Recent advances in the synthesis of 2-deoxy-glycosides

Carbohydrate Research 344 (2009) 1911–1940

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Carbohydrate Research

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Recent advances in the synthesis of 2-deoxy-glycosides

*

Dianjie Hou, Todd L. Lowary

Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, Alberta, Canada T6G 2G2

a r t i c l e i n f o

a b s t r a c t

Article history:

Glycosides of 2-deoxy-sugars, monosaccharides in which the hydroxyl group at C-2 is replaced with a

hydrogen atom, occur widely in natural products and therefore have been the subject of intense synthetic

activity. The report summarizes recent advances in this area, with a particular focus on work published

since an earlier review on the topic, in 2000 (Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385–

8417).

Received 23 June 2009

Accepted 29 July 2009

Available online 3 August 2009

Keywords:

Synthesis

2-Deoxy-glycosides

Oligosaccharides

Methodology

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1911

1.1. General features of the 2-deoxy-glycosidic bond . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1912

1.2. Factors governing 2-deoxy glycosidic bond formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1912

2. Scope. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1912

3. Use of thioglycoside donors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1913

3.1. Direct synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1913

3.2. Indirect synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1916

3.3. 1,2-Migration–glycosylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1917

4. Use of activated oxygen derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1919

4.1. Direct synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1919

4.2. Indirect synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923

5. Use of glycosyl halides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1926

6. Use of glycals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1929

6.1. Direct synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1929

6.2. Indirect synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1931

7. De novo synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1933

8. Applications to natural product synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1936

9. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1939

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1939

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1939

1. Introduction

as the skeletal sugar component. Other examples of such

molecules are the 2,6-dideoxy-hexoses. All diastereomers of the

2,6-dideoxy-hexoses (Fig. 1) occur in nature and have been found

to inﬂuence the biological activity of the molecules in which they

are contained.⁴In particular, 2,6-dideoxy-hexoses are frequently

present in antibiotics and anti-cancer agents such as anthracy-

clines, angucyclines, aureolic acid antibiotics, cardiac glycosides,

enediynes, macrolides, and pluramycins.^1–3,5Often, the occurrence

of the deoxy-sugar components is crucial for the pharmacology

and bioactivity of the drug.^6,7

2-Deoxy-sugars, monosaccharides in which the hydroxyl group

at C-2 is replaced with a hydrogen atom, are an important class of

carbohydrates that occur widely in natural products.^1–3Notably,

2-deoxy-D-erythro-pentose (2-deoxy-D-ribose) is present in DNA

* Corresponding author. Tel.: +1 780 492 1861.

E-mail address: tlowary@ualberta.ca (T.L. Lowary).

doi:10.1016/j.carres.2009.07.013

1912

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

HO

O

HO

O

HO

OH

HO

OH

HO

OH

-boivinose

2,6-didoxy- -xylo-

hexose

D

-olivose

-digitoxose

2,6-dideoxy- -ribo-

hexose

D

-oliose

D

2,6-dideoxy-

D

-lyxo-

2,6-dideoxy-

D

-arabino-

hexose

OH

O

HO

OH

HO

OH

L

-boivinose

L

-digitoxose

L

-oliose

L-olivose

L

2,6-didoxy- -xylo-

2,6-dideoxy- -ribo-

2,6-dideoxy-

L-lyxo-

2,6-dideoxy- -arabino-

hexose

Figure 1. Examples of naturally occurring 2,6-dideoxy-hexoses.

1.1. General features of the 2-deoxy-glycosidic bond

two faces of the ring, which adopts a half-chair conformation.

When a nucleophile approaches from the axial face, hyperconjuga-

tion between the one of the non-bonding orbitals of the ring oxy-

gen and the anti-bonding orbital of the developing bond helps to

stabilize the transition state, which resembles a chair conformer.

This interaction is often referred to as the kinetic anomeric effect.¹⁴

In contrast, when the nucleophile attacks from the equatorial face,

in order for the appropriate orbital overlap to be present the tran-

sition state must develop as a boat-like species. This boat-like tran-

sition state is of higher energy than the chair-like transition state;

therefore, the axial linkage is preferred.

As recognition of the biological importance of 2-deoxy-sugars

has increased, so too have efforts to develop chemical methods

for the assembly of oligosaccharides containing these residues.^5,8

However, once deoxygenation at C-2 of a glycosyl donor has been

performed, the construction of the glycosidic bonds in a stereocon-

trolled fashion becomes a challenge. As outlined below, the ab-

sence of groups at C-2 that can act to direct the reaction often

leads to syntheses of 2-deoxy-glycosides as mixtures of anomers.

Another consideration is that 2-deoxy-glycosides can be more dif-

ﬁcult to manipulate compared to the C-2 hydroxylated analogues

because of their greater susceptibility to hydrolysis.⁹

Thus, in the synthesis of 2-deoxy-glycosides in which the group

at C-2 is the non-participating hydrogen atom, the anomeric effect

leads to the preferential formation of the a-glycoside. The selectiv-

1.2. Factors governing 2-deoxy glycosidic bond formation

ity of these reactions is, however, often not complete and various

factors such as temperature, protecting group, solvent, promoter,

and the leaving group affect actual glycosylation outcomes, includ-

ing yield and stereoselectivity. Nevertheless, the important conclu-

sion from this discussion is that the stereocontrolled formation of

equatorial (usually b-) glycosides by this approach is difﬁcult.

If one wants to prepare the equatorial 2-deoxy-glycosides, the

most common method is an indirect approach, which is shown

in Figure 4. In this case, the neighboring group participation of a

C-2 substituent is used as a control element in the glycosylation

reaction. The neighboring group Y is often a halogen, sulfur, or

selenium, which can be introduced either several steps before

the glycosylation reaction or during the reaction by use of a glycal

donor. When this group is axial, it is proposed that participation

leads to an intermediate in which the b-face is blocked, which

favors attack. Alternatively, when this participating group is

equatorial, the formation of a b-glycoside is possible. Following

glycosylation, the C-2 substituent is removed to give the 2-

deoxy-glycoside. The drawbacks of this strategy are that it requires

two steps, and that the group at C-2 must be initially installed with

the appropriate conﬁguration. It should be mentioned that direct

evidence for the participation of this substituent is, in most cases,

lacking, and it is also possible that the stereocontrol arises simply

from negative steric or electrostatic interactions between the

incoming nucleophile and the (typically bulky) directing group at

C-2.^15–19

Glycosidic bond formation is a complex process¹⁰that is often

governed by the anomeric effect, which promotes axial (usually

a

-) glycoside formation.¹¹The anomeric effect is the preference

for the axial orientation of electronegative substituents, such as ha-

lides, and O-alkyl, O-aryl, S-alkyl, S-aryl derivatives, when they are

attached to the anomeric center of a pyranose ring.^12,13A widely

accepted explanation for the anomeric effect is that the electron-

withdrawing axial substituent (the

a

-anomer for

D

-sugars in the

⁴C₁conformation) is stabilized by hyperconjugation between an

unshared electron pair on O-5 and anti-bonding (

the axial (exocyclic) C–X bond (Fig. 2).¹³

r

^*) orbital of

With this background in mind, a more detailed discussion of

glycosidic bond formation in 2-deoxy-sugars can be considered.

The reaction pathways available to an oxocarbenium ion (III) with

a substituent at C-2 that cannot stabilize the positive charge by

participation (e.g., H) are shown in Figure 3. Such an oxocarbenium

ion can be generated either by promoter-assisted departure of the

leaving group from an activated donor (I) or, less commonly, by the

addition of a proton (Y = H⁺) to a glycal (II). The positive charge at

the anomeric center in IV is stabilized by resonance from O-5. The

nucleophile can react with the oxocarbenium ion from one of the

n

O

σ∗

2. Scope

X

To date, a variety of approaches for the synthesis of 2-deoxy-

glycosides in high yield and stereoselectivity have been developed.

In 2000, Marzabadi and Franck compiled the progress in this area

for the period 1988–1999.⁸In addition, studies focusing mainly

Figure 2. Stabilization of an axial C–X bond at the anomeric center of a pyranose

ring by the anomeric effect.

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1913

electrophile Y⁺

O

promoter

-X

O

Y

O

Y

RO

X

I

III

II

O-agly

aglycone from

equatorial

aglycone from

axial

O

Y

O

RO

O-agly

Y

IV

more stable TS

less stable TS

O-agly

O

flip

O

Y

RO

O-agly

RO

Y

O-agly

Y

favored

disfavored

Y = non-participating group

Figure 3. Glycosylation process with a non-participating group at C-2 position.

Ferrier rearrangement²¹and enzymatic synthesis of 2-deoxy-gly-

cosides are not covered. In addition, the formation of glycosides

of sialic acid (N-acetylneuraminic acid) is not discussed because

glycosylation reactions of this particularly unique ‘2-deoxy-sugar’

have been the subject of a number of reviews.^22–24

In the coverage below, the syntheses are organized by donor

type. Use of thioglycosides is presented ﬁrst, followed by the use

of activated oxygen derivatives, glycosyl halides, and then glycals.

These sections are further divided by methods that can be used for

‘direct’ and ‘indirect’ synthesis of 2-deoxy glycosides. The former

are those that use 2-deoxy-glycosyl donors while the latter involve

donors containing a group at C-2 that is reduced following glyco-

sylation. A section describing the application of these methods to

natural product synthesis is also included, as is a discussion of de

novo approaches to 2-deoxysugar glycosides.

O

RO

V

electrophile Y⁺

Y

..

Y

O

RO

O-agly

VI

VII

HO-aglycone

RO

O

O-agly

RO

Y

..

IX

VIII

3. Use of thioglycoside donors

3.1. Direct synthesis

electrophile Y⁺

O

Thioglycosides are one of the most popular donors for glycosyl-

ation reactions,^25,26and these species have been widely used as do-

nors for the formation of 2-deoxy-glycosidic linkages via both

direct and indirect approaches. For example, Hirama²⁷and co-

V

Y = participating group

Figure 4. Glycosylation process with a participating group at C-2 position.

workers reported that AgPF₆is a useful activator for

a-selective

glycosylation of 2-deoxy-thioglycoside donors (Scheme 1), and this

method was broadly applied to 2-deoxy-thioglycoside systems

on the biochemical aspects of 2-deoxy-sugars and the mechanistic

aspects of deoxy-sugar formation were reviewed in 1997,²1999,²⁰

2000,¹and 2002.³More recently, a review on the synthesis and

occurrence of deoxy-sugars, including the 2-deoxy-sugars, has ap-

peared, but glycosylation methods were not included in the

coverage.⁴

such as those derived from

ose, -olivomycarose, and

between the b-thioglycoside of

(2) (Scheme 1) in dichloromethane with the use of AgPF₆as the

sole promoter. This reaction gave a mixture of glycosides enriched

L

-mycarose,

-olivose. One example is the coupling

-mycarose (1) and cyclopentanol

L-kedarosamine, L-digitox-

L

D

L

in the a-anomer (a/b = 14:1, 0 °C, 2 h).

The objective of this review is to summarize recent progress to-

ward establishing reliable chemical methods for the efﬁcient prep-

aration of 2-deoxy-glycosides and the application of these methods

to suitable target molecules. The focus here is on work reported

since the Marzabadi and Franck review,⁸and the coverage has been

limited such that the synthesis of 2,3-dideoxy-glycosides by the

In other studies, three simple alcohols, phenethyl alcohol,

t-BuOH, and i-Pr₂CHOH were screened as acceptors to test the

scope of the methodology. It was shown that when both the

phenylthio- and ethylthio-2-deoxy-glycosides were activated with

AgPF₆–DTBMP (2,6-di-tert-butyl-4-methylpyridine) and an alcohol

acceptor (2–3 equiv), the corresponding 2-deoxy-glycosides were

1914

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

O

AgPF₆

CH₂Cl₂

OH

O

OH

O

HO

SPh

+

TESO

88%

α:β = 14:1

1

2

3

Scheme 1. Glycosylation between 1 and 2 promoted by AgPF6.²⁷

producedin 75–99%yields. Whenthereaction wasperformedat 0 °C

for 0.5–2 h, the -selectivity varied from 1:1 to 1:0 :b. With other

silverpromoters(e.g., AgOTf), theselectivitywas lower. It is interest-

ing to note thatwith the -olivomycarose donor 4, the :b ratio selec-

tivity (1:8.1) is inverted using the same conditions (Scheme 2).

However, the authors did not provide the yield of this reaction.

Despite the high selectivity of the reaction, no mechanistic work

addressing the selectivity was provided. The method has, however,

been used by other groups to synthesize analogues of doxorubicin,

In another study, Paul and Jayaraman described a facile prepa-

ration of either - or b-2-deoxy-glycosides from a common

a

2-deoxy-thioglycoside donor, and applied this methodology to

the synthesis of a series of 2-deoxy-disaccharides.³²By employing

the thiophilic activator N-iodosuccinimide–triﬂic acid (NIS–TfOH),

3,4,6-tri-O-acetylated donors (e.g., 10, Scheme 4) were treated

with seven different substituted phenols and naphthols in dichlo-

L

a

romethane to afford the corresponding

products.

a-glycosides as the major

a clinically used anti-cancer agent that possess an

a

-linked

Studies of this NIS–TfOH mediated glycosylation indicated that

solvents greatly inﬂuenced the stereochemical outcome. For exam-

ple, a change of solvent from acetonitrile to dichloromethane gave

a signiﬁcant increase in the amount of the b-anomer. The authors

2,6-dideoxy-sugar moiety.^28–30

In another study involving thioglycoside donors, Ye and co-

workers have recently described an efﬁcient method for the highly

a-stereoselective formation of 2-deoxy-glycosides using a pre-acti-

ascribed this to the formation of an

a result of a reaction between the solvent acetonitrile and the

-face of the oxocarbenium intermediate. However, this solvent

effect was not enough to completely invert the stereoselectivity

of the reaction, and, at best, a 3:2 :b ratio was produced.

a

-glycosyl nitrilium ion³³as

vation approach.³¹The pre-activation procedure refers to the com-

plete activation and consumption of the glycosyl donor to generate

a reactive intermediate (e.g., a glycosyl triﬂate) in situ prior to the

addition of the alcohol acceptor. In this investigation, a series of

3,4-O-carbonate protected thioglycoside donors were treated with

a panel of acceptor alcohols. One example, in which the 2,6-dide-

oxysugar thioglycoside 7 was reacted with the glucose-derived

alcohol 8, is shown in Scheme 3. Glycosylations were performed

at ꢀ72 °C in dichloromethane using benzenesulﬁnyl morpholine

(BSM) and triﬂic anhydride (Tf₂O) as the promoter system. The

a

Nevertheless, the 2-deoxy-b-glycosides can be prepared from

the same precursor thioglycosides by a different reaction proto-

col.³²In this approach (Scheme 5), the thioglycoside 10 is con-

verted to the glycosyl bromide upon reaction with bromine in

dichloromethane. Treatment of the crude glycosyl bromide with

a THF solution of a phenoxide generated in situ from the phenol

and LHMDS affords the b-glycosylated product in more than 90%

yield, presumably via an S_N2-like mechanism.

coupling reactions proceeded with exclusive

87% yield.

a-selectivity and in

The authors proposed that the high

the formation of a highly reactive b-glycosyl triﬂate intermediate

after preactivation of the thioglycoside. After addition of the alco-

hol, this species would form the a-glycoside by way of an S_N2-like

displacement reaction. The presence of 3,4-O-carbonate protecting

group in the glycosyl donor was suggested to be essential to en-

a

-selectivity resulted from

A polymer-assisted solution-phase approach to 2-deoxy-glyco-

sides using thioglycosides as glycosyl donors, has been reported

by Kirschning and co-workers (Scheme 6).³⁴The use of polymer-

supported reagents simpliﬁes the work-up and puriﬁcation to only

ﬁltration.^35,36In the key glycosylation step, 2-deoxy-thiopyrano-

sides were activated by functionalized polymers bearing a thio-

philic promoter in the presence of various alcohols to afford the

hance the

a-selectivity due to its ability to act as conformational

constraint. However, a detailed description of this conformational

effect, or experimental studies attempting to detect the presence

of glycosyl triﬂate intermediates, was not reported.

expected 2-deoxy-glycosides. Moderate to good

/b ratio ranged from 1.4:1 to 4:1) was observed when

no-conﬁgured thiopyranosides (e.g., 14) were employed. In

a

-selectivity (the

a

D-arabi-

AgPF₆/DTBMP

CH₂Cl₂

O

OCH-i-Pr₂

SPh +

O

i-Pr₂CHOH

TESO

α:β = 1:8.1

HO

4

5

6

Scheme 2. Glycosylation between 4 and 5 under conditions reported by Hirama and co-workers.²⁷

O

OH

O

BSM, Tf₂O

O

BnO

O

+

CH₂Cl₂, -72 °C

O

BnO

87%

OMe

STol

α only

BnO

OMe

7

8

9

Scheme 3. Glycosylation of 8 with 7 under conditions developed by Ye and co-workers.³¹

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1915

OH

OAc

HO

AcO

1. NIS, TfOH, CH₂Cl₂

2. NaOCH₃/MeOH

O

+

HO

AcO

SEt

α:β

= 5.7:1

85% - 90%

O

11

12

10

Scheme 4. Synthesis of aryl 2-deoxy-

a

-glycosides by Paul and Jayaraman.³²

1. Br₂, CH₂Cl₂

OH

HO

OAc

AcO

2. 4-methyl phenol, LHMDS, THF

O

3. NaOCH₃/MeOH

HO

AcO

SEt

α:β

= 1:19

10

13

> 90%

Scheme 5. Synthesis of aryl 2-deoxy-b-glycosides by Paul and Jayaraman.³²

OAc

O

1.

NMe₃I(O₂CCF₃)₂

AcO

O

SPh

AcO

14

O

+

OPiv

O

2.

NMe₂

HO

PivO

OPiv

O

PivO

OPiv

76%

PivO

16

α:β

= 1.6:1

15

SPh

O

1.

2.

O

NMe₃I(OTs)OH

OAc

OPiv

O

OAc

17

O

PivO

OPiv

+

OAc

NMe₂

72%

HO

PivO

OPiv

O

18

OPiv

PivO

α:β = 100:0

15

Scheme 6. Polymer-assisted solution-phase synthesis of 2-deoxy-glycosides by Kirschning and co-workers.³⁴

O

Ph

O

SPh

Ph

O

BnO

O

Ph₂SO/Tf₂O, TTBP

-60 °C

BnO

19

+

O

61%

α:β = 1:4

OH

O

21

O

20

Scheme 7. Glycosylation 19 with 20 as described by Crich and Vinogradova.³⁷

contrast,

sively the

L

-lyxo-conﬁgured thiopyranosides (e.g., 17) gave exclu-

-anomers in good yields. The authors provided no ratio-

b-D-arabino-hexopyranoside (19, Scheme 7). These reactions were

a

achieved through activation of the donor with a combination of di-

phenyl sulfoxide (Ph₂SO) and triﬂic anhydride (Tf₂O) in the pres-

ence of 2,4,6-tri-tert-butylpyrimidine (TTBP) at ꢀ60 °C, followed

by the addition of the acceptor alcohol. A range of acceptors were

nale to explain the observed stereoselectivity.

In another study, Crich and Vinogradova³⁷reported glycosyla-

tions with phenyl 4,6-O-benzylidene-3-O-benzyl-2-deoxy-1-thio-

1916

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

used, and the yields ranged from 30% to 75% but selectivity was

modest to poor, ranging from a minimum of 1:1.5 /b to a maxi-

mum of 4:1 /b.

These studies were carried out to probe the mechanism and

scope of the Crich b-mannopyranoside synthesis,^38,39in which

advantage is taken of a cyclic protecting group to generate signiﬁ-

(Scheme 8) involved Wittig–Horner oleﬁnation of a protected pen-

tose derivative and subsequent electrophilic cyclization induced by

elemental iodine. For example, oleﬁnation of the 2,3,5-tri-O-ben-

zyl-xylose (22) gave a Z/E mixture of alkenyl sulfanyl derivatives

(23) in 60% yield. Generation of the thioglycosides was achieved

under optimized conditions that involved cyclization using iodoni-

um dicollidine perchlorate (IDCP) in acetonitrile, affording phenyl

a

cant quantities of

a-mannopyranosyl triﬂates, which undergo an

S_N2-like displacement upon addition of the alcohol. The lack of

stereoselectivity in the glycosylation of 19 (a ‘2-deoxy-mannose’

system) was ascribed to the instability of the corresponding glyco-

syl triﬂate, which in turn leads to high concentrations of an

oxocarbenium ion that reacts with the acceptor to give glycoside

mixtures. Indeed, low-temperature (ꢀ60 °C) NMR studies of the

product mixture initially formed upon activation of 19 showed

only trace amounts of the resonances expected for the glycosyl tri-

ﬂate intermediate.

2-deoxy-2-iodo-1-thio-gulopyranoside (24), as a 1:10

in 77% yield. Treatment of glycosyl donor 24 with methyl 4,6-O-

benzylidene-3-O-benzyl- -glucopyranoside (25, Scheme 9) or

cholesterol 27 under typical activation conditions (NIS–TfOH) pro-

vided the corresponding products, 26 and 28, in yields of 61% and

a/b mixture

a-D

66% with an a/b ratio of 1:16 and 1:8, respectively.

The preference for the formation of the b-glycoside was ratio-

nalized on the basis of the reaction proceeding through one of

two possible oxocarbenium ion conformers (29 or 30, Fig. 5).

Although previous studies⁴¹indicated that 30 should be more sta-

ble than 29, glycosylation of 30 in a stereoelectronically favored

manner¹⁴would require the nucleophile to attack from the bottom

face of the ring, which would be disfavored due to steric hindrance

arising from the C-3 benzoyloxy group. On the other hand, the

favored attack of the alcohol on 29 would proceed with less steric

congestion and hence, although 29 is less stable, it is also the most

reactive.

3.2. Indirect synthesis

Recent investigations have also explored the use of thioglyco-

sides possessing a substituent at C-2 for the preparation of 2-

deoxy-glycosides. Although, in principle, this group can control

the glycosylation stereocontrol by participation, in the cases

described below an alternate rationale is provided. A new protocol,

which utilizes phenyl 2-deoxy-2-iodo-1-thio-pyranosides as the

glycosylating agents, has been developed by Castillón and

co-workers.⁴⁰The preparation of this type of glycosyl donor

In a later study, Castillón and co-workers developed a ‘one-pot’

electrophile-induced cyclization–glycosylation sequence from the

acyclic alkenyl sufanyl derivative to furnish the 2-deoxy-2-iodo

OBn

BnO

OBn

O

IDCP

Ph₂P(O)CH₂SPh

CH₃CN

O

I

OH

THF, n-BuLi

OH

SPh

77%

α:β = 1:10

60%

Z/E=1:4

OBn

24

OBn

23

OBn

22

Scheme 8. Preparation of 2-deoxy-2-iodo-1-thio-

D

-gulopyranoside from 2,3,5-tri-O-benzyl-

D

-xylose.⁴⁰

OBn

BnO

Ph

O

SPh

O

I

2.2 eq. NIS, 0.2 eq. TfOH

CH₂Cl₂

OBn

24

BnO

OBn

BnO

O

+

61%

α:β = 1:16

O

I

O

Ph

O

OMe

BnO

OBn

BnO

HO

OMe

26

25

OBn

BnO

2.2 eq. NIS, 0.2 eq. TfOH

CH₂Cl₂

O

I

+

ROH

SPh

OR

66%

α:β = 1:8

I

OBn

24

OBn

28

27

H

R =

Scheme 9. Glycosylation of 25 and cholesterol 27 with 2-iodo-thioglycoside 24 as described by Castillon and co-workers.⁴⁰

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1917

OR

1. NIS, ROH

2. AgOTf

O

X

OR

OH

OR

BnO

SPh

RO

O

OR

70%

O

I

OBn

OR

BnO

α:β

= 11:89

I

33

RO

34

35

X = I

X = H

Bu₃SnH, Et₃B, O₂,

Toluene, 79%

29

30

Figure 5. Pyranosyl oxocarbenium ions 29 and 30.⁴⁰

H

R =

glycosides directly (Scheme 10).⁴²Five acylic donors were exam-

ined with a variety of glycosyl acceptors including cholestanol,

Scheme 11. Application of the cyclization–glycosylation procedure to the synthesis

of 2,6-dideoxy-glycoside 35.⁴²

cholesterol (27), and methyl 4,6-O-benzylidene-3-O-benzyl-a-D-

glucopyranoside (25) using NIS–TfOH activation in dichloromethane.

The glycosylation reactions provided the products in yields

ranging from 50% to 76%. In all cases, the glycosidic bond formed

as the major isomers was trans to the iodine substituent at C-2.

The selectivities for the trans products varied from a low of

75:25 to a high of 97:3, and this stereochemical preference can

be rationalized in a manner analogous to that described above

(Fig. 5).

With the glycosylation methodology established, two represen-

tative 2-deoxy-2-iodo-glycosides were treated with Bu₃SnH under

radical conditions to afford the corresponding 2-deoxy-glycosides.

These reactions proceeded in 67–75% yield, thus demonstrating

the potential of the method for synthesizing 2-deoxy-glycosides.

The utility of the methodology was further established by its appli-

cation to the synthesis of a model 2,6-dideoxy-glycoside (35) re-

lated to the pregnane glycoside (Scheme 11).

In a related investigation, the Castillón group has prepared

2-deoxy-2-phenylselenyl-thioglycosides to synthesize 2-deoxy-

glycosides.⁴³The synthetic route toward this new class of glycosyl

donors is similar to that described above for the 2-iodo-derivative

24 (Scheme 12). Starting from the protected furanose derivative,

oleﬁnation gave the expected alkenyl sufanyl derivative (31),

which then underwent a selenonium ion-mediated 6-endo cycliza-

tion to generate the glycosyl donor 37. When using N-(phenylse-

lenenyl)phthalimide (NPSP) 36 and ZnI₂as the promoters, the

cyclization reactions were sluggish, and yields between 15% and

60% of the desired products were obtained; however, total regio-

and stereoselectivity were observed.

Glycosylations were performed by treating a mixture of the

2-deoxy-2-phenylselenenyl-1-thioglycosyl donor 37 and the alco-

hol (e.g., 25) with NIS–TfOH in toluene–dioxane (1:3). This protocol

typically gave the desired products in yields of 50–70% (Scheme 12)

and was particularly effective with donors leading to 2-deoxy-2-

reactions to the 2-deoxy-glycosides can also be achieved by radical

deselenylation with tin hydride reagents.⁴⁴

3.3. 1,2-Migration–glycosylations

Thioglycosides possessing a good leaving group at C-2 in a

trans-conﬁguration to the sulfur have been shown to undergo a

tandem 1,2-migration–glycosylation sequence when treated with

the appropriate promoters and an alcohol (Fig. 6). These reactions

are proposed to proceed through the intramolecular displacement

of a leaving group at C-2 by the neighboring nucleophilic sulfur

atom at C-1 together with concomitant glycosylation. The forma-

tion of a transient episulfonium intermediate is often invoked,

although there is not deﬁnitive proof for its existence.^19,45–52

Nevertheless, the intermediacy of such species is an attractive

postulate as it explains the high stereoselectivity of the process,

in which the relationship between the group at C-1 and C-2 in

the product is trans. Desulfurization of the resulting 2-thio-

glycosides affords the corresponding 2-deoxy-glycosides. In earlier

reports, donors such as 2-O-phenoxythiocarbonyl thioglycosides,⁴⁵

2,3-orthoester-protected thioglycosides,^46,47or 2-sulfonyloxysele-

noglycosides^48,49have been employed as precursors to the forma-

tion of 2-deoxy-glycosides by this route.

Yu and Yang have demonstrated the use of phenyl 2,3-O-thi-

onocarbonyl-1-thio-a-L-rhamnopyranosides (e.g., 39) as effective

donors for the preparation of 2-deoxy-b-glycosides by this

approach.^47,53As illustrated in Scheme 13, typical reactions were

performed in dichloromethane at room temperature using MeOTf

as the promotor. Under these conditions, the expected 2-thio-b-

glycosides (41) were obtained with complete stereocontrol in

64–90% yield. The list of acceptors includes benzyl alcohol,

cyclohexanol, cholesterol, and three monosaccharide alcohols.

Analogous transformations, leading to complex trisaccharides,

have also been achieved using this method.

phenylselenenyl-b-D-gulopyranosides (a/b, 1:14; 50%) and 2-deoxy-

2-phenylselenenyl-b-D-allopyranosides (38,

a/b, 1:4; 66%). Although

not described in this paper, the conversion of the products of these

Ph

O

OBn

3 eq. NIS,

BnO

0.2 eq. TfOH

Ph

O

OBn

O

OH

CH₂Cl₂

O

BnO

SPh

+

BnO

O

I

O

OMe

65%

BnO

HO

OMe

α:β

= 17:83

OBn

31

25

32

Scheme 10. Electrophile-induced cyclization–glycosylation sequence for the preparation of 2-deoxy-2-iodoglycosides.⁴²

1918

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

OBn

OH

O

ZnI₂

+

SPh

N

Se

BnO

SPh

BnO

15%

SePh

O

OBn

37

Ph

BnO

31

36

O

2.2 eq. NIS,

0.2 eq. TfOH

OBn

BnO

O

Ph

O

OBn

toluene/dioxane (1:3)

O

SPh

+

BnO

O

66%

α:β = 1:4

SePh

O

OMe

HO

BnO

OMe

OBn

SePh

38

OBn

37

25

Scheme 12. Glycosylation of 25 with 2-phenylseleno-2-deoxy-thioglycoside 37 as described by Castillón and co-workers.⁴³

L

(51) containing two 2-deoxyfuranosyl residues, which is a poten-

tial inhibitor of mycobacterial arabinosyltransferases⁵⁷as illus-

trated in Scheme 14.

promoter

R"OH

O

OR"

RO

SR'

The same group also described the potential and scope of the

pyranoside counterparts (Fig. 8), 52 and 55) in these glycosylation

reactions, particularly in the preparation of 2,6-dideoxy-sugar gly-

cosides.⁵⁵Glycosylation of a panel of alcohols with 52 and 55 affor-

ded the corresponding 2-deoxy-2-thiotolyl glycoside products 53

and 56 in generally excellent yields with exclusive stereoselectivi-

ty. In this case, the 2-thiotolyl group was readily removed upon

reaction with tri-n-butyltin hydride and AIBN to give the corre-

sponding 2-deoxypyranosides 54 and 57. This method was suc-

cessfully applied to the synthesis of the disaccharide unit in

apoptolidin and the trisaccharide moiety of Olivomycin A.

In a follow-up study, a series of experiments aimed at under-

standing the mechanism of the 2,3-anhydrosugar migration–gly-

cosylation reaction were performed.¹⁹In these mechanistic

studies, a range of techniques were employed, including low-tem-

perature ¹H NMR spectroscopy, computational studies, chemical

synthesis, and the measurement of deuterium kinetic isotope ef-

fects. Although episulfonium ion intermediates had previously

been proposed to explain the typically high stereoselectivity ob-

served in this⁵⁴and similar migration–glycosylation pro-

cesses,^19,45–52the data obtained all pointed to the intermediacy

of an oxacarbenium ion.

SR'

O

promoter

R"OH

SR'

L

OR"

L = leaving group

Figure 6. General 1,2-migration–glycosylation sequence.

In a related investigation, the Castillón group has prepared 2-

deoxy-2-phenylselenyl-thioglycosides to synthesize 2-deoxy-gly-

cosides.⁴³The synthetic route toward this new class of glycosyl

donors is similar to that described above for the 2-iodo-derivative

24 (Scheme 12). Starting from the protected furanose derivative,

oleﬁnation gave the expected alkenyl sufanyl derivative (31), which

then underwent a selenonium ion-mediated 6-endo cyclization to

generate the glycosyl donor 37. When using N-(phenylselene-

nyl)phthalimide (NPSP) 36 and ZnI₂as the promoters, the cycliza-

tion reactions were sluggish, and yields between 15% and 60% of

the desired products were obtained; however, total regio- and ste-

reoselectivity were observed.

When simple and activated primary carbohydrate alcohols are

used, the reaction proceeds efﬁciently by treatment with 10 equiv

of 4 Å molecular sieves in dichloromethane at reﬂux. Alternatively,

with less reactive secondary carbohydrate alcohols, one equivalent

of copper(II) triﬂate is needed to promote the glycosylation. The

method was successfully applied to the synthesis of a trisaccharide

The deuterium kinetic isotope effects measured in this investi-

gation represent the ﬁrst direct experimental evidence of the nat-

ure of the intermediates formed in reactions of this type. On the

basis of these investigations, it was proposed that the high stere-

oselectivity of the reaction occurs by ‘inside-attack’^58,59of the

nucleophile onto the lowest energy conformer of the oxacarbeni-

um ion intermediate, which adopts the ³E conformation (Fig. 9).

SPh

O

MeOTf (1.2 eq)

O

MeO

O

MeO

O

SPh

DTBMP(1.5 eq)

HO

+

O

CH₂Cl₂, RT

90%

O

MeS

S

39

40

41

Scheme 13. 1,2-Migration–glycosylation protocol developed by Yu and Yang.^47,53

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1919

OR

BzO

OR

OH

BzO

OH

O

ROH

H₂

O

Lewis Acid

Raney Nickel

STol

44

42

43

Figure 7. Two-step preparation of 2-deoxy-glycosides from 2,3-anhydrosugar thioglycosides.⁵⁴

OBz

R'O

O

BzO

STol

Cu(OTf)₂,

CH₂Cl₂

OBz

TBDPSO

O

OMe

OR

+

85%

O

OMe

O

OH

46

O

45

BzO

STol

Ac₂O,

Pyridine,

DMAP

100%

47

R = H, R' = TBDPS

R = Ac, R' = TBDPS

48

TBAF, THF, 79%

49 R = Ac, R' = H

BzO

STol

Cu(OTf)₂,

4Å MS,

O

CH₂Cl₂

76%

BzO

STol

O

HO

O

1. H₂, RaNi, EtOH

OBz

O

OH

O

2. NaOCH₃, CH₃OH

OH

O

63% over 2 steps

OMe

OAc

OMe

OH

O

BzO

STol

HO

51

50

Scheme 14. Synthesis of trisaccharide 51.⁵⁴

O

BzO

HO

BzO

O

OR

HO

STol

52

53

54

OR

OH

O

STol

O

PMBO

STol

56

57

55

Figure 8. Structures of 2,3-anhydropyranosyl thioglycoside donors (52 and 55), glycosylation products (53 and 56), and 2,6-dideoxy-targets (54 and 57).⁵⁵

applied to the direct preparation of 2-deoxy-glycosides. In one re-

cent investigation, Kim reported the application of (2⁰-car-

boxyl)benzyl (CB) glycosides as glycosyl donors for the direct

synthesis of 2-deoxy-pyranosides.⁶⁰An illustrative example is

shown in Scheme 15, where activation of the readily accessible

3,4,6-tri-O-benzyl-protected 2-deoxy-pyranosyl CB glycoside 58

4. Use of activated oxygen derivatives

4.1. Direct synthesis

A number of different classes of activated oxygen derivatives

are used in the synthesis of glycosidic bonds, and most have been

1920

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

ROH

OH

BzO

OR

BzO

H

BzO

OH

O

ROH

O

HO

Lewis Acid

TolS

STol

42

favoured

43

³E

E₃

Figure 9. Proposed model for stereoselectivity in migration–glycosylation reactions with 42.¹⁹

BnO

O

58

BnO

O

Tf₂O, DTBMP

-78 °C, CH₂Cl₂

OBn

OH

+

O

OBn

O

BnO

α

91%, only

O

BnO

HO

BnO

OMe

60

BnO

OMe

59

Scheme 15. Use of (2⁰-carboxyl)-benzyl (CB) glycosides in the synthesis of 2-deoxy-

a

-glycosides.⁶⁰

with Tf₂O–DTBMP (2,6-di-tert-butyl-4-methylpyridine) and the

secondary alcohol 59 gave the disaccharide product 60 in excellent

yield and stereoselectivity. In these reactions, it was shown that

glycosylation of hindered secondary carbohydrate alcohols in

which the other hydroxyl groups were protected with arming pro-

The mechanism used to explain the stereoselectivity of the pro-

cess assumed that the excellent b-selectivity in reactions involving

63 (Fig. 10) derived from an S_N2-like displacement mechanism of

an a-glycosyl triﬂate intermediate that is formed in situ. The lack

of, or poor, b-selectivity in reactions with primary alcohols was

interpreted to indicate that these glycosylations proceed via the

oxocarbenium ion intermediate 64. No mechanistic work was per-

formed to support these proposals and, in light of the study by

Crich and Vinogradova³⁷(see Scheme 7) it is likely that another

mechanism is operating. In particular, the failure to detect a triﬂate

tecting groups (acetals or benzyl ethers) exhibited high

ity ( /b ratio ranged from 9.4:1 to -only). However, almost equal

amounts of - and b-anomers were formed when primary alcohols

a-selectiv-

a

were used, regardless of the nature of groups protecting the other

acceptor hydroxyl groups.

It should be noted that a change of the O-4 and O-6 protecting

groups on the donor from benzyl ethers to a benzylidene acetal

completely reverses the stereoselectivity from

Speciﬁcally, when the 4,6-O-benzylidene-protected donor 61 was

treated with the same hindered secondary alcohols under the

same reaction conditions, the b-anomer was favored (a/b ratio

ranged from 1:8 to b-only) in good yield. As was seen with the

tri-O-benzylated donor 58, glycosylation of the primary alcohol

acceptors afforded an anomeric mixture of disaccharides with no

signiﬁcant stereoselectivity in most cases.

a to b (Scheme 16).

OTf

O

Ph

O

Ph

O

BnO

OTf

63

64

Figure 10.

a

-Glycosyl triﬂate 63 and oxocarbenium ion 64.⁶⁰

O

Ph

O

BnO

O

61

O

OBn

O

Tf₂O, DTBMP

-78 °C, CH₂Cl₂

Ph

O

OH

+

O

BnO

OBn

BnO

OMe

β

72%, only

O

62

HO

BnO

OMe

59

Scheme 16. Use of (2⁰-carboxyl)-benzyl (CB) glycosides in the synthesis of 2-deoxy-b-glycosides.⁶⁰

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1921

species derived from donors with the protecting group pattern

present in 63³⁷suggest that such species may not be viable inter-

mediates in these reactions.

In another recent investigation, a unique approach to the syn-

thesis of 2-deoxy-glycosides based on the oxidative activation of

glycosyl trichloroacetimidates with I₂at ꢀ94 °C has been devel-

oped by Takahashi and co-workers.⁶¹This approach successfully

In the same paper, it was shown that allyl 2,6-dideoxy-glyco-

sides can be employed in direct glycosylations using BF₃ꢁEt₂O as

the promoter (Scheme 19). Three allyl 2,6-dideoxy-glycosides, pro-

tected with either ester or benzyl ether protecting groups at C-3

and C-4, were employed in BF₃ꢁEt₂O-mediated glycosylations with

the same panel of glycosyl acceptors used with the trichloroace-

timidate donors. The glycosylations provided the disaccharides in

provides excellent b-selectivity: up to b:

a

> 95:5 in some reactions.

good yields (65–85%) as mainly the

the stereoselectivities observed with these allyl glycoside donors,

no rationale was provided. However, the -selectivity presumably

arises as a consequence of the kinetic anomeric effect, as described

above (see Section 1.2).

Glycosyl phosphites have also been used in the direct synthesis

of 2-deoxy-glycosides. In a study published in 2005, Toshima and

co-workers examined the activation of 2-deoxy-sugar phosphite

donors using a heterogeneous solid acid, montmorillonite K-10

(Scheme 20).⁶³Glycosylations using 3,4,6-O-tribenzyl-protected

2-deoxy-pyranosyl phosphite (81) and 3-O-benzyl-4-O-benzoyl

olivosyl diethyl phosphite (84) as donors were performed in Et₂O

at ꢀ78 °C in the presence of 100 wt % montmorillonite K-10. The

acceptors screened included primary and secondary carbohydrate

derivatives, as well as primary and secondary simple alcohols.

a-anomer. With regard to

Both the 3-O-benzyl-4-O-benzylsulfonyl-olivosyl (65, Scheme 17)

and 3,4-O-dibenzoyl-digitoxosyl (68) imidates have been investi-

gated and coupled with aglycones that include a range of primary

and secondary carbohydrate alcohols. Protection of the hydroxyl

group at C-4 in the donor with an electron-withdrawing benzyl-

sulfonate group, rather than a benzyl ether, gave higher b-selectiv-

a

ity (b:a > 95:5) and better reaction yields. The high b-selectivity in

the glycosylation when 3,4-O-dibenzoyl digitoxosyl imidate (68)

was used as a donor was proposed to result from neighboring

group participation by the axially oriented benzoyl group at C-3.

No rationale was provided to explain the stereoselectivity of reac-

tions involving donor 65, which lacks a group that can participate

to generate the b-glycoside.

The 4-O-benzylsulfonyl-oliosyl trichloroacetimidate (70, Fig. 11)

and 4-O-benzylsulfonyl-amicetoxyl trichloroacetimidate (71) were

also screened against olivosyl, mono-amicetosyl, and di-amicetosyl

acceptors (66, 72, and 73, respectively) under the established

conditions, to provide mixtures of di- and trisaccharides in yields

Reaction yields ranged from 70% to 97%, and a:b ratios varied from

a low of 29:71 to a high of 10:90. Diethyl ether was found to be the

best solvent for these reactions. The origin of the b-selectivity for

this reaction was not studied. However, because the product did

not anomerize under the reaction conditions, it was suggested that

the product distribution was the result of kinetic control.

In related work, Sulikowski has developed a one-pot sequential

glycosylation protocol to construct b-linked 2-deoxy-oligosaccha-

rides by taking advantage of the differential rates of activation of

glycosyl phosphites possessing different alkyl groups.⁶⁴By moni-

toring a competitive glycosylation reaction in anhydrous toluene-

d₈at ꢀ100 °C using ³¹P NMR spectroscopy, it was established that

the diethyl phosphite donor 87 (Fig. 12) is more reactive than the

pinacol phosphite donor (88). The protocol was used to synthesize

the trisaccharide 89 in 50% overall yield, by carrying out the two

glycosylations in a single reaction vessel. The stereoselectivity of

both reactions favored the b-anomer, but the origin of this prefer-

ence was not discussed.

of 57–95%. In all cases, the b-glycoside was favored, with the b:a ra-

tio ranging from 60:40 to 80:20. To demonstrate the power of the

methodology, a tetrasaccharide containing four b-(1?4)-linked

olivose residues (74) was efﬁciently prepared.

Another specialized method, limited to the synthesis of

2-deoxy-a-glycosides, has been developed by Boons and co-

workers.⁶²A 2-deoxy-glucopyranosyl trichloroacetimidate donor

having a participating (S)-(phenylthiomethyl)benzyl moiety at

C-6 was prepared and used in TMSOTf-mediated reactions with a

range of acceptor substrates (Scheme 18). The glycosylation reac-

tions led to the corresponding disaccharides in excellent yields

(92–95%) with excellent

a-selectivity; the a/b ratio ranged from

8:1 to 15:1. Similar glycosylations employing 2-deoxy-glucopyran-

osyl trichloroacetimidate donors with a benzyl ether or an acetyl

ester at C-6 provided disaccharides as mixtures of anomers (the

Another example of the direct synthesis of 2-deoxy-glycosides

with activated oxygen derivatives is the use of a novel 1,6-lactone

best a/b ratio was 5:1).

O

I₂, 1.5 equiv

BnSO₂O

BnO

Et₃SiH, 0.1 equiv

O

CCl₃

O

BzO

−94 °C, toluene

BnSO₂O

BnO

65

+

O

NH

94%

OMe

O

β:α > 95:5

BzO

HO

67

66

OMe

O

I₂, 1.5 equiv.

BzO

Et₃SiH, 0.1 equiv.

CCl₃

O

BzO

-94 °C, toluene

BzO

O

NH

68

90%

OMe

+

OBz

β:α

> 95:5

O

BzO

HO

69

66

OMe

Scheme 17. Synthesis of 2-deoxy-glycosides by oxidation of glycosyl trichloroacetimidates with I₂.⁶¹

1922

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

BnSO₂O

BnO

O

BnSO₂O

O

CCl₃

O

CCl₃

NH

O

NH

71

70

O

HO

BzO

HO

OMe

66

72

73

O

HO

O

HO

OMe

74

Figure 11. Structure of donors 70, 71, acceptors 66, 72, 73, and tetrasaccharide 74.⁶¹

Ph

O

PhS

Ph

O

AcO

PhS

O

CCl₃

O

75

TMSOTf

-78 °C, CH₂Cl₂

AcO

NH

O

+

93%

OBz

O

HO

α:β = 12:1

OBz

O

BzO

OMe

77

OMe

76

Scheme 18. Synthesis of 2-deoxy-

a

-glycosides via using a trichloroacetimidate donor with a participating group attached to O-6.⁶²

O

AcO

HO

BF₃•Et₂O

O

0°C to rt, CH₂Cl₂

AcO

BzO

+

O

AcO

85%

O

BzO

OAll

BzO

OMe

α:β = 14:1

BzO

78

79

BzO

OMe

80

Scheme 19. Use of allyl glycosides in the direct synthesis of 2-deoxy-glycosides.⁶²

donor (90, Scheme 21) in which the carboxylic acid acts as the

leaving group in the reaction.⁶⁵Using this approach, Murphy and

co-workers synthesized 90 and treated it with one of four accep-

tors including trimethylsilyl azide, methyl trimethylsilyl ether,

cyclohexyl trimethylsilyl ether, and a trimethylsilyl-protected

threonine derivative 91 using tin (IV) chloride (0.33–1 equiv).

22, when treated with NaH in dioxane at room temperature, can

react with allyl bromide, 1-bromo-2,4-dinitrobenzene, and pri-

mary carbohydrate triﬂates such as 94 to afford the corresponding

2-deoxy-b-glycosides. The yields are around 90% and the products

are obtained with high b-selectivity (a/b ranged from 1:18 to

1:20). However, reactions with secondary triﬂates 96 and 97

(Fig. 13) failed, which is not unexpected given previous literature

demonstrating the limitations of the anomeric alkylation in the

synthesis of carbohydrate glycosides.^67,68

The lactols 98 and 99 (Fig. 14), derived from glucose and galact-

ose were also screened against allyl bromide, 1-ﬂuoro-2,4-dinitro-

benzene, and primary carbohydrate triﬂates (100–102) under the

established conditions. These reactions provided mixtures of

The yields ranged from 41% to 66%, and only a-linked 2-deoxy-glu-

curonides were obtained. Because the glycosylation proceeded

with an inversion of conﬁguration at C-1, it was proposed that

the reaction proceeded by way of an S_N2 mechanism.

In a recent investigation, Shair and Morris reported a novel ap-

proach to form highly stereoselective 2-deoxy-b-glycosides using

anomeric O-alkylation/arylation.⁶⁶Lactol 93, shown in Scheme

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1923

BnO

O

BnO

OP(OEt)₂

Montmorillonite K-10

(100 wt%)

BnO

O

81

O

Et₂O, -78°C

O

+

BnO

70%

α:β = 29:71

O

OMe

HO

83

BnO

OMe

82

O

BzO

BnO

OP(OEt)₂

OMe

Montmorillonite K-10

(100 wt%)

O

84

BzO

BnO

O

Et₂O, -78°C

O

+

89%

α:β = 17:83

O

HO

O

86

O

85

Scheme 20. Use of glycosyl phosphites in the preparation of 2-deoxy-glycosides.⁶³

to repulsion between the alkoxide and the ring oxygen lone pair

MP

O

MP

O

leads to selective generation of the b-glycoside (Fig. 15).⁶⁹

O

P

BnO

O

OP(OEt)₂

4.2. Indirect synthesis

87

88

The preparation of 2-deoxy-glycosides by an indirect approach

using activated oxygen derivatives has also been reported. In one

example, donors bearing thioacetyl functionality at C-2 leads to

the stereoselective synthesis of 2-deoxy-b-glycosides, through

neighboring group participation. An example of this approach,

which has been developed by Knapp and Kirk, is shown in Scheme

23.⁷⁰Glycosylation of various alcohols with 1,2,3,4,6-penta-

MP

O

MP

O

BnO

AcO

89

O,S,O,O,O-acetyl-2-thio-b-D-glucopyranose (105) was performed

OMe

in dichloromethane in the presence of 0.5 equiv of TMSOTf. A range

of acceptors were used, and in all cases only the b-linked disaccha-

rides were obtained in good yields (70–85%). The formation of an

intermediate oxathiolium ion (106) is proposed to give rise to

the high level of b-selectivity in these glycosylation reactions. Fol-

lowing glycosylation, reductive removal of the thioacetyl group

with Raney Nickel provided the corresponding 2-deoxy-b-glyco-

sides in yields of 73–77%.

A large volume of work in this area involves glycosyl donors

possessing 2-deoxy-2-iodo- and 2-bromo-2-deoxy-glycosyl func-

tionality (e.g., 109 and 110, Fig. 16). Both glycosyl acetates and tri-

chloroacetimidates serve as stereoselective glycosylating agents.^8,71,72

MP =

MeO

Figure 12. Structure of compounds 87, 88, and 89.⁶⁴

2-deoxy-b-glycosides in yields of 61–90%. In all cases, the b-glyco-

side was favored with b: ratios ranging from 8:1 to 20:1.

The explanation for the high b-selectivity was proposed to in-

volve the rapid equilibrium between axial and equatorial alkox-

ides. The enhanced nucleophilicity of the equatorial alkoxide, due

a

O

CO₂H

O

TMSO

N₃

SnCl₄, 1 equiv

CH₂Cl₂, 10 h

AcO

OAc

O

+

O

α

41%, only

CO₂Me

OAc

N₃

CO₂Me

4 equiv

91

1 equiv

90

92

Scheme 21. Use of 1,6-lactones in the preparation of 2-deoxy-glycosides.⁶⁵

1924

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

O

N₃

PMBO

OH

93

O

N₃

O

NaH, dioxane, 23 °C

PMBO

+

O

BnO

OTf

90%

α:β = 1:20

O

BnO

OBn

95

OBn

94

Scheme 22. Stereoselective 2-deoxy-b-glycosides using anomeric O-alkylation/arylation.⁶⁶

glucopyranosyl acetates (109)⁷¹or 2-deoxy-2-iodo-

a-D-glucopyr-

anosyl trichloroacetimidates (110)⁷²as the glycosyl donors pro-

ceeded in dichloromethane with excellent b-stereoselectivities

(in most cases, P19:1) using either TMSOTf or TBSOTf as the pro-

moter. To investigate the origin of the high b-selectivity of these

glycosylations, Roush and Chong used constrained 4,6-O-benzyli-

dene-2-deoxy-2-iodo-glucopyranosyl glycosyl imidates 111 and

112 (Fig. 17) to probe the likely reaction pathway.⁷⁶Glycosylations

were performed by addition of catalytic TBSOTf to a solution of

imidate 111 or 112 and acceptor 79, 113, or 114 in dichlorometh-

ane in the presence of 4 Å molecular sieves. It was found that the

O

BnO

O

TfO

O

OTf

O

96

97

Figure 13. Structure of secondary triﬂates 96 and 97.⁶⁶

reactions were still highly b-selective (the b/a ratio ranged from

86:14 to b only).

An S_N2-like displacement pathway was ruled out because the

stereoselectivity of glycosylation was independent of the starting

donor conﬁguration. Given the conformational constraint of the

benzylidene acetal, the b-selectivity of the reaction was proposed

to arise from the key reactive intermediate 115, in which the

pseudoaxial orientation of the iodine substituent hinders approach

OBn

O

OBn

BnO

O

BnO

OH

98

99

of the nucleophile from the a-face (Fig. 18). However, the iodoni-

um ion intermediate 116, which is difﬁcult to distinguish experi-

mentally from 115, could be also invoked to rationalize the

b-selectivity.

OTf

OBn

OTf

O

OTf

As an extension of these investigations, in 2003, Durham and

Roush reported the use of 2-deoxy-2-halo-galactopyranosyl

acetates and trichloroacetimidates for the synthesis of 2-deoxy-

O

BnO

O

b-D-lyxo-hexopyranosides (‘2-deoxy-b-D A

-galactopyranosides’).⁷⁷

OAll

O

OAll

number of 2-bromo-2-deoxy and 2-deoxy-2-iodo-glycosyl donors

were evaluated in these investigations. When subjected to TBSOTf-

promoted glycosylation, donors such as 117–122 (Fig. 19), displayed

modest b-selectivity in yields of 38–93% in reactions with acceptors

113 and 79.

100

101

Figure 14. Structure of compounds 98–102.⁶⁶

102

The large amounts of

a-glycosides produced in these reac-

tions suggest that oxocarbenium ions instead of halonium ion

intermediates play an important role in the glycosylation reac-

tions of 2-deoxy-2-halo-galactopyranose donors. Therefore, the

introduction of the cyclic 3,4-protecting group may encourage

the key reactive intermediate (123, Fig. 20) to adopt the indi-

cated boat-like conformation with the C(2)–X substituent in a

pseudoaxial position. This would direct the glycosylation in a

b-selective manner.

electron-electron

repulsion

O

M

RO

O

M

104

103

Thus, the 3,4-carbonate or isopropylidene protected 2,6-dide-

oxy-2-iodo-galactopyranosyl acetates 124 and 125, and the 2-bro-

mo-2-deoxy-galactopyranosyl trichloroacetimidates 126 and 127

(Fig. 21), were also screened against acceptors 113 and 79. Donors

124 and 127 demonstrated only modest selectivity. The b-glyco-

Figure 15. Proposed basis for the stereoselectivity in Shair’s 2-deoxy-glycosides

synthesis.⁶⁶

The facile reductive removal of the halogen following glycosylation

allows for the easy formation of 2-deoxy-glycosides.

side was favored with the b:a ratio ranging from 50:50 to 84:16.

A leader in this area has been the Roush group, who has developed

a series of powerful reagents for the assembly of 2-deoxy-glyco-

However, 6-deoxy donors 125 and 126 displayed good b-selectivity

in reactions with 113 and 79 in yields of 62%–88% and b:

a ratios

sides.^71–75For example, reactions employing 2-deoxy-2-iodo-b-

D

-

ranging from 84:16 to 95:5.

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1925

AcO

O

OAc

AcO

SAc

O

105

AcO

H

AcO

TMSOTf

-78 °C (0.5 h), -30 °C (1 h)

+

H

O

S

TfO

OH

O

106

O

70%

20

β only

AcO

O

AcO

O

SAc

O

Ra-Ni

77%

O

108

107

Scheme 23. Stereoselective synthesis of 2-deoxy-b-glycosides using a thioacetyl moiety at C-2 as a participating group.⁷⁰

OR

OTs

Br

BnO

AcO

O

I

O

I

O

RO

OAc

NH

CCl₃

O

NH

CCl₃

O

BnO

TBSO

NH

CCl₃

O

X

I

117

118

119

X = I

X= Br

109

110

Figure 16. Donors 109 and 110.^71,72

OBn

BnO

O

I

O

Ph

O

Ph

O

I

OAc

O

NH

CCl₃

O

BnO

TBSO

X

I

NH

CCl₃

O

122

120

121

X = I

X= Br

111

112

HO

BzO

O

Ph

O

HO

O

BzO

Ph

HO

BzO

O

BzO

OMe

O

HO

OMe

HO

BzO

113

79

BzO

OMe

Figure 19. Structure of a series of 2-deoxy-2-halo-galactopyranosyl donors and

acceptors used in the Durham and Roush approach.⁷⁷

79

113

114

Figure 17. Structure of donors 111, 112, and acceptors 79, 113, 114.⁷⁶

R₂

O

R₃

O

β

H

OTBS

O

Ph

O

α

O

I

R₁

X

115

116

123

Figure 20. Stereochemical consideration of the key reactive intermediate 123.⁷⁷

Figure 18. Oxocarbenium ion intermediate 115 and iodonium ion intermediate

116.⁷⁶

1926

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

OBz

prepared

from

3-O-t-butyldimethylsilyl-4-O-benzoyl-D-olival

O

(138) by reaction with the polymer-supported iodate reagent

(Scheme 26). The product was obtained, together with its stereo-

isomer 140, in 86% combined yield.

With donor 139 prepared, it was treated with a polymer-bound

silyl triﬂate and structurally diverse acceptors, resulting in the for-

O

I

O

OAc

O

I

124

125

mation of

a-linked disaccharides with complete stereocontrol

(Scheme 27). The list of acceptors includes simple alcohols, carbo-

OBn

hydrate-derived acceptors, steroids, and (ꢀ)-linalool. In some

O

cases, pure

a-glycosides were obtained in almost quantitative

O

yield, and the lowest yield was 81%. This method was extended

O

to the preparation of a steroid-derived glycoconjugate, as well as

Br

NH

CCl₃

O

trisaccharide composed of two

oxy-hexose

-rhodinose.⁸⁰

D-olivose units and the 2,3,6-tride-

NH

CCl₃

O

L

126

127

Figure 21. Structure of donors 124–127.⁷⁷

5. Use of glycosyl halides

Glycosyl halides, one of the oldest classes of glycosyl donors,⁸¹

have also been used for the preparation of 2-deoxy-glycosides.

However, a limitation of using glycosyl halides deoxygenated at

C-2 is their signiﬁcant tendency for hydrolysis. Thus, a signiﬁcant

amount of these reactions have involved glycosyl ﬂuorides, the

most stable of the glycosyl halides, or rely on deoxygenation after

glycosylation. In other cases, the 2-deoxy-glycosyl halide was gen-

erated and used with minimal puriﬁcation.

One recent example of the use of glycosyl halides in this area

was performed by Toshima et al., who have described a stereose-

lective synthesis of 2-deoxy-b-glycosides using a heterogeneous

solid acid, montmorillonite K-10.⁸²The glycosylation was per-

formed by exposure of the 2,6-dideoxy-2-iodo-b-glucopyranosyl

ﬂuoride 142 to an alcohol (used in twofold excess) in dichloro-

methane at room temperature using 50 wt % montmorillonite K-

10 in the presence of 50 wt % 5 Å molecular sieves (Scheme 28).

The acceptor alcohols included cyclohexylmethanol, n-octanol, iso-

propanol, cyclohexanol, and glucopyranoside derivatives with a

free hydroxyl group at C-4 and C-6. For all alcohols explored, the

corresponding 2-deoxy-b-glycosides were obtained in yields of

Once developed, this methodology was applied to the synthesis

of the CDEF and CDE 2,6-dideoxy tetrasaccharide and trisaccharide

unit of Durhamycins A and B.⁷⁸These compounds, produced by

Actinoplanes durhamensis, are potent inhibitors of HIV Tat transac-

tivation and contain 2-deoxy-b-linked oligosaccharide moieties

(Fig. 22).⁷⁹

As shown in Scheme 24, glycosylation of acetate 128 with galac-

topyranosyl trichloroacetimidate 126 was achieved by treatment

with TBSOTf at ꢀ78 °C, affording the corresponding b-linked disac-

charide 129 in 94% yield. This product was converted in three steps

into glycosyl ﬂuoride 131, which was then glycosylated with imi-

date 132 to provide trisaccharide 133 in 86% yield with 93:7 b:

a

selectivity.

Similarly, the CDEF tetrasaccharide was obtained by linking the

disaccharide acceptor 131 to imidate donor 136 using the same

catalytic conditions (Scheme 25). The route to the product began

with glycosyl acetate 128 and imidate 134, which were coupled

to provide b-disaccharide 135 in 94% yield. Conversion of 135 to

imidate 136 was done using standard procedures, and the product

was used to glycosylate 131, giving b-tetrasaccharide 137 in 74%

yield.

88–97% and the a:b ratios ranged from 18:82 to 7:93. The stereose-

lectivity of the reactions favored the b-anomer, but the origin of

As described above for the thioglycoside donors, the synthesis

of 2-deoxy-glycosides through the use of polymer-supported thio-

philic reagents has been developed by Kirschning et al.⁸⁰A similar

approach has been used in the preparation of 2-deoxy-2-iodo

donors for the preparation of 2-deoxy-glycosides. The key glycosyl

this preference was not discussed.

In subsequent work, the Toshima group reported that the 3,4,6-

tri-O-benzyl-2-deoxy-a-glucopyranosyl ﬂuoride 145 can be used

to glycosylate cyclohexylmethanol (143, used in twofold excess)

in 98% yield with a:b = 88:12 using the 5 wt % of a novel heteroge-

neous solid acid SO₄–ZrO₂at 25 °C (Scheme 29).⁸³The catalyst is

also successful in glycosylating n-octanol, isopropanol, cyclohexa-

nol, as well as primary and secondary carbohydrate alcohols. The

donor, 2,6-dideoxy-2-iodo-

a-

D-mannopyranosyl acetate 139, was

yields ranged from 53% to 98% and

low of 80:20 to a high of 88:12.

a:b ratios were found from a

OMe OH

H

O

HO

O

HO

A striking observation was that the stereoselectivity of the gly-

cosylation was reversed from to b when diethyl ether was used

as a solvent. In this solvent, the best case was an :b ratio of

15:85, which was observed when the 3,4,6-tri-O-benzyl-2-deoxy-

-xylo-hexopyranosyl ﬂuoride 145 was treated with n-octanol

O

Me

a

O

OH

a

H

OH OH

O

a-D

OAc

O

by employing 100 wt % of the SO₄–ZrO₂activator in the presence

of 500 wt % 5 Å molecular sieves at 0 °C (Scheme 30). Seven alco-

hols were glycosylated using this method and the yields ranged

O

HO

O

HO

O

R

from 50% to 99%, and the minimum a:b ratio was 33:67.

Other work on the use of glycosyl halides in the preparation of

2-deoxy-glycosides include investigations by Nicolaou et al., in

which the scope of a 1,2-selenium migration to generate 2-sele-

no-glycosyl ﬂuorides was probed.⁴⁴The reaction was performed

using both soluble and solid-phase intermediates starting from

O

HO

Durhamycin A, R =

HO

Durhamycin B, R = H

three b-selenopyranosides with the D-gluco, 6-deoxy-D-gluco, and

Figure 22. Structure of Durhamycins A and B.

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1927

O

TBSOTf (0.1 equiv)

-78 °C, CH₂Cl₂

O

I

O

AcO

O

I

OAc

AcO

HO

+

O

OAc

O

94%, β only

Br

O

NH

128

126

129

CCl₃

HF•Py, CH₂Cl₂

79-89%

1. K₂CO₃, MeOH, 93%

2. CH₃C(OCH₃)₃, 30 min,

H₂O, 91%

O

OAc

O

AcO

O

AcO

O

HO

I

Br

I

F

Br

F

131

130

O

TBSOTf (0.05 equiv)

-78 °C, CH₂Cl₂

NH

AcO

O

I

86%, α/β=7:93

CCl₃

132

OAc

O

I

O

I

AcO

O

Br

F

133

Scheme 24. Synthesis of the CDE trisaccharide of Durhamycins A and B by Roush and Durham.⁷⁸

O

AcO

OAc

HO

I

TBSOTf (0.05 equiv)

-78 °C, CH₂Cl₂

94%, β only

128

O

I

O

I

AcO

O

OAc

AcO

+

O

I

135

AcO

NH

O

1. H₂NNH₂, MeOH/CH₂Cl₂

2. DBU (0.25 equiv)

CCl₃CN/CH₂Cl₂

94% over two steps

CCl₃

134

O

I

NH

O

AcO

O

AcO

I

CCl₃

136

OAc

O

TBSOTf (0.04 equiv)

O

AcO

O

0 °C, CH₂Cl₂

74%, β only

HO

I

Br

F

131

OAc

O

I

O

I

AcO

O

AcO

O

I

Br

F

137

Scheme 25. Synthesis of the CDEF tetrasaccharide of Durhamycins A and B by Roush and Durham.⁷⁸

1928

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

I(OAc)₂

NMe₃

I

O

BzO

+

OAc

TBSO

α-

D

-manno:β-

D-gluco=2.7:1

I

OAc

86%

138

139

140

Scheme 26. Preparation of 2-deoxy-2-iodo-glycosyl acetate donor 139 using a polymer-supported reagent.⁸⁰

I

O

BzO

TBSO

Et

I

O

BzO

Si

OAc

TBSO

139

OTf

+

O

Et₂O, -70 to 10 °C

OPiv

O

OH

then

PivO

OPiv

O

OPiv

NMe₂

PivO

97%

OPiv

141

15

Scheme 27. Formation of 2-deoxy-2-iodo-glycosides from reaction of 139 with polymer-supported Lewis acids.⁸⁰

Montmorillonite K-10

O

I

AcO

HO

O

CH₂Cl₂, 5Å MS, 25°C

AcO

F

+

I

95%

α:β = 9:91

142

143

144

Scheme 28. Synthesis of 2-deoxy-glycosides from 2-deoxy-2-iodo-glycosyl ﬂuoride derivative 142.⁸²

SO₄/ZrO₂(5 wt%)

MeCN, 25°C

BnO

O

HO

+

98%

O

F

α:β = 88:12

145

143

146

Scheme 29.

a

-Selective glycosylations of alcohols by 145 using a SO₄–ZrO₂promoter in acetonitrile solvent.⁸³

SO₄/ZrO₂(100 wt%)

BnO

O

5Å MS (500 wt%)

BnO

O(CH₂)₇CH₃

CH₃(CH₂)₇OH

+

BnO

Et₂O, 0°C

F

96%

α:β = 15:85

145

147

148

Scheme 30. b-Selective glycosylations of alcohols by 145 using a SO₄–ZrO₂promoter in diethyl ether solvent.⁸³

D

-xylo conﬁguration. These compounds were prepared from the

ated from the polymer obtained in 95% yield, by radical deselena-

tion with n-Bu₃SnH.

corresponding glycosyl trichloroacetimidates as shown in Scheme 31.

The polymer-bound case will be discussed here. Reaction of 149

with the tributylstannyl ether of resin-bound selenol was used to

prepare the polymer-loaded b-selenopyranoside 150. Next, the

acetate protecting group was removed and the resulting com-

pound 151 was treated with TBSOTf and 2,6-lutidine to give com-

pound 152.

An analogous series of transformations was performed to pro-

duce soluble selenoglycosides for solution-phase synthesis.⁴⁴In

these cases, the resin-bound selenol used in the conversion of

149 into 150 was replaced with benzeneselenol. For the solution-

phase cases, the key glycosylation step (the transformation of

153 into 155) provided the 2-deoxy-2-seleno-a-glycoside in yields

Compound 152 was treated with diethylaminosulfur triﬂuoride

(DAST), leading to a stereospeciﬁc 1,2-migration of the selenium

group, with simultaneous installation of a ﬂuoride group at C-1

(Scheme 32). Exposure of this polymer-bound 2-seleno-glycosyl

ﬂuoride 153 to alcohol 154 in the presence of SnCl₂, afforded the

of 66–95%.

In conjunction with other work on the use of glycosyl iodides as

glycosylating agents, Gervay-Hague and Lam⁸⁴have used these

compounds as reagents for the synthesis of 2-deoxy-glycosides

and 2,6-dideoxy-glycosides. The glycosyl iodides were efﬁciently

prepared from the corresponding anomeric acetate (e.g., 157) upon

a-glycoside 155 in 89% yield. The 2-deoxy-glycoside 156 was liber-

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1929

O

NH

PMBO

AcO

BF₃•Et₂O

SeSnnBu₃

PMBO

AcO

Se

O

CCl₃

AcO

90%

149

150

= polystyrene

NaOCH₃

CH₃OH

95%

TBSOTf

O

PMBO

2,6-lutidine

PMBO

HO

Se

TBSO

80%

HO

152

HO

151

Scheme 31. Preparation of polymer-bound b-selenoglycoside compound 152.⁴⁴

reaction with trimethylsilyl iodide (TMSI, Scheme 33). The forma-

tion of the

both the direct and indirect syntheses of 2-deoxy-glycosides are

possible. In the case of direct conversion, the reaction proceeds

through an anomeric oxocarbenium ion intermediate produced

by the addition of an acid to the double bond. In the majority of

these cases, the axial (a-) glycoside is formed as the major product

due to the preference for the alcohol to add to this oxocarbenium

a

-glycosyl iodide was demonstrated by ¹H NMR spec-

troscopic data, which showed a dramatic downﬁeld shift of the

anomeric proton (to d 6.95). After removal of the solvent, the mix-

ture was dissolved in THF and a solution of KHMDS, 18-crown-6,

and O-cresol or 1-naphthol was added, resulting in exclusive for-

mation of b-O-aryl-glycosides in good yields. In the case of reac-

tions with 158, nucleophilic displacement with the potassium

anions of o-cresol and 2-naphthol provided the b-glycoside in

42% and 49% yields, respectively. The low yields were ascribed to

the propensity of the 2,6-dideoxy-glucosyl iodide to undergo 1,2-

elimination under the basic reaction conditions. Presumably, the

excellent b-selectivity results from an S_N2-like substitution of the

iodide with aryloxy anions. To date, this method has not been ap-

plied to the preparation of alkyl 2-deoxy-glycosides.

ion in a manner favored by the anomeric effect.

A number of protic and Lewis acids have been used to activate

glycals in the presence of an alcohol leading to 2-deoxy-glyco-

sides.^86–92A recent paper by Yadav et al. reported a mild and efﬁ-

cient method for preparing 2-deoxy-glycosides from glycals using

the CeCl₃ꢁ7H₂O–NaI reagent system (Scheme 34).⁹³Glycals such

as 3,4,6-tri-O-acetyl-

D

-glucal, 3,4,6-tri-O-acetyl-D-galactal, and

3,4-di-O-acetyl-D-xylal were evaluated to determine the scope

and generality of this protocol, and a range of simple alcohol accep-

tors (e.g., allyl alcohol, n-octanol, phenyl allyl alcohol, and (E)-hex-

2-en-1-ol) were examined. The reactions proceeded smoothly in

the presence of the promotor in acetonitrile at reﬂux, resulting in

6. Use of glycals

the exclusive formation of 2-deoxy-a-glycosides in yields of 78–

90%. In the absence of sodium iodide, however, the reactions

6.1. Direct synthesis

underwent Ferrier rearrangement to afford the corresponding

Glycals, cyclic enol ether derivatives of sugars that have a dou-

ble bond between C-1 and C-2, have been increasingly used in the

preparation of oligosaccharides^10,85and it is therefore not surpris-

ing that a number of groups have used these compounds as inter-

mediates in the preparation of 2-deoxy-glycosides. With glycals,

2,3-unsaturated hexopyranosides in favor of the 2-deoxy-

a-

glycosides.

In later work, the Yadav group disclosed that the glycals can be

used for the synthesis of 2-deoxy-thioglycosdes using gallium(III)

Se

O

DAST, CH₂Cl₂

PMBO

TBSO

O

Se

PMBO

TBSO

100%

HO

F

152

153

OBz

HO

154

SnCl₂, CH₂Cl₂

89%

Se

O

PMBO

TBSO

nBu₃SnH, AIBN

PMBO

TBSO

OBz

95%

O

156

155

Scheme 32. Conversion of polymer-bound selenoglycoside 152 into 2-deoxy-glycoside 156 by way of a glycosyl ﬂuoride intermediate.⁴⁴

1930

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

TMSI, CH₂Cl₂

0°C, 15 min

O

AcO

100%

I

OAc

157

158

KHMDS

18-C-6, THF

0°C, 15 min

Me

O

AcO

O

HO

+

42%

β only

I

158

159

160

Scheme 33. Synthesis of 2-deoxy-glycosyl iodide 158 and its use in the preparation of aryl 2-deoxy-glycosides.⁸⁴

trichloride as a catalyst (Scheme 35).⁹⁴Reactions between 3,4,6-

tri-O-acetyl- -glucal, 3,4,6-tri-O-acetyl- -galactal, and 3,4-di-O-

acetyl- -xylal, and ten substituted thiophenols and thionaphthols

provided thioglycosides in 75–95% yields with a high -selectivity

(the /b ratio ranged from 8:2 to 19:1). Not unsurprisingly, reac-

tions of substance with electron-donating substituents on the aro-

matic ring gave higher yields than for those bearing the electron-

withdrawing substituents.

mixtures of products in which the

a 3:1 ratio over the b-isomer. However, some reactions with the

glucal derivatives gave only the -glycoside as the sole product.

a-isomer was favored by about

D

a

Through the use of a deuterium-labeling experiment, the authors

concluded that the selectivity of the reaction is determined not

in the oleﬁn activation step, but in the transfer of the nucleophile

to the complex formed between the glycal and the catalyst. Prod-

uct yields ranged from 56% to 86%, and the catalyst system also al-

lows for the use of sulfonamides and thiols as nucleophiles.

Another recently reported method, developed by Vankar and

co-workers,⁹⁷involves the ceric ammonium nitrate (CAN) oxida-

tion of the glucal 169 and galactal 166 in the presence of an alcohol

(Scheme 38). The couplings were performed in anhydrous acetoni-

trile in the presence of the alcohol and 2 mol % of CAN as a catalyst.

Galactal 166 gave the 2-deoxy-glycoside in 60% yield with modest

a

In a similar series of reactions, Colinas and co-workers have de-

scribed the optimization of a simple method for producing N-sulfo-

nyl glycosides using 3,4,6-tri-O-benzyl-D-galactal (166) or 3,4,6-

tri-O-benzyl-glucal (169) as donor (Scheme 36).⁹⁵The glycosyla-

tion protocol was performed with 1.1 equiv of sulfonamide in

dichloromethane catalyzed by 5 mol % HBrꢁPPh₃. A range of sulfon-

amides bearing alkyl or aryl moieties serve as acceptors in the

reaction. In all cases, only the 2-deoxy-b-sulfonamidoglycosides

were isolated. Sulfonamides with more sterically demanding

groups required stronger conditions, for example, heating at reﬂux

in dichloromethane for over 12 h, and these substrates afforded the

corresponding products in lower yields. It was suggested that the

b-selectivity of the process results from the preferential attack of

the sterically demanding sulfonamide from the less hindered equa-

torial position. Alternatively, it was proposed that the reaction is

a

-selectivity. Another eight examples were performed using both

simple and carbohydrate alcohols, which led to products in yields

of 26–78% with modest to excellent selectivity for the -glycoside.

a

On the other hand, reactions between glucal 169 and simple alco-

hols such as methanol, allyl alcohol, cyclohexanol, and t-butanol

led to the formation of 2-deoxy-glycosides in 34–65% yield

together with the corresponding Ferrier by-product. The Ferrier

by-products can be suppressed by using four equivalents of CAN.

It was proposed that the reaction proceeds via the generation of

HNO₃in solution, which then protonates the glycal, generating

an oxocarbenium ion that reacts with the alcohol.

under thermodynamic control and that the a-sulfonamide product

could isomerize to the b-isomer under the conditions of the reac-

tion. However, no mechanistic studies were performed to test

these hypotheses.

In a follow-up of previous work from the Falck and Mioskowski

Another approach to 2-deoxy-

by a high-oxidation-state rhenium-oxo complex, was developed

by Toste and co-workers (Scheme 37).⁹⁶3,4,6-Tri-O-benzyl-

-glu-

cal (169) and 3,4,6-tri-O-benzyl- -galactal (166), as well as related

a-glycosides, involving catalysis

groups,⁸⁷Wandzik and Bieg examined the stereoselectivity of the

addition of various alcohols to L-rhamnal derivatives promoted

D

by triphenylphosphine hydrobromide (TPHB).⁹⁸The stereoselectiv-

ity of the outcome in the Falck–Mioskowski method is inﬂuenced

by the protecting group at C-3 in the glycal. Signiﬁcant predomi-

D

derivatives with different protecting groups, underwent the reac-

tion with a range of alcohols when performed in toluene in the

presence of 1 mol % of [ReOCl₃(SMe₂)(Ph₃PO)] as the catalyst. The

catalytic system tolerated a number of commonly used protecting

groups, including isopropylidene acetals, silyl ethers, acetates, and

benzoates.

nance of the

dimethylsilyl-

a

L

anomer was obtained when 4-O-acetyl-3-O-t-butyl-

-rhamnal (177, Scheme 39) was used in reactions

with glycerol derivatives and monosaccharide alcohols. It was

proposed that the use of the bulky t-butyldimethylsilyloxy group

at the C-3 position blocks the approach of the nucleophile from

the bottom face of the ring, and leading to the observed

Reactions with the galactal derivatives proceeded with com-

plete

a-selectivity, whereas the glucal derivatives generally gave

a-stereoselectivity.

In a related investigation, Kirschning and co-workers showed

that polymer-bound diphenylphosphine hydrobromide can be em-

ployed in the activation of glycals to suppress the formation of by-

products arising from the Ferrier rearrangement (Scheme 40).⁹⁹It

was further demonstrated that only 0.1 mol % of the polymer-at-

tached catalyst can promote two glycosylations in a one-pot proce-

AcO

CeCl₃·7H₂O-NaI

CH₃CN, reflux

O

BnOH

+

AcO

87%

OBn

dure. For instance, addition of disilylated

L-fucal (182) to the

161

162

163

reaction mixture after coupling of -fucal derivative (180) to deca-

L

restrictine (179) to generate 181, initiated the second glycosyla-

tion, affording glycoconjugate 183 in 62% overall yield and with

Scheme 34. Synthesis of 2-deoxy-

a-glycosides from glycals using the CeCl₃ꢁ7H₂O–

NaI reagent system.⁹³

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1931

AcO

5 mol % GaCl₃

CH₂Cl₂, 20 min

SH

O

AcO

O

+

AcO

95%

α/β=9:1

S

OMe

161

164

165

-thioglycosides from glycals using the GaCl₃.⁹⁴

Scheme 35. Synthesis of 2-deoxy-

a

OBn

5 mol % HBr·PPh₃

CH₂Cl₂, 1.5 h

O

BnO

Bn

O

S

O

+

86%

only β

S

BnO

NH

BnO

Bn

H₂N

166

167

168

BnO

O

5 mol % HBr·PPh₃

CH₂Cl₂, reflux, 15 h

Bn

O

BnO

O

S

O

S

O

BnO

O

Tol

+

N

Bn

64%

BnO

Tol

H

β

only

169

170

171

Scheme 36. Formation of N-sulfonyl glycosides from benzylated glycals using catalytic HBrꢁPPh₃.⁹⁵

BnO

O

BnO

OH

BnO

O

Toluene, rt

1 mol % ReOCl₃(SMe₂)(Ph₃PO)

O

BnO

+

O

64%

α:β = 3.5:1

O

169

20

172

OBn

BnO

O

OBn

O

BnO

HO

Toluene, rt

1 mol % ReOCl₃(SMe₂)(Ph₃PO)

O

BzO

+

O

BnO

BzO

O

86%

α only

BzO

OMe

BzO

OMe

166

79

173

Scheme 37. [ReOCl₃(SMe₂)(Ph₃PO)]-catalyzed formation of 2-deoxy-glycosides from glycals.⁹⁶

excellent selectivity (only the

cosylation steps).

a-anomer was produced in both gly-

lectivity (19:1

184 (Scheme 41).

a-gluco:b-manno) upon reaction with b-diketone

The direct activation of cycloadduct 185 with acid promoters in

nitromethane led to the sluggish formation of b-glycosides.

Improvement on the reaction could be accomplished by conversion

of the unsaturated ketone into an allyl acetate or the corresponding

allyl t-butyldimethylsilyl ether, by reduction of the ketone and

derivatization (Scheme 42).

Subsequent glycosylation of these modiﬁed cycloadducts 186

and 187, was achieved by reaction with an alcohol and methyl

triﬂate in either nitromethane or dichloromethane, which provided

exclusively the b-glycosides (Scheme 43). The yields of glyco-

sides obtained ranged from 38% to 89%. Desulfurization was

6.2. Indirect synthesis

The indirect synthesis of 2-deoxy-glycosides has also been per-

formed using a number of different approaches. In one particularly

elegant study, Capozzi and co-workers reported that carbohydrate-

fused 1,4-oxathiine derivatives, prepared by cycloaddition reaction

of glycals with oxothioheterodienes, are effective donors for the

stereospeciﬁc synthesis of 2-deoxy-2-thio-b-glycosides.¹⁰⁰For

example, starting from 3,4,6-tri-O-benzyl-

co adduct (185) was obtained in 83% yield and excellent stereose-

D-glucal (169), the a-glu-

1932

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

OBn

2 mol% CAN

CH₃CN

BnO

O

BnOH

+

60%

α:β = 3.5:1

OBn

166

169

162

174

CH₃CN

2 mol% CAN

CH₃OH

BnO

OBn

O

BnO

O

BnO

+

OMe

175

176

56%

α:β = 1.7:1

38%

α:β = 5:1

Ferrier by-product

Scheme 38. Activation of glycals with CAN for the synthesis of 2-deoxy-glycosides.⁹⁷

O

OH

O

Ph₃P-HBr

O

CH₂Cl₂, RT

AcO

TBDMSO

+

O

78%

α only

O

TBDMSO

O

177

20

178

Scheme 39. Triphenylphosphine hydrobromide promoted glycosylation of glycals.⁹⁸

O

PPh₂HBr

CH₂Cl₂

OAc

O

+

OAc

O

OAc

HO

OTES

HO

OAc

OTES

HO

179

180

181

O

PPh₂HBr

CH₂Cl₂

62%

α only

OTES

TESO

182

O

OAc

O

OAc

O

OTES

O

OTES

TESO

183

Scheme 40. Preparation of 183 through a one-pot diglycosylation process.⁹⁹

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1933

OBn

BnO

O

SNPhth

O

BnO

Pyridine, CHCl₃,

60°C

O

BnO

S

+

O

83%

O

α:β=19:1

O

169

184

Scheme 41. Cycloaddition between glucal 169 and b-diketone 184.¹⁰⁰

185

ty and Zhou have described a highly stereoselective approach to

the cardiac glycoside digitoxin and its trisaccharide moiety digox-

ose from achiral 2-acylfuran.^101,102The key steps of the synthetic

strategy involve the iterative application of the palladium-cata-

lyzed glycosylation of a pyranone derivative 191 (obtained in three

steps from 2-acyl furan), Myers’ reductive 1,3-alkene transposi-

tion,^103,104and diastereoselective dihydroxylation (Scheme 44).

In the presence of 5 mol % Pd and 10 mol % PPh₃, glycosylation

of the C-4 secondary alcohol in 192 with 2 equivalents of pyranone

191 provided the b-(1?4)-linked disaccharide 193 in 78% yield.

Reduction of the ketone under Luche conditions¹⁰⁵and isomeriza-

tion of the double bond gave 194 in 75% yield over the two steps.

Dihydroxylation with a catalytic amount of osmium tetroxide and

N-methyl-morpholine oxide gave a 90% yield of disaccharide 195.

Iteration of this approach led to the target molecule digitoxin

199 (Scheme 45).

OBn

1. LiAlH₄, THF

2. Pyridine, Ac₂O

O

BnO

94% over two steps

S

O

AcO

185

186

OBn

O

1. LiAlH₄, THF

BnO

2. Pyridine, TBSOTf

S

O

87% over two steps

O

TBSO

In 2008, O’Doherty and Zhou applied a similar strategy to the

preparation of the

olivose trisaccharide portion in Landomycin A (Scheme 46).¹⁰⁶

The glycosylation of disaccharide acceptor 201 and -pyranone

a-L-rhodinose-(1?3)-b-D-olivose-(1?4)-b-D-

185

187

a

-L

Scheme 42. Synthesis of 186 and 187.¹⁰⁰

200 afforded the trisaccharide pyranone 202 in 95% yield with

complete stereocontrol at anomeric center. Luche reduction pro-

ceeded in 93% yield to give exclusively the alcohol, which had in-

verted stereochemistry compared to the target compound.

Mitsunobu reaction afforded the desired product 203 in 97% yield.

After removal of benzoate, diimide reduction of the oleﬁn and desi-

lylation, the repeating trisaccharide unit of Landomycin A, 204,

was successfully achieved.

accomplished using Raney Nickel in wet THF to afford the corre-

sponding 2-deoxy-b-glycosides in 51–69% yield.

7. De novo synthesis

De novo synthesis of 2-deoxy-glycosides starting from non-car-

bohydrate precursors by employing asymmetric synthesis has

been carried out with increasing frequency. For example, O’Doher-

Another fundamentally different approach to 2-deoxy-glyco-

sides has been reported by McDonald et al. (Scheme 47). Key to

OBn

O

BnO

O

MeOTf,0.2 eq.

BnO

2 eq.

OH

+

CH₃NO₂

89%

S

O

S

O

H

AcO

186

188

OBn

O

BnO

HO

O

TMSOTf, 0.02 eq.

2 eq.

+

S

O

CH₂Cl₂

68%

TBSO

H

187

189

Scheme 43. Glycosylation of alcohols with 186 and 187.¹⁰⁰

190

1934

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

O

OBoc

O

Pd (0) / PPh₃

191

+

O

OBn

78%

O

OAc

193

HO

OBn

OAc

192

1. NaBH₄, CeCl₃

92%

2. NBSH, PPh₃, DEAD

82%

O

OsO₄/NMO

90%

O

HO

OBn

O

OBn

OAc

OH

OAc

194

195

Scheme 44. The key steps used in the de novo synthesis.¹⁰²

O

OBoc

O

Pd (0) / PPh₃

90%

O

191

+

O

ODig

O

OAc

ODig

OAc

O

HO

197

OAc

1. NaBH₄, CeCl₃, 93%

196

2. NBSH, PPh₃, DEAD, 89%

O

ODig

O

OAc

198

1. OsO₄/NMO, 91%

2. LiOH, 83%

O

ODig

O

HO

O

OH

199

O

OH

Dig =

Scheme 45. Synthesis of target molecule digitoxin 199.¹⁰²

their method is a tungsten-catalyzed alkynol cycloisomerization,

which is applied to the synthesis of 6-deoxy-glycals.¹⁰⁷This sin-

gle-step cycloisomerization is accomplished when the alkynol sub-

strates (e.g., 205) are photolyzed at 350 nm in THF at reﬂux in the

presence of triethylamine using catalytic amounts of W(CO)₆

(25 mol %). The reaction was shown to be applicable to the prepa-

77–98%. The successful endo-selectivity is highly dependent on

maintaining anaerobic conditions, as the exocyclization by-prod-

uct is produced when such conditions are not used. This cycloiso-

merization transformation has been accomplished, for instance,

with alkynol substrates 205, providing the corresponding D-ribo

glycal 206 in 98% yield, as shown in Scheme 47. To synthesize oli-

gosaccharides via this approach, the glycal product (206) is reacted

ration D-ribo, L-lyxo, D-arabino, L-xylo conﬁgured glycals in yields of

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1935

OBoc

O

TBSO

OBn

O

Pd (0) / PPh₃

95%

200

TBS

+

O

202

O

TBSO

HO

OBn

O

TBS

201

1. NaBH₄, CeCl₃,

93%

2. p-NO₂PhCO₂H,

PPh₃, DIAD,

97%

1. K₂CO₃,

MeOH

99%

O

2. NBSH,

Et₃N,

TBSO

OBn

HO

O

OBn

O

HO

86%

TBS

O

3. TBAF

97%

204

203

OH

OPNBz

Scheme 46. Synthesis of the repeating trisaccharide 204 in Landomycin A.¹⁰⁶

with an alkynol (207) in the presence of HBrꢁPPh₃to generate a

product (208) that, following removal of the benzoate ester, is a

substrate for the application of the W(CO)₆-catalyzed cycloisomer-

ization reaction. In the case of 208, the reaction gave the 2-deoxy-

disaccharide glycal 209 in 96% yield.

pyrrolidine solvent. The remaining acetate protective groups of

215 were then removed to give digitoxin 199.

Another de novo approach is a [4+2]-based protocol for the prep-

aration of the simple 2-deoxy N-glycosides, which has been reported

by Dujardin and co-workers (Scheme 49).¹⁰⁹This heterocycloaddi-

tion method involves the use of N-vinyl-2-oxazolidinones as a

chiral dienophile. Under Eu(fod)₃(10 mol %)-catalyzed conditions,

a variety of dienophiles were reacted with 4-tert-butoxymethylene

pyruvic acid ester (217) to afford heteroadducts with a nearly total

endo-selectivity and a high facial selectivity (from 95:5 to 98:2) in

yields of 40–66%. The adducts derived from N-vinyl-2-oxazolidinon-

This strategy can be iterated and has been applied for the synthe-

sis of digitoxin.¹⁰⁸As shown in Scheme 48, the synthesis used protic

acid-catalyzed stereoselective glycosylation of glycal 210 with alky-

nyl alcohol 207. Upon reaction with Ph₃P–HBr in toluene, the reac-

tion provided the 2-deoxy-glycoside with excellent anomeric

stereoselectivity on multimillimol scale. Reductive debenzoylation

and tungsten carbonyl catalyzed endo-selective cycloisomerization

of alkynol substrate followed by acetylation gave the trisaccharide

glycal 212. Ph₃P–HBr-catalyzed glycosylation in CHCl₃between

the trisaccharide glycal 212 and digitoxigenin aglycone 213 afforded

es could then be converted to either D-arabino or L-arabino conﬁg-

ured 2-deoxy-N-b-glycosyl oxazolidinones. The transformations in

this sequence include reduction of the ester at C-6 to the hydroxy-

methyl group and subsequent regio- and stereoselective hydrobora-

tion–oxidation of the double bond. As a consequence, the ﬁnal

N-glycosyl oxazolidinones were isolated in 32–58% overall yields

and in a high overall diastereomeric purity (>98% in all cases).

a b:

a

60:40 mixture of 2⁰-deoxyglycoconjugate (Scheme 48).

Deprotection of the TBS protective groups of 214 was achieved by

ammonium hydrogen ﬂuoride in dimethylformamide–N-methyl-

25 mol % W(CO)₆

Me

OH

O

H

Et₃N, THF

TBSO

hv (350 nm),50-65 °C

98%

TBSO

1 mol % Ph₃P-HBr

206

OTBS

toluene

88%, β:α = 97:3

OBz

205

H

2. DIBAL, CH₂Cl₂

-78 °C

HO

99%

OTBS

207

OH

25 mol % W(CO)₆

H

O

DABCO, THF

TBSO

O

TBSO

65 °C, hv (360 nm)

TBSO

OTBS

TBSO

209

TBSO

96%

208

Scheme 47. De novo synthesis of 2-deoxy-b-glycosides using McDonald’s cycloisomerization strategy.¹⁰⁷

1936

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

OBz

H

HO

OH

1. 1 mol % Ph₃P-HBr

OTBS

,

toluene

H

71%,

207

O

β:α = 99:1

O

HO

O

+

O

2. DIBAL, CH₂Cl₂

-78 °C

O

OTBS

OH

OTBS

211

AcO

O

98%

OAc

TBSO

1. 25 mol % W(CO)₆,

DABCO, THF,

65 °C,

210

hv (360 nm)

2. Ac₂O, Et₃N,

DMAP,

CH₂Cl₂

81% over 2 steps

O

AcO

O

OAc

OTBS

212

O

TBSO

OH

1 mol % Ph₃P-HBr

,

CHCl₃

82%, β:α = 3:2

HO

213

O

OH

O

RO

O

OR

OR'

214 R = Ac, R' = TBS

215 R = Ac, R' = H

(NH₄)HF₂

DMF/NMP, 70°C

NaOMe, MeOH

40% over 2 steps

199 R = R' = H, digitoxin

Scheme 48. Synthesis of the digitoxin 199.¹⁰⁸

O-t-Bu

MeO

OH

O

t-BuO

O

217

1. DIBAH, BF₃•Et₂O

O

N

-78°C

HO

O

t-BuO

N

O

N

Ph

O

2. BH₃·Me₂S, THF

MeO₂C

10 mol % Eu(fod)₃

54%

3. Me₃NO, diglyme

Ph

110°C

Ph

44%

218

219

216

Scheme 49. De novo synthesis of 2-deoxy-N-b-glycosyl oxazolidinone 219.¹⁰⁹

Apoptolidin (Fig. 23), isolated from the soil bacteria Nocardiopsis

8. Applications to natural product synthesis

sp. by Hayakawa et al. in 1997, contains a 20-membered macrocy-

clic ring and carries a disaccharide moiety consisting of

D-oleand-

The methods discussed in the previous sections have, in most

cases, been applied to preparation of biologically relevant oligosac-

charides. While a few of these were discussed above, additional

examples are summarized in this section.

rose and

L

-olivomycose, as well as a 6-deoxy-glucose residue.^110,111

Roush and co-workers reported the construction of the

2-deoxy-b-glycosidic linkage in the disaccharide moiety by

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1937

employing their 2-deoxy-2-iodo-glycosyl acetate donors (Scheme

50).¹¹²Speciﬁcally, treatment of a mixture of 2-deoxy-2-iodo-b-

glucopyranosyl acetate 220 and acceptor 221 with 1.0 equiv of

TBSOTf at 0 °C gave the desired 2-deoxy-b-disaccharide 222 in

60% yield without the formation of regio- or stereoisomers. The

activated disaccharide acetate 224, which serves as the glycosyl

donor for glycosylation of late stage intermediates en route to

completion of a total synthesis of apoptolidin A, was accomplished

by a two-step procedure. Treatment of 222 with ceric ammonium

nitrate (CAN), followed by acetylation provided the targeted disac-

charide donor 224 in 87% yield as a ca. 6:4 mixture of anomeric

acetates.

of the total synthesis of apoptolidin proceeded in a three-step

procedure. Initially, installment of a TES group onto the tertiary

alcohol afforded 229 in 84% yield. Exposing 229 to Raney Nickel re-

sulted in the removal of the two thiophenyl groups and the benzyl

moiety in 92% yield. After treatment of the resulting lactol 230

with DAST, the activated glycosyl donor 231 was obtained in quan-

titative yield in a 3:1 ratio of anomers.

A third approach to this target was reported by Koert and co-

workers, who reported the successful application of the 2-deoxy-

2-phenylthio-glucopyranosylimidate (233) to assemble the

2-deoxy-b-disaccharide unit in apoptolidin (Scheme 52).¹¹⁴The

key glycosidic linkage was formed by treatment of acceptor 232

and donor 233 in the presence of TMSOTf, leading to the disaccha-

ride 234 in 87% yield with a 95:5 b-selectivity. The glycosylation in

diethyl ether gave better yield than that performed in dichloro-

methane. Subsequently, the tosylate in 234 was converted into

an iodide by treatment with NaI in N,N⁰-dimethylformamide

(DMF) at 90 °C. The preparation of the protected 2-deoxy-disaccha-

ride 236 was accomplished by reductive removal of the iodo and

the thioaryl groups upon n-Bu₃SnH and AIBN in toluene at 100 °C.

The preparation of the 2-deoxy-b-disaccharide unit toward the

total synthesis of apoptolidin described by the Crimmins group

employed a glycosylation between 238 and 239 in the presence

of Ag₂O–silica gel (Scheme 53).¹¹⁵The glycosyl bromide 238 was

generated in situ by exposure of hemiacetal 237 to Me₃SiBr in ben-

zene. The reaction between 238 and 239 produced the desired 2-

The same disaccharide moiety was prepared by, Nicolaou

et al.¹¹³using a method involving 1,2-phenylsulfeno migration to

prepare a 2-deoxy-2-phenylthio glycosyl ﬂuoride (226), a crucial

donor in directing the formation of desired b-linkage (Scheme

51). In the preparation of this donor, the 6-deoxy-a-manno-thio-

glycoside 225 was treated with DAST, which gave glycosyl ﬂuoride

226 in quantitative yield, accompanied by inversion of conﬁgura-

tion at C-2. Glycosylation between glycosyl ﬂuoride 226 and accep-

tor 227 in diethyl ether, promoted by tin(II) chloride, furnished the

desired 2-deoxy-b-glycoside 228 in 45% yield together with its

3-O-regioisomer (26% yield). Glycosylation of C-3-protected deriv-

atives (TMS, TBS, and OAc) failed, presumably due to steric shield-

ing exerted by the protecting group over the neighboring C-4

position. The activated glycosyl donor 231 used for the completion

deoxy-b-disaccharide 240 in 68% yield in a b:a ratio of 6:1. Only

trace amounts of disaccharide linked via the tertiary hydroxyl

group were detected. Protection of the tertiary hydroxyl group

using triethylsilyl triﬂate and 2,6-lutidine in dichloromethane fol-

lowed by hydrogenolysis with 10% Pd/C in ethanol afforded the

hemiacetal 241 in 72% yield over two steps.

O

MeO

OH

HO

Landomycin A, a member of the angucycline antibiotic family,

was ﬁrst reported in 1990 from Streptomyces cyanogen. The mole-

O

OH

O

cule bears a hexasaccharide comprising two repeating

a-L-rhodi-

4-O-methyl-6-deoxy-L-glucose

trisaccharides.^116,117

OH

H

nose-(1?3)-b- -olivose-(1?4)-b- -olivose

D

OMe

HO

O

OMe

Yu and co-workers utilized phenyl 2,3-O-thionocarbonyl-1-thio-

glycosides 242 as a precursor for the stereoselective synthesis of

b-linkage in this trisaccharide (Scheme 54).¹¹⁸The iterative glyco-

sylation steps in the synthetic approach, for example, coupling of

4-hydroxy thioglycoside 243 and donor 242, was performed in

the presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) and

MeOTf, providing b-(1?4)-linked disaccharide 244 in 88% yield.

OH

O

HO

MeO

O

HO

Construction of the

a-glycosidic bond was achieved by using 1,4-

di-O-acetyl- -rhodinose 246 as donor. Removal of 2-thiophenyl

L

3-O-methyl-

D-olivose

L-olivomycose

groups and benzyl protecting groups was accomplished by Raney

Nickel at 40 °C, affording the target hexasaccharide 249.

Figure 23. Structure of apoptolidin.

OPMB

TBSOTf

4Å MS

O

I

O

TBSO

O

TBSO

MeO

HO

O

+

MeO

OAc

CH₂Cl₂, 0°C

60%

HO

221

I

220

222

1. CAN, CH₃CN:H₂O

OH

O

OAc

2. Ac₂O, DMAP,

Pyridine

O

I

TBSO

O

I

TBSO

O

MeO

O

MeO

O

87%

HO

over two steps

I

223

224

Scheme 50. Key glycosylation reaction in synthesis of the apoptolidin disaccharide moiety by Roush and co-workers.¹¹²

1938

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

OH

O

TBSO

MeO

DAST

100%

TBSO

MeO

OBn

F

SPh

O

225

SPh

226

HO

227

SPh

OBn

SnCl₂(3.0 equiv)

Et₂O, 0°C to RT

O

228 R = H

TBSO

MeO

O

TESOTf

45%

O

2,6-lutidine

84%

229 R = TES

RO

SPh

Ra-Ni

92%

F

OH

O

DAST

100%

O

TBSO

MeO

O

TBSO

MeO

O

TESO

230

231

Scheme 51. Key steps in the synthesis of the apoptolidin disaccharide moiety by Nicolaou et al.¹¹³

OTs

O

TMSOTf

Et₂O

−60 °C → −40 °C

O

TBSO

MeO

TBSO

MeO

O

HO

TESO

O

+

87%

PhS

NH

CCl₃

O

β:α > 95:5

TESO

234

232

233

1. NaI, DMF, 90°C

I

2. n-Bu₃SnH, AIBN,

toluene, 100°C

O

TBSO

MeO

TBSO

MeO

O

70% over two steps

PhS

TESO

236

235

Scheme 52. Key steps in the synthesis of the apoptolidin disaccharide moiety by Koert and co-workers.¹¹⁴

O

TBSO

MeO

Me₃SiBr

benzene

TBSO

MeO

OH

Br

OBn

237

238

Ag₂O-SiO₂

O

HO

CH₂Cl₂, -78°C

68%, β:α = 6:1

HO

239

1. TESOTf, 2,6-lutidine

CH₂Cl₂

2. H₂, Pd/C, EtOH

OBn

OH

O

TBSO

MeO

TBSO

MeO

O

72%

TESO

HO

241

240

Scheme 53. Key steps in the synthesis of the apoptolidin disaccharide moiety by Crimmins and Long.¹¹⁵

D. Hou, T. L. Lowary / Carbohydrate Research 344 (2009) 1911–1940

1939

S

O

MeOTf (1.4 equiv)

DTBMP, CH₂Cl₂

O

BnO

O

BnO

HO

O

+

PhS

SPh

SMe

SPh

β

88%, only

242

243

244

OAc

O

BnO

O

OMP

O

PhS

O

OAc

246

O

OMP

BnO

HO

PhS

O

SMe

TBSOTf, CH₂Cl₂,

-78°C

PhS

O

SMe

70%

247

OAc

245

O

RO

O

OMP

HO

R'

O

RO

O

HO

R'

O

248

R = Bn, R' = PhS

OH

Raney Ni,

EtOH/THF

40°C,

57%

249

R = R' = H

OMe

MP =

Scheme 54. Synthesis of the Landomycin A hexasaccharide by Yu and Wang.¹¹⁸

best stereoselectivities are typically obtained when the glycosyla-

tions are performed under mild reaction conditions; the inﬂuence

of other factors such as a protecting group pattern in both glycosyl

donor and glycosyl acceptor, solvent effects, and steric hindrance

must be taken into consideration; however, in general these effects

are not well understood. Clearly, this is an area that would beneﬁt

from detailed mechanistic investigation.

9. Summary

This review concentrated on the most recent progress in the

development of methods for the synthesis of 2-deoxy-glycosides.

Several approaches have been outlined. As was true at the time

of an earlier review on this topic,⁸a number of strategies for the

synthesis of 2-deoxy-glycosides rely on an indirect approach in

which the presence of a group such as a halide, alkylthio, or alk-

ylseleno substituent at the C-2 position directs the stereoselectiv-

ity of the reaction. These substituents generally promote highly

selective glycosylations either through anchimeric assistance, or

by inducing conformational effects in the donor that favor forma-

tion of the product in which the algycone is trans to the group at

C-2. In addition, the presence of the substituent at C-2, being elec-

tron-withdrawing compared to a hydrogen, minimizes anomeriza-

tion under acidic glycosylation conditions. However, these methods

require a subsequent reduction step of the group at C-2.

On the other hand, the direct strategy, which uses 2-deoxy-gly-

copyranosyl donors to form the 2-deoxy-glycoside in only one step,

is more efﬁcient and has been the focus of a number of more recent

studies. ‘Stable’ glycosyl donors, for example, glycosyl acetates, ﬂu-

orides, thioglycosides, and glycals, are widely employed in both di-

rect and indirect strategies, offering reliable and efﬁcient methods

for the preparation of 2-deoxy-glycosides. The trichloroacetimi-

date donors have been particularly useful for the glycosylation of

less reactive acceptors. Regardless of the selected technique, the

Acknowledgments

The authors thank the Natural Sciences and Engineering Re-

search Council of Canada, The University of Alberta and the Alberta

Ingenuity Centre for Carbohydrate Science for support.

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Article Doi

Recent advances in the synthesis of 2-deoxy-glycosides

DOI: 10.1016/j.carres.2009.07.013

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Full text of DOI:10.1016/j.carres.2009.07.013

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