Synthesis of Symmetrical Dodeco-6,7-diuloses

European Journal of Organic Chemistry

Accepted Article

Title: Synthesis of symmetrical dodeco-6,7-diuloses

Authors: Marius Bayer, Simon Stocker, Cäcilia Maichle-Mössmer, and

Thomas Ziegler

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000615

Link to VoR: https://doi.org/10.1002/ejoc.202000615

01/2020

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Synthesis of symmetrical dodeco-6,7-diuloses

Marius Bayer,^[a]Simon Stocker,^[a]Cäcilia Maichle-Mössmer,^[a]and Thomas Ziegler*^[a]

Dedicated to Professor Franz Effenberger on the occasion of his 90^thBirthday

Abstract: Dodeco-6,7-diuloses represent a rare class of sugars

and can be considered as anomerically linked di-hexoses with two

hemiacetal functions in the middle. Here, the synthesis of three

symmetrical dodeco-6,7-diuloses (gluco-gluco, galacto-galacto,

manno-manno) is described. For their preparation four synthetic

strategies were pursued, whose mutual key step, the connection

of the anomeric centers, is particularly emphasized. Specifically,

CC-bond forming methods are employed, such as a Grubbs

metathesis, a stannyl glycal homocoupling reaction, a coupling of

a sulfinyl glycal with a sugar lactone and a Ramberg-Bäcklund

rearrangement. Since the ring closure via hemiacetal formation of

Figure 1. Hemiacetalic ring-closures of dodeco-6,7-diuloses.

the target compounds cannot be predicted, intensive NMR

spectroscopic structure elucidation of the diuloses was performed.

This structural diversity of vicinal diuloses enhances scientific

attraction and provides

a larger scope of retrosynthetic

approaches to gain access to these compounds. Nevertheless,

there are only two examples mentioned in the literature for the

synthesis of higher (C ≥ 10) symmetrical diuloses. In both cases,

the crucial key step was the connection of the anomeric centers

followed by an oxidation and deprotection sequence. To this end,

Mochizuki and Shiozaki used a coupling reaction of a stannyl

glucal with a glucono lactone,^[12]whereas Menzel and Ziegler

performed the anomeric connection by means of a Grubbs

metathesis (Figure 2).^[13]The ambition of Menzel’s work was the

synthesis and structural elucidation of the hypoglycemic active

deco-5,6-diulose Peltalosa which was isolated from the roots and

rhizomes of the Mexican plant Psacalium peltatum, due to the fact

that its stereochemistry is yet unknown.^[14]

Introduction

Carbohydrates are the most abundant class of natural products

and play a major role in biological and biochemical processes in

living systems.^[1]Besides naturally occuring glycoconjugates,

synthetically designed sugar mimetics attained considerable

interest in current carbohydrate research.^[2]Especially stable

structures resisting enzymatic degradation are of significant

importance, for instance, due to their eligibility to act as

glycosidase inhibitors.^[3,4]In this context, bicyclic and 1,2-

annulated sugars emerged as highly potential candidates and the

development of new synthetic methodologies for this group of

carbohydrates became attractive over the last two decades.^[5–11]

The emphasis of this work will be on the synthesis of symmetrical

dodeco-6,7-diuloses which depict a rather rare class of bicyclic

disaccharides. In their open-chain form, dodeco-6,7-diuloses can

be represented either as vicinal di-ketones preferring to constitute

six-membered hemiacetals like 1,2-annulated sugars (type A) or

anomerically 1,1’-connected scaffolds which can be regarded as

trehalose analogues (type B) (Figure 1).

Figure 2. Higher symmetrical diuloses in the literature: D-gluco-L-gulo-dodeco-

6,7-diulose (Mochizuki 1997), L-manno-D-erythro-Deco-5,6-diulose and L-gulo-

D-erythro-Deco-5,6-diulose (Menzel 2014).

In this study, we examined the applicability of Menzel’s protocol

for the preparation of homologous dedeco-6,7-diuloses.

Furthermore, we expanded the spectrum of synthetic options and

accentuated the significance of the imperative anomeric

connection as the key step in every suggested route as well.

Therefore, we employed nucleophilic glycal derivates as versatile

[a]

Prof. Dr. Thomas Ziegler

Institute of Organic Chemistry, University of Tuebingen

Auf der Morgenstelle 18, 72076 Tuebingen, Germany

E-mail: thomas.ziegler@uni-tuebingen.de

www.uni-tuebingen.de/ziegler

Supporting information for this article is given via a link at the end of

the document.((Please delete this text if not appropriate))

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precursors. Stannylated glycals perform homocoupling reactions

under Stille conditions to furnish endo-glycalic dimers,^[15]whereas

phenylsulfinyl glycals attack carbohydrate lactones in the

presence of a strong lithium base in a similar fashion as described

by Mochizuki and Shiozaki. In addition, we present the formation

of dimeric exo-glycals via a Ramberg-Bäcklund reaction using

sulfone bridged dipyranosides. Oxidation and deprotection of the

C1-C1’ linked intermediates provided the appropriate dodeco-6,7-

diuloses in all cases.

annulated dipyranose conformations of the resulting plain

carbohydrates (Figure 2). In an endeavour to apply this

methodology to the synthesis of homologous longer chain

dodeco-6,7-diuloses, we commenced with the preparation of the

completely protected D-glucose derivative

literature procedure.^[16]The application of

1

according to

tert-butyl-

a

dimethylsilyl-ether as an additional protection group at position 4

seemed to be suitable for our purpose for this protecting group is

insensitive towards oxidative conditions and its removal can be

performed simultaneously along with the hydrolysis of the

acetonide groups in acidic milieu.

Results and Discussion

First, the thioacetal function in 1 was cleaved by oxidation using

N-bromosuccinimide to afford aldehyde

2 in 91% yield

Grubbs-Metathesis

(Scheme 1). Treatment of the aldehyde with methyl triphenyl

phosphonium bromide and n-butyllithium resulted in the formation

of terminal hept-1-enitol 3 in 87% yield. In order to accomplish the

anomeric coupling of two hept-1-enitols, we employed an olefin-

metathesis similar to previous one.^[13]However, contrary to the

previously high yielding reaction when using Hoveyda-Grubbs

second generation-catalyst,^[17]we isolated merely 17% of the

appropriate coupling product under the same conditions.

Presumably, the bulky TBDMS-groups are to be to blame for the

moderate conversion. Therefore, we deployed the sterically less

demanding Stewart-Grubbs catalyst^[18]which implies two tolyl-

entities attached to the NHC-ligand, unlike the Hoveyda-Grubbs

Inspired by the diulose structure of the hypoglycemic active

natural product Peltalosa, first investigations on the synthesis of

deco-5,6-diuloses has been described by our group in 2014.^[13]

Starting from the aldopentoses L- and D-arabinose, the

corresponding 3,4:5,6-di-O-isopropylidene-protected hex-1-

enitols were prepared by a Wittig olefination. Next, a metathesis-

hydroxylation-oxidation sequence was used for the conversion of

the hex-1-enitols into the symmetrical deco-5,6-diuloses, which

were obtained as open-chain vicinal diketones in their fully

protected form. After acidic removal of the isopropylidene acetals,

X-Ray and NMR analysis were employed to determine the 1,2-

Scheme 1. Synthesis of D-gluco-L-gulo-Dodeco-6,7-diulose 7a via Grubbs metathesis.

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catalyst which contains two mesityl-groups at the same positions.

Indeed, the yields were increased up to 57%, obtained as an

inseparable diastereomeric mixture of E-4 and Z-4 (4:1). The

following cis-selective dihydroxylation of the alkene-mixture E-

4/Z-4 with OsO₄and N-methylmorpholine N-oxide gave two

chromatographically separable diols syn-5 and anti-5 in 72% and

8% yield, respectively. The anticipated C₂-symmetry of the major-

product syn-5, which resulted in the stereoselective osmoylation

of E-4 from the sterically more accessible face, was proved by

¹³C-NMR-experiment since only six signals between 65 and

85 ppm were detectable. Furthermore, diamond-shaped crystals

suitable for X-ray crystallography were obtained by

experiments confirmed that the bis-dihydroxylation occurs in a

cis-selective manner from the si-face, as the coupling constants

match those of a gluco- for 10a and a galacto-configuration for

10b. Eventually, debenzylation with palladium on activated

charcoal under hydrogen-atmosphere yielded the desired

products 7a and 7b quantitatively. Compound 7a was previously

prepared

from

3,4,6-tri-O-benzyl-1-stannyl-D-glucal

via

stereospecific addition reaction of lithioglucal to 2,3,4,6-tetra-O-

benzyl-D-glucono-1,5-lactone.^[12]

recrystallization

of

syn-5

in

n-hexane

(Scheme 1).

Dihydroxylation of Z-4 resulted in the formation of the

unsymmetrical minor product anti-5. Thus, the determination of

E-4 as the major diastereomer as it occurred in previous olefin

metathesis was verified. Next, examinations have been carried

out on the oxidation of diol syn-5 in order to convert it efficiently

into the corresponding diketone 6. For this purpose, we confined

our attempts to DMSO-mediated Swern-type oxidation methods

as these provided the best results for similar cases.^[13,19]Classical

Swern oxidation (oxalyl chloride)^[20]and the alternative Omura-

Scheme 2. Synthesis of D-gluco-L-gulo-Dodeco-6,7-diulose 7a and D-galacto-

L-galacto-Dodeco-6,7-diulose 7b via stannyl glycal homocoupling.

Sharma-Swern

modification

(trifluoroacetic

anhydride)^[21]

proceeded imperfectly and exhibited solely the mono-oxidized α-

hydroxy ketone here. Fortunately, oxidation under Albright-

Goldman conditions (acetic anhydride)^[22]turned out to be the

method of choice, for it is known to succeed for hindered alcohols

and can be performed at elevated temperatures. Consequently,

we converted the diol syn-5 into the vicinal diketone 6 with DMSO

and acetic anhydride at 100 °C in 89% yield. Finally, the

protection groups were removed synchronously with trifluoracetic

acid (TFA) to afford dodeco-6,7-diulose 7a in 88% yield.

Sulfoxide-lactone coupling

Since our ambition was to synthesize all symmetrical dodeco-6,7-

diuloses regardless of their configuration, we had to find a route

in which the dihydroxylation of the endo-glycal entity proceeds

selectively from the less favorable re-side. Accordingly, a glucal

moiety had to be converted to a mannose derivative. Common

methods for resolving similar problems are based on substrate-

directing reagents such as molybdenum catalysts,^[23]

Homo-coupling of stannyl glycals

vanadylacetyl

acetonate

(VO(acac)₂)^[7,24]

or

meta-

chloroperbenzoic acid (mCPBA)^[24,25]for an epoxidation.

Thereafter, hydrolysis of the oxirane leads stereoselectively to the

desired configuration. The prerequisite for the application of these

procedures in our case was the presence of a hydroxyl group

adjacent to the double bond which can coordinate the oxidizing

agent to the re-side. Thus, a protection group strategy with

isopropylidene and TBDMS was applied, allowing the orthogonal

deprotection of the allyl position. Attempts to stereoselectively

dihydroxylate endo-glucal dimers analogous to 9a and 9b with

unprotected allyl-positions under the conditions mentioned above,

In a previous study we scrutinized the palladium-catalyzed homo-

coupling reaction of stannylated glycals 8a and 8b for the

preparation of endo-glucal dimers 9a and 9b.^[15]In continuation,

these dimeric enol ethers were now utilized as precursors for the

synthesis of the glucose-dimer 7a and its galactose configurated

counterpart 7b as follows.

Benzylated glucal- and galactal-dimers 9a and 9b were treated

with OsO₄and N-methylmorpholine N-oxide under standard

Upjohn conditions to furnish the symmetrical diuloses 10a and

1

10b in 81% and 89% yield, respectively (Scheme 2). H-NMR-

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resulted in inseparable diastereomeric mixtures since both, the

epoxidation and the subsequent ring-opening occurred

simultaneously at two double bonds. In order to minimize the

formation of various diastereomers, disaccharide scaffolds were

synthesized in which only one glucal moiety had to be oxidized.

Parts of the synthesis presented here have already been

published under the focus of an unexpected rearrangement of an

epoxide to an oxetane.^[26]For better comprehension, our previous

results will be explained briefly. First, the coupling of the anomeric

centers was accomplished by the attack of a lithiated glucal on a

sugar lactone similar to the synthesis of Mochizuki and

Shiozaki.^[12]These authors used stannylated glycals as

precursors which could be converted in situ into the

corresponding highly reactive lithiated glycals by the addition of

n-butyllithium. In 2008 Koncienski et al. reported an alternative

preparation of lithiated glycals by treatment of phenylsulfinyl

glycals with phenyllithium.^[27]Since phenylsulfinyl glycals are

more easily accessible and non-toxic compared to their

stannylated counterparts we chose the known 4,6-isopropylidene-

3-tert-butyldimethylsiliyl-protected phenylsulfinyl glucal 11^[15]as

our starting compound (Scheme 3). Treatment of 11 with

1 equivalent of phenyllithium followed by quenching with

mannono-lactone 12^[28]after 5 minutes furnished the coupling

product 13 in 80% yield as an anomeric mixture (α:β, 1:5). Next,

the anomeric position of the furanose moiety was esterified with

acetic anhydride. Subsequent desilylation was performed with

tetra-n-butylammonium fluoride (TBAF) to excavate the rigid allyl

alcohol system that enables the aspired β-selective epoxidation.

The best epoxidation results were obtained using the Camps

reagent (mCPBA/KF).^[25,29]However, the pure β-epoxide 14 could

not be isolated because of a reversible rearrangement to an

oxetane-bridged disaccharide 15. If the reaction was quenched

early, merely an epoxide-oxetane mixture in a ratio of 8:1 could

be obtained, whereas the formation of oxetane was preferred by

extending the reaction times. The structure of 15 was confirmed

by X-ray crystallography and a mechanistic suggestion for the

unusual rearrangement involving an ester group migration was

provided in our early work.^[26]

In order to avoid such an epoxide-oxetane-rearrangement, the

acetic ester was replaced by an ether protecting group. Thus, the

tertiary alcohol group in compound 13 was masked under

standard benzylation conditions with benzyl bromide and sodium

hydride to afford 16 quantitatively as an inseparable anomeric

mixture (α:β, 1:3.7). After cleavage of the silyl ether with TBAF,

allyl alcohol 17 (α:β, 1:3.7) could be obtained in 98% yield. Next,

the diastereoselective β-epoxidation with Camps reagent was

investigated, and indeed, the rearrangement to oxetane could be

prevented. At this point, the two anomers could be completely

Scheme 3. Synthesis of D-manno- D-manno -Dodeco-6,7-diulose 7c via sulfoxide-lactone coupling.

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separated chromatographically and the oxiranes 18β and 18α

The ¹³C-NMR spectrum of the latter indicates an asymmetric

structure, whereby the stereo descriptors of the anomeric centers

have to be α and β. After we were able to isolate the fully protected

double-sided manno-configured dodeco-6,7-diulose 20, the

protecting groups were cleaved off. Debenzylation of 20 with

palladium on activated charcoal under hydrogen atmosphere

afforded 21 quantitatively. 21 could also be prepared from

compound 15 in a yield of 47% under iron chloride catalyzed

oxetane opening with simultaneous isopropylidenation and acetyl

cleavage. Finally, the acetonides were removed with TFA in an

aqueous tetrahydrofuran solution to afford the target molecule 7c

in quantitative yield.

were isolated in 68% and 11% yields, respectively.

Based on compounds 18β and 15, experiments were first

performed in which first the anomeric protecting groups were

cleaved, followed by acid-catalyzed ring-opening reactions of the

O-heterocycles (epoxide ring in 18β and oxetane ring in 15),

which take place simultaneously with the removal of the

isopropylidene groups. In both cases, however, the formation of

the symmetrical target molecule, as was observed in the case of

compounds 7a and 7b, could not be verified by NMR

spectroscopy. Instead, a product mixture was obtained which

leads to the assumption that the ring-opening of the epoxide and

oxetane rings occured non-selectively and resulted in a mixture of

the desired manno- and the unwanted gluco-configuration. Since

the separation of unprotected mixtures of saccharides generally

proves to be rather difficult, this approach was also not a feasible

option in our situation. We have therefore decided to develop a

synthesis in which both disaccharide units bear the manno-

configuration prior to the final deprotection step. Thus, the oxirane

ring-opening of compound 18β was induced by ferric chloride

catalysis in acetone. The synchronous acetonide protection of the

released hydroxyl groups gave diulose 19 in 44% yield. It is worth

mentioning in this context that a re-acetalation from 1,3-linked

dioxane to a 1,2-linked dioxolane takes place. This was evident

from the chemical shifts of the quaternary carbon atoms in the

¹³C-NMR spectrum of compound 19 (dioxane 97–101 ppm;

dioxolane 108–111 ppm).^[30]Compound 19 was unfortunately not

obtained as a single substance though. The coupling constants of

the major product correspond to those of two mannose fragments.

However, it could not be determined whether it was a mixture of

anomers or gluco- and manno-configured diastereomers.

Nevertheless, the remaining alcohol group in 19 was benzylated

and afforded the diulose 20 in anomerically pure form in 85% yield.

Ramberg-Bäcklund reaction

In 1998 Taylor^[31]and Franck^[32]independently described a new

method for the preparation of C-glycosides via a Ramberg-

Bäcklund rearrangement. Starting from sulfonyl glycosides, exo-

glycals are formed by in situ halogenations followed by base-

induced 1,3-elimination under exclusion of sulfur dioxide. The

easy availability of the starting materials made this approach a

powerful tool for preparing a broad number of new exo-glycals,

which in turn play an important role in the synthesis of C-

glycosidic antibiotics,^[33]glycolipids^[34]or glycopeptides.^[35]

Furthermore, Ramberg-Bäcklund reactions were used to prepare

methylene-

and

ethylene-bridged

trehalose

interested in exploiting this synthetic pathway to gain access to

anomerically linked exo-glucal dimers in which the carbon spacer

between glycoside moieties is completely removed.

We started our synthesis with literature-known peracetylated 1,1-

thio-di-glycopyranoside 22 (Scheme 4).^[39]Since it had proved

successful to conduct the Ramberg-Bäcklund reaction with

benzyl-protected sulfonyl glycosides, the acetyls were replaced

by benzyl ethers. The removal of the acetic esters was performed

Scheme 4. Synthesis of D-gluco-L-gulo-Dodeco-6,7-diulose 7a via Ramber-Bäcklund reaction.

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under standard Zemplén conditions with sodium methanolate,

subsequent benzylation with benzyl bromide and sodium hydride

then gave the thio-bi-glucopyranoside 23 in 88% yield. Next, the

thio group in 23 was oxidized to a sulfone group by mCPBA and

compound 24 could be isolated in 89% yield. For the synthesis of

exo-glucals, two modifications of the Ramberg-Bäcklund reaction

are commonly applied. While Meyer used carbon tetrachloride for

halogenation and potassium hydroxide as the base,^[40]Chan

thereby defining the constitution. The HMBC-NMR spectrum of

compound 7a revealed coupling constants for H-2 and H-11 to the

anomeric carbons C-6 and C-7, whereas in compound 7b the

protons H-3 and H-10 coupled to C-6 and C-7 (Supporting

Information). Consequently, it could be proven unambiguously

that diulose 7a is present as a 6,7-linked trehalose analogue

(type B) and 7b in a more highly annulated form (type A). The

stereo descriptors of the anomeric centers could be defined

considering the NOESY couplings of the anomeric hydroxyl

groups with the surrounding axial protons and were determined

as ββ at both 7a and 7b. Apparently, both compounds occur in

their energetically most favorable form with the fewest possible

axially standing hydroxyl groups. However, if a type B constitution

is predominant, the anomeric alcohols align themselves axially,

allowing a more undisturbed rotation of the pyranose-linking bond.

In the case of the twice manno-configured diulose 7c, there is no

sterically preferred structure, since all discussed variants feature

four axial hydroxyl groups. Indeed, the ¹³C-NMR spectrum reveals

four symmetrical and two asymmetrical isomers in solution. Due

to the high complexity of the NMR spectra and frequent signal

overlays, the stereochemistry of the individual isomers could not

be unambiguously determined. However, the ratios could be

determined by integrating the signals of the anomeric alcohols

and are shown in Table 1. In summary, the following trend could

be noted when inspecting the NMR spectra of the target

employed

a

heterogeneous

system

consisting

of

dibromodifluoromethane and aluminum oxide coated with

potassium hydroxide.^[41]By means of Chan’s protocol (CBr₂F₂,

KOH/Al₂O₃, CH₂Cl₂, t-BuOH, rt), a large number of exo-glucals

could be obtained in high yields. However, sterically demanding

tetra-substituted alkenes could only be prepared using the more

forcing Meyer conditions (CCl₄, KOH, aq. t-BuOH, 60 °C).^[37,42]

However, with regard to the transformation of sulfonyl bi-

glucopyranoside 24 to the highly substituted exo-glucal dimer 25,

we could not confirm this tendency. Under Meyer’s conditions no

conversion could be observed at all, whereas Chan’s method

furnished product 25 as an inseparable diastereomeric mixture

(E:Z, 10:1) in 69% yield. In order to finally achieve the envisaged

diulose scaffold 26, the double bond was dihydroxylated. For

steric reasons though, harsh conditions for epoxidation with

dimethyldioxirane (DMDO) and subsequent acidic hydrolysis with

TFA were mandatory. Thus, compound 26 could only be obtained

in 66% yield. Finally, the benzyl ethers were removed by

hydrogenation with palladium on charcoal to give 7a in

quantitative yield.

compounds. Dodeco-6,7-diuloses, which have

a sterically

preferred conformation, adopt this conformation in solution. If no

conformation is favored, all four symmetric isomers that are

converted into each other and further asymmetric isomers that

occur during the conversion can be observed. This tendency may

serve to finally clarify the configuration of the hypoglycemically

active deco-5,6-diulose Peltalosa. Since the NMR spectrum of

Peltalosa exhibits a symmetrical isomerically pure compound,^[14]

the number of possible configurations could be restricted to two

diuloses (arabino-arabino or xylo-xylo). However, Menzel's work

excluded the possibility that Peltalosa consists of two arabinose

units. Thus, it appeared to be most probable that Peltalosa is a

double xylo-configured deco-5,6-diulose, which is present as a

type B ββ isomer.

Structure determination by NMR spectroscopy

Detailed NMR spectroscopic investigations were carried out to

gain insights into the actual structures of the synthesized diuloses

7a, 7b and 7c. Based on the assumption that the compounds are

symmetrical with two pyranose (six-membered) rings, four

different structural options are possible: two constitutional

isomers (type A and type B; Figure 1) with αα- or ββ-conformation

of the anomeric centers which could be distinguished by HMBC-

and NOESY-NMR spectroscopy. The results of the structural

evaluation are summarized in Table 1. Due to the symmetry of the

molecules there are 6 carbon atoms, each of which has a

spectroscopically equivalent counterpart (C-1 = C-12, C-2 = C-11

etc.) and thus, for simplification, the couplings were only displayed

for one side. HMBC couplings could be used to identify which two

hydroxyl groups were involved in the hemiacetal formation

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Table 1. NMR-spectroscopic structure elucidation of the target compounds 7a, 7b and 7c.

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Compound

HMBC couplings^[a]

NOESY couplings^[a]

Structure^[b]

Constitution / anomeric

Configuration

7a

H-2: C-6

H-11: C-7

OH-6: H-2, H-4, H-8

OH-7: H-5, H-9, H-11

type B / ββ

H-3: C-7

H-10: C-6

OH-6: H-8, H-10

OH-7: H-3, H-5

7b

type A / ββ

7c^[c]

4 symmetrical isomers (S₁, S₂, S₃and S₄)

+ 2 asymmetrical isomers (A₁and A₂)

―

ratio

S₁: S₂

:

S₃: S₄: A₁: A₂

3.57 : 1.96 : 1.47 : 1.00 : 1.78 : 1.30

[a] All NMR spectra were measured in DMSO-d₆and are provided in the supporting information. [b] The HMBC and NOESY couplings

have each been illustrated just for one side of the symmetrical molecule. [c] For none of the six isomers the stereochemistry could

be determined by NMR spectroscopy.

Conclusions

flexible structures preferably adopt double hemiacetal forms with

the least hydroxyl groups in axial orientation.

In this work we have demonstrated that dodeco-6,7-diuloses can

be prepared using a variety of synthetic strategies. Starting from

aldohexoses, four different methods were applied in which the

intermolecular linkage of two anomeric carbons plays a central

role. Thus, the interconnection of two open-chain terminal sugar

alkenes was achieved by Grubbs metathesis, stannylated glycals

were fused to endo-glycalic dimers via a Stille-like homocoupling

reaction and a phenylsulfinyl glucal was added by base-induced

attack on a carbohydrate lactone. In addition, a Ramberg-

Bäcklund rearrangement could be employed to generate a

directly anomerically linked exo-glucalic dimer. Subsequently, all

C1-C1' bridged derivatives could be converted into the desired

target compounds by oxidation and removal of the protecting

groups and a total of three dodeco-6,7-diuoses (gluco-gluco,

galacto-galacto, manno-manno) could be isolated. NMR-

spectroscopic investigations indicated that these highly

Experimental Section

General Methods: All reactions were performed under an

atmosphere of nitrogen using solvents dried by standard

procedures. Reaction progress was monitored by TLC on

Polygram SIL G/UV₂₅₄silicagel plates from Macherey & Nagel.

Detection of spots was effected by charring with sulphuric acid

(5% in ethanol), staining by spraying the plates with an alkaline

aqueous solution of potassium permanganate or by inspection of

the TLC plates under UV light (254 nm). For the R_fvalues of

products 2, 7a, 7b, 7c, 13 and 21 ranges were given, since the

compounds are likely to decompose or anomerically rearrange on

the TLC plates. Preparative flash chromatography was performed

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on silica gel (0.032–0.063 mm) from Macherey & Nagel, using

plastic cartridges from Götec. The flowrate was regulated by a

Sykam S1122 solvent delivery system. For preparative RP C18

chromatography fully end-capped silica gel 100 from Sigma

Aldrich was used. NMR spectra were recorded with the following

spectrometers: Bruker Avance III HD 400 (¹H: 400.2 MHz; ¹³C:

100.6 MHz), Bruker Avance III HDX 600 (¹H: 600.2 MHz; ¹³C:

150.9 MHz) and Bruker Avance III HDX 700 (¹H: 700.3 MHz; ¹³C:

176.1 MHz); and calibrated for the solvent signal (¹H: CDCl₃:

 = 7.26 ppm; acetone-d₆:  = 2.05 ppm; dichloromethane-d₂:

m/z 397.2018 calcd for C₁₈H₃₄O₆SiNa, 397.2017; anal. C 57.36,

H 9.25, calcd for C₁₈H₃₄O₆Si, C 57.72, H 9.15.

5-O-(tert-Butyldimethylsilyl)-3,4:6,7-di-O-isopropylidene-1,2-

dideoxy-D-gluc-1-enitol

(3):

A

solution

of

methyl

triphenylphosphonium bromide (17.5 g, 48.0 mmol) in THF

(60 mL) was treated dropwise with n-butyllithium (1.6 M in n-

hexane, 29.9 mL, 48.0 mmol) at −20 °C. After 15 min the orange

solution was warmed to room temperature and stirring was

continued for 1 h. The reaction mixture was cooled again to –

20 °C and a solution of 2 (4.50 g, 12.0 mmol) in THF (60 mL) was

added slowly. The resulting suspension was brought to ambient

temperature and was stirred for 14 h until TLC indicated complete

conversion of the starting material. Subsequently the mixture was

diluted with diethyl ether (300 mL) and the reaction was quenched

by addition of sat. aq. NH₄Cl-solution (24 mL). The suspension

was filtered through silica gel and the filter cake was washed with

ethyl acetate (3 L). The filtrate was evaporated until 300 mL

remained. The organic residue was washed with brine (3 ×

100 mL), dried with Na₂SO₄and the solvent was removed. After

purification of the crude product by column chromatography

(petroleum ether / ethyl acetate, 20:1) 3 (3.86 g, 10.4 mmol, 87%)

was isolated as a colorless oil. R_f= 0.53 (petroleum ether / ethyl

acetate, 10:1). [α]²_D⁰=+11.4 (c = 1.0, CHCl₃). ¹H-NMR (400 MHz,

CDCl₃): (ppm) = 5.85 (ddd, 1H, J_2,1a= 17.2 Hz, J_2,1b= 10.4 Hz,

J_2,3= 6.8 Hz, H-2), 5.40 (ddd, 1H, J_1a,2= 16.9 Hz, J = 1.4 Hz, J =

1.3 Hz, H-1a), 5.26 (ddd, 1H, J_1b,2= 10.4 Hz, J = 1.2 Hz, J =

1.0 Hz, H-1b), 4.36 (dd, 1H, J_3,4= 8.1 Hz, J_3,2= 7.1 Hz, H-3),

4.06–4.12 (m, 1H, H-6), 3.87–3.97 (m, 3H, H-5, H-7a, H-7b), 3.69

(dd, 1H, J_4,3= 8.2 Hz, J_4,5= 4.4 Hz, H-4), 1.41, 1.41, 1.39, 1.32

(4s, 12H, C(CH₃)₂), 0.91 (s, 9H, SiC(CH₃)₃), 0.12, 0.11 (2s, 6H,

SiCH₃). ¹³C-NMR (101 MHz, CDCl₃): (ppm) = 135.9 (C-2), 118.7

(C-1), 109.0, 108.6 (C(CH₃)₂), 82.9 (C-4), 77.9 (C-3), 76.8 (C-6),

71.9 (C-5), 65.8 (C-7), 27.1, 27.0, 26.6 (C(CH₃)₂), 26.2

(SiC(CH₃)₃), 25.4 (C(CH₃)₂), 18.5 (SiC(CH₃)₃), –3.8, –3.9 (SiCH₃).

HRESIMS m/z 395.2226 calcd for C₁₉H₃₆O₅SiNa, 395.2224; anal.

C 61.50, H 9.82, calcd for C₁₉H₃₆O₅Si, C 61.25, H 9.74.

 = 5.32 ppm;

DMSO-d₆:

 = 2.50 ppm;

¹³C:

CDCl₃:

 =77.16 ppm; acetone-d₆:  = 29.92 ppm; dichloromethane-d₂:

 = 54.0 ppm; DMSO-d₆:  = 39.51 ppm). All NMR-assignments

were proven by 2D-experiments to be correct. ESI-TOF-HRM

spectrometry was performed on

a

Bruker MAXIS 4G

spectrometer. Elemental analyses were obtained from

a

HEKAtech Euro EA 3000 apparatus. Optical rotations were

determined with a Perkin-Elmer Polarimeter 341 in a 10 cm

cuvette at 20 °C with a wavelength of 589 nm (Na-lamp). Melting

points were measured with a Büchi Melting Point M-560

apparatus.

4-O-(tert-Butyldimethylsilyl)-2,3:5,6-di-O-isopropylidene-D-

glucose (2): To a stirred solution of 1 (1.80 g, 3.74 mmol) in 95%

aq. acetone (20 mL) was added N-bromosuccinimide (1.47 g,

8.24 mmol) at –10 °C in portions. After 10 min TLC showed

complete consumption of the starting material and the reaction

was quenched by addition of Na₂S₂O₃(2.5 g) and NaHCO₃

(2.5 g). The mixture was warmed to ambient temperature, the

organic solvent was removed and the aqueous residue was

diluted with CHCl₃(100 mL). Subsequently, the organic phase

was washed with brine (3 × 50 mL) and dried with Na₂SO₄.

Purification by column chromatography (petroleum ether / ethyl

acetate, 5:1) gave 2 (1.27 g, 3.40 mmol, 91%) as a pale yellow oil.

R_f= 0.27–0.41 (petroleum ether / ethyl acetate, 5:1). [α]²_D⁰=+10.4

1

(c = 1.0, CHCl₃). H-NMR (400 MHz, CDCl₃): (ppm) = 9.79 (d,

1H, J_1,2= 1.3 Hz, H-1), 4.39 (dd, 1H, J_2,1= 1.3 Hz, J_2,3= 7.3 Hz,

H-2), 4.07–4.15 (m, 2H, H-3, H-5), 4.03 (dd, 1H, J = 8.1 Hz, J =

6.3 Hz, H-6a), 3.82–3.90 (m, 2H, H-4, H-6b), 1.47, 1.40, 1.36,

1.31 (4s, 12H, C(CH₃)₂), 0.89 (s, 9H, SiC(CH₃)₃), 0.12, 0.11 (2s,

6H, SiCH₃). ¹³C-NMR (101 MHz, CDCl₃): (ppm) = 201.0 (C-1),

110.9, 109.2 (C(CH₃)₂), 80.8 (C-2), 79.2 (C-3), 76.6 (C-5), 73.4

(C-4), 66.8 (C-6), 26.7, 26.7, 26.2 (C(CH₃)₂), 26.1 (SiC(CH₃)₃),

25.3 (C(CH₃)₂), 18.5 (SiC(CH₃)₃), –3.9, –4.1 (SiCH₃). HRESIMS

(E,Z)-3,10-Di-O-(tert-butyldimethylsilyl)-1,2:4,5:8,9:11,12-

tetra-O-isopropylidene-6,7-dideoxy-D-gluco-L-gulo-dodec-6-

enitol (E/Z-4):

A reaction mixture containing 3 (1.72 g,

4.62 mmol) and Stewart-Grubbs catalyst (10 mol%, 26 mg,

46 µmol) in toluene (10 mL) was stirred at 80 °C for 48 h.

Subsequently, the solvent was removed and the crude product

was purified by column chromatography (petroleum ether / ethyl

10.1002/ejoc.202000615

European Journal of Organic Chemistry

FULL PAPER

acetate, 20:1). An inseparable diastereomeric mixture of E-4 and

the crude product by column chromatography (petroleum ether /

ethyl acetate, 10:1) furnished syn-5 (1.22 g, 1.62 mmol, 72%)

and anti-5 (143 mg, 0.190 mmol, 8%) each as white solids.

Recrystallization of syn-5 in n-hexane provides rhombic crystals

suitable for X-ray structural analysis. The X-ray crystal structure

was uploaded at the cambridge crystallographic data centre with

the deposition number CCDC 1998924.

Z-4 (E/Z, 4:1, 939 mg, 1.31 mmol, 57%) was obtained as a yellow

oil.

E-4 (major diastereomer): R_f= 0.38 (petroleum ether / ethyl

1

acetate, 10:1). H-NMR (400 MHz, CDCl₃): (ppm) = 5.92 (dd,

2H, J = 3.0 Hz, J = 1.5 Hz, H-6, H-7), 4.40–4.44 (m, 2H, H-5, H-

8), 4.03–4.08 (m, 2H, H-2, H-11), 3.85–3.97 (m, 6H, H-1a, H-1b,

H-3, H-10, H-12a, H-12b), 3.70 (dd, 2H, J = 8.2 Hz, J = 4.2 Hz, H-

4, H-9), 1.40, 1.40, 1.38, 1.31 (4s, 24H, C(CH₃)₂), 0.90 (s, 18H,

SiC(CH₃)₃), 0.12, 0.10 (2s, 12H, SiCH₃). ¹³C-NMR (101M Hz,

CDCl₃): (ppm) = 130.7 (C-6, C-7), 108.9, 108.7 (C(CH₃)₂), 83.3

(C-4, C-9), 76.9 (C-2, C-11), 76.5 (C-5, C-8), 72.0 (C-3, C-10),

66.1 (C-1, C-12), 27.1, 27.0, 26.6 (C(CH₃)₂), 26.2 (SiC(CH₃)₃),

25.4 (C(CH₃)₂), 18.5 (SiC(CH₃)₃), –3.7, –3.9 (SiCH₃).

syn-5 (major diastereomer): R_f= 0.37 (petroleum ether / ethyl

acetate, 5:1). [α]²_D⁰= 0 (c = 1.0, CHCl₃). M.p. 174 °C (n-hexane).

¹H-NMR (400 MHz, CDCl₃): (ppm) = 4.11–4.22 (m, 4H, H-2, H-

5, H-8, H-11), 4.00–4.08 (m, 4H, H-4, H-9, H-1a, H-12a), 3.97 (dd,

J = 5.1 Hz, J = 4.0 Hz, 2H, H-3, H-10), 3.90 (dd, J = 7.3 Hz, 2H,

H-1b, H-12b), 3.77 (d, J_6,5= J_7,8= 8.3 Hz, 2H, H-6, H-7), 3.05 (br.

s, 2H, OH), 1.42, 1.40, 1.36, 1.33 (4s, 24H, C(CH₃)₂), 0.90 (s, 18H,

SiC(CH₃)₃), 0.14, 0.14 (2s, 12H, SiCH₃). ¹³C-NMR (101 MHz,

CDCl₃): (ppm) = 109.3, 108.8 (C(CH₃)₂), 82.5 (C-4, C-9), 76.9

(C-2, C-11), 75.9 (C-5, C-8), 73.3 (C-3, C-10), 72.7 (C-6, C-7),

66.5 (C-1, C-12), 27.3, 27.2, 26.6 (C(CH₃)₂), 26.2 (SiC(CH₃)₃),

25.3 (C(CH₃)₂), 18.5 (SiC(CH₃)₃), –3.7, –3.9 (SiCH₃). HRESIMS

m/z 773.4300 calcd for C₃₆H₇₀O₁₂Si₂Na, 773.4298; anal. 57.36, H

9.46, calcd for C₃₆H₇₀O₁₂Si₂, C 57.57, H 9.39.

Z-4 (minor diastereomer): R_f= 0.33 (petroleum ether / ethyl

acetate, 10:1). ¹H-NMR (400 MHz, CDCl₃, significant signals):

(ppm) = 5.60 (dd, 1H, J = 6.1 Hz, J = 1.8 Hz, H-6, H-7), 4.60–

4.65 (m, 1H, H-5, H-8).

¹³C-NMR (101 MHz, CDCl₃): (ppm) = 132.8 (C-6, C-7), 109.3

(C(CH₃)₂), 83.6 (C-4, C-9), 76.1 (C-2, C-11)*, 72.7 (C-5, C-8)*,

72.5 (C-3, C-10)*, 65.0 (C-1, C-12), 27.3, 27.1, 26.5 (C(CH₃)₂),

26.1 (SiC(CH₃)₃), 25.2 (C(CH₃)₂), 18.5 (SiC(CH₃)₃), –3.9, –4.1

(SiCH₃). HRESIMS m/z 739.4245 calcd for C₃₆H₆₈O₁₀Si₂Na,

739.4243; anal. C 60.19, H 9.50, calcd for C₃₆H₆₈O₁₀Si₂, C 60.30,

H 9.56.

anti-5 (minor-diastereomer): R_f= 0.26 (petroleum ether / ethyl

acetate, 5:1). [α]²_D⁰= –6.3 (c = 1.0, CHCl₃). M.p. 107 °C (n-

hexane). ¹H-NMR (400 MHz, CDCl₃): (ppm) = 4.05–4.29 (m, 6H,

H-2, H-4, H-5, H-8, H-9, H11), 3.87–4.05 (m, 6H, H-1a, H-1b, H-

3, H-10, H-12a, H-12b), 3.83 (dd, J = 5.6 Hz, J = 1.0 Hz, 1H, H-

6), 3.72–3.79 (m, 1H, H-7), 3.00 (br. s, 2H, OH), 1.43, 1.41, 1.40,

1.39, 1.35, 1.33, 1.32 (7s, 24H, C(CH₃)₂), 0.91, 0.90 (s, 18H,

SiC(CH₃)₃), 0.13, 0.13, 0.12 (3s, 12H, SiCH₃). ¹³C-NMR

(101 MHz, CDCl₃): (ppm) = 109.8, 109.3, 108.7, 108.7 (C(CH₃)₂),

83.0, 78.7, 77.3, 77.2, 76.6, 76.6 (C-2, C-4, C-5, C-8, C-9, C-11),

76.5 (C-7), 73.2, 72.5 (C-3, C-10), 68.7 (C-6), 66.6, 66.1 (C-1, C-

12), 27.6, 27.5, 27.2, 27.0, 26.7, 26.6 (C(CH₃)₂), 26.2, 26.2

(SiC(CH₃)₃), 25.4, 25.2 (C(CH₃)₂), 18.6, 18.5 (SiC(CH₃)₃), –3.6, –

3.8, –3.9, –4.1 (SiCH₃). HRESIMS m/z 773.4297 calcd for

C₃₆H₇₀O₁₂Si₂Na, 773.4298; anal. C 57.48, H 9.48, calcd for

C₃₆H₇₀O₁₂Si₂, C 57.57, H 9.39.

*Signals can be interchanged

3,10-Di-O-(tert-butyldimethylsilyl)-1,2:4,5:8,9:11,12-tetra-O-

isopropylidene-D-erythro-L-galacto-L-gulo-dodecositol (syn-

5) and 3,10-Di-O-(tert-butyldimethyl-silyl)-1,2:4,5:8,9:11,12-

tetra-O-isopropylidene-D-erythro-L-gulo-L-gulo-dodecositol

(anti-5): To a stirred solution of diasteromeric mixture E/Z-4 (E/Z,

4:1) (1.63 g, 2.27 mmol) and N-methylmorpholine N-oxide

(1.86 g, 15.9 mmol) in acetone (40 mL) and water (8 mL) was

added OsO₄(4% in water, 2.9 mL, 0.454 mmol) at room

temperature. After 20 h TLC showed complete conversion of the

starting material and the reaction mixture was diluted with ethyl

acetate (80 mL). To reduce the Os(VIII)-species, sat. aq.

Na₂S₂O₃-solution (8 mL) was added and stirring was continued

for further 20 min. Sodium chloride was added till saturation and

the organic layer was separated, washed with sat. aq. Na₂S₂O₃-

solution (3 × 50 mL) and brine (2 x 50 mL). The organic layer was

dried with MgSO₄and the solvent was removed. Purification of

3,10-Di-O-(tert-butyldimethylsilyl)-1,2:4,5:8,9:11,12-tetra-O-

isopropylidene-D-gluco-L-gulo-dodeco-6,7-diulose (6): To a

solution of syn-5 (553 mg, 0.74 mmol) in DMSO (5.5 mL) was

added acetic anhydride (2.1 mL, 22.2 mmol) and the reaction

mixture was stirred for 2 h at 100 °C until TLC indicated complete

consumption of the starting material. The volatile compounds

10.1002/ejoc.202000615

European Journal of Organic Chemistry

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were removed and the crude residue was purified by column

chromatography (petroleum ether / ethyl acetate, 10:1) to furnish

6 (495 mg, 0.66 mmol, 89%) as a yellow viscous liquid. R_f= 0.80

(petroleum ether / ethyl acetate, 3:1). [α]²_D⁰= +25,3 (c = 1.0,

HRESIMS m/z 853.3711 calcd for C₅₄H₅₄O₈Na, 853.3711; anal. C

78.19, H 6.55, calcd for C₅₄H₅₄O₈, C 78.05, H 6.55.

2,6:7,11-Dianhydro-5,8-dideoxy-1,3,4,9,10,12-hexakis-O-

benzyl-D-threo-L-galo-dodeco-5,7-dienitol (9b):^[15]Following

general procedure A dimer 9b was obtained as a yellow, viscous

oil and was prepared from 8b in 84% yield by stirring the reaction

mixture for 2 h. A mixture of petroleum ether / ethyl acetate 5:1

containing 0.5% triethylamine was used as the eluent for column

chromatography. R_f= 0.46 (petroleum ether / ethyl acetate 3:1).

CHCl₃). ¹H-NMR (400 MHz, CDCl₃): (ppm) = 4.97 (d, J_5,4= J_8,9

6.7 Hz, 2H, H-5, H-8), 4.36 (dd, J_4,5= J_8,9= 6.7 Hz, J_4,3= J_9,10

=

4.5 Hz, 2H, H-4, H-9), 4.07 (dd, J = 6.2 Hz, J = 6.2 Hz, 2H, H-2,

H-11), 4.00–4.04 (m, 2H, H-1a, H-12a), 3.89–3.94 (m, 4H, H-1b,

H-3, H-10, H-12b), 1.45, 1.39, 1.29, 1.28 (4s, 24H, C(CH₃)₂), 0.90

(s, 18H, SiC(CH₃)₃), 0.14, 0.12 (2s, 12 H, Si(CH₃)₂). ¹³C-NMR

(100 MHz, CDCl₃): (ppm) = 199.3 (C-6, C-7), 111.3, 108.9

(C(CH₃)₂), 79.3 (C-5, C-8), 77.6 (C-4, C-9), 76.5 (C-2, C-11), 73.1

(C-3, C-10), 66.5 (C-1, C-12), 26.7, 26.5, 26.0 (C(CH₃)₂), 26.0

(SiC(CH₃)₃), 25.2 (C(CH₃)₂), 18.3 (SiC(CH₃)₃), –4.1, –4.1

[α]²_D⁰= –44.4 (c = 1.0, CHCl₃). H-NMR (400 MHz, in CDCl₃): 

1

(ppm) = 7.26−7.33 (m, 30H, Ph), 5.49 (d, J_5,4= J_8,9= 3.2 Hz, 2H,

H-5, H-8), 4.85 (d, J = 11.9 Hz, 2H, PhCH₂), 4.57–4.70 (m, 6H,

PhCH₂), 4.45–4.53 (m, 4H, PhCH₂), 4.22–4.29 (m, 4H, H-2, H-4,

H-9, H-11), 3.94 (dd, J_3,2= J_10,11= 3.1 Hz, J_3,4= J_10,9= 3.1 Hz, 2H,

H-3, H-10), 3.75−3.84 (m, 4H, H-1a, H-1b, H-12a, H-12b). ¹³C-

NMR (101 MHz, in CDCl₃):  (ppm) = 146.6 (C-6, C-7), 138.7,

138.6, 138.3, 128.5, 128.5, 128.4, 128.2, 127.9, 127.7, 127.6 (Ph),

97.7 (C-5, C-8), 76.5 (C-2, C-11), 73.5, 73.2 (PhCH₂), 71.5 (C-3,

C-10), 71.1 (C-4, C-9), 71.0 (PhCH₂), 68.4 (C-1, C-12). HRESIMS

m/z 853.3713 calcd for C₅₄H₅₄O₈Na, 853.3711; anal. C 77.95, H

6.76, calcd for C₅₄H₅₄O₈, C 78.05, H 6.55.

(Si(CH₃)₂).

HRESIMS

m/z

801.4249

calcd

for

C₃₆H₆₆O₁₂Si₂NaMeOH, 801.4247.

General procedure A for homocoupling of stannyl glycals 8a

and 8b:^[15]

A solution of stannylated glycal 8a or 8b (1 mmol scale) in DMF

(10 mL) was treated PdCl₂(CH₃CN)₂(0.1 eq) and copper-1-

thiophene-2-carboxylate (CuTC) (1 eq). The dark suspension was

stirred at ambient temperature. After complete consumption of the

starting material (TLC) silicagel (500 wt%) was added and the

solvent was evaporated. The residue was purified by column

chromatography.

General procedure B for bis-dihydroxylation of 9a and 9b:

To a solution of glycal-dimer 9a or 9b (0.5 mmol scale) in a

solvent mixture of thf, t-BuOH and water (5/1/1, 7 mL) was added

N-methylmorpholine N-oxide (3 eq.) and OsO₄(4% in water,

0.1 eq.) at ambient temperature. After complete transformation of

the starting material, the reaction was quenched by addition of sat.

aq. Na₂S₂O₃-solution (5 mL) and stirring was continued for 30 min.

Subsequently the aqueous layer was extracted with ethyl acetate

(3 ×10 mL), the combined organic layers were washed with brine

(2 ×10 mL) and dried with Na₂SO₄. The solvent was evaporated

and the residue was purified by column chromatography.

2,6:7,11-Dianhydro-5,8-dideoxy-1,3,4,9,10,12-hexakis-O-

benzyl-D-erythro-L-gulo-dodeco-5,7-dienitol (9a):^[15]Following

general procedure A dimer 9a was obtained as a white solid and

was prepared from 8a in 90% yield by stirring the reaction mixture

for 10 min. A mixture of petroleum ether / ethyl acetate 7:1

containing 0.5% Et₃N was used as the eluent for column

chromatography. R_f= 0.60 (petroleum ether / ethyl acetate 2:1).

[α]²_D⁰= –39.5 (c = 1.0, CHCl₃). M.p. 114 °C (acetone). H-NMR

1

1,3,4,9,10,12-Hexakis-O-benzyl-D-gluco-L-gulo-dodeco-6,7-

diulose (10a): Following general procedure B 10a was obtained

as a white foam and was prepared from 9a in 89% yield by stirring

the reaction mixture for 20 h. A mixture of petroleum ether / ethyl

acetate 3:1 was used as the eluent for column chromatography.

R_f= 0.30 (petroleum ether / ethyl acetate 2:1). [α]²_D⁰= +50.3 (c =

(400 MHz, in CDCl₃):  (ppm) = 7.28–7.37 (m, 30H, Ph), 5.55 (d,

J_5,4= J_8,9= 2.9 Hz, 2H, H-5, H-8), 4.85 (d, J = 11.4 Hz, 2H, PhCH₂),

4.55–4.71 (m, 10H, PhCH₂), 4.31 (dd, J_4,3= J_9,10= 5.9 Hz, J_4,5

=

J_9,8= 3.0 Hz, 2H, H-4, H-9), 4.15 (ddd, J_2,3= J_11,10= 8.3 Hz, J =

3.9 Hz, J = 3.9 Hz, 2H, H-2, H-11), 3.91 (dd, J_3,2= J_10,11= 8.4 Hz,

J_3,4= J_10,9= 6.1 Hz, 2H, H-3, H-10), 3.80–3.88 (m, 4H, H-1a, H-

1b, H-12a, H-12b). ¹³C-NMR (101 MHz, in CDCl₃):  (ppm) =

147.3 (C-6, C-7), 138.5, 138.4, 138.3, 128.5, 128.1, 127.9, 127.7,

127.7 (Ph), 98.0 (C-5, C-8), 77.6 (C-2, C-11), 76.1 (C-4, C-9), 74.4

(C-3, C-10), 73.7, 73.5, 70.5 (PhCH₂), 68.7 (C-1, C-12).

1

1.0, CHCl₃). H-NMR (400 MHz, in CDCl₃): (ppm) = 7.18–7.37

(m, 30H, Ph), 4.79–4.94 (m, 6H, PhCH₂), 4.63 (br. s, 2H, OH),

4.50–4.58 (m, 4H, PhCH₂), 4.42 (d, J = 12.1 Hz, 2H, PhCH₂), 4.09

(d, J_5,4= J_8,9= 9.2 Hz, 2H, H-5, H-8), 3.97 (ddd, J = 10.0 Hz, J =

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European Journal of Organic Chemistry

FULL PAPER

2.4 Hz, J = 2.4 Hz, 2H, H-2, H-11), 3.82 (dd, J_4,3= J_9,10= 9.2 Hz,

J_4,5= J_9,8= 9.2 Hz, 2H, H-4, H-9), 3.60–3.76 (m, 6H, H-1a, H-1b,

H-3, H-10, H-12a, H-12b), 3.34 (br. s., 2H, OH). ¹³C-NMR

(101 MHz, CDCl₃): (ppm)= 138.9, 138.3, 138.2, 128.6, 128.5,

128.5, 128.1, 128.0, 127.9, 127.9, 127.8, 127.8 (Ph), 97.7 (C-6,

C-7), 83.0 (C-4, C-9), 77.2 (C-3, C-10), 75.6, 75.1, 73.3 (PhCH₂),

72.6 (C-5, C-8), 71.5 (C-2, C-11), 68.0 (C-1, C-12). HRESIMS m/z

921.3821 calcd for C₅₄H₅₈O₁₂Na, 921.3821; anal. C 72.28, H 6.61,

calcd for C₅₄H₅₈O₁₂, C 72.14, H 6.50.

CH₂Cl₂(3 × 20 mL) and the combined organic layers were dried

with Na₂SO₄. Removing of the solvent followed by column

chromatography (methylene chloride / ethyl acetate 5:1) furnished

13 (2.77 mg, 4.97 mmol, 80%, anomeric mixture α:β, 1:5) as a

colorless crystalline solid. R_f= 0.22–0.46 (methylene chloride /

ethyl acetate 5:1).

1

13β^*(major anomer): H-NMR (400 MHz, CDCl₃): (ppm) = 5.04

(d, J_5,4= 2.2 Hz, 1H, H-5), 4.82 (dd, J_9,8= 5.7 Hz, J_9,10= 3.5 Hz,

1H, H-9), 4.53 (d, J_8,9= 5.9 Hz, 1H, H-8), 4.38–4.44 (m, 1H, H-11),

4.33–4.35 (m, 1H, H-4), 4.15 (dd, J_10,11= 7.2 Hz, J_10,9= 3.5 Hz,

1H, H-10), 4.07–4.11 (m, 1H, H-12a), 4.03 (dd, J = 8.7 Hz, J =

4.9 Hz, 1H, H-12b), 3.86–3.95 (m, 2H, H-1a, H-1b), 3.71–3.76 (m,

2H, H-2, H-3), 2.77 (s, 1H, OH), 1.50, 1.44, 1.42, 1.40, 1.38, 1.31

(6s, 18H, C(CH₃)₂), 0.87 (s, 9H, SiC(CH₃)₃), 0.07, 0.06 (2s,

6H,SiCH₃). ¹³C-NMR (101 MHz, CDCl₃): (ppm) = 150.4 (C-6),

113.3, 109.1 (C(CH₃)₂), 104.3 (C-5), 103.4 (C-7), 99.4 (C(CH₃)₂),

86.7 (C-8), 80.0 (C-9), 79.4 (C-10), 73.2 (C-11), 72.9 (C-3), 70.2

(C-2), 68.2 (C-4), 66.7 (C-12), 61.7 (C-1), 28.9, 26.8, 25.8

(C(CH₃)₂), 25.7 (SiC(CH₃)₃), 25.4, 25.0, 19.1 (C(CH₃)₂), 18.1

(SiC(CH₃)₃), –4.4, –4.8 (SiCH₃).

1,3,4,9,10,12-Hexakis-O-benzyl-D-galacto-L-galacto-dodeco-

6,7-diulose (10b): Following general procedure B 10b was

obtained as a yellow foam and was prepared from 9b in 89% yield

by stirring the reaction mixture for 60 h. A mixture of petroleum

ether / ethyl acetate 2:1 was used as the eluent for column

chromatography. R_f= 0.58 (petroleum ether / ethyl acetate 1:1).

[α]²_D⁰= +36.3 (c = 1.0, CHCl₃). ¹H-NMR (400 MHz, in CDCl₃):

(ppm) = 7.22–7.35 (m, 30H, Ph), 4.89 (d, J = 11.9 Hz, 2H,

PhCH₂), 4.64–4.74 (m, 4H, PhCH₂), 4.54–4.61 (m, 4H, H-5, H-8,

PhCH₂), 4.39–4.48 (m, 4H, PhCH₂), 4.16 (dd, J_2,1a= J_11,12a= J_2,1b

= J_11,12b= 6.7 Hz, 2H, H-2, H-11), 3.98 (d, J_3,4= J_10,9= 1.8 Hz, 2H,

H-3, H-10), 3.79 (dd, J_4,5= J_9,8= 9.8 Hz, J_4,3=J_9,10= 2.8 Hz, 2H,

H-4, H-9), 3.63 (dd, J_1a,1b= J_12a,12b= 9.2 Hz, J_1a,2= J_12a,11= 7.8 Hz,

2H, H-1a, H-12a), 3.52 (dd, J_1b,1a= J_12b,12a= 9.3 Hz, J_1b,2= J_12b,11

= 5.6 Hz, 2H, H-1b, H-12b). ¹³C-NMR (101 MHz, CDCl₃): (ppm)

= 139.0, 138.4, 138.2, 128.6, 128.5, 128.3, 127.9, 127.9, 127.8,

127.8, 127.6, 127.4 (Ph), 98.1 (C-6, C-7), 80.0 (C-4, C-9), 74.2

(PhCH₂), 73.6 (PhCH₂, C-3, C-10), 72.7 (PhCH₂), 70.7 (C-2, C-

11), 68.7 (C-1, C-12), 68.6 (C-5, C-8). HRESIMS m/z 921.3838

calcd for C₅₄H₅₈O₁₂Na, 921.3821; anal. C 72.22, H 6.56, calcd for

C₅₄H₅₈O₁₂, C 72.14, H 6.50.

1

13α^*(minor anomer): H-NMR (400 MHz, CDCl₃): (ppm) = 5.07

(d, J_5,4= 2.1 Hz, 1H, H-5), 4.79 (dd, J_9,8= 6.0 Hz, J_9,10= 3.7 Hz,

1H, H-9), 4.62 (d, J_8,9= 6.0 Hz, 1H, H-8), 4.34–4.35 (m, 2H, H-4,

H-11), 4.10–4.11 (m, 1H, H-12a), 4.01–4.02 (m, 1H, H-12b),

3.85–3.88 (m, 2H, H-1a, H-1b, 3.76–3.80 (m, 3H, H-2, H-3, H-10),

2.77 (s, 1H, OH), 1.57, 1.49, 1.42, 1.40, 1.36 (5s, 18H, C(CH₃)₂),

0.88 (s, 9H, SiC(CH₃)₃), 0.08, 0.07 (2s, 6H, SiCH₃). ¹³C-NMR

(101 MHz, CDCl₃): (ppm) = 150.8 (C-6), 113.6, 109.3 (C(CH₃)₂),

103.1 (C-5), 100.6 (C-7), 99.6 (C(CH₃)₂), 80.7 (C-8), 80.0 (C-9),

78.6 (C-10), 73.2 (C-11), 72.8 (C-3), 70.3 (C-2), 67.8 (C-4), 67.2

(C-12), 61.7 (C-1), 28.9, 26.9, 25.9 (C(CH₃)₂), 25.8 (SiC(CH₃)₃),

25.2, 24.6, 19.0 (C(CH₃)₂), 18.2 (SiC(CH₃)₃), –4.4, –4.8 (SiCH₃).

HRESIMS m/z 581.2757 calcd for C₂₉H₄₈O₁₀SiNa, 581.2752; anal.

C 58.37, H 8.21, calcd for C₂₉H₄₈O₁₀Si, C 58.04, H 8.39.

2,6-Anhydro-5-deoxy-4-O-(tert-butyldimethylsilyl)-

1,3:8,9:11,12-tri-O-isopropylidene-D-arabino-L-gulo-dodeco-

7-ulo-6-enitol (13):^[26]To a suspension of 11 (2.62 g, 6.18 mmol)

and grounded molecular sieve (3 Å, 30 mg) in THF (40 mL) was

added phenyllithium (1.9 M in Bu₂O, 3.57 mL, 6.79 mmol) at

−78 °C over a period of 15 min. After 5 min a further solution

containing 12 (1.75 g, 6.79 mmol) in THF (20 mL) was added

dropwise over a period of 30 min. Subsequently the reaction

mixture was stirred for 2 h at the same temperature before the

cooling bath was removed. The reaction was quenched by

addition of sat. aq. NH₄Cl-solution (60 mL) at ambient

temperature and the molecular sieve was filtered off. The organic

layer was separated, the aqueous layer was extracted with

*Anomers 13β and 13α could be interchanged

5,6-Anhydro-7-O-acetyl-1,3:8,9:11,12-tri-O-isopropylidene-β-

D-manno-β-D-manno-dodeco-6,7-diulo-2,6-pyranose-7,10-

furanose (14) and 5,7-Anhydro-6-O-acetyl-1,3:8,9:11,12-tri-O-

isopropylidene-β-D-manno-β-D-manno-dodeco-6,7-diulo-2,6-

pyranose-7,10-furanose (15):^[26]

Acetylation: A solution of 13 (0.5 mmol scale) and DMAP

(0.2 eq.) in triethylamine (7 mL) was treated with acetic anhydride

10.1002/ejoc.202000615

European Journal of Organic Chemistry

FULL PAPER

(10 eq.) at 0 °C. After stirring for 12 h at ambient temperature until

TLC indicated complete transformation of the starting material,

the reaction mixture was diluted with ethyl acetate (20 mL). The

organic phase was washed with 1 N hydrochloric acid (3 × 10 mL),

sat. aq. NH₄Cl-solution (1 × 10 mL) and brine (1 × 10 mL). The

solution was dried with Na₂SO₄, the solvent was removed and the

crude product was purified by column chromatography (petroleum

ether / ethyl acetate 5:1) to afford the acetylated product as a

colorless crystalline solid in 96% yield.

10), 3.85–4.06 (m, 5H, H-1a, H-3, H-4, H-12a, H-12b), 3.77 (dd,

J = 10.7 Hz, J = 10.7 Hz, 1H, H-1b), 3.66 (d, J_5,4= 2.4 Hz, 1H, H-

5), 3.49 (ddd, J = 10.2 Hz, J = 10.2 Hz, J = 5.7 Hz, 1H, H-2), 2.38

(br. s., 1H, OH), 2.06 (s, 3H, COCH₃), 1.57, 1.48, 1.42, 1.39, 1.35,

1.33 (6s, 18H, C(CH₃)₂). ¹³C-NMR (101 MHz, CDCl₃): (ppm) =

169.2 (CO), 114.2, 109.2 (C(CH₃)₂), 107.9 (C-7), 99.7 (C(CH₃)₂),

86.2 (C-8), 85.0 (C-6), 82.9 (C-10), 79.9 (C-9), 73.2 (C-11), 73.0

(C-3), 70.6 (C-2), 69.9 (C-4), 66.4, 61.7 (C-1), 57.3 (C-5), 29.1,

27.0, 25.6, 25.3, 24.6 (C(CH₃)₂), 21.9 (COCH₃), 19.3 (C(CH₃)₂).

HRESIMS m/z 525.1945 calcd for C₂₃H₃₄O₁₂Na, 525.1943.

Desilylation: The acetylated product was dissolved in THF

(5 mL) and TBAF (1.0 M in THF, 1.5 eq.) was added at 0 °C. The

reaction mixture was warmed to room temperature and stirring

was continued for 20 h until complete conversion of the starting

material was detected by TLC. Subsequently, the solution was

diluted with CH₂Cl₂(10 mL) and washed with brine (3 × 5 mL).

The aqueous phase was extracted with CH₂Cl₂(2 × 10 mL) and

the combined organic phases were dried with Na₂SO₄. The

solvent was evaporated and the residue was purified by column

chromatography (petroleum ether / ethyl acetate 2:1 containing

0.5% Et₃N). The desilylated product was obtained as a white

amorphous solid in 71%.

Quenching the reaction after 40 h and filtering off the solid

mCPBA/KF complex in the meantime furnished 15 as a white

crystalline solid in 70% yield. A mixture of petroleum ether / ethyl

acetate 2:1 was used as the eluent for column chromatography.

R_f= 0.51 (petroleum ether / ethyl acetate 1:2). [α]²_D⁰= +18.5 (c =

1.0, CHCl₃). M.p. 151 °C (n-hexane / ethyl acetate). ¹H-NMR

(400 MHz, DMSO-d₆): (ppm) = 5.30 (d, J_OH,₄= 5.3 Hz, 1H, OH),

4.89 (d, J_8,9= 5.5 Hz, 1H, H-8), 4.78 (d, J_5,4= 4.5 Hz, 1H, H-5),

4.67 (dd, J_9,8= 5.6 Hz, J_9,10= 3.9 Hz, 1H, H-9), 4.23 (ddd, J_11,10

=

6.6 Hz, J = 6.6 Hz, J = 5.5 Hz, 1H, H-11), 3.95–4.04 (m, 2H, H-3,

H-12a), 3.82–3.90 (m, 2H, H-1a, H-12b), 3.79 (dd, J_10,11= 7.2 Hz,

J_10,9= 3.9 Hz, 1H, H-10), 3.71 (ddd, J_4,3= 9.5 Hz, J_4,5

=

Epoxidation / Oxetane-shift: To a solution of mCPBA (2.5 eq.)

in CH₂Cl₂(10 mL) was added potassium fluoride (5 eq.) and the

resulting suspension was stirred for 30 min at ambient

temperature. A solution containing the desilylated product

(0.5 mmol scale) in CH₂Cl₂(10 mL) was added in one portion and

stirring was continued for 2 h (epoxidation). To enforce the

rearrangement to the oxetanes the reaction mixture was stirred

for 20 h, the white precipitate was filtered off and the solution was

stirred for further 20 h. The reaction was quenched by addition of

sat. aq NaHCO₃-solution (10 mL) and sat. aq. Na₂S₂O₃-solution

(10 mL). Subsequently, the aqueous layer was extracted by

CH₂Cl₂(3 × 10 mL), the combined organic layers were dried with

Na₂SO₄, the solvent was removed and the crude product was

purified by column chromatography.

4.9 Hz,J_4,OH= 4.9 Hz, 1H, H-4), 3.58–3.68 (m, 2H, H-1b H-2), 2.07

(s, 3H, COCH₃), 1.45, 1.44, 1.33, 1.32, 1.30, 1.26 (6s, 18H,

C(CH₃)₂). ¹³C-NMR (101 MHz, DMSO-d₆): (ppm) = 169.4 (CO),

112.8 (C(CH₃)₂), 111.9 (C-7), 108.3 (C(CH₃)₂), 98.9 (C(CH₃)₂),

97.4 (C-6), 81.9 (C-5), 78.9 (C-10), 78.2 (C-8), 78.0 (C-9), 72.8

(C-11), 70.1 (C-3), 69.1 (C-2), 67.1 (C-4), 66.1 (C-12), 60.9 (C-1),

28.8, 26.5, 25.7, 25.6, 25.2 (C(CH₃)₂), 20.7 (COCH₃), 18.8

(C(CH₃)₂). HRESIMS m/z 525.1932 calcd for C₂₃H₃₄O₁₂Na,

525.1943; anal. C 55.08, H 7.11, calcd for C₂₃H₃₄O₁₂, C 54.97, H

6.82.

2,6-Anhydro-5-deoxy-7-O-benzyl-4-O-(tert-

butyldimethylsilyl)-1,3:8,9:11,12-tri-O-isopropylidene-α/β-D-

manno-D-lyxo-dodeco-6-enitol (16): To a solution of 13 (200 mg,

0.358 mmol) and benzyl bromide (85 μL, 0.716 mmol) in DMF

(2 mL) was added sodium hydride (60% in mineral oil, 29 mg,

0.716 mmol) at 0 °C. Subsequently the reaction mixture was

brought to ambient temperature and stirring was continued for 3 h,

until TLC showed complete transformation of the starting material.

The reaction was quenched by addition of methanol and the

solvent was removed. The residue was diluted with ethyl acetate

(15 mL) and the solution was washed with water (2 × 5 mL) and

Quenching the reaction after 2 h afforded a mixture of 14 and 15

(8:1) as a white amorphous solid in 94% yield. A mixture of

petroleum ether / ethyl acetate 3:1 containing 0.5% Et₃N was

used as the eluent for column chromatography. R_f= 0.58

(petroleum ether / ethyl acetate 1:2).

1

14: H-NMR (400 MHz, CDCl₃): (ppm) = 4.96 (d, J_8,9= 6.0 Hz,

1H, H-8), 4.91 (dd, J_9,8= 6.0 Hz, J_9,10= 3.9 Hz, 1H, H-9), 4.31–

4.38 (m, 1H, H-11), 4.20 (dd, J_10,11= 6.6 Hz, J_10,9= 3.9 Hz, 1H, H-

10.1002/ejoc.202000615

European Journal of Organic Chemistry

FULL PAPER

brine (2 × 5 mL). Afterwards the aqueous phase was extracted

with methylene chloride (2 × 10 mL) and the combined organic

phases were dried with Na₂SO₄. The solvent was removed and

the crude product was purified by column chromatography

(methylene chloride / ethyl acetate, gradient 100:1 – 1:1) to isolate

16 (229 mg, 0.353 mmol, 99%, anomeric mixture α:β, 1:3.7) as a

colorless amorphous solid. R_f= 0.38 (chloroform).

(m, 1H, H-2), 1.49, 1.41, 1.37, 1.33, 1.31, 1.27 (6s, 18H, C(CH₃)₂).

¹³C-NMR (101 MHz, acetone-d₆): (ppm) = 148.6 (C-6), 139.5,

129.1, 128.9, 128 (Ph), 113.4, 109.3 (C(CH₃)₂), 108.3 (C-7), 106.8

(C-5), 100.1 (C(CH₃)₂), 87.2 (C-8), 80.9 (C-9), 80.6 (C-10), 74.2

(C-3), 74.1 (C-11), 71.0 (C-2), 67.9 (C-4), 67.3 (C-12), 65.1

(PhCH₂), 62.4 (C-1), 27.1, 26.4, 25.8, 25.3, 19.5 (C(CH₃)₂).

HRESIMS m/z 557.2348 calcd for C₂₈H₃₈O₁₀Na, 557.2357.

1

16β (major anomer): H-NMR (400 MHz, acetone-d₆): (ppm) =

5,6-Anhydro-7-O-benzyl-1,3:8,9:11,12-tri-O-isopropylidene-

β-D-manno-β-D-manno-dodeco-6,7-diulo-2,6-pyranose-7,10-

furanose (18β) and 5,6-Anhydro-7-O-acetyl-1,3:8,9:11,12-tri-

O-isopropylidene-α-D-manno-β-D-manno-dodeco-6,7-diulo-

2,6-pyranose-7,10-furanose (18α): To a solution of mCPBA

(1.61 g, 7.20 mmol) in CH₂Cl₂(40 mL) was added potassium

fluoride (837 mg, 14.4 mmol) and the resulting suspension was

stirred for 30 min at room temperature. A solution containing 15

(1.54 g, 2.88 mmol) in CH₂Cl₂(20 mL) was added in one portion

and stirring was continued for 3 h until TLC indicated complete

consumption of the starting material. The reaction was quenched

by addition of sat. aq. NaHCO₃-solution (20 mL) and sat. aq.

Na₂S₂O₃-solution (20 mL). Subsequently the aqueous layer was

extracted by CH₂Cl₂(3 × 20 mL), the combined organic layers

were dried with Na₂SO₄, the solvent was removed and the crude

product was purified by column chromatography (petroleum ether

/ ethyl acetate 3:1 containing 0.5% Et₃N). 18β (1.08 g, 1.96 mmol,

68%) and 18α (173 mg, 0.314 mmol, 11%) were isolated as white

crystalline solids.

7.29–7.36 (m, 5H, Ph), 5.14 (d, J_5,4= 2.1 Hz, 1H, H-5), 4.85 (dd,

J_9,8= 5.7 Hz, J_9,10= 3.3 Hz, 1H, H-9), 4.57 (d, J_8,9= 5.7 Hz, 1H,

H-8), 4.38–4.47 (m, 4H, H-4, H-11, PhCH₂), 4.01–4.07 (m, 3H, H-

10, H-12a, H-12b), 3.80–3.89 (m, 2H, H-1a, H-1b), 3.74–3.77 (m,

1H, H-3), 3.63–3.67 (m, 1H, H-2), 1.50, 1.42, 1.37, 1.36, 1.32,

1.27 (6s, 18H, C(CH₃)₂), 0.90 (s, 9H, SiC(CH₃)₃), 0.11, 0.10 (2s,

6H, SiCH₃). ¹³C-NMR (101 MHz, acetone-d₆): (ppm) = 148.9 (C-

6), 139.5, 129.1, 128.9, 128.3 (Ph), 113.5, 109.2 (C(CH₃)₂), 108.4

(C-7), 106.8 (C-5), 100.1 (C(CH₃)₂), 87.3 (C-8), 81.0 (C-9), 80.6

(C-10), 74.2 (C-11), 74.2 (C-3), 71.0 (C-2), 69.4 (C-4), 67.2 (C-

12), 65.3 (PhCH₂), 62.3 (C-1), 27.0, 26.4, 26.3 (C(CH₃)₂), 26.2

(SiC(CH₃)₃), 25.9, 25.4, 19.5 (C(CH₃)₂), 18.8 (SiC(CH₃)₃), –4.0, –

4.5 (SiCH₃). HRESIMS m/z 671.3209 calcd for C₃₄H₅₂O₁₀SiNa,

671.3222.

2,6-Anhydro-5-deoxy-7-O-benzyl-1,3:8,9:11,12-tri-O-

isopropylidene-α/β-D-manno-D-lyxo-dodeco-6-enitol

(17):

TBAF (1.0 M in THF, 5.98 mL, 5.89 mmol) was added to a

solution of 16 (1.91 g, 2.94 mmol) in THF (20 mL) at 0 °C. The

reaction mixture was warmed to room temperature and stirring

was continued until complete conversion of the starting material

was detected by TLC. Subsequently the solution was diluted with

CH₂Cl₂(50 mL) and washed with brine (3 × 20 mL). The aqueous

phase was extracted with CH₂Cl₂(2 × 30 mL) and the combined

organic phases were dried with Na₂SO₄. The solvent was

evaporated and the residue was purified by column

chromatography (petroleum ether / ethyl acetate 2:1 containing

0.5% Et₃N). 17 (1.54 g, 2.88 mmol, 98%, anomeric mixture α:β,

1:3.7) was obtained as a colorless amorphous solid. R_f= 0.31

(petroleum ether / ethyl acetate 2:1).

18β (major product): R_f= 0.40 (chloroform / ethyl acetate 2:1).

[α]²_D⁰= +1.1 (c = 1.0, CHCl₃). M.p. 77 °C (n-hexane / ethyl

acetate).¹H-NMR (400 MHz, acetone-d₆): (ppm) = 7.32–7.44 (m,

4H, Ph), 7.25–7.31 (m, 1H, Ph), 4.85 (dd, J_9,8= 5.9 Hz, J_9,10

=

3.7 Hz, 1H, H-9), 4.66–4.70 (m, 2H, PhCH₂, H-8), 4.63 (br. s., 1H,

OH), 4.61 (d, J = 11.7 Hz, 1H, PhCH₂), 4.36 (dd, J = 12.1 Hz, J =

6.1 Hz, 1H, H-11), 4.00–4.05 (m, 3H, H-4, H-12a, H-12b), 3.97

(dd, J_10,11= 5.9 Hz, J_10,9= 3.7 Hz, 1H, H-10), 3.85 (dd, J_3,2

10.2 Hz, J_3,4= 8.2 Hz, 1H, H-3), 3.79 (dd, J_1a,1b= 10.9 Hz, J_1a,2

=

5.6 Hz, 1H, H-1a), 3.65 (dd, J_1b,1a= J_1b,2= 10.5 Hz, 1H, H-1b),

3.56 (d, J_5,4= 2.4 Hz, 1H, H-5), 3.50 (ddd, J_2,1b= J_2,3= 10.2 Hz,

J_2,1a= 5.5 Hz, 1H, H-2), 1.48, 1.44, 1.33, 1.29 (4s, 18H, C(CH₃)₂).

¹³C-NMR (101 MHz, acetone-d₆): (ppm)= 139.3, 129.2, 128.7,

128.4 (Ph), 113.6, 109.2 (C(CH₃)₂), 106.6 (C-7), 99.8 (C(CH₃)₂),

87.4 (C-8), 84.8 (C-6), 81.3 (C-10), 80.5 (C-9), 74.0 (C-11), 73.7

(C-3), 71.2 (C-2), 70.1 (C-4), 66.9 (C-12), 65.0 (PhCH₂), 62.2 (C-

1), 58.3 (C-5), 29.5, 27.1, 26.0, 25.8, 24.8, 19.4 (C(CH₃)₂).

1

17β (major anomer): H-NMR (400 MHz, acetone-d₆): (ppm) =

7.27–7.35 (m, 5H, Ph), 5.22 (d, J_5,4= 2.1 Hz, 1H, H-5), 4.84 (dd,

J_9,8= 5.9 Hz, J_9,10= 3.4 Hz, 1H, H-9), 4.57 (d, J_8,9= 5.7 Hz, 1H,

H-8), 4.38–4.44 (m, 3H, H-11, PhCH₂), 4.24–4.30 (m, 2H, OH, H-

4), 4.07–4.11 (m, 1H, H-12a), 3.98–4.02 (m, 2H, H-10, H-12b),

3.82–3.91 (m, 2H, H-1a,H-1b), 3.75–3.80 (m, 1H, H-3), 3.56–3.63

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HRESIMS m/z 573.2302 calcd for C₂₈H₃₈O₁₁Na, 573.2306; anal.

(C-2), 67.4 (C-12), 66.9 (C-1), 66.1 (PhCH₂), 27.2, 27.1, 26.2,

25.7, 25.6, 25.2, 24.7, 23.8 (C(CH₃)_2.HRESIMS m/z 631.2718

calcd for C₃₁H₄₄O₁₂Na, 631.2725; anal. C 61.29, H 7.39, calcd for

C₃₁H₄₄O₁₂, C 61.17, H 7.29.

C 60.72, H 7.11, calcd for C₂₈H₃₈O₁₁, C 61.08, H 6.96.

18α (minor product): R_f= 0.24 (chloroform / ethyl acetate 2:1).

[α]²_D⁰= –43.7 (c = 1.0, CHCl₃). M.p. 80 °C (n-hexane). H-NMR

1

*stereo descriptors α/β could be interchanged

(400 MHz, acetone-d₆): (ppm) = 7.19–7.43 (m, 5H, H-Ph), 4.77–

4.91 (m, 4H, PhCH₂, H-8, H-9), 4.63 (d, J_OH,4= 5.8 Hz, 1H, OH),

4.40 (ddd, J_11,10= 6.9 Hz, J_11,12a= J_11,12b= 5.9 Hz, 1H, H-11), 4.11

(dd, J_10,11= 7.1 Hz, J_10,9= 4.2 Hz, 1H, H-10), 3.97–4.06 (m, 3H,

H-4, H-12a, H-12b), 3.79–3.89 (m, 2H, H-1a, H-3), 3.66 (dd, J_1b,1a

= J_1b,2= 10.4 Hz, 1H, H-1b), 3.46–3.58 (m, 2H, H-2, H-5), 1.46,

1.44, 1.37, 1.32, 1.29 (5s, 18H, C(CH₃)₂). ¹³C-NMR (101 MHz,

acetone-d₆): (ppm) = 140.3, 128.9, 128.7, 128.1 (Ph), 114.0,

109.5 (C(CH₃)₂), 105.0 (C-7), 99.9 (C(CH₃)₂), 88.8 (C-6), 83.2 (C-

9), 80.9 (C-8), 80.7 (C-10), 74.6 (C-11), 73.6 (C-3), 71.7 (C-2),

70.0 (C-4), 67.4 (C-12), 67.1 (PhCH₂), 62.3 (C-1), 59.2 (C-5), 27.2,

25.9, 25.8, 24.9, 19.3 (C(CH₃)₂). HRESIMS m/z 573.2297 calcd

for C₂₈H₃₈O₁₁Na, 573.2306; anal. C 60.82, H 6.96, calcd for

C₂₈H₃₈O₁₁, C 61.08, H 6.96.

6,7-Di-O-benzyl-1,2:4,5:8,9:11,12-tetra-O-isopropylidene-α-D-

manno-β-D-manno-dodecose (20): To a solution of 19 (250 mg,

0.411 mmol) and benzyl bromide (97μL, 0.822 mmol) in DMF

(5 mL) was added sodium hydride (60% in mineral oil, 33 mg,

0.822 mmol). After 3 h TLC showed complete conversion of the

starting material and the reaction was quenched by addition of

methanol. The solvent was evaporated and the crude residue was

diluted in ethyl acetate (15 mL). Then the solution was washed

with water (2 × 5 mL) and brine (5 mL) and was dried with Na₂SO₄.

Finally, the solvent was removed and the crude product was

purified by column chromatography (petroleum ether / ethyl

acetate 5:1) to afford 20 (244 mg, 0.349 mmol, 85%) as a white

foam. R_f= 0.55 (petroleumether / ethylacetate 2:1). [α]²_D⁰= –12.7

1

(c = 1.0, CHCl₃). M.p. 51 °C. H-NMR (400 MHz, acetone-d₆):

6-O-Benzyl-1,2:4,5:8,9:11,12-tetra-O-isopropylidene-D-

(ppm) = 7.45–7.53 (m, 2H, Ph), 7.17–7.36 (m, 8H, Ph), 5.30 (d,

J_8,9= 6.5 Hz, 1H, H-8), 5.15 (d, J = 13.2 Hz, 1H, PhCH₂), 5.05 (d,

J = 12.0 Hz, 1H, PhCH₂), 4.96 (d, J = 13.1 Hz, 1H, PhCH₂), 4.84

(ddd, J = 6.2 Hz, J = 4.0 Hz, J = 1.8 Hz, 2H, H-4, H-9), 4.73 (d,

J_5,4= 6.0 Hz, 1H, H-5), 4.65 (d, J = 12.0 Hz, 1H, PhCH₂), 4.35–

4.48 (m, 3H, H-2, H-10, H-11), 4.00–4.13 (m, 5H, H-1a, H-1b, H-

3, H-12a, H-12b), 1.54, 1.51, 1.36, 1.33, 1.30, 1.28, 1.27 (7s, 24H,

C(CH₃)₂). ¹³C-NMR (101 MHz, acetone-d₆):  = 141.8, 140.1,

129.2, 128.8, 128.5, 128.1, 128.0, 127.5 (Ph), 113.0, 112.5

(C(CH₃)₂), 110.0 (C-7), 109.3 (C-6), 109.2, 109.1 (C(CH₃)₂), 88.1

(C-5), 83.7 (C-8), 82.4 (C-3), 80.3 (C-9), 79.8 (C-4), 79.2 (C-10),

74.9 (C-11), 74.2 (C-2), 66.9 (PhCH₂), 66.9 (C-12)*, 66.8 (C-1)*,

65.9 (PhCH₂), 27.2, 27.0, 25.9, 25.8, 25.6, 25.4, 23.9, 23.8

(C(CH₃)₂). *signals could be interchanged. HRESIMS m/z

721.3192 calcd for C₃₈H₅₀O₁₂Na, 721.3195; anal. C 65.02, H 7.35,

calcd for C₃₈H₅₀O₁₂, C 65.31, H 7.21.

manno-β-D-manno-dodeco-7-ulose (19): To a solution of 18β

(645 mg, 1.17 mmol) in acetone (15 mL) was added a solution of

ferric chloride (57 mg, 0.35 mmol) in acetone (5 mL) at –10 °C.

The reaction mixture was brought to room temperature and

stirring was continued for 4 h until complete consumption of the

starting material was detected by TLC. Afterwards the reaction

was quenched by addition of sat. aq. NaHCO₃-solution (3 mL) and

the acetone was removed. The remaining brown aqueous residue

was extracted with CH₂Cl₂(5 × 10 mL) and the combined organic

phases were dried with Na₂SO_4.Purification of the crude product

by column chromatography (petroleum ether / ethyl acetate 3:1)

gave 19 (314 mg, 0.516 mmol, 44%, anomeric mixture, α:β*, 8:1)

as a white foam. R_f= 0.68 (petroleum ether / ethyl acetate 1:1).

19α^*(major product): ¹H-NMR (400 MHz, CD₂Cl₂): (ppm) = 7.26–

7.35 (m, 5H, Ph), 4.98–5.05 (m, 2H, H-8, PhCH₂), 4.70–4.77 (m,

2H, H-4, H-9), 4.66 (d, J_5,4= 6.0 Hz, 1H, H-5), 4.62 (d, J = 12.1 Hz,

1H, PhCH₂), 4.35–4.42 (m, 2H, H-2, OH), 4.25–4.33 (m, 1H, H-

11), 4.09 (dd, J = 8.7 Hz, J = 6.4 Hz, 1H, H-1a), 4.01–4.06 (m, 2H,

H-10, H-12a), 3.97 (ddd, J = 6.0 Hz, J = 1.8 Hz, 2H, H-1b, H-3),

3.91 (dd, J = 8.7 Hz, J = 5.1 Hz, 1H, H-12b), 1.56, 1.49, 1.39, 1.36,

1.34, 1.32, 1.28 (7s, 24H, C(CH₃)₂). ¹³C-NMR (101 MHz CD₂Cl₂):

(ppm) = 139.5, 128.9, 128.1, 127.9 (Ph), 113.3, 112.9, 109.5,

109.4 (C(CH₃)₂), 108.9 (C-6), 105.7 (C-7), 87.6 (C-5), 81.7 (C-3),

81.4 (C-8), 80.3 (C-9), 79.4 (C-4), 78.7 (C-10), 74.0 (C-11), 73.6

1,2:4,5:8,9:11,12-Tetra-O-isopropylidene-D-manno-D-manno-

dodecose (21):

From 15: To a solution of 15 (538 mg, 1.07 mmol) in acetone

(10 mL) was slowly added another solution of ferric chloride

(52 mg, 0.321 mmol) in acetone (5 mL) at –10 °C. The reaction

mixture was brought to room temperature and stirring was

continued for 48 h until complete consumption of the starting

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material was detected by TLC. Subsequently the reaction was

quenched with sat. aq. NaHCO₃-solution (5 mL) and the acetone

was removed. The aqueous brown residue was extracted with

ethyl acetate (3 × 20 mL) and the combined organic layers were

dried with Na₂SO₄. The solvent was evaporated and the crude

product was purified by column chromatography (petroleum ether

/ ethyl acetate 3:2) to furnish 21 (260 mg, 0.501 mmol, 47%) as a

white crystalline solid.

reaction progress could be detected by TLC and the excess of

sodium hydride was quenched by slowly addition of methanol

(5 mL). The solvent was evaporated and the residue was

dissolved in ethyl acetate (60 mL). Subsequently the organic

phase was washed with water (2 ×20 mL), brine (2 ×20 mL) and

was dried with Na₂SO₄. Purification by column chromatography

(petroleum ether / ethyl acetate 7:1) afforded 23 (599 mg,

0.555 mmol, 88%) as a white amorphous solid. R_f= 0.40

(petroleum ether / ethyl acetate 4:1). [α]²_D⁰= –13.4 (c = 1.0, CHCl₃).

M.p. 104 °C (n-hexane). ¹H-NMR (400 MHz, in CDCl₃): (ppm) =

7.17–7.39 (m, 40H, Ph), 4.78–4.96 (m, 10H, H-1, PhCH₂), 4.74 (d,

J = 10.6 Hz, 2H, PhCH₂), 4.54–4.61 (m, 4H, PhCH₂), 4.50 (d, J =

12.0 Hz, 2H, PhCH₂), 3.54–3.73 (m, H-2, H-3, H-4, H-6a, H-6b),

3.34–3.45 (m, 2H, H-5). ¹³C-NMR (101 MHz, CDCl₃): (ppm) =

138.7, 138.3, 138.2, 128.5, 128.5, 128.4, 128.4, 128.0, 127.9,

127.9, 127.8, 127.7, 127.7 (Ph), 86.9 (C-3)^*, 82.0 (C-1)^*, 81.9 (C-

2)^*, 79.3 (C-5), 78.1 (C-4)^*, 75.8, 75.3, 75.0, 73.5 (PhCH₂), 69.0

(C-6). HRESIMS m/z 1101.4567 calcd for C₆₈H₇₀O₁₀SNa,

1101.4582; anal. C 75.68, H 6.60, S 2.83, calcd for C₆₈H₇₀O₁₀S,

C 75.67, H 6.54, S 2.97.

From 20: 20 (44 mg, 0.0629 mmol) was dissolved in THF (3 mL)

and palladium (10% on activated charcoal, 18 mg, 0.0169 mmol)

was added. The reaction mixture was stirred for 5 h under

hydrogen-atmosphere until TLC showed complete conversion of

the educt. The black solid was separated by centrifugation and

the residue was suspended in diethyl ether and centrifuged again

(3 × 10 mL). Evaporation of the solvent followed by column

chromatographic purification (petroleum ether / ethyl acetate 1:1)

gave 21 (32 mg, 0.0617 mmol, 98%) as a white crystalline solid.

R_f= 0.31 (petroleum ether / ethyl acetate 1:1) is slowly converting

into an anomeric mixture R_f= 0.31–0.49 (petroleum ether / ethyl

1

acetate 1:1). H-NMR (400 MHz, acetone-d₆): (ppm) = 5.08 (d,

*Signals C-1 and C-2 as well as C-3 and C-4 can be interchanged

J_8,9= 6.1 Hz, 1H, H-8), 4.76–4.87 (m, 3H, H-4, H-9, OH), 4.69 (s,

1H, OH), 4.59–4.63 (d, J_5,4= 6.0 Hz, 1H, H-5), 4.33–4.39 (m, 1H,

H-2), 4.20–4.26 (m, 2H, H-3, H-11), 4.11 (dd, J = 8.6 Hz, J =

4.8 Hz, 1H, H-12a), 3.89–4.00 (m, 4H, H-1a, H-1b, H-10, H-12b),

1.50, 1.45, 1.36, 1.32, 1.32, 1.28, 1.26 (7s, 24H, C(CH₃)₂). ¹³C-

NMR (101 MHz, acetone-d₆): (ppm) = 112.8, 112.7, 109.2, 108.9

(C(CH₃)₂), 106.9 (C-6), 105.3 (C-7), 86.7 (C-5), 81.3 (C-9), 81.1

(C-8), 80.4 (C-3), 80.1 (C-4), 78.9 (C-10), 74.4 (C-11), 74.4 (C-2),

67.3 (C-12), 66.7 (C-1), 27.3, 27.2, 26.2, 25.7, 25.6, 25.5, 24.7,

23.8 (C(CH₃)₂). HRESIMS m/z 541.2255 calcd for C₂₄H₃₈O₁₂Na,

541.2256; anal. C 55.35, H 7.59, calcd for C₂₄H₃₈O₁₂, C 55.59, H

7.39.

2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-2,3,4,6-tetra-O-

benzyl-1-sulfonyl-β-D-glucopyranoside (24): A Solution of 23

(1.68 g, 1.56 mmol) and mCPBA (77%, 1.05 g, 4.67 mmol) in

CH₂Cl₂(20 mL) was stirred for 16 h at ambient temperature. The

R_F-values of the educt and the product are to similar, though the

reaction progress was monitored by emergence and

disappearance of the appropriate sulfoxide intermediate (R_f=

0.81; petroleum ether / ethyl acetate 1:1). The reaction was

quenched by addition of sat. aq. Na₂S₂O₃-solution (10 mL) and

sat. aq. NaHCO₃-solution (10 mL) and the aqueous layer was

extracted with methylene chloride (3 × 20 mL). After drying with

Na₂SO₄, the solvent was removed and the crude product was

purified by column chromatography (petroleum ether / ethyl

acetate 5:1). 24 (1.54 g, 1.39 mmol, 89%) was obtained as a

colorless highly viscous oil. R_f= 0.87 (petroleum ether / ethyl

acetate 1:1). [α]²_D⁰= +10.7 (c = 1.0, CHCl₃). ¹H-NMR (400 MHz, in

CDCl₃): (ppm) = 7.38–7.44 (m, 4H, Ph), 7.14–7.33 (m, 36H, Ph),

5.04 (d, J = 9.9 Hz, 2H, PhCH₂), 4.94 (d, J = 11.1 Hz, 2H, PhCH₂),

4.85 (d, J = 11.1 Hz, 2H, PhCH₂), 4.76 (dd, J = 10.5 Hz, J = 6.2 Hz,

4H, PhCH₂), 4.65 (d, J_1,2= 9.8 Hz, 2H, H-1), 4.51 (d, J = 11.0 Hz,

2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-2,3,4,6-tetra-O-

benzyl-1-thio-β-D-glucopyranoside (23): To a solution of 22

(436 mg, 0.628 mmol) in methanol (10 mL) was added ammonia

(7 N in methanol, 0.5 mL) and the mixture was stirred for 2 h at

room temperature until TLC showed complete conversion of the

starting material. The volatile compounds were removed and the

remaining deprotected disaccharide (225 mg, 0.628 mmol) was

dissolved in DMF (10 mL). Addition of benzyl bromide (1.19 mL,

10.1 mmol) followed by treatment with sodium hydride (60% in

mineral oil, 400 mg, 10.1 mmol) in portions at 0 °C, initiated the

reaction. After stirring for 20 h at room temperature, no further

2H, PhCH₂), 4.37–4.46 (m, 4H, PhCH₂), 4.13 (dd, J_2,1= J_2,3

=

9.3 Hz, 2H, H-2), 3.71 (dd, J_3,2= J_3,4= 8.9 Hz, 2H, H-3), 3.48–3.58

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(m, 4H, H-4, H-6a), 3.41 (dd, J_6b,6a= 11.0 Hz, J_6b,5= 5.4 Hz, 2H, H-

6b), 3.22 (ddd, J_5,4= 9.8 Hz, J_5,6b= 5.3 Hz, J_5,6a= 1.4 Hz, 2H, H-

5). ¹³C-NMR (101 MHz, CDCl₃): (ppm) = 138.4, 138.0, 138.0,

137.8, 128.7, 128.6, 128.5, 128.5, 128.1, 128.0, 127.8 (Ph), 87.5

(C-1), 86.4 (C-3), 79.7 (C-5), 77.4 (C-4), 76.6 (C-2), 76.0, 75.4,

75.1, 73.5 (PhCH₂), 68.7 (C-6). HRESIMS m/z 1133.4464 calcd

for C₆₈H₇₀O₁₂SNa, 1133.4480; anal. C 73.38, H 6.39, S 2.33,

calcd for C₆₈H₇₀O₁₂S, C 73.49, H 6.35, S 2.88.

removed and the remaining crude product was dissolved in THF

(4 mL) and water (1 mL) followed by addition of TFA (10 μL,

0.129 mmol). After stirring for 20 h, the solution was diluted with

toluene (2 mL) and the volatile components were evaporated.

Initially the crude product was purified by column chromatography

(petroleum ether / ethyl acetate 5:1) and subsequently by

recrystallization (n-hexane / ethyl acetate) to afford 26 (279 mg,

0.259 mmol, 66%) as white crystalline needles. R_f= 0.45

(methylene chloride). [α]²_D⁰= +4.8 (c = 1.0, CHCl₃). M.p. 123 °C

(n-hexane / ethyl acetate). ¹H-NMR (400 MHz, acetone-d₆):

(ppm) = 7.20–7.42 (m, 40H, Ph), 4.80–5.03 (m, 10H, PhCH₂,

OH), 4.70–4.80 (m, 4H, PhCH₂), 4.59–4.67 (m, 4H, PhCH₂), 4.02–

4.20 (m, 6H, H-2, H-4, H-5, H-8, H-9, H-11), 3.75–3.86 (m, 4H, H-

1a, H-1b, H-12a, H-12b), 3.64 (dd, J = 9.9 Hz, J = 8.3 Hz, 2H, H-

3, H-10). ¹³C-NMR (101 MHz, acetone-d₆): (ppm) = 140.0, 139.7,

139.6, 138.7, 129.4, 129.2, 129.2, 128.8, 128.7, 128.5, 128.4

(Ph), 98.4 (C-6, C-7), 84.0 (C-4, C-9), 81.2 (C-5, C-8), 79.9 (C-3,

C-10), 75.9, 75.9, 75.5, 73.8 (PhCH₂), 73.2 (C-2, C-11), 70.1 (C-

1, C-12). HRESIMS m/z 1101.4738 calcd for C₆₈H₇₀O₁₂Na,

1101.4760; anal. C 75.61, H 6.69, calcd for C₆₈H₇₀O₁₂, C 75.67,

H 6.54.

(E,Z)-2,6:7,11-Dianhydro-1,3,4,5,8,9,10,12-octa-O-benzyl-D-

gluco-L-gulo-dodeco-6-enitol (E/Z-25):

A

suspension of

KOH/Al₂O₃(25% w/w, 6 g) in t-BuOH (20 mL) and CH₂Cl₂(2 mL)

was treated with a solution of 24 (1.11 g, 1.00 mmol) in CH₂Cl₂

(3 mL). The reaction mixture was cooled to 0 °C and CBr₂F₂

(2.73 mL, 30 mmol) was added in one portion. Complete

consumption of the starting material was detected after 20 h and

the suspension was diluted with CH₂Cl₂(20 mL). The solid

KOH/Al₂O₃-compund was separated by filtration through Celite ®

and the filtrate was evaporated. Purification of the crude product

by column chromatography (petroleum ether / ethyl acetate

20:1containing 0.5% triethylamine) furnished an inseparable

diastereomeric mixture of E-25 and Z-25 (E/Z, 10:1*, 725 mg,

0.694 mmol, 69%) as a colorless oil.

Preparation of the target compounds 7a, 7b and 7c

E-25 (major diastereomer): R_f= 0.69 (petroleum ether / ethyl

General procedure C for debenzylation of 10a, 10b and 26:

1

acetate, 2:1). H-NMR (400 MHz, acetone-d₆): (ppm) = 7.18–

To a solution of benzylated diulose 10a, 10b or 26 (0.1 mmol

scale) in THF (5 mL) was added palladium (10% on activated

charcoal, 0.4 eq) and the suspension was stirred at room

temperature under hydrogen for 24 h until complete consumption

of the starting material was detected. After diluting the mixture

with methanol (10 mL), the black solid was separated by

centrifugation. The residue was suspended in methanol and

centrifuged again (2 × 10 mL). Subsequently, the solvent was

removed and the crude product was purified by RP-C18

chromatography (acetonitrile / water, 2:1).

7.49 (m, 40H, Ph), 5.03 (d, J_5,4= J_8,9= 2.1 Hz, 2H, H-5, H-8), 4.40–

4.82 (m, 16H, PhCH₂), 4.29 (ddd, J = 9.5 Hz, J = 3.6 Hz, J =

3.6 Hz, 2H, H-2, H-11), 3.98 (dd, J_4,3= J_9,10= 5.3 Hz, J_4,5= J_9,8

= 2.1 Hz, 2H, H-4, H-9), 3.65–3.80 (m, 6H, H-1a. H-1b, H-3, H-

10, H-12a, H-12b). ¹³C-NMR (101 MHz, acetone-d₆): (ppm) =

140.0, 139.7, 139.7, 139.4 (Ph), 137.4 (C-6, C-7), 129.1, 129.1,

129.1, 128.8, 128.8, 128.7, 128.5, 128.3, 128.3, 128.3 (Ph), 82.4

(C-4, C-9), 78.2 (C-3, C-10), 76.1 (C-2, C-11), 73.8, 73.5 (PhCH₂),

72.2 (C-5, C-8), 71.7, 70.8 (PhCH₂), 70.4 (C-1, C-12). HRESIMS

m/z 1067.4696 calcd for C₆₈H₆₈O₁₀Na, 1067.4705.

D-gluco-L-gulo-Dodeco-6,7-diulose (7a):

*Diastereomers E-25 and Z-25 can be interchanged.

From 10a and 26: Following general procedure C, 7a was isolated

1,3,4,5,8,9, 10,12-Octa-O-benzyl-D-gluco-L-gulo-dodeco-6,7-

diulose (26): To a solution of E/Z-25 (410 mg, 0.392 mmol) in

degased acetone (3 mL) was added DMDO (0.107 M in acetone,

4.39 mL, 0.470 mmol) at –80 °C over a period of 15 min. After

12 h, the reaction mixture was warmed to ambient temperature

and stirring was continued for 1 h until TLC (CH₂Cl₂) showed

complete transformation of the starting material. The solvent was

as a white solid in quantitative yield.

From 6: A solution of 6 (300 mg, 0.40 mmol) in THF/water-mixture

(1:1, 2 mL) was treated with trifluoroacetic acid (300 µL,

4.0 mmol) and the yellow solution was stirred at ambient

temperature for 4 h until TLC showed complete transformation of

the starting material. The volatile components were evaporated

and the crude product first was purified by RP-C18

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chromatography (acetonitrile / water, 2:1) followed by NP

quaternary OH-signals) (ppm) = 6.24 (1H, s, A₂), 6.07 (2H, s, S₃),

5.85 - 5.92 (3H, m, S₄, A₂), 5.54 (2H, br. s., S₁), 5.48 (2H, s, S₂),

5.44 (1H, br. s., A₁), 5.14 (1H, d, J = 1.7 Hz, A₁). ¹³C-NMR

(176 MHz, DMSO-d₆, quaternary carbons) (ppm) = 107.9 (S₁),

105.3 (S₄), 104.0 (A₁), 100.3 (A₂), 99.5 (A₂), 97.6 (A₁), 97.5 (S₂),

96.6 (S₃). HRESIMS m/z 381.1000 calcd for C₁₂H₂₂O₁₂Na,

381.1004.

chromatography (chloroform

/ methanol, 3:2). Unprotected

diulose 7a (125 mg, 0.35 mmol, 88%) was obtained as a white

crystalline solid. R_f= 0.05–0.20 (chloroform / methanol, 2:1).

[α]²_D⁰= +49.3 (c = 1.0, acetonitrile / water, 1:1). M.p. 122 °C. H-

1

NMR (700 MHz, DMSO-d₆): (ppm) = 5.87 (2H, s, OH-6, OH-7),

5.80 (2H, d, J_OH-5,5= J_OH-8,8= 6.0 Hz, OH-5, OH-8), 4.83 (2H, d,

J_OH-3,3= J_OH-10,10= 5.6 Hz, OH-3, OH-10), 4.75 (2H, d, J_OH-4,4= J_OH-

*For none of the six isomers the stereochemistry could be

determined

= 4.9 Hz, OH-4, OH-9), 4.25 (2H, dd, J_OH-1,1a= J_OH-12,12a

=

9,9

5.6 Hz, J_OH-1,1b= J_OH-12,12b= 5.6 Hz, OH-1, OH-12), 3.55–3.64 (6H,

m, H-1a, H-2, H-5, H-8, H-11, H-12a), 3.43–3.50 (4H, m, H-1b, H-

4, H-9, H-12b), 3.06 (2H, ddd, J_3,2= J_10,11= 9.1 Hz, J_3,4= J_10,9

=

Acknowledgments

9.1 Hz, J_3,OH-3= J_10,OH-10= 5.4 Hz, H-3, H-10). ¹³C-NMR (176 MHz,

DMSO-d₆):  (ppm) = 97.2 (C-6, C-7), 73.6 (C-4, C-9), 73.1 (C-2,

C-11), 71.3 (C-5, C-8), 70.1 (C-3, C-10), 61.0 (C-1, C-12).

HRESIMS m/z 357.1043 calcd for C₁₂H₂₂O₁₂−H, 357.1039.

We thank Petra Schülzle (elemental analysis), Dr. Dorothee

Wistuba, Claudia Kruse, Dr. Peter Haiss (mass spectra), Priska

Kolb, Dr. Norbert Grzegorzek and Dominik Brzecki (NMR) for their

contributions to this work.

D-galacto-L-galacto-Dodeco-6,7-diulose 7b

Keywords: disaccharide • diulose • C-glycoside •Grubbs-

metathesis • Ramberg-Bäcklund reaction • oxidation

From benzylated diulose 10b: Following general procedure C, 7b

was isolated as a white solid in quantitative yield. R_f= 0.05–0.20

(chloroform / methanol, 2:1). [α]²_D⁰= −35.9 (c = 1.0, water). M.p.

76 °C. ¹H-NMR (600 MHz, DMSO-d₆): (ppm) = 5.42 (2H, br. s.,

OH-6, OH-7), 4.71 (2H, br. s., OH-4, OH-9), 4.30 (4H, br. s., OH-

1, OH-5, OH-8, OH-12), 3.71 (2H, d, J = 5.7 Hz, OH-2, OH-11),

3.39 - 3.66 (12H, m, H-1a, H-1b, H-2, H-3, H-4, H-5, H-8, H-9, H-

10, H-11, H-12a, H-12b). ¹³C-NMR (151 MHz, DMSO-d₆) (ppm)

= 95.5 (C-6, C-7), 74.4 (C-5, C-8), 71.5 (C-3, C-10), 70.2 (C-2, C-

11), 68.4 (C-4, C-9), 62.9 (C-1, C-12). HRESIMS m/z 357.1044

calcd for C₁₂H₂₂O₁₂−H, 357.1039.

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Synthesis of Symmetrical Dodeco-6,7-diuloses

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