Matsuda-Heck Arylation of Glycals for the Stereoselective Synthesis of Aryl C-Glycosides

Article abstract of DOI:10.1021/acs.joc.9b02410

The methoxymethyl-protected glycal l-amicetal, synthesized de novo from l-ethyl lactate through tandem ring-closing metathesis-isomerization sequence, undergoes a highly trans-diastereoselective Heck-type coupling reaction with various arene diazonium salts to furnish 2,3-unsaturated aryl C-glycosides in moderate to excellent yields. The products can be further functionalized, e.g., by hydrogenation, epoxidation, or dihydroxylation to furnish 2,3,6-tridesoxy, 2,3-anhydro-6-desoxy, or 6-desoxy aryl C-glycosides, respectively. The method was applied to the synthesis of an α-configured 6-desoxy-gliflozin derivative.

Full text of DOI:10.1021/acs.joc.9b02410

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Article
Matsuda-Heck Arylation of Glycals for the
stereoselective Synthesis of Aryl C-Glycosides
Fabian Otte, and Bernd Schmidt
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02410 • Publication Date (Web): 16 Oct 2019
Downloaded from pubs.acs.org on October 22, 2019
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Matsuda-Heck Arylation of Glycals for the stereoselective Synthesis of Aryl C-
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Glycosides
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Fabian Otte and Bernd Schmidt*
Universitaet Potsdam, Institut fuer Chemie, Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-
Golm, Germany
e-mail: bernd.schmidt@uni-potsdam.de
Table of contents graphic:
F4BN2
Tandem RCM-
isomerization
O
O
Ru
OCH3
MOMO
MOMO
Matsuda-
Heck
Pd
Dihydroxylation
O
O
Os
MOMO
MOMO
OH
OH
Matsuda-Heck arylation...
• highly trans-diastereoselective
• ligand-free and at ambient temperature
• 16 examples
OCH3
OCH3
Abstract:
The MOM-protected glycal L-amicetal, synthesized de novo from L-ethyl lactate through
tandem RCM-isomerization sequence, undergoes a highly trans-diastereoselective Heck-type
coupling reaction with various arene diazonium salts to furnish 2,3-unsaturated aryl C-
glycosides in moderate to excellent yields. The products can be further functionalized, e. g. by
hydrogenation, epoxidation or dihydroxylation to furnish 2,3,6-tridesoxy, 2,3-anhydro-6-
desoxy or 6-desoxy aryl C-glycosides, respectively. The method was applied to the synthesis
of an -configured 6-desoxy-gliflozin derivative.
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Introduction
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Aryl C-glycosides are hydroxylated tetrahydropyrans or –furans substituted with an arene at
the anomeric position.1 In contrast to actual glycosides, such as phlorizin (1),2 the arene is linked
in these compounds to the oxacycle via a C-C-bond, rather than a C-O-bond, resulting in a high
hydrolytic and metabolic stability.3 Many aryl C-glycosides occur in nature and were isolated
from various sources: medermycin (2), for example, is an antibiotic produced by Streptomyces
sp.,4 whereas aspalathin (3) is a plant secondary metabolite found in rooibos tea.5 Aspalathin
(3), chemically a dihydrochalcone-C-glucoside, and phlorizin (1), chemically a
dihydrochalcone-O-glucoside, were both found to have blood glucose and lipid lowering
effects.6 Their structures inspired the development of the so-called gliflozins for the treatment
of diabetes type II, which are more active drugs than the natural products, inter alia due to their
improved pharmacokinetic properties.7 Dapagliflozin (4) is the most well-known gliflozin and
it was the first drug of this class ever approved (Figure 1).8
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HO
OH
OH
HO
OH
OH
OH
O
O
O
O
HO
HO
HO
HO
OH
OH
O
OH
1
3
Aspalathin ( )
Phlorizin ( )
OH
OH
O
O
O
Cl
O
O
O
O
HO
HO
O
OH
HO
2
4
Dapagliflozin ( )
Medermycin ( )
OH
N(CH3)2
Figure 1. Structures of phlorizin (1), medermycin (2), aspalathin (3) and dapagliflozin (4).
Chemical syntheses of C-glycosides in general3,9-11 and aryl C-glycosides in particular12-15 have
been reviewed. Traditional syntheses of aryl C-glycosides rely on a Friedel-Crafts-type
coupling of an electrophilic glycosyl donor, e. g. a glycosyl halide, with an arene.16 These
transformations work well with electron rich arenes but require the presence of strong Lewis
acids and give predominantly -anomers. Another very successful and mostly -selective
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method uses strongly nucleophilic aromatic organometallic reagents which react with
carbohydrate derived lactones, followed by reduction of the intermediate hemiacetals.17,18 The
complementary approach, the addition of nucleophilic glycosyl donors to electrophilic arene
precursors, has also been explored but is less commonly used.19 Palladium catalyzed coupling
reactions, which are among the most versatile C-C-bond forming reactions available, have early
been investigated for the synthesis of aryl C-glycosides. In these pioneering works glycals were
coupled with aryl iodides,20 aryl mercury21 or aryl tin compounds22 in Heck or Heck-type
reactions, or stannylated glycals were reacted with aryl halides in a Stille cross coupling.23 More
recently, Walczak and coworkers described efficient and highly -stereoselective cross
coupling reactions of anomeric stannanes and aryl iodides or diaryliodonium salts24-27 as a route
to aryl C-glycosides. Although impressive successes in the total synthesis of complex naturally
occurring aryl C-glycosides were achieved using these Pd-catalyzed reactions, their use
remained limited because often high catalyst loadings, long reaction times and high
temperatures were required.
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Over the past few years, the introduction of the gliflozins elicited a renewed interest in the
development of methods for the synthesis of aryl C-glycosides. In this regard, Pd-catalyzed
coupling reactions were investigated mainly with a view to identify alternative coupling
partners that are conveniently accessible and storable, but at the same time sufficiently reactive
to perform the coupling reaction with reasonably low catalyst loadings and close to equimolar
ratios of the reactants.28-33 Highly reactive electrophilic coupling partners that fulfill these
criteria are arene diazonium salts.34-36 Heck-type coupling reactions of these reagents were
pioneered by Matsuda and coworkers and are therefore commonly referred to as Matsuda-Heck
reactions.37 The group of Correia38-43 and our group44-46 discovered that arene diazonium
tetrafluoroborates are very useful reagents for the site-selective arylation of cyclic enamides
and cyclic enol ethers, respectively. By using this method, Correia and co-workers synthesized
inter alia the pyrrolidine alkaloid (-)-codonopsin,38 our group synthesized both enantiomers of
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the antibiotic plant metabolite centrolobine and their non-natural epimers44 and Tong and co-
workers developed a synthesis of the musellarins, natural products with a diarylheptanoid
skeleton (Scheme 1).47 In the course of a project directed at the olefin metathesis based de novo
synthesis of glycals (1,2-unsaturated carbohydrates with a cyclic enolether structure) we
disclosed a single example for an aryl C-glycoside synthesis via Matsuda-Heck arylation.48
Parallel to a systematic investigation into the synthesis of aryl C-glycosides via Matsuda-Heck
arylation of pyranoid glycals in our group,49 the groups of Ye50 and Kandasamy51 disclosed
syntheses of aryl C-glycosides using Matsuda-Heck arylations of tri-O-benzyl glucal and some
other 3-oxygenated glycals. These transformations proceed with transposition of the double
bond and debenzylation to give 3-keto-aryl-C-glycosides. Our approach, disclosed herein, starts
from a 3,6-deoxygenated glycal and leads to 2,3-unsaturated aryl C-glycosides (Scheme 1).
The C2-C3 double bond is amenable to various functionalization reactions, which contributes
to the synthetic utility of this approach to aryl C-glycosides.
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Scheme 1. Literature precedence for Matsuda-Heck arylations of glycals and related
heterocycles and this work.
Previous work:
Correia and co-workers:38
PGO
ArN2BF4
Pd-cat.
PGO
H3CO2C
N
Ar
N
H3CO2C
Schmidt and co-workers:44
PGO
HO
ArN2BF4
O
O
Ar
Pd-cat., then
deprotection
Ye and co-workers50 and Kandasamy and co-workers:51
OPG
OPG
ArN2BF4
O
Ar
Ar
O
Pd-cat.
PGO
PGO
O
O
OBn
O
This work:
PGO
ArN2BF4
Pd-cat.
PGO
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Results and discussion
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Synthesis of the glycal. We chose L-amicetal, the glycal of L-amicetose, as a starting material
for this investigation. Amicetose is a rare 2,3,6-tridesoxy sugar52 which is found in
oligosaccharide side chains of anti tumor antibiotics such as the kigamicins.53 In other anti-
tumor antibiotics, e. g. urdamycins,54 related 2,6-didesoxy sugars are linked to anthracyclines
through a C-C-bond to form aryl C-glycosides. We have previously synthesized methoxyethoxy
methyl (MEM) protected L-amicetal and used this building block for the synthesis of highly
desoxygenated disaccharides.55 Acid catalyzed cleavage of MEM groups is known to be more
facile than other alkoxy methyl ethers,56 but the additional signals in the ether region of the 1H-
NMR spectrum complicate structural assignment due to overlap with relevant signals. For these
reasons the methoxymethyl (MOM) protecting group was chosen in the present study. The
synthesis of MOM-protected L-amicetal (9) was accomplished by adaptation of our previously
published synthesis:55 starting from compound 5 (synthesized in two steps from L-ethyl
lactate)55 the MOM-group was introduced using methoxymethylbromide to give 6,57,58 which
was next desilylated to the homoallylic alcohol 7.57,58 Williamson allylation furnished the RCM
precursor 8, which was then subjected to the conditions of a tandem RCM-isomerization
sequence59,60 to give the desired enantiopure protected amicetal 9 in good overall yield and in
quantities of up to one gram per batch (Scheme 2).
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Scheme 2. Synthesis of MOM-protected L-amicetal (9).
OTBS
OTBS
MOMBr; NEt(i-Pr)2
CH2Cl2, 40 °C
TBAF•3H2O
THF, 40 °C
HO
MOMO
5
6
(91%)
NaH, THF, 65 °C
Br
A
(5 mol-%), toluene,
20 °C; then add
OH
O
MOMO
MOMO
2-propanol, NaOH
110 °C
7
8
(86%)
(quant.)
O
PCy3
Cl
Ru
O
OH
Ph
Cl
MOMO
HO
L-Amicetose
PCy3
1st generation
Grubbs' catalyst (
9
(83%)
A
)
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Optimization of Matsuda-Heck coupling conditions. We know from our previous
experiences with Matsuda-Heck reactions and reports by other groups that the solvent, the
presence or absence of a base and the molar ratio of the coupling partners are important
parameters. The most commonly used precatalysts are either Pd(OAc)2 or Pd-dba complexes
without additional stabilizing ligands such as phosphines. Phosphines even have detrimental
effects, because they promote the decomposition of the arene diazonium salts and should
therefore be avoided.61,62 From mechanistic studies by Correia and coworkers it is known that
improved yields can be obtained in Matsuda-Heck reactions if the precatalyst is stirred with the
arene diazonium salt for a certain period of time prior to addition of the alkene.63 This
observation has been explained by the formation of a catalytically particularly active cationic
Pd--aryl complex. Although Correia’s mechanistic investigations were performed with Pd-
dba precatalysts in acetonitrile, we found that a delay between addition of the precatalyst and
the olefin to the diazonium salt also gives improved results in methanol and with Pd(OAc)2 as
the precatalyst.64 For these reasons we used a variant of Correia’s delayed-addition protocol by
default. The optimization study was performed with glycal 9 and 4-methoxybenzene diazonium
salt 10a, which were used in an equimolar ratio in the first experiments. As solvents methanol
and acetonitrile were tested, and for both solvents the effect of added NaOAc as a base was
investigated (Table 1, entries 1 – 4). In both solvents no conversion to the coupling product
11a was observed in the absence of a base, whereas isolated yields of 45% were obtained in
methanol (entry 1) and 76% in acetonitrile (entry 3) when three equivalents of NaOAc were
present from the outset. In the following experiments the molar ratio of the coupling partners
was varied. It turned out that the originally used 1 : 1 ratio of olefin 9 and diazonium salt 10a
was optimal, and that the isolated yields of coupling product 11a decreased notably with
increasing amounts of the diazonium salt (entries 6 – 9). In summary, optimized conditions for
the Matsuda-Heck coupling of glycal 9 and diazonium salt 10a use equimolar ratios of the
reactants, acetonitrile as a solvent and added NaOAc as a base.
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Table 1. Optimization of coupling conditions.
5
6
7
solvent; base (optional)
Pd(OAc)2 (5 mol-%)
10 min. at 20 °C
OCH3
OCH3
O
9
then add (1.0 equiv.)
F4BN2
10a
8
9
MOMO
11a
(n equiv.)
10
11
12
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entry equiv. of 10a solvent
base (equiv.)
NaOAc (3.0)
--
yield of 11a (%)
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
0.9
1.1
1.2
1.5
2.0
methanol
methanol
45
< 5
76
< 5
72
74
62
56
43
acetonitrile NaOAc (3.0)
acetonitrile --
acetonitrile NaOAc (3.0)
acetonitrile NaOAc (3.0)
acetonitrile NaOAc (3.0)
acetonitrile NaOAc (3.0)
acetonitrile NaOAc (3.0)
To test the reliability of these optimization experiments we applied the conditions listed in
entries 1 – 4 to the Matsuda-Heck coupling of cis-configured 6-phenyl glycal 12,43 which was
available from a previous research project (Scheme 3). The same trend as for the trans-
configured glycal 9 was observed: under base-free conditions only unreacted starting material
was recovered in methanol and in acetonitrile, whereas in the presence of NaOAc the coupling
product rac-13 was obtained, again with a higher yield in acetonitrile. Under all conditions
listed in table 1, the Matsuda-Heck coupling products 11a and rac-13 were obtained as single
diastereomers with a trans-configuration of the substituents  to the ring oxygen. Assignment
of this relative configuration is based on NOESY-experiments with another derivative and will
be discussed in the following section.
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Scheme 3. Application of optimized conditions to 6-phenyl glycal rac-12.
5
6
O
7
8
9
solvent; NaOAc (3.0 equiv.)
TBSO
OCH3
Pd(OAc)2 (5 mol-%)
10 min. at 20 °C
12
rac-
O
12
then add
(1.0 equiv.)
+
10
11
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OCH3
TBSO
13
rac-
F4BN2
(53% in methanol,
61% in acetonitrile)
10a
(1.0 equiv.)
Table 2. Scope of coupling reactions with glycal 9.
Acetonitrile
R2
NaOAc (3.0 equiv.)
R2
R3
R1
Pd(OAc)2 (5 mol-%)
10 min. at 20 °C
R3
F4BN2
R1
O
9
then add (1.0 equiv.)
MOMO
10
11
entry 10ref
R1
R2
H
H
H
H
H
H
H
R3
H
11
yield (%)
1
10a45
OCH3
H
11a 76
11b 85
2
10b65
10c66
10d67
10e68
10f69
10g65
10h70
10i71
H
3
F
H
11c
55
4
Cl
H
11d 62
5
Br
H
11e
11f
69
96
6
OH
CH3
H
7
H
11g 64
11h 22
8
CO2C2H5
H
H
9
H
OCH3
CH3
CO2CH3
H
H
11i
11j
30
42
10
11
12
13
14
15
10j72
10k73
10l74
H
H
H
H
11k 22
11l 64
H
OCH3
10m66
10n45
10o69
H
H
CO2CH3 11m 45
OCH3
OH
Br
H
H
11n 77
11o 59
CO2CH3
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Scope of Matsuda-Heck coupling reactions with glycal 9. The optimized conditions were
applied to several substituted arene diazonium salts 10a-o (Table 2). Almost all para-
substituted diazoniums salts undergo the desired coupling reaction in synthetically useful
yields. Two notable outliers are 10h, substituted with an electron withdrawing ester group, that
couples only in a low yield of 22% to the aryl C-glycoside 11h (entry 8) and 10f with a strongly
electron donating OH group. In the latter case a nearly quantitative yield of the corresponding
coupling product 11f was obtained (entry 6). The lowest yields were detected for the meta-
substituted diazonium salts 10i-k (entries 9 – 11), whereas the yields for the ortho-substituted
arene diazonium salts 10l,m (entries 12, 13) – although supposedly more hindered – are
significantly higher. Fair to good isolated yields were also obtained for the meta,para-
disubstituted arene diazonium salts 10n,o with an electron donating substituent in the para-
position (entries 14, 15).
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Assignment of the relative configuration based on NMR-methods. Complete signal
assignments based on 2D-NMR methods were performed for the para-chloro substituted
coupling product 11d and the diaryl substituted coupling product rac-13. Indicative for the
observed C2,C6-trans-configuration are, in the case of 11d, strong NOE interactions between
the methyl group at C2 and the proton H6, and between H2 and the ortho-protons of the para-
chlorophenyl substituent at C6 (Figure 2).
H
Cl
H
H
OCH3
H2 H6
H2 H6
H3C
O
O
MOMO
TBSO
H3
H3
rac-
11d
13
Figure 2. Selected NOE-interactions in coupling products 11d and rac-13.
The C2,C3-trans-configuration is supported by an NOE interaction between the methyl group
at C2 and proton H3. In the case of rac-13 an NOE-interaction between H2 and the ortho-protons
of the para-methoxyphenyl group as well as an interaction between H6 and the phenyl
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substituent at C2 indicate a C2,C6-trans-configuration. The cis-configuration of the C2-phenyl
group and the C3-OTBS-group is not only supported by an NOE-interaction, but also by a very
small 3J(H2,H3) value.
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Selective C-C-double bond functionalization of Matsuda-Heck coupling products. We first
investigated the hydrogenation of the C4-C5-double bond with a view to the synthesis of
tridesoxy aryl C-glycosides. For efficiency reasons we aimed at a one-pot sequence of Matsuda-
Heck coupling and hydrogenation with the use of just one precatalyst for both steps (Table 3).
In a first approach the Matsuda-Heck arylation of glycal 9 with diazonium salt 10a was
conducted under the optimized conditions shown in table 1, entry 3 and followed by the addition
of activated charcoal (to generate Pd on charcoal in situ) and saturating the reaction mixture
with hydrogen (entry 1).75-77 Although the starting material was fully consumed and the reaction
was chemoselective, this approach nevertheless turned out to be unsatisfactory due to a
substantial degree of epimerization. We isolated the expected hydrogenation product
(2S,3R,6R)-14 in 65% yield, but also its thermodynamically more stable epimer (2S,3R,6S)-14
in 17% yield. We assume that the epimerization proceeds through a Lewis-acid mediated ring
opening of the tetrahydropyran ring with cleavage of the O1-C6-bond, rotation around the C5-
C6-bond and recyclization to the more favourable epimer with three equatorially oriented
substituents. This mechanism has previously been proposed by Suzuki and coworkers to
rationalize similar epimerization reactions observed during Hf-mediated aryl-C-glycosylation
reactions.78 To avoid the use of molecular hydrogen and simplify the experimental protocol we
then investigated reductive Heck conditions. Reductive Heck reactions were pioneered by
Cacchi and Arcadi for enones79 and by Grigg and coworkers for intramolecular Heck reactions,
using formic acid in combination with tertiary amines79,80 or sodium formate as a base,81
respectively. Recently, reductive Heck reactions have attracted renewed interest, in particular
with a view to realizing an asymmetric version82 and to control regioselectivity issues in the
reaction of unactivated olefins.83,84
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Table 3. Optimization of one-pot Matsuda-Heck arylation/hydrogenation conditions.
4
5
6
7
OCH3
10a
OCH3
OCH3
OCH3
(1.0 equiv.)
O
F4BN2
O
O
O
+
+
Precatalyst (n mol %), solvent,
base (n equiv.), T1 (°C), t1 (h);
then add reagent(s), T2 (°C), t2 (h)
8
9
MOMO
MOMO
MOMO
MOMO
(2S,3R,6R)-
9
11a
14
14
(2S,3R,6S)-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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45
46
entry Precatalyst
(mol %)
solvent
Base
T1 (°C) / t1 (h) / Reagent(s)
11a (%)a)
(2S,3R,6R)-14 (%)a) (2S,3R,6S)-14 (%)a)
(n equiv.)
NaOAc (3)
T2 (°C)
20/20
t2 (h)
16/16 H2 (1 bar); C
1
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OH)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
CH3CN
CH3CN
CH3CN
CH3CN
n. d.
77
65
17
2
NaOCHO (3) 20
NaOCHO (3) 20/82
NEt(i-Pr)2 (3) 20
16
--
n. d.
n. d.
n. d.
n. d.
42
n. d.
n. d.
n. d.
n. d.
19
3
12/6
3
--
77
4b)
5
--
n. d.
56
2-propanol NaOCHO (3) 20
2-propanol NaOCHO (3) 20/82
2-propanol NaOCHO (3) 20/82
2-propanol NaOCHO (3) 20/82
16
--
6
12/6
12/6
12/6
--
n. d.
n. d.
n. d.
7b)
8
--
n. d.
43
n. d.
17
NaOAc (3 equiv.)
9c)
CH3CN
NaOAc (3)
20/20
16/16 Pd/C (1.5 mol %), n. d.
H2 (1 bar)
68
n. d.
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6
10b) Pd(OAc)2 (5)
11 Pd(OAc)2 (5)
2-propanol NaOCHO (3) 20/82
12/6
12/6
p-TSA (3 equiv.)
n. d.
n. d.
n. d.
n. d.
65
2-propanol NaOCHO (3) 20/82
Bi(OTf)3 (3 equiv.) n. d.
7
8
9
b)
c)
a)Isolated yields; n. d.: not determined. No conversion, glycal 9 was recovered. Reaction mixture filtered through celite, CH3CN evaporated and
residue dissolved in methanol.
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14
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17
18
19
20
21
22
23
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9
First, NaOAc was replaced by sodium formate under otherwise identical conditions (entry 2).
We could not observe any hydrogenated products 14, but isolated the dihydropyran 11a in a
yield comparable to that obtained under the optimized Matsuda-Heck coupling conditions
shown in table 1, entry 3. The same result was obtained when the reaction mixture was heated
to reflux (entry 3). Tertiary amines can also serve as a hydride source in reductive Heck
reactions82 and we therefore tested ethyldiisopropylamine as a base and reducing agent, but to
no avail. In the presence of this base the Matsuda-Heck coupling is completely inhibited and
the glycal 9 was quantitatively recovered (entry 4). Recently, reductive Heck reactions of
enones and aryl iodides were found to proceed in 2-propanol,85 which prompted us to
investigate this solvent instead of acetonitrile. At ambient temperature and with sodium formate
as a base we observed only the Matsuda-Heck product 11a, but in a notably lower yield
compared to the reaction in acetonitrile (entry 5). Heating the mixture to reflux after completion
of the coupling step resulted in the formation of both epimers 14, which were isolated in yields
of 42% and 19%, respectively (entry 6). In order to suppress the epimerization we tested
Pd(OH)2 as a supposedly less acidic precatalyst, but under these conditions the Matsuda-Heck
coupling failed completely and glycal 9 was recovered (entry 7). Therefore, we returned to the
conditions listed in entry 6, but used additional NaOAc as a base to reduce the Lewis acidity of
the precatalyst and to neutralize the Brønsted acid formed during the Matsuda-Heck reaction
more efficiently, but the amount of the epimerization product (2S,3R,6S)-14 could not be
reduced by this measure (entry 8). This prompted us to test a more elaborate two-step protocol
(entry 9) that involved filtration of the reaction mixture through celite after completion of the
coupling step in order to remove the Pd-residues, a solvent switch to methanol and addition of
commercial Pd/C followed by saturation of the reaction mixture with hydrogen. Gratifyingly,
under these conditions no epimerization was observed and the product (2S,3R,6R)-14 was
isolated in 68% yield. This observation suggests that the Pd/C generated in situ by addition of
activated charcoal after the completed Matsuda-Heck step (entry 1) contains a higher degree of
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14
15
16
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18
19
20
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22
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unreduced and Lewis-acidic Pd than the commercial Pd/C used for the epimerization free
sequence (entry 9). The complex nature of Pd/C and resulting differences in reactivity have
been thoroughly investigated, inter alia by Felpin and coworkers, and were summarized in
reviews.75,77,86 Having identified epimerization-free hydrogenation conditions we next aimed at
a selective epimerizing reductive Matsuda-Heck reaction, starting from the conditions listed in
entry 6. As mentioned above, acids are known to promote the epimerization and we therefore
tested p-toluene sulfonic acid and Bi(OTf)3 as Brønsted or Lewis-acidic additives. Both acids
were present from the outset. With p-toluene sulfonic acid no Matsuda-Heck coupling occurred
and glycal 9 was recovered (entry 10), but with Bi(OTf)3 the epimer (2S,3R,6S)-14 was
selectively formed and isolated in 65% yield (entry 11).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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56
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58
59
60
We also investigated oxidative C-C-double bond functionalization reactions. The epoxidation
of 11a with m-CPBA is highly stereoselective and gives dihydropyran oxide 15 in high yield.
The osmium-catalyzed dihydroxylation of 11a also proceeds in good yield and with formation
of a single diastereomer 16 (Scheme 4). The configurations assigned to the oxidation products
15 and 16 are based on an analysis of the coupling constants and were corroborated by 2D-
NMR methods.
Scheme 4. Oxidative C-C-double bond functionalization.
OCH3
O
MOMO
m-CPBA
CH2Cl2
K2Os(OH)6 (5 mol %)
11a
NMO, CH3SO2NH2
acetone/water/t-BuOH
20 °C, 16 h
20 °C, 16 h
OCH3
OCH3
O
O
MOMO
MOMO
OH
OH
O
15
16
(80%)
(86%)
Application to the synthesis of an -6-desoxygliflozin. The gliflozins are aryl C-glycosides
with a characteristic 3-benzylaryl substituent that is structurally inspired by the chalcone moiety
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in phlorizin or aspalathin. As outlined in the introduction, the gliflozins are prescription drugs
for lowering blood glucose levels by inhibition of the sodium glucose transport protein (SGLT-
2).7 We concluded our investigation into desoxy aryl-C glycoside syntheses based on Matsuda-
Heck reactions with the synthesis of an hitherto unknown -6-desoxygliflozin 25. The required
3-benzylarene diazonium salt 22 was synthesized in four steps from commercially available
benzyl alcohol 17, which was converted to the benzyl bromide 1887 using Appel conditions
(Scheme 5). As the next step for the generation of the diarylmethane 20 a Suzuki-Miyaura
coupling of benzyl bromide 18 and boronic acid 19 was envisaged. Suzuki-Miyaura coupling
reactions of benzyl derivatives were first reported in the 1990’s88 and found to proceed in
general less efficiently than the analogous coupling reactions with aryl halides.89 This has led
to several modifications and improvements, including the use of potassium aryltrifluoroborates
instead of arylboronic acids,89 more elaborate precatalysts90 and the development of special
conditions for chemoselective cross coupling at benzyl or aryl positions.91 Taylor and
coworkers have reported that the cross coupling of 18 and 19 to diarylmethane 20 proceeds
with a low amount of the succinimide (succ) ligated Pd-catalyst [trans-PdBr(N-succ)(PPh3)2],
using both coupling partners in equimolar ratios.90 Unfortunately, commercial availability of
this precatalyst is nowadays limited and its synthesis has, to the best of our knowledge, not been
sufficiently documented. For these reasons we investigated simple catalyst systems with
commercially available components for the Suzuki-Miyaura coupling of 18 and 19 (Table 4).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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29
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32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Synthesis of 3-benzylaryl diazonium salt 22.
OCH3
OCH3
PPh3, CBr4
CH2Cl2, 0 °C, 4 h
19
(HO)2B
OH
Br
O2N
O2N
O2N
PdCl2 (5 mol %), PPh3
Cs2CO3, toluene
110 °C, 16 h
20
(71%)
17
18
(89%)
(table 4, entry 11)
OCH3
OCH3
Pd/C (10 wt-%)
H2, methanol, 20 °C, 16 h
HBF4, tert-BuONO
CH3CN, 0 °C, 1 h
F4BN2
H2N
22
(93%)
21
(78%)
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Table 4. Optimization of the Suzuki-Miyaura coupling for the synthesis of diarylmethane 20.
5
6
entry Precatalyst
Ligand (equiv.) Base (equiv.)
equiv. of 19 yield (%) of 20
7
8
9
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
--
--
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
2.00
1.50
1.20
0.83
0.66
0.50
< 5
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
--
Cs2CO3 (3.0)
--
3
PPh3 (3.0)
PPh3 (3.0)
--
< 5
40
4
Cs2CO3 (3.0)
--
5
< 5
19
6
PdCl2
--
Cs2CO3 (3.0)
--
7
PdCl2
PPh3 (3.0)
PPh3 (3.0)
PPh3 (3.0)
PPh3 (3.0)
PPh3 (3.0)
PPh3 (3.0)
PPh3 (3.0)
PPh3 (3.0)
< 5
63
8
PdCl2
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
9
PdCl2
66
10
11
12
13
14
PdCl2
66
PdCl2
71
PdCl2
30
PdCl2
n. d.a)
n. d.a)
PdCl2
a)n. d.: not determined; inseparable mixture of 18 and 20.
Initially, a catalyst system of Pd(OAc)2 in combination with the ligand PPh3 and the base
Cs2CO3 was tested, using equimolar ratios of 18 and 19, toluene as a solvent and a reaction
temperature of 110 °C (Table 4, entries 1 – 4). To achieve a notable conversion, the presence
of the ligand and the base is necessary. Under these conditions (entry 4) the coupling product
was isolated in 40% yield. With PdCl2 as a precatalyst the yield could be significantly improved
to 63% under otherwise identical conditions (entry 5). Based on this catalytic system, the ratio
of reactants was varied (entries 9 – 14). The highest yield of cross coupling product 20 was
eventually achieved with 1.2 equivalents of the boronic acid 19 (entry 11).
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The synthesis of diazonium salt 22 commenced with the reduction of the nitro group and
subsequent diazotation of the intermediate 3-benzylaniline 21. Only few diazonium salts with
a diarylmethane skeleton, as present in compound 22, have been described in the literature, e.
g. the unsubstituted parent compound 3-benzylbenzene diazonium tetrafluoroborate, which has
been used for the synthesis of an indole via a Japp-Klingemann reaction.92 We are not aware of
any applications of arene diazonium salts of this general structure in Matsuda-Heck reactions
or other Pd-catalyzed coupling reactions, but we have in earlier investigations discovered that
arene diazonium salts with a benzyloxy substituent undergo Matsuda-Heck coupling reactions
in much lower yields than the analogous alkoxyarene diazonium salts.45 This might be attributed
to a complexation of the Pd to the -system of the pendant aromatic substituent during the
catalytic cycle, which prompted us to test diazonium salt 22 in Matsuda-Heck reactions with
the commonly used benchmark olefins methylacrylate, allyl alcohol and acrolein before
investigating the coupling with glycal 9 (Table 5). For all three olefins a successful coupling
could be realized. Strikingly, the optimal reaction conditions differ notably for methyl acrylate
(entry 2: methanol, base-free conditions) and acrolein (entry 11: acetonitrile, basic conditions),
but in both cases the respective coupling products 23a and 23c could be obtained in high yields.
Under other conditions, the yields were either substantially lower or the reaction failed
completely. Matsuda-Heck couplings with allyl alcohol have been reported to be notoriously
difficult,93 but could be accomplished with diazonium salt 22 in moderate yields under base-
free conditions in methanol (entry 6) as well as under basic conditions in acetonitrile (entry 7).
Under both conditions the aldehyde 23b, arising from a -hydride elimination in the direction
of the hydroxy group and subsequent tautomerization, was the only isolable product.
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
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45
46
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49
50
51
52
53
54
55
56
57
58
59
60
These results suggest that depending on the coupling partner either methanol without added
base or acetonitrile in combination with a base are privileged reaction conditions. Although the
latter conditions normally give better results with cyclic enol ethers, both sets of conditions
were tested for the coupling of diazonium salt 22 and glycal 9 (Scheme 6).
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Table 5. Coupling reactions of diarylmethane diazonium salt 22 with benchmark substrates.
5
6
7
8
olefin (1.2 equiv.)
Pd(OAc)2 (5 mol %)
NaOAc (n equiv.)
OCH3
OCH3
F4BN2
R
solvent (0.05 M)
20 °C, 16 h
22
23
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
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52
53
54
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58
59
60
entry olefin
solvent
NaOAc
R
23 yield
(n equiv.)
(%)
1
H2C=CHCO2CH3
H2C=CHCO2CH3
H2C=CHCO2CH3
H2C=CHCO2CH3
H2C=CHCH2OH
H2C=CHCH2OH
H2C=CHCH2OH
H2C=CHCH2OH
H2C=CHCHO
methanol
methanol
CH3CN
CH3CN
methanol
methanol
CH3CN
CH3CN
methanol
methanol
CH3CN
CH3CN
3
0
3
0
3
0
3
0
3
0
3
0
E-CH=CHCO2CH3 23a 30
E-CH=CHCO2CH3 23a 85
E-CH=CHCO2CH3 23a 40
E-CH=CHCO2CH3 23a < 5
2
3
4
5
CH2CH2CHO
CH2CH2CHO
CH2CH2CHO
CH2CH2CHO
E-CH=CHCHO
E-CH=CHCHO
E-CH=CHCHO
E-CH=CHCHO
23b <5
23b 37
23b 38
23b < 5
23c < 5
23c < 5
23c 86
23c < 5
6
7
8
9
10
11
12
H2C=CHCHO
H2C=CHCHO
H2C=CHCHO
Contrary to the results obtained in the optimization study, base-free methanol turned out to give
superior results in this case. The isolated yield of coupling product 24 was 64% under these
conditions, whereas only 24% of 24 were isolated under the standard conditions for cyclic enol
ethers. Dihydroxylation of the C4-C5-double bond was accomplished with high trans-
diastereoselectivity and gave the -configured desoxy aryl C-glycoside 25 with a gliflozin
skeleton.
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Scheme 6. Synthesis of an -6-desoxy gliflozin 23.
5
6
7
8
Pd(OAc)2 (5 mol %)
9
methanol; then add
20 °C, 16 h (64%)
or
OCH3
F4BN2
Pd(OAc)2 (5 mol %)
acetonitrile, NaOAc (3 equiv.)
9
22
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
then add , 20 °C, 16 h (24%)
OCH3
K2Os(OH)6 (4 mol %)
NMO, CH3SO2NH2
O
acetone/water/t-BuOH
MOMO
OCH3
20 °C, 16 h
24
O
O
MOMO
MOMO
OH
9
OH
25
(55%)
Conclusions
In summary, we have demonstrated that Pd-catalyzed coupling reactions of arene diazonium
salts with de novo synthesized highly deoxygenated glycals provide a convenient access to
desoxy aryl C-glycosides. In contrast to previous approaches, the coupling reactions
investigated in this contribution proceed with formation of a C-C-double bond which is
amenable to further functionalization. As an application example the synthesis of an a-
configured desoxy gliflozin derivative has been described.
Experimental Section
General methods. All experiments were conducted in dry reaction vessels under an atmosphere
of dry nitrogen. Solvents were purified by standard procedures. Unless otherwise stated,
1
reaction mixtures were heated with silicon oil baths. H NMR spectra were obtained at 300
MHz or 500 MHz in CDCl3 with CHCl3 (δ = 7.26 ppm) as an internal standard. Coupling
constants are given in Hz. 13C NMR spectra were recorded at 75 MHz or 125 MHz in CDCl3
with CDCl3 (δ = 77.1 ppm) as an internal standard. Whenever the solubility of the sample was
insufficient in CDCl3, it was replaced by DMSO-d6 (DMSO-d5 as internal standard for 1H NMR
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spectroscopy,  = 2.50 ppm, DMSO-d6 as internal standard for 13C NMR spectroscopy,  = 39.5
5
6
7
8
1
13
ppm). In all cases where signal assignments are given for H- and C-NMR data, these are
based on 2D-NMR-spectra such as H,H-COSY, HSQC, HMBC and NOESY. IR spectra were
recorded as ATR-FTIR spectra. Wavenumbers (ṽ) are given in cm1. The peak intensities are
defined as strong (s), medium (m) or weak (w). Low- and high resolution mass spectra were
obtained by EI-TOF or ESI-TOF. Although arene diazonium tetrafluoroborates are in general
thermally very stable and we have never experienced any cases of violent decomposition, we
recommend that these compounds are handled with care. The following compounds were
synthesized according to literature procedures: 5,57,58 10a,45 10b,65 10c,66 10d,67 10e,68 10f,69
10g,65 10h,70 10i,71 10j,72 10k,73 10l,74 10m,66 10n,45 10o.69
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(tert-Butyldimethylsilyloxy)-3-(methoxymethoxy)-pent-4-ene (6).57,58 A solution of 5
(1.50 g, 6.9 mmol) in dry and degassed CH2Cl2 (75 mL) was cooled to 0 °C. Methoxymethyl
bromide (1.13 mL, 13.9 mmol) and diisopropylethylamine (4.47 mL, 25.7 mmol) were added
slowly at 0 °C. The mixture was warmed to ambient temperature and then heated at 40 °C for
12 h. After completion of the reaction (TLC), the reaction was quenched by addition of water
(20 mL), the organic layer was separated and the aqueous phase was extracted with MTBE (3
times, 20 mL each). The combined organic extracts were washed with brine, dried with MgSO4,
filtered and evaporated in vacuo. The residue was purified by column chromatography on silica
(hexanes / MTBE 10 : 1) to furnish 6 (1.64 g, 6.3 mmol, 91%): colourless liquid; [α]D23 53.7
(c 0.22, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 5.73 (ddd, J = 16.9, 10.8, 7.4 Hz, 1H), 5.30 -
5.19 (m, 2H), 4.69 (d, J = 6.6 Hz, 1H), 4.58 (d, J = 6.6 Hz, 1H), 3.90 – 3.75 (m, 2H), 3.37 (s, 3
H), 1.15 (d, J = 5.9 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 135.7, 118.8, 94.1, 81.8, 70.9, 55.6, 26.0, 19.8, 18.3, 4.4, 4.5; IR (ATR) ṽ 2930
(w), 1248 (m), 1095 (m), 1026 (s), 826 (s); HRMS (ESI) calcd for C13H28O3SiNa [M+Na]+
283.1705, found 283.1686.
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(2S, 3R)-3-(Methoxymethoxy)pent-4-en-2-ol (7).57,58 To a solution of 6 (1.60 g, 6.1 mmol) in
THF (70 mL) was added TBAF•3H2O (3.87 g, 12.3 mmol) and the solution was stirred at 40 °
C until complete conversion (TLC). After cooling to ambient temperature, the mixture was
diluted with diethyl ether (30 mL) and washed with brine. The organic layer was separated,
dried with MgSO4, filtered and evaporated in vacuo. The residue was purified by column
chromatography on silica (pentane / diethylether 5 : 1) to give 7 (0.90 g, 6.1 mmol, quant.):
colourless liquid; [α]D23 112.4 (c 0.25, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 5.65 (ddd, J =
17.1, 10.6, 7.6 Hz, 1H), 5.21 (dm, J = 10.4 Hz, 1H), 5.15 (dm, J = 17.1 Hz, 1H), 4.59 (d, J =
6.7 Hz, 1H), 4.48 (d, J = 6.6 Hz, 1H), 3.85 – 3.70 (m, 2H), 3.26 (s, 3H), 2.79 (s (br.), 1H), 1.03
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(d, J = 6.4 Hz, 3H); C{1H} NMR (75 MHz, CDCl3) δ 134.0, 119.6, 94.0, 81.7, 69.1, 55.3,
17.9; IR (ATR) ṽ 3449 (w), 2889 (w), 1404 (w),1026 (s); HRMS (ESI) calcd for C7H14O3Na
[M+Na]+ 169.0841, found 169.0857.
(3R, 4S)-4-Allyloxy-3-(methoxymethoxy)pent-1-ene (8). To a solution of 7 (0.88 g, 6.0
mmol) in dry and degassed THF (30 mL) was added NaH (60 wt-% dispersion in mineral oil,
0.48 g, 12.0 mmol). The mixture was heated at 65 °C for 1 h, cooled to ambient temperature
and allyl bromide (1.45 g, 12.0 mmol) was added. The mixture was heated at 65 °C for 12 h,
cooled to ambient temperature, and the reaction was quenched by careful addition of a saturated
aq. solution of NH4Cl (10 mL). The aqueous phase was separated and extracted three times
with MTBE (20 mL each). The combined organic extracts were dried with MgSO4, filtered and
evaporated in vacuo. The residue was purified by column chromatography on silica (hexanes /
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MTBE 20 : 1) to give 8 (0.96 g, 5.2 mmol, 86%): colourless liquid; [α]D 74.3 (c 0.25,
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 5.91 (ddt, J = 15.9, 10.9, 5.5 Hz, 1H), 5.82 – 5.70 (m,
1H), 5.32 – 5.21 (3H), 5.13 (dm, J = 10.4 Hz, 1H), 4.70 (d, J = 6.6 Hz, 1H), 4.60 (d, J = 6.7 Hz,
1H), 4.09 – 4.01 (m, 3H), 3.54 (qd, J = 6.4, 3.9 Hz, 1H), 3.37 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 135.4, 135.2, 118.8, 116.6, 94.2, 79.7, 77.0, 70.3, 55.5, 15.8;
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IR (ATR) ṽ 2887 (w), 1647 (w), 1152 (m), 1096 (m), 1030 (s), 917 (s); HRMS (ESI) calcd for
C10H19O3 [M+H]+ 187.1334, found 187.1338.
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(2S, 3R)-3-(Methoxymethoxy)-2-methyl-3.4-dihydro-2H-pyran (9). To a solution of 8 (1.00
g, 5.4 mmol) in dry and degassed toluene (35 mL) was added first generation Grubbs’ catalyst
A (0.22 g, 5 mol-%) and the solution was stirred at ambient temperature until TLC revealed
complete consumption of the starting material (ca. 3 h). 2-Propanol (7 mL) and NaOH (0.21 g,
5.3 mmol) were added and the mixture was heated at 110 °C until TLC showed complete
conversion of the intermediate RCM product (ca. 1 h). The solvent was evaporated in vacuo
and the residue was purified by column chromatography on silica (pentane / diethyl ether / 5 :
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1) to furnish 9 (0.71 g, 4.5 mmol, 83%): colourless liquid; [α]D 90.7 (c 0.25, CH2Cl2); H
NMR (300 MHz, CDCl3) δ 6.28 (dm, J = 6.0 Hz, 1H), 4.75 (d, J = 6.8 Hz, 1H), 4.67 (d, J = 6.8
Hz, 1 H), 4.64 – 4.58 (m, 1H), 3.87 (dq, J = 6.6, 6.4 Hz, 1H), 3.58 (ddd, J = 7.0, 6.6, 6.6 Hz,
1H), 3.38 (s, 3H), 2.34 (dm, J = 16.6 Hz, 1H), 2.04 (dm, J = 16.6 Hz, 1H), 1.30 (d, J = 6.4 Hz,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 142.8, 97.6, 95.3, 73.5, 73.4, 55.6, 26.2, 17.7; IR (ATR)
ṽ 2934 (w), 1654 (m). 1240 (m), 1031 (s), 732 (m); HRMS (ESI) calcd for C8H15O3 [M+H]+
159.1021, found 159.1016.
(2R*, 3R*, 6S*)-tert-Butyl((6-(4-methoxyphenyl)-2-phenyl-3,6-dihydro-2H-pyran-3-
yl)oxy)-dimethylsilane (rac-13). To a solution of diazonium salt 10a (111 mg, 0.50 mmol) in
dry and degassed acetonitrile (10 mL) were added NaOAc (123 mg, 1.50 mmol) and Pd(OAc)2
(5.6 mg, 5 mol-%). The mixture was stirred at ambient temperature for 10 min., followed by
addition of rac-12 (145 mg, 0.50 mmol). The reaction mixture was then stirred at ambient
temperature for 16 h, diluted with MTBE (10 mL) and washed with water (20 mL). The organic
layer was separated and the aqueous layer was extracted three times with MTBE (20 mL each).
The combined organic extracts were dried with MgSO4, filtered and evaporated. The residue
was purified by column chromatography (hexanes / MTBE 10 : 1) to yield rac-13 (120 mg,
0.31 mmol, 61%): colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 7.5 Hz, 2H, ortho-H
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(Ph)), 7.32 (d, J = 8.8 Hz, 2H, ortho-H (C6H4OCH3)), 7.29 (dd, J = 7.5, 7.5 Hz, 2H, meta-H
(Ph)), 7.22 (tt, J = 7.5, 1.3 Hz, 1H, para-H (Ph)), 6.85 (d, J = 8.8 Hz, 2H, meta-H (C6H4OCH3)),
6.22 (dd, J = 10.2, 2.8 Hz, 1H, H5), 6.19 (ddd, J = 10.2, 4.3, 1.4 Hz, 1H, H4), 5.42 (d, J = 1.8
Hz, 1H, H6), 4.66 (d, J = 2.7 Hz, 1H, H2), 4.14 – 4.08 (m, 1H, H3), 3.79 (s, 3H, OCH3), 0.76 (s,
9H, tert-Bu), 0.16 (s, 3H, Si(CH3)2)), 0.32 (s, 3H, Si(CH3)2)); 13C{1H} NMR (75 MHz,
CDCl3) δ 159.4 (C(OCH3)), 139.4 (ipso-C (Ph)), 131.6 (ipso-C (C6H4OCH3)), 130.5 (C5), 129.5
(ortho-C (C6H4OCH3)), 128.5 (C4), 127.8 (ortho-C (Ph)), 127.7 (meta-C (Ph)), 127.2 (para-C
(Ph)), 113.8 (meta-C (C6H4OCH3)), 74.6 (C2), 74.0 (C6), 65.8 (C3), 55.4 (OCH3), 25.9
(C(CH3)3), 18.3 (C(CH3)3), 4.9 (Si(CH3)2), 5.1 (Si(CH3)2); IR (ATR) ṽ 2928 (w), 1608 (w),
1510 (m), 1246 (s), 1077 (s); HRMS (ESI) calcd for C24H32O3Si [M+] 396.2121, found
396.2133.
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General procedure for the Matsuda-Heck coupling of arene diazonium salts 10 and L-
amicetal (9) under optimized conditions. To a solution of the appropriate arene diazonium
salt 10 (0.25 mmol) in dry and degassed acetonitrile were added NaOAc (61.5 mg, 0.75 mmol)
and Pd(OAc)2 (2.8 mg, 5 mol-%). The mixture was stirred at ambient temperature for 10 min.
before L-amicetal 9 (40.0 mg, 0.25 mmol) was added. The reaction mixture was stirred for 16
h, diluted with MTBE (10 mL) and washed with water (20 mL). The organic layer was separated
and the aqueous layer was extracted three times with MTBE (10 mL each). The combined
organic extracts were dried with MgSO4, filtered and evaporated. The residue was purified by
column chromatography on silica (hexanes / MTBE 10 : 1) to furnish the coupling products 11.
(2S, 3R, 6R)- 3-(Methoxymethoxy)-6-(4-Methoxyphenyl)-2-methyl-3,6-dihydro-2H-pyran
(11a). Following the general procedure, diazonium salt 10a (56 mg, 0.25 mmol) was converted
to 11a (51 mg, 0.19 mmol, 76%): colourless oil; [α]D25 +2.4 (c 0.25, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 7.33 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.11 - 5.97 (2H), 5.16 (m,
1H), 4.80 (d, J = 6.9 Hz, 1H), 4.71 (d, J = 6.9 Hz, 1H), 3.85 (dm, J = 7.0 Hz, 1H), 3.79 (s, 3H),
3.66 (dq, J = 7.0, 6.3 Hz, 1H), 3.42 (s, 3H), 1.24 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (75 MHz,
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CDCl3) δ 159.4, 132.0, 130.4, 129.6, 127.1, 113.8, 95.9, 74.5, 73.2, 67.6, 55.7, 55.3, 18.1; IR
(ATR) ṽ 2933 (w), 1609 (w), 1510 (m), 1245 (m), 1097 (m), 1032 (s), 814 (m); HRMS (ESI)
calcd for C15H20O4Na [M+Na]+ 287.1259, found 287.1266.
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(2S, 3R, 6R)-3-(Methoxymethoxy)-6-phenyl-2-methyl-3.6-dihydro-2H-pyran (11b).
Following the general procedure, diazonium salt 10b (40 mg, 0.25 mmol) was converted to 11b
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(50 mg, 0.21 mmol, 85%): colourless oil; [α]D 2.9 (c 0.30, CH2Cl2); H NMR (300 MHz,
CDCl3) δ 7.26 – 7.48 (m, 5H), 6.11 – 6.02 (m, 2H), 5.22 (s, 1H), 4.80 (d, J = 6.9 Hz, 1H), 4.72
(d, J = 6.9 Hz, 1H), 3.87 (dm, J = 6.8 Hz, 1H), 3.70 (dq, J = 6.4, 6.4 Hz, 1H), 3.42 (s, 3H), 1.27
(d, J = 6.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 140.2, 130.4, 128.5, 128.1, 127.9, 127.2,
96.1, 74.6, 73.6, 68.4, 55.7, 18.1; IR (ATR) ṽ 2887(w), 1451 (m), 1274 (m), 1100 (s), 1035 (s);
HRMS (ESI) calcd for C14H19O3 [M+H]+ 235.1334, found 235.1351.
(2S, 3R, 6R)-6-(4-Fluorophenyl)-3-(methoxymethoxy)-2-methyl-3,6-dihydro-2H-pyran
(11c). Following the general procedure, diazonium salt 10c (53 mg, 0.25 mmol) was converted
to 11c (35 mg, 0.14 mmol, 55%): colourless oil; [α]D23 54.5 (c 0.25, CH2Cl2); 1H NMR (500
MHz, CDCl3) δ 7.30 - 7.45 (m, 2H), 6.97 - 7.09 (m, 2H), 6.07 (ddd, J = 10.4, 2.2, 1.8 Hz, 1H),
6.02 (ddd, J = 10.4, 2.6, 1.2 Hz, 1H), 5.17 (q, J = 2.2 Hz, 1H), 4.80 (d, J = 6.9 Hz, 1H), 4.72
(d, J = 6.9 Hz, 1H), 3.85 (dm, J = 6.7 Hz, 1H), 3.67 (dq, J = 6.4, 6.4 Hz, 1H), 3.42 (s, 3H), 1.25
(d, J =6.3 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 162.59 (d, J = 245.3 Hz), 135.8 (d, J =
3.2 Hz), 130.2, 129.9 (d, J = 8.2 Hz), 127.3, 115.4 (d, J = 21.3 Hz), 96.9, 74.2, 72.8, 68.1, 55.8,
18.0; IR (ATR) ṽ 2887 (w), 1602 (w), 1507 (m), 1222 (m), 1035 (s); HRMS (ESI) calcd for
C14H18O3F [M+H]+ 253.1240, found 253.1257.
(2S, 3R, 6R)-6-(4-Chlorophenyl)-3-(methoxymethoxy)-2-methyl-3,6-dihydro-2H-pyran
(11d). Following the general procedure, diazonium salt 10d (57 mg, 0.25 mmol) was converted
to 11d (42 mg, 0.16 mmol, 62%): colourless oil; [α]D24 +29.2 (c 0.25, CH2Cl2); 1H NMR (500
MHz, CDCl3) δ 7.34 (dm, J = 8.7 Hz, 2H, ortho-H (C6H4Cl)), 7.31 (dm, J = 8.7 Hz, 2H, meta-
H (C6H4Cl)), 6.07 (ddd, J = 10.4, 2.0, 1.6 Hz, 1H, H4), 6.02 (ddd, J = 10.4, 2.4, 1.0 Hz, 1H,
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H5), 5.15 (q, J = 2.2 Hz, 1H, H6), 4.79 (d, J = 6.9 Hz, 1H, OCHHOCH3), 4.71 (d, J = 6.9 Hz,
1H, OCHHOCH3), 3.85 (dm, J = 6.8 Hz, 1H, H3), 3.65 (dq, J = 6.4, 6.4 Hz, 1H, H2), 3.42 (s,
3H, OCH3), 1.25 (d, J = 6.4 Hz, 3H, C2(CH3)); 13C{1H} NMR (75 MHz, CDCl3) δ 138.8 (ipso-C
(C6H4Cl)), 133.9 (C-Cl), 129.9 (C5), 129.4 (ortho-C (C6H4Cl)), 128.7 (meta-C (C6H4Cl)), 127.6
(C4), 96.1 (OCH2OCH3), 74.4 (C3), 72.8 (C6), 68.5 (C2), 55.7 (OCH3), 18.0 (C2(CH3)); IR
(ATR) ṽ 2886 (w), 1489 (w), 1149 (m), 1091 (s), 1036 (s); HRMS (ESI) calcd for C14H18O3Cl
[M+H]+ 269.0944, found 269.0946.
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(2S, 3R, 6R)-6-(4-Bromophenyl)-3-(methoxymethoxy)-2-methyl-3,6-dihydro-2H-pyran
(11e). Following the general procedure, diazonium salt 10e (68 mg, 0.25 mmol) was converted
to 11e (54 mg, 0.17 mmol, 69%): colourless oil; [α]D24 79.4 (c 0.25, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 7.48 (d, J =8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.07 (ddd, J = 10.4, 2.1, 1.6
Hz, 1H), 6.01 (ddd, J = 10.4, 2.5, 1.1 Hz, 1H), 5.15 (q, J = 2.1 Hz, 1H), 4.79 (d, J = 6.9 Hz,
1H), 4.71 (d, J = 6.9 Hz, 1H), 3.85 (dm, J = 6.7 Hz, 1H), 3.65 (dq, J = 6.4, 6.4 Hz, 1H), 3.42
(s, 3H), 1.25 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 139.1, 131.6, 129.8, 129.8,
127.5, 122.1, 96.0, 74.2, 72.8, 68.3, 55.8, 18.0; IR (ATR) ṽ 2886 (w), 1589 (w), 1486 (m), 1146
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(m), 1035 (s); HRMS (ESI) calcd for C14H18O3 Br [M+H]+ 313.0439, found 313.0435.
(2S, 3R, 6R)-6-(4-Hydroxyphenyl)-3-(methoxymethoxy)-2-methyl-3,6-dihydro-2H-pyran
(11f). Following the general procedure, diazonium salt 10f (52 mg, 0.25 mmol) was converted
to 11f (60 mg, 0.24 mmol, 96%): colourless oil; [α]D25 +16.9 (c 0.25, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 7.24 (d, J = 8.3 Hz, 2H), 6.75 (d, J = 8.3 Hz, 2H), 6.66 (s(br.), 1H), 5.95 – 6.13
(2H), 5.18 – 5.15 (m, 1H), 4.83 (d, J = 6.9 Hz, 1H), 4.75 (d, J = 6.9 Hz, 1H), 3.89 (dm, J = 6.9
Hz, 1H), 3.72 (dq, J = 6.3, 6.3 Hz, 1H), 3.44 (s, 3H), 1.25 (d, J = 6.3 Hz, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 156.0, 131.2, 130.7, 129.9, 126.8, 115.4, 95.9, 74.6, 73.2, 67.8, 55.8, 18.1;
IR (ATR) ṽ 3339 (m), 2934 (w), 1612 (m), 1513 (m), 1096 (m), 1032 (s), 720 (m); HRMS (ESI)
calcd for C14H18O4 [M]+ 250.1205, found 250.1193.
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(2S, 3R, 6R)-3-(Methoxymethoxy)-2-methyl-6-(p-tolyl)-3,6-dihydro-2H-pyran (11g).
Following the general procedure, diazonium salt 10g (52 mg, 0.25 mmol) was converted to 11g
(40 mg, 0.16 mmol, 64%): colourless oil; [α]D24 27.9 (c 0.25, CH2Cl2); 1H-NMR (300 MHz,
CDCl3) δ 7.31 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.09 – 6.01 (m, 2H), 5.20 – 5.17
(m, 1H), 4.81 (d, J = 6.9 Hz, 1H), 4.72 (d, J = 6.9 Hz, 1H), 3.86 (dm, J = 7.0 Hz, 1H), 3.68 (dq,
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J = 6.4, 6.4 Hz, 1H), 3.43 (s, 3H), 2.35 (s, 3H), 1.25 (d, J = 6.3 Hz, 3H); C{1H} NMR (75
MHz, CDCl3) δ 137.7, 137.0, 130.4, 129.2, 128.2, 127.1, 96.0, 74.6, 73.5, 68.0, 55.7, 21.3, 18.2;
IR (ATR) ṽ 2886 (m), 1513 (m), 1145 (m), 1096 (m), 1035 (s), 780 (m); HRMS (ESI) calcd for
C15H21O3 [M+H]+ 249.1491, found 249.1480.
(2S, 3R, 6R)-3-(Methoxymethoxy)-6-(4-ethoxycarbonylphenyl)-2-methyl-3,6-dihydro-2H-
pyran (11h). Following the general procedure, diazonium salt 10h (66 mg, 0.25 mmol) was
converted to 11h (17 mg, 0.06 mmol, 22%): colourless oil; [α]D24 +16.2 (c 0.25, CH2Cl2); 1H-
NMR (300 MHz, CDCl3) δ 8.03 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H) 6.11 – 6.03 (m,
2H), 5.24 – 5.22 (m, 1H), 4.79 (d, J = 6.9 Hz, 1H), 4.71 (d, J = 6.9, 1H), 4.37 (q, J = 7.1 Hz,
2H), 3.86 (dm, J = 6.6 Hz, 1H), 3.67 (dq, J = 6.4, 6.4 Hz, 1H), 3.41 (s, 3H), 1.39 (t, J = 7.1,
3H), 1.27 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.5, 145.4, 141.3, 130.3,
129.9, 127.7, 116.4, 96.1, 74.4, 73.1, 68.9, 61.0, 55.7, 18.0, 14.5; IR (ATR) ṽ 2887 (m), 1716
(s), 1610 (m), 1367 (m), 1274 (s), 1100 (s), 1038 (s); HRMS (ESI) calcd for C17H23O5 [M+H]+
307.1545, found 307.1523.
(2S, 3R, 6R)-3-(Methoxymethoxy)-6-(3-methoxyphenyl)-2-methyl-3,6-dihydro-2H-pyran
(11i). Following the general procedure, diazonium salt 10i (56 mg, 0.25 mmol) was converted
to 11i (20 mg, 0.08 mmol, 30%): colourless oil; [α]D25 47.2 (c 0.25, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 7.27 (dd, J = 7.9, 7.9 Hz, 1H), 6.99 (dm, J = 7.9 Hz, 1H), 6.97 (s, 1H), 6.84
(ddd, J = 7.9, 2.4, 1.1 Hz, 1H), 6.10 – 6.01 (m, 2H), 5.19 – 5.16 (m, 1H), 4.79 (d, J = 6.9 Hz,
1H), 4.71 (d, J = 6.9 Hz, 1H), 3.86 (dm, J = 6.9 Hz, 1H), 3.81 (s, 3H), 3.70 (dq, J = 6.5, 6.5 Hz,
1H), 3.42 (s, 3H), 1.27 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.1, 141.9,
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130.3, 129.5, 127.3, 120.4, 113.8, 113.6, 96.1, 74.7, 73.5, 68.5, 55.7, 55.4, 18.1; IR (ATR) ṽ
2934 (w), 1600 (w), 1488 (w), 1452 (m), 1099 (m), 1032 (s); HRMS (ESI) calcd for C15H21O4
[M+H]+ 265.1440, found 265.1460.
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(2S, 3R, 6R)-3-(Methoxymethoxy)-2-methyl-6-(3-methylphenyl)-3,6-dihydro-2H-pyran
(11j). Following the general procedure, diazonium salt 10j (51 mg, 0.25 mmol) was converted
to 11j (26 mg, 0.11 mmol, 42%): colourless oil; [α]D25 +60.9 (c 0.50, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 7.05 – 7.30 (m, 4H), 6.10 – 6.01 (m, 2H), 5.18 (s, 1H), 4.81 (d, J = 6.9 Hz, 1H),
4.73 (d, J = 6.9 Hz, 1H), 3.86 (dm, J = 6.8 Hz, 1H), 3.72 (dq, J = 6.4, 6.4 Hz, 1H), 3.43 (s, 3H),
2.36 (s, 3H), 1.27 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 140.1, 138.2, 130.6,
128.8, 128.7, 128.4, 127.0, 125.2, 96.1, 74.6, 73.6, 68.4, 55.7, 21.5, 18.1; IR (ATR) ṽ 2933 (w),
1721 (w), 1606 (w), 1277 (m), 1149 (m), 1100 (m), 1030 (s); HRMS (ESI) calcd for C15H21O3
[M+H]+ 249.1491, found 249.1483.
(2S, 3R, 6R)-3-(Methoxymethoxy)-6-(3-methoxycarbonylphenyl)-2-methyl-3,6-dihydro-
2H-pyran (11k). Following the general procedure, diazonium salt 10k (66 mg, 0.25 mmol) was
converted to 11k (16 mg, 0.05 mmol, 22%): colourless oil; [α]D24 +103.4 (c 0.25, CH2Cl2); 1H
NMR (300 MHz, CDCl3) δ 8.06 (dd, J = 1.7, 1.7 Hz, 1H), 7.97 (ddd, J = 7.8, 1.5, 1.5 Hz, 1H),
7.63 (ddd, J = 7.7, 1.5, 1.5 Hz, 1H), 7.43 (dd, J = 7.7, 7.7 Hz, 1H), 6.11 (d, J = 10.6 Hz, 1H),
6.07 (d, J = 10.5 Hz, 1H), 5.26 – 5.22 (m, 1H), 4.80 (d, J = 6.9 Hz, 1H), 4.72 (d, J = 6.9 Hz,
1H), 3.91 (s, 3H), 3.86 (dm, J = 6.6 Hz, 1H), 3.67 (dq, J = 6.4, 6.4 Hz, 1H), 3.42 (s, 3H), 1.27
(d, J = 6.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 167.1, 140.9, 132.3, 130.7, 129.9, 129.2,
129.1, 128.6, 127.7, 96.1, 74.4, 73.0, 68.7, 55.7, 52.2, 18.0; IR (ATR) ṽ 2887 (w), 1722 (s),
1443 (m), 1286 (s), 1037 (s); HRMS (ESI) calcd for C16H21O5 [M+H]+ 293.1389, found
293.1385.
(2S, 3R, 6R)-3-(Methoxymethoxy)-6-(2-methoxyphenyl)-2-methyl-3,6-dihydro-2H-pyran
(11l). Following the general procedure, diazonium salt 10l (56 mg, 0.25 mmol) was converted
to 11l (42 mg, 0.16 mmol, 64%): colourless oil; [α]D25 +11.9 (c 0.25, CH2Cl2); 1H NMR (300
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MHz, CDCl3) δ 7.40 (dd, J = 7.5, 1.8 Hz, 1H), 7.28 (ddd, J = 7.9, 7.9, 1.7 Hz, 1H), 6.93 (ddd,
J = 7.5, 7.5, 1.0 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.04 (ddd, J = 10.4, 1.9, 1.9 Hz, 1H), 6.98
(ddd, J = 10.4, 2.4, 1.1 Hz, 1H), 5.64 (ddd, J = 2.1, 2.1, 2.1 Hz, 1H), 4.81 (d, J = 6.9 Hz, 1H),
4.74 (d, J = 6.9 Hz, 1H), 3.86 (s, 3H), 3.85 (dm, J = 6.9 Hz, 1H), 3.79 (dq, J = 6.3, 6.3 Hz, 1H),
3.43 (s, 3H), 1.28 (d, J = 6.1 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 157.6, 130.9, 129.2,
128.7, 128.1, 126.4, 120.4, 111.1, 96.0, 74.5, 68.6, 67.9, 55.9, 55.7, 18.0; IR (ATR) ṽ 2933 (w),
1728 (w), 1600 (w), 1489 (w), 1242 (m), 1093 (m), 1027 (s); HRMS (ESI) calcd for C15H21O4
[M+H]+ 265.1440, found 265.1452.
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(2S, 3R, 6R)-3-(Methoxymethoxy)-6-(2-methoxycarbonylphenyl)-2-methyl-3,6-dihydro-
2H-pyran (11m). Following the general procedure, diazonium salt 10m (63 mg, 0.25 mmol)
was converted to 11m (33 mg, 0.11 mmol, 45%): colourless oil; [α]D25 57.5 (c 0.23, CH2Cl2);
1H NMR (300 MHz, CDCl3) δ 7.82 (dd, J = 7.7, 1.3 Hz, 1H), 7.61 (dd, J = 7.8, 1.2 Hz, 1H),
7.47 (ddd, J = 7.6, 7.6, 1.4 Hz, 1H), 7.34 (ddd, J = 7.6, 7.6, 1.3 Hz, 1H), 6.11 (ddd, J = 10.0,
2.8, 1.0 Hz, 1H), 5.98 – 6.06 (2H), 4.79 (d, J = 6.9 Hz, 1H), 4.72 (d, J = 6.9 Hz, 1H), 3.90 (s,
3H), 3.79 – 3.84 (m, 1H), 3.77 (dq, J = 6.3, 6.3 Hz, 1H), 3.41 (s, 3H), 1.26 (d, J = 6.3 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 168.5, 141.4, 131.6, 131.5, 130.3, 130.3, 128.7, 127.6,
126.0, 95.9, 73.8, 69.7, 69.2, 55.6, 52.2, 17.6; IR (ATR) ṽ 2950 (w), 1722 (s), 1434 (w), 1270
(m), 1130 (m), 1040 (s); HRMS (ESI) calcd for C16H21O5 [M+H]+ 293.1389, found 293.1386.
(2S, 3R, 6R)-6-(3-Bromo-4-methoxyphenyl)-3-(methoxymethoxy)-2-methyl-3,6-dihydro-
2H-pyran (11n). Following the general procedure, diazonium salt 10n (75 mg, 0.25 mmol) was
converted to 11n (66 mg, 0.19 mmol, 77%): colourless oil; [α]D25 26.1 (c 0.47, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ 7.58 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 6.87 (d, J
= 8.5 Hz, 1H), 6.06 (ddd, J = 10.4, 2.1, 2.1 Hz, 1H), 5.99 (ddd, J = 10.4, 2.9, 1.5 Hz, 1H), 5.12
(q, J = 2.1 Hz, 1H), 4.79 (d, J = 6.9 Hz, 1H), 4.71 (d, J = 6.9 Hz, 1H), 3.88 (s, 3H), 3.84 (dm, J
= 6.9 Hz, 1H), 3.63 (dq, J = 6.4, 6.4 Hz, 1H), 3.42 (s, 3H), 1.24 (d, J = 6.3 Hz, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 155.7, 133.6, 133.2, 129.8, 128.5, 127.6, 111.7, 111.7, 96.0, 74.3,
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1032 (s). HRMS (EI) calcd for C15H19O4 Br [M+] 342.0461, found 342.0452.
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2-Hydroxy-5-((2R, 5R, 6S)-5-(methoxymethoxy)-6-methyl-5,6-dihydro-2H-pyran-2-
yl)methylbenzoate (11o). Following the general procedure, diazonium salt 10o (66 mg, 0.25
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mmol) was converted to 11o (45 mg, 0.15 mmol, 59%): colourless oil; [α]D +14.6 (c 0.25,
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 10.76 (s, 1H), 7.84 (d, J = 2.3 Hz, 2H), 7.52 (dd, J =
8.6, 2.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.08 (ddd, J = 10.4, 2.2, 1.9 Hz, 1H), 6.01 (ddd, J =
10.4, 2.7, 1.3 Hz, 1H), 5.13 (q, J = 2.2 Hz, 1H), 4.79 (d, J = 6.9 Hz, 1H), 4.71 (d, J = 6.9 Hz,
1H), 3.93 (s, 3H), 3.84 (dm, J = 6.6 Hz, 1H), 3.63 (dq, 6.4, 6.4 Hz, 1H), 3.42 (s, 3H), 1.24 (d, J
= 6.3 Hz, 3H); C{1H} NMR (75 MHz, CDCl3) δ 170.6, 161.5, 135.8, 130.9, 129.9, 129.6,
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127.6, 117.8, 112.1, 96.0, 74.2, 72.7, 68.0, 55.7, 52.4, 18.0; IR (ATR) ṽ 3169 (w), 2952 (w),
1675 (m), 1271 (m), 1088 (m), 1033 (s), 794 (m); HRMS (ESI) calcd for C16H20O6 [M]+
308.1260, found 308.1262.
(2S,3R,6R)-3-(Methoxymethoxy)-6-(4-methoxyphenyl)-2-methyl-tetrahydro-2H-pyran
((2S,3R,6R)-14)
and
(2S,3R,6S)-3-(Methoxymethoxy)-6-(4-methoxy-phenyl)-2-
methyltetrahydro-2H-pyran ((2S,3R,6S)-14). One-pot Matsuda-Heck coupling
/
hydrogenation sequence (table 3, entry 1). To a solution of diazonium salt 10a (56 mg, 0.25
mmol) in acetonitrile (5 mL) were added Pd(OAc)2 (2.8 mg, 5 mol %) and NaOAc (61.5 mg,
0.75 mmol) and the mixture was stirred at ambient temperature for 10 minutes. Glycal 9 (40.0
mg, 0.25 mmol) was added and the mixture was stirred at ambient temperature for 16 h.
Activated charcoal (4 mg) was added and the mixture was diluted with methanol (10 mL). It
was flushed with hydrogen and vigorously stirred under an atmosphere of hydrogen for 16 h.
The mixture was filtered through a pad of celite, which was rinsed with ethyl acetate (30 mL).
The solution was dried with MgSO4, filtered and all volatiles were removed in vacuo. The
residue was purified by column chromatography on silica using a hexanes / MTBE mixture (10
: 1 (v/v)) as eluent to furnish (2S,3R,6R)-14 (43 mg, 0.16 mmol, 65%) and (2S,3R,6S)-14 (11
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