De novo asymmetric syntheses of C-4-substituted sugars via an iterative dihydroxylation strategy

Carbohydrate Research 341 (2006) 1505–1521

De novo asymmetric syntheses of C-4-substituted sugars via

an iterative dihydroxylation strategy

Md. Moinuddin Ahmed and George A. O’Doherty^*

Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA

Received 12 February 2006; received in revised form 10 March 2006; accepted 19 March 2006

Available online 17 April 2006

Abstract—A short and highly eﬃcient route to various C-4 substituted sugar lactones has been developed. The key to the overall

transformation is the sequential osmium-catalyzed dihydroxylation reaction of substituted 2,4-dienoates and an allylic substitution

at the C-4 position. When the Sharpless AD-mix procedure is used in a matched sense for the second dihydroxylation reaction, it

results in an exceedingly diastereo- and enantioselective synthesis of several C-4-substituted sugars.

Keywords: Diastereoselective dihydroxylation; Fluorosugars; Deoxysugars; Asymmetric synthesis

1. Introduction

via routes, which are amenable to the installation of var-

ious C-6 substituents.

Over the years, considerable eﬀorts have been made

toward the development of new synthetic routes to

monosaccharides.¹The desire for these new routes was

engendered by medicinal chemist’s want for unnatural

sugar analogues for structure activity relationship stud-

ies.²Of particular interest is the de novo preparation of

these carbohydrates, that is, from achiral starting mate-

rials using asymmetric catalysis. The original de novo

approach by Sharpless and Masamune³was recently

taken up by McMillan (iterative aldol strategy)⁴and

us (both an Achmatowicz^ꢀ,5and an iterative dihydroxyl-

ation strategy^6–8). Herein, we present the full account of

our study of the diastereoselectivity in the second of the

sequential dihydroxylations, which in turn resulted in

the discovery of a concise route to several C-4-substi-

tuted sugars using the Sharpless dihydroxylation for

enantiocontrol. These studies resulted in a ﬁve-step syn-

thesis of glucono-, altrono-, and galactono-d-lactones,

2. Results and discussion

Because a bis-dihydroxylation installs a hydroxyl group

at every carbon atom, it appears to be an ideal method for

an eﬃcient carbohydrate synthesis (1a to 3a, Scheme 1).

There were, however, issuesassociatedwithregioselectivity

O

OH

AD- *

α

**

AD-

β

3a

EtO

89%

OBn

OH OBn

O

1a

2a

HO

O

OH OH

then

Py TsOH

C₆H₆

O

EtO

OBn

OH OH OBn

57%

in 2 steps

OH

3a

4a

*

α

AD- = 2% OsO₄, 2.1% (DHQ)₂PHAL, 3 eq K₃Fe(CN)₆, 3 eq K₂CO₃, 1 eq

**

= 10% OsO₄, 12% (DHQD)₂PHAL, 6

β

*

MeSO₂NH₂in 1:1 t-BuOH/H O; AD-

eq K₃Fe(CN)₆, 3 eq K₂CO₃, 3 eq NaHCO₃, 1 eq MeSO₂NH₂in 2:1 t-BuOH/H₂O

Corresponding author. Tel.: +1 304 293 3435x6444; fax: +1 800 293

4904; e-mail: George.ODoherty@mail.wvu.edu

2

^ꢀAn Achmatowicz reaction is the oxidative rearrangement of furyl

alcohols to 2-substituted 6-hydroxy-2H-pyran-3(6H)-ones. For its use

in de novo carbohydrate synthesis see Ref. 5.

Scheme 1. Enantio- and diastereoselective synthesis of galactono-c-

lactone.

doi:10.1016/j.carres.2006.03.024

1506

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

O

OH

O

OH OH

O

OH OH

OsO₄/L

EtO

or

X

R

OH

X

R

OH

X

R

5

6

7

X = H, F, OPMP

O

HO

Py TsOH

C₆H₆

O

6 or 7

or

R

X

8

X

9

Scheme 2. Diastereoselectivity studies of C-4 substituted-d-hydroxyenoate dihydroxylations.

(which double bond reacts ﬁrst), enantioselectivity (the

facial selectivity of the ﬁrst dihydroxylation) and double

diastereoselectivity (a balance between substrate and

catalyst stereocontrol) that needed to be addressed

before this concept could be put into practice.^9,10These

problems, as well as their ultimate solutions, came to light

from our continuing study of the Sharpless dihydroxyla-

tion of di- and tri-enoates.^11,12Thus, our successful

strategy, outlined below, is an iterative and highly stereo-

controlled oxidation of both double bonds in dienoate 1a,

which establishes all the stereocenters in galactono-c-

lactone 4a (Scheme 1).

At the outset, we had already known that following

the Sharpless protocol dienoates react with good regio-

and enantiocontrol to give 4,5-dihydroxyenoates. Thus,

exposing dienoate 1a to the typical Sharpless AD-mix

procedure (2% OsO₄, 2.1% (DHQ)₂PHAL, 3 equiv

K₃Fe(CN)₆/K₂CO₃, 1 equiv MeSO₂NH₂), diol 2a was

isolated in good yield (89%) and enantiomeric excess

(90% ee).^ꢁ,13Key to the success of this reaction sequence

is that the second double bond does not react under the

reaction conditions because of conﬂicting diastereo-

controlling issues (mismatching reagent and substrate

control). Consequently, when diol 2a is exposed to the

pseudo-enantiomeric reagent AD-b^**(10% OsO₄, 12%

(DHQD)₂PHAL, 6 equiv K₃Fe(CN)₆, 3 equiv NaHCO₃,

3 equiv K₂CO₃, and 1 equiv MeSO₂NH₂), a second

matched dihydroxylation reaction occurs. After lacton-

ization with pyridinium toluenesulfonate, galactono-c-

lactone 4a was isolated in good yield (Scheme 1, 57%).

A convenient outcome of performing two asymmetric

reactions in sequence is that for all practical purposes,

product 4a is formed in both enantiomerically and dia-

stereomerically pure form (>96% ee and de).^6b

(X = OPMP) and smaller (X = H) groups. Additionally,

we thought that the ﬂuoro-case (X = F) could help

delineate the eﬀect in terms of steric versus dipolar

eﬀects. We planned to prepare the C-4 substituted-d-

hydroxyenoate 5 by means of palladium p-allyl reaction

(Scheme 3).⁶Unfortunately, in the ﬂuoro case, the palla-

dium reaction failed, so we settled for the preparation of

a diastereomer via an inversion reaction (Scheme 4).

Upon applying the Sharpless AD mix-a conditions to

dienoates 1a–c, diols 2a–c were easily synthesized in

good yields (80–89%) and enantiomeric excess (80–

90% ee) (Scheme 3). Diols 2a–c were converted into cyc-

lic carbonates 10a–c (87–96% yield). Treatment of 10a–c

with a catalytic amount of palladium (0) source and

triphenylphosphine (1 mol % Pd(0)/PPh₃) and a mild

hydride source (3 equiv Et₃N/HCO₂H) gave the reduced

alcohols 11a–c in good yields (80–90%) and with no loss

of enantiomeric excess.^§,14

With the successful preparation of the reduced C-4-

deoxy-analogues 11a–c, we next investigated the use of

oxygen nucleophiles. While many alcohol nucleophiles

were investigated, only phenols gave products in good

yields and with excellent regio- and stereocontrol

(Scheme 3).¹⁵Thus, treatment of a CH₂Cl₂solution^–

of carbonates 10a–c with a catalytic amount of palla-

dium (0) (1 mol % Pd(0), 2 mol % PPh₃) and p-methoxy-

phenol as the nucleophile provided the protected

alcohols 12a–c in good yields (85–90%), with no loss

of enantiomeric excess.^k

Buoyed by the success of using phenols as nucleo-

philes in the palladium catalyzed p-allyl reaction, we

looked into the possibility of using ﬂuoride ion as a

nucleophile (10a to 13a, Scheme 4). Unfortunately, we

found that exposing 10a to various ﬂuoride sources

(TBAF, HF/Et₃N, HF/Pyridine, etc.) and catalytic pal-

ladium (1 mol %; 1:2 ratio of Pd/PPh₃) failed to produce

These results encouraged us to study the diastereo-

selectivity and the substrate versus reagent control that

occurs in the second dihydroxylation of various C-4

substituted-d-hydroxy enoates (e.g., 5 to 6 or 7, Scheme

2). We were interested in gauging the eﬀects of replacing

the C-4 hydroxyl group of diol 2 with both larger

^§It is interesting to note that the choice of THF as solvent for this

reaction is critical.¹⁴

^–In contrast to the reduction reaction (10 to 11), CH₂Cl₂was the

preferred solvent for these reactions.⁶

^kWe have found that this reaction works for various phenols; however,

simple alcohols (e.g., benzyl alcohol) did not participate in this

reaction.

^ꢁAll enantioexcesses were determined by examining the ¹H NMR and/

or ¹⁹F NMR of a corresponding Mosher ester.¹³

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

1507

O

OH OH

O

OH

2% OsO₄/NMO

t-BuOH/Acetone

(Cl₃CO)₂CO

Py/CH₂Cl₂

R

AD-α*

11a-c

EtO

10a-c

EtO

R

OH

R

16a: R = OBn; 95%; dr = 1:1

16b: R = CH₃; 90%; dr = 1:1

16c: R = H; 85%; dr = 1:1

1a; R= OBn

1b; R= CH₃

1c; R= H

2a; R= OBn, 89%, 90% ee

2b; R= CH₃, 84%, 85% ee

2c; R= H, 80%, 80% ee

O

OH OH

*

β

AD-

R

11a-c

O

OH

EtO

t-BuOH/H₂O

HCOOH/Et₃N

R

OH

0.5% Pd₂(DBA)₃CHCl₃

1% PPh₃

EtO

16a: R = OBn; 80%; dr = 14:1

16b: R = CH₃; 80%; dr = 10:1

16c: R = H; 81%; dr = 9:1

O

11a; R= OBn, 90%, 90% ee

11b; R= CH₃, 83%, 85% ee

11c; R= H, 80%, 80% ee

10a: R = OBn; 87%

10b: R = CH₃; 96%

10c: R = H; 90%

O

OH OH

*

α

AD-

t-BuOH/H₂O

R

11a-c

O

OH

R

EtO

H₃CO

OH

/ Et₃N

EtO

10a-c

17a: R = OBn; 80%; dr = 16:1

17b: R = CH₃; 86%; dr = 11:1

17c: R = H; 85%; dr = 10:1

0.5% Pd₂(DBA)₃CHCl₃

2% PPh₃

OPMP

12a; R= OBn, 90%, 90% ee

12b; R= CH₃, 90%, 85% ee

12c; R= H, 85%, 80% ee

*

β

AD- = 2% OsO₄, 2.1% (DHQD)₂PHAL, 3 eq K₃Fe(CN)₆,

3 eq K₂CO₃, 1eq MeSO₂NH₂

*

α

AD- = 2% OsO₄, 2.1% (DHQ)₂PHAL, 3 eq K₃Fe(CN)₆, 3 eq K₂CO₃,

1eq MeSO₂NH₂in 1:1 t-BuOH/H₂O

Scheme 5. Dihydroxylation of C-4-substituted-d-hydroxyenoates.

Scheme 3. Enantioselective synthesis of C-4-substituted-d-hydroxy-

enoates.

O

OH OH

O

OH

R

2% OsO₄/NMO

t-BuOH/Acetone

12a-c

EtO

OBn

Pd(0)/PPh₃

HF 3NEt₃

EtO

O

OH OPMP

10a

2a

X

F

18a: R = OBn; 82%; dr = 7:1

18b: R = CH₃; 80%; dr = 6:1

18c: R = H; 77%; dr = 6:1

13a

O

F F

NEt₂

O

OH OH

*

β

AD-

R

EtO

C₇H₁₆, 98

2 h, 70%

C

EtO

˚

t-BuOH/H₂O

F

14a

OBn

OH

OH OPMP

18a: R = OBn; 86%, dr = 25:1

18b: R = CH₃; 85%, dr = 20:1

18c: R = H; 83%, dr = 20:1

O

10% HCl

EtOH, 60%

14a

EtO

F

15a

OBn

*

β

AD- = 2% OsO₄, 2.1% (DHQD)₂PHAL, 3 eq K₃Fe(CN)₆,

3 eq K₂CO₃, 1eq MeSO₂NH₂

Scheme 4. Diastereoselective synthesis of C-4-ﬂuoro-d-hydroxyenoate

15a.

Scheme 6. Diastereoselective dihydroxylation of C-4 PMP-protected

d-hydroxyenoate.

13a. Typically, only a C-4 ketone product was isolated,

which could have been produced via a C-5 to C-4

hydride migration.

preparation of several sugar stereoisomers (Schemes 5–

7). Thus, when alcohols 11a–c were exposed to the achi-

ral Upjohn conditions (OsO₄/NMO), 1:1 mixtures of

16a–c were formed. In contrast, when alcohols 11a–c

were subjected to Sharpless asymmetric dihydroxylation

conditions (2% OsO₄and 2.1% (DHQD)₂PHAL), triols

16a–c were obtained in approximately 80% yield and

high diastereomeric ratios >9:1. Similarly, when alco-

hols 11a–c were subjected to pseudo-enantiomeric

Sharpless asymmetric dihydroxylation conditions (2%

OsO₄and 2.1% (DHQ)₂PHAL), the diastereomeric tri-

ols 16a–c were formed in approximately the same yields

and diastereoselectivity (ꢀ80% yield and >10:1 dr). As a

consequence of performing two asymmetric dihydroxyl-

ation reactions, the major diastereomers 16a–c and

17a–c were isolated in essentially enantiomerically pure

form (>96% ee).

In contrast, we could easily synthesize the diastereo-

mer of 13a (i.e., 15a) via a highly diastereoselective

inversion reaction (2a to 14a, then 15a). Thus, when diol

2a was subjected to N,N-diethyl-a,a-diﬂuoro(meta-

methylbenzyl)amine (DFMBA)¹⁶in heptane at 98 ꢁC

for 2 h, a C-4-ﬂuoro-d-benzoyloxyenoate 14a was

obtained in 70% yield with high diastereoselectivity.

Deprotection of the benzoyl group with 10% HCl in

EtOH aﬀorded C-4-ﬂuoro-d-hydroxy enoate 15a in

60% yield and with no loss of enantiomeric excess

(Scheme 4).^13,16

With ample supplies of several C-4-substituted-d-

hydroxy enoates (11a–c, 12a–c and 15a) in hand, we

next examined the possibility of a diastereoselective

dihydroxylation on the second double bond for the

1508

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

Not surprisingly, the strong substrate diastereocontrol

O

OH OH

2% OsO₄/NMO

associated with the second dihydroxylation reaction was

abated with the removal of the C-4 hydroxyl group.

Thus, triols 16a–c were formed with a minor diastereo-

mer (ent-17a–c), where the formation of ent-17a–c came

primarily from the minor enantiomer present in 11a–c

(ent-11a–c). Once these minor diastereomers were

removed by silica gel chromatography, triols 16a–c were

obtained in both diastereomerically and enantiomeri-

cally pure form (Scheme 5).

In contrast, the substrate control in the second

dihydroxylation was increased when the C-4 hydroxyl

group was converted into a PMP ether (Scheme 6).

Thus, exposure of 12a–c to the Upjohn conditions pro-

vided 18a–c in improved diastereomeric ratios (>6:1)

and yields (>77%). As with 2a, PMP-ethers 12a–c

reacted in a diastereomerically matched sense with the

OsO₄/(DHQD)₂PHAL reagent system producing triol

products 18a–c in exceedingly high diastereomeric ratios

(>20:1) and good yields (83–86%). As before, the triols,

which were produced from this matched dihydroxyl-

ation sequence, were isolated in nearly enantiomerically

pure form (Scheme 6).^ꢀꢀ,10Not surprisingly, when 12a–c

were dihydroxylated with the mismatched reagent sys-

tem OsO₄/(DHQ)₂PHAL, poor ratios of triol products

were produced.

While we were not able to prepare the directly compa-

rable C-4 ﬂuoride 13a, we were able to prepare anti-dia-

stereomer 15a. It has been previously shown that the

corresponding C-4/C-5 anti-diols exhibit poor diastereo-

control in the achiral dihydroxylation reaction.¹⁷In con-

trast to those anti-diols, much greater diastereocontrol

was observed. When the 4-ﬂuoro-d-hydroxyenoate 15a

was subjected to the typical Upjohn procedure, they re-

acted with achiral OsO₄to aﬀord triol 19a in 5:1 diaste-

reomeric ratio and good yield (90%). Once again, the

substrate/reagent matched eﬀect can be seen; when C-

4-ﬂuoro-d-hydroxy enoate 15a was subjected to Sharp-

less asymmetric dihydroxylation reactions using the

matched reagent system (2% OsO₄and 2.1%

(DHQ)₂PHAL), triol 19a was obtained in good yield

(86%) and increased 7:1 dr. However, when the mis-

matched reagent system (2% OsO₄and 2.1%

(DHQD)₂PHAL) was used, triol 20a was isolated in

good yield (85%) but low diastereomeric ratio (2:1)

(Scheme 7).^ꢁꢁ

15a

EtO

t-BuOH/Acetone

90%

OH

F

OBn

19a, dr = 5:1

O

OH OH

*

α

AD-

15a

+ 20a

matched

EtO

86%

OH

19a, dr = 7:1

F

OBn

O

OH OH

β

AD-

+ 19a

mis-matched

85%

OH

20a, dr = 2:1

F

OBn

Scheme 7. Diastereoselective dihydroxylation of 4-ﬂuoro-d-hydroxy-

enoates.

O

OH OH

HO

O

R

Py TsOH

C₆H₆

EtO

R

OH

16a-c

21a: R = OBn; 95%

21b: R = CH₃; 80%

21c: R = H; 80%

O

OH OH

HO

O

Py TsOH

C₆H₆

R

O

EtO

R

HO

OH

17a-c

22a: R = OBn; 95%

22b: R = CH₃; 80%

22c: R = H; 83%

O

HO

AcO

O

Py TsOH

C₆H₆

Ac₂O/Py

18a-c

R

AcO

OPMP

24a: R = OBn; 95%

24b: R = CH₃; 94%

24c: R = H; 90%

23a: R = OBn; 85%

23b: R = CH₃; 86%

23c: R = H; 80%

O

AcO

HO

Py TsOH

Ac₂O/Py

95%

O

19a

C₆H_6,90%

OBn

HO

F

26a

F

25a

Scheme 8. Synthesis of C-4-substituted-glucono-, galactono-, and

altrono-d-lactone.

To assign the relative stereochemistry of the dihydr-

oxylation products (16–19, Scheme 8), the major diaste-

reomers were converted to the corresponding lactones

and the relevant ¹H NMR coupling constants were mea-

sured. This was easily accomplished with mild acid.

Thus, triols 16a–c were converted to lactones 21a–c in

excellent yields (80–95%) upon treatment with 5% pyrid-

inium toluenesulfonate in benzene. As with 4-deoxy-

gluconolactones 21a–c, the stereochemistry of 22a–c

was easily assigned from analysis of the relevant

¹H–¹H coupling constants.

Similarly, when triols 18a–c were treated under identi-

cal conditions, galactonolactones 23a–c were produced

in 80–86% yield. At this stage, the relative stereochemis-

^ꢀꢀFor a discussion of the use of the Sharpless AD-mix reagent in a

matched/mismatched case, see Refs. 9 and 10.

^ꢁꢁIt is interesting to note that when 15a reacts with mismatched OsO₄/

(DHQD)₂PHAL reagent, the reagent controls the stereoselectivity

for the major isomer.

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

1509

O

27a was isolated as the major isomer in good yield (80%)

and diastereoselectivity (dr = 6:1). Similarly, the mis-

matched reagent system (2% OsO₄and 2.1% (DHQD)₂-

PHAL) produces diol 28a in equally good yield (80%)

but lower diastereoselectivity (dr = 3:1) (Scheme 9).

To assign the stereochemistry of the dihydroxylation

products, the C-5 m-cresyl ester of 27a was deprotected

with 10% HCl in ethanol, which aﬀorded triol 19a in

75% yield. Subsequent conversion to the corresponding

lactone 25a was achieved in excellent yield (90%).

O

OH O

2% OsO₄/NMO

14a

+ 28a

t-BuOH/Acetone EtO

90%

OH

F

OBn

27a, dr = 5:1

O

OH O

*

α

80%

AD-

14a

+ 28a

matched

EtO

OH

F

OBn

27a, dr = 6:1

O

OH

O

3. Conclusion

*

+ 27a

mis-matched

β

AD-

14a

80%

OH

F

OBn

In summary, a highly enantio- and diastereoselective

procedure for the preparation of various C-4 and C-6

substituted sugar d-lactones has been developed. Our

strategy for the synthesis of either enantiomer of these

sugars provides rapid and practical access to important

sugars, which should be of use for further oligosaccha-

ride synthesis. Critical to the success of this approach

was the unique use of a regio- and stereospeciﬁc palla-

dium p-allyl reaction for alcohol diﬀerentiation and pro-

tection. When the palladium p-allyl reaction was used

for a reduction, an even more ﬂexible procedure resulted

in the syntheses of 4-deoxysugars. In addition, the

synthesis of 4-deoxy-4-ﬂuoro-altrono-d-lactone was

achieved. Finally, by selecting the order in which the

Sharpless reagents were used, both ^D- and L-sugars were

produced.

28a, dr = 3:1

O

HO

Py TsOH

10 % HCl

O

19a

27a

C₆H_6,90%

EtOH, 75%

OBn

F

25a

Scheme 9. Diastereoselective dihydroxylation of 4-ﬂuoro-d-benzoyl-

oxyenoates.

try could be assigned by analysis of ¹H–¹H-coupling

constants.^§§This was easily accomplished on the diace-

tates 24a–c, which were readily prepared using acetic

anhydride and pyridine in 90–95% yield (Scheme 8).

When triol 19a was treated with 5% pyridinium toluene-

sulfonate in benzene, altronolactone 25a was produced

in 90% yield. At this stage, the relative stereochemistry

could be assigned by analysis of H–¹H-coupling con-

1

4. Experimental

stants.^––This was easily accomplished on diacetate

26a, which was readily prepared using acetic anhydride

and pyridine in 95% yield (Scheme 8).

4.1. General methods and materials

Finally, we also investigated the diastereoselective

dihydroxylation of 4-ﬂuoro-d-benzoyloxy enoate 14a.

Unfortunately, no improvement in diastereoselectivity

was observed. Thus, when 4-ﬂuoro-d-benzoyloxy enoate

14a subjected to the typical Upjohn procedure, triol 27a

in 5:1 diastereomeric ratio was produced in good yield

(90%). The substrate/reagent matched/mismatched

eﬀect was also observed when 4-ﬂuoro-d-benzoyloxy

enoate 14a was subjected to Sharpless asymmetric

dihydroxylation. Thus, when the matched reagent sys-

tem (2% OsO₄and 2.1% (DHQ)₂PHAL) was used, diol

¹H and ¹³C NMR spectra were recorded on Jeol

(270 MHz) and Varian VXR-600 (600 MHz) spectro-

meters. Chemical shifts are reported relative to internal

1

(CH₃)₄Si (d 0.00 ppm) or CDCl₃(d 7.26 ppm) for H

spectra and CDCl₃(d 77.0 ppm) for ¹³C spectra. Infra-

red (IR) spectra were obtained on a Prospect MIDAC

FT-IR spectrometer. Optical rotations were measured

with a Jasco DIP-370 digital polarimeter in the solvent

speciﬁed. Melting points were determined with Electro-

thermal Mel-Temp apparatus and are uncorrected.

Flash column chromatography was performed on ICN

reagent 60 (60–200 mesh) silica gel. Analytical thin-layer

chromatography was performed with precoated glass-

^§§Particularly revealing coupling constants were those between the two

axial protons at C-2 and C-3 (e.g., for 24a, J_2,3= 10.2 Hz) and

between the equatorial proton at C-4 and the two axial protons at C-

3 and C-5 (e.g., for 24a, J_3,4= 2.4 Hz and J_4,5= 1.4 Hz).

^––Particularly revealing coupling constants were those between the two

axial protons at C-2 and C-3 (e.g., for 26a, J_2,3= 10.2 Hz) and

between the equatorial proton at C-4 and the two protons (e.g. axial

at C-3 and equatorial at C-5; for 26a, J_3,4= 2.4 Hz and

J_4,5= 2.4 Hz).

˚

backed plates (Whatman K6F 60 A, F₂₅₄) and visualized

by quenching of ﬂuorescence and by charring after treat-

ment with p-anisaldehyde or phosphomolybdic acid or

potassium permanganate stain. R_fvalues were obtained

by elution in the stated solvent ratios (v/v). Ether, THF,

CH₂Cl₂, and Et₃N were dried by passing through an

activated alumina column with argon gas pressure.

1510

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

Commercial reagents were used without puriﬁcation

unless otherwise noted. Melting points are uncorrected.

Air and/or moisture-sensitive reactions were carried

out under an atmosphere of argon/nitrogen using

oven-dried glassware and standard syringe/septa

techniques.

orously at 0 ꢁC for 4 h. The reaction was quenched by

the addition of solid sodium sulﬁte (100 mg) at rt. Then

the mixture was ﬁltered through a pad of Celite/Florisil

and eluted with 20 mL of 50% EtOAc/CH₃OH. The

combined organic layers were dried over anhydrous

sodium sulfate. The solvent was removed under reduced

pressure and replaced with benzene (2 mL) and CH₃OH

(2 mL). To this solution was added pyridinium toluene-

sulfonate (16 mg, 0.07 mmol, 10 mol %) and the mixture

was heated at reﬂux for 3 h. The reaction was cooled to

rt and after removal of the solvents in vacuo, ﬂash chro-

matography on silica gel (3:7, hexanes/EtOAc) aﬀorded

4a as a viscous oil (108 mg, 57%); R_f(10% CH₃OH/

EtOAc) = 0.53; ½aꢁ²_D⁵29.3 (c 1.0, CH₃OH); IR (thin ﬁlm):

3396, 2928, 2874, 1779, 1455, 1366, 1316, 1215, 1179,

4.2. (E,4S,5S)-Ethyl 6-(benzyloxy)-4,5-dihydroxyhex-2-

enoate (2a)

Into a 250 mL round bottomed ﬂask were added 60 mL

of t-BuOH, 60 mL of water, K₃Fe(CN)₆(24.7 g,

75 mmol), K₂CO₃(10.35 g, 75 mmol), MeSO₂NH₂

(2.37 g, 25 mmol), (DHQ)₂PHAL (409 mg, 0.52 mmol,

2.1 mol %), and OsO₄(127 mg, 0.5 mmol, 2 mol %).

The mixture was stirred at rt for about 15 min and then

cooled to 0 ꢁC. To this solution was added (2E,4E)-ethyl

6-(benzyloxy)hexa-2,4-dienoate 1a (6.15 g, 25 mmol),

and the reaction was stirred vigorously at 0 ꢁC over-

night. The reaction was quenched by the addition of

solid sodium sulﬁte (300 mg) at rt. EtOAc (40 mL) was

added to the reaction mixture and after separation of

the layers, the aqueous phase was further extracted with

the organic solvent (2 · 30 mL). The combined organic

layers were washed with brine and dried over anhydrous

sodium sulfate. After removal of the solvents in vacuo,

ﬂash chromatography on silica gel (7:3, hexanes/EtOAc)

aﬀorded 6.23 g (89% yield) of 2a as a light yellow oil; R_f

1092, 1027, 978, 905 cm^ꢂ^{1 1}H NMR (CD₃OD, 600

;

MHz): d 7.27 (m, 5H), 4.48 (br s, 2H), 4.40 (d, J =

8.4 Hz, 1H), 4.37 (dd, J = 8.4, 7.8 Hz, 1H), 4.15 (dd,

J = 7.8, 2.4 Hz, 1H), 3.99 (ddd, J = 6.6, 6, 2.4 Hz,

1H), 3.57 (dd, J = 9.6, 6.6 Hz, 1H), 3.52 (dd, J = 9.6,

6 Hz, 1H), 3.54 (br s, 3H); ¹³C NMR (CD₃OD, 150

MHz): d 176.3, 139.6, 129.5 (2C), 129.0, 128.8 (2C),

81.6, 75.8, 74.5 (2C), 71.9, 68.6; CIMS calculated for

[C₁₃H₁₆O₆+Na]⁺: 291.0845. Found: 291.0875.

4.4. (E)-Ethyl 3-((4S,5S)-5-((benzyloxy)methyl)-2-oxo-

1,3-dioxolan-4-yl)acrylate (10a)

25

(30% EtOAc/hexanes) = 0.13; ½aꢁ_Dꢂ20.4 (c 1.1,

Into a 250 mL round-bottomed ﬂask was placed 6.5 g

(23.2 mmol) of 2a in 25 mL of CH₂Cl₂and 10 mL

(116 mmol) of pyridine. The solution was cooled to

0 ꢁC and 7.6 g (25.6 mmol) of triphosgene in 50 mL of

CH₂Cl₂was added slowly with an addition funnel.

The reaction was stirred for 1.5 h and quenched by the

addition of saturated aqueous NH₄Cl (40 mL). The lay-

ers were separated and the aqueous layer was extracted

with ether (3 · 50 mL). The combined organic layers

were washed with saturated aqueous sodium bicarbon-

ate (30 mL), brine (25 mL), and dried over anhydrous

sodium sulfate. After removal of the solvents in vacuo,

ﬂash chromatography on silica gel (7:3, hexanes/EtOAc)

aﬀorded 10a as a clear, colorless oil (6.17 g, 87%); R_f

CH₂Cl₂); IR (thin ﬁlm): 3421, 2985, 2937, 2871, 1715,

1699, 1659, 1455, 1393, 1279, 1179, 1039, 984 cm^ꢂ1

;

¹H NMR (CDCl₃, 270 MHz): d 7.33 (m, 5H), 6.91

(dd, J = 15.6, 4.6 Hz, 1H), 6.14 (dd, J = 15.6, 1.8 Hz,

1H), 4.58 (d, J = 11.8 Hz, 1H), 4.53 (d, J = 11.8 Hz,

1H), 4.38 (ddd, J = 9.1, 4.6, 1.8 Hz, 1H), 4.19 (q, J =

7.1 Hz, 2H), 3.76 (ddd, J = 9.7, 5.5, 4.6 Hz, 1H), 3.65

(dd, J = 9.7, 3.9 Hz, 1H), 3.59 (dd, J = 9.7, 5.5 Hz,

1H), 2.92 (d, J = 4.7 Hz, 1H), 2.70 (d, J = 5.9 Hz, 1H),

1.28 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 67.5

MHz): d 166.2, 146.0, 137.3, 128.5 (2C), 127.9, 127.8

(2C), 122.4, 73.7, 72.1, 71.7, 71.4, 60.5, 14.1; GCMS:

280 [M]⁺.

25

(30% EtOAc/hexanes) = 0.37; ½aꢁ_Dꢂ54.7 (c 1.0,

4.3. (3S,4S,5R)-5-(2⁰-Benzyloxy-(1⁰S)-1⁰-hydroxyethyl)-

3,4-dihydroxy-dihydrofuran-2(3H)-one (4a)

CH₂Cl₂); IR (thin ﬁlm): 2983, 2938, 2908, 2872, 1806,

1721, 1665, 1496, 1454, 1369, 1304, 1272, 1174, 1111,

1

1032, 978 cm^ꢂ1; H NMR (CDCl₃, 600 MHz): d 7.34

Into a 50 mL round bottomed ﬂask were added 4 mL of

t-BuOH, 2 mL of water, K₃Fe(CN)₆(1.41 g, 4.2 mmol),

K₂CO₃(296 mg, 2.1 mmol), NaHCO₃(180 mg, 2.1

mmol), MeSO₂NH₂(68 mg, 0.71 mmol), (DHQD)₂-

PHAL (66 mg, 0.08 mmol, 12 mol %), and OsO₄

(18 mg, 0.07 mmol, 10 mol %). The mixture was stirred

at rt for about 15 min and then cooled to 0 ꢁC. To this

solution was added a solution of (E,4S,5S)-ethyl 6-(benz-

yloxy)-4,5-dihydroxyhex-2-enoate 2a (200 mg, 0.71

mmol) in 1 mL CH₂Cl₂and the reaction was stirred vig-

(m, 5H), 6.83 (dd, J = 15.6, 5.4 Hz, 1H), 6.14 (dd,

J = 15.6, 1.4 Hz, 1H), 5.17 (ddd, J = 6.6, 5.4, 1.2 Hz,

1H), 4.64 (d, J = 12 Hz, 1H), 4.58 (d, J = 12 Hz, 1H),

4.46 (ddd, J = 6.6, 3.6, 3.6 Hz, 1H), 4.24 (q,

J = 7.2 Hz, 2H), 3.75 (dd, J = 11.4, 3.6 Hz, 1H), 3.66

(dd, J = 11.4, 3.6 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H);

¹³C NMR (CDCl₃, 67.5 MHz): d 164.9, 153.5, 139.7,

136.7, 128.5 (2C), 128.1, 127.7 (2C), 124.5, 79.3, 76.4,

73.7, 67.7, 61.0, 14.1; CIMS calculated for

[C₁₆H₁₈O₆+Na]⁺: 329.1001. Found: 329.1003.

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

1511

4.5. (R,E)-Ethyl 6-(benzyloxy)-5-hydroxyhex-2-enoate

(11a)

mmol), K₂CO₃(2.07 g, 15 mmol), MeSO₂NH₂(475

mg, 5 mmol), (DHQD)₂PHAL (85 mg, 0.1 mmol,

2.1 mol %), and OsO₄(25.4 mg, 0.1 mmol, 2 mol %).

The mixture was stirred at rt for about 15 min and then

cooled to 0 ꢁC. To this solution was added 11a (1.32 g,

5 mmol) and the reaction was stirred vigorously at

0 ꢁC overnight. The reaction was quenched by the addi-

tion of solid sodium sulﬁte (100 mg) at rt and stirred for

15 min. Then the mixture was ﬁltered through a pad of

Celite/Florisil and eluted with 50 mL of 50% EtOAc/

CH₃OH. The combined organic layers were dried over

anhydrous sodium sulfate. After removal of the solvents

in vacuo, ﬂash chromatography on silica gel (3:7, hex-

anes/EtOAc) aﬀorded 1.19 g of 16a as a viscous oil

(14:1 dr, 80% yield). Major isomer: R_f(100% EtOAc) =

Into a 100 mL, round bottomed ﬂask ﬁtted with a con-

denser and maintained under nitrogen were placed 3 g

(9.8 mmol) of 10a, 50.7 mg (0.05 mmol, 0.5 mol %) of

Pd₂(DBA)₃ÆCHCl₃, 26 mg (0.1 mmol, 1 mol %) of

PPh₃, and 20 mL of THF. Et₃N (4 mL, 29.4 mmol)

and HCO₂H (0.902 mg, 19.6 mmol) were added and

the mixture was heated at reﬂux for 30 min. The reac-

tion was cooled to rt and quenched by the addition of

saturated aqueous sodium bicarbonate (20 mL). The

aqueous layer was extracted with ether (3 · 30 mL).

The organic layer was washed with brine (20 mL) and

dried with anhydrous sodium sulfate. After removal of

the solvents in vacuo, ﬂash chromatography on silica

gel (7:3, hexanes/EtOAc) aﬀorded 11a as a yellow oil

(2.32 g, 90%). Mosher ester analysis of this alcohol

25

0.44; ½aꢁ_D11.7 (c 2.0, CH₂Cl₂); IR (thin ﬁlm): 3470,

2982, 2953, 2927, 2867, 1732, 1454, 1396, 1370, 1299,

1260, 1212, 1096, 1027 cm^ꢂ1

;

¹H NMR (CDCl₃,

25

shows 90% ee; R_f(30% EtOAc/hexanes) = 0.32; ½aꢁ_D

600 MHz): d 7.32 (m, 5H), 4.56 (s, 2H), 4.31–4.21 (m,

3H), 4.13 (m, 1H), 4.08 (dd, J = 6, 1.8 Hz, 1H), 3.52

(dd, J = 9.6, 3.6 Hz, 1H), 3.42 (dd, J = 9.6, 7.2 Hz,

1H), 3.27 (br s, 1H), 2.77 (br s, 1H), 1.81 (ddd, J =

14.4, 9.6, 3 Hz, 1H), 1.68 (br s, 1H), 1.67 (ddd, J =

14.4, 9.6, 3.6 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); ¹³C

NMR (CDCl₃, 67.5 MHz): d 173.2, 137.7, 128.4 (2C),

127.8, 127.7 (2C), 74.4, 73.9, 73.3, 69.3, 67.4, 61.9,

36.5, 14.1; GCMS: 298 [M⁺], 281 [M⁺ꢂOH], 253

[M⁺ꢂOEt].

ꢂ3.2 (c 1.0, CH₂Cl₂); IR (thin ﬁlm): 3472, 2981, 2934,

2903, 2867, 1715, 1653, 1454, 1392, 1368, 1319, 1269,

1

1207, 1166, 1096, 1042, 982 cm^ꢂ1; H NMR (CDCl₃,

270 MHz): d 7.34 (m, 5H), 6.96 (ddd, J = 15.6, 7.2,

7.2 Hz, 1H), 5.89 (ddd, J = 15.6, 1.3, 1.3 Hz, 1H), 4.55

(s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.96 (m, 1H), 3.52

(dd, J = 9.5, 3.3 Hz, 1H), 3.38 (dd, J = 9.5, 7.1 Hz,

1H), 2.42–2.39 (m, 2H), 2.38 (d, J = 1.5 Hz, 1H), 1.28

(t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 67.5 MHz): d

166.1, 144.5, 137.6, 128.2 (2C), 127.6, 127.5 (2C),

123.4, 73.5, 73.1, 68.9, 60.0, 36.0, 14.0; GCMS: 264

[M⁺], 191 [M⁺ꢂCO₂Et].

4.8. (3S,4R,6R)-6-((Benzyloxy)methyl)-tetrahydro-3,4-

dihydroxypyran-2-one (21a)

4.6. (2S,3R,5R)-Ethyl 6-(benzyloxy)-2,3,5-trihydroxy-

hexanoate (16a)

To a solution of 16a (150 mg, 0.50 mmol) in benzene

(3 mL) was added pyridinium toluenesulfonate (6 mg,

0.03 mmol, 5 mol %), and the mixture was heated at re-

ﬂux for 5 h. The reaction was cooled to rt and quenched

by the addition of saturated aqueous sodium bicarbon-

ate (2 mL). The aqueous layer was extracted with ether

(3 · 20 mL). The organic layer was washed with brine

(10 mL) and dried with anhydrous sodium sulfate. After

removal of the solvents in vacuo, ﬂash chromatography

on silica gel (4:6, hexanes/EtOAc) aﬀorded 21a as a vis-

Into a 25 mL round bottomed ﬂask was added 11a

(132 mg, 0.5 mmol) followed by 1 mL of t-BuOH and

1 mL of acetone, and then the solution was cooled to

0 ꢁC. To this solution 0.35 mL of 50% NMO in H₂O

(1.5 mmol) and OsO₄(2.5 mg, 0.01 mmol, 2 mol %)

were added, and the reaction was stirred vigorously at

0 ꢁC overnight. The reaction was quenched by the addi-

tion of solid sodium sulﬁte (100 mg) at rt. Then the mix-

ture was ﬁltered through a pad of Celite/Florisil and

eluted with 20 mL of 50% EtOAc/CH₃OH. The com-

bined organic layers were dried over anhydrous sodium

sulfate. After removal of the solvents in vacuo, ﬂash

chromatography on silica gel (3:7 (v/v), hexanes/

EtOAc) aﬀorded 16a/17a as a viscous oil (141 mg, 1:1

dr, 95% yield).

25

cous oil (118 mg, 95%). R_f(100% EtOAc) = 0.33; ½aꢁ_D

ꢂ9.4 (c 1, CH₂Cl₂); IR (thin ﬁlm): 3420, 2927, 2921,

2869, 1740, 1453, 1367, 1231, 1177, 1096, 1026,

923 cm^ꢂ^{1 1}H NMR (CDCl₃, 270 MHz): d 7.32 (m,

;

5H), 4.56 (s, 2H), 4.49 (dddd, J = 10.6, 7.9, 3.9,

3.7 Hz, 1H), 4.04 (dd, J = 10.9, 3.9 Hz, 1H), 3.99 (d,

J = 10.9 Hz, 1H), 3.65 (dd, J = 10.6, 3.9 Hz, 1H), 3.57

(dd, J = 10.6, 4.1 Hz, 1H), 3.33 (br s, 1H), 2.76 (br s,

1H), 2.28 (ddd, J = 12.4, 4.1, 3.9 Hz, 1H), 2.11 (ddd,

J = 12.4, 10.6, 2.4 Hz, 1H); ¹³C NMR (CDCl₃,

67.5 MHz): d 172.8, 137.4, 128.5 (2C), 127.9, 127.7

(2C), 76.8, 74.1, 73.5, 71.1, 68.7, 32.1; GCMS: 252

[M⁺], 145 [M⁺ꢂOBn].

4.7. (2S,3R,5R)-Ethyl 6-(benzyloxy)-2,3,5-trihydroxy-

hexanoate (16a)

Into a 50 mL round bottomed ﬂask were added 10 mL

of t-BuOH, 10 mL of water, K₃Fe(CN)₆(4.93 g, 15

1512

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

4.9. (2R,3S,5R)-Ethyl 6-(benzyloxy)-2,3,5-trihydroxy-

hexanoate (17a)

4.2 Hz, 1H), 3.63 (d, J = 4.8 Hz, 1H), 2.29 (ddd,

J = 14.4, 9.6, 8.4 Hz, 1H), 1.99 (ddd, J = 14.4, 4.8,

4.2 Hz, 1H), 1.59 (br s, 1H); ¹³C NMR (CDCl₃,

67.5 MHz): d 173.3, 137.3, 128.5 (2C), 127.9, 127.7

(2C), 74.7, 73.6, 73.2, 71.0, 68.8, 32.7; GCMS: 252

[M⁺], 145 [M⁺ꢂOBn].

Into a 50 mL round bottomed ﬂask was added 10 mL of

t-BuOH, 10 mL of water, K₃Fe(CN)₆(4.93 g, 15 mmol),

K₂CO₃(2.07 g, 15 mmol), MeSO₂NH₂(475 mg,

5 mmol), (DHQ)₂PHAL (85 mg, 0.1 mmol, 2.1 mol %),

and OsO₄(25.4 mg, 0.1 mmol, 2 mol %). The mixture

was stirred at rt for about 15 min and then cooled to

0 ꢁC. To this solution was added 11a (1.32 g, 5 mmol),

and the reaction was stirred vigorously at 0 ꢁC over-

night. The reaction was quenched by the addition of

solid sodium sulﬁte (100 mg) at rt and stirred for 15 min.

Then the mixture was ﬁltered through a pad of Celite/

Florisil and eluted with 50 mL of 50% EtOAc/CH₃OH.

The combined organic layers were dried over anhydrous

sodium sulfate. After removal of the solvents in vacuo,

ﬂash chromatography on silica gel (2:8, hexanes/EtOAc)

aﬀorded 1.19 g of 17a as a viscous oil (16:1 dr, 80%

4.11. (E,4S,5S)-Ethyl 4,5-dihydroxyhept-2-enoate (2b)

Following the same procedure as described for com-

pound 2a (see Section 4.2), 2b was produced (1.18 g,

6.3 mmol) in 84% yield from 1b (1.15 g, 7.4 mmol) as a

25

viscous oil. R_f(30% EtOAc/hexane) = 0.26; ½aꢁ_Dꢂ14.0

(c 1.2, CH₂Cl₂); IR (thin ﬁlm): 3433, 2989, 2980, 2976,

2934, 2875, 1718, 1701, 1697, 1655, 1462, 1448, 1369,

1306, 1275, 1178, 1132, 1095, 1040, 976 cm^ꢂ^{1 1}H

;

NMR (CDCl₃, 600 MHz): d 6.93 (dd, J = 15.6, 4.8 Hz,

1H), 6.13 (dd, J = 15.6, 1.2 Hz, 1H), 4.20 (q,

J = 7.2 Hz, 2H), 4.14 (dddd, J = 10.2, 5.4, 1.8, 1.8 Hz,

1H), 3.48 (ddd, J = 9.6, 7.2, 4.8 Hz, 1H), 2.73 (d,

J = 4.8 Hz, 1H), 2.40 (d, J = 4.2 Hz, 1H), 1.62 (dqd,

J = 15, 7.2, 4.2 Hz, 1H), 1.51 (dqd, J = 15, 7.2, 3.6 Hz,

1H), 1.28 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H);

¹³C NMR (CDCl₃, 150 MHz): d 166.4, 146.9, 122.3,

75.3, 73.7, 60.5, 25.9, 14.1, 9.9; CIMS calculated for

[C₉H₁₆O₄+Na]⁺: 211.0940. Found: 211.0943.

25

yield). Major isomer: R_f(100% EtOAc) = 0.44; ½aꢁ_D

ꢂ7.4 (c 1.3, CH₂Cl₂); IR (thin ﬁlm): 3470, 2982, 2953,

2927, 2867, 1732, 1454, 1396, 1370, 1299, 1260, 1212,

1

1096, 1027 cm^ꢂ1; H NMR (CDCl₃, 270 MHz): d 7.33

(m, 5H), 4.56 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.24–

4.09 (m, 2H), 4.05 (dd, J = 7.3, 1.8 Hz, 1H), 3.49 (dd,

J = 9.5, 3.6 Hz, 1H), 3.40 (dd, J = 9.5, 7.1 Hz, 1H),

3.32 (d, J = 7.1 Hz, 1H), 3.13 (d, J = 2.7 Hz, 1H), 3.07

(br s, 1H), 1.84 (ddd, J = 14.4, 5.9, 3.7 Hz, 1H), 1.69

(ddd, J = 14.4, 3.3, 3.1 Hz, 1H), 1.28 (t, J = 7.1 Hz,

3H); ¹³C NMR (CDCl₃, 67.5 MHz): d 172.9, 137.6,

128.5 (2C), 127.9, 127.8 (2C), 74.1, 73.6, 73.4, 71.9,

70.1, 61.9, 35.8, 14.1; GCMS: 298 [M⁺], 281

[M⁺ꢂOH], 253 [M⁺ꢂOEt].

4.12. (E)-Ethyl 3-((4S,5S)-5-ethyl-2-oxo-1,3-dioxolan-4-

yl)acrylate (10b)

Following the same procedure as described for com-

pound 10a (see Section 4.4), 10b was produced (1.09 g,

5.1 mmol) in 96% yield from 2b (1 g, 5.3 mmol) as a vis-

25

cous oil. R_f(30% EtOAc/hexane) = 0.54; ½aꢁ_Dꢂ31.6 (c

4.10. (3R,4S,6R)-6-((Benzyloxy)methyl)-tetrahydro-3,4-

dihydroxypyran-2-one (22a)

1.5, CH₂Cl₂); IR (thin ﬁlm): 2996, 2987, 2982, 2969,

2938, 1811, 1724, 1666, 1465, 1368, 1343, 1306, 1271,

1183, 1105, 1044, 980 cm^ꢂ1

;

¹H NMR (CDCl₃,

To a solution of (2R,3S,5R)-ethyl 6-(benzyloxy)-2,3,5-

trihydroxyhexanoate 17a (150 mg, 0.50 mmol) in benz-

ene (3 mL) was added pyridinium toluenesulfonate

(6 mg, 0.03 mmol, 5 mol %), and the mixture was heated

at reﬂux for 5 h. The reaction was cooled to rt and

quenched by the addition of saturated aqueous sodium

bicarbonate (2 mL). The aqueous layer was extracted

with ether (3 · 10 mL). The organic layer was washed

with brine (10 mL) and dried with anhydrous sodium

sulfate. After removal of the solvents in vacuo, ﬂash

chromatography on silica gel (4:6, hexanes/EtOAc)

aﬀorded 22a as colorless crystals (118 mg, 95%). R_f

600 MHz): d 6.83 (dd, J = 15.6, 5.4 Hz, 1H), 6.18 (dd,

J = 15.6, 1.8 Hz, 1H), 4.82 (ddd, J = 7.2, 5.4, 1.2 Hz,

1H), 4.31 (ddd, J = 7.2, 7.2, 5.4 Hz, 1H), 4.22 (q,

J = 7.2 Hz, 2H), 1.86 (dq, J = 15, 7.2 Hz, 1H), 1.81

(dqd, J = 15, 7.2, 1.8 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H),

1.06 (t, J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃, 150 MHz):

d 164.9, 153.5, 139.3, 124.8, 82.3, 79.4, 61.1, 26.3, 14.1,

8.7; CIMS calculated for [C₁₀H₁₄O₅+Na]⁺: 237.0733.

Found: 237.0735.

4.13. (S,E)-Ethyl 5-hydroxyhept-2-enoate (11b)

25

(100% EtOAc) = 0.33; ½aꢁ_Dꢂ14.9 (c 0.7, CH₂Cl₂); mp

Following the same procedure as described for com-

pound 11a (see Section 4.5), 11b was produced

(135 mg, 0.76 mmol) in 84% yield from 10b (200 mg,

0.93 mmol) as a viscous oil. Mosher ester analysis of this

alcohol shows 85% ee; R_f(30% EtOAc/hexane) = 0.29;

57–58 ꢁC; IR (thin ﬁlm): 3420, 2924, 2860, 1747, 1454,

1367, 1328, 1242, 1208, 1126, 1096, 1027, 923 cm^ꢂ1

;

¹H NMR (CDCl₃, 600 MHz): d 7.35 (m, 5H), 4.74

(ddd, J = 9.0, 8.4, 4.8 Hz, 1H), 4.58 (s, 2H), 4.25 (d,

J = 7.8 Hz, 1H), 4.08 (ddd, J = 8.4, 7.8, 4.8 Hz, 1H),

3.69 (dd, J = 9.0, 4.8 Hz, 1H), 3.67 (dd, J = 9.0,

25

½aꢁ_D8.7 (c 1, CH₂Cl₂); IR (thin ﬁlm): 3434, 2973,

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

1513

2933, 2878, 1719, 1654, 1463, 1393, 1369, 1316, 1270,

14:1 dr) in 86% yield from 11b (50 mg, 0.29 mmol) as

a viscous oil. Major isomer: R_f(100% EtOAc/hex-

1

1211, 1171, 1113, 1044, 978 cm^ꢂ1; H NMR (CDCl₃,

25

600 MHz): d 6.95 (ddd, J = 15.6, 7.8, 7.2 Hz, 1H), 5.87

(dd, J = 15.6, 1.2 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H),

3.65 (dddd, J = 7.2, 6.6, 5.4, 4.8 Hz, 1H), 2.37 (ddd,

J = 15, 6.6, 4.8 Hz, 1H), 2.30 (ddd, J = 15, 8.4, 7.8 Hz,

1H), 2.07 (br s, 1H), 1.52 (dqd, J = 7.2, 7.2, 4.8 Hz,

1H), 1.46 (dqd, J = 7.8, 7.2, 6.6 Hz, 1H), 1.25 (t,

J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); ¹³C NMR

(CDCl₃, 150 MHz): d 166.3, 145.2, 123.8, 71.8, 60.2,

39.6, 29.9, 14.2, 9.8; CIMS calculated for [C₉H₁₆O₃+

Na]⁺: 195.0992. Found: 195.1006.

ane) = 0.29; ½aꢁ_Dꢂ4.1 (c 0.8, CH₂Cl₂); IR (thin ﬁlm):

3459, 2971, 2931, 1738, 1507, 1448, 1374, 1301, 1261,

1

1214, 1140, 1079, 1028, 939 cm^ꢂ1; H NMR (CDCl₃,

600 MHz): d 4.30 (q, J = 7.2 Hz, 2H), 4.21–4.17 (m,

1H), 4.06 (dd, J = 6, 1.8 Hz, 1H), 3.87–3.83 (m, 1H),

3.28 (br s, 1H), 3.15 (d, J = 6 Hz, 1H), 2.52 (br s, 1H),

1.81–1.75 (m, 2H), 1.72 (ddd, J = 14.4, 3, 3 Hz, 1H),

1.54 (ddd, J = 14.4, 7.2, 6.6 Hz, 1H), 1.32 (t,

J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H); ¹³C NMR

(CDCl₃, 150 MHz): d 172.9, 73.7, 73.4, 72.9, 62.0,

39.0, 30.9, 14.1, 9.6; CIMS calculated for [C₉H₁₈O₅+

Na]⁺: 229.1046. Found: 229.1052.

4.14. (2S,3R,5S)-Ethyl 2,3,5-trihydroxyheptanoate (16b)

Following the same procedure as described for com-

pound 16a (see Section 4.7) the 16b was produced

(71 mg, 10:1 dr) in 80% yield from 11b (75 mg,

0.44 mmol) as a viscous oil. Major isomer: R_f(100%

4.17. (3R,4S,6S)-6-Ethyl-tetrahydro-3,4-dihydroxypyran-

2-one (22b)

Following the same procedure as described for com-

pound 22a (see Section 4.10), 22b was produced

(30 mg, 0.20 mmol) in 80% yield from 17b (50 mg,

0.26 mmol) as a viscous oil. R_f(50% EtOAc/hex-

25

EtOAc) = 0.29; ½aꢁ_D1.3 (c 0.8, CH₂Cl₂); IR (thin ﬁlm):

3485, 2972, 2959, 2936, 1735, 1507, 1465, 1443, 1370,

1287, 1219, 1180, 1108, 1036, 981 cm^ꢂ^{1 1}H NMR

;

25

(CDCl₃, 600 MHz): d 4.30 (q, J = 7.8 Hz, 1H), 4.28 (q,

J = 7.8 Hz, 1H), 4.23 (m, 1H), 4.09 (dd, J = 6, 1.8 Hz,

1H), 3.88 (m, 1H), 3.23 (d, J = 3.6 Hz, 1H), 2.69 (d,

J = 7.8 Hz, 1H), 2.08 (d, J = 4.8 Hz, 1H), 1.84–1.67

(m, 2H), 1.57–1.51 (m, 2H), 1.31 (t, J = 7.8 Hz, 3H),

0.96 (t, J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃, 150 MHz):

d 173.2, 73.8, 70.3, 69.7, 62.1, 39.6, 30.4, 14.1, 9.9; CIMS

calculated for [C₉H₁₈O₅+Na]⁺: 229.1046. Found:

229.1049.

ane) = 0.22; ½aꢁ_Dꢂ5.8 (c 0.66, CH₂Cl₂); IR (thin ﬁlm):

3468, 2972, 2959, 2936, 1745, 1507, 1465, 1443, 1370,

1287, 1219, 1180, 1108, 1036, 981 cm^ꢂ^{1 1}H NMR

;

(CDCl₃, 600 MHz): d 4.50 (dddd, J = 10.8, 7.2, 5.4,

3 Hz, 1H), 4.31 (d, J = 7.8 Hz, 1H), 3.99 (ddd, J = 8.4,

7.8, 3.6 Hz, 1H), 3.31 (br s, 1H), 2.62 (br s, 1H), 2.13

(ddd, J = 15, 10.8, 8.4 Hz, 1H), 1.96 (ddd, J = 15, 3.6,

3.6 Hz, 1H), 1.76 (ddq, J = 14.4, 7.8, 7.2 Hz, 1H), 1.65

(dqd, J = 14.4, 7.2, 6.6 Hz, 1H), 1.02 (t, J = 7.2 Hz,

3H); ¹³C NMR (CDCl₃, 150 MHz): d 173.8, 76.9, 73.0,

69.7, 35.9, 27.9, 9.4; CIMS calculated for [C₇H₁₂O₄+

Na]⁺: 183.0627. Found: 183.0624.

4.15. (3S,4R,6S)-6-Ethyl-tetrahydro-3,4-dihydroxypyran-

2-one (21b)

Following the same procedure as described for com-

pound 21a (see Section 4.8), 21b was produced (30 mg,

0.20 mmol) in 80% yield from 16b (50 mg, 0.26 mmol)

4.18. (2S,3R,5S)-Ethyl 2,3,5-trihydroxyhexanoate (11c)

25

as a viscous oil. R_f(100% EtOAc) = 0.21; ½aꢁ_Dꢂ21.2

Following the same procedure as described for com-

pound 11a (see Section 4.5), 11c was produced (0.22 g,

9:1 dr) in 81% yield from 10c (0.23 g, 1.4 mmol) as a vis-

cous oil. Major isomer: R_f(50% EtOAc/hexane) = 0.16;

(c 0.5, CH₂Cl₂); IR (thin ﬁlm): 3468, 2972, 2959, 2936,

1745, 1507, 1465, 1443, 1370, 1287, 1219, 1180, 1108,

1

1036, 981 cm^ꢂ1; H NMR (CDCl₃, 600 MHz): d 4.27

25

(dddd, J = 10.2, 7.8, 6.6, 3 Hz, 1H), 4.04 (ddd,

J = 11.4, 10.2, 3.6 Hz, 1H), 3.97 (d, J = 10.2 Hz, 1H),

3.35 (br s, 1H), 2.72 (br s, 1H), 2.26 (ddd, J = 13.8,

7.2, 3.6 Hz, 1H), 1.82 (ddd, J = 13.2, 11.4, 1.8 Hz,

1H), 1.81–1.68 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H); ¹³C

NMR (CDCl₃, 150 MHz): d 173.0, 79.6, 74.3, 69.2,

35.2, 28.7, 9.1; CIMS calculated for [C₇H₁₁O₄+Na₂]⁺:

205.0447. Found: 205.0445.

½aꢁ_Dꢂ6 (c 0.4, CH₂Cl₂); IR (thin ﬁlm): 3485, 2972, 2959,

2936, 1735, 1507, 1465, 1443, 1370, 1287, 1219, 1180,

1

1108, 1036, 981 cm^ꢂ1; H NMR (CDCl₃, 600 MHz): d

4.29 (dd, J = 4.2, 1.8 Hz, 1H), 4.27 (q, J = 7.2 Hz,

1H), 4.22 (ddd, J = 10.2, 6, 3.6 Hz, 1H), 4.16 (dqd,

J = 9.6, 6, 2.4 Hz, 1H), 4.08 (dd, J = 6, 2.4 Hz, 1H),

3.29 (d, J = 6 Hz, 1H), 2.82 (d, J = 4.2 Hz, 1H), 2.80

(d, J = 6.6 Hz, 1H), 1.88 (ddd, J = 15, 9.6, 3 Hz, 1H),

1.62 (ddd, J = 15, 8.4, 3.6 Hz, 1H), 1.31 (t, J = 7.2 Hz,

3H), 1.27 (d, J = 6 Hz, 3H); ¹³C NMR (CDCl₃,

150 MHz): d 173.2, 73.8, 69.7, 65.1, 62.1, 41.5, 23.6,

14.1; CIMS calculated for [C₈H₁₆O₅+Na]⁺: 215.0889.

Found: 215.0892.

4.16. (2R,3S,5S)-Ethyl 2,3,5-trihydroxyheptanoate (17b)

Following the same procedure as described for com-

pound 17a (see Section 4.9), 17b was produced (51 mg,

1514

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

4.19. (3S,4R,6S)-Tetrahydro-3,4-dihydroxy-6-methyl-

pyran-2-one (16c)

4.22. (E,4S,5S)-Ethyl 4-(4-methoxyphenoxy)-6-(benzyl-

oxy)-5-hydroxyhex-2-enoate (12a)

Following the same procedure as described for com-

pound 16a (see Section 4.7), 16c was produced (30 mg,

0.20 mmol) in 80% yield from 11c (50 mg, 0.26 mmol)

Into a 100 mL round bottomed ﬂask ﬁtted with a con-

denser and maintained under nitrogen were placed 3 g

(9.8 mmol) of 10a, 50.7 mg (0.49 mmol, 0.5 mol %) of

Pd₂(DBA)₃ÆCHCl₃, 51 mg (0.19 mmol, 2 mol %) of

PPh₃, and 30 mL of CH₂Cl₂. Et₃N (1.3 mL, 9.8 mmol)

and p-methoxyphenol (2.43 g, 19.6 mmol) were added

and the mixture was heated at reﬂux for 30 min. The

reaction was cooled to rt and quenched by the addition

of saturated aqueous sodium bicarbonate (20 mL). The

aqueous layer was extracted with ether (3 · 30 mL).

The organic layer was washed with brine (20 mL) and

dried with anhydrous sodium sulfate. After removal of

the solvents in vacuo, ﬂash chromatography on silica

gel (7:3, hexanes/EtOAc) aﬀorded 12a as a yellow oil

(3.4 g, 90%). Mosher ester analysis of this alcohol shows

25

as a viscous oil. R_f(50% EtOAc/hexane) = 0.14; ½aꢁ_D

ꢂ2.5 (c 1, CH₂Cl₂); IR (thin ﬁlm): 3431, 2924, 1642,

1507, 1465, 1443, 1370, 1287, 1180, 1126, 1036 cm^ꢂ1

;

¹H NMR (CDCl₃, 600 MHz) d 4.47 (dqd, J = 12, 6,

3.6 Hz, 1H), 3.99 (dd, J = 9.6 Hz, 1H), 4.05 (ddd,

J = 13.8, 9.6, 3.6 Hz, 1H), 3.41 (br s, 1H), 2.76 (br s,

1H), 2.28 (ddd, J = 14.4, 3.6, 3 Hz, 1H), 1.83 (ddd,

J = 13.8, 12, 11.4 Hz, 1H), 1.44 (d, J = 6 Hz, 3H); ¹³C

NMR (CDCl₃, 150 MHz): d 173.1, 75.0, 74.1, 69.1,

37.5, 20.7; CIMS calculated for [C₆H₉O₄+Na₂]⁺:

191.0291. Found: 191.0301.

25

90% ee; R_f(30% EtOAc/hexanes) = 0.32; ½aꢁ_D22.5 (c

4.20. (2R,3S,5S)-Ethyl 2,3,5-trihydroxyhexanoate (17c)

1.1, CH₂Cl₂); IR (thin ﬁlm): 3484, 2980, 2954, 2923,

2869, 1716, 1660, 1506, 1454, 1368, 1303, 1276, 1227,

Following the same procedure as described for com-

pound 17a (see Section 4.9), 17c was produced (0.23 g,

10:1 dr) in 85% yield from 11c (0.23 g, 1.4 mmol) as a

viscous oil. Major isomer: R_f(50% EtOAc/hex-

1180, 1109, 1036, 983 cm^ꢂ1

;

¹H NMR (CDCl₃,

600 MHz): d 7.33 (m, 5H), 6.98 (dd, J = 15.6, 5.4 Hz,

1H), 6.81 (m, 4H), 6.07 (dd, J = 15.6, 1.8 Hz, 1H),

4.86 (ddd, J = 5.4, 4.8, 1.8 Hz, 1H), 4.56 (d,

J = 12 Hz, 1H), 4.53 (d, J = 12 Hz, 1H), 4.18 (q, J =

7.8 Hz, 1H), 4.16 (q, J = 7.8 Hz, 1H), 4.01 (ddd,

J = 10.2, 6, 5.4 Hz, 1H), 3.76 (s, 3H), 3.68 (dd,

J = 9.6, 4.8 Hz, 1H), 3.60 (dd, J = 9.6, 5.4 Hz, 1H),

2.58 (d, J = 5.4 Hz, 1H), 1.27 (t, J = 7.8 Hz, 3H); ¹³C

NMR (CDCl₃, 67.5 MHz): d 165.7, 154.5, 151.6,

143.5, 137.6, 128.4 (2C), 127.8 (3C), 123.8, 117.0 (2C),

114.6 (2C), 78.4, 73.6, 72.3, 69.9, 60.6, 55.6, 14.1; CIMS

calculated for [C₂₂H₂₆O₆+Na]⁺: 409.1627. Found:

409.1621.

25

ane) = 0.16; ½aꢁ_D2.6 (c 1, CH₂Cl₂); IR (thin ﬁlm):

3459, 2971, 2931, 1738, 1507, 1448, 1374, 1301, 1261,

1

1214, 1140, 1079, 1028, 939 cm^ꢂ1; H NMR (CDCl₃,

600 MHz):

d 4.31 (q, J = 7.2 Hz, 1H), 4.29 (q,

J = 7.2 Hz, 1H), 4.19 (ddd, J = 9.6, 3, 2.4 Hz, 1H),

4.11 (dddd, J = 15.6, 6.6, 6, 3 Hz, 1H), 4.05 (d,

J = 2.4 Hz, 1H), 3.14 (br s, 2H), 1.82 (ddd, J = 14.4,

10.2, 9.6 Hz, 1H), 1.69 (ddd, J = 14.4, 6, 3 Hz, 1H),

1.58 (br s, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.25 (d,

J = 6.6 Hz, 3H); ¹³C NMR (CDCl₃, 150 MHz): d

172.9, 73.7, 72.7, 67.8, 61.9, 41.2, 24.0, 14.1; CIMS cal-

culated for [C₈H₁₆O₅+Na]⁺: 215.0889. Found:

215.0892.

4.23. (2S,3S,4R,5S)-Ethyl 4-(4-methoxyphenoxy)-6-

(benzyloxy)-2,3,5-trihydroxyhexanoate (18a)

4.21. (3R,4S,6S)-Tetrahydro-3,4-dihydroxy-6-methyl-

pyran-2-one (22c)

Into a 25 mL round bottomed ﬂask was added 12a

(193 mg, 0.5 mmol) and followed by 1 mL of t-BuOH,

1 mL of acetone and then the solution was cooled to

0 ꢁC. To this solution 0.35 mL of 50% NMO in H₂O

(1.5 mmol) and OsO₄(2.5 mg, 0.01 mmol, 2 mol %) were

added, and the reaction was stirred vigorously at 0 ꢁC

overnight. The reaction was quenched by the addition

of solid sodium sulﬁte (100 mg) at rt. Then the mixture

was ﬁltered through a pad of Celite/Florisil and eluted

with 20 mL of 50% EtOAc/CH₃OH. The combined or-

ganic layers were dried over anhydrous sodium sulfate.

After removal of the solvents in vacuo, ﬂash chromato-

graphy on silica gel (6:4, hexanes/EtOAc) aﬀorded 18a

(172 mg, 7:1 dr, 82% yield) as a viscous oil. Major iso-

Following the same procedure as described for com-

pound 22a (see Section 4.10), 22c was produced

(36 mg, 0.21 mmol) in 83% yield from 17c (50 mg,

0.26 mmol) as a viscous oil. R_f(50% EtOAc/hex-

25

ane) = 0.14; ½aꢁ_Dꢂ32.1 (c 1, CH₂Cl₂); IR (thin ﬁlm):

3431, 2924, 1642, 1507, 1465, 1443, 1370, 1287, 1180,

1

1126, 1036 cm^ꢂ1; H NMR (CDCl₃, 600 MHz): d 4.74

(dqd, J = 11.4, 6, 3.6 Hz, 1H), 4.31 (d, J = 7.8 Hz,

1H), 4.01 (ddd, J = 8.4, 7.8, 3 Hz, 1H), 3.49 (br s,

1H), 2.86 (br s, 1H), 2.13 (ddd, J = 15, 10.8, 8.4 Hz,

1H), 1.98 (ddd, J = 15, 3.6, 3 Hz, 1H), 1.41 (d,

J = 6 Hz, 3H); ¹³C NMR (CDCl₃, 150 MHz): d 173.7,

73.1, 72.1, 69.6, 38.1, 20.7; CIMS calculated for

[C₆H₉O₄+Na₂]⁺: 191.0291. Found: 191.0301.

25

mer: R_f(90% EtOAc/hexanes) = 0.43; ½aꢁ_D5.4 (c 1.0,

CH₂Cl₂); IR (thin ﬁlm): 3533, 2983, 2957, 2869, 1747,

1653, 1593, 1506, 1466, 1455, 1372, 1296, 1220, 1184,

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

1515

1044 cm^ꢂ1

;

¹H NMR (CDCl₃, 600 MHz): d 7.28 (m,

J = 11.4 Hz, 1H), 4.28 (d, J = 11.4 Hz, 1H), 4.17 (ddd,

J = 10.2, 1.8, 1.2 Hz, 1H), 3.81 (br s, 1H), 3.74 (s,

3H), 3.72 (d, J = 6.6 Hz, 2H), 3.21 (br s, 1H); ¹³C

NMR (CDCl₃, 150 MHz): d 172.1, 154.8, 153.5, 137.0,

128.4 (2C), 127.9 (2C), 127.8, 117.7 (2C), 114.6 (2C),

78.2, 76.7, 73.5, 71.8, 70.4, 67.0, 55.7; CIMS calculated

for [C₂₀H₂₂O₇+Na]⁺: 397.1257. Found: 397.1285.

5H), 6.98 (m, 2H), 6.80 (m, 2H), 4.49 (dd, J = 9,

1.8 Hz, 1H), 4.46 (d, J = 11.4 Hz, 1H), 4.43 (d,

J = 11.4 Hz, 1H), 4.35–4.29 (m, 3H), 3.76 (s, 3H), 4.28

(q, J = 7.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 1H), 3.67 (dd,

J = 9.6, 6 Hz, 1H), 3.55 (dd, J = 9.6, 6 Hz, 1H), 3.18

(d, J = 5.4 Hz, 1H), 2.89 (d, J = 8.4 Hz, 1H), 2.62 (d,

J = 7.8 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H); ¹³C NMR

(CDCl₃, 67.5 MHz): d 173.4, 154.4, 152.4, 137.5, 128.4

(2C), 127.8 (3C), 117.1 (2C), 114.7 (2C), 76.6, 73.4,

71.1, 70.6, 70.1, 69.3, 62.1, 55.6, 14.1; CIMS calculated

for [C₂₂H₂₈O₈+Na]⁺: 443.1682. Found: 443.1668.

4.26. (3S,4R,5R,6S)-5-(4-Methoxyphenoxy)-6-((benzyl-

oxy)methyl)-tetrahydro-3,4-diacetoxypyran-2-one (24a)

To a solution of 23a (150 mg, 0.4 mmol) in CH₂Cl₂

(2 mL) were added excess Ac₂O (0.6 mL, 2 mmol), pyr-

idine (0.3 mL, 4 mmol) and a catalytic amount of

DMAP (2.5 mg, 5 mol %). The reaction was stirred for

1 h, after which 10 mL ether and 10 mL of saturated

NH₄Cl were added to remove excess base. The organic

layer was washed with 10 mL CuSO₄solution, 10 mL

brine and the aqueous layer was further extracted with

ether (3 · 10 mL). The combined organic layers were

dried over Na₂SO₄and the solvent was removed

in vacuo. The crude product was puriﬁed by ﬂash chro-

matography on silica gel (4:1, hexanes/EtOAc) to yield

24a (174 mg, 95% yield) as a viscous oil. R_f(40%

4.24. (2S,3S,4R,5S)-Ethyl 4-(4-methoxyphenoxy)-6-

(benzyloxy)-2,3,5-trihydroxyhexanoate (18a)

Into a 50 mL round bottomed ﬂask were added 10 mL

of t-BuOH, 10 mL of water, K₃Fe(CN)₆(4.93 g,

15 mmol), K₂CO₃(2.07 g, 15 mmol), MeSO₂NH₂

(475 mg, 5 mmol), (DHQD)₂PHAL (85 mg, 0.1 mmol,

2.1 mol %), and OsO₄(25 mg, 0.1 mmol, 2 mol %). The

mixture was stirred at rt for about 15 min and then

cooled to 0 ꢁC. To this solution was added 12a (2.00 g,

5 mmol) in 4 mL CH₂Cl₂, and the reaction was stirred

vigorously at 0 ꢁC overnight. The reaction was quenched

by the addition of solid sodium sulﬁte (100 mg) at rt and

stirred for 15 min. Then the mixture was ﬁltered through

a pad of Celite/Florisil and eluted with 50 mL of 50%

EtOAc/CH₃OH. The combined organic layers were

dried over anhydrous sodium sulfate. After removal of

the solvents in vacuo, ﬂash chromatography on silica

gel (6:4, hexanes/EtOAc) aﬀorded 1.8 g (86% yield) of

18a as a viscous oil (25:1 dr). R_f(90% EtOAc/hex-

25

EtOAc/hexanes) = 0.38; ½aꢁ_Dꢂ59.7 (c 1.0, CH₂Cl₂);

IR (thin ﬁlm): 2953, 2922, 2876, 2863, 1754, 1507,

1455, 1373, 1209, 1087, 1034, 929 cm^ꢂ^{1 1}H NMR

;

(CDCl₃, 270 MHz): d 7.29 (m, 3H), 7.19 (m, 2H), 6.94

(m, 2H), 6.79 (m, 2H), 5.49 (d, J = 10.2 Hz, 1H), 5.41

(dd, J = 10.2, 2.4 Hz, 1H), 5.04 (dd, J = 2.4, 1.4 Hz,

1H), 4.73 (ddd, J = 7.3, 7.1, 1.4 Hz, 1H), 4.46 (d,

J = 11.4 Hz, 1H), 4.38 (d, J = 11.4 Hz, 1H), 3.78 (d,

J = 7.1 Hz, 2H), 3.77 (s, 3H), 2.15 (s, 3H), 1.82 (s,

3H); ¹³C NMR (CDCl₃, 67.5 MHz): d 170.2, 170.1,

165.7, 154.9, 152.9, 136.9, 128.4 (2C), 128.0, 127.9

(2C), 117.7 (2C), 114.6 (2C), 76.5, 73.6, 73.2, 71.4,

69.4, 66.3, 55.6, 20.5, 20.4; CIMS calculated for

[C₂₄H₂₆O₉+Na]⁺: 481.1475. Found: 481.1466.

25

anes) = 0.43; ½aꢁ_D5.4 (c 1.0, CH₂Cl₂); for the remaining

spectral data see Experimental 4.23.

4.25. (3S,4S,5S,6S)-5-(4-Methoxyphenoxy)-6-((benzyl-

oxy)methyl)-tetrahydro-3,4-dihydroxypyran-2-one (23a)

To a solution of 18a (200 mg, 0.48 mmol) in benzene

(3 mL) was added pyridinium toluenesulfonate (6 mg,

0.03 mmol, 5 mol %) and the mixture was heated at re-

ﬂux for 5 h. The reaction was cooled to rt and quenched

by the addition of saturated aqueous sodium bicarbon-

ate (2 mL). The aqueous layer was extracted with ether

(3 · 10 mL). The organic layer was washed with brine

(10 mL) and dried with anhydrous sodium sulfate. After

removal of the solvents in vacuo, ﬂash chromatography

on silica gel (4:6, hexanes/EtOAc) aﬀorded 23a as a

viscous oil (160 mg, 85%): R_f(90% EtOAc/hex-

4.27. (E,4S,5S)-Ethyl 4-(4-methoxyphenoxy)-5-hydroxy-

hept-2-enoate (12b)

Following the same procedure as described for com-

pound 12c (see Section 4.32), 12b was produced

(1.23 g, 4.1 mmol) in 90% yield from 10b (1 g, 4.6 mmol)

as a viscous oil. Mosher ester analysis of this alcohol

25

shows 85% ee; R_f(20% EtOAc/hexane) = 0.22; ½aꢁ_D

37.8 (c 1, CH₂Cl₂); IR (thin ﬁlm): 3485, 2977, 2963,

2936, 2903, 2878, 1717, 1658, 1508, 1465, 1443, 1393,

1369, 1302, 1225, 1180, 1037, 980 cm^ꢂ^{1 1}H NMR

;

25

anes) = 0.40; ½aꢁ_Dꢂ26.8 (c 2, CH₂Cl₂); IR (thin ﬁlm):

(CDCl₃, 600 MHz): d 6.95 (dd, J = 15.6, 6 Hz, 1H),

6.83 (m, 2H), 6.79 (m, 2H), 6.04 (dd, J = 15.6, 1.8 Hz,

1H), 4.52 (ddd, J = 6, 6, 1.2 Hz, 1H), 4.18 (q,

J = 7.2 Hz, 1H), 4.16 (q, J = 7.2 Hz, 1H), 3.75 (s, 3H),

3.69 (dddd, J = 7.2, 6, 5.4, 4.8 Hz, 1H), 2.48 (d,

J = 4.8 Hz, 1H), 1.67 (dqd, J = 15, 7.2, 4.2 Hz, 1H),

3396, 2929, 2922, 1740, 1506, 1455, 1368, 1328, 1220,

1103, 1034, 923, 830 cm^ꢂ1

;

¹H NMR (CDCl₃,

600 MHz): d 7.26 (m, 3H), 7.03 (m, 4H), 6.78 (m, 2H),

4.8 (dd, J = 2.4, 1.8 Hz, 1H), 4.59 (d, J = 10.2 Hz,

1H), 4.54 (ddd, J = 7.2, 6.6, 1.8 Hz, 1H), 4.36 (d,

1516

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

1.55 (dqd, J = 15, 7.2, 4.8 Hz, 1H), 1.27 (t, J = 7.2 Hz,

3H), 1.02 (t, J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃,

150 MHz): d 165.7, 154.5, 151.6, 143.8, 124.1, 117.1

(2C), 114.6 (2C), 81.5, 74.7, 60.6, 55.6, 25.6, 14.1, 9.8;

CIMS calculated for [C₁₆H₂₂O₅+Na]⁺: 317.1359.

Found: 317.1344.

172.8, 154.6, 153.7, 117.7 (2C), 114.6 (2C), 82.1, 77.9,

71.8, 70.1, 55.6, 24.2, 9.6; CIMS calculated for

[C₁₄H₁₈O₆+Na]⁺: 305.0995. Found: 305.0971.

4.31. (3S,4S,5S,6S)-5-(4-Methoxyphenoxy)-6-ethyl-

tetrahydro-3,4-diacetoxypyran-2-one (24b)

4.28. (2S,3S,4R,5S)-Ethyl 4-(4-methoxyphenoxy)-2,3,5-

trihydroxyheptanoate (18b)

Following the same procedure as described for com-

pound 24a (see Section 4.26), 24b was produced

(0.12 g, 0.32 mmol) in 94% yield from 23b (100 mg,

0.35 mmol) as a viscous oil. R_f(50% EtOAc/hex-

Following the same procedure as described for com-

pound 18a (see Section 4.23), 18b was produced

(89 mg, 0.27 mmol) in 80% yield from 12b (100 mg,

0.34 mmol) as a viscous oil (6:1 dr). Major isomer: R_f

25

ane) = 0.58; ½aꢁ_D56.5 (c 0.4, CH₂Cl₂); IR (thin ﬁlm):

1748, 1507, 1443, 1374, 1209, 1085, 1033, 795 cm^ꢂ1

;

¹H NMR (CDCl₃, 600 MHz): d 6.88 (m, 2H), 6.82 (m,

2H), 5.47 (d, J = 10.2 Hz, 1H), 5.41 (dd, J = 10.2,

2.4 Hz, 1H), 4.81 (dd, J = 2.4, 1.2 Hz, 1H), 4.45 (ddd,

J = 7.2, 6.6, 1.2 Hz, 1H), 3.74 (s, 3H), 2.16 (s, 3H),

1.86 (s, 3H), 1.98 (dqd, J = 15, 7.8, 7,2 Hz, 1H), 1.75

(dqd, J = 15, 7.8, 4.8 Hz, 1H), 1.01 (t, J = 7.8 Hz, 3H);

¹³C NMR (CDCl₃, 150 MHz): d 170.4, 170.1, 166.1,

154.9, 152.8, 117.4 (2C), 114.8 (2C), 80.5, 74.8, 72.0,

69.1, 55.7, 23.2, 20.5 (2C), 9.6; CIMS calculated for

[C₁₈H₂₂O₈+Na]⁺: 389.1206. Found: 389.1224.

25

(50% EtOAc/hexane) = 0.30; ½aꢁ_Dꢂ3.1 (c 2, CH₂Cl₂);

IR (thin ﬁlm): 3485, 2963, 2936, 2905, 2876, 1736,

1508, 1464, 1442, 1393, 1370, 1288, 1227, 1182, 1110,

1037, 981 cm^ꢂ^{1 1}H NMR (CDCl₃, 600 MHz) d 6.98

;

(m, 2H), 6.81 (m, 2H), 4.35 (d, J = 5.4 Hz, 1H), 4.32–

4.29 (m, 2H), 4.27 (q, J = 7.2 Hz, 2H), 3.91 (ddd,

J = 8.4, 7.2, 6 Hz, 1H), 3.75 (s, 3H), 3.30 (d, J = 6 Hz,

1H), 2.97 (d, J = 4.2 Hz, 1H), 2.23 (d, J = 4.8 Hz, 1H),

1.59 (dqd, J = 15, 7.2, 3.6 Hz, 1H), 1.57 (dqd, J = 15,

7.2, 4.8 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H), 0.95 (t,

J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃, 150 MHz): d

173.5, 154.4, 152.6, 117.1 (2C), 114.7 (2C), 78.7, 72.5,

71.2, 70.2, 62.2, 55.6, 26.7, 14.1, 10.4; CIMS calculated

for [C₁₆H₂₄O₇+Na]⁺: 351.1414. Found: 351.1429.

4.32. (E,4S,5S)-Ethyl 4-(4-methoxyphenoxy)-5-hydroxy-

hex-2-enoate (12c)

Into a 50 mL round bottomed ﬂask ﬁtted with a con-

denser and maintained under nitrogen was placed 1 g

(5 mmol) of 10c, 26 mg (0.025 mmol, 0.5 mol %) of

Pd₂(DBA)₃ÆCHCl₃, 26.2 mg (0.1 mmol, 2 mol %) of

PPh₃, and 10 mL of CH₂Cl₂. Et₃N (0.7 mL, 5 mmol)

and p-methoxyphenol (3.1 g, 25 mmol) were added and

the mixture was allowed to stirr at rt for 12 h. The reac-

tion was quenched by the addition of saturated aqueous

sodium bicarbonate (10 mL). The aqueous layer was ex-

tracted with ether (3 · 20 mL). The organic layer was

washed with brine (10 mL) and dried with anhydrous

sodium sulfate. After removal of the solvents in vacuo,

ﬂash chromatography on silica gel (6:1, hexanes/EtOAc)

aﬀorded 12c as a yellow oil (1.19 g, 85%). Mosher ester

analysis of this alcohol shows 80% ee; R_f(40% EtOAc/

4.29. (2S,3S,4R,5S)-Ethyl 4-(4-methoxyphenoxy)-2,3,5-

trihydroxyheptanoate (18b)

Following the same procedure as described for com-

pound 18a (see Section 4.24), 18b was produced

(0.47 g, 1.4 mmol) in 85% yield from 12b (0.5 g,

1.7 mmol) as a viscous oil (20:1 dr). R_f(50% EtOAc/hex-

25

ane) = 0.30; ½aꢁ_Dꢂ3.1 (c 2, CH₂Cl₂); for the remaining

spectral data see Experimental 4.28.

4.30. (3S,4S,5S,6S)-5-(4-Methoxyphenoxy)-6-ethyl-

tetrahydro-3,4-dihydroxypyran-2-one (23b)

Following the same procedure as described for com-

pound 23a (see Section 4.25), 23b was produced

(220 mg, 0.77 mmol) in 86% yield from 18b (300 mg,

0.9 mmol) as a viscous oil. R_f(50% EtOAc/hex-

25

hexanes) = 0.37; ½aꢁ_D46.9 (c 2, CH₂Cl₂); IR (thin ﬁlm):

3484, 2980, 2933, 2905, 2890, 1717, 1659, 1511, 1466,

1369, 1276, 1225, 1179, 1093, 1036, 984 cm^ꢂ^{1 1}H

;

25

ane) = 0.28; ½aꢁ_Dꢂ47.4 (c 2.2, CH₂Cl₂); IR (thin ﬁlm):

NMR (CDCl₃, 600 MHz): d 6.92 (dd, J = 15.6, 6 Hz,

1H), 6.81 (m, 2H), 6.78 (m, 2H), 6.04 (dd, J = 15.6,

1.8 Hz, 1H), 4.44 (ddd, J = 6.6, 6, 1.2 Hz, 1H), 4.16

(q, J = 7.2 Hz, 1H), 4.14 (q, J = 7.2 Hz, 1H), 3.92 (qd,

J = 6.6, 3.6 Hz, 1H), 3.73 (s, 3H), 2.79 (d, J = 3.6 Hz,

1H), 1.26 (d, J = 6.6 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H);

¹³C NMR (CDCl₃, 150 MHz): d 165.6, 154.5, 151.5,

143.5, 124.1, 117.1 (2C), 114.6 (2C), 83.0, 69.5, 60.5,

55.5, 18.3, 14.1; CIMS calculated for [C₁₅H₂₀O₅+Na]⁺:

303.1203. Found: 303.1219.

3438, 2970, 2938, 2926, 1740, 1506, 1464, 1442, 1370,

1290, 1224, 1141, 1106, 1035, 876 cm^ꢂ^{1 1}H NMR

;

(CDCl₃, 600 MHz): d 7.06 (m, 2H), 6.82 (m, 2H), 4.63

(dd, J = 2.4, 1.8 Hz, 1H), 4.57 (d, J = 10.8 Hz, 1H),

4.29 (ddd, J = 7.8, 6, 1.8 Hz, 1H), 4.18 (ddd, J = 10.8,

3.6, 2.4 Hz, 1H), 3.77 (s, 3H), 3.22 (d, J = 5.4 Hz, 1H),

2.67 (d, J = 4.8 Hz, 1H), 1.97 (dq, J = 19.2, 7.8 Hz,

1H), 1.74 (dq, J = 19.2, 7.8 Hz, 1H), 0.93 (t,

J = 7.8 Hz, 3H); ¹³C NMR (CDCl₃, 150 MHz): d

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

1517

4.33. (2S,3S,4R,5S)-Ethyl 4-(4-methoxyphenoxy)-2,3,5-

trihydroxyhexanoate (18c)

(59 mg, 0.16 mmol) in 90% yield from 23c (50 mg,

0.18 mmol) as a viscous oil. R_f(70% EtOAc/hex-

25

ane) = 0.76; ½aꢁ_Dꢂ85.6 (c 0.3, CH₂Cl₂); IR (thin ﬁlm):

Following the same procedure as described for com-

pound 18a (see Section 4.23), 18c was produced

(86 mg, 0.27 mmol) in 77% yield from 12c (100 mg,

0.36 mmol) as a viscous oil (6:1 dr). Major isomer: R_f

1748, 1507, 1443, 1374, 1209, 1085, 1033, 795 cm^ꢂ1

;

¹H NMR (CDCl₃, 600 MHz): d 6.88 (m, 2H), 6.82 (m,

2H), 5.48 (d, J = 10.2 Hz, 1H), 5.41 (dd, J = 10.2,

2.4 Hz, 1H), 4.75 (qd, J = 6.6, 1.2 Hz, 1H), 4.72 (dd,

J = 2.4, 1.2 Hz, 1H), 3.77 (s, 3H), 2.16 (s, 3H), 1.86 (s,

3H), 1.49 (d, J = 6.6 Hz, 3H); ¹³C NMR (CDCl₃,

150 MHz): d 170.4, 170.3, 166.2, 154.6, 152.9, 117.6

(2C), 114.7 (2C), 89.2, 76.4, 75.3, 72.1, 55.6, 20.5 (2C),

17.1; CIMS calculated for [C₁₇H₂₀O₈+Na]⁺: 375.1050.

Found: 375.1040.

25

(100% EtOAc) = 0.50; ½aꢁ_D5.1 (c 1, CH₂Cl₂); IR (thin

ﬁlm): 3433, 2980, 2976, 2933, 2906, 1735, 1507, 1443,

1371, 1327, 1291, 1220, 1153, 1112, 1045, 992,

828 cm^ꢂ^{1 1}H NMR (CDCl₃, 600 MHz): d 6.97 (m,

;

2H), 6.80 (m, 2H), 4.35 (d, J = 6 Hz, 1H), 4.30–4.21

(m, 3H), 4.28 (q, J = 7.2 Hz, 1H), 4.26 (q, J = 7.2 Hz,

1H), 3.74 (s, 3H), 3.47 (d, J = 6 Hz, 1H), 3.44 (d,

J = 6.6 Hz, 1H), 2.70 (d, J = 7.8 Hz, 1H), 1.29 (t,

J = 7.2 Hz, 3H), 1.27 (t, J = 6.6 Hz, 3H); ¹³C NMR

(CDCl₃, 150 MHz): d 173.5, 154.3, 152.6, 117.0 (2C),

114.7 (2C), 79.1, 71.3, 70.3, 66.9, 62.1, 55.6, 19.2, 14.1;

CIMS calculated for [C₁₅H₂₂O₇+Na]⁺: 337.1257.

Found: 337.1285.

4.37. (E,2S,3R)-5-(Ethoxycarbonyl)-1-(benzyloxy)-3-

ﬂuoropent-4-en-2-yl 3-methylbenzoate (14a)

Into a 10 mL round bottomed Teﬂon PFA tube were

added 2a (1.3 g, 4.6 mmol), N,N-diethyl-a,a-diﬂuoro-

(meta-methylbenzyl)amine (DFMBA, 1.98 g, 9.3 mmol),

and heptane (2 mL). The mixture was stirred at 98 ꢁC

for about 2 h. After completion of the reaction, the

mixture was poured into aqueous NaHCO₃and ex-

tracted with ether (3 · 25 mL). The combined organic

layers were dried over anhydrous sodium sulfate. After

removal of the solvents in vacuo, ﬂash chromatography

on silica gel (1:9, EtOAc/hexanes) aﬀorded 1.3 g of 14a

as a viscous oil (70% yield, 90% ee). R_f(40% EtOAc/hex-

4.34. (2S,3S,4R,5S)-Ethyl 4-(4-methoxyphenoxy)-2,3,5-

trihydroxyhexanoate (18c)

Following the same procedure as described for com-

pound 18a (see Section 4.24), 18c was produced

(280 mg, 0.89 mmol) in 83% yield from 12c (300 mg,

1.07 mmol) as a viscous oil (20:1 dr). R_f(100%

25

EtOAc) = 0.50; ½aꢁ_D5.1 (c 1, CH₂Cl₂); For the remain-

ane) = 0.58; ½aꢁ_D19.5 (c 1.5, CH₂Cl₂); IR (thin ﬁlm):

ing spectral data see Section 4.33.

2981, 2924, 2872, 1718, 1665, 1590, 1454, 1367, 1300,

1270, 1194, 1180, 1100, 1037, 976 cm^ꢂ^{1 1}H NMR

;

4.35. (3S,4S,5S,6S)-5-(4-methoxyphenoxy)-tetrahydro-

3,4-dihydroxy-6-methylpyran-2-one (23c)

(CDCl₃, 600 MHz): d 7.84 (m, 2H), 7.33 (m, 7H), 7.01

(ddd, J = 20.4, 15.6, 4.8 Hz, 1H), 6.17 (ddd, J = 15.6,

1.8, 1.8 Hz, 1H), 5.47 (dddd, J = 48, 4.8, 4.2, 1.8 Hz,

1H), 5.45 (ddd, J = 20.4, 9.6, 1.8 Hz, 1H), 4.58 (d, J =

12 Hz, 1H), 4.54 (d, J = 12 Hz, 1H), 4.22 (q,

J = 7.2 Hz, 2H), 3.82 (ddd, J = 10.8, 6, 1.8 Hz, 1H),

3.75 (dd, J = 10.8, 4.8 Hz, 1H), 2.41 (s, 3H), 1.29 (t,

J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃, 150 MHz): d

165.7, 165.4, 140.3 (d, J = 18.5 Hz), 138.2, 137.5,

134.1, 130.3, 129.3, 128.4 (2C), 128.3, 127.8 (2C),

127.6, 126.9, 123.6 (d, J = 11.1 Hz), 90.1 (d, J =

177.7 Hz), 73.4, 72.9 (d, J = 23.1 Hz), 66.9 (d,

J = 6.5 Hz), 60.7, 21.2, 14.1; CIMS calculated for

[C₂₃H₂₅FO₅+Na]⁺: 423.1578. Found: 423.1579.

Following the same procedure as described for com-

pound 23a (see Section 4.25), 23c was produced

(66 mg, 0.25 mmol) in 80% yield from 18c (100 mg,

0.31 mmol) as a viscous oil. R_f(70% EtOAc/hex-

25

ane) = 0.16; ½aꢁ_Dꢂ84.3 (c 1, CH₂Cl₂); IR (thin ﬁlm):

3416, 2980, 2976, 2933, 1733, 1507, 1443, 1326, 1222,

1155, 1106, 1033, 829 cm^ꢂ1

;

¹H NMR (CDCl₃,

600 MHz): d 7.03 (m, 2H), 6.81 (m, 2H), 4.56 (d,

J = 10.2 Hz, 1H), 4.54 (qd, J = 6.6, 1.8 Hz, 1H), 4.46

(dd, J = 2.4, 1.8 Hz, 1H), 4.20 (dd, J = 10.2, 2.4 Hz,

1H), 4.10 (br s, 1H), 3.75 (s, 3H), 3.55 (br s, 1H), 1.39

(d, J = 6.6 Hz, 3H); ¹³C NMR (CDCl₃, 150 MHz): d

172.8, 154.8, 153.7, 117.8 (2C), 114.6 (2C), 79.2, 76.9,

71.9, 69.8, 55.6, 17.0; CIMS: Calculated for

[C₁₃H₁₆O₆+Na]⁺: 291.0839. Found: 291.0832.

4.38. (E,4R,5S)-Ethyl 6-(benzyloxy)-4-ﬂuoro-5-hydroxy-

hex-2-enoate (15a)

To a solution of 14a (500 mg, 1.25 mmol) in EtOH

(3 mL) was added 10% HCl in EtOH (0.5 mL), and

the mixture was heated at reﬂux for 24 h. Then EtOH

was removed under reduced pressure, ﬂash chromato-

graphy on silica gel (8:2, hexanes/EtOAc) aﬀorded 15a

as a viscous oil (211 mg, 60%). Mosher ester analysis

4.36. (3S,4R,5R,6S)-5-(4-Methoxyphenoxy)-tetrahydro-

3,4-diacetoxy-6-methylpyran-2-one (24c)

Following the same procedure as described for com-

pound 24a (see Section 4.26), 24c was produced

1518

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

of this alcohol showed 90% ee; R_f(40% EtOAc/hex-

4.40. (2R,3R,4S,5S)-Ethyl 6-(benzyloxy)-4-ﬂuoro-2,3,5-

trihydroxyhexanoate (19a)

25

ane) = 0.36; ½aꢁ_D24.6 (c 2.2, CH₂Cl₂); IR (thin ﬁlm):

3435, 2981, 2924, 2872, 1718, 1590, 1454, 1367, 1300,

1270, 1194, 1180, 1100, 1037, 976 cm^ꢂ1

;

¹H NMR

To a solution of 15a (100 mg, 0.35 mmol) in 0.5 mL of

t-BuOH/0.5 mL of acetone were added 0.25 mL of 50%

NMO in H₂O (125 mg, 1.06 mmol) and 1.8 mg OsO₄

(0.007 mmol, 2 mol %). The reaction mixture was stirred

vigorously at 0 ꢁC overnight. The reaction was

quenched by the addition of solid sodium sulﬁte

(50 mg) at rt and ﬁltered through a pad of Celite and

eluted with CH₃OH and dried over sodium sulfate.

Then the solvent was removed under reduced pressure

and ﬂash chromatography on silica gel (1:1, hexanes/

EtOAc) aﬀorded 19a as a viscous oil (101 mg, 90%,

5:1 dr). Major isomer: R_f(40% EtOAc/hexane) = 0.15;

(CDCl₃, 600 MHz):

d 7.35 (m, 5H), 7.02 (ddd,

J = 21.6, 15.6, 4.2 Hz, 1H), 6.14 (ddd, J = 15.6, 1.8,

1.8 Hz, 1H), 5.12 (dddd, J = 46.8, 6.6, 4.2, 1.8 Hz,

1H), 4.57 (br s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.93

(ddd, J = 21.6, 6.6, 4.8 Hz, 1H), 3.64 (dd, J = 4.8,

1.8 Hz, 1H), 3.63 (dd, J = 4.8, 1.8 Hz, 1H), 2.50 (d,

J = 6 Hz, 1H), 2.49 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H);

¹³C NMR (CDCl₃, 150 MHz): d 165.7, 141.6 (d,

J = 17.2 Hz), 137.4, 128.5 (2C), 127.9, 127.8 (2C),

122.9 (d, J = 11.6 Hz), 91.1 (d, J = 176.5 Hz), 73.6,

71.4 (d, J = 23.9 Hz), 69.5 (d, J = 4.5 Hz), 60.7, 21.2,

14.1; CIMS calculated for [C₁₅H₁₉FO₄+Na]⁺:

305.1159. Found: 305.1161.

25

½aꢁ_Dꢂ2.1 (c 2.7, CH₂Cl₂); For the remaining spectral

data see Section 4.39.

4.39. (2R,3R,4S,5S)-Ethyl 6-(benzyloxy)-4-ﬂuoro-2,3,5-

trihydroxyhexanoate (19a)

4.41. (2S,3S,4S,5S)-Ethyl 6-(benzyloxy)-4-ﬂuoro-2,3,5-

trihydroxyhexanoate (20a)

Into a 50 mL round bottomed ﬂask were added 3 mL of

t-BuOH, 3 mL of water, K₃Fe(CN)₆(350 mg,

1.06 mmol), K₂CO₃(147 mg, 1.06 mmol), MeSO₂NH₂

(34 mg, 0.35 mmol), (DHQ)₂PHAL (5.8 mg, 7.4 lmol,

2.1 mol %), and OsO₄(1.8 mg, 7.0 lmol, 2 mol %). The

mixture was stirred at rt for about 15 min and then

cooled to 0 ꢁC. To this solution was added 15a

(100 mg, 0.35 mmol) and the reaction was stirred vigor-

ously at 0 ꢁC overnight. The reaction was quenched by

the addition of solid sodium sulﬁte (50 mg) at rt. EtOAc

(10 mL) was added to the reaction mixture and after

separation of the layers, the aqueous phase was further

extracted with EtOAc (2 · 10 mL). The combined

organic layers were washed with brine and dried over

anhydrous sodium sulfate. After removal of the solvents

in vacuo, ﬂash chromatography on silica gel (1:1, hex-

anes/EtOAc) aﬀorded 19a as a viscous oil (96 mg,

86%, 7:1 dr). Major isomer: R_f(40% EtOAc/hex-

Into a 50 mL round bottomed ﬂask were added 3 mL of

t-BuOH, 3 mL of water, K₃Fe(CN)₆(350 mg,

1.06 mmol), K₂CO₃(147 mg, 1.06 mmol), MeSO₂NH₂

(34 mg, 0.35 mmol), (DHQD)₂PHAL (5.8 mg, 7.4 lmol,

2.1 mol %), and OsO₄(1.8 mg, 7.0 lmol, 2 mol %). The

mixture was stirred at rt for about 15 min and then

cooled to 0 ꢁC. To this solution was added 15a

(100 mg, 0.35 mmol) and the reaction was stirred vigor-

ously at 0 ꢁC overnight. The reaction was quenched by

the addition of solid sodium sulﬁte (50 mg) at rt. EtOAc

(10 mL) was added to the reaction mixture and after

separation of the layers, the aqueous phase was further

extracted with EtOAc (2 · 10 mL). The combined

organic layers were washed with brine and dried over

anhydrous sodium sulfate. After removal of the solvents

in vacuo, ﬂash chromatography on silica gel (1:1, hex-

anes/EtOAc) aﬀorded 20a as a viscous oil (95 mg,

85%, 2:1 dr). Major isomer: R_f(40% EtOAc/hex-

25

ane) = 0.15; ½aꢁ_Dꢂ2.1 (c 2.7, CH₂Cl₂); IR (thin ﬁlm):

ane) = 0.14; ½aꢁ_Dꢂ3.2 (c 1.0, CH₂Cl₂); IR (thin ﬁlm):

3402, 3033, 2922, 2862, 1736, 1496, 1453, 1365, 1216,

1

1072, 1026, 811 cm^ꢂ1; H NMR (CDCl₃, 600 MHz): d

7.33 (m, 5H), 4.60 (ddd, J = 46.6, 8.4, 6.6 Hz, 1H),

4.58 (br s, 2H), 4.39 (dd, J = 6.6, 1.2 Hz, 1H), 4.29 (q,

J = 7.2 Hz, 2H), 4.22 (ddd, J = 13.2, 6.6, 1.2 Hz, 1H),

4.14 (dddd, J = 16.2, 6.6, 6, 5.4 Hz, 1H), 3.72 (dd,

J = 9.6, 6 Hz, 1H), 3.66 (dd, J = 9.6, 6.6 Hz, 1H), 3.49

(d, J = 5.4 Hz, 1H), 3.33 (d, J = 6.6 Hz, 1H), 3.09 (d,

J = 4.8 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H); ¹³C NMR

(CDCl₃, 150 MHz): d 172.8, 137.3, 128.5 (2C), 128.0,

127.8 (2C), 89.1 (d, J = 175.4 Hz), 73.7, 71.8 (d,

J = 25.5 Hz), 71.2 (d, J = 24.7 Hz), 70.0 (d,

J = 3.5 Hz), 69.9 (d, J = 5.8 Hz), 62.1, 14.1; CIMS cal-

culated for [C₁₅H₂₁FO₆+Na]⁺: 339.1214. Found:

339.1217.

7.33 (m, 5H), 4.64 (ddd, J = 46.2, 7.8, 3 Hz, 1H), 4.55

(br s, 2H), 4.38 (d, J = 3 Hz, 1H), 4.26 (q, J = 7.2 Hz,

2H), 4.22 (ddd, J = 12.5, 3.6, 2.4 Hz, 1H), 4.12 (dddd,

J = 12, 6.6, 5.4, 2.4 Hz, 1H), 3.69 (dd, J = 9.6, 6 Hz,

1H), 3.63 (dd, J = 9.6, 5.4 Hz, 1H), 3.30 (d,

J = 4.2 Hz, 1H), 2.08 (d, J = 9 Hz, 1H), 2.88 (d,

J = 6.6 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); ¹³C NMR

(CDCl₃, 150 MHz): d 172.8, 137.3, 128.5 (2C), 128.0,

127.8 (2C), 89.1 (d, J = 175.4 Hz), 73.7, 71.8 (d, J =

25.5 Hz), 71.2 (d, J = 24.7 Hz), 70.0 (d, J =

3.5 Hz), 69.9 (d, J = 5.8 Hz), 62.1, 14.1; CIMS calcu-

lated for [C₁₅H₂₁FO₆+Na]⁺: 339.1214. Found:

339.1217.

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

1519

25

4.42. (2S,3R,4R,5R)-5-(Ethoxycarbonyl)-1-(benzyloxy)-

3-ﬂuoro-4,5-dihydroxypentan-2-yl 3-methylbenzoate

(27a)

½aꢁ_Dꢂ4.1 (c 2.3, CH₂Cl₂); For the remaining spectral

data see Section 4.42.

4.44. (2S,3R,4S,5S)-5-(Ethoxycarbonyl)-1-(benzyloxy)-

3-ﬂuoro-4,5-dihydroxypentan-2-yl 3-methylbenzoate

(28a)

Into a 50 mL round bottomed ﬂask were added 4 mL of

t-BuOH, 4 mL of water, K₃Fe(CN)₆(370 mg, 1.13

mmol), K₂CO₃(155 mg, 1.13 mmol), MeSO₂NH₂(36

mg, 0.38 mmol), (DHQ)₂PHAL (6.1 mg, 7.9 lmol,

2.1 mol %), and OsO₄(1.9 mg, 7.5 lmol, 2 mol %). The

mixture was stirred at rt for about 15 min and then

cooled to 0 ꢁC. To this solution was added 14a

(150 mg, 0.38 mmol) and the reaction was stirred vigor-

ously at 0 ꢁC overnight. The reaction was quenched by

the addition of solid sodium sulﬁte (50 mg) at rt. EtOAc

(15 mL) was added to the reaction mixture and after

separation of the layers, the aqueous phase was further

extracted with EtOAc (2 · 10 mL). The combined

organic layers were washed with brine and dried over

anhydrous sodium sulfate. After removal of the solvents

in vacuo, ﬂash chromatography on silica gel (3:1, hex-

anes/EtOAc) aﬀorded 27a as a viscous oil (130 mg,

80%, 6:1 dr). Major isomer: R_f(50% EtOAc/hex-

Into a 50 mL round bottomed ﬂask were added 4 mL of

t-BuOH, 4 mL of water, K₃Fe(CN)₆(370 mg, 1.13

mmol), K₂CO₃(155 mg, 1.13 mmol), MeSO₂NH₂(36

mg, 0.38 mmol), (DHQD)₂PHAL (6.1 mg, 7.9 lmol,

2.1 mol %), and OsO₄(1.9 mg, 7.5 lmol, 2 mol %). The

mixture was stirred at rt for about 15 min and then

cooled to 0 ꢁC. To this solution was added 14a (150

mg, 0.38 mmol) and the reaction was stirred vigorously

at 0 ꢁC overnight. The reaction was quenched by the

addition of solid sodium sulﬁte (50 mg) at rt. EtOAc

(15 mL) was added to the reaction mixture and after

separation of the layers, the aqueous phase was further

extracted with EtOAc (2 · 10 mL). The combined or-

ganic layers were washed with brine and dried over

anhydrous sodium sulfate. After removal of the solvents

in vacuo, ﬂash chromatography on silica gel (3:1, hex-

anes/EtOAc) aﬀorded 28a as a viscous oil (130 mg,

80%, 3:1 dr). Major isomer: R_f(50% EtOAc/hex-

25

ane) = 0.43; ½aꢁ_Dꢂ4.13 (c 2.3, CH₂Cl₂); IR (thin ﬁlm):

3455, 3032, 2924, 1720, 1608, 1590, 1454, 1369, 1273,

1196, 1099, 1078, 1022, 930, 864 cm^ꢂ1

;

¹H NMR

25

(CDCl₃, 600 MHz): d 7.87 (m, 2H), 7.30 (m, 7H), 5.73

(dddd, J = 24, 6.6, 4.2, 2.4 Hz, 1H), 4.91 (ddd, J =

46.2, 8.4, 2.4 Hz, 1H), 4.60 (br s, 2H), 4.43 (d, J = 6,

1H), 4.34 (ddd, J = 8.4, 8.4, 6, 1H), 4.29 (qd, J = 7.2,

1.8 Hz, 1H), 4.28 (qd, J = 7.2, 1.8 Hz, 1H), 3.98 (dd,

J = 10.8, 6 Hz, 1H), 3.81 (dd, J = 10.8, 4.2 Hz, 1H),

3.31 (d, J = 8.4 Hz, 1H), 3.29 (d, J = 6 Hz, 1H), 2.40

(s, 3H), 1.29 (t, J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃,

150 MHz): d 172.8, 165.8, 138.2, 137.1, 134.1, 130.3,

129.5, 128.4 (2C), 128.3, 127.9, 127.7 (2C), 126.9, 91.1

(d, J = 179.4 Hz), 73.5, 71.6 (d, J = 20.1 Hz), 70.0 (d,

J = 25.9 Hz), 69.9 (d, J = 2.2 Hz), 66.8 (d, J = 8.1 Hz),

62.2, 21.2, 14.1; CIMS calculated for [C₁₅H₂₇FO₇+

Na]⁺: 457.1633. Found: 457.1635.

ane) = 0.42; ½aꢁ_D7.2 (c 1, CH₂Cl₂); IR (thin ﬁlm):

3456, 3032, 2924, 1725, 1608, 1590, 1455, 1369, 1276,

1200, 1101, 1026, 744 cm^ꢂ1

;

¹H NMR (CDCl₃,

600 MHz): d 7.86 (m, 2H), 7.29 (m, 7H), 5.53 (dddd,

J = 15, 6.6, 4.2, 2.4 Hz, 1H), 5.06 (ddd, J = 47.4, 6,

4.8 Hz, 1H), 4.61 (d, J = 12 Hz, 1H), 4.56 (d,

J = 12 Hz, 1H), 4.40 (dd, J = 4.2, 2.4, 1H), 4.29 (q,

J = 7.2, Hz, 2H), 4.16 (ddd, J = 21, 4.8, 2.4, 1H), 3.94

(ddd, J = 10.8, 6 Hz, 1H), 3.81 (dd, J = 10.8, 6.6 Hz,

1H), 3.22 (d, J = 4.2 Hz, 1H), 2.97 (d, J = 7.2 Hz, 1H),

2.40 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃,

150 MHz): d 172.5, 165.7, 138.2, 137.6, 134.1, 130.3,

129.3, 128.4 (2C), 128.3, 128.2, 127.8, 127.6, 126.9,

91.2 (d, J = 175.9 Hz), 73.4, 70.7 (d, J = 7.9 Hz), 70.6

(d, J = 11.6 Hz), 67.2 (d, J = 4.6 Hz), 62.3 (d, J =

28.3 Hz), 60.3, 21.1, 14.0; CIMS calculated for

[C₁₅H₂₇FO₇+Na]⁺: 457.1633. Found: 457.1635.

4.43. (2S,3R,4R,5R)-5-(Ethoxycarbonyl)-1-(benzyloxy)-

3-ﬂuoro-4,5-dihydroxypentan-2-yl 3-methylbenzoate

(27a)

4.45. (2R,3R,4S,5S)-Ethyl 6-(benzyloxy)-4-ﬂuoro-2,3,5-

trihydroxyhexanoate (19a)

To a solution of 14a (100 mg, 0.25 mmol) in 0.5 mL of

t-BuOH/0.5 mL of acetone were added 0.18 mL of 50%

NMO in H₂O (88 mg, 0.75 mmol) and 1.8 mg OsO₄

(5.0 lmol, 2 mol %). The reaction mixture was stirred

vigorously at 0 ꢁC overnight. The reaction was

quenched by the addition of solid sodium sulﬁte

(50 mg) at rt and ﬁltered through a pad of Celite and

eluted with CH₃OH and dried over sodium sulfate.

Then the solvent was removed under reduced pressure,

ﬂash chromatography on silica gel (3:1 (v/v), hexanes/

EtOAc) aﬀorded 27a as a viscous oil (98 mg, 90%, 5:1

dr). Major isomer: R_f(50% EtOAc/hexane) = 0.43;

To a solution of 27a (100 mg, 0.23 mmol) in EtOH

(2 mL) was added 10% HCl in EtOH (0.3 mL) and the

mixture was heated at reﬂux for 24 h. Then EtOH was

removed under reduced pressure and ﬂash chromatogra-

phy on silica gel (1:1, hexanes/EtOAc) aﬀorded 19a as a

viscous oil (55 mg, 75%). R_f(60% EtOAc/hexane) =

25

0.20; ½aꢁ_Dꢂ2.1 (c 2.7, CH₂Cl₂); IR (thin ﬁlm): 3402,

3033, 2922, 2862, 1736, 1496, 1453, 1365, 1216, 1072,

1

1026, 811 cm^ꢂ1; H NMR (CDCl₃, 600 MHz): d 7.33

(m, 5H), 4.60 (ddd, J = 46.6, 8.4, 6.6 Hz, 1H), 4.58

1520

Md. M. Ahmed, G. A. O’Doherty / Carbohydrate Research 341 (2006) 1505–1521

(br s, 2H), 4.39 (dd, J = 6.6, 1.2 Hz, 1H), 4.29 (q,

J = 7.2 Hz, 2H), 4.22 (ddd, J = 13.2, 6.6, 1.2 Hz, 1H),

4.14 (dddd, J = 16.2, 6.6, 6, 5.4 Hz, 1H), 3.72 (dd,

J = 9.6, 6 Hz, 1H), 3.66 (dd, J = 9.6, 6.6 Hz, 1H), 3.49

(d, J = 5.4 Hz, 1H), 3.33 (d, J = 6.6 Hz, 1H), 3.09 (d,

J = 4.8 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H); ¹³C NMR

(CDCl₃, 150 MHz): d 172.8, 137.3, 128.5 (2C), 128.0,

127.8 (2C), 89.1 (d, J = 175.4 Hz), 73.7, 71.8 (d,

J = 25.5 Hz), 71.2 (d, J = 24.7 Hz), 70.0 (d, J =

3.5 Hz), 69.9 (d, J = 5.8 Hz), 62.1, 14.1; CIMS

calculated for [C₁₅H₂₁FO₆+Na]⁺: 339.1214. Found:

339.1217.

phy on silica gel (4:1, hexane/EtOAc) to yield 26a.

(24 mg, 95%) as a viscous oil. R_f(40% EtOAc) = 0.37;

25

½aꢁ_D4.9 (c 2, CH₂Cl₂); IR (thin ﬁlm): 2872, 1751,

1454, 1373, 1216, 1103, 1057, 748 cm^ꢂ^{1 1}H NMR

;

(CDCl₃, 600 MHz): d 7.33 (m, 5H), 5.75 (ddd, J =

16.8, 10.2, 2.4 Hz, 1H), 5.69 (dd, J = 10.2, 2.4 Hz,

1H), 5.14 (ddd, J = 48, 2.4, 2.4 Hz, 1H), 4.80 (dddd,

J = 16.8, 4.8, 2.4, 2.4 Hz, 1H), 4.64 (d, J = 12 Hz, 1H),

4.53 (d, J = 12 Hz, 1H), 3.74 (ddd, J = 10.8, 4.8,

2.4 Hz, 1H), 3.71 (dd, J = 10.8, 2.4 Hz, 1H), 2.15 (s,

3H), 2.13 (s, 3H); ¹³C NMR (CDCl₃, 150 MHz): d

169.9, 169.6, 165.4, 136.5, 128.5 (2C), 128.1, 127.8

(2C), 88.7 (d, J = 160.9 Hz), 78.7 (d, J = 20.8 Hz),

74.0, 68.7 (d, J = 16.8 Hz), 67.8, 67.0, 20.6, 20.4; CIMS

calculated for [C₁₇H₁₉FO₇+Na]⁺: 377.3167. Found:

377.3169.

4.46. (3R,4R,5R,6S)-6-((Benzyloxy)methyl)-5-ﬂuoro-

tetrahydro-3,4-dihydroxypyran-2-one (25a)

To a solution of 19a (50 mg, 0.50 mmol) in benzene

(1 mL) was added pyridinium toluenesulfonate (1.5

mg, 5.7 lmol, 5 mol %), and the mixture was heated at

reﬂux for 5 h. The reaction was cooled to rt and

quenched by the addition of saturated aqueous sodium

bicarbonate (0.5 mL). The aqueous layer was extracted

with ether (3 · 10 mL). The organic layer was washed

with brine (10 mL) and dried with anhydrous sodium

sulfate. After removal of the solvents in vacuo, ﬂash

chromatography on silica gel (1:1, hexanes/EtOAc)

aﬀorded 25a as a viscous oil (28 mg, 90%). R_f(60%

Acknowledgments

We are grateful to NIH (GM63150) and NSF (CHE-

0415469) for the support of our research program and

NSF-EPSCoR (0314742) for a 600 MHz NMR at

WVU.

References

25

EtOAc) = 0.19; ½aꢁ_Dꢂ1.4 (c 1.5, CH₂Cl₂); IR (thin ﬁlm):

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3404, 3032, 2872, 1742, 1497, 1454, 1367, 1200, 1103,

1

1025, 957, 917 cm^ꢂ1; H NMR (CDCl₃, 600 MHz): d

7.30 (m, 5H), 5.01 (ddd, J = 49.2, 1.8, 1.2 Hz, 1H),

4.75 (dd, J = 10.8, 1.8 Hz, 1H), 4.57 (d, J = 12 Hz,

1H), 4.50 (ddd, J = 16, 10.8, 1.2 Hz, 1H), 4.47 (d,

J = 12 Hz, 1H), 4.37 (dddd, J = 16.8, 10.8, 2.4, 1.8 Hz,

1H), 3.74 (br s, 1H), 3.68 (ddd, J = 10.8, 4.2, 2.4 Hz,

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Article Doi

De novo asymmetric syntheses of C-4-substituted sugars via an iterative dihydroxylation strategy

DOI: 10.1016/j.carres.2006.03.024

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Full text of DOI:10.1016/j.carres.2006.03.024

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