Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction

Monatshefte für Chemie - Chemical Monthly

https://doi.org/10.1007/s00706-019-02438-y

ORIGINAL PAPER

Synthesis of 3‑deoxy‑2‑uloses via the indium‑mediated allylation

reaction

Manuel Gintner¹· Christian Denner¹· Christoph Schmölzer¹· Michael Fischer¹· Peter Frühauf²·

Hanspeter Kählig¹· Walther Schmid¹

Received: 21 March 2019 / Accepted: 20 April 2019

Abstract

We utilized the indium-mediated allylation reaction for the synthesis of carbohydrate structures containing the 3-deoxy-

2-ulose motif, a barely investigated compound class. The stereoselective outcome can be controlled by the presence or

absence of a chelating group in α-position to the carbonyl function. By introduction of an UV-active allyl building block,

we enabled epimer separation by HPLC towards the synthesis of 3-deoxy-^d-glycero-d-galacto-2-nonulose, the carboxyl-

reduced analogue of widely distributed 3-deoxy-d-glycero-d-galacto-nonulosonic acid (Kdn). Ozonolysis of the introduced

2-C-methylidenepropan-1-ol motif provided the desired 3-deoxy-2-uloses.

Graphical abstract

O₃

Br

OH

O

OH

O

R

3-Deoxy-2-uloses

Keywords Carbohydrates · 3-Deoxy-2-uloses · Indium-mediated allylation · Organometallic compounds · Ozonolysis

Introduction

The indium-mediated allylation reaction has proven to be an

efcient and reliable C–C bond formation method ofering

Dedicated to Professor Dr. Heinz Falk on the happy occasion of

man y advantages over traditional organometallic compounds

his 80th birthday anniversary.

[1–3]. Typically, it allows for high regio-, enantio-, as well

as diastereoselectivity and tolerates a wide range of func-

tional groups [4–7]. Moreover, indium-mediated allylations

can be performed in water, rendering the possibility to fully

avoid the use of dry and fammable solvents. This allows

for safer and environmentally friendly c hemistry, satisfy-

ing the demands of green chemistry [1–4]. The reactions

generally proceed under mild conditions at room tempera-

ture without any promoter, in contrast to the use of other

metals such as zinc or tin, which requires acid catalysis,

elevated temperatures or sonication, often leading to increas-

ing amounts of undesired side products [8, 9]. Because of

Walther Schmid: deceased, Dec 2017.

Electronic supplementary material The online version of this

article (https://doi.org/10.1007/s00706-019-02438-y) contains

supplementary material, which is available to authorized users.

* Manuel Gintner

manuel.gintner@univie.ac.at

1

Institute of Organic Chemistry, University of Vienna,

Vienna, Austria

2

Institute of Analytical Chemistry, University of Vienna,

Vienna, Austria

Vol.:(0123456789)

1 3

M. Gintner et al.

OH

COOH

OH

COOH

representing an interesting and rare subcategory of the

ketose family. Being the C-1 reduced analogue of naturally

essential ulosonic acids, these structures have potential

biological importance and therefore are attractive target

molecules [16]. A naturally occurring representative is

3-deoxy-^d-erythro-2-hexulose (3-deoxy-d-fructose, 5),

whic h has been found in mammalian blood and urine

[17–19] in concentrations that are elevated in diabetes

[20 ]. As degradation product, it arises from 3-deoxyglu-

cosone (6), a key intermediate in the nonenzymatic polym-

erization and browning of proteins by glucose (Maillard

reaction), which is also formed in vivo by d-fructose

[21], d-fructose-3-phosphate [22], or Amadori adducts

to proteins [19 ]. In mammals, a signifcant proportion of

3-deoxyglucosone (6) is reduced to 3-deoxy-d-erythro-

2-hexulose (5) presumably to decrease its r eactivity, thus

being less damaging to tissues (Scheme 1) [23].

OH

HO

O

AcHN

HO

1

2

OH

HO

OH

COOH

NHAc

HO

O

AcHN

HO

COOH

OH

4

3

Fig. 1 Natural products (Neu5Ac, 1), (Kdn, 2), (Kdo, 3), (Leg, 4)

synthesized via an indium-mediated allylation reaction

Scheme 1

HO

2-oxoaldehyde

reductase

OH

O

OH

An earlier approach of our group regarding the syn-

thesis of 3-deoxy-2-uloses utilized the indium-mediated

allylation reaction employing allyl bromide for the elonga-

tion of diferent aldoses, such as N-acetyl-^d-mannosamine

or d-erythrose (Scheme 2). The terminal allyl moiety of 8

was subsequently oxidized using potassium permanganate

under acidic conditions yielding the desired 3-deoxy-2-ul-

ose functionality in 9. However, the acidity of the 3-deoxy

position prohibited standard de-O-acetylation methods as

elimination product 10 was formed exclusively. Hence, a

thioketal moiety was introduced at position C-2 to give 11

and enabled de-O-acetylation to 12. Final removal of the

thioketal yielded 3-deoxy-2-ulose 13 [24].

HO

OH

HO

O

6

5

its superior reactivity, the indium-mediated allylation has

been applied in numerous natural product syntheses by us

and others, e.g. N-acetylneuraminic acid (Neu5Ac, 1) [10,

11 ], 3-deoxy-d-glycero-d-galacto-nonulosonic acid (Kdn, 2)

[12], 3-deoxy-d-manno-2-octulosonic acid (Kdo, 3) [13] or

legionaminic acid (Leg, 4) [14, 15] (Fig. 1).

An intriguing compound class t hat has hardly been

addressed by organic synthesis is the 3-deoxy-2-ulose

Scheme 2

AcO/HO

OH/OAc

NHAc

OH/OAc

O

AcO/HO

R =

OH

R =

R

10

AcO/HO

2-NHAc-

AcO/HO

-erythro

D

-manno

D

NaOMe

MeOH

1) allyl bromide, In

2) Ac₂O, pyr, 4-DMAP

KMnO₄

AcO

R

O

OAc

OH

R

7

9

8

EtSH, SnCl₂.2H₂O,

CH₂Cl_2,microwave

NaOMe

MeOH

NBP

O

HO

AcO

R

HO

EtS SEt

OH

R

12

13

11

1 3

Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction

Herein, we report a novel approach towards 3-deoxy-

2-uloses by elongating selected aldoses using 2-(bromome-

thyl)prop-2-en-1-ol (14) in an indium-mediated allylation

reaction. The presence or absence of a chelating group next

to the carbonyl function directs the formation of the corre-

sponding syn- or anti-product respectively, as we verify dur-

ing the synthesis of 3-deoxy-d-erythro-2-hexulose (5) and

3-deoxy-d-gluco-2-octulose (15). Thus, introduction of an

appropriate protecting group in α-position provides diaste-

reoselective control. A benzyl protected allyl building block

(2-(benzyloxymethyl)allyl bromide, 16) can be employed to

enable UV detection for epimer separation by HPLC of the

epimeric mixture obtained after the elongation reaction.

used. Final ozonolysis of the elongated aldoses provided the

desired 3-deoxy-2-uloses in good to excellent yields.

2,3-O-Isopropylidene-^d-glyceraldehyde (17) has been

synthesized from d-mannitol via a known isopropylidene-

protection procedure [27] and subsequent oxidative diol

cleavage [28]. During the indium-mediated allylation, the

absolute confguration of the newly formed stereocenter at

position C-4 is infuenced by the presence or absence of

a chelating group in α-position to the reacting carbonyl

function. Hence, an isopropylidene-protected hydroxyl

function in neighboring position acts as weak chelating

group and allows for the preferred formation of the anti-

product (2,3-dideoxy-5,6-O-isopropylidene-2-C-methyl-

idene-d-erythro-hexitol, anti-21) as demonstrated by the

elongation of 2,3-O-isopropylidene-d-glyceraldehyde (17)

(Scheme 3). The resulting epimeric mixture was separated

by column chromatography. Removal of the isopropylidene

group under acidic conditions and subsequent ozonolysis

furnished the keto functionality at position C-2. 3-Deoxy-

d-erythro-2-hexulose (5) was obtained in a yield of 35%

over 3 steps.

Results and discussions

The indium-mediated allylation using 2-(bromome-

thyl)prop-2-en-1-ol (14) was applied on three different

aldoses—2,3-O-isopropylidene-d-glyceraldehyde (17),

d-arabinose (18), and d-mannose (19)—introducing a

2-C-methylidenepropan-1-ol motif. Allyl component 14

was synthesized starting from triethyl phosphonoacetate

(20) performing a known Horner-Wadsworth-Emmons

protocol [25 ], followed by bromination [25] and DIBAL-

H-reduction [26]. Due to the volatility of the allyl building

block 14, the yield for its preparation is modest. After allyla-

tion, the generated epimeric mixtures could be separated by

conventional silica gel chromatography, when employing

2,3-O-isopropylidene-d-glyceraldehyde (17) and d-arabinose

(18) as starting materials. However, for the separation of the

epimers obtained from the elongation of d-mannose (19),

HPLC had to be performed. To enable UV-detection during

HPLC, a benzyl protected allyl building block 16 has been

The allylation of d-arabinose (18) employing 2-(bro-

momethyl)prop-2-en-1-ol (14) favored the formation of

the corresponding syn-product (1,4,5,6,7,8-hexa-O-acetyl-

2,3-dideoxy-2-C-methylidene-d-gluco-octitol, syn-23) due

to the strong chelating hydroxyl group in α-position to the

aldehyde function. Per-O-acetylation facilitated epimer sepa-

ration via column chromatography. Zemplén saponifcation

provided 2,3-dideoxy-2-C-methylidene-d-gluco-octitol (24).

The stereochemical relation between the initial α-substituent

and the newly formed hydroxyl group of compound 24 has

been confrmed by X-ray analysis (Fig. 2). Subsequent ozo-

nolysis generated the keto function at position C-2. 3-Deoxy-

d-gluco-2-octulose (15) was obtained in a yield of 47% over

3 steps (Scheme 4).

Scheme 3

Br

OH

O

OH

14

OH

+

O

In, EtOH

O

sonication

75%, 54% de

syn -21

anti

-21

17

1 M HCl

THF/H₂O

86%

O₃

OH

CH₂Cl₂/MeOH

-78 °C

OH

O

OH

HO

DMS

71%

HO

OH

22

5

1 3

M. Gintner et al.

d-arabinose (18). However, separation of the generated

epimers in both, their unprotected or per-O-acetylated

form, could not be accomplished via column chromatog-

raphy. Also, performing ozonolysis directly after allylation

followed by per-O-acetylation to compounds syn-/anti-26

did not facilitate isolation of the epimers, but led to an even

more complex compound mixture containing epimers, their

corresponding anomers as well as side products by elimina-

tion, which turned out to be inseparable by conventional

column chromatography (Scheme 5).

Fig. 2 X-ray analysis of compound 24 confrming its d-gluco-confg-

We decided to tackle this challenge using HPLC. To ena-

ble detection via UV-absorbance, we employed 2-(benzy-

loxymethyl)allyl bromide (16) as allyl species for the elonga-

tion in the indium-mediated allylation reaction. Compound

16 was synthesized starting from triethyl phosphonoacetate

(20) according to a known Horner-Wadsworth-Emmons pro-

tocol [25] to provide ethyl 2-(hydroxymethyl)acrylate (27).

uration

The elongation of d-mannose (19) utilizing allyl

species 14 preferred the formation of the syn-product

(1,4,5,6,7,8,9-hepta-O-acetyl-2,3-dideoxy-2-C-methyl-

idene-d-glycero-d-galacto-nonitol, syn-25) according to

Scheme 4

1) In, EtOH/H₂O

Br OH

14

sonication

OAc OAc

OH

O

OAc

+

AcO

2) Ac₂O, pyr,

4-DMAP

80%, 52% de

HO

OAc OAc

syn-23

anti -23

18

MeONa, MeOH

DOWEX W50 H⁺

>99%

O₃

OH

HO

CH₂Cl₂/MeOH

-78 °C

OH OH

O

OH

HO

OH

PPh₃

78%

OH OH

OH

24

15

1) In, EtOH/H₂O

Br OH

Scheme 5

14

sonication

OH

OAc OAc OAc

OH

AcO

OAc

O

HO

2) Ac₂O, pyr, 4-DMAP

60%, 69% de

OH

OAc OAc

syn -/anti -25

19

1) In, EtOH/H₂O

Br

OH

14

sonication

AcO

OAc

AcO

OAc

O

side products

AcO

2) O_3,CH₂Cl₂/MeOH

-78 °C, DMS

3) Ac₂O, pyr, 4-DMAP

syn

-/anti -26

1 3

Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction

O-Benzylation was achieved using benzyl trichloroacetimi-

date (28) whic h was synthesized according to a known

procedure [29, 30]. Early benzylation in the allyl building

block synthesis decreases the volatility of subsequent inter-

mediates, thus facilitating the workup processes. DIB AL-H-

reduction and bromination via Appel reaction [31, 32] gave

allyl species 16 in a yield of 37% over 4 steps (Sc heme 6).

Allylation of d-mannose (19) using compound 16 gave

a mixture of epimers in a ratio of 4:1. Due to the presence

of a strong chelating hydroxyl group next to the reacting

carbonyl function, we termed the major product syn-31. The

epimeric mixture was per-O-acetylated and purifcation via

normal-phase HPLC was conducted (Scheme 7). Although

separation of the epimers (syn-/anti-31) was accomplished

using heptane/ethyl acetate as eluent (6:1 v/v), elaborate

conditions such as cooling of the column to 15 °C were

necessary to give two separated peaks at retention times

of 107 and 112 min on an analytical scale (Fig. 3). Hav-

ing overcome this demanding separation problem in prin-

ciple, upscaling to a semi-preparative scale has not been

conducted yet. Observed yields and diastereoselectivities

of performed indium-mediated allylation reactions are pre-

sented in Table 1.

2-C-methylidenepropan-1-ol motif. Depending on the ini-

tial substrate, epimer separation by column chromatography

was facilitated via protecting group manipulations. In case

of ^d-mannose, a benzyl protected allyl species was employed

for the elongation to introduce UV-activity to the com-

pounds, thus allowing for separation of the epimeric mix-

ture using HPLC. Subsequent ozonolysis gave the respective

3-deoxy-2-ulose in good to excellent yields. By this method

the stereochemical outcome can be controlled by the intro-

duction of an appropriate protecting group in α-position to

the carbonyl function prior to the elongation, emphasizing

the indium-mediated allylation reaction as a powerful tool

for the synthesis of 3-deoxy-2-uloses.

Experimental

¹H and ¹³C NMR spectra were recorded on a Bruker AV III

400, Bruker AV III 600, or Bruker AV III HD 700 respec-

tively. Chemical shifts (δ) are reported in parts per million

(ppm) and spectra were calibrated using solvent signals of

CDCl₃or D₂O. Signal multiplicity is indicated by one or

more of the following: s (singlet); d (doublet); t (triplet);

q (quartet); m (multiplet); br (broad). NMR analysis was

assisted by the spin simulation software DAISY (part of

Bruker Top Spin software). Assignment of anomers was

achieved by NOESY-NMR experiments. High resolution

mass spectra (HRMS) were recorded on a Bruker maXis

UHR-TOF spectrometer in ESI mode. Optical rotations were

measured on a Schmidt-Haensch Digital Polarimeter Unipol

Conclusion

We developed a straightforward method for the synthe-

sis of 3-deoxy-2-uloses. Elongation of simple aldoses

via an indium-mediated allylation reaction introduced a

NH

Scheme 6

Cl₃C OBn

28

TfOH

O

CH₂O, K₂CO₃

EtO P

HO

OEt

BnO

Br

OEt

EtO

H₂O

74%

Et₂O

87%

20

DIBAL-H

27

29

CBr₄, PPh₃

BnO

OH

CH₂Cl₂, -78 °C

74%

CH₂Cl₂, 0 °C

78%

16

30

Scheme 7

1) In, EtOH/H₂O

Br OBn

16

OH

OAc OAc OAc

sonication

OH

AcO

OBn

AcO

OBn

O

HO

2) Ac₂O, pyr,

4-DMAP

45%, 60% de

OH

OAc OAc

19

syn-31

anti -31

1 3

M. Gintner et al.

Fig. 3 Separation of epimeric mixture (syn-/anti-31) by HPLC: Macherey–Nagel NUCLEODUR® 100-5 column, 15 °C column temperature,

detection at 254 nm, eluents: 1: heptane/ethyl acetate=86/14, 2: heptane/ethyl acetate=80/20, 3: heptane/ethyl acetate=87/13

Table 1 Yields and diastereoselectivities observed in the indium-

from commercial suppliers and were used without further

mediated allylation reactions

purifcation.

Starting material

Allyl species Product Com-

Syn/anti

1:3

bined

Ethyl 2‑(bromomethyl)acrylate A known procedure [25]

was used for the synthesis of ethyl 2-(bromomethyl)-

acrylate. Starting from 33.63 g triethyl phosphonoacetate

(20, 150.0 mmol), 18.43 g of ethyl 2-(bromomethyl)acrylate

(95.46 mmol) with a yield of 64% over 2 steps was obtained.

NMR signals correspond to published NMR data [25].

yield/%

2,3-O-isopropylidene- 14

d-glyceraldehyde

(17)

d-arabinose (18)

d-mannose (19)

anti-21 75

14

16

syn-23 80^a

syn-25^b60^a

syn-31^b45^a

3:1

5:1

4:1

2‑(Bromomethyl)prop‑2‑en‑1‑ol (14) A known procedure

[26] was used for the synthesis of compound 14. Starting

from 5.02 g ethyl 2-(bromomethyl)acrylate (26.0 mmol),

2.40 g of compound 14 (15.9 mmol) with a yield of 61%

was obtained. NMR signals correspond to published NMR

data [26].

^aCombined yields after allylation and subsequent per-O-acetylation

^bReferring to results obtained by us [5–7, 9, 14, 16] and others [1–4,

10–13, 15], which confrm the infuence of t he s trong chelating ef ect

of a hydr oxyl group in α-position to the carbonyl function, we termed

the major products syn-25 and syn-31, respectively

2,3‑O‑Isopropylidene‑^d‑glyceraldehyde (17) Compound

17 was prepared according to a known isopropylidene pro-

tection procedure [27] and oxidative 1,2-diol cleavage pro-

tocol [28]. Starting from 25.10 g ^d-mannitol (137.8 mmol),

2.706 g of compound 17 (207.9 mmol) was obtained with a

yield of 75% over 2 steps. NMR signals were found to cor-

respond to NMR data in the literature [28].

L 2000. Sonication was performed using a Bandelin Sonorex

Digiplus DL 512 H ultrasonic unit. Ozonolysis was executed

operating an Anseros COM-AD-04 ozone generator. HPLC

analyses were carried out on a Knauer system using Mach-

erey-Nagel NUCLEODUR^®100-5 and NUCLEODUR^®

100-3 C₁₈ec columns. Column chromatography was per-

formed using Macherey-Nagel silica gel 60 (0.04–0.063 mm,

240–400 mesh). TLC monitoring was carried out on pre-

coated Merck silica gel 60 F₂₅₄glass plates. Compounds

were visualized by treatment with a Mo–Ce(SO₄)₂complex

solution (48 g (NH₄)₆Mo₇O₂₄and 2 g CeSO₄in 1 dm³10%

H₂SO₄) followed by heating. Filtrations over celite were per-

formed with Celite® S by Sigma-Aldrich®. Solvents were

distilled, if necessary, prior to use. Reagents were purchased

2,3‑Dideoxy‑5,6‑O‑isopropylidene‑2‑C‑methyl‑

idene‑d‑erythro‑hexitol (anti‑21, C₁₀H₁₈O₄) 2,3-O-Iso-

propylidene-d-glyceraldehyde (17, 108 mg, 0.830 mmol)

and 175 mg 2-(bromomethyl)prop-2-en-1-ol (14, 1.16 mmol,

1.4 equiv.) were dissolved in 5 cm³ethanol. Indium pow-

der (133 mg, 1.16 mmol, 1.4 equiv.) was added and the

1 3

Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction

suspension was sonicated at 45 °C for 18 h. The reaction

mixture was cooled to room temperature and the pH was

adjusted to 7 with 1 M aqueous sodium hydroxide solu-

tion. The suspension was fltered over a plug of celite which

was subsequently rinsed with 20 cm³ethanol. The fltrate

was concentrated under reduced pressure and the epimeric

mixture was purifed by column chromatography with hep-

tane/ethyl acetate (1:3 v/v) as eluent to give 97 mg com-

pound anti-21 (0.48 mmol) as white solid and 29 mg syn-21

(0.143 mmol) as colorless oil (75%, 54% de).

2H, H-5, H-6b), 2.462 (dd, ²J_3a,3b=14.8 Hz, ³J_3a,4=2.3 Hz,

2

3

1H, H-3a), 2.154 (dd, J_3b,3a= 14.8 Hz, J_3b,4= 10.2 Hz,

1H, H-3a) ppm; ¹³C NMR (150.93 MHz, D₂O, 25 °C):

δ=144.72 (C-2), 112.63 (C-1′), 74.60 (C-5), 69.92 (C-4),

64.28 (C-1), 62.42 (C-6), 35.79 (C-3) ppm; HRMS (ESI⁺):

+

m/z = 185.0774 ([M + Na]⁺), calcd. for C₇H₁₄NaO₄

185.0784; [ꢀ]²⁰= − 7.8 (c = 0.3, methanol); R_f= 0.5

D

(dichloromethane/methanol=4:1).

3‑Deoxy‑d‑erythro‑hexulose (5) Compound 22 (126 mg,

0.777 mmol) was dissolved in 6 cm³methanol and 6 cm³

dichloromethane and the solution was cooled to − 78 °C.

Ozone was led through the reaction mixture via a gas inlet

tube until the solution’s color turned yellow. The mixture was

purged with air for 10 min and 171 mm³of dimethyl sulfde

(2.33 mmol, 3 equiv.) was added. The reaction solution was

slowly warmed to 0 °C and the pH was adjusted to 7 with

1 M aqueous sodium hydroxide solution. The cooling bath

was removed and the mixture was stirred at ambient tem-

perature for 6 h. The mixture was concentrated and purifed

by column chromatography with dichloromethane/methanol

(4:1 v/v) as eluent to give 91 mg compound 5 (0.554 mmol,

71%) as colorless oil. ¹H NMR (700.40 MHz, D₂O,

25 °C): β-pyranose:α-furanose:keto isomer:β-furanose:α-

pyranose=1.00:0.40:0.32:0.30:0.17; δ (β-pyranose)=4.118

anti-21: ¹H NMR (600.25 MHz, CDCl₃, 25 °C): δ=5.118

(s, 1H, H-1′a), 4.987 (s, 1H, H-1′b), 4.067 (m, 2H, H-1),

4.014 (m, 1H, H-6a), 4.964 (m, 1H, H-5), 3.907 (m, 1H,

H-6b), 3.741 (m, 1H, H-4), 3.492 (s br, 1H, OH), 3.320 (s

br, 1H, OH), 2.435 (d, ²J_3a,3b= 14.3 Hz, 1H, H-3a), 2.137

2

(dd, ²J_3b,3a=14.3 Hz, J_3b,4=9.2 Hz, 1H, H-3b), 1.401 (s,

3H, CH₃), 1.333 (s, 3H, CH₃) ppm; ¹³C NMR (150.93 MHz,

CDCl₃, 25 °C): δ = 145.21 (C-2), 114.89 (C-1′), 109.33

(C(CH₃)₂), 78.41 (C-5), 71.27 (C-4), 66.41 (C-1), 65.90

(C-6), 37.93 (C-3), 26.69 (CH₃), 25.34 (CH₃) ppm; HRMS

+

(ESI⁺): m/z=225.1102 ([M+Na]⁺), calcd. for C₁₀H₁₈NaO₄

225.1097; [ꢀ]²⁰=+0.5 (c=6.5, methanol); R_f=0.5 (hep-

D

tane/ethyl acetate=1:3).

3

(ddd, J_4,3a= 12.5 Hz, J_4,3b= 5.0 Hz, J_4,5= 3.3 Hz, 1H,

1

syn-21: H NMR (600.25 MHz, CDCl₃, 25 °C): δ =5.134

H-4), 4.026 (dd, ²J_6a,6b=12.8 Hz, ³J_6a,5=1.4 Hz, 1H, H-6a),

3

(s, 1H, H-1′a), 4.972 (s, 1H, H-1′b), 4.156–4.097 (m, 2H,

H-1), 4.089–4.003 (m, 2H, H-5, H-6a), 3.819–3.746 (m, 1H,

H-6b), 3.745–3.655 (m, 1H, H-4), 3.492 (s br, 1H, OH),

3.320 (s br, 1H, OH), 2.434 (d, ²J_3a,3b=14.2 Hz, 1H, H-3a),

3.875 (ddd, J_5,4= 3.3 Hz, J_5,6b= 2.2 Hz, J_5,6a= 1.4 Hz,

1H, H-5), 3.765 (dd, ²J_6b,6a=12.8 Hz, ³J_6b,5=2.2 Hz, 1H,

2

H-6b), 3.516 (d, J_1a,1b= 11.6 Hz, 1H, H-1a), 3.510 (d,

²J_1b,1a= 11.6 Hz, 1H, H-1b), 1.832 (dd, J_3a,3b= 13.6 Hz,

2

3

2

2.137 (dd, J_3b,3a= 14.2 Hz, J_3b,4= 9.2 Hz, 1H, H-3b),

1.401 (s, 3H, CH₃), 1.333 (s, 3H, CH₃) ppm; ¹³C NMR

(150.93 MHz, CDCl₃, 25 °C): δ = 145.41 (C-2), 114.62

(C-1′), 109.77 (C(CH₃)₂), 78.69 (C-5), 71.90 (C-4), 66.58

(C-1), 66.17 (C-6), 38.17 (C-3), 26.78 (CH₃), 25.42 (CH₃)

ppm; HRMS (ESI⁺): m/z=225.1098 ([M+Na]⁺), calcd. for

C₁₀H₁₈NaO₄⁺225.1097; [ꢀ]²⁰=+0.8 (c=2.6, methanol);

R_f=0.4 (heptane/ethyl aceta^Dte=1:3).

³J_3a,4= 12.5 Hz, 1H, H-3a), 1.823 (dd, J_3b,3a= 13.6 Hz,

³J_3b,4=5.0 Hz, 1H, H-3b) ppm; δ (α-furanose)=4.277 (ddd,

³J_4,3a=7.4 Hz, ³J_4,5=4.5 Hz, ³J_4,3b=4.1 Hz, 1H, H-4), 4.172

(ddd, ³J_5,6b=5.6 Hz, ³J_5,4=4.5 Hz, ³J_5,6a=3.7 Hz, 1H, H-5),

3.725 (dd, ²J_6a,6b=12.3 Hz, ³J_6a,5=3.7 Hz, 1H, H-6a), 3.619

(dd, ²J_6b,6a=12.3 Hz, ³J_6b,5=5.6 Hz, 1H, H-6b), 3.569 (d,

²J_1a,1b= 11.9 Hz, 1H, H-1a), 3.562 (d, J_1b,1a= 11.9 Hz,

2

3

1H, H-1b), 2.446 (dd, J_3a,3b= 14.2 Hz, J_3a,4= 7.4 Hz,

1H, H-3a), 1.951 (dd, ²J_3b,3a=14.2 Hz, ³J_3b,4=4.1 Hz, 1H,

H-3b) ppm; δ (keto isomer)=4.433 (d, ²J_1a,1b=19.0 Hz, 1H,

2,3‑Dideoxy‑2‑C‑methylidene‑d‑erythro‑hexitol (22,

C₇H₁₄O₄) Compound anti-21 (182 mg, 0.900 mmol) was

dissolved in 5 cm³water and 5 cm³tetrahydrofuran and the

pH was adjusted to 4 with 1 M aqueous hydrochloride solu-

tion. After complete consumption of the starting material

as monitored by TLC, the solution was neutralized using

saturated aqueous sodium hydrogen carbonate solution. The

mixture was concentrated and purifed by column chroma-

tography with dichloromethane/methanol (4:1 v/v) as elu-

ent to give 126 mg compound 22 (0.777 mmol, 86%) as

colorless oil. ¹H NMR (600.25 MHz, D₂O, 25 °C): δ=5.148

(s, 1H, H-1′a), 5.035 (s, 1H, H-1′b), 4.122–4.033 (m, 2H,

H-1), 3.844–3.736 (m, 2H, H-4, H-6a), 3.638–3.583 (m,

2

H-1a), 4.370 (d, J_1b,1a= 19.0 Hz, 1H, H-1b), 4.112 (ddd,

³J_4,3b= 9.2 Hz, J_4,5= 6.6 Hz, J_4,3a= 3.5 Hz, 1H, H-4),

3

2

3

3.750 (dd, J_6a,6b= 11.8 Hz, J_6a,5= 3.3 Hz, 1H, H-6a),

3

3.626 (ddd, J_5,6b= 7.0 Hz, J_5,4= 6.6 Hz, J_5,6a= 3.3 Hz,

1H, H-5), 3.593 (dd, ²J_6b,6a=11.8 Hz, ³J_6b,5=7.0 Hz, 1H,

2

3

H-6b), 2.763 (dd, J_3a,3b= 16.2 Hz, J_3a,4= 3.5 Hz, 1H,

2

3

H-3a), 2.683 (dd, J_3b,3a= 16.2 Hz, J_3b,4= 9.2 Hz, 1H,

3

H-3b) ppm; δ (β-furanose) = 4.429 (ddd, J_4,3b= 7.2 Hz,

³J_4,3a= 7.1 Hz, J_4,5= 5.5 Hz, 1H, H-4), 3.950 (ddd,

3

³J_5,6b= 6.2 Hz, J_5,4= 5.5 Hz, J_5,6a= 3.9 Hz, 1H, H-5),

3

3.770 (dd, ²J_6a,6b=12.1 Hz, ³J_6a,5=3.9 Hz, 1H, H-6a), 3.673

(dd, ²J_6a,6b=12.1 Hz, J_6b,5=6.2 Hz, 1H, H-6b), 3.602 (s,

3

1 3

M. Gintner et al.

2

3

1

2H, H-1), 2.290 (dd, J_3a,3b=13.6 Hz, J_3a,4=7.1 Hz, 1H,

syn-23: H NMR (600.25 MHz, CDCl₃, 25 °C): δ =5.422

2

3

3 3

H-3a), 2.171 (dd, J_3b,3a= 13.6 Hz, J_3b,4= 7.2 Hz, 1H,

(dd, J_6,7= 7.3 Hz, J_6,5= 3.9 Hz, 1H, 6-H), 5.278 (dd,

3

H-3b) ppm; δ (α-pyranose)= 4.159 (dddd, J_4,3a= 5.1 Hz,

³J_5,4= 6.9 Hz, J_5,6= 3.9 Hz, 1H, 5-H), 5.186 (ddd,

³J_4,3b=3.4 Hz, ³J_4,5=3.1 Hz, ³J_4,6b=0.9 Hz, 1H, H-4), 3.937

(dd, ²J_6a,6b=11.5 Hz, ³J_6a,5=9.6 Hz, 1H, H-6a), 3.814 (ddd,

³J_5,6a=9.6 Hz, ³J_5,6b=4.9 Hz, ³J_5,4=3.1 Hz, 1H, H-5), 3.662

(ddd, ²J_6b,6a=11.5 Hz, ³J_6b,5=4.9 Hz, ³J_6b,4=0.9 Hz, 1H,

³J_4,3b=9.2 Hz, ³J_4,5=6.9 Hz, ³J_4,3a=3.6 Hz, 1H, 4-H), 5.141

(d, ²J_1′a,1′b=0.9 Hz, 1H, 1′-Ha), 5.059 (ddd, ³J_7,6=7.3 Hz,

³J_7,8b= 5.4 Hz, J_7,8a= 3.1 Hz, 1H, 7-H), 5.028 (d,

3

²J_1′b,1′a= 0.9 Hz, 1H, 1′-Hb), 4.608 (d, J_1a,1b= 13.2 Hz,

2

H-6b), 3.500 (d, J_1a,1b= 11.8 Hz, 1H, H-1a), 3.470 (d,

1H, 1-Ha), 4.443 (d, J_1b,1a= 13.2 Hz, 1H, 1-Hb), 4.244

²J_1b,1a= 11.8 Hz, 1H, H-1b), 1.995 (dd,²J_3a,3b= 14.5 Hz,

(dd, J_8a,8b= 12.5 Hz, J_8a,7= 3.1 Hz, 1H, 8-Ha), 4.117

2

3

³J_3a,4= 5.1 Hz, 1H, H-3a), 1.940 (dd, J_3b,3a= 14.5 Hz,

(dd, J_8b,8a= 12.5 Hz, J_8b,7= 5.4 Hz, 1H, 8-Hb), 2.459

(dd, ²J_3a,3b=14.3 Hz, ³J_3a,4=3.6 Hz, 1H, 3-Ha), 2.300 (dd,

²J_3b,3a=14.3 Hz, ³J_3b,4=9.2 Hz, 1H, 3-Hb), 2.1304 (s, 3H,

OAc), 2.0856 (s, 3H, OAc), 2.0620 (s, 3H, OAc), 2.0582

(s, 3H, OAc), 2.0491 (s, 3H, OAc), 2.0153 (s, 3H, OAc)

ppm; ¹³C NMR (150.93 MHz, CDCl₃, 25 °C): δ = 170.58

((C=O)–CH₃), 170.48 ((C=O)–CH₃), 169.96 ((C=O)–

CH₃), 169.90 ((C=O)–CH₃), 169.80 ((C=O)–CH₃), 169.79

((C=O)–CH₃), 138.69 (2-C), 117.53 (1′-C), 70.72 (5-C),

69.24 (4-C), 68.63 (7-C), 68.59 (6-C), 66.22 (1-C), 61.49

(8-C), 34.73 (3-C), 20.86 ((C=O)–CH₃), 20.75 ((C=O)–

CH₃), 20.68 ((C=O)–CH₃), 20.66 ((C=O)–CH₃), 20.60

((C=O)–CH₃), 20.52 ((C=O)–CH₃) ppm; HRMS (ESI⁺):

m/z = 497.1634 ([M + Na]⁺), calcd. for C₂₁H₃₀O₁₂Na⁺

497.1635;[ꢀ]²⁰=+0.3 (c=1.0, dichloromethane); R_f=0.4

(heptane/ethy^Dl acetate=1:1).

2

3

³J_3b,4= 3.4 Hz, 1H, H-3b) ppm; ¹³C NMR (176.12 MHz,

D₂O, 25 °C): δ (β-pyranose) = 97.40 (C-2), 67.53 (C-1),

67.25 (C-5), 64.95 (C-4), 64.01 (C-6), 32.31 (C-3) ppm;

δ (α-furanose) = 105.84 (C-2), 85.74 (C-5), 71.31 (C-4),

65.18 (C-1), 61.52 (C-6), 41.49 (C-3) ppm; δ (keto iso-

mer)=211.83 (C-2), 74.34 (C-5), 68.00 (C-1), 67.88 (C-4),

62.41 (C-6), 41.45 (C-3) ppm; δ (β-furanose) = 105.49

(C-2), 86.26 (C-5), 70.98 (C-4), 65.43 (C-1), 62.53 (C-6),

41.52 (C-3) ppm; δ (α-pyranose)=96.49 (C-2), 66.82 (C-4),

66.15 (C-5), 65.79 (C-1), 58.72 (C-6), 34.39 (C-3) ppm;

¹H NMR signals correspond to published NMR data [33].

HRMS (ESI⁺): m/z = 187.0579 ([M + Na]⁺), calcd. For

C₆H₁₂NaO₅⁺187.0577; [ꢀ]²⁰= − 3.4 (c=1.1, methanol);

D

R_f=0.4 (dichloromethane/methanol=4:1).

1,4,5,6,7,8‑Hexa‑O‑acetyl‑2,3‑dideoxy‑2‑C‑methyl‑

idene‑d‑gluco‑octitol (syn‑23, C₂₁H₃₀O₁₂) 2-(Bromome-

thyl)prop-2-en-1-ol (14, 616 mg, 4.08 mmol, 1.5 equiv.) was

dissolved in 16 cm³ethanol and 4 cm³water. Indium powder

(468 mg, 4.08 mmol, 1.5 equiv.) and 408 mg d-arabinose

(18, 2.72 mmol) were added and the suspension was soni-

cated at 45 °C for 6 h. The reaction mixture was fltered over

celite which was subsequently rinsed with 20 cm³ethanol.

The fltrate was evaporated yielding a colorless oil. The oil

was taken up in 10 cm³pyridine, treated with 10 cm³acetic

anhydride, and cooled to 0 °C. 4-(Dimethylamino)pyridine

(17 mg, 0.14 mmol, 0.05 equiv.) was added and the solution

was stirred for 3 h while reaching room temperature. After

no further conversion was observed via TLC analysis, the

reaction mixture was diluted with toluene forming a homog-

enous pressure-maximum azeotrope with pyridine [34], thus

facilitating concentration. The residue was taken up in 30

cm³ethyl acetate and was washed with water (3×10 cm³)

and 10 cm³brine. The organic layer was dried over magne-

sium sulfate, fltered and concentrated yielding a colorless

oil. Separation of the resulting epimers was achieved via col-

umn chromatography using heptane/ethyl acetate (1:1 v/v)

as eluent to give 779 mg compound syn-23 (1.64 mmol) as

colorless oil and 250 mg compound anti-23 (0.527 mmol)

as colorless oil (80%, 51% de).

anti-23: ¹H NMR (400.27 MHz, CDCl₃, 25 °C):

3

δ = 5.431 (dd, J_6,7= 8.7 Hz, J_6,5= 2.7 Hz, 1H, 6-H),

3

5.272 (dd, J_5,4= 7.5 Hz, J_5,6= 2.7 Hz, 1H, 5-H), 5.134

3

(ddd, J_4,3a= 8.2 Hz, J_4,5= 7.5 Hz, J_4,3b= 4.5 Hz, 1H,

2

4-H), 5.093 (d, J_1′a,1′b= 0.9 Hz, 1H, 1′-Ha), 5.068 (ddd,

³J_7,6=8.7 Hz, ³J_7,8b=5.5 Hz, ³J_7,8a=2.8 Hz, 1H, 7-H), 4.983

(d, ²J_1′b,1′a=0.9 Hz, 1H, 1′-Hb), 4.560 (d, ²J_1a,1b=13.2 Hz,

2

1H, 1-Ha), 4.515 (d, J_1b,1a= 13.2 Hz, 1H, 1-Hb), 4.208

2

3

(dd, J_8a,8b= 12.5 Hz, J_8a,7= 2.8 Hz, 1H, 8-Ha), 4.068

2

3

(dd, J_8b,8a= 12.5 Hz, J_8b,7= 5.5 Hz, 1H, 8-Hb), 2.333

(dd, ²J_3a,3b=14.3 Hz, ³J_3a,4=8.2 Hz, 1H, 3-Ha), 2.306 (dd,

²J_3b,3a= 14.3 Hz, J_3b,4= 4.5 Hz, 1H, 3-Hb), 2.085 (s, 3H,

3

OAc), 2.077 (s, 3H, OAc), 2.073 (s, 3H, OAc), 2.053 (s, 3H,

OAc), 2.039 (s, 3H, OAc), 1.988 (s, 3 H, OAc) ppm; ¹³C

NMR (100.66 MHz, CDCl₃, 25 °C): δ = 170.58 ((C=O)–

CH₃), 170.56 ((C=O)–CH₃), 170.06 ((C=O)–CH₃), 169.90

((C=O)–CH₃), 169.87 ((C=O)–CH₃), 169.77 ((C=O)–CH₃),

139.00 (2-C), 116.68 (1‘-C), 70.57 (5-C), 68.12 (7-C),

68.04 (6-C), 67.56(4-C), 66.22 (1-C), 61.89 (8-C), 35.38

(3-C), 20.55–20.89 (6×(C=O)–CH₃) ppm; HRMS (ESI⁺):

m/z = 497.1633 ([M + Na]⁺), calcd. for C₂₁H₃₀O₁₂Na⁺

497.1629; R_f=0.4 (heptane/ethyl acetate=1:1).

2,3‑Dideoxy‑2‑C‑methylidene‑d‑gluco‑octitol (24,

C₉H₁₈O₆) Compound syn‑23 (133 mg, 0.280 mmol) was

dissolved in 10 cm³methanol and the solution was treated

with 2 mg sodium methoxide (0.037 mmol, 0.13 equiv.).

1 3

Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction

3

The mixture was stirred for 3 h until no further conversion

could be observed via TLC analysis. The solution was neu-

tralized using DOWEX W50 ion exchange resin (H⁺form)

which was subsequently fltered. The fltrate was concen-

trated to give 62 mg compound 24 (0.28 mmol,>99%) as

a white solid. Single crystals were grown by recrystalliza-

²J_8b,8a= 12.0 Hz, J_8b,7= 6.0 Hz, 1H, 8-Hb), 3.456 (s, 2H,

2

3

1-Ha, 1-Hb), 2.024 (dd, J_3a,3b= 14.9 Hz, J_3a,4= 3.7 Hz,

2

3

1H, 3-Ha), 1.782 (ddd, J_3b,3a= 14.9 Hz, J_3b,4= 2.8 Hz,

⁴J_3b,5= 1.0 Hz, 1H, 3-Hb) ppm; δ (keto isomer) = 4.435

(dd, ²J_1a,1b=19.2 Hz, ⁴J_1a,3b=0.6 Hz, 1H, 1-Ha), 4.380 (dd,

4

²J_1b,1a= 19.2 Hz, J_1b,3b= 0.6 Hz, 1H, 1-Hb), 4.257 (ddd,

1

3

tion in water/acetone [29]. H NMR (600.25 MHz, D₂O,

³J_4,3a= 9.4 Hz, J_4,5= 5.7 Hz, J_4,3b= 3.5 Hz, 1H, 4-H),

25 °C): δ=5.159 (d, ²J_1′a,1‘b=1.2 Hz, 1H, 1′-Ha), 5.046 (d,

3.827 (dd, J_8a,8b= 12.0 Hz, J_8a,7= 3.0 Hz, 1H, 8a-H),

2

3

²J_1′b,1′a=1.2 Hz, 1H, 1′-Hb), 4.098 (d, ²J_1a,1b=14.5 Hz, 1H,

3.773 (ddd, J_7,6= 8.2 Hz, J_7,8b= 6.3 Hz, J_7,8a= 3.0 Hz,

3

2

1-Ha), 4.090 (d, J_1b,1a= 14.5 Hz, 1H, 1-Hb), 3.941 (ddd,

1H, 7-H), 3.740 (dd, ³J_5,4=5.7 Hz, ³J_5,6=2.4 Hz, 1H, 5-H),

3

2

3

³J_4,3b= 9.5 Hz, J_4,5= 5.7 Hz, J_4,3a= 3.9 Hz, 1H, 4-H),

3.655 (dd, J_8b,8a= 12.0 Hz, J_8b,7= 6.3 Hz, 1H, 8-Hb),

2

3

3.823 (dd, J_8a,8b= 11.9 Hz, J_8a,7= 3.0 Hz, 1H, 8-Ha),

3.627 (dd, J_6,7= 8.2 Hz, J_6,5= 2.4 Hz, 1H, 6-H), 2.750

3

2

3

3.772 (ddd, J_7,6= 8.2 Hz, J_7,8b= 6.3 Hz, J_7,8a= 3.0 Hz,

(dd, J_3a,3b= 16.3 Hz, J_3a,4= 9.4 Hz, 1H, 3-Ha), 2.713

3

2

3

4

1H, 7-H), 3.711 (dd, J_5,4= 5.7 Hz, J_5,6= 2.3 Hz, 1H,

(dddd, J_3b,3a= 16.3 Hz, J_3b,4= 3.5 Hz, J_3b,1a= 0.6 Hz,

3

5-H), 3.689 (dd, J_6,7= 8.2 Hz, J_6,5= 2.3 Hz, 1H, 6-H),

⁴J_3b,1b= 0.6 Hz, 1H, 3-Hb) ppm; δ (α-furanose) = 4.614

2

3

3.643 (dd, J_8b,8a= 11.9 Hz, J_8b,7= 6.3 Hz, 1H, 8-Hb),

(ddd, J_4,3a= 6.3 Hz, J_4,5= 4.4 Hz, J_4,3b= 3.3 Hz, 1H,

2

3

2.419 (dd, J_3a,3b= 14.5 Hz, J_3a,4= 3.9 Hz, 1H, 3-Ha),

2.216 (dd, ²J_3b,3a=14.5 Hz, ³J_3b,4=9.5 Hz, 1H, 3-Hb) ppm;

¹³C NMR (150.93 MHz, D₂O, 25 °C): δ = 144.47 (2-C),

112.94 (1′-C), 71.96 (5-C), 71.32 (6-C), 71.05 (7-C), 70.59

(4-C), 64.25 (1-C), 62.78 (8-C), 36.29 (3-C) ppm; HRMS

(ESI⁺): m/z=245.0998 ([M+Na]⁺), calcd. for C₉H₁₈O₆Na⁺

4-H), 4.294 (dd, J_5,6= 5.0 Hz, J_5,4= 4.4 Hz, 1H, 5-H),

3

3.921 (dd, J_6,7= 6.8 Hz, J_6,5= 5.0 Hz, 1H, 6-H), 3.814

2

3

(dd, J_8a,8b= 12.0 Hz, J_8a,7= 3.3 Hz, 1H, 8-Ha), 3.785

3

(ddd, J_7,8b= 6.9 Hz, J_7,6= 6.8 Hz, J_7,8a= 3.3 Hz, 1H,

7-H), 3.678 (dd, ²J_8b,8a=12.0 Hz, ³J_8b,7=6.9 Hz, 1H, 8-Hb),

2

3.653 (s, 2H, 1-Ha, 1-Hb), 2.305 (dd, J_3a,3b= 14.5 Hz,

2

245.0996; m.p.: 124–126 °C;[ꢀ]²⁰= − 0.1 (c=1.0, water);

³J_3a,4= 6.3 Hz, 1H, 3-Ha), 2.241 (dd, J_3b,3a= 14.5 Hz,

D

R_f=0.7 (1-butanol/acetone/water=4:4:2).

³J_3b,4= 3.3 Hz, 1H, 3-Hb) ppm; δ (β-furanose) = 4.538

3

(ddd, J_4,3a= 5.6 Hz, J_4,5= 4.1 Hz, J_4,3b= 1.9 Hz, 1H,

3

CCDC 1899885 contains the supplementary crystallo-

graphic data for compound 24. These data can be obtained

from The Cambridge Crystallographic Data Centre, www.

ccdc.cam.ac.uk/data_request/cif.

4-H), 4.122 (dd, J_5,6= 5.3 Hz, J_5,4= 4.1 Hz, 1H, 5-H),

3

3.979 (dd, J_6,7= 6.9 Hz, J_6,5= 5.3 Hz, 1H, 6-H), 3.814

(dd, ²J_8a,8b=11.6 Hz, ³J_8a,7=3.3 Hz, 1H, 8-Ha), 3.789 (ddd,

³J_7,6=6.9 Hz, ³J_7,8b=6.9 Hz, ³J_7,8a=3.3 Hz, 1H, 7-H), 3.677

(dd, ²J_8b,8a=11.6 Hz, ³J_8b,7=6.9 Hz, 1H, 8-Hb), 3.597 (d,

2

3‑Deoxy‑d‑gluco‑octulose (15, C₈H₁₆O₇) Compound

24 (51 mg, 0.23 mmol) was dissolved in 10 cm3 methanol

and 10 cm3 dichloromethane and the solution was cooled

to − 78 °C. Ozone was led through the reaction mixture

via a gas inlet tube until the solution’s color turned blue.

The mixture was purged with air for 15 min, treated with

121 mg triphenylphosphine (0.46 mmol, 2.0 equiv.) and

stirred overnight at room temperature. The solvents were

removed under reduced pressure and the residue was taken

up in 20 cm³dichloromethane and 20 cm³water. The

aqueous phase was washed with dichloromethane (3× 10

cm³). The aqueous layer was concentrated and the result-

ing oil was purified by column chromatography using

dichloromethane/methanol (4:1 v/v) as eluent to give

40 mg compound 15 (0.18 mmol, 78%) as a colorless oil.

¹H NMR (600.25 MHz, D₂O, 25 °C): β-pyranose:keto

isomer:α-furanose:β-furanose: = 1.00:0.19:0.18:0.09; δ

²J_1a,1b= 11.8 Hz, 1H, 1-Ha), 3.589 (d, J_1b,1a= 11.8 Hz,

2

3

1H, 1-Hb), 2.417 (dd, J_3a,3b= 14.3 Hz, J_3a,4= 5.6 Hz,

2

3

1H, 3-Ha), 2.055 (dd, J_3b,3a= 14.3 Hz, J_3b,4= 1.9 Hz,

1H, 3-Hb) ppm; ¹³C NMR (150.93 MHz, D₂O, 25 °C): δ

(β-pyranose)=97.25 (2-C), 69.97 (7-C), 68.09 (1-C), 67.98

(4-C), 67.15 (6-C), 66.24 (5-C), 63.57 (8-C), 30.70 (3-C)

ppm; δ (keto isomer) = 212.14 (2-C), 72.33 (5-C), 71.65

(6-C), 71.64 (7-C), 69.36 (4-C), 68.55 (1-C), 63.35 (8-C),

42.15 (3-C) ppm; δ (α-furanose) = 105.37 (2-C), 81.19

(5-C), 72.52 (4-C), 72.24 (7-C), 71.18 (6-C), 66.09 (1-C),

62.97 (8-C), 44.01 (3-C) ppm; δ (β-furanose) = 105.96

(2-C), 83.67 (5-C), 72.56 (4-C), 72.28 (7-C), 71.58 (6-C),

65.73 (1-C), 62.97 (8-C), 42.58 (3-C) ppm; HRMS (ESI⁺):

m/z = 247.0791 ([M + Na]⁺), calcd. For C₉H₁₈O₆Na⁺

247.0788;= [ꢀ]²⁰0.3 (c=1.0, water); R_f=0.5 (1-butanol/

acetone/water (5^D:4:1).

3

(β-pyranose) = 4.120 (dd, J_6,7= 9.0 Hz, J_6,5= 1.4 Hz,

1,4,5,6,7,8,9‑Hepta‑O‑acetyl‑2,3‑dideoxy‑2‑C‑methyl‑

idene‑^d‑glycero‑d‑galacto‑nonitol (syn‑25, C₂₄H₃₄O₁₄)

d-Mannose (200 mg, 19, 1.11 mmol) and 251 mg 2-(bro-

momethyl)prop-2-en-1-ol (14, 1.67 mmol, 1.5 equiv.) were

dissolved in 8 cm³ethanol and 2 cm³water. Indium pow-

der (191 mg, 1.67 mmol, 1.5 equiv.) was added and the

3

1H, 6-H), 4.111 (ddd, J_4,3a= 3.7 Hz, J_4,5= 3.6 Hz,

³J_4,3b= 2.8 Hz, 1H, 4-H), 3.862 (ddd, J_5,4= 3.6 Hz,

3

³J_5,6= 1.4 Hz, J_5,3b= 1.0 Hz, 1H, 5-H), 3.855 (ddd,

4

³J_7,6=9.0 Hz, ³J_7,8b=6.0 Hz, ³J_7,8a=2.9 Hz, 1H, 7-H), 3.835

(dd, ²J_8a,8b=12.0 Hz, ³J_8a,7=2.9 Hz, 1H, 8-Ha), 3.664 (dd,

1 3

M. Gintner et al.

suspension was sonicated at 45 °C for 18 h. The reaction

mixture was cooled to room temperature and the pH was

adjusted to 7 with 1 M aqueous sodium hydroxide solution.

The suspension was fltered over a plug of celite which was

subsequently rinsed with 30 cm³of methanol. The fltrate

was concentrated under reduced pressure and the residue

was dissolved in 6 cm³pyridine and 6 cm³acetic anhy-

dride. The mixture was cooled with an ice bath, treated with

7 mg 4-(dimethylamino)pyridine (0.06 mmol, 0.5 equiv.)

and stirred overnight. The mixture was concentrated and

the addition of toluene facilitated the process by forming

a homogenous pressure-maximum azeotrope with pyridine

[34]. The residue was taken up in 20 cm³ethyl acetate and

was washed with water (3×10 cm³) and 10 cm³brine. The

organic layer was dried over magnesium sulfate, fltered and

concentrated. The epimeric mixture syn-/anti-25 could be

partially separated from the per-O-acetylated starting mate-

rial by performing column chromatography using heptane/

ethyl acetate (10/1 v/v) as eluent. However, the respec-

tive epimers could not be isolated. The conversion of 60%

(542 mg mixture with 1,2,3,4,6-penta-O-acetyl-^d-mannose,

0.672 mmol of epimeric products) over two steps and the

diastereoselective excess of 69% could be determined by

means of NMR.

magnesium sulfate, fltered, and concentrated. The residue

was purifed by column chromatography using heptane/ethyl

acetate (19/1 14/1 v/v) as eluent to give 3.70 g ethyl 2-(ben-

zyloxymethyl)acrylate (29, 16.8 mmol, 87%) as a yellowish

liquid. ¹H NMR (600.25 MHz, CDCl₃, 25 °C): δ=7.407–

7.326 (m, 4H, H-7, H-8), 7.326–7.270 (m, 1H, H-9), 6.324

(dd, ³J_4a,3=1.5 Hz, ²J_4a,4b=1.4 Hz, 1H, H-4a), 5.927 (dd,

2

³J_4b,3= 1.9 Hz, J_4b,4a= 1.4 Hz, 1H, H-4a), 4.594 (s, 2H,

3

H-5), 4.248 (dd, J_3,4b= 1.9 Hz, J_3,4a= 1.5 Hz, 2H, H-3),

4.226 (q, ³J_1′,2′=7.2 Hz, 2H, H-1′), 1.304 (t, ³J_2′,1′=7.2 Hz,

3H, H-2′) ppm; ¹³C NMR (150.93 MHz, CDCl₃, 25 °C):

δ = 166.04 (C-1), 138.23 (C-6), 137.57 (C-2), 128.56

(C-8), 127.82 (C-9), 127.77 (C-7), 125.81 (C-4), 72.89

(C-5), 68.52 (C-3), 60.85 (C-1′), 14.34 (C-2′) ppm; HRMS

+

(ESI⁺): m/z=243.0992 ([M+Na]⁺), calcd. for C₁₃H₁₆NaO₃

243.0992; R_f=0.5 (heptane/ethyl acetate=4:1).

2 ‑ ( B e n z y l ox y m e t hy l ) ‑ p r o p ‑ 2 ‑ e n ‑ 1 ‑ o l ( 3 0 ,

C₁₁H₁₄O₂) Ethyl 2-(benzyloxymethyl)acrylate (29, 3.70 g,

16.8 mmol) was dissolved in anhydrous dichloromethane

and cooled to − 78 °C. DIBAL-H solution (39 cm³, 1 M in

dichloromethane, 39 mmol, 2.3 equiv.) was slowly added

over 30 min. After stirring for an hour at − 78 °C, the solu-

tion was allowed to warm to 0 °C using an ice bath. The

reaction was stopped by slowly adding 75 cm³of a satu-

rated potassium sodium tartrate solution. The ice bath was

removed and the mixture was stirred overnight at room tem-

perature. The organic layer was separated and the aqueous

phase was extracted with dichloromethane (3 × 50 cm³).

The combined organic layers were washed with 50 cm³

brine, dried over magnesium sulfate, fltered, and concen-

trated. The residue was purifed by column chromatography

using heptane/ethyl acetate (4/1 v/v) as eluent to give 2.21 g

2-(benzyloxymethyl)-prop-2-en-1-ol (30 , 12.4 mmol, 74%)

as a yellowish oil. ¹H NMR (600.25 MHz, CDCl₃, 25 °C):

δ = 7.400–7.319 (m, 4H, H-7, H-8), 7.319–7.272 (m, 1H,

H-9), 5.211 (dd, ²J_4a,4b=1.7 Hz, ³J_4a,3=0.9 Hz, 1H, H-4a),

5.161 (dd, ²J_4b,4a=1.7 Hz, ³J_4b,3=1.0 Hz, 1H, H-4b), 4.528

(s, 2H, H-5), 4.206 (d, ³J_1,OH=5.4 Hz, 2H, H-1), 4.106(dd,

³J_3,4b=1.0 Hz, ³J_3,4a=0.9 Hz, 2H, H-3), 1.895 (m, 1H, OH)

ppm; ¹³C NMR (150.93 MHz, CDCl₃, 25 °C): δ = 145.14

(C-2), 138.08 (C-6), 128.60–127.90 (C-7, C-8, C-9), 113.75

(C-4), 72.50 (C-5), 72.00 (C-3), 64.81 (C-1) ppm; HRMS

Ethyl 2‑(benzyloxymethyl)acrylate (29, C₁₃H₁₆O₃) A

suspension of 386 mg sodium hydride (60% dispersion,

9.65 mmol, 0.5 equiv.) in 30 cm³anhydrous diethyl ether

under argon was cooled to 0 °C. Benzyl alcohol (4.0 cm³,

39 mmol, 2 equiv.) was slowly added and the reaction mix-

ture was stirred for 30 min at 0 °C. Subsequently, 3.9 cm³

trichloroacetonitrile (39 mmol, 2 equiv.) was slowly added

and the solution was allowed to stir at room temperature for

three hours. The reaction was stopped by the addition of 30

cm³saturated aqueous bicarbonate solution. The aqueous

phase was extracted with diethyl ether (3×30 cm³) and the

combined organic layers were dried over magnesium sulfate.

After fltration, the eluate was concentrated to give crude

benzyl 2,2,2-trichloroacetminidate (28) in form of a brown

oil. To a mixture of 2.51 g ethyl 2-(hydroxymethyl)acrylate

(27, 19.3 mmol) in 50 cm³anhydrous diethyl ether under

argon, 170 mm³trifuoromethanesulfonic acid (1.92 mmol,

0.1 equiv.) was added followed by freshly prepared crude

benzyl 2,2,2-trichloroacetimidate (28, 39 mmol, 2 equiv.).

The solution was stirred for 42 h at room temperature. After

complete consumption of the starting material, 30 cm³

aqueous hydrochloric acid solution (2 M) was added and

the mixture was stirred for 10 min. The organic phase was

separated and washed with saturated bicarbonate solution

(2×30 cm³) followed by 30 cm³of brine. After concentra-

tion, 50 cm³heptane was added to the resulted white pre-

cipitate and the suspension was fltered and washed with

30 cm³of heptane. The organic solution was dried over

+

(ESI⁺): m/z=201.0887 ([M+Na]⁺), calcd. for C₁₁H₁₄NaO₂

201.0886; R_f=0.5 (heptane/ethyl acetate=1:1).

2‑(Benzyloxymethyl)allyl bromide (16, C₁₁H₁₃BrO) Tri-

phenylphospine (3.47 g, 13.2 mmol, 2 equiv.) and 4.39 g

tetrabromomethane (13.24 mmol, 2 equiv.) were dissolved in

150 cm³of anhydrous dichloromethane under argon, cooled

to 0 °C and stirred for 15 min. Subsequently, a solution of

1.18 g compound 30 (6.62 mmol) in 15 cm³anhydrous

dichloromethane was added. The reaction was monitored by

1 3

Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction

TLC and was completed after 3 h. After concentration, the

residue was dissolved in 50 cm³diethyl ether, and 50 cm³of

heptane was added under stirring. The resulting precipitate

was fltered over celite and washed with 10 cm³heptane.

The eluate was washed with water (3×50 cm³) and 50 cm³

brine, dried over magnesium sulfate, fltered, and concen-

trated. The residue was purifed by column chromatogra-

phy using heptane/ethyl acetate (19/1 v/v) as eluent to give

1.24 g 2-(benzyloxymethyl)allyl bromide (16, 5.14 mmol,

and the diastereoselective excess of 60% could be deter-

mined by means of NMR. HRMS (ESI⁺): m/z = 617.2209

+

([M + Na]⁺), calcd. for C₂₉H₃₈NaO₁₃617.2205; R_f= 0.5

(heptane/ethyl acetate=1:1).

syn-31 : ¹H NMR (600.25 MHz, CDCl₃, 25 °C): δ=7.400–

7.309 (m, 4H, H-3″, H-4″), 7.309–7.266 (m, 1H, H-5″),

3

5.433 (dd, J_6,5= 10.0 Hz, J_6,7= 2.0 Hz, 1H, H-6), 5.316

1

3

78%) as colorless liquid. H NMR (600.25 MHz, CDCl₃,

(dd, J_7,8= 8.6 Hz, J_7,6= 1.97 Hz, 1H, H-7), 5.189 (dd,

3

25 °C): δ = 7.511–7.326 (m, 4H, H-7, H-8), 7.326–7.272

³J_5,6= 10.0 Hz, J_5,4= 2.0 Hz, 1H, H-5), 5.127 (ddd,

3

(m, 1H, H-9), 5.359 (ddd, ²J_4a,4b= 1.2 Hz, J_4a,3= 0.8 Hz,

³J_4,3b=9.3 Hz, ³J_4,3a=4.0 Hz, ³J_4,5=2.0 Hz, 1H, H-4), 5.071

(m, 1H, H-1″a), 4.981 (ddd, ³J_8,7=8.6 Hz, ³J_8,9b=5.4 Hz,

³J_8,9a= 2.9 Hz, 1H, H-8), 4.955 (s, 1H, H-1″b), 4.506 (d,

3

³J_4a,1= 0.8 Hz, 1H, H-4a), 5.271 (ddd, J_4b,3= 1.3 Hz,

3

²J_4b,4a= 1.2 Hz, J_4b,1= 0.2 Hz, 1H, H-4b), 4.537 (s, 2H,

3

2

H-5), 4.156 (dd, J_3,4b= 1.3 Hz, J_4a,3= 0.8 Hz, 2H, H-3),

²J_1′a,1′b= 11.9 Hz, 1H, H-1′a), 4.406 (d, J_1′b,1′a= 11.9 Hz,

3

2

3

4.053 (dd, J_1,4a= 0.8 Hz, J_1,4b= 0.2 Hz, 2H, H-1) ppm;

¹³C NMR (150.93 MHz, CDCl₃, 25 °C): δ=142.51 (C-2),

138.14 (C-6), 128.58–127.88 (C-7, C-8, C-9), 117.44 (C-4),

72.59 (C-5), 70.49 (C-3), 33.21 (C-1) ppm; HRMS (ESI⁺):

m/z = 263.0038 ([M + Na]⁺), calcd. for C₁₁H₁₃BrNaO⁺

263.0042; R_f=0.5 (heptane/ethyl acetate=14:1).

1H, H-1′b), 4.211 (dd, J_9a,9b= 12.5 Hz, J_9a,8= 2.9 Hz,

2

1H, H-9a), 4.095 (d, J_1a,1b= 12.75 Hz, 1H, H-1a), 4.021

(dd, ²J_9b,9a=12.5 Hz, ³J_9b,8=5.4 Hz, 1H, H-9b), 3.886 (d,

²J_1b,1a=12.75 Hz, 1H, H-1b), 2.328 (dd, ²J_3a,3b=14.2 Hz,

³J_3a,4= 4.0 Hz, 1H, H-3a), 2.126 (dd, J_3b,3a= 14.2 Hz,

2

³J_3b,4= 9.3 Hz, 1H, H-3b), 2.127 (s, 3H, OAc), 2.085 (s,

3H, OAc), 2.058 (s, 3H, OAc), 2.035 (s, 3H, OAc), 2.007 (s,

3H, OAc), 1.994 (s, 3H, OAc) ppm; ¹³C NMR (150.93 MHz,

CDCl₃, 25 °C): δ=170.69 ((C=O)–CH₃), 170.39 ((C=O)–

CH₃), 170.16 ((C=O)–CH₃), 170.10 ((C=O)–CH₃), 170.09

((C=O)–CH₃), 169.81 ((C=O)–CH₃), 141.16 (C-2), 138.41

(C-2″), 128.52 (C-4″), 127.89 (C-3″), 127.75 (C-5″), 116.23

(C-1″), 72.46 (C-1), 71.97 (C-1′), 69.67 (C-5), 68.35 (C-8),

68.08 (C-4), 67.65 (C-7), 67.18 (C-6), 62.06 (C-9), 35.32

(C-3), 21.08 ((C=O)–CH₃), 20.98 ((C=O)–CH₃), 20.93

((C=O)–CH₃), 20.85 ((C=O)–CH₃), 20.83 ((C=O)–CH₃),

20.75 ((C=O)–CH₃) ppm.

4 , 5 , 6 , 7 , 8 , 9 ‑ H e x a ‑ O ‑ a c e t y l ‑ 1 ‑ O ‑ b e n ‑

zyl‑2,3‑dideoxy‑2‑C‑methylidene‑d‑glycero‑d‑ga-

lacto‑nonitol (syn‑31, C₂₉H₃₈O₁₃) d-Mannose (19,

200 mg, 1.11 mmol) and 401 mg 2-(benzyloxymethyl)

allyl bromide (16, 1.67 mmol, 1.5 equiv.) were dissolved

in 8 cm³ethanol and 2 cm³water. Indium powder (191 mg,

1.67 mmol, 1.5 equiv.) was added and the suspension was

sonicated at 45 °C for 18 h. The reaction mixture was cooled

to room temperature and the pH was adjusted to 7 with 1 M

aqueous sodium hydroxide solution. The suspension was

fltered over a plug of celite which was subsequently rinsed

with 30 cm³of methanol. The fltrate was concentrated and

the residue was dissolved in 6 cm pyridine and 6 cm³acetic

anhydride. The mixture was cooled with an ice bath, treated

with 7 mg 4-(dimethylamino)pyridine (0.06 mmol, 0.5

equiv.) and stirred overnight. The reaction mixture was con-

centrated and the addition of toluene facilitated the process

by forming a homogenous pressure-maximum azeotrope

with pyridine [34]. The residue was taken up in 20 cm³ethyl

acetate and was washed with water (3×10 cm³) and 10 cm³

brine. The organic layer was dried over magnesium sulfate,

fltered, and concentrated. The epimeric mixture could be

separated from the per-O-acetylated starting material by per-

forming column chromatography using heptane/ethyl acetate

(2/1 v/v) as eluent. The epimers syn-31 and anti-31 could

not be separated by conventional column chromatography

but by HPLC using a Macherey–Nagel NUCLEODUR®

100–5 column. For successful separation, the column was

cooled to 15 °C. The analytes were detected at 254 nm and

the eluent applied consisted of heptane/ethyl acetate=86/14.

The conversion of 45% (298 mg, 0.501 mmol) over two steps

anti-31: ¹H NMR (600.25 MHz, CDCl₃, 25 °C): δ=7.400–

7.309 (m, 4H, H-3″, H-4″), 7.309–7.266 (m, 1H, H-5″),

3

5.411 (dd, J_6,5= 9.4 Hz, J_6,7= 2.2 Hz, 1H, H-6), 5.371

3

(dd, J_7,8= 9.2 Hz, J_7,6= 2.2 Hz, 1H, H-7), 5.202 (dd,

³J_5,6=9.4 Hz, ³J_5,4=2.2 Hz, 1H, H-5), 5.118 (s, 1H, H-1″a),

5.067 (ddd, ³J_4,3a=10.8 Hz, ³J_4,5=2.2 Hz, ³J_4,3b=0.5 Hz,

3

1H, H-4), 5.051 (ddd, J_8,7= 9.2 Hz, J_8,9b= 5.4 Hz,

³J_8,9a= 2.8 Hz, 1H, H-8), 4.955 (s, 1H, H-1′’b), 4.544 (d,

²J_1′a,1′b= 12.0 Hz, 1H, H-1′a), 4.481 (d, J_1′b,1′a= 12.0 Hz,

2

3

1H, H-1′b), 4.203 (dd, J_9a,9b= 12.5 Hz, J_9a,8= 2.8 Hz,

1H, H-9a), 4.036 (dd, ²J_9b,9a=12.5 Hz, ³J_9b,8=5.4 Hz, 1H,

2

H-9b), 3.945 (d, J_1a,1b= 12.7 Hz, 1H, H-1a), 3.907 (d,

²J_1b,1a= 12.7 Hz, 1H, H-1b), 2.518 (dd, J_3a,3b= 15.1 Hz,

2

³J_3a,4= 10.8 Hz, 1H, H-3a), 2.349 (dd, J_3b,3a= 15.1 Hz,

2

³J_3b,4= 0.5 Hz, 1H, H-3b), 2.079 (s, 3H, OAc), 2.062 (s,

6H, 2xOAc), 2.050 (s, 3H, OAc), 2.046 (s, 3H, OAc), 1.957

(s, 3H, OAc) ppm; ¹³C NMR (150.93 MHz, CDCl₃, 25 °C):

δ=170.41–169.89 (6x((C=O)-CH₃)), 141.38 (C-2), 138.46

(C-2″), 128.48 (C-4″), 127.83 (C-3″), 127.70 (C-5″), 115.10

(C-1″), 73.07 (C-1), 72.02 (C-1′), 70.82 (C-4), 69.82 (C-5),

1 3

M. Gintner et al.

18. Kato H, van Chuyen N, Shinoda Y, Sekiya F, Hayase F (1990)

Biochim Biophys Acta 1035:71

68.06 (C-8), 67.82 (C-7), 67.59 (C-6), 61.99 (C-9), 31.89

(C-3), 21.08–20.75 (6x(C=O)-CH₃) ppm.

19. Wells-Knecht KJ, Lyons TJ, McCance DR, Thorpe SR, Feather

MS, Baynes JW (1994) Diabetes 43:1152

Acknowledgements Open access funding provided by University of

Vienna. We would like to thank the NMR centre for NMR analysis,

the mass spectrometry centre for mass analysis and A. Roller for X-ray

crystallographic analysis. We also thank T. Wrodnigg and J. Schörghu-

ber for critical comments on the manuscript.

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Res 289:77

Open Access This article is distributed under the terms of the Crea-

tive Commons Attribution 4.0 International License (http://creativeco

mmons.org/licenses/by/4.0/), which permits unrestricted use, distribu-

tion, and reproduction in any medium, provided you give appropriate

credit to the original author(s) and the source, provide a link to the

Creative Commons license, and indicate if changes were made.

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1 3

Article Doi

Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction

DOI: 10.1007/s00706-019-02438-y

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