CH3)2 ), 28.4 and 26.4 (C(CH3)2b); HRMS: m/z [M+Na] calcd
for C8H14O5Na 213.0739; found: 213.0747.
a), 4.23 (ddd,
a
4.5. 2,3:4,5-Di-O-isopropylidene-L-xylose methyl-d3 hemiacetal
(8)
a
a
NMR data for the major isomer: 1H NMR (600 MHz, CD3OD): d
4.56 (d, 1H, J1,2 = 5.7 Hz, H-1), 4.23 (ddd, 1H, J4,3 = 3.6, J4,5a = 6.8,
J4,5b = 7.5 Hz, H-4), 4.03 (dd, 1H, J5a,4 = 6.8, J5a,5b = 8.2 Hz, H-5a),
4.00 (dd, 1H, J3,4 = 3.6, J3,2 = 7.5 Hz, H-3), 3.92 (dd, 1H, J2,1 = 5.7,
J2,3 = 7.5 Hz, H-2), 3.89 (dd, 1H, J5b,4 = 7.5, J5b,5a = 8.2 Hz, H-5b),
1.40 (s, 3H, C(CH3)2), 1.39 (s, 6H, C(CH3)2), 1.35 (s, 3H, C(CH3)2);
13C NMR (150 MHz, CD3OD): d 111.1 and 110.5 (C(CH3)2), 99.3
(C-1), 80.2 (C-2), 78.6 (C-3), 77.2 (C-4), 67.0 (C-5), 54.1 (m,
OCD3), 27.5, 27.4, 26.6 and 26.0 (C(CH3)2).
a
a
a
a
a
a
a
a
a
a
NMR data for the minor isomer: 1H NMR (600 MHz, CD3OD): d
4.50 (d, 1H, J1,2 = 5.7 Hz, H-1), 4.22 (ddd, 1H, J4,3 = 3.7, J4,5a = 6.7,
J4,5b = 7.5 Hz, H-4), 4.02 (dd, 1H, J5a,4 = 6.7, J5a,5b = 8.2 Hz, H-5a),
3.95 (dd, 1H, J3,4 = 3.7, J3,2 = 7.5 Hz, H-3), 3.89 (dd, 1H, J2,1 = 5.7,
J2,3 = 7.5 Hz, H-2), 3.88 (dd, 1H, J5b,4 = 7.5, J5b,5a = 8.2 Hz, H-5b),
1.40 (s, 9H, C(CH3)2), 1.35 (s, 3H, C(CH3)2); 13C NMR (150 MHz,
CD3OD): d 111.0 and 110.5 (C(CH3)2), 99.6 (C-1), 80.6 (C-2), 79.0
(C-3), 77.0 (C-4), 67.0 (C-5), 54.4 (m, OCD3), 27.4, 27.4, 26.6 and
26.0 (C(CH3)2).
4.3. 2,3-O-Isopropylidene-b-L-ribofuranose (4) and 3,4-O-
isopropylidene-b- -ribopyranose (5)
L
The acetonation of L-ribose (1.5 g, 10 mmol) was carried out fol-
lowing the same procedure as for 2. The reaction mixture was stir-
red for 19 h at room temperature, filtered, and evaporated to
dryness. The evaporation residue was purified by column chroma-
tography (silica gel, petroleum ether/EtOAc 1:1) providing, after
evaporation of the solvents, 4 (0.85 g, 45%) as a colorless oil and
5 (0.89 g, 47%) as white needles after recrystallization from EtOAc.
4.6. 1,1-Di-O-acetyl-2,3:4,5-di-O-isopropylidene-L-xylose
hydrate (9)
Analytical data for compound 4: ½a D24
ꢁ
+21.3 (c 1.02, CHCl3), lit.12
½
a 2D0
ꢁ
ꢂ25.9 (c 1.1, CHCl3) for
D
-isomer; 1H NMR (600 MHz, CD3OD):
To a solution of 7 (250 mg, 1 mmol) in pyridine (5 mL) was
added Ac2O (380 L, 4 mmol). The reaction mixture was stirred
d 5.25 (s, 1H, H-1), 4.77 (dd, 1H, J3,4 = 0.8, J3,2 = 5.9 Hz, H-3), 4.52 (d,
1H, J2,3 = 5.9 Hz, H-2), 4.19 (ddd, 1H, J4,3 = 0.8, J4,5a = 4.4,
J4,5b = 5.5 Hz, H-4), 3.62 (dd, 1H, J5a,4 = 4.4, J5a,5b = 11.6 Hz, H-5a),
3.58 (dd, 1H, J5b,4 = 5.5, J5b,5a = 11.6 Hz, H-5b), 1.44 and 1.30 (each
l
at room temperature for 23 h, poured into a mixture of crushed
ice and saturated aqueous Na2CO3 (50 mL), and extracted with
CH2Cl2 (2 ꢃ 30 mL). The combined organic fractions were washed
with saturated aqueous NaHCO3 (50 mL), dried over Na2SO4, and
evaporated to obtain a yellowish syrup. The syrup was purified
by column chromatography (silica gel, hexane/EtOAc, 4:1) to yield
s, each 3H, C(CH3)2); 13C NMR (150 MHz, CD3OD):
d 113.1
(C(CH3)2), 103.9 (C-1), 88.6 (C-4), 87.9 (C-2), 83.4 (C-3), 64.3 (C-
5), 26.7 and 24.9 (C(CH3)2); HRMS: m/z [M+Na] calcd for C8H14O5Na
213.0739; found: 213.0743.
9 (285 mg, 79%) as a colorless oil: ½a D24
ꢁ
+15.3 (c 1.03, CHCl3), lit.23
Analytical data for compound 5: mp 116–119 °C, lit.26 115–
½
a 2D0
ꢁ
ꢂ24.3 (c 0.5, MeOH) for
D
-isomer; 1H NMR (600 MHz, CDCl3):
117 °C; ½a 2D4
ꢁ
+61.4 (c 0.97, MeOH), lit.26
½
a 2D0
ꢁ
ꢂ85 (c 1.1, H2O) for
d 6.95 (d, 1H, J1,2 = 4.5 Hz, 1 H, H-1), 4.19 (ddd, 1H, J4,3 = 4.2,
J4,5a = 6.6, J4,5b = 7.1 Hz, H-4), 4.18 (dd, 1H, J2,1 = 4.5, J2,3 = 7.2 Hz,
H-2), 4.10 (dd, 1H, J3,4 = 4.2, J3,2 = 7.2 Hz, H-3), 4.07 (dd, 1H,
J5a,4 = 6.6, J5a,5b = 8.3 Hz, H-5a), 3.90 (dd, 1H, J5b,4 = 7.1,
J5b,5a = 8.3 Hz, H-5b), 2.13 and 2.12 (each s, each 3H, OAc), 1.46,
1.45, 1.43 and 1.39 (each s, each 3H, C(CH3)2); 13C NMR
(150 MHz, CDCl3): d 168.5 and 168.5 (COCH3), 111.1 and 109.9
(C(CH3)2), 87.5 (C-1), 76.6 (C-2), 76.6 (C-3), 75.4 (C-4), 65.7 (C-5),
27.2, 26.7, 26.2 and 25.5 (C(CH3)2), 20.8 and 20.7 (COCH3); HRMS:
m/z [M+Na] calcd for C15H24O8Na 355.1369; found: 355.1372.
D
-isomer; 1H NMR (600 MHz, CD3OD): d 4.88 (d, 1H, J1,2 = 6.9 Hz,
H-1), 4.51 (dd, 1H, J3,2 = 3.3, J3,4 = 6.8 Hz, H-3), 4.28 (ddd, 1H,
J4,3 = 6.8, J4,5a = 3.4, J4,5b = 3.5 Hz, H-4), 3.79 (dd, 1H, J5a,4 = 3.4,
J5a,5b = 12.7 Hz, H-5a), 3.57 (dd, 1H, J2,3 = 3.3, J2,1 = 6.9 Hz, H-2),
3.52 (dd, 1H, J5b,4 = 3.5, J5b,5a = 12.7 Hz, H-5b), 1.47 and 1.34 (each
s, each 3H, C(CH3)2); 13C NMR (150 MHz, CD3OD):
d 110.8
(C(CH3)2), 95.4 (C-1), 76.2 (C-3), 75.0 (C-4), 70.9 (C-2), 63.9 (C-5),
27.1 and 25.4 (C(CH3)2); HRMS: m/z [M+Na] calcd for C8H14O5Na
213.0739; found: 213.0753.
4.4. 2,3:4,5-Di-O-isopropylidene-aldehydo-L-xylose (7)
4.7. 2,3-O-Isopropylidene-L-rhamnofuranose (11)
L-Xylose (1 g, 6.7 mmol) was dissolved in DMF (17 mL) followed
A solution of -rhamnose monohydrate (1.8 g, 10 mmol) in DMF
L
by the addition of DMP (1.6 mL, 13.3 mmol). The reaction was
started by the addition of Smopex-101 H+ (128 mg, 0.33 mmol)
and the reaction mixture was stirred at room temperature for
24.5 h. The reaction was stopped by filtration of the catalyst fol-
lowed by evaporation. The crude product was purified by column
chromatography (silica gel, petroleum ether/EtOAc 1:1) providing
7 (0.74 g, 48%) as a colorless oil: 1H NMR (600 MHz, CDCl3): d
(25 mL) was concentrated under reduced pressure at 60 °C to re-
move crystal water. The syrup obtained was redissolved in DMF
(25 mL) followed by the addition of DMP (2.5 mL, 20 mmol). The
reaction was initiated by the addition of Smopex-101 H+
(200 mg, 0.5 mmol) and the reaction mixture was stirred at room
temperature for 23 h. The reaction mixture was filtered and con-
centrated to give a yellowish syrup which was purified by column

1554
J. J. Forsman, R. Leino / Carbohydrate Research 345 (2010) 1548–1554
chromatography (silica gel, hexane/EtOAc 2:1) to obtain pure 11
C(CH3)2), 1.37 (d, 3H, J6,5 = 6.0 Hz, H-6); 13C NMR (150 MHz, CDCl3):
d 200.0 (C-1), 111.9 and 109.2 (C(CH3)2), 83.3 (C-2), 82.3 (C-4), 77.9
(C-3), 75.9 (C-5), 27.4, 27.0, 26.8 and 26.3 (C(CH3)2), 18.4 (C-6);
HRMS: m/z [M+H] calcd for C12H21O5 245.1389; found: 245.1392.
(1.67 g, 82%) as a colorless oil in a 10:1
1.01, H2O), lit.31
5.43 (d, 1H, J1,OH = 2.3 Hz, H-1
J1,OH = 12.1 Hz, H-1b), 4.90 (dd, 1H, J3,4 = 3.9, J3,2 = 6.0 Hz, H-3
4.82 (dd, 1H, J3,4 = 3.6, J3,2 = 6.2 Hz, H-3b), 4.63 (d, 1H,
J2,3 = 6.0 Hz, H-2 ), 4.54 (dd, 1H, J2,1 = 3.6, J2,3 = 6.2 Hz, H-2b),
4.07 (ddq, 1H, J5,OH = 5.7, J5,6 = 6.3, J5,4 = 7.3 Hz, H-5 ), 4.07 (cov-
ered, 1H, H-5b), 3.95 (dd, 1H, J4,3 = 3.9, J4,5 = 7.3 Hz, H-4 ), 3.86
(d, 1H, JOH,1 = 12.1 Hz, OH-1b), 3.33 (dd, 1H, J4,3 = 3.6, J4,5 = 7.8 Hz,
H-4b), 2.56 (d, 1H, JOH,5 = 5.7 Hz, OH-5 ), 2.51 (d, 1H, JOH,1 = 2.3 Hz,
OH-1 ), 2.24 (d, 1H, JOH,5 = 5.1 Hz, OH-5b), 1.55 (s, 3H, C(CH3)2b),
1.49 (s, 3H, C(CH3)2 ), 1.39 (s, 3H, C(CH3)2b), 1.35 (d, 3H,
J6,5 = 6.5 Hz, CH3-6b), 1.34 (d, 3H, J6,5 = 6.3 Hz, CH3-6 ), 1.33 (s,
3H, C(CH3)2
); 13C NMR (150 MHz, CDCl3): d 113.4 (C(CH3)2b),
112.7 (C(CH3)2 ), 101.0 (C-1 ), 96.9 (C-1b), 85.4 (C-2 ), 83.5 (C-
), 79.8 (C-4b), 79.7 (C-3b), 78.7 (C-2b), 66.7 (C-
), 66.3 (C-5b), 25.9 (C(CH3)2 ), 25.8 and 24.8 (C(CH3)2b), 24.5
), 20.6 (C-6b), 20.4 (C-6 ); HRMS: m/z [M+Na] calcd for
C9H16O5Na 227.0895; found: 227.0898.
a
/b ratio: ½a 2D4
ꢁ
+15.5 (c
½
a 2D0 +17.6 (H2O); 1H NMR (600 MHz, CDCl3): d
ꢁ
a
), 5.03 (dd, 1H, J1,2 = 3.6,
a
),
Acknowledgments
a
a
Financial support to J.J.F. from the Finnish National Glyco-
science Graduate School and Rector of Åbo Akademi University is
gratefully acknowledged. The authors also wish to thank Mattias
Roslund for technical assistance with the large-scale experiments
and Markku Reunanen for recording the HRMS analysis.
a
a
a
a
a
Supplementary data
a
a
a
a
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2010.05.002.
4a), 80.1 (C-3a
5a
a
(C(CH3)2
a
a
References
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4.8. 3,4-O-Isopropylidene-
isopropylidene-aldehydo-
L
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To a solution of
L-fucose (0.5 g, 3 mmol) in DMF (10 mL) was
added MP (580 L, 6 mmol). The reaction was initiated by the addi-
l
tion of Smopex-101 H+ (58 mg, 0.15 mmol) and the reaction mix-
ture was stirred at room temperature for 24 h. The reaction was
stopped by filtration and the solvent and excess of reagents were
removed by evaporation. The crude product was purified by col-
umn chromatography (silica gel, hexane/EtOAc 2:1) to give pure
13 (380 mg, 61%) in a 1:2 a/b ratio and 14 (193 mg, 26%) as color-
less oils. A crystalline sample of compound 14 was obtained by
sublimation during drying under reduced pressure. Analytical data
for compound 13: ½a D24
ꢁ
ꢂ89.3 (c 0.97, MeOH), lit.32
½
a 2D7
+86 (c 2.0,
ꢁ
H2O) for
D
-isomer; 1H NMR (600 MHz, CD3OD): d 5.00 (d, 1H,
J1,2 = 3.6 Hz, H-1b), 4.38 (d, 1H, J1,2 = 8.2 Hz, H-1a), 4.36 (dq, 1H,
J5,4 = 2.3, J5,6 = 6.6 Hz, H-5b), 4.17 (dd, 1H, J3,4 = 5.7, J3,2 = 7.2 Hz,
H-3b), 4.08 (dd, 1H, J4,5 = 2.3, J4,3 = 5.7 Hz, H-4b), 4.04 (dd, 1H,
J4,5 = 2.1, J4,3 = 5.4 Hz, H-4
H-3 ), 3.94 (dq, 1H, J5,4 = 2.1, J5,6 = 6.6 Hz, H-5
J2,1 = 3.6, J2,3 = 7.2 Hz, H-2b), 3.35 (dd, 1H, J2,3 = 7.4, J2,1 = 8.2 Hz,
H-4 ), 1.49 (s, 3H, C(CH3)2 ), 1.47 (s, 3H, C(CH3)2b), 1.33 (d, 3H,
J6,5 = 6.6 Hz, CH3-6 ), 1.33 (s, 6H, C(CH3)2 and C(CH3)2b), 1.26 (d,
3H, J6,5 = 6.7 Hz, CH3-6b); 13C NMR (150 MHz, CD3OD): d 110.6
(C(CH3)2 ), 109.9 (C(CH3)2b), 97.5 (C-1 ), 93.5 (C-1b), 81.0
(C-3 ), 77.9 (C-4 ), 77.6 (C-3b), 77.3 (C-4b), 75.6 (C-2 ), 71.3
(C-2b), 70.0 (C-5 ), 64.3 (C-5b), 28.5 and 26.6 (C(CH3)2
and 26.4 (C(CH3)2b), 17.0 (CH3-6
a
), 3.97 (dd, 1H, J3,4 = 5.4, J3,2 = 7.4 Hz,
17. Davoren, J. E.; Harcken, C.; Martin, S. F. J. Org. Chem. 2007, 73, 391.
18. Falomir, E.; Murga, J.; Ruiz, P.; Carda, M.; Marco, J. A. J. Org. Chem. 2003, 68,
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Catal. A: Chem. 2002, 182-183, 555.
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21. Gandi, G. K.; Silva, V. M. T. M.; Rodrigues, A. E. Chem. Eng. Sci. 2007, 62, 907.
22. (a) Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 87; (b) Gelas, J.; Horton, D.
Carbohydr. Res. 1978, 67, 371; (c) Gelas, J.; Horton, D. Carbohydr. Res. 1979, 71,
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23. Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 95.
24. Angyal, S. J. Angew. Chem., Int. Ed. Engl. 1969, 8, 157.
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Carbohydr. Res. 1982, 100, 75.
a
a
), 3.60 (dd, 1H,
a
a
a
a
a
a
a
a
a
a
a), 28.4
a), 16.8 (CH3-6b); HRMS: m/z
[M+Na] calcd for C9H16O5Na 227.0895; found: 227.0899.
Analytical data for compound 14: mp 62–64 °C; ½a D24
ꢂ4.2
ꢁ
26. Gelas, J.; Horton, D. Carbohydr. Res. 1975, 45, 181.
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30. Gelas, J.; Horton, D. Heterocycles 1981, 16, 1587.
31. Freudenberg, K.; Wolf, A. Ber. 1926, 59, 836.
32. Morgenlie, S. Carbohydr. Res. 1975, 41, 77.
(c 0.45, CHCl3), lit.33
½
a 2D5
ꢁ
ꢂ16.3 (c 1, CHCl3); 1H NMR (600 MHz,
CDCl3): d 9.77 (d, 1H, J1,2 = 0.8 Hz, H-1), 4.48 (dd, 1H, J2,1 = 0.8,
J2,3 = 6.1 Hz, H-2), 4.10 (dd, 1H, J3,2 = 6.1, J3,4 = 7.1 Hz, H-3), 4.04
(dq, 1H, J5,6 = 6.0, J5,4 = 7.8 Hz, H-5), 3.65 (dd, 1H, J4,3 = 7.1,
J4,5 = 7.8 Hz, H-4), 1.49, 1.43, 1.39 and 1.37 (each s, each 3H,
33. Gao, D.; O’Doherty, G. A. Org. Lett. 2005, 7, 1069.