gem-Difluoro-carbasugars, the cases of mannopyranose and galactopyranose

Carbohydrate Research 342 (2007) 1689–1703

gem-Diﬂuoro-carbasugars, the cases of mannopyranose

and galactopyranose

a

c

Joao Sardinha,^a,bSamuel Guieu, Aurelie Deleuze, M. Carmen Fernandez-Alonso,

´

´ ˆ

´

˜

b

a

d

c

´

Amelia Pilar Rauter, Pierre Sinay, Jerome Marrot, Jesus Jimenez-Barbero and

¨

Matthieu Sollogoub^a,*

^aUniversite´ Pierre et Marie Curie-Paris 6, Institut de Chimie Mole´culaire (FR 2769), ENS, UMR CNRS 8642, 75005 Paris, France

b

o

Departamento de Quı´mica e Bioquı´mica, Faculdade de Ciencias da Universidade de Lisboa, Edifıcio C8, 5 Piso,

ˆ

1749-016 Lisboa, Portugal

´

^cDepartamento de Estructura y Funcio´n de Proteı´nas, Centro de Investigaciones Biolo´gicas, CSIC, Ramiro de Maeztu 9,

28040 Madrid, Spain

^dInstitut Lavoisier, Universite´ de Versailles-Saint-Quentin, 45, Avenue des Etats-Unis, 78035 Versailles Cedex, France

Received 13 February 2007; received in revised form 7 May 2007; accepted 11 May 2007

Available online 23 May 2007

Abstract—5a-Diﬂuoro-5a-carbamannopyranose (gem-diﬂuoro-carbamannopyranose) and 5a-diﬂuoro-5a-carbagalactopyranose

(gem-diﬂuoro-carbagalactopyranose), close congeners of their respective natural sugars, in which the endocyclic oxygen atom has

been replaced by a gem-diﬂuoromethylene group, were synthesized from ^D-mannose and D-galactose, using a rearrangement

strategy.

Keywords: Carbasugars; Fluorine; Mimics; Inositol

1. Introduction

ognized by the corresponding proteins,⁴in addition to

the frequently found sugar–aromatic interaction.⁵To

overcome this disadvantage we envisaged the synthesis

of ﬂuorinated analogues, which would hopefully induce

conformational bias through stereoelectronic eﬀects as

well as provide key polar groups for the interaction with

potential receptors.⁶We have ﬁrst synthesized 5a,5a⁰-

diﬂuoro-5a-carbaglucopyranose (gem-diﬂuoro-carba-

glucose)⁷and we wish to present herein the synthesis

of gem-diﬂuoro-carbamannopyranose and gem-diﬂuoro-

carbagalactopyranose (Fig. 1).

Our strategy is based on a Lewis acid induced rear-

rangement of an enolether possessing an electron-donat-

ing group as illustrated in Scheme 1.⁸

We successfully applied this reaction to the synthesis

of carbasugars, carbadisaccharides⁹and more recently

to gem-diﬂuoro-carbaglucose.⁷In this case, we used

an original electron-donating group: a cobalt cluster

that is conveniently also a precursor of the CH₂OH

Carbasugars are strictly deﬁned as sugar analogues in

which the endocyclic oxygen atom has been replaced

by a methylene group. This family of sugar mimics has

found its application as conformational probes of the

bound state of carbohydrates linked to proteins.¹The

conversion of the acetal function of the sugar into an

ether, making the glycosidic bond stable to hydrolysis,

is the underlying principle of this application. However,

it is obvious that these compounds, as C-glycosyl com-

pounds,²show distinct structural features to those pres-

ent in natural oligosaccharides, especially regarding the

stereoelectronic eﬀects at the anomeric centre.³More-

over, the interaction of saccharides with receptors

requires the presentation of key polar regions to be rec-

*

Corresponding author. Tel.: +33

matthieu.sollogoub@upmc.fr

1

44 32 33 35; e-mail:

doi:10.1016/j.carres.2007.05.021

1690

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

OH OH OH

F

O

HO

F

HO

OH

gem-difluoro-carba-

α-D-glucopyranose

carba-α-D-glucopyranose

α-D-glucopyranose

Figure 1. a-D-Glucopyranose and its carbocyclic analogues.

the protected alcohol 2 was prepared in 68% yield,

through a selective silylation, benzylation and desilyla-

tion sequence. After Swern oxidation of the primary

alcohol of 2, the triple bond was installed via a Corey–

Fuchs reaction¹¹and methylation of the alkyne aﬀorded

4. Cleavage of the para-methoxyphenyl (PMP) group

and subsequent oxidation allowed the formation of lac-

tone 5, which was then transformed into the key dif-

luoroalkene 6 in 89% yield (Scheme 3).

The key intermediate 6 was next engaged in the rear-

rangement step through cobalt cluster formation, fol-

lowed by the addition of TIBAL in the same pot.

Removal of the cobalt on the transient carbocyclic clus-

ter aﬀorded 58% of rearranged product as a 3:1 mixture

of two isomers, 7 and 8, respectively. The presence of the

axial benzyloxy group induces a lower stereoselectivity

of the reduction of the transient ketone compared to

that obtained in the gluco series (Scheme 4).

LA

O

EDG

O

EDG

O

EDG

L.A.

Scheme 1. General scheme for the Lewis acid induced rearrangement.

function that will be needed further on in the synthesis.

The selected Lewis acid was the triisobutylaluminium

(TIBAL), which also conveniently reduces in situ the

formed ketone (Scheme 2).

2. Results and discussion

2.1. Synthesis of gem-diﬂuoro-a-^D-carbamannopyranose

Starting from known para-methoxyphenyl mannopyr-

anoside 1,¹⁰eﬃciently synthesized from D-mannose,

OH

Co₂CO₆

F

Co₂CO₆

F

TIBAL

O

HO

BnO

F

BnO

OH

HO

OH

F

gem-difluorocarba-

α-D-glucopyranose

Scheme 2. Rearrangement-based strategy towards gem-diﬂuoro-carbasugars.

Br

OH

OBn

O

OBn

O

Ref 10

i

ii

HO

BnO

D-Mannose

OPMP

BnO

OPMP

1

2

3

OBn

O

OBn

O

OBn

O

iv, v

iii

vi

BnO

F

O

OPMP

F

5

4

6

Scheme 3. Synthesis of diﬂuoroalkene 6. Reagents and conditions: (i) (1) TBDMSCl, DMAP, pyridine, rt, 150 min; (2) BnBr, NaH, DMF, rt, 16 h;

(3) TBAF, THF, rt, 2 h, 68% over three steps; (ii) (1) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, ꢀ60 ꢁC to rt, 2 h; (2) CBr₄, PPh₃, CH₂Cl₂, rt, 4 h, 68% over 2

steps; (iii) (1) BuLi, THF, ꢀ78 ꢁC to ꢀ20 ꢁC, 2 h; (2) MeI, HMPA, ꢀ78 ꢁC to rt, 17 h, 79%; (iv) CAN, CH₃CN–H₂O–toluene (1:1:1), 0 ꢁC, 1 h, 70%;

˚

(v) PCC, MS 4 A, CH₂Cl₂, rt, 1 h, 83%; (vi) CBr₂F₂, HMPT, THF, rt, 89%.

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

1691

F

OBn

O

i, ii

BnO

F

BnO

OH

F

6

OH

7, 41%

8, 17%

F

Scheme 4. Rearrangement of diﬂuoroalkene 6. Reagents and conditions: (i) (1) Co₂(CO)₈, CH₂Cl₂, 1 h; (2) TIBAL, CH₂Cl₂, rt, 1 h; (ii) CAN, Et₃N,

acetone, 2 h, 58% (7:8, 3:1).

OH

BnO

OH

HO

F

BnO

i

ii

F

BnO

HO

OH

10, quant. yield

7

9

gem-difluorocarba-

α-D-mannopyranose

OH

F

HO

F

BnO

iii

iv

F

BnO

HO

OH

8

11

12, quant. yield

gem-difluorocarba-

β-D-mannopyranose

Scheme 5. Synthesis of gem-diﬂuoro-a and b-D-carbamannopyranose. Reagents and conditions: (i) (1) Pd–CaCO₃, H₂, EtOAc, 2 h; (2) O₃, CH₂Cl₂,

ꢀ78 ꢁC, 2 min; (3) NaBH₄, CH₂Cl₂–EtOH (1:5), rt, 45 min, 38% over three steps; (ii) Pd–C, H₂, MeOH, 3 h, quant. yield; (iii) (1) Pd–CaCO₃, H₂,

EtOAc, 2 h; (2) O₃, CH₂Cl₂, ꢀ78 ꢁC, 2 min; (3) NaBH₄, CH₂Cl₂–EtOH (1:5), rt, 30 min, 62% over three steps; (iv) Pd–C, H₂, MeOH, 6 h, quant.

yield.

Both isomers 7 and 8 were next easily converted into

gem-diﬂuoro-a- and -b-^D-carbamannopyranoses (10

and 12) through a partial hydrogenation of the triple

bond and then reductive ozonolysis, which aﬀorded 9

and 11 in 38% and 62% yield, respectively. Final depro-

tective hydrogenolysis of 9 and 11 yielded gem-diﬂuoro-

a-^D-carbamannopyranose 10 and gem-diﬂuoro-b-D-

carbamannopyranose 12, respectively (Scheme 5).

The usual partial hydrogenation and reductive ozon-

olysis of 18 aﬀorded a diol that was diﬃcult to analyse

spectroscopically. We hence isolated its acetylated deriv-

ative 20, which could be fully characterized; its full

deprotection aﬀorded gem-diﬂuoro-carba-a-^D-galacto-

pyranose 21. The equatorial isomer 19 on the other

hand was converted into gem-diﬂuoro-carba-b-^D-galac-

topyranose 23 in the usual straightforward manner

(Scheme 8).

2.2. Synthesis of gem-diﬂuoro-carba-a and b-^D-

galactopyranoses

2.3. Structural studies

The known primary alcohol 13, obtained from ^D-galact-

ose according to the literature,¹²was transformed into

the methylated alkyne 15 through Swern oxidation

and Corey–Fuchs reaction. The PMP group was cleaved

to obtain the corresponding free sugar, oxidation and

oleﬁnation of the lactone aﬀorded the key gem-di-

ﬂuoroalkene 17 (Scheme 6).

Formation of the cluster on 17, followed by TIBAL

induced rearrangement and subsequent removal of the

cobalt aﬀorded the carbocyclic products, 18 and 19, as

an almost 1:1 mixture of axial and equatorial alcohols

in 64% yield (Scheme 7).

The structure of these molecules was studied by means

of X-ray crystallography and ab initio calculations to

ascertain the possible steric and stereoelectronic factors

associated with the presence of the diﬂuoromethylene

group. It is well known that the presence of the ano-

meric eﬀect strongly modiﬁes the structural properties

of pyranose rings, especially in the vicinity of the

anomeric centre. Two diﬀerent levels of theory were

employed for comparison purposes. The key structural

data for the four compounds are given in Table 1, while

the coordinates are gathered in Supplementary data and

are available from the authors upon request.

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J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

Br

OBn

OH

Br

O

i

O

Ref 12

D-Galactose

BnO

OPMP

BnO

OBn

13

14

BnO

ii

iii

iv, v

O

OBn

OPMP

OH

BnO

F

OBn

15

16

17

F

Scheme 6. Synthesis of diﬂuoroalkene 17. Reagents and conditions: (i) (1) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, ꢀ78 ꢁC to rt, 2 h; (2) CBr₄, PPh₃,

CH₂Cl₂, 0 ꢁC!rt, 3 h, 71% over 2 steps; (ii) (1) BuLi, THF, ꢀ78 ꢁC to ꢀ40 ꢁC, 2 h; (2) MeI, HMPA, ꢀ78 ꢁC to rt, 48 h, 78%; (iii) CAN, acetone–

H₂O (3:1), 5 min; (iv) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, ꢀ78 ꢁC to rt; (v) CBr₂F₂, HMPT, THF, ꢀ10 ꢁC to rt, 33%, over 3 steps.

F

BnO

O

i, ii

F

OH

F

BnO

OBn

OH

F

17

18, 35%

19, 29%

Scheme 7. Rearrangement of diﬂuoroalkene 17. Reagents and conditions: (i) (1) Co₂(CO)₈, CH₂Cl₂, 1 h; (2) TIBAL, CH₂Cl₂, ꢀ78 ꢁC to rt, 45 min;

(ii) CAN, Et₃N, acetone, 30 min, 64% over three steps.

F

OAcF

OH F

BnO

OH

HO

F

i, ii

iii, iv

OH

BnO

OH

OAc

21, quant. yield

18

20

gem-difluorocarba-

α-D-galactopyranose

OH F

OH

F

BnO

F

v

vi

OH

HO

OH

BnO

23, quant. yield

19

22

gem-difluorocarba-

β-D-galactopyranose

Scheme 8. Synthesis of gem-diﬂuoro-carba-a- and -b-D-galactopyranose. Reagents and conditions: (i) (1) Pd–CaCO₃, H₂, EtOAc, 2 h; (2) O₃,

CH₂Cl₂, ꢀ78 ꢁC, 2 min; (3) NaBH₄, CH₂Cl₂–EtOH (1:5), 57% over three steps; (ii) Ac₂O, pyr, 2 h, rt, quant. yield; (iii) MeONa, MeOH, 1 h, rt,

quant. yield; (iv) Pd–C, H₂, MeOH, 3 h, quant. yield; (v) (1) Pd–CaCO₃, H₂, EtOAc, 2 h; (2) O₃, CH₂Cl₂, ꢀ78 ꢁC, 2 min; (3) NaBH₄, CH₂Cl₂–EtOH

(1:5), 51% over three steps; (vi) Pd–C, H₂, MeOH, 3 h, quant. yield.

˚

According to the interatomic distances, it can be

observed that the six-membered ring does not suﬀer

any noticeable distortion. All the C–C bonds range be-

tween 1.514 and 1.529 A, independently of the conﬁgu-

ration of the centres or the presence of the gem-

method employed. A maximum diﬀerence of 0.04 A is

observed for C–C bonds between the X-ray experimen-

tal and predicted data. For the C–O distances, the max-

˚

imum discrepancy amounts to 0.01 A (MP2) or 0.10 A

(QCISD). According to the calculations, a small

decrease of the C1–O1 distance is observed in the two

diﬂuoro moiety, and of the theoretical or experimental

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

1693

Table 1. Structural data for the gem-diﬂuoro derivatives synthesized in the present work, obtained from X-ray crystallography and theoretical

calculations^a

˚

Bond distance (A)

Compound

a-Man (10)

b-Man (12)

a-Gal (21)

b-Gal (23)

QCISD

MP2

QCISD

MP2

X-ray

MP2

C1–C2

C1–CF₂

C5–CF₂

C2–C3

C1–O1

C2–O2

C3–O3

C4–O4

F_ax–CF

F_eq–CF

1.533

1.527

1.523

1.527

1.423

1.416

1.423

1.433

1.375

1.383

1.529

1.523

1.518

1.523

1.424

1.417

1.425

1.434

1.377

1.386

1.527

1.520

1.519

1.409

1.425

1.422

1.433

1.379

1.388

1.530

1.525

1.523

1.408

1.424

1.421

1.432

1.377

1.384

1.527

1.521

1.529

1.415

1.422

1.423

1.434

1.399

1.373

1.523

1.517

1.515

1.525

1.416

1.423

1.424

1.435

1.403

1.376

1.525

1.516

1.514

1.529

1.421

1.432

1.426

1.433

1.381

1.369

1.518

1.515

1.521

1.411

1.422

1.423

1.434

1.396

1.377

^aGeometry optimizations at MP2/6-31G level (MP2 column) with GAUSSIAN98, as well as single-and double-quadratic conﬁguration interaction

(QCISD column) theory were used to calculate geometrical parameters. This latter method represents a higher level treatment of electron

correlation, which usually provides greater accuracy. Frequency calculations for each conformer were performed to assess their validity as proper

minima.¹³

b-OH galactose and mannose derivatives, with respect

to the rest of the C–O bonds in the two molecules.

Moreover, the distance becomes the usual one (1.42–

˚

1.43 A), when the calculations are performed for the

monoﬂuoro analogues (both at axial or equatorial

orientations, data not shown). Therefore, it seems that

there is an inﬂuence of the gem-diﬂuoro moiety on the

C1–O1 distance for the equatorial derivatives.

The existence of stereoelectronic eﬀects is more evi-

dent at the gem-diﬂuoro centre, which obviously con-

tains two strongly electronegative atoms attached to

one carbon atom.¹⁴One of the C–F bonds is clearly

shorter than the other one, resembling the anomeric

centre in regular pyranoses. This fact is also clearly ob-

served in the X-ray structure of 21 (Fig. 2). Nevertheless,

the diﬀerences are more evident when the QCISD and

˚

the MP2 protocols (0.026–0.027 A) are used than for

˚

the X-ray experimental technique (0.012 A). The C–F

˚

distances are 0.003–0.004 A shorter for the QCISD than

for the MP2 method, approaching the experimental

distances in the solid state. Regarding the diﬀerence

Figure 2. X-ray structure of compound 21.

between the equatorial and axial C–F bonds, the pre-

dicted diﬀerence is even more evident for the galactose

derivatives. Curiously, the F_eq–CF distance is shorter

than the F_ax–CF one for the galactose derivatives,

according to both theoretical and experimental data,

while the opposite trend is calculated for the mannose

analogues, for which the F_ax–CF bond is predicted to

be shorter. Previous X-ray analysis of other gem-diﬂu-

oro cyclohexanone-like compounds have shown similar

distances for the pseudoaxial and pseudoequatorial C–

2.4. Conclusion

In conclusion, we have synthesized, four new gem-diﬂu-

oro-carbasugars analogues of mannose and galactose,

and shown that some electronic eﬀects were induced

by the CF₂moiety, slightly modifying interatomic bond

distances. We now have to convert these compounds

into disaccharide or glycoconjugate mimics, such as lac-

tosamine or psychosine, which will be attractive candi-

dates for probing the capacity of the CF₂group to

mimic the carbohydrate endocyclic oxygen particularly

in terms of conformation of the aglycon, an important

feature for eﬃcient sugar–protein interactions.¹⁶

15

˚

F linkages (only 0.006 A). The corresponding dis-

tances for the monoﬂuoro analogues are always notice-

˚

ably larger (between 1.41 and 1.43 A), thus indicating

the existence of stereoelectronic eﬀects at the gem-diﬂu-

oro moiety.

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J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

3. Experimental

MHz): d 7.46–7.35 (m, 15H, H arom. Bn), 6.96 (d, 2H,

J = 9.1 Hz, H arom. OPMP), 6.86 (d, 2H, J = 9.2 Hz,

H arom. OPMP), 5.48 (d, 1H, J_1,2= 1.9 Hz, H-1), 5.03

(d, 1H, J = 10.9 Hz, CHPh), 4.90 (d, 1H, J = 12.3 Hz,

CHPh), 4.81 (d, 1H, J = 11.7 Hz, CHPh), 4.80 (d, 1H,

J = 12.4 Hz, CHPh), 4.77 (d, 1H, J = 11.8 Hz, CHPh),

4.76 (d, 1H, J = 10.9 Hz, CHPh), 4.19 (dd, 1H,

3.1. General

Optical rotations were measured at 20 2 ꢁC with a

Perkin–Elmer Model 241 digital polarimeter, using a

10 cm, 1 mL cell. Mass spectra (CI (ammonia) and

1

FAB) were obtained with a JMS-700 spectrometer. H

J_2,3= 2.8, J_3,4= 9.3 Hz, H-3), 4.15 (t, 1H, J_3,4= J_4,5=

NMR spectra were recorded at 250 MHz with a Bruker

AC-250 or at 400 MHz with a Bruker DRX 400 for

¨

solns in CDCl₃, CD₃OD, C₆D₆or D₂O at room temper-

ature. Assignments were conﬁrmed by COSY experi-

ments. ¹³C NMR spectra were recorded at 63 MHz

with a Bruker AC-250 or at 100.6 MHz with a Bruker

¨

DRX 400 spectrometer. Assignments were conﬁrmed

by J-mod technique and HMQC. ¹⁹F NMR spectra were

9.2 Hz, H-4), 4.03 (t, 1H, J_1,2= J_2,3= 2.3 Hz, H-2),

3.85–3.82 (m, 3H, H-5, H-6a, H-6b), 3.81 (s, 3H,

OCH₃), 2.04 (s, 1H, OH); ¹³C NMR (CDCl₃,

100 MHz): d 154.97, 149.94 (2C arom. quat. OPMP),

138.35, 138.27, 138.04 (3C arom. quat. Bn), 128.40–

127.62 (15CH arom. Bn), 117.65, 114.58 (4CH arom.

OPMP), 97.32 (C-1), 79.87 (C-3), 75.21 (CH₂Ph), 74.71

(C-2), 74.52 (C-4), 73.06 (CH₂Ph), 72.81 (C-5), 72.41

(CH₂Ph), 62.05 (C-6), 55.57 (OCH₃); CIMS m/z:

[M+NH₄]⁺, 574; CIMS: [M+NH₄]⁺calcd for C₃₄H₄₀-

O₇N, 574.2805; found: 574.2808.

¨

recorded at 235 MHz with a Bruker AC-250. Reactions

¨

were monitored by thin-layer chromatography (TLC)

on a precoated plate of Silica Gel 60 F₂₅₄(layer thick-

ness 0.2 mm; E. Merck, Darmstadt, Germany) and

detection by charring with H₂SO₄or with 0.2% w/v cer-

ium sulfate and 5% ammonium molybdate in 2 M

H₂SO₄. Flash column chromatography was performed

on Silica Gel 60 (230–400 mesh, E. Merck). TIBAL

was purchased from Aldrich as 1 M solution in toluene.

3.3. para-Methoxyphenyl 2,3,4-tri-O-benzyl-7,7-dibromo-

6,7-dideoxy-a-^D-manno-hept-6-enopyranoside (3)

DMSO (1.13 mL, 15.9 mmol) was added dropwise to a

solution of oxalyl chloride (1.18 mL, 13.8 mmol) in

CH₂Cl₂(80 mL) at ꢀ60 ꢁC under argon. After 15 min,

a mixture of 2 (5.90 g, 10.6 mmol) in CH₂Cl₂(60 mL)

was added dropwise. After 40 min, Et₃N (4.47 mL,

31.8 mmol) was added and the mixture was let warm

up to room temperature. After 30 min, water (150 mL)

was added and the aqueous layer was extracted with

CH₂Cl₂(3 · 50 mL). The organic layers were dried

(MgSO₄) and concentrated in vacuo. The product

(yellow oil) was directly engaged in the next step

(R_f= 0.75 cyclohexane–EtOAc, 1:1). A solution of

CBr₄(7.04 g, 21.2 mmol) in CH₂Cl₂(60 mL) was added

dropwise to a solution of PPh₃(11.07 g, 42.4 mmol) in

CH₂Cl₂(60 mL) at 0 ꢁC under argon atmosphere. After

20 min, a solution of the product of the previous step

(7.23 g, 10.6 mmol) in CH₂Cl₂(80 mL) was added drop-

wise and the mixture was let warm up to rt. After 1.5 h,

water (150 mL) was added and the aqueous layer was

extracted with CH₂Cl₂(3 · 50 mL). The organic layers

were dried (MgSO₄) and concentrated in vacuo. Column

chromatography (cyclohexane–EtOAc, 6:1) of the resi-

due gave 3 (5.13 g, 68% over 2 steps) as a white solid:

3.2. para-Methoxyphenyl 2,3,4-tri-O-benzyl-a-^D-manno-

pyranoside (2)

TBDMSCl (1.48 g, 7.70 mmol) and N,N-dimethylami-

nopyridine (50 mg, 0.41 mmol) were added to a solution

of 1 (2.00 g, 7.00 mmol) in pyridine (11 mL) at 0 ꢁC un-

der argon. After stirring for 3 h at room temperature,

the mixture was diluted with EtOAc (10 mL), washed

with a satd soln of NH₄Cl (10 mL) and aq NaHCO₃

(10 mL), dried (MgSO₄) and concentrated in vacuo.

The product (white solid) was directly engaged in the

next step (R_f= 0.8, EtOAc/ⁱPrOH/H₂O, 3:3:1). NaH

(856 mg, 21.4 mmol) was added to a solution of the

product of the previous step (1.90 g, 4.75 mmol) in

DMF (40 mL) at 0 ꢁC, and after 15 min BnBr

(2.00 mL, 17.1 mmol) was added. After stirring for

16 h at room temperature, MeOH (10 mL) was added

and the mixture was concentrated in vacuo. The product

(yellow oil) was directly engaged in the next step

(R_f= 0.7, cyclohexane–EtOAc, 2:1). TBAF (3.00 g,

9.5 mmol) was added to a solution of the product of

the previous step (3.18 g, 4.75 mmol) in THF (5 mL).

After 2 h, EtOAc (20 mL) and water (30 mL) were

added, and the aqueous layer was extracted with EtOAc

(2 · 20 mL). The organic layers were dried (MgSO₄) and

concentrated in vacuo. Column chromatography (cyclo-

hexane–EtOAc, 4:1) of the residue gave 2 (1.79 g, 68%

over 3 steps) as a white solid: mp 79–80 ꢁC (cyclo-

20

mp 82–83 ꢁC (cyclohexane–EtOAc); ½aꢁ_D+66.0 (c 0.10,

1

CHCl₃); R_f= 0.7 (cyclohexane–EtOAc, 2:1); H NMR

(CDCl₃, 400 MHz): d 7.34–7.21 (m, 15H, H arom.

Bn), 6.84 (d, 2H, J = 8.1 Hz, H arom. OPMP), 6.42

(d, 2H, J = 9.1 Hz, H arom. OPMP), 6.37 (d, 1H,

J_5,6= 8.7 Hz, H-6), 5.24 (d, 1H, J_1,2= 1.8 Hz, H-1),

4.78 (d, 1H, J = 10.8 Hz, CHPh), 4.74 (d, 1H,

J = 12.3 Hz, CHPh), 4.67 (s, 2H, CH₂Ph), 4.62 (d, 1H,

J = 11.6 Hz, CHPh), 4.60 (d, 1H, J = 11.0 Hz, CHPh),

4.41 (t, 1H, J_4,5= J_5,6= 9.1 Hz, H-5), 4.04 (dd, 1H,

20

hexane–EtOAc); ½aꢁ_D+79.3 (c 0.10, CHCl₃); R_f= 0.1

(cyclohexane–EtOAc, 4:1); ¹H NMR (CDCl₃, 400

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

1695

J_2,3= 3.0, J_3,4= 9.4 Hz, H-3), 3.82 (t, 1H, J_3,4= 9.6 Hz,

H-4), 3.86 (dd, 1H, J_1,2= 1.8, J_2,3= 3.2 Hz, H-2), 3.68

(s, 3H, OCH₃); ¹³C NMR (CDCl₃, 100 MHz): d

155.12, 150.01 (C arom. quat. OPMP), 138.33 (C arom.

quat. Bn), 137.92 (2C arom. quat. Bn), 135.67 (C-6),

128.43–127.65 (15CH arom. Bn), 118.08, 114.53 (4CH

arom. OPMP), 97.53 (C-1), 95.64 (@CBr₂), 79.42 (C-

3), 77.50 (C-4), 75.32 (CH₂Ph), 74.74 (C-2), 73.12

(CH₂Ph), 72.81 (CH₂Ph), 72.63 (C-5), 55.57 (O–CH₃);

CIMS m/z: [M+NH₄]⁺, 726.20 (25%), 728.20 (50%),

730.20 (25%); CIMS: [M+NH₄]⁺calcd for

C₃₅H₃₈O₆NBr₂, 726.1066 (49.1%), 728.1049 (100.0%),

730.1038 (55.2%); found, 726.1050 (52.2%), 728.1039

(100.0%), 730.1033 (58.5%).

582.2861. Anal. Calcd for C₃₆H₃₆O₆: C, 76.57; H, 6.43.

Found: C, 76.13; H, 6.38.

3.5. 2,3,4-Tri-O-benzyl-6,6,7,7-tetradehydro-6,7,8-tri-

deoxy-^D-manno-octono-1,5-lactone (5)

To a solution of 4 (1.74 g, 3.08 mmol) in a 1:1:1 mixture

of H₂O/acetonitrile/toluene, ammonium cerium(IV)

nitrate (16.90 g, 30.80 mmol) was added at 0 ꢁC. After

45 min, the mixture was washed with a satd aq NaHCO₃

(100 mL), and the aqueous layer was extracted with

EtOAc (3 · 40 mL). The organic layers were dried

(MgSO₄) and concentrated in vacuo. Filtration on silica

gel (cyclohexane–EtOAc, 10:1) of the residue gave the

lactol as an orange oil (982 mg, 70%). This product

was directly engaged in the next step (R_f= 0.3 cyclohex-

3.4. para-Methoxyphenyl 2,3,4-tri-O-benzyl-6,6,7,7-

tetradehydro-6,7,8-trideoxy-a-^D-manno-octopyranoside

(4)

˚

ane–EtOAc, 2:1). Molecular sieve 4 A (1.74 g) was

added to a solution of the product of the previous step

(1.23 g, 2.69 mmol) in CH₂Cl₂(100 mL). After 30 min,

PCC (1.74 g, 8.07 mmol) was added. After 1 h, diethyl

ether (100 mL) was added, the mixture ﬁltered through

silica gel and concentrated in vacuo. Column chroma-

tography (cyclohexane–EtOAc, 4:1) of the residue gave

5 (820 mg, 67%) as a white solid: mp 94–95 ꢁC (cyclo-

A 2.5 M solution of butyllithium in hexane (3.36 mL,

8.4 mmol) was added dropwise to a solution of 3

(3.00 g, 4.2 mmol) in THF (75 mL) at ꢀ70 ꢁC under

argon and the mixture was let warm up to 0 ꢁC. After

1 h, iodomethane (5.26 mL, 84.5 mmol) and HMPA

(2.94 mL, 16.9 mmol) were added dropwise at ꢀ70 ꢁC

and the mixture was let warm up to room temperature.

After 18 h, diethyl ether (50 mL) and water (100 mL)

were added and the aqueous layer was extracted with

diethyl ether (3 · 40 mL). The organic layers were com-

20

hexane–EtOAc); ½aꢁ_D+10.9 (c 1.00, CHCl₃); R_f= 0.5

(cyclohexane–EtOAc, 2:1); ¹H NMR (CDCl₃,

400 MHz): d 7.44–7.26 (m, 15H, H arom.), 5.08 (d,

1H, J = 11.9 Hz, CHPh), 4.84 (d, 1H, J = 12.3 Hz,

CHPh), 4.81 (qd, 1H, J_5,8= 2.2, J_4,5= 7.0 Hz, H-5),

4.68 (d, 1H, J = 12.3 Hz, CHPh), 4.63 (d, 1H, J =

11.9 Hz, CHPh), 4.56 (d, 1H, J = 11.7 Hz, CHPh),

bined and washed with

a satd soln of CuSO₄

(2 · 80 mL). The organic phase was dried (MgSO₄)

and concentrated in vacuo. Column chromatography

(cyclohexane–EtOAc, 10:1) of the residue gave 4

4.51 (d, 1H, J = 11.7 Hz, CHPh), 4.34 (d, 1H, J_2,3

=

2.8 Hz, H-2), 4.06 (dd, 1H, J_3,4= 1.7, J_2,3= 2.4 Hz,

H-3), 3.98 (dd, 1H, J_3,4= 1.2, J_4,5= 7.2 Hz, H-4), 1.89

(d, 3H, J_5,8= 2.1 Hz, H-8); ¹³C NMR (CDCl₃,

100 MHz): d 168.45 (C-1), 137.58, 137.11, 136.75 (3C

arom. quat. Bn), 128.52–127.79 (15CH arom. Bn), 84.86

(C alcyn.), 80.57 (C-4), 77.15 (C-3), 74.97 (C-2), 74.20

(C alcyn.), 72.87 (CH₂Ph), 72.80 (CH₂Ph), 72.50

(CH₂Ph), 69.54 (C-5), 3.67 (C-8); CIMS m/z:

[M+NH₄]⁺, 474; CIMS: [M+NH₄]⁺calcd for

C₂₉H₃₂O₅N, 474.2280; found, 474.2283. Anal. Calcd for

C₂₉H₂₈O₅: C, 76.30; H, 6.18. Found: C, 76.02; H, 5.99.

20

(1.878 g, 79%) as a white foam: ½aꢁ_D+66.8 (c 1.0,

1

CHCl₃); R_f= 0.4 (cyclohexane–EtOAc, 4:1); H NMR

(CDCl₃, 400 MHz): d 7.37–7.46 (m, 15H, H arom.

Bn), 6.98 (d, 2H, J = 9.2 Hz, H arom. OPMP), 6.86

(d, 2H, J = 9.2 Hz, H arom. OPMP), 5.45 (d, 1H,

J_1,2= 2.0 Hz, H-1), 5.02 (d, 1H, J = 10.6 Hz, CHPh),

4.95 (d, 1H, J = 10.6 Hz, CHPh), 4.87 (d, 1H,

J = 12.5 Hz, CHPh), 4.83 (d, 1H, J = 11.7 Hz, CHPh),

4.82 (d, 1H, J = 12.4 Hz, CHPh), 4.74 (d, 1H,

J = 11.7 Hz, CHPh), 4.51 (dq, 1H, J_5,8= 2.0,

J_4,5= 9.3 Hz, H-5), 4.11 (dd, 1H, J_4,5= 9.3,

J_3,4= 9.4 Hz, H-4), 4.05 (dd, 1H, J_2,3= 3.0,

J_3,4= 9.4 Hz, H-3), 3.97 (dd, 1H, J_1,2= 2.3,

J_2,3= 2.8 Hz, H-2), 3.82 (s, 3H, OCH₃), 1.93 (d, 3H,

J_5,8= 2.2 Hz, H-8); ¹³C RMN (CDCl₃, 100 MHz): d

154.98, 149.99 (2C arom. quat. OPMP), 138.47,

138.42, 138.01 (3C arom. quat. Bn), 128.38–127.55

(15CH arom. Bn), 117.50, 114.60 (4CH arom. OPMP),

97.00 (C-1), 81.74 (C alcyn.), 79.10 (C-4), 76.50 (C al-

cyn.), 78.80 (C-3), 75.50 (CH₂Ph), 74.70 (C-2), 72.90

(CH₂Ph), 72.80 (CH₂Ph), 63.90 (C-5), 55.60 (OCH₃),

3.70 (C-8); CIMS m/z: [M+NH₄]⁺, 582; CIMS:

[M+NH₄]⁺calcd for C₃₆H₄₀O₆N, 582.2856; found,

3.6. 2,6-Anhydro-3,4,5-tri-O-benzyl-7,7,8,8-tetradehydro-

1,7,8,9-tetradeoxy-1,1-diﬂuoro-^D-manno-non-1-enitol (6)

CBr₂F₂(107 lL, 1.17 mmol) and HMPT (213 lL,

1.17 mmol) were added to a solution of 5 (107 mg, 235

lmol) in THF (10 mL) at ꢀ20 ꢁC. The reaction mixture

was slowly warm up to 10 ꢁC and a white precipitate ap-

peared, then HMPT (640 lL, 3.52 mmol) was added and

the mixture was warm up to room temperature. After

1 h, diethyl ether (10 mL) was added; the mixture was

washed with satd soln of CuSO₄(3 · 10 mL), and the

organic layer was dried (MgSO₄), ﬁltered and concen-

1696

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

trated in vacuo. Column chromatography (cyclohexane–

EtOAc, 6:1) of the residue gave 6 (103 mg, 89%) as a

4.72 (d, 1H, J = 12.0 Hz, CHPh), 4.69 (d, 1H,

J = 12.1 Hz, CHPh), 4.59 (d, 1H, J = 11.9 Hz, CHPh),

4.26–4.21 (m, 1H, H-1), 4.08 (t, 1H, J_3,4= J_4,58.0 Hz,

H-4), 3.94–3.91 (m, 1H, H-2), 3.85 (dd, 1H, J_2,3= 3.2,

J_3,4= 7.9 Hz, H-3), 3.34 (ddq, 1H, J_5,8= 2.3,

J_4,5= 8.8, J_5,Fax= 23.1Hz, H-5), 2.27 (t, 1H,

J = 1.5 Hz, OH), 1.85 (d, 3H, J_5,8= 2.4 Hz, H-8); ¹³C

NMR (CDCl₃, 100 MHz): d 138.30, 138.17, 137.95 (3C

arom. quat.), 128.51–127.59 (15CH arom. Bn), 120.42

20

white solid: mp 133–134 ꢁC (cyclohexane–EtOAc); ½aꢁ_D

+27.2 (c 0.1, CHCl₃); R_f= 0.6 (cyclohexane–EtOAc,

2:1); ¹H NMR (CDCl₃, 400 MHz): d 7.45–7.30 (m,

15H, H arom.), 4.97 (s, 2H, CH₂Ph), 4.79 (d, 1H,

J = 12.6 Hz, CHPh), 4.63 (d, 1H, J = 11.9 Hz, CHPh),

4.59 (d, 1H, J = 11.9 Hz, CHPh), 4.38 (d, 1H,

J = 12.6 Hz, CHPh), 4.17–4.12 (m, 2H, H-2, H-5), 4.35

(dd, 1H, J_3,4= 3.0, J_2,3= 6.1 Hz, H-3), 3.52 (dd, 1H,

J_3,4= 3.7, J_4,5= 9.1 Hz, H-4), 1.96 (s, 3H, H-8); ¹³C

1

(t, J_C,F= 250.6 Hz, CF₂), 80.16 (C alcyn.), 78.34,

77.26, 75.91 (C-2, C-3, C-4), 74.84 (C alcyn.), 72.93

1

2

NMR (CDCl₃, 100 MHz): d 153.91 (dd, J_C,F= 282.3,

J_C,F= 295.7 Hz, CF₂), 138.24, 137.80, 137.28 (3C

(2CH₂Ph), 72.86 (CH₂Ph), 68.77 (t, J_C,F= 24.4 Hz, C-

1

2

1), 38.96 (t, J_C,F= 21.8 Hz, C-5), 3.65 (C-8); ¹⁹F

0

arom. quat. Bn), 128.34–127.68 (15CH arom. Bn),

NMR (CDCl₃, 250 MHz):

d

ꢀ108.35 (d, 1F,

2

0

111.75 (dd, J_C,F= 13.7, J_C,F= 41.3 Hz, C-1), 83.43

J_F,F= 255.1 Hz), ꢀ105.60 (d, 1F, J_F,F= 259.6 Hz);

CIMS m/z: [M+NH₄]⁺; CIMS: [M+NH₄]⁺calcd for

C₃₀H₃₄F₂O₄N, 510.2456; found, 510.2449.

5

0

(C alcyn.), 80.17 (dd, J_C,F= 1.4, J_C,F= 3.0 Hz, C-4),

78.26 (C-5), 75.91 (CH₂Ph), 75.38 (C alcyn.), 72.49 (t,

³J_C,F= 2.2 Hz, C-2), 71.76 (CH₂Ph), 69.87 (CH₂Ph),

67.61 (t, J_C,F2.9 Hz, C-3), 3.74 (C-8); ¹⁹F NMR

3.7.2. 2,3,4-Tri-O-benzyl-6,6,7,7-tetradehydro-6,7,8-tri-

deoxy-5a-diﬂuoro-5a-carba-b-^D-manno-octopyranose (8).

4

0

(CDCl₃, 250 MHz): d ꢀ111.76 (dd, 1F, J 2.4, J_F,F

20

61.2 Hz), ꢀ96.01 (dd, J 2.4, J_F,F61.2 Hz, Hz) ; CIMS

Compound 8: ½aꢁ_D+18.5 (c 0.4, CHCl₃); ¹H NMR

0

m/z: [M+NH₄]⁺, 508; CIMS: [M+NH₄]⁺calcd for

(CDCl₃, 400 MHz): d 7.41–7.29 (m, 15H, H arom.),

5.12 (d, 1H, J = 11.7 Hz, CHPh), 4.93 (d, 1H,

J = 10.4 Hz, CHPh), 4.85 (d, 1H, J = 11.9 Hz, CHPh),

4.84 (d, 1H, J = 10.3 Hz, CHPh), 4.75 (d, 1H,

J = 11.8 Hz, CHPh), 4.64 (d, 1H, J = 11.7 Hz, CHPh),

4.08 (t, 1H, J_3,4= J_4,5= 9.4 Hz, H-4), 4.02 (br d, 1H,

J = 3.0 Hz, H-2), 3.74–3.66 (m, 1H, H-1), 3.54 (dd,

1H, J_2,3= 2.5, J_3,4= 9.1 Hz, H-3), 2.95–2.86 (m, 2H,

H-5, OH), 1.88 (d, 3H, J_5,8= 2.3 Hz, H-8); ¹³C NMR

(CDCl₃, 100 MHz): d 138.56, 138.54, 138.45 (3C arom.

quat.), 128.94–127.92 (15CH arom. Bn), 81.79 (C-3),

81.09 (C alcyn.), 78.34, 77.95 (C-2, C-4), 76.12 (C al-

cyn.), 75.42 (CH₂Ph), 74.13 (2CH₂Ph), 70.65 (br s, C-

1), 4.13 (C-8); ¹⁹F NMR (CDCl₃, 250 MHz): d

C₃₀H₃₂F₂O₄N, 508.2299; found, 508.2302.

3.7. Rearrangement of (6) into 2,3,4-tri-O-benzyl-6,6,7,7-

tetradehydro-6,7,8-trideoxy-5a-diﬂuoro-5a-carba-a-^D-

manno-octopyranose (7) and 2,3,4-tri-O-benzyl-6,6,7,7-

tetradehydro-6,7,8-trideoxy-5a-diﬂuoro-5a-carba-b-^D-

manno-octopyranose (8)

Co₂(CO)₈(50 mg, 0.15 mmol) was added to a solution

of diﬂuoroalkene 6 (50 mg, 0.10 mmol) in CH₂Cl₂

(6 mL) under argon. After stirring at room temperature

for 1 h, TLC (cyclohexane–EtOAc, 4:1) indicated com-

pletely complexation of the starting material. A 1 M

solution in toluene of TIBAL (1.5 mL, 1.5 mmol) was

added dropwise over a period of 30 min. After 1 h the

mixture was diluted with CH₂Cl₂(15 mL) and washed

with a satd aq NaHCO₃(10 mL). The organic phase

was dried (MgSO₄), ﬁltered and concentrated under

reduced pressure. The crude product was dissolved in

acetone (10 mL) and Et₃N (0.014 mL, 0.10 mmol) and

CAN (550 mg, 1.0 mmol) were added. After stirring at

room temperature for 1 h, TLC (cyclohexane–EtOAc,

4:1) indicated completion of the reaction and the forma-

tion of two products. The mixture was concentrated in

vacuo and chromatographed (cyclohexane–EtOAc,

8:1) to aﬀord 7 (20.6 mg, 41%) as a colourless oil and

8 (8.3 mg, 17%) as a colourless oil.

0

ꢀ102.13 (d, 1F, J_F,F= 248.4 Hz), ꢀ116.21 (br s, 1F);

CIMS m/z: [M+NH₄]⁺; CIMS: [M+H]⁺calcd for

C₃₀H₃₁F₂O₄, 493.2190; found, 493.2181.

3.8. 2,3,4-Tri-O-benzyl-5a-diﬂuoro-5a-carba-a-^D-manno-

pyranose (9)

Pd–CaCO₃(10%, 2 mg) was added to a solution of 7

(8.0 mg, 0.02 mmol) in EtOAc (1 mL). Three purges of

vacuo/argon were performed, followed by ﬁve purges

of vacuo/H₂. After stirring for 2 h at room temperature

under hydrogen (2 atm), the mixture was ﬁltered

through a Rotilabo^ꢂNylon 0.45 lm ﬁlter, the solvent

evaporated and the product was directly engaged in

the next step. Ozone gas was bubbled through a solution

of the product of the previous step (8.0 mg, 0.02 mmol)

in CH₂Cl₂(15 mL) at ꢀ78 ꢁC until the solution obtained

a blue colouration. Oxygen was then bubbled through

the solution for 1 min and then DMS (3 drops) was

added. The solution was allowed to warm to room tem-

perature over a period of 30 min and the solvent was

3.7.1. 2,3,4-Tri-O-benzyl-6,6,7,7-tetradehydro-6,7,8-tri-

deoxy-5a-diﬂuoro-5a-carba-a-^D-manno-octopyranose (7).

20

Compound 7: ½aꢁ_D+15.2 (c 0.5, CHCl₃); ¹H NMR

(CDCl₃, 400 MHz): d 7.41–7.30 (m, 15H, H arom.),

4.87 (d, 1H, J = 10.8 Hz, CHPh), 4.78 (d, 1H,

J = 10.7 Hz, CHPh), 4.75 (d, 1H, J = 11.8 Hz, CHPh),

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

1697

removed in vacuo. The product obtained was dissolved in

a mixture of 5:1 ethanol–CH₂Cl₂(3.5 mL) and NaBH₄

(2.0 mg, 0.05 mmol) was added carefully. After stirring

for 45 min at room temperature, TLC (cyclohexane–

EtOAc, 2:1) showed no trace of starting material. MeOH

(10 mL) was added, the solvent removed, the residue

coevaporated with MeOH (3 · 10 mL), and then puriﬁed

by ﬂash chromatography (cyclohexane–EtOAc, 3:1) to

of vacuo/argon were performed, followed by ﬁve

purges of vacuo/H₂. After stirring for 2 h at room

temperature under hydrogen (2 atm), the mixture

was ﬁltered through a Rotilabo^ꢂNylon 0.45 lm ﬁlter,

the solvent evaporated and the product was directly

engaged in the next step. Ozone gas was bubbled

through a solution of the product of the previous step

(9.9 mg, 0.02 mmol) in CH₂Cl₂(15 mL) at ꢀ78 ꢁC

until the solution obtained a blue colouration. Oxy-

gen was then bubbled through the solution for

1 min and then DMS (2 drops) was added. The solu-

tion was allowed to warm to room temperature over

a period of 30 min and the solvent was removed in

vacuo. The product obtained was dissolved in a mixture

of ethanol/CH₂Cl₂(4:1, 5 mL) and NaBH₄(5.0 mg,

0.05 mmol) was added carefully. After stirring for

30 min at room temperature, TLC (cyclohexane–

EtOAc, 2:1) showed no trace of starting material.

MeOH (10 mL) was added, the solvent removed, the

residue coevaporated with MeOH (3 · 10 mL), and

then puriﬁed by ﬂash chromatography (cyclohexane–

EtOAc, 5:1) to yield 11 (6.0 mg, 62%) as a colourless

20

yield 9 (3.0 mg, 38%) as a colourless oil; ½aꢁ_D+8.3 (c

1

0.2, CHCl₃), H NMR (CDCl₃, 400 MHz): d 7.37–7.29

(m, 15H, H arom. Bn), 4.84 (d, 1H, J = 11.2 Hz, CHPh),

4.73–4.64 (m, 5H, 5 CHPh), 4.16–4.12 (m, 1H, H-1), 4.10

(t, 1H, J_3,4= J_4,5= 8.1 Hz, H-4), 3.97–3.94 (m, 4H, H-2,

H-3, H-6a, H-6b), 2.56–2.45 (m, 2H, H-5, OH), 2.31 (br s,

1H, OH); ¹³C NMR (CDCl₃, 100 MHz): d 138.32, 138.27,

138.25 (3C arom. quat. Bn), 128.96–128.18 (15CH arom.

1

0

3

Bn), 123.30 (dd, J_C,F= 245.3, J_C,F= 248.7 Hz, CF₂),

3

0

79.50 (C-3), 76.94 (dd, J_C,F= 1.9, J_C,F= 6.3 Hz, C-

4), 76.36 (br s, C-2), 74.75 (CH₂Ph), 73.60 (CH₂Ph),

73.54 (CH₂Ph), 69.94 (dd, ²J_C,F= 22.0, ²J_C,F= 26.8 Hz,

0

C-1), 59.80 (t, ³J_C,F= 4.5 Hz, C-6), 46.98 (t,

²J_C,F= 20.1 Hz, C-5); ¹⁹F NMR (CDCl₃, 235 MHz): d

20

ꢀ103.28 (d, 1F, J_F,F= 258.2 Hz), ꢀ109.84 (d, 1F,

oil; ½aꢁ_D+12.6 (c 0.3, CHCl₃), ¹H NMR (CDCl₃,

0

J_F,F= 257.8 Hz); CIMS: [M+NH₄]⁺calcd for

400 MHz): d 7.40–7.29 (m, 15H, H arom. Bn),

0

C₂₈H₃₄O₅NF₂, 502.2405; found, 502.2426.

5.14 (d, 1H, J = 11.7 Hz, CHPh), 5.01 (d, 1H,

J = 10.7 Hz, CHPh), 4.83 (d, 1H, J = 11.7 Hz,

CHPh), 4.79 (d, 1H, J = 11.7 Hz, CHPh), 4.77 (d,

1H, J = 10.7 Hz, CHPh), 4.65 (d, 1H, J = 11.7 Hz,

CHPh), 4.22 (t, 1H, J_3,4= J_4,5= 10.1 Hz, H-4), 4.08

(br d, 1H, J_1,2= J_2,3= 3.3 Hz, H-2) 4.05–4.02 (m,

2H, H-6a, H-6b), 3.75–3.64 (m, 1H, H-1), 3.64 (dd,

1H, J_2,3= 2.5, J_3,4= 9.4 Hz, H-3), 2.81 (d, 1H,

J_1,OH= 11.2 Hz, OH), 2.23 (br s, 1H, OH), 1.99

(ddt, 1H, J = 4.5, J_4,5= 10.1 Hz, J_5,Fax= 28.2 Hz,

3.9. 5a-Diﬂuoro-5a-carba-a-^D-mannopyranose (10)

Pd–C (10%, 2 mg) was added to a solution of 9 (3.0 mg,

4 lmol) in MeOH (1 mL). Three purges of vacuo/argon

were performed, followed by ﬁve purges of vacuo/H₂.

After stirring for 2 h at room temperature under hydro-

gen (2 atm), the mixture was ﬁltered through a

Rotilabo^ꢂNylon 0.45 lm ﬁlter and the solvent evapo-

rated to aﬀord gem-diﬂuoro-carba-a-^D-mannopyranose

H-5); ¹³C NMR (CDCl₃, 100 MHz):

d

138.50,

20

10 (0.8 mg, 100%); ½aꢁ_Dꢀ4.4 (c 0.27, MeOH) ¹H

138.12, 138.02 (3C arom. quat. Bn), 129.05–127.93

1

NMR (CD₃OD, 400 MHz): 4.01–3.96 (m, 3H, H-2, H-

6a, H-6b), 3.91–3.84 (m, 2H, H-1, H-4), 3.78 (dd, 1H,

(15CH arom. Bn), 122.07 (t, J_C,F= 247.4 Hz, CF₂),

4

3

83.22 (d, J_C,F= 1.5 Hz, C-3), 76.89 (d, J_C,F= 9.2 Hz,

C-2), 76.47 (d, C-4), 76.02

³J_C,F= 8.7 Hz,

(CH₂Ph), 75.61 (CH₂Ph), 73.79 (CH₂Ph), 70.77 (dd,

J_2,3= 3.5, J_3,4= 8.7 Hz, H-3), 2.27 (dddt, 1H, J_5,6a

=

J_5,6b5.0, J_5,Feq= 6.3, J_4,5= 9.7, J_5,Fax= 25.8 Hz, H-5);

¹³C NMR (CD₃OD, 100 MHz): d 123.25 (t, J_C,F

=

J_C,F= 19.4, J_C,F= 23.5 Hz, C-1), 58.73 (dd, J_C,F=

1

2

3

0

3

2

247.0 Hz, CF₂), 72.47 (C-3), 71.97 (d, J_C,F= 5.9 Hz,

3.6, J_C,F= 4.8 Hz, C-6), 48.42 (t, J_C,F= 20.4 Hz,

C-5); ¹⁹F NMR (CDCl₃, 235 MHz): d ꢀ103.76 (d,

2

0

C-2), 71.36 (dd, J_C,F= 21.9, J_C,F= 28.2 Hz, C-1),

3

69.47 (d, J_C,F= 7.8 Hz, C-4), 58.19 (dd, J_C,F= 3.5,

J_C,F= 4.7 Hz, C-6), 47.05 (t, J_C,F= 19.7 Hz, C-5);

1F, J_Feq,Fax= 251.9 Hz), ꢀ120.13 (d, 1F, J_Feq,Fax

=

3

2

251.3 Hz); FABMS: [M+Na]⁺calcd for C₂₈H₃₀O₅-

F₂Na, 507.1959; found, 507.1960.

0

¹⁹F NMR (CD₃OD, 235 MHz): d ꢀ106.35 (dd, 1F,

J_5,Feq= 5.9, J_Feq,Fax= 260.9 Hz, F_eq), ꢀ111.80 (ddd,

1F, J = 6.0, J_5,Fax= 25.8, J_Feq,Fax= 260.1 Hz, F_ax);

CIMS: [M+NH₄]⁺calcd for C₇H₁₆O₅NF₂, 232.0997;

found, 232.0991.

3.11. 5a,5a⁰-Diﬂuoro-5a-carba-b-D-mannopyranose (12)

Pd–C (10%, 3 mg) was added to a solution of 11 (6.0 mg,

12 lmol) in MeOH (3 mL). Three purges of vacuo/

argon were performed, followed by ﬁve purges of vacuo/

H₂. After stirring for 6 h at room temperature under

hydrogen (2 atm), the mixture was ﬁltered through a

Rotilabo^ꢂNylon 0.45 lm ﬁlter and the solvent evapo-

rated to aﬀord gem-diﬂuoro-carba-a-^D-mannopyranose

3.10. 2,3,4-Tri-O-benzyl-5a-diﬂuoro-5a-carba-b-^D-

mannopyranose (11)

Pd–CaCO₃(10%, 5 mg) was added to a solution of 8

(9.5 mg, 0.02 mmol) in EtOAc (3 mL). Three purges

1698

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

20

1

12 (2.7 mg, 100%); ½aꢁ_Dꢀ9.1 (c 0.2, MeOH) H NMR

(D₂O, 400 MHz): d 4.09–4.06 (m, 1H, H-2) 3.99–3.84

(m, 3H, H-1, H-6a, H-6b), 3.68 (t, 1H,

J_3,4= J_4,5= 10.4 Hz, H-4), 3.54 (dd, 1H, J_2,3= 3.2,

J_3,4= 9.9 Hz, H-3), 1.91 (br d, 1H, J_5,Fax= 28.4 Hz,

J_3,4= 2.8 Hz, H-4), 3.82 (s, 3H, OCH₃), 3.67 (dd, 1H,

J_3,4= 2.9, J_2,3= 9.7 Hz, H-3); ¹³C NMR (CDCl₃,

100 MHz): d 155.29, 151.41 (2C arom. quat. OPMP),

138.45, 138.15, 137.77 (3C arom. quat. Bn), 135.57 (C-

6), 128.46–127.60 (15CH arom. Bn), 118.55, 114.61

(4CH arom. OPMP), 102.88 (C-1), 91.89 (@CBr₂),

81.59 (C-3), 78.80 (C-2), 75.42 (C-5), 75.35 (CH₂Ph),

74.58 (CH₂Ph), 74.00 (C-4), 73.39 (CH₂Ph), 55.59

(OCH₃); CIMS: [M+NH₄]⁺calcd for C₃₅H₃₁O₆NBr₂,

726.1066 (49.1%), 728.1049 (100.0%), 730.1038

(55.2%); found, 726.1079 (53.9%), 728.1056 (100.0%),

730.1069 (54.9%). Anal. Calcd for C₃₅H₃₄O₆Br₂: C,

59.17; H, 4.82. Found: C, 58.91; H, 4.85.

H-5); ¹³C NMR (D₂O, 100 MHz):

d 122.82 (t,

¹J_C,F= 249.7 Hz, CF₂), 73.08 (d, J_C,F= 1.8 Hz, C-3),

4

3

2

71.25 (d, J_C,F= 9.1 Hz, C-2), 69.81 (dd, J_C,F= 18.0,

J_C,F= 21.3 Hz, C-1), 67.46 (d, J_C,F= 9.7 Hz, C-4),

2

3

0

3

0

56.43 (dd, J_C,F= 1.8, J_C,F= 4.8 Hz, C-6), 47.50 (t,

²J_C,F= 19.9 Hz, C-5); ¹⁹F NMR (D₂O, 235 MHz): d

ꢀ104.37 (dq, 1F, J_5,Feq= J_1,Feq= 5.5, J_Feq,Fax

=

247.6 Hz, F_eq), ꢀ120.86 (ddd, 1F, J_1,Fax= 23.1, J_5,Fax

28.8, J_Feq,Fax= 247.6 Hz, F_ax); CIMS: [M+H]⁺calcd

for C₇H₁₃O₅F₂, 215.0731; found, 215.0728.

3.13. para-Methoxyphenyl 2,3,4-tri-O-benzyl-6,6,7,7-

tetradehydro-6,7,8-trideoxy-b-^D-galacto-octopyranoside

(15)

3.12. para-Methoxyphenyl 2,3,4-tri-O-benzyl-7,7-di-

bromo-6,7-dideoxy-b-^D-galacto-hept-6-enopyranoside (14)

A 2.5 M solution of butyl lithium in hexane (2.0 mL,

5.1 mmol) was added dropwise to a solution of 14

(1.8 g, 2.5 mmol) in THF (50 mL) at ꢀ78 ꢁC under ar-

gon. The solution was stirred for 2 h at ꢀ40 ꢁC and

then cooled to ꢀ78 ꢁC. MeI (1.6 mL, 25.0 mmol) was

added dropwise followed by the HMPA (4.4 mL,

25.0 mmol). The mixture was allowed to reach room

temperature, and stirred for 48 h. The reaction mixture

was concentrated under reduced pressure, the crude

dissolved in ether (200 mL) washed with water

(100 mL) and then with a satd soln of CuSO₄

(2 · 75 mL). The organic phase was dried (MgSO₄), ﬁl-

tered and concentrated in vacuo. The residue was puri-

ﬁed by column chromatography (cyclohexane–EtOAc,

To a solution of oxalyl chloride (0.6 mL, 7.2 mmol) in

anhydrous CH₂Cl₂(30 mL), DMSO (1.0 mL,

14.4 mmol) was added dropwise at ꢀ78 ꢁC under argon.

After 15 min a solution of 4-methoxyphenyl 2,3,4-tri-O-

benzyl-b-^D-galactopyranoside 13 (2.0 mg, 3.6 mmol) in

anhydrous CH₂Cl₂(15 mL) was added dropwise. After

1 h, Et₃N (2.8 mL, 19.8 mmol) was added and the reac-

tion mixture was allowed to reach room temperature.

After 45 min, water was added (80 mL) and the aqueous

layer was extracted with CH₂Cl₂(3 · 50 mL). The

organic layers were combined, dried (MgSO₄), ﬁltered

and concentrated under reduced pressure. The crude

aldehyde was azeotroped with toluene and used without

further puriﬁcation. A solution of tetrabromomethane

(2.4 g, 7.2 mmol) in dry CH₂Cl₂(15 mL) was added to

a solution of triphenylphosphane (3.8 g, 14.4 mmol) in

dry CH₂Cl₂(30 mL) at 0 ꢁC under argon. The mixture

was stirred at room temperature for 15 min. The result-

ing bright orange slurry was cooled to 0 ꢁC, the solution

of the aldehyde (2.0 g, 3.6 mmol) in anhydrous CH₂Cl₂

(15 mL) was added and the resulting mixture was stirred

for 2 h at room temperature. Water (80 mL) and

CH₂Cl₂(100 mL) were added. The organic layer was

dried (MgSO₄) and concentrated. The residue was chro-

matographed (cyclohexane–EtOAc, 15:1) to aﬀord 14

20

10:1) to give 15 (1.1 g, 78%) as a syrup; ½aꢁ_Dꢀ29.7 (c

1.0, CHCl₃); ¹H NMR (CDCl₃, 400 MHz): d 7.56–

7.34 (m, 15H, H arom. Bn), 7.12 (d, 2H, J = 9.0 Hz,

H arom. OPMP), 6.87 (d, 2H, J = 9.0 Hz, OPMP),

5.09 (d, 1H, J = 11.7 Hz, CHPh), 5.07 (d, 1H,

J = 10.3 Hz, CHPh), 5.03 (d, 1H, J = 12.0 Hz, CHPh),

4.92 (d, 1H, J = 10.8 Hz, CHPh), 4.87 (d, 1H,

J_1,2= 7.7 Hz, H-1) 4.76 (d, 1H, J = 12.0 Hz, CHPh),

4.71 (d, 1H, J = 11.9 Hz, CHPh), 4.21 (dd, 1H,

J_4,5= 0.8, J_5,8= 2.0 Hz, H-5), 4.13 (dd, 1H,

J_1,2= 7.8, J_2,3= 9.7 Hz, H-2), 3.93 (dd, 1H,

J_4,5= 0.6, J_3,4= 3.0 Hz, H-4), 3.82 (s, 3H, OCH₃),

3.58 (dd, 1H, J_3,4= 3.0, J_2,3= 9.7 Hz, H-3), 1.90 (d,

3H, J_5,8= 2.2 Hz, H-8); ¹³C NMR (CDCl₃,

100 MHz): d 155.20, 151.62 (2C arom. quat. OPMP),

138.52, 138.38, 138.21 (3C arom. quat. Bn), 128.39–

127.46 (15CH arom. Bn), 118.70, 114.38 (4CH arom.

OPMP), 102.97 (C-1), 82.61 (C alcyn.), 80.96 (C-3),

78.72 (C-2), 75.75 (C-4), 75.33 (CH₂Ph), 74.81 (C al-

cyn.) 74.55 (CH₂Ph), 72.74 (CH₂Ph), 65.97 (C-5),

55.56 (OCH₃), 3.67 (C-8); CIMS: [M+NH₄]⁺calcd

for C₃₆H₄₀O₆N, 582.2856; found, 582.2858. Anal.

Calcd for C₃₆H₃₆O₆: C, 76.57; H, 6.43. Found: C,

76.64; H, 6.45.

20

(1.8 g, 71% over two steps) as a yellow oil; ½aꢁ_Dꢀ43.4

1

(c 1.40, CHCl₃); H NMR (CDCl₃, 400 MHz): d 7.43–

7.36 (m, 15H, H arom. Bn), 7.08 (d, 2H, J = 9.1 Hz,

H arom. OPMP), 6.88 (d, 2H, J = 9.0 Hz, H arom.

OPMP), 6.71 (d, 1H, J_5,6= 7.1 Hz, H-6), 5.08 (d, 1H,

J = 10.9 Hz, CHPh), 5.03 (d, 1H, J = 11.8 Hz, CHPh),

4.93 (d, 1H, J_1,2= 7.5 Hz, H-1), 4.92 (d, 1H,

J = 11.3 Hz, CHPh), 4.88 (d, 1H, J = 11.8 Hz, CHPh),

4.80 (d, 1H, J = 11.8 Hz, CHPh), 4.76 (d, 1H,

J = 11.8 Hz, CHPh), 4.14 (dd, 1H, J_1,2= 7.7,

J_2,3= 9.7 Hz, H-2), 4.11 (dd, 1H, J_4,5= 0.9,

J_5,6= 7.2 Hz, H-5), 3.94 (dd, 1H, J_4,5= 0.8,

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

1699

3.14. 2,3,4-Tri-O-benzyl-6,6,7,7-tetradehydro-6,7,8-tri-

deoxy-a-b-^D-galacto-octopyranose (16)

ic layers were combined, dried (MgSO₄), ﬁltered and

concentrated under reduced pressure. The crude lactone

was azeotroped with toluene and used without further

To a solution of 15 (45.0 mg, 0.08 mmol) in a 3:1 mix-

ture of acetone/H₂O (2 mL) was added ammonium

cerium(IV) nitrate (310.0 mg, 0.56 mmol). The resulting

clear orange solution was stirred at room temperature

for 5 min. The mixture was partially concentrated under

reduced pressure, diluted with dichloromethane (10 mL)

and washed with water (5 mL). The organic layer was

dried (MgSO₄) and concentrated. The residue was puri-

ﬁed by column chromatography (cyclohexane–EtOAc,

4:1) to give 16 (26.1 mg, 71%) as an orange oil and as

a 3:1 mixture of a and b anomers; extracted data for a

puriﬁcation. To a solution of 2,3,4-tri-O-benzyl-

6,6,7,7-tetradehydro-6,7,8-trideoxy-^D-galacto-octono-1,5-

lactone (0.44 g, 0.96 mmol) in anhydrous THF (25 mL)

was added, with a cooled syringe, CBr₂F₂(0.9 mL,

9.60 mmol) at ꢀ10 ꢁC under argon. HMPT (1.7 mL,

9.60 mmol) was added dropwise and the mixture was al-

lowed to reach room temperature. After 1 h HMPT

(3.5 mL, 19.20 mmol) was added and the reaction mix-

ture stirred for 2 h at room temperature. The reaction

mixture was concentrated under reduced pressure and

then was diluted with ether (100 mL) and water

(50 mL). The organic layer was separated, washed with

a satd soln of CuSO₄(2 · 30 mL), dried (MgSO₄), ﬁl-

tered and the solvent was removed in vacuo. The residue

was puriﬁed by ﬂash chromatography (cyclohexane–

EtOAc, 25:1) to aﬀord 17 (155.9 mg, 33%) as a colourless

1

anomer; H NMR (CDCl₃, 400 MHz): d 7.49–7.30 (m,

15H, H arom. Bn), 5.33 (d, 1H, J_1,2= 3.5 Hz, H-1),

4.99 (d, 1H, J = 11.9 Hz, CHPh), 4.93 (d, 1H,

J = 11.9 Hz, CHPh), 4.85 (d, 1H, J = 11.7 Hz, CHPh),

4.75–4.70 (m, 4H, 3CHPh, H-5), 4.44 (dd, 1H,

J_1,2= 3.5, J_2,3= 9.5 Hz, H-2), 3.94 (dd, 1H, J_4,5= 1.6,

J_3,4= 2.9 Hz, H-4), 3.89 (dd, 1H, J_3,4= 2.9,

J_2,3= 9.6 Hz, H-3), 3.03 (br s, 1H, OH), 1.87 (d, 3H,

J_5,8= 2.2 Hz, H-8); ¹³C NMR (CDCl₃, 100 MHz): d

138.43, 138.38, 138.02 (3C arom. quat. Bn), 128.40–

127.49 (15CH arom. Bn), 91.87 (C-1), 82.42 (C alcyn.),

77.41 (C-3), 76.63 (C-4), 75.93 (C-2), 75.27 (C alcyn.),

74.63 (CH₂Ph), 73.60 (CH₂Ph), 72.74 (CH₂Ph), 62.60

(C-5), 3.64 (C-8); extracted data for b anomer; ¹H

NMR (CDCl₃, 400 MHz): d 7.49–7.30 (m, 15H, H

arom. Bn), 5.01–4.90 (m, 3H, 3CHPh), 4.81 (d, 1H,

J = 11.1 Hz, CHPh), 4.77 (d, 1H, J = 11.9 Hz, CHPh),

4.75–4.70 (m, 2H, CHPh, H-1), 4.27 (quintet, 1H,

J_4,5= J_5,8= 2.0 Hz, H-5), 3.90–3.87 (m, 1H, H-4), 3.80

(dd, 1H, J_1,2= 6.8, J_2,3= 9.0 Hz, H-2), 3.58 (dd, 1H,

J_3,4= 2.9, J_2,3= 9.0 Hz, H-3) 3.53 (br s, 1H, OH), 1.87

(d, 3H, J_5,8= 2.2 Hz, H-8); ¹³C NMR (CDCl₃,

100 MHz): d 138.43–138.02 (3C arom. quat. Bn),

128.40–127.49 (15CH arom. Bn), 97.21 (C-1), 82.42 (C

alcyn.), 80.36 (C-3), 79.87 (C-2), 75.50 (C-4), 75.27 (C

alcyn.), 74.74 (CH₂Ph), 74.35 (CH₂Ph), 72.86 (CH₂Ph),

65.61 (C-5), 3.60 (C-8); CIMS: [M+NH₄]⁺calcd for

C₂₉H₃₄O₅N, 476.2437; found, 476.2442.

22

oil; ½aꢁ_D+36.8 (c 0.6, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d 7.41–7.30 (m, 15H, H arom. Bn), 4.93–4.91

(m, 1H, H-5), 4.89 (d, 1H, J = 12.3 Hz, CHPh), 4.74

(d, 1H, J = 12.1 Hz, CHPh), 4.70 (d, 1H, J = 10.5 Hz,

CHPh), 4.67 (d, 1H, J = 12.2 Hz, CHPh), 4.61 (d, 1H,

J = 11.8 Hz, CHPh), 4.35 (d, 1H, J = 11.8 Hz, CHPh),

4

4.31 (dd, 1H, J_2,F= 3.4, J_2,3= 5.7 Hz, H-2), 4.09 (dd,

1H, J_4,5= 2.8, J_3,4= 5.5 Hz, H-4), 4.00–3.98 (m, 1H,

H-3), 1.85 (d, 3H, J_5,8= 2.2 Hz, H-8); ¹³C NMR

1

(CDCl₃, 100 MHz):

d

156.20 (dd, J_C,F= 280.2,

1

0

J_C,F= 293.5 Hz, CF₂) 139.11, 138.28, 137.85 (3C arom.

quat. Bn), 128.83–127.60 (15CH arom. Bn), 84.73 (C

4

alcyn.), 75.57 (d, J_C,F= 1.6 Hz, C-3), 75.00 (C

alcyn.), 73.89 (C-4), 73.10 (CH₂Ph), 72.43 (CH₂Ph),

3

71.57 (t, J_C,F= 3.3 Hz, C-2), 70.70 (CH₂Ph), 68.45

4

(t, J_C,F= 1.6 Hz, C-5), 4.45 (C-8); ¹⁹F NMR

0

(CDCl₃, 235 MHz): d ꢀ97.22 (d, 1F, J_F,F67.5 Hz),

0

ꢀ111.64 (dd, 1F, J_2,F= 2.4, J_F,F61.1 Hz); FABMS:

[M+Na]⁺calcd for C₃₀H₂₈O₄F₂Na, 513.1853; found,

518.1849.

3.16. Rearrangement of (17) into 2,3,4-tri-O-benzyl-

6,6,7,7-tetradehydro-6,7,8-trideoxy-5a-diﬂuoro-5a-carba-

a-^D-galacto-octopyranose (18) and 2,3,4-tri-O-benzyl-

6,6,7,7-tetradehydro-6,7,8-trideoxy-5a-diﬂuoro-5a-carba-

b-^D-galacto-octopyranose (19)

3.15. 2,6-Anhydro-3,4,5-tri-O-benzyl-7,7,8,8-tetrade-

hydro-1,7,8,9-tetradeoxy-1,1-diﬂuoro-^D-galacto-non-

1-enitol (17)

Co₂(CO)₈(0.15 g, 0.45 mmol) was added to a solution of

diﬂuoroalkene 17 (0.15 g, 0.30 mmol) in CH₂Cl₂

(15 mL) under argon. After stirring at room temperature

for 1 h, TLC (cyclohexane–EtOAc, 4:1) indicat com-

pletely complexation of the starting material. The reac-

tion mixture was cooled to ꢀ78 ꢁC and a 1 M solution

in toluene of TIBAL (2.40 mL, 2.40 mmol) was added

dropwise over a period of 15 min. The mixture was

allowed to reach room temperature and stirred for 1 h.

The mixture was diluted with CH₂Cl₂(20 mL) and

To a solution of oxalyl chloride (0.16 mL, 1.92 mmol) in

anhydrous CH₂Cl₂(10 mL), DMSO (0.27 mL,

3.84 mmol) was added dropwise at ꢀ78 ꢁC under argon.

After 15 min a solution of 16 (0.44 mg, 0.96 mmol) in

anhydrous CH₂Cl₂(15 mL) was added dropwise. After

1 h, Et₃N (0.74 mL, 5.28 mmol) was added and the reac-

tion mixture was allowed to reach room temperature.

After 45 min, water was added (20 mL) and the aqueous

layer was extracted with CH₂Cl₂(3 · 40 mL). The organ-

1700

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

washed with a satd aq NaHCO₃(15 mL). The organic

phase was dried (MgSO₄), ﬁltered and concentrated

under reduced pressure. The crude product was dissolved

in acetone (10 mL) and Et₃N (0.03 mL, 0.30 mmol) and

CAN (0.82 g, 1.5 mmol) were added. After stirring at

room temperature for 30 min, TLC (cyclohexane–

EtOAc, 4:1) indicated completion of the reaction and

the formation of two products. The mixture was concen-

trated in vacuo and chromatographed (cyclohexane–

EtOAc, 8:1) to aﬀord 18 (52 mg, 35%) as a colourless

oil and 19 (42 mg, 29%) as a colourless oil.

3.17. 1,6-Di-O-acetyl-2,3,4-tri-O-benzyl-5a-diﬂuoro-5a-

carba-a-^D-galactopyranose (20)

Pd–CaCO₃(10%, 2 mg) was added to a solution of 18

(51 mg, 0.10 mmol) in EtOAc (4 mL). Three purges of

vacuo/argon were performed, followed by ﬁve purges

of vacuo/H₂. After stirring for 2 h at room temperature

under hydrogen (2 atm), the mixture was ﬁltered

through a Rotilabo^ꢂNylon 0.45 lm ﬁlter, the solvent

evaporated and the product was directly engaged in

the next step. Ozone gas was bubbled through a solution

of the product of the previous step (51 mg, 0.10 mmol)

in CH₂Cl₂(40 mL) at ꢀ78 ꢁC until the solution obtained

a blue colouration (typically 2 min). Oxygen was then

bubbled through the solution for 1 min and then DMS

(5 drops) was added. The solution was allowed to warm

to room temperature over a period of 30 min and the

solvent was removed in vacuo. The product obtained

was dissolved in a mixture of 4:1 ethanol/CH₂Cl₂

(5 mL) and NaBH₄(26 mg, 0.70 mmol) was added care-

fully. After stirring for 45 min at room temperature,

TLC (cyclohexane–EtOAc, 2:1) indicated complete con-

sumption of starting material (R_f= 0.33) and the forma-

tion of a major product (R_f= 0.19). MeOH (10 mL) was

added, the solvent removed, and the residue coevapo-

rated with MeOH (3 · 10 mL). The crude product was

dissolved in pyridine (1 mL), Ac₂O (0.5 mL) was added

dropwise and the mixture was stirred overnight at room

temperature. The reaction mixture was concentrated un-

der reduced pressure (azeotroped with toluene) and

puriﬁed by ﬂash chromatography (cyclohexane–EtOAc,

3.16.1. 2,3,4-Tri-O-benzyl-6,6,7,7-tetradehydro-6,7,8-tri-

deoxy-5a-diﬂuoro-5a-carba-a-^D-galacto-octopyranose (18).

20

1

Compound 18: ½aꢁ_D+33.5 (c 1.0, CHCl₃); H NMR

(CDCl₃, 250 MHz): d 7.37–7.20 (m, 15H, H arom.

Bn), 4.80–4.55 (m, 6H, 6CHPh), 4.13 (dt, 1H, J_1,2

=

J_1,Feq= 3.0, J_1,Fax= 7.1 Hz, H-1), 4.01 (dd, 1H,

J_1,2= 3.2, J_2,3= 8.9 Hz, H-2), 3.93 (t, 1H, J_3,4

J_4,5= 2.8 Hz, H-4), 3.74 (dd, 1H, J_3,4= 3.0, J_2,3

=

8.9 Hz, H-3), 3.16 (br d, 1H, J_5,Fax= 28.5 Hz, H-5),

2.51 (br s, 1H, OH); ¹³C NMR (C₆D₆, 63 MHz): d

139.42, 139.26, 138.54 (3C arom. quat. Bn), 128.62–

1

127.66 (15CH arom. Bn), 120.32 (t, J_C,F= 251.5 Hz,

CF₂), 80.59 (C alcyn.), 78.29 (C-3), 77.50 (br s, C-2),

76.35 (d, ³J_C,F= 6.5 Hz, C-4), 75.66 (CH₂Ph),

73.35 (2CH₂Ph), 72.78 (C alcyn.), 70.36 (br s, C-1),

2

36.94 (t, J_C,F= 20.8 Hz, C-5), 3.41 (C-8); ¹⁹F

NMR (C₆D₆, 235 MHz): d ꢀ102.44 (d, 1F, J_Feq,Fax

=

247.8 Hz), ꢀ107.53 (d, 1F J_Feq,Fax= 248.9 Hz); CIMS:

[M+NH₄]⁺calcd for C₃₀H₃₄O₄NF₂, 510.2456; found,

510.2441.

20

2:1) to yield 20 (32.4 mg, 57%), as a colourless oil; ½aꢁ_D

1

+39.4 (c 0.8, CHCl₃); H NMR (CDCl₃, 400 MHz): d

7.39–7.29 (m, 15H, H arom. Bn), 5.68 (dt, 1H,

J_1,2= 3.2, J_1,F= 6.9 Hz, H-1) 5.01 (br d, 1H,

J = 10.8 Hz, CHPh), 4.91 (d, 1H, J = 11.7 Hz, CHPh),

4.76 (d, 1H, J = 11.7 Hz, CHPh), 4.74 (d, 1H,

J = 11.1 Hz, CHPh), 4.61 (d, 1H, J = 11.6 Hz, CHPh),

4.60 (d, 1H J = 11.0 Hz, CHPh), 4.45 (dd, 1H,

J_5,6a= 4.8, J_6a,6b= 11.2 Hz, H-6a) 4.31–4.22 (m, 2H,

H-2 and H-6b), 4.07 (ddd, 1H, J = 2.6, J = 3.0,

3.16.2. 2,3,4-Tri-O-benzyl-6,6,7,7-tetradehydro-6,7,8-tri-

deoxy-5a-diﬂuoro-5a-carba-b-^D-galacto-octopyranose (19).

20

Compound 19: ½aꢁ_Dꢀ15.1 (c 0.8, CHCl₃); ¹H NMR

(CDCl₃, 400 MHz): d 7.37–7.29 (m, 15H, H arom. Bn),

4.92 (br d, 3H, J = 10.3 Hz, 3CHPh), 4.79 (d, 1H,

J = 11.1 Hz, CHPh), 4.75 (d, 3H, J = 12.0 Hz, CHPh),

4.71 (d, 1H, J = 11.9 Hz, CHPh), 4.07–4.02 (m, 2H, H-

2, H-4) 3.74 (ddd, 1H, J_1,Feq= 6.8, J_1,2= 8.7,

J_1,Fax= 15.3 Hz, H-1), 3.53 (dd, 1H, J_3,4= 2.0,

J_2,3= 8.7 Hz, H-3), 2.90 (br d, 1H, J_5,Fax= 23.6 Hz, H-

5), 1.84 (d, 3H, J_5,8= 2.4 Hz H-8); ¹³C NMR (CDCl₃,

100 MHz): d 138.83, 138.56, 138.32 (3C arom. quat.

Bn), 128.92–127.89 (15CH arom. Bn), 119.50 (dd,

J = 5.7 Hz,

H-4),

3.84

(dd,

1H,

J_3,4= 2.8,

J_2,3= 9.9 Hz, H-3), 2.52 (br d, 1H, J_5,Fax= 27.0 Hz,

H-5), 2.16 (s, 3H, OAc), 2.00 (s, 3H, OAc); ¹³C NMR

(CDCl₃, 100 MHz): d 171.01, 169.58 (2C quat. OAc)

138.90, 138.75, 138.08 (3C arom. quat. Bn), 128.81–

1

127.90 (15CH arom. Bn), 120.16 (dd, J_C,F= 249.0,

1

0

J_C,F= 245.1, J_C,F= 255.4 Hz, CF₂), 81.50 (C alcyn.),

J_C,F= 251.2 Hz, CF₂), 79.49 (C-3), 75.72 (d,

3

81.17 (C-3), 79.36 (d, J_C,F= 6.3 Hz, C-2 or C-4), 75.87

(d, J_C,F= 6.8 Hz, C-2 or C-4), 75.81 (CH₂Ph), 75.09

³J_C,F= 5.7 Hz, C-2), 75.46 (CH₂Ph), 74.37 (CH₂Ph),

73.12 (CH₂Ph), 73.11 (d, J_C,F= 9.5 Hz, C-4), 69.53

3

2

0

(CH₂Ph), 74.22 (br s, C-1), 73.41 (CH₂Ph), 71.48 (C

(dd, J_C,F= 20.6, J_C,F= 36.5 Hz, C-1), 58.92 (C-6),

42.50 (br s, C-5), 21.26 (CH₃, OAc), 21.24 (CH₃,

OAc); ¹⁹F NMR (CDCl₃, 235 MHz): d ꢀ105.11 (d,

2

alcyn.), 38.72 (t, J_C,F= 21.0 Hz, C-5), 4.15 (C-8); ¹⁹F

NMR (CDCl₃, 235 MHz):

d

ꢀ102.08 (d, 1F,

J_Feq,Fax= 247.0 Hz), ꢀ117.05 (br s, 1F); CIMS:

[M+NH₄]⁺calcd for C₃₀H₃₄O₄NF₂, 510.2456; found,

510.2463.

1F, J_Feq,Fax= 260.9 Hz), ꢀ109.21 (d, 1F, J_Feq,Fax

=

260.9 Hz); CIMS: [M+NH₄]⁺calcd for C₃₂H₃₈O₇NF₂,

586.2616; found, 586.2610.

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

1701

3.18. 5a-Diﬂuoro-5a-carba-a-D-galactopyranose (21)

of a major product (R_f= 0.27). MeOH (10 mL) was

added, the solvent removed, the residue coevaporated

with MeOH (3 · 10 mL), and then puriﬁed by ﬂash

chromatography (cyclohexane–EtOAc, 3:1) to yield 22

To a solution of 20 (25 mg, 0.043 mmol) in MeOH, was

added dropwise a 1 M solution of NaOMe (1 mL) and

the mixture was stirred for 6 h at rt. The reaction mix-

ture was neutralized with acid resin Amberlite IR 120

(H⁺), ﬁltered and concentrated under reduced pressure.

The product was directly engaged in the next step. Pd–

C (10%, 2 mg) was added to a solution of the diol

(21 mg, 0.043 mmol) in MeOH (1.5 mL). Three purges

of vacuo/argon were performed, followed by ﬁve

purges of vacuo/H₂. After stirring for 3 h at room tem-

perature under hydrogen (2 atm), the mixture was ﬁl-

tered through a Rotilabo^ꢂNylon 0.45 lm ﬁlter and

the solvent evaporated to aﬀord gem-diﬂuoro-carba-a-

D-galactopyranose 21 (9.3 mg, 100%) as a white crystal-

20

(14.8 mg, 51%), as a colourless oil; ½aꢁ_Dꢀ19.1 (c 1.0,

1

CHCl₃); H NMR (CDCl₃, 400 MHz): d 7.41–7.28 (m,

15H, H arom. Bn), 5.02 (d, 1H, J = 11.9 Hz, CHPh),

4.96 (d, 1H, J = 11.1 Hz, CHPh), 4.82 (d, 3H,

J = 11.3 Hz, 3CHPh), 4.68 (d, 1H, J = 11.9 Hz, CHPh),

4.17 (d, 1H, J_3,4= 3.0 Hz, H-4) 4.06 (t, 1H, J_1,2

J_2,3= 9.0 Hz, H-2), 3.99 (dd, 1H, J_5,6a= 4.3, J_6a,6b

=

10.9 Hz, H-6), 3.87 (t, 1H, J_5,6b= J_6a,6b= 10.5 Hz,

H-6b), 3.76 (dt, 1H, J_1,2= J_1,Feq= 8.5, J_1,Fax= 16.7 Hz,

H-1), 3.58 (dd, 1H, J_3,4= 2.6, J_2,3= 9.1 Hz, H-3), 2.70

(br s, 1H, OH), 2.04 (br d, 1H, J_5,Fax= 24.5 Hz, H-5),

1.64 (br s, 1H, OH); ¹³C NMR (CDCl₃, 100 MHz): d

138.87, 138.61, 138.24 (3C arom. quat. Bn), 128.98–

20

line solid; mp 232 ꢁC (MeOH); ½aꢁ_D+1.8 (c 0.8,

1

MeOH); H NMR (CD₃OD, 400 MHz): d 4.18 (ddd,

127.09 (15CH arom. Bn), 121.55 (dd, J_C,F= 244.0,

1

0

1H, J = 3.0, J_3,4= 3.2, J = 6.0 Hz, H-4) 4.00–3.85 (m,

4H, H-1, H-2, H-6a, H-6b), 3.78 (dd, 1H, J_3,4= 3.3,

J_2,3= 9.8 Hz, H-3), 2.36 (ddq, 1H, J = 4.4, J = 8.1,

J_C,F= 252.7 Hz, CF₂), 82.53 (C-3), 79.67 (d,

³J_C,F= 7.9 Hz, C-2), 75.97 (CH₂Ph), 74.83 (CH₂Ph),

74.63 (br s, C-1), 73.73 (CH₂Ph), 72.12 (d,

J_5,Fax= 31.4 Hz,

H-5);

¹³C

NMR

(CD₃OD,

³J_C,F= 9.0 Hz,

C-4),

56.73

(dd,

³J_C,F= 2.6,

1

3

2

0

100 MHz):

d

123.07 (dd, J_C,F= 246.1, J_C,F

=

J_C,F= 4.3 Hz, C-6), 46.47 (t, J_C,F= 19.8 Hz, C-5);

¹⁹F NMR (CDCl₃, 235 MHz): d ꢀ104.79 (br d, 1F,

258.5 Hz, CF₂), 72.53 (dd, J_C,F= 20.4, ²JC_,F

2

0

3

33.1 Hz, C-1), 70.64 (C-3), 68.78 (d, J_C,F= 7.3 Hz,

C-2), 67.35 (d, J_C,F= 10.1 Hz, C-4) 55.72 (dd,

J_Feq,Fax= 251.0 Hz), ꢀ119.52 (br d, 1F, J_Feq,Fax

=

3

256.7 Hz); CIMS: [M+H]⁺calcd for C₂₈H₃₁O₅F₂,

485.2140; found, 485.2143.

3

2

0

J_C,F= 2.2, J_C,F= 3.5 Hz, C-6), 43.70 (t, J_C,F

=

19.7 Hz, C-5); ¹⁹F NMR (CD₃OD, 235 MHz): d

ꢀ107.23 (dd, 1F, J_5,Feq= 5.0, J_Feq,Fax= 256.3 Hz,

3.20. 5a-Diﬂuoro-5a-carba-b-^D-galactopyranose (23)

F_eq), ꢀ111.19 (dd, 1F, J_5,Fax= 31.0, J_Feq,Fax

=

255.7 Hz, F_ax); CIMS: [M+NH₄]⁺calcd for

C₇H₁₆O₅NF₂, 232.0997; found, 232.1002.

Pd–C (10%, 2 mg) was added to a solution of 22

(18 mg, 0.04 mmol) in MeOH (3 mL). Three purges of

vacuo/argon were performed, followed by ﬁve purges

of vacuo/H₂. After stirring for 2 h at room temperature

under hydrogen (2 atm), the mixture was ﬁltered

through a Rotilabo^ꢂNylon 0.45 lm ﬁlter and the sol-

vent evaporated to aﬀord gem-diﬂuoro-carba-b-^D-

galactopyranose 23 (7.2 mg, 91%) as a colourless oil;

3.19. 2,3,4-Tri-O-benzyl-5a-diﬂuoro-5a-carba-b-^D-galac-

topyranose (22)

Pd–CaCO₃(10%, 2 mg) was added to a solution of 19

(30 mg, 0.06 mmol) in EtOAc (3 mL). Three purges of

vacuo/argon were performed, followed by ﬁve purges

of vacuo/H₂. After stirring for 2 h at room temperature

under hydrogen (2 atm), the mixture was ﬁltered

through a Rotilabo^ꢂNylon 0.45 lm ﬁlter, the solvent

evaporated and the product was directly engaged in

the next step. Ozone gas was bubbled through a solution

of the product of the previous step (30 mg, 0.06 mmol)

in CH₂Cl₂(40 mL) at ꢀ78 ꢁC until the solution obtained

a blue colouration (typically 2 min). Oxygen was then

bubbled through the solution for 1 min and then DMS

(4 drops) was added. The solution was allowed to warm

to room temperature over a period of 30 min and the

solvent was removed in vacuo. The product obtained

was dissolved in a mixture 4:1 ethanol/CH₂Cl₂(5 mL)

and NaBH₄(20 mg, 0.42 mmol) was added carefully.

After stirring for 30 min at room temperature, TLC

(cyclohexane–EtOAc, 2:1) indicated complete consump-

tion of starting material (R_f= 0.40) and the formation

20

½aꢁ_Dꢀ16.2 (c 0.5, MeOH); ¹H NMR (CD₃OD,

400 MHz):

d 4.17 (ddd, 1H, J = 2.6, J_3,4= 3.0,

J = 5.3 Hz, H-4) 4.01–3.95 (m, 2H, H-6a, H-6b), 3.76

(dt, 1H, J_2,F= 1.2, J_1,2= J_2,3= 9.8 Hz, H-2), 3.55

(ddd, 1H, J_1,Feq= 6.4, J_1,2= 9.8, J_1,Fax= 20.1 Hz,

H-1), 3.44 (dd, 1H, J_3,4= 3.2, J_2,3= 9.7 Hz, H-3),

2.06 (br d, 1H, J_5,Fax= 27.4 Hz, H-5); ¹³C NMR

1

(CD₃OD, 100 MHz): d 122.17 (dd, J_C,F= 243.2,

1

2

0

J_C,F= 250,0 Hz, CF₂), 74.64 (t, J_C,F= 20.4 Hz,

4

C-1), 73.89 (d, J_C,F= 1.8 Hz, C-3), 71.29 (d,

³J_C,F= 9.0 Hz, C-2), 67.68 (d, J_C,F= 9.8 Hz, C-4)

3

0

55.49 (dd, J_C,F= 2.4, J_C,F= 4.7 Hz, C-6), 46.18 (t,

²J_C,F= 19.4 Hz, C-5); ¹⁹F NMR (CD₃OD, 235 MHz):

d ꢀ108.52 (ddd, 1F, J_1,Feq= 5.2, J_5,Feq= 10.5, J_Feq,Fax

=

247.0 Hz, F_eq), ꢀ123.80 (ddd, 1F, J_1,Fax= 20.1,

J_5,Fax= 29.8,

J_Feq,Fax= 247.0 Hz,

F_ax);

CIMS:

[M+NH₄]⁺calcd for C₇H₁₆O₅NF₂, 232.0997; found,

232.0988.

1702

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

3.21. Ab initio calculations

Supplementary data

The calculations were performed on HP Cluster Super-

dome computer, at the Supercomputing Centre of Gali-

cia, Spain (CESGA). Full geometry optimizations were

performed with ^GAUSSIAN98¹³for a,b-gem-diﬂuoro-

carbagalactopyranose, a,b-gem-diﬂuoro-carbamanno-

pyranose, a,b-gem-diﬂuoro-carbaglucopyranose and

the corresponding mono-ﬂuorinated analogues using

Møller-Plesset calculations, speciﬁcally, at the MP2/6-

31G(d,p) level of theory. Vibrational frequency calcula-

tions were performed to characterize the nature of each

conformer.

Supplementary data associated with this article can be

found, in the online version, at doi:10.1016/j.carres.

2007.05.021.

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Acknowledgements

13. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.

E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;

Montgomery, J. A.; Stratmann, R. E.; Burant, J. C.;

Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;

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The authors thank Fundac¸ao para a Cieˆncia e Tecnolo-

˜

gia (FCT Portugal) for research grant (Joao Sardinha)

˜

and the Franco Spanish program PICASSO for useful

travel money.

J. Sardinha et al. / Carbohydrate Research 342 (2007) 1689–1703

1703

Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.;

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Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,

A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;

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Article Doi

gem-Difluoro-carbasugars, the cases of mannopyranose and galactopyranose

DOI: 10.1016/j.carres.2007.05.021

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