Syntheses of four D- and L-hoxoses via diastereoselective and enantioselective dihydroxylation reactions

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Carbohydrate Research 328 (2000) 17–36

Syntheses of four

D

- and -hexoses via diastereoselective

L

and enantioselective dihydroxylation reactions

Joel M. Harris, Mark D. Kera¨nen, Hang Nguyen ¹, Victor G. Young ²,

George A. O’Doherty *

Department of Chemistry, Uni6ersity of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, USA

Received 25 October 1999; accepted 4 January 2000

Abstract

An expeditious approach to various protected hexoses has been developed by the use of the Sharpless catalytic

asymmetric dihydroxylation reaction. Applying the Sharpless catalytic asymmetric dihydroxylation reaction on

vinylfuran, diols with high enantioexcess are produced. The resulting diols can be stereoselectively transformed into

either protected

-talose and gulose have been synthesized in 19% overall yields, respectively. Using a modiﬁed strategy, both

protected - and

D- or L-mannose in ﬁve steps and approximately 39% yield from furfural. Similarly, both D- and

L

D

L

-gulo- and allo-sugar-d-lactones were synthesized in eight steps and ꢀ20% overall yield from

Keywords: Vinylfuran; Talose; Allose; Mannose; Gulose; Dihydroxylation; Sugar lactone; AD mix; Enantioselective synthesis

1. Introduction

to the hexoses [6]³. We are particularly inter-

ested in studying oligosaccharide analogs of

The de novo enantioselective synthesis of

the hexoses stands as a challenge to asymmet-

ric catalysis (for a good review, see Ref. [1]).

Despite some germinal efforts toward the

hexoses, notably by Masamune and Sharpless

(epoxidation) [2], Danishefsky (Diels–Alder)

(for a review, see Ref. [3a], and for improved

catalysis, see Ref. [3b]), Johnson and Hudlicky

(enzymatic desymmetrization) [4] and Wong

and Sharpless (osmium/enzyme) [5], there still

does not exist a practical, nonenzymatic route

the all

D

-, all

L

-, and mixed

D

- and

L

-oligo-

-gu-

sugar structures, such as the

D

-mannose-

L

lose portion of bleomycin [7] (for a synthesis

of bleomycin see Ref. [7a]). Herein, we would

like to present our discovery of an expeditious

* Corresponding author. Tel.: +1-612-6258862; fax: +1-

612-6267541.

E-mail address: odoherty@chem.umn.edu (G.A. O’Do-

herty).

Fig. 1. Retrosynthetic scheme for protected

mannopyranose.

D- and L-

¹University of Minnesota Undergraduate Research Oppor-

tunity Program (UROP) participant.

²Corresponding author for questions regarding the X-ray

structure.

³Recently Wong has developed a route to a mixture of

glucose and fructose using an enzymatic process [6].

PII: S0008-6215(00)00031-8

18

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

Scheme 1.

route to either mannose, gulose or talose using

Sharpless’s dihydroxylation reaction to set the

generation of vinylfuran constitutes a signiﬁ-

cant improvement in terms of overall efﬁ-

ciency. Crucial to our approach to the hexoses

is a simple, three-step route toward pyranone

8 from diol 2 (Scheme 2). We envision 8 as the

linchpin molecule that will be amenable for

the synthesis of all the possible stereoisomers

of the hexoses.

D

- or

used.

We initially targeted the differentially pro-

tected - and -mannose 1 as building blocks

L-conﬁguration depending on the ligand

D

L

for the oligosaccharide assembly (Fig. 1). We

desired a route in which the synthetic efﬁ-

ciency was better than traditional protection–

deprotection strategies from mannose and is

Furan diol.—We have found that the key

furan diol 2 could be prepared from furfural 4

via an asymmetric dihydroxylation of vinyl-

furan. This was most easily accomplished by a

one-pot Peterson oleﬁnation–Sharpless dihy-

droxylation procedure. This in situ use of

vinylfuran allows for much higher yields of

diol 2 without any loss of enantioexcess.

Preparation of the trimethylsilylmethylmag-

nesium chloride Grignard reagent from

chloromethyltrimethylsilane and magnesium,

followed by addition of furfural, gave excel-

lent yields of b-hydroxysilane 5. Washing a 2

M ether solution of furan 5 with 1 N HCl

produces a 2 M vinylfuran solution, which can

be used as is in the AD-mix reaction after

washing with saturated aqueous NaHCO₃.

The 2 M solution of vinylfuran was used

directly in the t-BuOH/H₂O AD-mix reaction

mixture developed by Sharpless [10,14]. The

(DHQ)₂PHAL ligand gave an 85% yield of

amenable to both

D- and

L

-mannose. The

ideal synthesis should also start from a com-

mercially available starting material that is

even cheaper than

outlined below has led to a highly stereocon-

trolled synthesis of - or -mannose in only

D

-mannose^4,5. The strategy

D

L

ﬁve steps and in approximately 39% yield

from furfural (Scheme 4) [8].

2. Results and discussion

In order to accomplish this goal we, as have

others, recognized that substituted furyl

carbinols possess the proper C-5 stereochem-

istry for the hexopyranoses (for a good review

see Ref. [9]). Our approach relies upon the use

of catalytic asymmetric osmium chemistry on

vinylfuran 3 developed by us [10] and

Ogasawara [11]⁶and augments the earlier

work of Achmatowicz [12]. A key part of this

sequence is our ability to convert furfural into

an ether solution of vinylfuran (Scheme 1)

[13]⁷. This one-step in situ process for the

⁴According to the Aldrich Catalog on a per-gram basis

-mannose costs 35 times more than furfural and for L-man-

D

nose the cost ratio is 4000:1.

⁵Furfural is commercially produced by Great Lakes Chem-

ical Co. [8].

⁶Ogasawara has previously demonstrated the asymmetric

dihydroxylation of vinylfuran and applied it toward the syn-

thesis of

D- and L-levoglucosenone and hexoses [11].

⁷Wittig technology provides vinylfuran in yields of the

order of 10%. Previous practical approaches to vinylfuran

involve a four-step sequence from furfural that involves a

stoichiometric Cu-promoted decarboxylation of 3-furyl-

propanoic acid [13].

Scheme 2.

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

19

(R)-diol 2(R) from furfural in 92% ee^8,9. The

(DHQD)₂PHAL ligand afforded (S)-diol 2(S)

in an 85% yield with a 90% ee [15]¹⁰.

Diol 2 can be selectively protected with

TBSCl (90%) or PivCl (85%) to give furan 6a

and 6b, respectively. Both 6a and 6b smoothly

rearrange to hemiacetal 7a and 7b when oxi-

dized with NBS in aqueous THF [12b,16].

Hemiacetals 7a and 7b exist as an equilibrat-

ing mixture of anomers, diastereomerically en-

riched mixtures of 7a equilibrate to a 1:1

mixture of anomers in deuterated chloroform.

Our hopes of taking advantage of the differ-

ence in reactivities of axial versus equatorial

anomeric alcohols were realized when hemi-

acetal 7a and 7b were treated with benzoyl

chloride at −78 °C to produce pyranone 8a

and 8b as the major diastereomers (\20:1).

This result appears to be general for acid

chlorides, as pivaloyl chloride reacts to give 8c

and 8d (\10:1) with similar selectivity, where

as TBSCl reacted with 7a to give approxi-

mately a 1:1 mixture of anomers¹¹. With the

two stereocenters of 8a–d introduced, the

molecule was poised for introduction of the

remaining functionality of the hexoses

(Scheme 2). All four pyranones 8a–d were

stereoselectively reduced under the Luche con-

ditions (NaBH₄–CeCl₃, −78 °C) [17] to give

alcohols 9a–d, respectively¹²as the only ob-

servable stereoisomer (\95%), each in 95%

yield. The relative conﬁguration of 9a–d was

assigned based upon the ꢀ10 Hz coupling

constant between the protons at C-4 and C-5

(Scheme 3).

Scheme 3.

The enantioexcess of diol 2 can be improved

(\97% ee) by a simple recrystallization of the

dibenzoate 10 from hexanes, which can be

easlily converted to 6a or 6b via a hydrolysis–

protection sequence. The absolute conﬁgura-

tion is based upon the Sharpless mnemonic

[14] and Mosher ester analysis [15].

Scheme 4.

Mannose.—Allylic alcohol 9a can be pro-

tected without puriﬁcation to give ethyl car-

bonate

9e.

Two

partially

protected

mannosugars were produced via a completely

diastereoselective dihydroxylation to give 1a

and 1b both in ꢀ90% yield (Scheme 4) (for a

review of diastereoselection in the osmium

catalyzed dihydroxylation reaction see Ref.

[18]). A differentially protected mannose was

easily achieved upon treatment of diol 1b with

trimethylorthoacetate to form a cyclic or-

thoester in situ, which was subsequently hy-

drolyzed to the axial acetate 1c. The

differentially protected mannosugar 1c was

formed in a 62% yield with a regioselectivity

greater than 25:1¹³. The relative conﬁguration

of 1a was determined by examining relevant

coupling constants and NOEs from a series of

⁸Although we were concerned about an adverse solvent

effect caused by the presence of ether, Ogasawara has ob-

served identical ee values in t-BuOH/H₂O [11a].

⁹The (R)-diol 2 has been prepared on a half-mole scale

with no reduction of enantioselectivity. Similarly the (S)-diol

2 has been prepared on a quarter-mole scale.

¹⁰The enantioexcesses were determined by examining the

¹H and ¹⁹F NMR spectra of the Mosher esters of 6a and 6b

[15].

¹H NMR, H,¹H-COSY, and H NOE experi-

ments. Particularly telling were the coupling

constants between hydrogens at C-1 and C-2

(2 Hz), C-2 and C-3 (3.5 Hz), C-3 and C-4 (9

1

¹¹The selective benzoylation allows for the simple puriﬁca-

tion of 8a without resorting to tedious chromatographic

separation. BzCl at room temperature with excess Et₃N gave

a 4:1 mixture of isomers, whereas, with 1 equivalent of Et₃N

gave a 1:1 mixture. Achmatowicz has previously shown that

molecules related to 7a gave a 1:1 mixture of methoxy

anomers with MeOH–acid [12a].

¹³A mixture of axial and equatorial acetates was produced

upon treatment of 1b with 1 equivalent of Ac₂O, which

allowed for easy detection of the \25:1 mixture by H NMR

¹²Mosher ester analysis of 9a showed that recrystallized

enone 8a had signiﬁcantly increased enantioexcess (\96%

ee).

1

spectroscopy.

20

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

Hz), C-4 and C-5 (10 Hz), and NOEs from

hydrogens C-1 and C-5 to hydrogens at C-4

and C-3, respectively.

on the pivolate group and hydrogens at C-2,

C-3 and C-5 of talose triol 12. Similarly, the

relative and absolute conﬁguration of the gu-

lose sugar 13 was conﬁrmed by single-crystal

X-ray analysis.

Scheme 5.

Gulose and talose.—The rare hexose sugars,

gulose and talose, can also be prepared from

the diastereomeric allylic alcohol 11. The C-4

isomer of allylic alcohol 9c was produced by

performing a Mitsunobu reaction sequence

(Scheme 5). Key to this transformation is the

selective hydrolysis of a p-nitrobenzoyl ester

in the presence of the anomeric ester. Al-

though this operation can be performed on

benzoate 9a, more reproducible results are

observed when pivolate 9c is used. Exposure

of 9c to the Mitsunobu reaction conditions

(PPh₃, DEAD, p-nitrobenzoic acid (PNBOH))

yielded a p-nitrobenzoic ester (65%), which

was selectively hydrolyzed with Et₃N in

MeOH to yield the axial alcohol 11 (90%) [19].

Access to 11 extends this versatile synthetic

strategy to other hexoses, as illustrated by the

synthesis of a protected talose 12 and gulose

13 (Scheme 6). Treatment of allylic alcohol 11

with OsO₄–NMO in t-BuOH–H₂O afforded

an 80% yield of the protected gulose isomer 13

[20]¹⁴. Amazingly, the protected talose isomer

12 can be selectively produced upon treatment

of 11 with the TMEDA adduct of OsO₄(80%)

[20]¹⁵. Unfortunately for this system, the hy-

droxy-directed delivery of a cis diol seems to

require an axial alcohol, since exposure of 9a

to the identical conditions only yielded the

mannose isomer 1a. The relative conﬁgura-

tions of 12 were determined by examining

relevant coupling constants and NOEs from a

Scheme 6.

Fig. 2. Retrosynthetic scheme for a 6-protected

lactone.

D-mannono-

Sugar lactones.—In the context of our re-

search program aimed at the synthesis of C-

glycoside natural products (for an application

of sugar lactones toward the synthesis of a

papulacandin see Ref. [21]), we were looking

for an easy entry into a d-lactone sugar with

the manno stereochemistry 14 (Fig. 2). To this

end we targeted the a,b-unsaturated-d-lactone

15 as a potentially versatile entry point for the

synthesis of these sugars, as well as analogs

related to styryllactone 16 [22]. Our approach

to synthesize sugar lactones relies upon an

efﬁcient enantioselective and diastereoselective

oxidation and reduction sequence.

1

series of H NMR, H,¹H-COSY, and H

NOE experiments. Some representative exam-

ples are the W-coupling between hydrogens at

C-2 and C-4, and NOEs between the methyls

Substituted a,b-unsaturated d-lactones (e.g.

styryllactones) are an important class of natu-

ral products and many synthetic methodolo-

gies have been employed to synthesize this

core structure [23]. One of the most useful

methodologies employed is the kinetic resolu-

¹⁴For a recent eight-step synthesis of gulose from

L-xylose.

Dondoni appraises L

-gulose at $2000 g⁻¹[7d].

¹⁵Less than 5% of the gulose isomer was formed. These

conditions were chosen for the hydroxy directed delivery of a

cis diol [20].

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

21

SOTf or PivCl to give 17a and 17b,

respectively. Deprotection of the anomeric

benzoyl group proved troublesome, with the

best results obtained using Et₃N, MeOH, H₂O

in a 1:5:1 ratio, giving lactol 18a or 18b in

50–60% yield. Oxidation of 18a or 18b with

MnO₂provided the a,b-unsaturated-d-lactone

19a or 19b in 75–85% yield.

Having established the feasibility of prepar-

ing the a,b-unsaturated d-lactone 19a and 19b

with complete enantio- and diastereocontrol,

we turned our attention to improving the efﬁ-

ciency of the route to the general structure of

a,b-unsaturated-d-lactones. The obvious dis-

advantage of the route in Scheme 7 is the

requisite protection of the C-1 and C-4 hy-

droxyl groups. A signiﬁcant reduction in steps

could be achieved by oxidation of lactol 7a to

ketolactone 20, provided the carbonyl groups

could be reductively differentiated (Scheme 8).

Similar approaches have been used by other

groups using CrO₃and acetic acid [28]. A

potential problem of this shorter route is the

possible racemization or b-elimination in the

ketolactone. We envisioned using a reagent

for fast oxidation of lactol 7a to ketolactone

20 that would be immediately compatible for

exposure to Luche conditions¹⁶. This was most

easily accomplished by Jones oxidation fol-

lowed by Luche reduction (Scheme 8).

Treatment of an acetone solution of 7a with

a slight excess of Jones reagent produced keto-

lactone 20 in ꢀ20 min. Upon completion the

reaction mixture was quenched with isopropyl

alcohol, washed with a saturated NaHCO₃

solution, and extracted with ether. After sol-

vent exchange (ether to MeOH), 20 was

treated with NaBH₄to yield differentially pro-

tected d-lactone 21 in 60–70% yield over two

steps with no loss of enantiomeric excess. The

observed stereoselectivity of the reduction is

explained by the apparent hydride attack on

the less hindered face of the molecule [29]¹⁷.

Protection of the allylic alcohol using PivCl,

Ac₂O, or ClCO₂Et provided 22a, 22b, or 22c

in 80, 94, and 90% yields, respectively. The

Scheme 7.

tion of 2-furylcarbinols developed by Honda

[24], Sato [25], and augmented by Zhou [26].

This strategy employs the kinetic resolution of

racemic 2-furylcarbinols with the Sharpless

epoxidation reaction conditions to produce an

optically active pyranone product resulting

from the selective, fast oxidation of only one

enantiomer of the racemic 2-furylcarbinols.

The optically pure pyranone or 2-furyl-

carbinol products of the kinetic resolution can

both be used in the synthesis of natural prod-

ucts (secondary furyl alcohols have been re-

solved both chemically and enzymatically, see

Ref. [27a,b]; for enzymatic resolutions see Ref.

[27c]).

We envisioned extending our earlier work

to synthesize these useful building blocks from

pyranone 8a–d with differentiated oxygen

functionality in a limited number of steps and

avoiding a kinetic resolution (Scheme 7). The

alcohol functionality at C-1 and C-4 needed to

be differentiated. This was easily accom-

plished by protection of 9a and 9b with TB-

¹⁶Ketolactone 20 decomposed when attempting to purify

by silica gel chromatography.

¹⁷Various selectivities have been observed depending on

the steric bulk of the substituent at C-5 [29].

Scheme 8.

22

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

1

displayed H NOE from the endo methyl of

the acetonide to the hydrogen at C-5, indicat-

ing that the substituent at C-5 controls the

facial selectivity of dihydroxylation as op-

posed to the C-4 substitution. Some represen-

tative coupling constants for the gulose sugar

24b are the cis-axial–equatorial coupling con-

stant between the hydrogens at C-5 and C-4

(2.5 Hz), the trans–diequatorial coupling con-

stant between the hydrogens at C-4 and C-3

(4.5 Hz), and the lack of W-couplings and

NOEs between the hydrogens at C-5 and C-3.

Similarly, representative coupling constants

for the allose sugar 26 were trans-diaxial cou-

pling constant between the hydrogens at C-5

and C-4 (9 Hz), cis-axial–equatorial coupling

constant between the hydrogens at C-4 and

C-3 (2.1 Hz), and cis coupling constant be-

tween the hydrogens at C-3 and C-2 (2.4 Hz).

In summary, we have developed a practical,

ﬁve-step synthesis of differentially protected

diastereomeric lactone 23 can be prepared

from 21 by a Mitsunobu reaction [19], fol-

lowed by hydrolysis of the p-nitrobenzoyl

group in 70% yield over two steps (Scheme 9).

The allylic alcohol 23 was also protected as a

TBS ether to form 19a, which conﬁrms the

diastereoselectivity of the reduction of keto-

lactone 20. This not only provides a shorter

route to lactones 21 and 23, but also provides

the d-lactone in a higher overall yield (ꢀ45%

to 21 and 32% 23 from diol 2 as compared to

ꢀ20% to 19 from diol 2).

Scheme 9.

Finally, four sugar lactones were stereose-

lectively prepared by dihydroxylation of a,b-

unsaturated d-lactones 22b–d and 19a with

OsO₄(Scheme 10). Treatment of the protected

allylic alcohols 22b–d with a catalytic amount

of OsO₄and a 50% aqueous solution of NMO

yields the gulonolactone 24b–d in ꢀ60%

yields, whereas, the bis-TBS ether 19a reacted

to give the allonolactone 26 in 73% yield. The

relative conﬁgurations of 24b–d and 26 were

determined by examining relevant coupling

D

- and -mannose sugars from furfural (39%

L

yield) via highly diastereoselective and enan-

tioselective dihydroxylation reactions. This

route is amenable to multigram-scale prepara-

tion. Further study of the diastereoselection of

the dihydroxylation reaction allowed for the

extension of this methodology to protected

and -gulose and - and -talose sugars in

comparable yields (19%). Finally, - and

gulono- and allonopyranolactones can also be

produced with equal efﬁciency (in 8 steps and

ꢀ20% overall yield from furfural). We are

currently investigating an epoxide ring open-

ing approach to the other isomers of the

hexoses as well as rare deoxy sugars. We feel

D

-

L

D

L

D

L

-

1

constants and NOEs from a series of H

1

NMR, H,¹H-COSY, and H NOE experi-

ments. Additional support for the stereochem-

ical assignment was realized by the conversion

of 24d and 26 into their corresponding ace-

tonides 25 and 27. Both lactones 25 and 27

this new efﬁcient route to -sugars will be very

beneﬁcial for the synthesis of natural and

unnatural oligosaccharides.

L

3. Experimental

General methods.—Liquid chromatography

was performed using (ﬂash chromatography)

of the indicated solvent system on ICN

reagent Silica Gel 60 (60–200 mesh). Ether

and tetrahydrofuran were distilled from ben-

zophenone and sodium metal. Dichloro-

methane and triethylamine were distilled

from calcium hydride. Hexanes refers to the

Scheme 10.

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

23

Phases were separated and the aq layer was

extracted (2×50 mL) with Et₂O and com-

bined with the organic layer. The organic

layer was washed (2×50 mL) with satd aq

NaHCO₃and added to a solution of 300 mL

of t-BuOH, 750 mL of H₂O, 50 g of AD-mix-

a, 133 g of K₃Fe(CN)₆, and 56 g of K₂CO₃at

0 °C. The solution was vigorously stirred with

a mechanical stirrer for 12 h at 0 °C. The

reaction was slowly quenched with (500 mL)

satd aq Na₂SO₃. The phases were separated,

and the aq layer was extracted (6×100 mL)

with EtOAc. The organic layer was washed

with satd aq NaHCO₃(2×100 mL), brine

(2×100 mL), dried (Na₂SO₄), and concen-

trated under reduced pressure. The crude

product was puriﬁed by silica gel ﬂash chro-

matography eluting with 2:3 Et₂O–hexanes to

yield 25.0 g (0.195 mol, 85%) of 2: R_f0.37 (1:1

Et₂O–hexanes); [h]²_D¹+32.0° (c 2.17, CH₂Cl₂);

IR (thin ﬁlm, cm⁻¹) 3390, 2933, 2881, 1684,

1505, 1464, 1228; ¹H NMR (300 MHz,

CDCl₃) l 7.30 (dd, J 1.8, 0.6 Hz, 1 H), 6.27

(dd, J 4.0, 1.8 Hz, 1 H), 6.23 (dd, J 4.0, 0.6

Hz, 1 H), 4.71 (t, J 5.9 Hz, 1 H), 4.54 (bs, 2

H), 3.74 (d, J 5.9 Hz, 2 H); ¹³C NMR (75

MHz, CDCl₃) l 153.9, 142.3, 110.5, 107.0,

68.4, 65.0; CIHRMS Calcd for [C₆H₈O₃+

NH₄]⁺: 146.0817. Found: 146.0822; Anal.

Calcd for C₆H₈O₃: C, 56.23; H, 6.30. Found:

C, 56.04; H, 6.20.

petroleum fraction bp 40–60 °C. Commercial

reagents were used without puriﬁcation unless

1

otherwise noted. H and ¹³C spectra were

recorded on Varian 200, 300 and 500 MHz

spectrometers. Chemical shifts are reported

relative to internal tetramethylsilane (l 0.00

1

ppm) or CDCl₃(l 7.26 ppm) for H and

CDCl₃(l 77.0 ppm) for ¹³C. Air- and/or

moisture-sensitive reactions were carried out

under an atmosphere of nitrogen using oven-

dried glassware and standard syringe–septa

techniques. Melting points are uncorrected.

Combustion analyses were performed by M-

H-W Laboratories, Phoenix, AZ.

1 - (2 - Furyl) - 2 - trimethylsilanylethan - 1 - ol

(5).—Magnesium turnings (10.1 g, 0.415 mol)

were placed in a 1-L 3-neck round-bottom

ﬂask and a condenser along with a side arm

addition funnel were attached. The apparatus

was ﬂame dried (3×), each time ﬂushing with

nitrogen. Chloromethyltrimethylsilane (42.4 g,

0.346 mol) in 200 mL of Et₂O were added

slowly to the dry magnesium. After the addi-

tion, the solution was reﬂuxed for 1 h. Freshly

distilled furfural (25.0 mL, 0.302 mol) and 300

mL of Et₂O were added slowly to the Grig-

nard reagent at 0 °C, and the solution was

stirred for 3 h at 0 °C and 9 h at room

temperature (rt). The reaction was quenched

with 200 mL of satd aq NH₄Cl and extracted

(3×100 mL) with Et₂O. The organic layer

was washed with satd aq NaHCO₃(2×50

mL), brine (2×50 mL), dried (Na₂SO₄), and

concentrated under reduced pressure to give

the b-hydroxy silane 5 in 90% yield (50.1 g,

0.272 mol): R_f0.58 (3:7 Et₂O–hexanes); IR

(thin ﬁlm, cm⁻¹) 3390, 2950, 2895, 1655,

(1R)-1-(2-Furyl)-2-tert-butyldimethylsilanyl-

oxyethanol (6a).—Diol 2 (0.986 g, 7.70

mmol), 15 mL of CH₂Cl₂, and 5.5 mL of Et₃N

were added to a round-bottom ﬂask and

cooled to 0 °C. A catalytic amount (50 mg,

0.41 mmol) of DMAP was added, followed by

addition of tert-butylchlorodimethylsilane

(1.19 g, 7.89 mmol), and the solution was

stirred at 0 °C for 6 h. The reaction was

quenched with 1 M NaHSO₄and extracted

(3×25 mL) with Et₂O, washed with satd aq

NaHCO₃(2×20 mL), and dried (Na₂SO₄).

The crude product was puriﬁed by silica gel

ﬂash chromatography eluting with 1:3 Et₂O–

hexanes to yield 1.69 g (6.97 mmol, 91%) of

6a: R_f0.55 (3:7 Et₂O–hexanes); [h]²_D¹+15.9°

(c 1.37, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 3447,

1

1505, 1250; H NMR (300 MHz, CDCl₃) l

7.28 (dd, J 1.8, 0.7 Hz, 1 H), 6.24 (dd, J 3.1,

1.8 Hz, 1 H), 6.13 (d, J 3.3 Hz, 1 H), 4.77 (dd,

J 8.8, 6.9 Hz, 1 H), 3.13 (bs, 1 H), 1.28 (dd, J

14.1, 8.8 Hz, 1 H), 1.23 (dd, J 14.1, 6.8 Hz, 1

H), −0.10 (s, 9 H); ¹³C NMR (75 MHz,

CDCl₃) l 157.7, 141.6, 110.1, 105.5, 65.6, 24.8,

−1.4; CIHRMS Calcd for [C₉H₁₆O₂Si]⁺:

184.0920. Found: 184.0905.

(1R)-1-(2-Furyl)ethan-1,2-diol (2).—The b-

hydroxy silane (44.2 g, 0.240 mol) and 120 mL

of Et₂O were added to a 500-mL round-bot-

tom ﬂask, followed by addition of 120 mL of

1 M HCl, and the solution was stirred for 1 h.

1

2954, 2930, 2884, 2857, 1471, 1463, 1361; H

NMR (300 MHz, CDCl₃) l 7.37 (dd, J 1.8,

0.9 Hz, 1 H), 6.35 (dd, J 3.3, 1.8 Hz, 1 H),

24

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

mp 82–83 °C; R_f0.50 (1:4 EtOAc–hexanes);

[h]²_D¹59.4° (c 2.06, CH₂Cl₂); IR (thin ﬁlm,

cm⁻¹) 3016, 2977, 1714, 1601, 1504, 1452,

1397, 1317, 1262; ¹H NMR (500 MHz,

CDCl₃) l 8.08 (ddd, J 8.0, 2.0, 1.5 Hz, 2 H),

8.00 (ddd, J 7.5, 2.0, 1.5 Hz, 2 H), 7.56 (ddd,

J 9.0, 1.5, 1.0 Hz, 1 H), 7.53 (ddd, J 8.0, 2.0,

1.5 Hz, 1 H), 7.43 (m, 5 H), 6.55 (d, J 2.5 Hz,

1 H), 6.53 (dd, J 7.5, 4.0 Hz, 1 H), 6.40 (dd, J

3.5, 2.0 Hz, 1 H), 4.90 (dd, J 11.5, 8.0 Hz, 1

H), 4.81 (dd, J 11.5, 4.5 Hz, 1 H); ¹³C NMR

(125 MHz, CDCl₃) l 166.1, 165.5, 149.3,

133.2, 133.1, 129.8, 129.7, 129.6, 129.5, 128.4,

(2 C), 110.5, 109.8, 66.9, 63.9; CIHRMS

Calcd for [C₂₀H₁₆O₅+NH₄]⁺: 354.1342.

Found: 354.1336; Anal. Calcd for C, 71.41; H,

4.78. Found: C, 71.40; H, 4.78.

6.33 (dd, J 3.3, 0.9 Hz, 1 H), 4.75 (dd, J 6.4,

4.6 Hz, 1 H), 3.86 (dd, J 10.1, 4.6 Hz, 1 H),

3.85 (dd, J 10.1, 6.7 Hz, 1 H), 3.04 (bs, 1 H),

0.90 (s, 9 H), 0.07 (s, 6 H); ¹³C NMR (75

MHz, CDCl₃) l 154.0, 142.0, 110.3, 107.1,

68.5, 65.9, 26.0, 18.4, −5.3; CIHRMS Calcd

for [(C₁₂H₂₂O₃Si)−H₂O]⁺: 225.1310. Found:

225.1296; Anal. Calcd for C, 59.47; H, 9.16.

Found: C, 59.80; H, 9.37.

1-[(2-Furan-2-yl)-2-hydroxy]ethyl pi6alate

(6b).—Diol 2 (1.96 g, 15.3 mmol), 30 mL of

CH₂Cl₂, and 1.62 mL of pyridine were added

to a round-bottom ﬂask and cooled to 0 °C. A

catalytic amount (93 mg, 0.77 mmol) of

DMAP was added, followed by addition of

pivaloyl chloride (1.89 mL, 15.3 mL), and the

solution was stirred at 0 °C for 12 h. The

reaction was quenched with satd aq NaHCO₃

(30 mL), extracted (3×25 mL) with Et₂O,

combined and dried (Na₂SO₄). The crude

product was puriﬁed by silica gel ﬂash chro-

matography eluting with 1:5 EtOAc–hexanes

to yield 2.76 g (13.0 mmol, 85%) of 6b: R_f0.33

(1:4 EtOAc–hexanes); [h]²_D¹+15.0° (c 2.76,

CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 3448, 2973,

(2R)-2-tert-Butyldimethylsilanyloxymethyl-

6-hydroxy-6H-pyran-3-one (7a).—Compound

6a (1.69 g, 6.97 mmol), 12 mL of THF, and 3

mL of H₂O were added to a round-bottom

ﬂask and cooled to 0 °C. Solid NaHCO₃(1.17

g, 13.9 mmol), NaOAc·3H₂O (0.950 g, 6.98

mmol), and NBS (1.24 g, 6.97 mmol) were

added to the solution, and the mixture was

stirred for 1 h at 0 °C. The reaction was

quenched with satd aq NaHCO₃(15 mL),

extracted (3×25 mL) with Et₂O, dried

(Na₂SO₄), concentrated under reduced pres-

sure and puriﬁed by silica gel chromatography

eluting with 1:4 EtOAc–hexanes to give 1.71 g

(6.62 mmol, 95%) of 7a: R_f0.40 (2:3 Et₂O–

hexanes); IR (thin ﬁlm, cm⁻¹) 3388, 2951,

1

1731, 1481, 1462, 1285; H NMR (500 MHz,

CDCl₃) l 7.38 (dd, J 1.9, 0.9 Hz, 1 H), 6.33

(dd, J 3.4, 2.0 Hz, 1 H), 6.30 (dd, J 3.2, 0.9

Hz, 1 H), 4.94 (dd, J 5.3, 5.3 Hz, 1 H), 4.37

(dd, J 11.5, 6.5 Hz, 1 H), 4.34 (dd, J 11.5, 4.9

Hz, 1 H), 2.74 (bs, 1 H), 1.17 (s, 9 H); ¹³C

NMR (75 MHz, CDCl₃) l 154.0, 142.0, 110.3,

107.1, 68.5, 65.9, 26.0, 18.4, −5.3; CIHRMS

Calcd for [(C₁₂H₂₂O₃Si)−H₂O]⁺: 225.1310.

Found: 225.1296. Anal. Calcd for C, 59.47; H,

9.16. Found: C, 59.80; H, 9.37.

1

2929, 2884, 2858, 1699, 1464, 1256; H NMR

(300 MHz, CDCl₃) major isomer l 6.93 (dd, J

10.3, 3.3 Hz, 1 H), 6.12 (dd, J 10.4, 0.6 Hz, 1

H), 5.79 (dd, J 5.1, 3.1 Hz, 1 H), 4.59 (dd, J

5.0, 2.8 Hz, 1 H), 4.02 (dd, J 11.2, 5 Hz, 1 H),

3.93 (dd, J 11.2, 2.0 Hz, 1 H), 0.87 (s, 9 H),

0.07 (s, 3 H), 0.06 (s, 3 H); ¹³C NMR (75

MHz, CDCl₃) major isomer l 194.9, 145.9,

128.1, 88.1, 76.7, 63.5, 25.8, 18.5, −5.2, −

5.3; CIHRMS Calcd for [(C₁₂H₂₂O₄Si)+H]⁺:

259.1366. Found: 259.1366; Anal. Calcd for

C, 55.79; H, 8.59. Found: C, 55.86; H, 8.45.

(2R) - 6 - Hydroxy - 3 - oxo - 3,6 - dihydro - 2H-

pyran-2-ylmethyl pi6alate (7b).—Compound

6b (2.42 g, 11.4 mmol), 30 mL of THF, and 10

mL of H₂O were added to a round-bottom

ﬂask and cooled to 0 °C. Solid NaHCO₃(1.92

g, 22.8 mmol), NaOAc·3H₂O (1.55 g, 11.4

(2R) - 1,2 - Di - O - benzoyl - 1 - (furan - 2 - yl)-

ethane-1,2-diol (10).—Diol 2 (25 g, 0.20 mol)

was dissolved in 400 mL of CH₂Cl₂, and 108

mL of Et₃N were added to the solution. A

catalytic amount of DMAP (1.19 g, 9.7 mmol)

and benzoyl chloride (68 mL, 0.59 mol) were

added to solution and stirred for 12 h. The

reaction was quenched with 150 mL satd aq

NaHSO₄, and the organic layer was washed

with 200 mL of satd aq NaHCO₃. The aq

layers were extracted (5×100 mL) with Et₂O

and the organic fractions were combined,

dried (MgSO₄), and concentrated, and the

products were recrystallized from hexanes to

yield 53 g (0.16 mol, 80%) of dibenzoate 10:

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

25

363.1628. Found: 363.1653; Anal. Calcd for

C, 62.95; H, 7.23. Found: C, 63.14; H, 7.42.

(2S,6R)-6-(Pi6aloyloxymethyl)-5-oxo-5,6-

dihydro-2H-pyran-2-yl benzoate (8b).—Com-

pound 7b (1.10 g, 4.82 mmol), 40 mL of

CH₂Cl₂, and 1.5 mL of Et₃N were added to a

round-bottom ﬂask and cooled to −78 °C. A

catalytic amount (30 mg, 0.25 mmol) of

DMAP and benzoyl chloride (0.84 mL, 7.2

mmol) were added, and the solution was

stirred for 3 h at −78 °C. The reaction was

quenched with 50 mL of satd aq NaHCO₃,

extracted (3×50 mL) with Et₂O, dried

(Na₂SO₄), and concentrated under reduced

pressure. The crude product was puriﬁed us-

ing silica gel ﬂash chromatography eluting

with 1:9 EtOAc–hexanes to give 1.12 g (3.37

mmol, 70%) of 8b: mp 87–89 °C; R_f0.38 (1:4

EtOAc–hexanes); [h]²_D¹−180.9° (c 1.59,

CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 2972, 1731,

1703, 1452, 1265; ¹H NMR (500 MHz,

CDCl₃) l 8.05 (dd, J 8.0, 1.5 Hz, 2 H), 7.62

(tt, J 8.0, 7.0, 1.5 Hz, 1 H), 7.47 (tt, J 8.0, 7.0,

1.5 Hz, 2 H), 7.08 (dd, J 10.0, 4.0 Hz, 1 H),

6.82 (dd, J 3.5 Hz, 1 H), 6.30 (dd, J 10.5 Hz,

1 H), 4.83 (dd, J 5.0, 3.0 Hz, 1 H), 4.54 (ddd,

J 12.0, 3.0 Hz, 1 H), 4.50 (dd, J 12.0, 5.0 Hz,

1 H), 1.14 (s, 9 H); ¹³C NMR (125 MHz,

CDCl₃) l 192.3, 177.9, 164.8, 142.2, 133.8,

129.8, 128.9, 128.8, 128.6, 87.3, 74.5, 62.2,

38.7, 26.9; CIHRMS Calcd for [C₁₈H₂₀O₆+

NH₄]⁺: 350.1604. Found: 350.1609; Anal.

Calcd for C, 65.04; H, 6.07. Found: C, 65.26;

H, 6.02.

(2S,6R) - 6 - (tert - Butyldimethylsilanyloxy-

methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl pi-

6alate (8c).—Compound 7a (2.22 g, 8.59

mmol), 30 mL of CH₂Cl₂, and 1.5 mL of Et₃N

were added to a round-bottom ﬂask and

cooled to −78 °C. A catalytic amount (53

mg, 0.43 mmol) of DMAP and pivaloyl chlo-

ride (1.06 mL, 8.59 mmol) were added, and

the solution was stirred for 3 h at −78 °C.

The reaction was quenched with 50 mL of

satd aq NaHCO₃, extracted (3×50 mL) with

Et₂O, dried (Na₂SO₄), and concentrated under

reduced pressure. The crude product was

puriﬁed using silica gel ﬂash chromatography

eluting with 1:9 EtOAc–hexanes to give 2.41 g

(7.04 mmol, 82%) of 8c: mp 88–90 °C; R_f0.45

(1:4 EtOAc–hexanes); [h]²_D¹−92.7° (c 0.89,

mmol), and NBS (2.23 g, 12.5 mmol) were

added to the solution, and the mixture was

stirred for 1 h at 0 °C. The reaction was

quenched with satd aq NaHCO₃(40 mL),

extracted (3×50 mL) with Et₂O, dried

(Na₂SO₄), concentrated under reduced pres-

sure, and puriﬁed by silica gel chromatogra-

phy eluting with 1:4 EtOAc–hexanes to give

2.47 g (10.8 mmol, 95%) of 7b: R_f0.24 (3:7

EtOAc–hexanes); IR (thin ﬁlm, cm⁻¹) 3436,

2974, 2937, 2874, 1732, 1700, 1481, 1369,

1

1286; H NMR (500 MHz, CDCl₃) major

isomer l 6.94 (dd, J 10.0, 3.5 Hz, 1 H), 6.13

(dd, J 10.0 Hz, 1 H), 5.67 (dd, J 3.5, 3.5 Hz,

1 H), 4.77 (dd, J 4.5, 3.0 Hz, 1 H), 4.50 (dd, J

12.0, 3.0 Hz, 1 H), 4.45 (dd, J 12.0, 4.5 Hz, 1

H), 4.17 (bs, 1 H), 1.13 (s, 9 H); ¹³C NMR

(125 MHz, CDCl₃) major isomer l 193.5,

178.5, 145.5, 127.4, 87.6, 72.9, 62.6, 38.8, 27.0;

CIHRMS Calcd for [(C₁₁H₁₆O₅)+H]⁺:

229.1076. Found: 229.1069.

(2S,6R) - 6 - (tert - Butyldimethylsilanyloxy-

methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl ben-

zoate (8a).—Compound 7a (1.54 g, 5.96

mmol), 20 mL of CH₂Cl₂, and 5 mL of Et₃N

were added to a round-bottom ﬂask and

cooled to −78 °C. A catalytic amount (75

mg, 0.61 mmol) of DMAP and benzoyl chlo-

ride (0.70 mL, 6.0 mmol) were added, and the

solution was stirred for 3 h at −78 °C. The

reaction was quenched with 50 mL of satd aq

NaHCO₃, extracted (3×50 mL) with Et₂O,

dried (Na₂SO₄), and concentrated under re-

duced pressure. The crude product was

puriﬁed using silica gel ﬂash chromatography

eluting with 1:9 EtOAc–hexanes to give 1.62 g

(4.47 mmol, 60%) of 8a: mp 107–110 °C; R_f

0.43 (2:3 Et₂O–hexanes); [h]²_D¹−178.75° (c

0.64, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 2935,

1

1716, 1690, 1454, 1264; H NMR (500 MHz,

CDCl₃) l 8.04 (dd, J 8.4, 1.4 Hz, 2 H), 7.58

(tt, J 7.5, 1.4 Hz, 1 H), 7.44 (tt, J 7.5, 1.5 Hz,

2 H), 7.04 (ddd, J 10.2, 3.5, 1.7 Hz, 1 H), 6.86

(dd, J 3.5, 1.7 Hz, 1 H), 6.30 (dd, J 10.4, 1.5

Hz, 1 H), 4.59 (dd, J 4.1, 2.3 Hz, 1 H), 4.10

(ddd, J 11.3, 4.1, 1.7 Hz, 1 H), 4.04 (ddd, J

11.3, 4.0, 1.7 Hz, 1 H), 0.83 (s, 9 H), 0.06 (s,

3 H), 0.04 (s, 3 H); ¹³C NMR (125 MHz,

CDCl₃) l 193.7, 164.8, 142.1, 133.5, 129.8,

129.2, 129.1, 128.4, 87.6, 77.9, 62.7, 25.7, 18.1,

−5.5; CIHRMS Calcd for [C₁₉H₂₆O₅Si+H]⁺:

26

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 2935, 2910,

was quenched with 20 mL of water. The layers

were separated, and the aq layer was extracted

with Et₂O (5×20 mL) and washed with 50

mL of brine. The combined organic extracts

were dried over MgSO₄, ﬁltered, concentrated

under reduced pressure, and puriﬁed by silica

gel chromatography eluting with 1:4 EtOAc–

hexanes to give 118 mg (0.323 mmol, 95%

yield) of alcohol 9a: R_f0.35 (1:4 EtOAc–hex-

anes); [h]²_D¹−85.9° (c 2.55, CH₂Cl₂); IR (thin

ﬁlm, cm⁻¹) 3458, 3012, 2928, 2871, 2855,

1727, 1451, 1264; ¹H NMR (500 MHz,

CDCl₃) l 8.08 (dd, J 8.5, 1.0 Hz, 2 H), 7.58

(ddd, J 8.5, 7.0, 1.0 Hz, 1 H), 7.45 (ddd, J 8.0,

1.5 Hz, 2 H), 6.49 (dd, J 1.5, 1.5 Hz, 1 H),

6.14 (ddd, J 10.5, 1.0 Hz, 1 H), 5.87 (dddd, J

10.5, 2.5 Hz, 1 H), 4.33 (dddd, J 9.0, 2.0 Hz,

1 H), 3.98 (dd, J 10.0, 4.5 Hz, 1 H), 3.87 (ddd,

J 13.0, 8.0, 5.0 Hz, 1 H), 3.77 (dd, J 10.0, 8.0

Hz, 1 H), 3.33 (s, 1 H), 0.89 (s, 9 H), 0.10 (s,

3 H), 0.09 (s, 3 H); ¹³C NMR (125 MHz,

CDCl₃) l 165.5, 134.2, 133.3, 129.9 (2 C),

128.4, 123.8, 88.5, 71.6, 67.1, 65.6, 25.8, 18.2,

1

2855, 1730, 1696, 1461, 1399, 1279; H NMR

(500 MHz, CDCl₃) l 6.92 (dd, J 10.5, 3.5 Hz,

1 H), 6.59 (d, J 3.5 Hz, 1 H), 6.23 (d, J 10.5

Hz, 1 H), 4.48 (dd, J 4.5, 3.0 Hz, 1 H), 4.06

(dd, J 11.5, 3.0 Hz, 1 H), 4.03 (dd, J 11.0, 4.0

Hz, 1 H), 1.23 (s, 9 H), 0.86 (s, 9 H), 0.06 (s,

3 H), 0.05 (s, 3 H); ¹³C NMR (125 MHz,

CDCl₃) l 193.9, 176.9, 142.5, 129.1, 87.0, 77.9,

62.7, 39.2, 27.0, 25.8, 18.3, −5.4 (2 C);

CIHRMS Calcd for [C₁₇H₃₀O₅Si+NH₄]⁺:

360.2206. Found: 360.2209; Anal. Calcd for

C, 59.62; H, 8.84. Found: C, 59.72; H, 8.59.

(2S,6R)-6-(Pi6aloyloxymethyl)-5-oxo-5,6-

dihydro-2H-pyran-2-yl pi6alate (8d).—Com-

pound 7b (4.1 g, 18 mmol), 36 mL of CH₂Cl₂,

and pyridine (2.9 mL, 36 mmol) were added

to a round-bottom ﬂask and cooled to −

78 °C. Pivaloyl chloride (4.4 mL, 36 mmol)

was added, and the solution was stirred for 4

h at −78 °C. The reaction was quenched with

50 mL of satd aq NaHCO₃, extracted (3×50

mL) with Et₂O, dried (Na₂SO₄), and concen-

trated under reduced pressure. The crude

product was puriﬁed using silica gel ﬂash

chromatography eluting with 1:3 Et₂O–hex-

anes to give 3.9 (12.6 mmol, 70%) of 8d: mp

71–73 °C; R_f0.67 (1:1 Et₂O–hexanes); [h]_D²¹

−5.5,

−5.6;

CIHRMS

Calcd

for

[C₁₉H₂₈O₅Si−C₇H₅O₂]⁺: 243.1416. Found:

243.1426; Anal. Calcd for C, 62.61; H, 7.75.

Found: C, 62.45; H, 7.74.

(2S,5S,6R)-6-(Pi6aloyloxymethyl)-5-hydroxy-

5,6-dihydro-2H-pyran-2-yl benzoate (9b).—

Compound 8b (125 mg, 0.376 mmol) was dis-

solved in 4 mL of CH₂Cl₂and cooled to

−78 °C with a dry ice–acetone bath. To the

solution, 2 mL of a 0.4 M solution of CeCl₃in

MeOH was added, followed by NaBH₄(19

mg, 0.488 mmol), and the solution was stirred

for 1.5 h. The reaction was warmed to 0 °C,

and 30 mL of Et₂O and 30 mL of H₂O were

added to the solution. The phases were sepa-

rated, and the aq layer was extracted with

(5×20 mL) of Et₂O. The organic fractions

were combined, dried (MgSO₄), concentrated,

and puriﬁed by silica gel chromatography

eluting with 1:4 EtOAc–hexanes to yield 123

mg (0.368 mmol, 98%) of alcohol 9b: R_f0.29

(3:7 EtOAc–hexanes); [h]²_D¹−40.2° (c 2.04,

CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 3484, 2960,

92.9° (c 1.52, CHCl₃); IR (thin ﬁlm, cm⁻¹

)

2976, 2936, 2874, 1732, 1704, 1480, 1462,

1

1280; H NMR (500 MHz, CDCl₃) l 6.94 (dd,

J 10.2, 3.6 Hz, 1 H), 6.53 (d, J 3.9 Hz, 1 H),

6.25 (d, J 10.5 Hz, 1 H), 4.70 (dd, J 5.7, 2.7

Hz, 1 H), 4.53 (dd, J 12.0, 2.7 Hz, 1 H), 4.43

(dd, J 12.0, 5.7 Hz, 1 H), 1.22 (s, 9 H), 1.15 (s,

9 H); ¹³C NMR (125 MHz, CDCl₃) l 192.5,

178.1, 176.8, 142.5, 128.6, 86.6, 74.4, 62.4,

39.3, 38.8, 27.1; FABHRMS Calcd for

[C₁₆H₂₄O₆+Na]⁺:

335.1492.

335.1470.

Found:

(2S,5S,6R)-6-(tert-Butyldimethylsilanyloxy-

methyl)-5-hydroxy-5,6-dihydro-2H-pyran-2-yl

benzoate (9a).—Enone 8a (125 mg, 0.343

mmol) was dissolved in 2 mL CH₂Cl₂and was

cooled to −78 °C in a dry ice–acetone bath

under a nitrogen atmosphere. To the solution

2 mL of a 0.4 M solution of CeCl₃in CH₃OH

was added. NaBH₄(20 mg, 0.53 mmol) was

added, and the reaction was allowed to stir at

−78 °C for 1.5 h. The reaction was allowed to

warm to 0 °C, diluted with 20 mL of Et₂O and

1

2925, 1729, 1452, 1267; H NMR (500 MHz,

CDCl₃) l 8.05 (dd, J 8.5, 1.5 Hz, 2 H), 7.57

(ddd, J 8.5, 7.5, 1.5 Hz, 1 H), 7.47 (ddd, J 8.5,

7.5, 1.5 Hz, 2 H), 6.54 (dd, J 2.0, 1.0 Hz, 1 H),

6.17 (d, J 10.5 Hz, 1 H), 5.88 (ddd, J 10.5, 2.5

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

27

separated and the aq layer was extracted with

(5×20 mL) of Et₂O. The organic fractions

were combined, dried (MgSO₄), concentrated,

and puriﬁed by silica gel chromatography

eluting with 1:3 Et₂O–hexanes to yield 29 mg

(0.092 mmol, 92%) of alcohol 9d: R_f0.25 (1:3

Et₂O–hexanes); [h]²_D¹36.1° (c 2.80, CHCl₃); IR

(thin ﬁlm, cm⁻¹) 3156, 2976, 2874, 1728,

Hz, 1 H), 4.54 (dd, J 12.5, 5.0 Hz, 1 H), 4.28

(dd, J 12.0, 2.0 Hz, 1 H), 4.09 (ddd, J 9.0, 6.0,

2.0 Hz, 1 H), 3.95 (dddd, J 9.5, 4.5, 2.0 Hz, 1

13

H), 2.90 (d, J 6.0 Hz, 1 H), 1.16 (s, 9 H); C

NMR (125 MHz, CDCl₃) l 179.7, 165.4,

134.6, 133.3, 129.8, 129.7, 128.4, 124.5, 88.9,

72.8, 63.3, 63.2, 38.9, 27.1; CIHRMS Calcd

for [C₁₈H₂₂O₆+NH₄]⁺: 352.1760. Found:

352.1739.

1

1480, 1462, 1283; H NMR (500 MHz, C₆D₆)

(2S,5S,6R)-6-(tert-Butyldimethylsilanyloxy-

methyl)-5-hydroxy-5,6-dihydro-2H-pyran-2-yl

pi6alate (9c).—Compound 8c (85 mg, 0.25

mmol) was dissolved in 1.5 mL of CH₂Cl₂and

cooled to −78 °C with a dry ice–acetone

bath. To the solution, 2 mL of a 0.4 M

solution of CeCl₃in MeOH was added, fol-

lowed by NaBH₄(12 mg, 0.30 mmol), and the

solution was stirred for 1.5 h. The reaction

was warmed to 0 °C, and 20 mL of Et₂O and

20 mL of H₂O were added to the solution.

The phases were separated and the aq layer

was extracted with (5×20 mL) of Et₂O. The

organic fractions were combined, dried

(MgSO₄), concentrated, and puriﬁed by silica

gel chromatography eluting with 1:9 EtOAc–

hexanes to yield 82 mg (0.24 mmol, 95%) of

alcohol 9c: R_f0.40 (1:4 EtOAc–hexanes); [h]_D²¹

l 6.36 (d, J 2.7 Hz, 1 H), 5.76 (dt, J 10.2, 1.2

Hz, 1 H), 5.34 (ddd, J 10.0, 2.7, 1.8 Hz, 1 H),

4.38 (dd, J 12.3, 5.4 Hz, 1 H), 4.18 (dd, J 12.3,

2.1 Hz, 1 H), 3.87 (ddd, J 9.3, 5.3, 2.1 Hz, 1

H), 3.79 (d, J 9.9 Hz, 1 H), 2.39 (bs, 1 H), 1.11

(s, 9 H), 1.08 (s, 9 H); ¹³C NMR (125 MHz,

CDCl₃) l 179.8, 177.4, 134.2, 124.7, 110.4,

88.2, 72.6, 66.5, 63.3, 39.0, 27.2; FABHRMS

Calcd for [C₁₆H₂₆O₆+Na]⁺: 337.1627.

Found: 337.1634.

(2S,5S,6R)-6-(tert-Butyldimethylsilanyloxy-

methyl)-5-ethoxycarbonyloxy-5,6-dihydro-2H-

pyran-2-yl benzoate (9e).—Compound 9a

(190 mg, 0.521 mmol) was dissolved in 5 mL

of CH₂Cl₂and cooled to −78 °C. Pyridine

(85 mL, 1.0 mmol) and DMAP (7 mg, 0.05

mmol) were added to the solution, followed

by ethyl chloroformate (75 mL, 0.78 mmol),

and the solution was stirred for 3 h. The

reaction was warmed to 0 °C, and 30 mL of

Et₂O and 30 mL of satd aq NaHCO₃were

added to the solution. The phases were sepa-

rated, and the aq layer was extracted (3×20

mL) with Et₂O. The organic fractions were

combined, dried (MgSO₄), concentrated, and

puriﬁed by silica gel chromatography eluting

with 1:4 Et₂O–hexanes to yield 185 mg (0.424

mmol, 81%) of carbonate 9e: R_f0.3 (1:4

Et₂O–hexanes); [h]²_D¹−20.3° (c 2.00, CH₂Cl₂);

IR (thin ﬁlm, cm⁻¹) 2925, 2841, 1725, 1256;

¹H NMR (500 MHz, CDCl₃) l 8.05 (dd, J 8.5,

1.0 Hz, 2 H), 7.58 (tt, J 8.5, 7.5, 1.5 Hz, 1 H),

7.44 (tt, J 7.5, 1.5 Hz, 2 H), 6.57 (d, J 3.0 Hz,

1 H), 6.17 (d, J 10.0 Hz, 1 H), 5.98 (ddd, J

10.0, 3.0, 2.0 Hz, 1 H), 5.33 (ddd, J 9.5, 3.5,

2.0 Hz, 1 H), 4.24 (q, J 14.5, 7.0 Hz, 2 H),

4.07 (ddd, J 9.0, 3.5, 3.5 Hz, 1 H), 3.83 (m, 2

H), 1.33 (t, J 7.5 Hz, 3 H), 0.84 (s, 9 H), 0.04

(s, 3 H), 0.03 (s, 3 H); ¹³C NMR (125 MHz,

CDCl₃) l 165.2, 154.3, 133.3, 130.6, 129.8,

128.4, 126.2, 88.7, 71.6, 68.1, 64.4, 62.2, 25.8,

18.3, 14.2, −5.4, −5.5; FABHRMS Calcd

−17.7° (c 1.42, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹

)

3496, 2957, 2929, 2857, 1742, 1472, 1463,

1

1280, 1255; H NMR (500 MHz, CDCl₃) l

6.22 (dd, J 3.0, 1.5 Hz, 1 H), 6.06 (dd, J 10.0,

1.5 Hz, 1 H), 5.74 (ddd, J 10.0, 3.0, 3.0 Hz, 1

H), 4.26 (dd, J 6.5, 2.0 Hz, 1 H), 3.94 (dd, J

8.0, 3.0 Hz, 1 H), 3.92 (dd, J 8.0, 3.0 Hz, 1 H),

3.74 (m, 2 H), 3.20 (d, J 2.5 Hz, 2 H), 1.22 (s,

9 H), 0.91 (s, 9 H), 0.11 (s, 3 H), 0.10 (s, 3 H);

¹³C NMR (125 MHz, CDCl₃) l 177.5, 134.8,

124.0, 87.7, 71.5, 67.1, 65.7, 38.0, 25.8, 18.2,

−5.5, −5.6; CIHRMS Calcd for [C₁₇H₃₂-

O₅Si−C₅H₉O₂]⁺: 243.1416. Found: 243.1416.

(2S,5S,6R) - 6 - (Pi6aloyloxymethyl) - 5-

hydroxy-5,6-dihydro-2H-pyran-2-yl pi6alate

(9d).—Compound 8d (31 mg, 0.10 mmol) was

dissolved in 0.5 mL of CH₂Cl₂and cooled to

−78 °C with a dry ice–acetone bath. To the

solution 1 mL of a 0.4 M solution of CeCl₃in

MeOH was added, followed by NaBH₄(3.8

mg, 0.10 mmol), and the solution was stirred

for 0.5 h. The reaction was warmed to 0 °C,

and 20 mL of Et₂O and 20 mL of NaHCO₃

were added to the solution. The phases were

28

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

Na₂SO₃, and the mixture was extracted (5×

for

[C₂₂H₃₂O₇Si−C₇H₅O₂]⁺:

315.1628.

20 mL) with Et₂O and washed with brine. The

combined organic extracts were dried

(MgSO₄), ﬁltered, concentrated, and puriﬁed

by silica gel chromatography eluting with 1:1

Et₂O–hexanes to give diol 1b as a white solid

in 75% yield: R_f0.30 (3:1 Et₂O–hexanes); [h]_D²¹

Found: 315.1596; Anal. Calcd for C, 60.52; H,

7.39. Found: C, 60.80; H, 7.25.

1-O-Benzoyl-6-O-tert-butyldimethylsilyl-h-

-mannopyranose (1a).—A round-bottom

D

ﬂask containing a 0.75 M solution of com-

pound 9a in 1:1 tert-butanol–acetone was

cooled to 0 °C with an ice water bath. A

molar excess of a 1:1 (w/w) solution of 4-

methylmorpholine-N-oxide in water was

added to the solution. After the solution was

cooled, a catalytic amount (2 mol%) of OsO₄

was added to the reaction. The reaction was

allowed to stir at 0 °C for 8 h. The reaction

was quenched with satd aq Na₂SO₃, and the

mixture was extracted (5×25 mL) with Et₂O

and washed with brine. The combined organic

extracts were dried (MgSO₄), ﬁltered, concen-

trated, and puriﬁed by silica gel chromatogra-

phy eluting with 3:1 Et₂O–hexanes to give

triol 1a as a white solid in 80% yield: mp

100–104 °C; R_f0.2 (3:1 Et₂O–hexanes); [h]_D²¹

−198.4° (c 1.25, CH₂Cl₂); IR (thin ﬁlm,

37.0° (c 2.00, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹

)

1

2924, 2850, 1732 1629, 1273; H NMR (200

Mhz, CDCl₃) l 8.00 (dd, J 7.0, 1.5 Hz, 2 H),

7.56 (tt, J 7.0, 1.5 Hz, 1 H), 7.40 (tt, J 7.0, 1.5

Hz, 2 H), 6.40 (s, 1 H), 5.10 (t, J 10.0 Hz, 1

H), 4.20 (q, J 14.0, 7.0 Hz, 2 H), 4.10 (s, 1 H),

3.90 (ddd, J 10.0, 3.0, 3.0 Hz, 1 H), 3.84 (d, J

3.0 Hz, 2 H), 3.46 (s, 1 H), 1.30 (t, J 7.0 Hz,

3 H), 0.90 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H);

¹³C NMR (60 MHz, C₆D₆) l 164.2, 155.4,

133.7, 129.8, 129.1, 128.6, 93.6, 73.0 (2 C),

70.4, 70.0, 64.8, 62.1, 25.8, 18.27, 14.1, −5.5;

FABHRMS Calcd for [C₂₂H₃₄O₉Si+H]⁺:

471.2050. Found: 471.2046.

2-O-Acetyl-1-O-benzoyl-3-O-ethoxycar-

bonyl-6-O-tert-butyldimethylsilyl-h- -manno-

D

1

cm⁻¹) 3461, 3024, 2963, 1715, 1272; H NMR

pyranose (1d).—To a round-bottom ﬂask con-

taining a 0.5 M solution of carbonate 1b in

benzene trimethylorthoacetate (5 equiv) and a

catalytic amount of p-toluenesulfonic acid (5

mol%) was added. The reaction was allowed

to stir until only the cyclic orthoester was

observed via its markedly less polar spot on

thin-layer chromatography (TLC) (R_f0.7, 1:4

Et₂O–hexanes). Upon formation of the or-

thoester, the solvent was removed under re-

duced pressure and was replaced by an equal

amount of THF and water to make the con-

centration approximately 0.4 M. The reaction

was allowed to stir until hydrolysis was com-

plete as seen by TLC (R_f0.3, 1:4 Et₂O–hex-

anes) producing exclusively the C-2 axial

acetate ester 1d as a clear, light yellow oil in a

60% yield from the diol: R_f0.30 (1:4 Et₂O–

hexanes); [h]²_D¹28.6° (c 2.36, CHCl₃); IR (thin

ﬁlm, cm⁻¹) 3492, 3066, 2931, 1736, 1629,

(300 MHz, DMSO) l 7.98 (d, J 6.0 Hz, 2 H),

7.70 (t, J 6.0 Hz, 1 H), 7.56 (t, J 6.0 Hz, 2 H),

6.09 (d, J 2.0 Hz, 1 H), 5.19 (d, J 4.0 Hz, 1 H),

4.91 (d, J 6.0 Hz, 1 H), 4.79 (d, J 6.0 Hz, 1 H),

3.87 (dd, J 11.5, 1.5, 1.0 Hz, 1 H), 3.79 (dd, J

4.0, 3.5, 2.0 Hz, 1 H), 3.70 (dd, J 9.0, 6.0, 3.5

Hz, 1 H), 3.66 (dd, J 6.0, 1.5 Hz, 1 H), 3.57

(ddd, J 10.0, 6.0, 1.5 Hz, 1 H), 3.49 (dd, J

10.0, 9.0, 6.0 Hz, 1 H), 0.78 (s, 9 H), −0.01

13

(s, 3 H), −0.02 (s, 3 H); C NMR (75 MHz,

CDCl₃) l 164.3, 133.1, 129.8, 129.6, 128.4,

128.1, 127.7, 127.2, 94.6, 75.2, 72.1, 68.6, 63.9,

25.7, 18.1, −5.4; FABHRMS Calcd for

[C₁₉H₃₀O₇Si+H]⁺:

399.1839.

Found:

399.1836; Anal. Calcd for C, 57.26; H, 7.59.

Found: C, 57.10; H, 7.71.

1-O-Benzoyl-6-O-tert-butyldimethylsilyl-3-

O-ethoxycarbonyl-h- -mannopyranose (1b).—

A round-bottom ﬂask containing a 0.75 M

solution of compound 9e in 1:1 tert-butanol–

acetone was cooled to 0 °C with an ice-water

bath. A molar excess of a 1:1 (w/w) solution

of 4-methylmorpholine-N-oxide in water was

added to the solution. A catalytic amount (2

mol%) of OsO₄was added to the reaction.

The reaction was allowed to stir at 0 °C for 8

h. The reaction was quenched with satd aq

D

1

1600, 1254; H NMR (300 MHz, CDCl₃) l

8.02 (dd, J 7.0, 1.2 Hz, 2 H), 7.58 (dt, J 7.0,

1.2 Hz, 1 H), 7.49 (dt, J 7.0, 1.2 Hz, 2 H), 6.36

(d, J 2.0 Hz, 1 H), 5.24 (m, 2 H), 4.24 (q, J

14.0, 7.0 Hz, 2 H), 3.89 (dt, J 10.0, 2.5 Hz, 1

H), 3.79 (m, 2 H), 2.18 (s, 3 H), 1.33 (t, J 7.0

Hz, 3 H), 0.09 (s, 9 H), 0.04 (s, 3 H), 0.02 (s,

3 H); ¹³C NMR (75 MHz, CDCl₃) l 170.1,

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

29

1

1472, 1278; H NMR (500 MHz, CDCl₃) l

6.33 (dd, J 3.0 Hz, 1 H), 6.29 (ddd, J 10.0, 6.0,

1.0 Hz, 1 H), 5.92 (dd, J 10.0, 3.0 Hz, 1 H),

4.03 (ddd, J 6.0, 6.0, 2.0 Hz, 1 H), 3.99 (td, J

7.5, 6.0, 2.0 Hz, 1 H), 3.88 (dd, J 16.5, 10.5

Hz, 1 H), 3.84 (dd, J 10.5, 6.0 Hz, 1 H), 2.05

(bs, 1 H), 1.21 (s, 9 H), 0.90 (s, 9 H), 0.09 (s,

3 H), 0.08 (s, 3 H); ¹³C NMR (125 MHz,

CDCl₃) l 177.3, 130.6, 126.9, 88.2, 72.8, 62.5,

61.3, 39.0, 27.0, 25.9, 18.3, −5.3, −5.4;

CIHRMS Calcd for [C₁₇H₃₂O₅SiꢀC₅H₉O₂]⁺:

243.1416. Found: 243.1415.

163.6, 155.3, 133.7, 129.7, 128.5, 128.0, 90.8,

72.7, 72.2, 71.3, 68.9, 64.7, 61.3, 25.6, 20.7,

18.0, 15.1, 14.0, −5.5, −5.7; FABHRMS

Calcd for [C₂₄H₃₆O₁₀Si+NH₄]⁺: 530.2422.

Found: 530.2408.

(2S,6R) - 6 - (tert - Butyldimethylsilanyloxy-

methyl) - 5 - (p - nitrobenzoyloxy) - 5,6 - dihydro-

2H-pyran-2-yl benzoate (not shown, Scheme

6).—Alcohol 9c (300 mg, 0.871 mmol) was

dissolved in 3 mL of THF. The solution was

cooled to 0 °C, and triphenylphosphine (456

mg, 1.74 mmol), p-nitrobenzoic acid (290 mg,

1.74 mmol), and diethyl azodicarboxylate (275

mL, 1.74 mmol) were added to the solution.

The solution was stirred for 12 h, quenched

with satd aq NaHCO₃(15 mL), and extracted

(5×20 mL) with Et₂O. The extracts were

dried (MgSO₄), concentrated, and puriﬁed by

silica gel chromatography eluting with 10%

EtOAc–hexanes to yield 280 mg (0.566 mmol,

65%) of the p-nitrobenzoic ester: R_f0.57 (1:4

EtOAc–hexanes); [h]²_D¹−181.3° (c 1.01,

CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 3055, 2957,

2930, 2883, 2857, 1728, 1531, 1344, 1320,

1-O-Pi6aloyl-6-O-tert-butyldimethylsilyl-h-

-talose (12).—A round-bottom ﬂask con-

D

taining a 0.75 M solution of alcohol 11 in

CH₂Cl₂was cooled to −78 °C with an ace-

tone–dry ice bath. To the stirring solution,

OsO₄(1.2 equiv) and N,N,N%N%-tetra-

methylethylenediamine (1.2 equiv) was added.

The solution was cooled and turned a dark

orange color. The reaction was allowed to stir

at −78 °C for 2 h. The reaction was warmed

to rt. The solvent was removed under reduced

pressure and replaced with equal volumes of

satd aq Na₂SO₃and THF to make the solu-

tion 0.25 M. The mixture was heated to reﬂux

for 3 h before the solution was poured onto

brine and extracted (5×25 mL) EtOAc. The

combined organic extracts were dried

(MgSO₄), concentrated and puriﬁed by silica

gel chromatography eluting with 1:1 Et₂O–

hexanes to give protected talose 12 as a white

solid in 80% yield: mp 134–135 °C; R_f0.5

(Et₂O); [h]²_D¹−53.6° (c 0.39, CH₂Cl₂); IR

(thin ﬁlm, cm⁻¹) 3475, 3250, 2956, 2936,

1

1270; H NMR (500 MHz, CDCl₃) l 8.29 (d,

J 8.5 Hz, 2 H), 8.21 (d, J 9.0 Hz, 2 H), 6.42 (d,

J 10.0, 5.5 Hz, 1 H), 6.41 (d, J 4.0 Hz, 1 H),

6.09 (dd, J 10.0, 3.0 Hz, 1 H), 5.38 (dd, J 6.0,

2.5 Hz, 1 H), 4.28 (ddd, J 7.0, 2.5 Hz, 1 H),

3.81 (d, J 7.0 Hz, 2 H), 1.24 (s, 9 H), 0.80 (s,

9 H), −0.01 (s, 3 H), −0.09 (s, 3 H); ¹³C

NMR (125 MHz, CDCl₃) l 177.2, 163.9,

150.7, 135.3, 130.8, 129.7, 126.2, 123.6, 87.7,

71.3, 63.6, 61.3, 39.1, 27.0, 25.7, 18.1, −5.49,

−5.65; CIHRMS Calcd for [C₂₄H₃₅O₈NSi+

NH₄]⁺: 511.2476. Found: 511.2474; Anal.

Calcd for C, 58.39; H, 7.15. Found: C, 58.36;

H, 7.20.

1

2856, 1737; H NMR (200 MHz, CDCl₃) l

6.23 (s, 1 H), 4.25 (s, 1 H), 4.00–3.96 (m, 2

H), 3.85–3.70 (m, 2 H), 1.55 (s, 3 H), 1.21 (s,

9 H), 0.88 (s, 9 H), 0.11 (s, 3 H), 0.10 (s, 3 H);

¹³C NMR (75 MHz, CDCl₃) l 176.0, 94.29,

71.6, 71.4, 70.0, 66.3, 64.5, 39.0, 27.0, 25.7,

18.2, −5.5, −5.6; CIHRMS Calcd for

(2S,5R,6R)-6-(tert-Butyldimethylsilanyloxy-

methyl)-5-hydroxy-5,6-dihydro-2H-pyran-2-yl

pi6alate (11).—The p-nitrobenzoic ester (64

mg, 0.13 mmol) was dissolved in 2 mL of

CH₃OH, and Et₃N (50 mL, 0.36 mmol) was

added to the solution. The solution was stirred

for 12 h, and the solution was concentrated

under reduced pressure. The crude product

was puriﬁed by silica gel chromatography (1:4

EtOAc–hexanes) to yield 41 mg (0.12 mmol,

92%) of alcohol 11: R_f0.22 (1:4 EtOAc–hex-

anes); [h]²_D¹−98.9° (c 1.23, CH₂Cl₂); IR (thin

ﬁlm, cm⁻¹) 3476, 2956, 2929, 2857, 1739,

[C₁₇H₃₄O₇Si+NH₄]⁺:

396.2418.

Found:

396.2418; Anal. Calcd for C, 53.94; H, 9.05.

Found: C, 53.99; H, 8.89.

1-O-Pi6aloyl-6-O-tert-butyldimethylsilyl-h-

-gulopyranose (13).—A round-bottom ﬂask

containing a 0.75 M solution of alcohol 11 in

1:1 tert-butanol–acetone was cooled to 0 °C

with an ice-water bath. A molar excess of a

1:1 (w/w) solution of 4-methylmorpholine-N-

D

30

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

H); ¹³C NMR (125 MHz, CDCl₃) l 165.5,

136.0, 133.1, 130.2, 129.9, 128.3, 123.8, 89.4,

75.0, 63.4, 62.1, 25.9, 25.8, 18.4, 18.0, −4.3,

−4.8, −5.1, −5.2; CIHRMS Calcd for

oxide in H₂O was added. After cooling, a

catalytic amount (2 mol%) of OsO₄was added

to the reaction, which was allowed to stir at

0 °C for 8 h. The reaction was quenched with

satd aq Na₂SO₃, and the mixture was ex-

tracted (5×25 mL) with Et₂O and washed

with brine. The combined organic extracts

were dried (MgSO₄), ﬁltered, concentrated,

and puriﬁed by silica gel chromatography

eluting with 1:1 Et₂O–hexanes to give pro-

tected gulose 13 in 80% yield: mp 109–112°C;

R_f0.5 (Et₂O); [h]²_D¹−42.7° (c 0.81, CH₂Cl₂);

IR (thin ﬁlm, cm⁻¹) 3440, 2957, 2933, 2852,

[C₂₅H₄₂O₅Si₂+NH₄]⁺:

496.2915.

Found:

496.2914; Anal. Calcd for C, 62.73; H, 8.85.

Found: C, 62.39; H, 8.71.

(2S,5S,6R) - 6 - (Pi6aloyloxymethyl) - 5-

pi6aloyloxy-5,6-dihydro-2H-pyran-2-yl ben-

zoate (17b).—Compound 9b (73 mg, 0.218

mmol) was dissolved in 2 mL of CH₂Cl₂, and

Et₃N (91 mL, 0.654 mmol) and DMAP (1.5

mg, 0.012 mmol) were added to the solution.

Pivaloyl chloride (40 mL, 0.327 mmol) was

added, and the solution was stirred at rt for 6

h. The reaction was quenched with 15 mL of

satd aq NaHCO₃and extracted (5×20 mL)

with Et₂O. The organic fractions were com-

bined, dried (MgSO₄), and concentrated. The

product was puriﬁed by silica gel chromatog-

raphy eluting with (1:9 EtOAc–hexanes) to

give 75 mg (0.18 mmol, 82%) of compound

1

1724; H NMR (200 MHz, CDCl₃) l 6.20 (d,

J 4.2 Hz, 1 H), 4.22 (dd, J 4.4, 4.2 Hz, 1 H),

4.12 (d, J 3.9 Hz, 1 H), 4.04 (d, J 3.9 Hz, 1 H),

4.02 (d, J 3.0 Hz, 1 H), 3.98 (d, J 6.0 Hz, 1 H),

3.97 (d, J 6.0 Hz, 1 H), 2.52 (bs, 3 H), 1.23 (s,

9 H), 0.89 (s, 9 H), 0.09 (s, 6 H); ¹³C NMR (75

MHz, CDCl₃) l 177.4, 92.6, 71.8, 70.0, 65.9,

65.2, 64.2, 39.0, 27.1, 25.8, −5.5, −5.6;

CIHRMS Calcd for [C₁₇H₃₄O₇Si+NH₄]⁺:

396.2418. Found: 396.2399; Anal. Calcd for

C, 53.94; H, 9.05. Found: C, 54.32; H, 8.83.

(2S,5S,6R)-6-(tert-Butyldimethylsilanyloxy-

methyl) - 5 - (tert - butyldimethylsilanyloxy)-5,6-

dihydro-2H-pyran-2-yl benzoate (17a).—

Compound 9a (25 mg, 0.069 mmol) was dis-

solved in 1 mL of CH₂Cl₂, cooled to −78 °C,

and 2,6-lutidine (25 mL, 0.207 mmol) was

added. The reaction was stirred for 3 h,

warmed to rt, and 10 mL of Et₂O and 10 mL

of satd aq NaHCO₃were added to the solu-

tion. The phases were separated, and the aq

layer was extracted (3×10 mL) with Et₂O.

The organic fractions were combined, dried

(MgSO₄), and concentrated, and the crude

product was puriﬁed by silica gel chromatog-

raphy, eluting with 3:7 CH₂Cl₂–hexanes to

give 24 mg (0.050 mmol, 73%) of pyran 17a:

R_f0.63 (1:1 CH₂Cl₂–hexanes); [h]²_D¹−21.0° (c

1.41, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 3062,

3021, 2955, 2929, 2857, 1730, 1602, 1472,

17b: R_f0.45 (1:9 EtOAc–hexanes); [h]_D²¹

−

)

3.22° (c 1.04, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹

1

2973, 2873, 1733, 1480, 1265; H NMR (500

MHz, C₆D₆) l 8.07 (dt, J 8.0, 1.5 Hz, 2 H),

7.09 (tt, J 8.5, 7.0, 1.5 Hz, 1 H), 7.00 (tt, J 8.0,

1.5 Hz, 2 H), 6.63 (dd, J 1.0 Hz, 1 H), 5.77

(ddd, J 10.0, 1.5 Hz, 1 H), 5.48 (ddd, J 9.5,

3.5, 2.0 Hz, 1 H), 5.42 (ddd, J 10.0, 3.0, 2.5

Hz, 1 H), 4.31 (ddd, J 9.5, 6.0, 1.5 Hz, 1 H),

4.26 (dd, J 12.0, 1.5 Hz, 1 H), 4.20 (dd, J 12.0,

13

6.0 Hz, 1 H), 1.14 (s, 9 H), 1.08 (s, 9 H); C

NMR (125 MHz, CDCl₃) l 178.1, 177.6,

165.2, 133.4, 131.4, 129.8, 129.7, 128.4, 125.8,

88.7, 69.7, 64.5, 62.3, 38.9, 38.8, 27.04, 26.98;

CIHRMS Calcd for [C₂₃H₃₀O₇+NH₄]⁺:

436.2335. Found: 436.2334.

(2S,5S,6R)-6-(tert-Butyldimethylsilanyloxy-

methyl)-5-(tert-butyldimethylsilanyloxy)-5,6-

dihydro-2H-pyran-2-ol

(18a).—Compound

17a (20 mg, 0.042 mmol) was dissolved in 0.5

mL of MeOH, 50 mL of Et₃N, and 50 mL of

H₂O and heated to reﬂux for 6 h. The solution

was concentrated and puriﬁed by silica gel

chromatography eluting with (1:9 EtOAc–

hexanes) to give 10 mg (0.025 mmol, 64%) of

alcohol 18a: mp 90–95 °C; R_f0.21 (1:9

EtOAc–hexanes); IR (thin ﬁlm, cm⁻¹) 3409,

1

1260; H NMR (500 MHz, CDCl₃) l 8.08 (dd,

J 8.5, 1.5 Hz, 2 H), 7.56 (ddd, J 8.5, 7.0, 1.5

Hz, 1 H), 7.43 (ddd, J 8.0, 7.0, 2.0 Hz, 2 H),

6.53 (dd, J 2.5, 1.0 Hz, 1 H), 6.04 (d, J 10.0,

1.0 Hz, 1 H), 5.83 (dddd, J 10.0, 2.5, 2.0 Hz,

1 H), 4.33 (dddd, J 10.0, 3.5, 2.0 Hz, 1 H),

3.84 (m, 3 H), 0.93 (s, 9 H), 0.86 (s, 9 H), 0.15

(s, 3 H), 0.13 (s, 3 H), 0.06 (s, 3 H), 0.05 (s, 3

1

2952, 2929, 2886, 2857, 1471, 1462, 1254; H

NMR (500 MHz, C₆D₆) major isomer l 5.76

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

31

2.0 Hz, 1 H), 4.18 (ddd, J 9.0, 3.0, 2.5 Hz, 1

H), 3.89 (dd, J 11.5, 2.5 Hz, 1 H), 3.84 (dd, J

11.5, 3.0 Hz, 1 H), 0.91 (s, 9 H), 0.89 (s, 9 H),

0.14 (s, 3 H), 0.13 (s, 3 H), 0.094 (s, 3 H),

(d, J 10.5 Hz, 1 H), 5.55 (ddd, J 10.5, 2.0, 2.0

Hz, 1 H), 5.21 (dd, J 2.5, 1.5 Hz, 1 H), 4.38

(ddd, J 10.0, 3.0, 1.5 Hz, 1 H), 3.95–3.84 (3

H), 2.73 (d, J 5.0 Hz, 1 H), 1.03 (s, 9 H), 0.96

(s, 9 H), 0.19 (s, 3 H), 0.18 (s, 3 H), 0.10 (s, 3

13

0.088 (s, 3 H); C NMR (125 MHz, CDCl₃) l

13

163.0, 149.8, 119.5, 83.0, 62.3, 61.0, 25.8, 25.6,

18.3, 17.9, −4.5, −5.0, −5.2, −5.4;

CIHRMS Calcd for [C₁₈H₃₆O₄Si₂+NH₄]⁺:

390.2496. Found: 390.2462.

H), 0.06 (s, 3 H); C NMR (125 MHz, C₆D₆)

major isomer l 134.1, 127.2, 89.2, 72.7, 64.0,

62.9, 26.2, 25.9, 18.7, 18.1, −4.2, −4.7, −

4.8, −5.1; CIHRMS Calcd for [C₁₈H₃₈-

O₄Si₂−H₂O+NH₄]⁺:

374.2543.

374.2547.

Found:

(2R,3S)-2-(Pi6aloyloxymethyl)-6-oxo-3,6-

dihydro-2H-pyran-3-yl pi6alate (19b).—Com-

pound 18b (21 mg, 0.066 mmol) was dissolved

in 3 mL of benzene, and activated MnO₂(100

mg, 1.15 mmol) was added to the solution.

The solution was heated at reﬂux for 12 h.

The solution was cooled to rt and ﬁltered

through a pad of Celite, washing with 100 mL

of Et₂O. The ﬁltrate was concentrated and

puriﬁed by silica gel chromatography eluting

with 1:9 EtOAc–hexanes to yield 18 mg

(0.058 mmol, 88%) of pure pyranone 19b: R_f

0.41 (1:4 EtOAc–hexanes); [h]²_D¹27.7° (c 0.84,

CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 2921, 2851,

(2S,5S,6R)-6-(Pi6aloyloxymethyl)-5-pi6al-

(18b).—

oyloxy-5,6-dihydro-2H-pyran-2-ol

Compound 17b (66 mg, 0.16 mmol) was dis-

solved in 2 mL of MeOH, 75 mL of Et₃N, and

75 mL of H₂O and heated to reﬂux for 6 h.

The solution was concentrated and puriﬁed by

silica gel chromatography eluting with (1:9

EtOAc–hexanes) to give 20 mg (0.093 mmol,

40%) of alcohol 18b: R_f0.20 (1:9 EtOAc–hex-

anes); IR (thin ﬁlm, cm⁻¹) 3469, 2974, 2934,

1

2874, 1733, 1481, 1283; H NMR (500 MHz,

C₆D₆) major isomer l 5.69 (d, J 10.5 Hz, 1 H),

5.54 (ddd, J 7.5, 3.5, 1.5 Hz, 1 H), 5.48 (dt, J

10.0, 2.5 Hz, 1 H), 5.05 (bs, 1 H), 4.36 (dd, J

12.0, 2.0 Hz, 1 H), 4.29 (dd, J 12.0, 4.5 Hz, 1

H), 4.19 (dddd, J 10.0, 4.5, 2.0 Hz, 1 H), 2.40

(t, J 6.0 Hz, 1 H), 1.20 (s, 9 H), 1.13 (s, 9 H).;

¹³C NMR (125 MHz, CDCl₃) major isomer l

177.7, 177.2, 129.5, 129.0, 89.2, 67.9, 64.9,

62.7, 39.0, 38.8, 27.3, 27.1; CIHRMS Calcd

for [C₁₆H₂₆O₆+NH₄]⁺: 332.2073. Found:

332.2072.

1

1737, 1480, 1462, 1367, 1280; H NMR (500

MHz, CDCl₃) l 6.76 (dd, J 10.0, 3.0 Hz, 1 H),

6.13 (dd, J 10.0, 2.0 Hz, 1 H), 5.52 (ddd, J 7.5,

3.0, 2.0 Hz, 1 H), 4.67 (ddd, J 7.5, 4.5, 3.0 Hz,

1 H), 4.33 (dd, J 12.0, 4.5 Hz, 1 H), 4.27 (dd,

J 12.0, 3.0 Hz, 1 H), 1.22 (s, 9 H), 1.21 (s, 9

H); ¹³C NMR (125 MHz, CDCl₃) 177.9,

177.2, 161.4, 143.4, 122.4, 77.7, 63.1, 61.2,

38.9, 38.8, 27.1, 26.9; CIHRMS Calcd for

[C₁₆H₂₄O₆+NH₄]⁺:

330.1933.

330.1917.

Found:

(5S,6R)-5-(tert-Butyldimethylsilanyloxy)-6-

(tert - butyldimethylsilanyloxymethyl)-5,6-dihy-

dropyran-2-one (19a).—Compound 18a (35

mg, 0.093 mmol) was dissolved in 3 mL of

benzene, and activated MnO₂(100 mg, 1.15

mmol) was added to the solution. The solu-

tion was heated at reﬂux for 12 h. The solu-

tion was cooled to rt and ﬁltered through a

pad of Celite, washing with 100 mL of Et₂O.

The ﬁltrate was concentrated and puriﬁed by

silica gel chromatography eluting with 1:9

EtOAc–hexanes to yield 26 mg (0.070 mmol,

75%) of pure pyranone 19a: R_f0.67 (1:4

EtOAc–hexanes); [h]²_D¹43.7° (c 1.19, CH₂Cl₂);

IR (thin ﬁlm, cm⁻¹) 2952, 2927, 2883, 2855,

(6R)-6-tert-Butyldimethylsilanyloxymethyl-

pyran-2,5-dione (20).—Compound 7a (460

mg, 1.79 mmol) was dissolved in 15 mL of

acetone, and Jones reagent (2.5 M) was

dripped in at rt until a yellow color persisted.

After 15 min the starting material was no

longer visible by TLC, and the solution was

ﬁltered through a pad a Celite and washed

with 150 mL of Et₂O. The Et₂O ﬁltrate was

washed with satd aq NaHCO₃(50 mL), and

the phases were separated. The organic layer

was dried (MgSO₄) and concentrated to yield

367 mg (1.43 mmol, 80%) of pure dione 20: R_f

0.40 (1:4 EtOAc–hexanes); [h]²_D¹55.8° (c 3.71,

CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 3949, 2928,

2892, 2856, 1719, 1697, 1461, 1360, 1306,

1

1747, 1471, 1251, 1216; H NMR (500 MHz,

CDCl₃) l 6.72 (dd, J 10.0, 2.5 Hz, 1 H), 5.91

(dd, J 10.0, 2.0 Hz, 1 H), 4.70 (ddd, J 9.0, 2.0,

1

1261; H NMR (500 MHz, CDCl₃) l 6.86 (d,

32

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

aq layer was extracted (5×10 mL) with Et₂O.

The organic fractions were combined, dried

(MgSO₄), and concentrated, and the crude

product was puriﬁed by silica gel chromatog-

raphy eluting with (1:9 EtOAc–hexanes) to

give 24 mg (0.07 mmol, 80%) of compound

J 10.0 Hz, 1 H), 6.73 (d, J 10.0 Hz, 1 H), 4.83

(dd, J 2.0, 1.5 Hz, 1 H), 4.01 (dd, J 12.5, 1.5

Hz, 1 H), 3.97 (dd, J 12.5, 2.0 Hz, 1 H), 0.74

13

(s, 9 H), −0.04 (s, 3 H), −0.07 (s, 3 H); C

NMR (125 MHz, CDCl₃) l 192.3, 160.5,

138.8, 136.1, 84.3, 65.1, 25.4, 17.9, −5.9,

−6.0; CIHRMS Calcd for [C₁₂H₂₀O₄Si+

NH₄]⁺: 274.1475. Found: 274.1484; Anal.

Calcd for C, 56.23; H, 7.87. Found: C, 56.10;

H, 7.68.

22a: R_f0.29 (1:9 EtOAc–hexanes); [h]_D²¹

−

172.5° (c 0.53, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹

)

1

2957, 2930, 2857, 1735, 1480, 1277, 1252; H

NMR (500 MHz, CDCl₃) l 7.05 (dd, J 10.0,

6.0 Hz, 1 H), 6.20 (d, J 10.0 Hz, 1 H), 5.28

(dd, J 6.0, 3.0 Hz, 1 H), 4.55 (ddd, J 7.5, 7.5,

3.0 Hz, 1 H), 3.88 (d, J 7.5 Hz, 2 H), 1.19 (s,

9 H), 0.87 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H);

¹³C NMR (125 MHz, CDCl₃) l 177.2, 162.3,

140.7, 124.9, 78.5, 60.8, 60.0, 39.0, 27.0, 25.7,

18.1, −5.5, −5.6; CIHRMS Calcd for

(5R,6R) - 6 - tert - Butyldimethylsilanyloxy-

methyl - 5 - hydroxy - 5,6 - dihydro - pyran - 2 - one

(21).—Compound 20 (870 mg, 3.39 mmol)

was dissolved in 10 mL of CH₂Cl₂, cooled to

−78 °C with a dry ice–acetone bath, and 17

mL of a 0.4 M solution of CeCl₃in MeOH

was added to the solution. NaBH₄(193 mg,

5.09 mmol) was added, and the solution was

stirred for 1.5 h. The solution was warmed to

rt, and 50 mL of Et₂O and 100 mL of H₂O

were added. The phases were separated, and

the aq layer was extracted (5×50 mL) with

Et₂O. The organic fractions were combined,

dried (MgSO₄), and concentrated, and the

crude product was puriﬁed by silica gel chro-

matography eluting with (1:4 EtOAc–hex-

anes) to give 840 mg (3.25 mmol, 96%) of

compound 21: R_f0.65 (3:7 EtOAc–hexanes);

[h]²_D¹−73.2° (c 0.90, CH₂Cl₂); IR (thin ﬁlm,

cm⁻¹) 3424, 2954, 2930, 2885, 2857, 1714,

[C₁₇H₃₀O₅Si+NH₄]⁺:

343.1941.

Found:

343.1941; Anal. Calcd for C, 59.62; H, 8.84.

Found: C, 59.80; H, 8.66.

(2R,3R) - 2 - (tert - Butyldimethylsilanyloxy-

methyl)-6-oxo-3,6-dihydro-2H-pyran-3-yl acet-

ate (22b).—Compound 21 (31 mg, 0.12 mmol)

was dissolved in 1.5 mL of CH₂Cl₂and 100

mL of pyridine was added to the solution.

Acetic anhydride (115 mL, 1.2 mmol) was

added, and the solution was stirred at rt for 8

h. The reaction was quenched with (10 mL) of

satd aq NaHCO₃and 10 mL of Et₂O. The

phases were separated, and the aq layer was

extracted (5×10 mL) with Et₂O. The organic

fractions were combined, dried (MgSO₄), and

concentrated, and the crude product was

puriﬁed by silica gel chromatography eluting

with (1:9 EtOAc–hexanes) to give 34 mg (0.11

mmol, 92%) of compound 22b: R_f0.33 (1:9

EtOAc–hexanes); [h]²_D¹−207° (c 2.26,

CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 2955, 2930,

1

1472, 1257; H NMR (500 MHz, C₆D₆) l 6.25

(dd, J 9.5, 6.0 Hz, 1 H), 5.73 (d, J 9.5 Hz, 1

H), 3.96 (dd, J 10.0, 7.0 Hz, 1 H), 3.87 (ddd,

J 7.0, 5.0, 3.0 Hz, 1 H), 3.79 (dd, J 10.0, 5.0

Hz, 1 H), 3.76 (m, 1 H), 3.00 (bs, 1 H), 0.98 (s,

9 H), 0.08 (s, 3 H), 0.07 (s, 3 H); ¹³C NMR

(125 MHz, C₆D₆) l 163.1, 144.2, 122.7, 79.9,

61.7, 60.4, 26.0, 18.4, −5.3, −5.4; CIHRMS

Calcd for [C₁₂H₂₂O₄Si+NH₄]⁺: 276.1631.

Found: 276.1631; Anal. Calcd for C, 55.79; H,

8.59. Found: C, 55.63; H, 8.45.

1

2886, 2857, 1747, 1472, 1372, 1252; H NMR

(500 MHz, CDCl₃) l 7.04 (dd, J 10.0, 6.0 Hz,

1 H), 6.17 (d, J 10.0 Hz, 1 H), 5.28 (dd, J 6.0,

3.0 Hz, 1 H), 4.52 (ddd, J 8.0, 7.5, 3.0 Hz, 1

H), 3.86 (d, J 7.5 Hz, 2 H), 2.05 (s, 3 H), 0.84

(2R,3R) - 2 - (tert - Butyldimethylsilanyloxy-

methyl)-6-oxo-3,6-dihydro-2H-pyran-3-yl pi-

6alate (22a).—Compound 21 (23 mg, 0.089

mmol) was dissolved in 1 mL of CH₂Cl₂,

cooled to 0 °C, and 75 mL of pyridine was

added, to the solution. Pivaloyl chloride (110

mL, 0.89 mmol) was added and the solution

was stirred for 8 h. The reaction was quenched

with (10 mL) of satd aq NaHCO₃and 10 mL

of Et₂O. The phases were separated, and the

13

(s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H); C NMR

(125 MHz, CDCl₃) l 169.6, 162.1, 140.4,

125.0, 78.0, 61.0, 59.9, 25.6, 20.4, 18.0, −5.6,

−5.8; FABHRMS Calcd for [C₁₄H₂₄O₅Si+

H]⁺: 301.1471. Found: 301.1477; Anal. Calcd

for C, 55.97; H, 8.06. Found: C, 55.87; H,

7.84.

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

33

1

1254; H NMR (500 MHz, CDCl₃) l 6.87 (dd,

J 10.0, 5.5 Hz, 1 H), 6.05 (d, J 9.5 Hz, 1 H),

4.30 (dd, J 5.0, 3.0 Hz, 1 H), 4.26 (ddd, J 8.0,

5.5, 3.0 Hz, 1 H), 3.94 (dd, J 10.5, 8.0 Hz, 1

H), 3.83 (dd, J 10.0, 5.0 Hz, 1 H), 0.88 (s, 9

H), 0.86 (s, 9 H), 0.10 (s, 3 H), 0.07 (s, 6 H),

(2R,3R) - 2 - (tert - Butyldimethylsilanyloxy-

methyl)-6-oxo-3,6-dihydro-2H-pyran-3-yl ethyl

carbonate (22c).—Compound 21 (32 mg, 0.12

mmol) was dissolved in 1.5 mL of CH₂Cl₂,

and 100 mL of pyridine was added to the

solution. Ethyl chloroformate (118 mL, 1.2

mmol) was added, and the solution was stirred

at rt for 8 h. The reaction was quenched with

(10 mL) of satd aq NaHCO₃and 10 mL of

Et₂O. The phases were separated, and the aq

layer was extracted (5×10 mL) with Et₂O.

The organic fractions were combined, dried

(MgSO₄), and concentrated, and the crude

product was puriﬁed by silica gel chromatog-

raphy eluting with (1:9 EtOAc–hexanes) to

give 37 mg (0.11 mmol, 92%) of compound

13

0.06 (s, 3 H); C NMR (125 MHz, CDCl₃) l

163.0, 144.5, 122.6, 80.7, 60.4, 60.2, 25.8, 25.6,

18.2, 18.0, −4.2, −4.9, −5.4, −5.5;

FABHRMS Calcd for [C₁₈H₃₆O₄Si₂+Na]⁺:

395.2045. Found: 395.2068.

(2R,3S) - 2 - (tert - Butyldimethylsilanyloxy-

methyl)-6-oxo-3,6-dihydro-2H-pyran-3-yl ben-

zoate (not shown, Scheme 11).—Compound 21

(34 mg, 0.13 mmol) was dissolved in 1.5 mL

of THF. The solution was cooled to 0 °C, and

triphenylphosphine (69 mg, 0.26 mmol), p-ni-

trobenzoic acid (44 mg, 0.26 mmol), and di-

ethyl azodicarboxylate (42 mL, 0.26 mmol)

were added to the solution. The solution was

stirred for 12 h, quenched with satd aq

NaHCO₃(15 mL), and extracted (5×20 mL)

with Et₂O. The extracts were dried (MgSO₄),

concentrated, and the crude product was

puriﬁed by silica gel chromatography eluting

with (1:9 EtOAc–hexanes) to give 48 mg (0.12

mmol, 92%) of the p-nitrobenzoate ester: R_f

0.13 (1:9 EtOAc–hexanes); [h]²_D¹127.8° (c

0.64, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 3112,

2929, 2857, 1735, 1607, 1528, 1472, 1388,

1350, 1322, 1266; ¹H NMR (500 MHz,

CDCl₃) l 8.30 (dt, J 9.0, 2.0, 2.0 Hz, 2 H),

8.21 (dt, J 9.0, 2.0, 2.0 Hz, 2 H), 6.90 (dd, J

9.5, 3.5 Hz, 1 H), 6.21 (dd, J 10.0, 1.0 Hz, 1

H), 5.84 (ddd, J 5.0, 4.0, 1.0 Hz, 1 H), 4.73

(dd, J 9.5, 4.5 Hz, 1 H), 3.93 (dd, J 11.5, 3.5

Hz, 1 H), 3.88 (dd, J 11.5, 5.5 Hz, 1 H), 0.85

(s, 9 H), 0.043 (s, 3 H), 0.040 (s, 3 H); ¹³C

NMR (125 MHz, CDCl₃) l 163.6, 161.3,

150.9, 140.3, 134.2, 131.0, 124.0, 123.7, 80.1,

64.8, 62.5, 25.7, 18.1, −5.60, −5.63;

CIHRMS Calcd for [C₁₉H₂₅O₇NSi+NH₄]⁺:

425.1744. Found: 425.1785.

22c: R_f0.28 (1:9 EtOAc–hexanes); [h]_D²¹

−

183° (c 1.87, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹

)

2956, 2931, 2886, 2857, 1745, 1472, 1372,

1

1341, 1260; H NMR (500 MHz, CDCl₃) l

7.07 (dd, J 9.5, 6.0 Hz, 1 H), 6.24 (d, J 9.5 Hz,

1 H), 5.21 (dd, J 5.5, 3.0 Hz, 1 H), 4.55 (ddd,

J 8.0, 5.5, 2.5 Hz, 1 H), 4.21 (dq, J 14.5, 7.5,

1.0 Hz, 2 H), 3.94 (dd, J 10.0, 9.0 Hz, 1 H),

3.90 (dd, J 10.0, 5.5 Hz, 1 H), 1.31 (t, J 7.5

Hz, 3 H), 0.87 (s, 9 H), 0.07 (s, 3 H), 0.06 (s,

3 H); ¹³C NMR (125 MHz, CDCl₃) l 161.9,

154.2, 139.7, 125.7, 78.0, 64.8, 63.7, 59.9, 25.7,

18.1, 14.2, −5.6, −5.8; FABHRMS Calcd

for [C₁₅H₂₆O₆Si+H]⁺: 331.1577. Found:

331.1573; Anal. Calcd for C, 54.52; H, 7.94.

Found: C, 54.72; H, 8.04.

(5R,6R) - 5 - tert - Butyldimethylsilanyloxy-

methyl - 6 - tert - butyldimethylsilanyloxymethyl-

5,6-dihydropyran-2-one

(22d).—Compound

21 (70 mg, 0.27 mmol) was dissolved in 1.5

mL of CH₂Cl₂, and 125 mL (1.1 mmol) of

2,6-lutidine was added to the solution. TB-

SOTf (125 mL, 0.54 mmol) was added and the

solution was stirred at 0 °C for 0.5 h. The

reaction was quenched with (10 mL) of satd

aq NaHCO₃and 10 mL of Et₂O. The phases

were separated and the aq layer was extracted

(5×10 mL) with Et₂O. The organic fractions

were combined, dried (MgSO₄), concentrated,

and the crude product was puriﬁed by silica

gel chromatography eluting with (1:9 EtOAc–

hexanes) to give 86 mg (0.23 mmol, 85%) of

compound 22d: R_f0.25 (1:9 EtOAc–hexanes);

[h]²_D¹−125.4° (c 0.56, CH₂Cl₂); IR (thin ﬁlm,

cm⁻¹) 2954, 2929, 2886, 2857, 1716, 1472,

(5S,6R) - 6 - tert - Butyldimethylsilanyloxy-

methyl - 5 - hydroxy - 5,6 - dihydro - pyran - 2 - one

(23).—The p-nitrobenzoate ester (51 mg, 0.13

mmol) was dissolved in 2.5 mL of methanol,

and triethylamine (55 mL, 0.38 mmol) was

added to the solution. The solution was stirred

for 12 h and then concentrated under reduced

pressure. The crude product was puriﬁed by

34

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

pyran-3-yl ethyl carbonate (24c).—Compound

22c (80 mg, 0.24 mmol) was dissolved in 1.5

mL of dichloromethane. A molar excess of a

1:1 (w/w) solution of 4-methylmorpholine-N-

oxide in water was added to the solution.

After the solution was cooled to 0 °C, a cata-

lytic amount (2 mol%) of OsO₄was added to

the reaction. The reaction was allowed to stir

at 0 °C for 3 h. The mixture was puriﬁed

directly by silica gel chromatography eluting

with (3:7 EtOAc–hexanes) to give 70 mg (0.19

mmol, 79%) of compound 24c: R_f0.2 (1:1

EtOAc–hexanes); [h]²_D¹19.8° (c 0.47, CH₂Cl₂);

IR (thin ﬁlm, cm⁻¹) 3446, 2955, 2930, 2886,

2857, 1755, 1472, 1374, 1259, 1198, 1111,

silica gel chromatography (1:4 EtOAc–hex-

anes) to yield 25 mg (0.10 mmol, 80%) of

compound 23: R_f0.15 (1:4 EtOAc–hexanes);

[h]²_D¹−20.5° (c 1.11, CH₂Cl₂); IR (thin ﬁlm,

cm⁻¹) 3432, 2954, 2929, 2857, 1712, 1472,

1

1256; H NMR (500 MHz, CDCl₃) l 6.83 (dd,

J 10.0, 2.5 Hz, 1 H), 5.95 (dd, J 10.0, 2.0 Hz,

1 H), 4.64 (ddd, J 9.5, 5.5, 2.0 Hz, 1 H), 4.31

(ddd, J 9.5, 7.0, 4.0 Hz, 1 H), 4.04 (dd, J 10.5,

4.0 Hz, 1 H), 3.89 (dd, J 10.5, 7.0 Hz, 1 H),

13

3.30 (bs, 1 H), 0.90 (s, 9 H), 0.12 (s, 6 H); C

NMR (125 MHz, CDCl₃) l 162.4, 148.8,

119.6, 80.0, 65.5, 64.0, 25.7, 18.2, −5.56,

−5.58; CIHRMS Calcd for [C₁₂H₂₂O₄Si+

NH₄]⁺: 276.1631. Found: 276.1626; Anal.

Calcd for C, 55.79; H, 8.59. Found: C, 55.61;

H, 8.59.

1

1041; H NMR (500 MHz, CDCl₃) l 5.30 (dd,

J 4.5, 2.5 Hz, 1 H), 4.89 (ddd, J 9.0, 6.5, 2.5

Hz, 1 H), 4.46 (ddd, J 4.5, 3.5, 1.5 Hz, 1 H),

4.41 (dd, J 3.0, 1.0 Hz, 1 H), 4.23 (dd, J 14.0,

7.0 Hz, 2 H), 3.87 (dd, J 10.0, 6.0 Hz, 1 H),

3.84 (dd, J 10.0, 9.0, 1 H), 3.25 (bs, 1 H), 2.88

(bs, 1 H), 1.33 (t, J 7.0 Hz, 3 H), 0.88 (s, 9 H),

0.07 (s, 3 H), 0.05 (s, 3 H); ¹³C NMR (75

MHz, CDCl₃) l 172.9, 153.8, 77.8, 71.2, 67.9,

67.7, 64.9, 59.8, 25.6, 18.1, 14.1, −5.6, −5.8;

FABHRMS Calcd for [C₁₅H₂₈O₈Si+H]⁺:

365.1632. Found: 365.1640.

(2R,3R,4R,5R) - 2 - (tert - Butyldimethylsila-

nyloxymethyl)-4,5-dihydroxy-6-oxotetrahydro-

pyran-3-yl acetate (24b).—Compound 22b (34

mg, 0.113 mmol) was dissolved in 0.6 mL of

tert-butanol and 0.6 mL of acetone. A molar

excess of a 1:1 (w/w) solution of 4-methylmor-

pholine-N-oxide in water was added to the

solution. After the solution was cooled to

0 °C, a catalytic amount (2 mol%) of OsO₄

was added to the reaction. The reaction was

allowed to stir at 0 °C for 8 h. The reaction

was quenched with satd aq Na₂SO₃and the

mixture was extracted (5×25 mL) with Et₂O

and washed with brine. The combined organic

extracts were dried (MgSO₄), ﬁltered, and con-

centrated. The product was puriﬁed by silica

gel chromatography eluting with (3:7 EtOAc–

hexanes) to give 23 mg (0.07 mmol, 62%) of

compound 24b: R_f0.11 (3:7 EtOAc–hexanes);

[h]²_D¹28.0° (c 1.08, CH₂Cl₂); IR (thin ﬁlm,

cm⁻¹) 3433, 2955, 2930, 2885, 2857, 1752,

(3R,4R,5R,6R) - 5 - tert - Butyldimethylsila-

nyloxy - 6 - tert - butyldimethylsilanyloxymethyl-

3,4-dihydroxytetrahydropyran-2-one (24d).—

Compound 22d (63 mg, 0.17 mmol) was

dissolved in 0.8 mL of tert-butanol and 0.8

mL of acetone. A molar excess of a 1:1 (w/w)

solution of 4-methylmorpholine-N-oxide in

water was added to the solution. After the

solution was cooled to 0 °C, a catalytic

amount (2 mol%) of OsO₄was added to the

reaction. The reaction was allowed to stir at

0 °C for 8 h. The reaction was quenched with

satd aq Na₂SO₃, and the mixture was ex-

tracted (5×25 mL) with Et₂O and washed

with brine. The combined organic extracts

were dried (MgSO₄), ﬁltered, and concen-

trated. The mixture was puriﬁed by silica gel

chromatography eluting with (3:7 EtOAc–

hexanes) to give 45 mg (0.11 mmol, 65%) of

compound 24d: R_f0.23 (3:7 EtOAc–hexanes);

[h]²_D¹33.8° (c 2.42, CH₂Cl₂); IR (thin ﬁlm,

cm⁻¹) 3370, 2954, 2928, 2885, 2856, 1730,

1

1374, 1227; H NMR (500 MHz, C₆D₆) l 5.43

(dd, J 4.5, 2.5 Hz, 1 H), 4.82 (ddd, J 8.0, 6.0,

2.5 Hz, 1 H), 4.07 (m, 2 H), 3.65 (dd, J 10.0,

6.0 Hz, 1 H), 3.59 (dd, J 10.0, 8.0 Hz, 1 H),

3.22 (bs, 1 H), 2.55 (bs, 1 H), 1.51 (s, 3 H),

0.86 (s, 9 H), −0.07 (s, 3 H), −0.09 (s, 3 H);

¹³C NMR (125 MHz, C₆D₆) l 173.3, 169.0,

78.2, 68.7, 68.6, 68.4, 60.5, 25.9, 20.2, 18.3,

−5.5, −5.7; Anal. Calcd for C, 50.28; H,

7.84. Found: C, 50.44; H, 7.97.

1

(2R,3R,4R,5R) - 6 - (tert - Butyldimethylsila-

nyloxymethyl)-4,5-dihydroxy-6-oxotetrahydro-

1472, 1361, 1256, 1207, 1115; H NMR (500

MHz, CDCl₃) l 4.65 (ddd, J 8.0, 6.0, 1.5 Hz,

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

35

0 °C, a catalytic amount (2 mol%) of OsO₄

was added to the reaction. The reaction was

allowed to stir at 0 °C for 2 h. The mixture

was puriﬁed directly by silica gel chromatog-

raphy eluting with (3:7 EtOAc–hexanes) to

give 27 mg (0.066 mmol, 73%) of compound

26: R_f0.17 (3:7 EtOAc–hexanes); [h]²_D¹30.2° (c

1.43, CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 3449,

2954, 2929, 2857, 1750, 1472, 1463, 1254,

1 H), 4.48 (dd, J 3.0, 1.5 Hz, 1 H), 4.24 (ddd,

J 5.5, 4.5, 1.0 Hz, 1 H), 4.22 (dd, J 4.5, 1.5

Hz, 1 H), 3.84 (dd, J 10.0, 8.0 Hz, 1 H), 3.79

(dd, J 10.0, 6.0 Hz, 1 H), 3.50 (bs, 1 H), 3.10

(bs, 1 H), 0.89 (s, 18 H), 0.134 (s, 3 H), 0.130

(s, 3 H), 0.08 (s, 3 H), 0.07 (s, 3 H); C NMR

(125 MHz, CDCl₃) l 173.8, 80.3, 70.1, 67.9,

67.6, 60.3, 25.9, 25.6, 18.3, 17.9, −4.7, −5.2,

13

−5.3,

−5.4; FABHRMS Calcd for

1

[C₁₈H₃₈O₆Si₂+Na]⁺:

429.2105.

Found:

1124; H NMR (300 MHz, C₆D₆) l 4.36 (ddd,

J 9.0, 1.8, 1.8 Hz, 1 H), 4.11 (dd, J 9.0, 2.1

Hz, 1 H), 4.04 (dd, J 2.4, 2.1 Hz, 1 H), 3.76

(d, J 2.1 Hz, 1 H), 3.58 (dd, J 1.5, 1.2 Hz, 1

H), 3.21 (bs, 1 H), 2.35 (bs, 1 H), 0.90 (s, 9 H),

0.88 (s, 9 H), 0.01 (s, 3 H), 0.00 (s, 6 H),

429.2092.

(4R,5R,6R,7R) - 7 - tert - Butyldimethylsila-

nyloxy-6-(tert-butyldimethylsilanyloxymethyl)-

2,2 - dimethyltetrahydro - [1,3]dioxolo[4,5 - c]-

pyran-4-one (25).—Compound 24d (27 mg,

0.066 mmol) was dissolved in 0.3 mL of ace-

tone. Excess 80 mL (0.66 mmol) 2,2-

dimethoxypropane was added followed by 1

mg of p-toluenesulfonic acid. The reaction

was allowed to stir at for 8 h. The reaction

was quenched with satd aq NaHCO₃, and the

mixture was extracted (5×5 mL) with Et₂O.

The combined organic extracts were dried

(MgSO₄), ﬁltered, and concentrated. The mix-

ture was puriﬁed by silica gel chromatography

eluting with (1:9 EtOAc–hexanes) to give 19

mg (0.043 mmol, 65%) of compound 25: R_f

0.5 (1:9 EtOAc–hexanes); [h]²_D¹10.4° (c 1.35,

CH₂Cl₂); IR (thin ﬁlm, cm⁻¹) 2931, 2858,

13

−0.04 (s, 3 H); C NMR (125 MHz, CDCl₃)

l 172.7, 81.1, 71.1, 69.2, 65.6, 60.8, 25.8, 25.6,

18.2, 17.9, −4.5, −5.0, −5.3, −5.5;

FABHRMS Calcd for [C₁₈H₃₈O₆Si₂+H]⁺:

407.2285. Found: 407.2278.

(4R,5R,6R,7R) - 7 - (tert - Butyldimethylsila-

nyloxy)-6-(tert-butyldimethylsilanyloxymethyl)-

2,2 - dimethyltetrahydro - [1,3]dioxolo[4,5 - c]-

pyran-4-one (27).—Compound 26 (4 mg, 0.01

mmol) was dissolved in 0.1 mL of acetone.

Excess 6 mL (0.05 mmol) 2,2-dimethoxy-

propane was added followed by 1 mg of p-

toluenesulfonic acid. The reaction was allowed

to stir at for 8 h. The reaction was quenched

with satd aq NaHCO₃, and the mixture was

extracted (5×5 mL) with Et₂O. The com-

bined organic extracts were dried (MgSO₄),

ﬁltered, and concentrated. The mixture was

puriﬁed by silica gel chromatography eluting

with (1:9 EtOAc–hexanes) to give 3 mg (0.007

mmol, 70%) of compound 26: R_f0.5 (1:9

EtOAc–hexanes); [h]²_D¹40.4° (c 1.15, CH₂Cl₂);

IR (thin ﬁlm, cm⁻¹) 2989, 2929, 2856, 1742,

1

1763, 1472, 1257, 1120, 1066; H NMR (500

MHz, CDCl₃) l 4.66 (d, J 7.0 Hz, 1 H), 4.48

(ddd, J 7.5, 4.5, 1.5 Hz, 1 H), 4.37 (dd, J 7.0,

3.5 Hz, 1 H), 4.04 (dd, J 3.5, 2.0 Hz, 1 H),

3.84 (dd, J 10.0, 4.5 Hz, 1 H), 3.75 (dd, J 10.5,

8.0 Hz, 1 H), 1.51 (s, 3 H), 1.37 (s, 3 H), 0.90

(s, 9 H), 0.87 (s, 9 H), 0.13 (s, 3 H), 0.11 (s, 3

13

H), 0.09 (s, 3 H), 0.08 (s, 3 H); C NMR (125

MHz, CDCl₃) l 167.3, 111.2, 76.5, 72.9 (2 C),

66.7, 59.9, 26.2, 25.8, 25.6, 24.1, 18.2, 17.9,

−4.6, −5.1, −5.41, −5.43; FABHRMS

Calcd for [C₂₁H₄₂O₆Si₂+H]⁺: 447.2598.

Found: 447.2600.

(3R,4R,5R,6R) - 5 - (tert - Butyldimethylsila-

nyloxy)-6-(tert-butyldimethylsilanyloxymethyl)-

3,4-dihydroxytetrahydropyran-2-one (26).—

Compound 19a (34 mg, 0.091 mmol) was dis-

solved in 1.0 mL of dichloromethane. A molar

excess of a 1:1 (w/w) solution of 4-methylmor-

pholine-N-oxide in water was added to the

solution. After the solution was cooled to

1

1463, 1373, 1253, 1133; H NMR (500 MHz,

CDCl₃) l 4.54 (d, J 7.0 Hz, 1 H), 4.52 (dd, J

7.0, 3.0 Hz, 1 H), 4.47 (ddd, J 8.5, 2.5, 2.5 Hz,

1 H), 4.16 (dd, J 8.0, 3.0 Hz, 1 H), 3.89 (d, J

2.5 Hz, 1 H), 1.50 (s, 3 H), 1.38 (s, 3 H), 0.91

(s, 9 H), 0.89 (s, 9 H), 0.14 (s, 3 H), 0.12 (s, 3

13

H), 0.08 (s, 3 H), 0.07 (s, 3 H); C NMR (125

MHz, CDCl₃) l 168.5, 111.3, 78.7, 74.8, 73.1,

65.2, 61.0, 26.4, 25.9, 25.6, 24.7, 18.3, 18.1,

−4.6, −4.9, −5.2, −5.4; FABHRMS Calcd

for [C₂₁H₄₂O₆Si₂+H]⁺: 447.2598. Found:

447.2601.

36

J.M. Harris et al. / Carbohydrate Research 328 (2000) 17–36

K.T. Kabuto, tetrahedron, 32 (1976) 1363. (c) A.G.M.

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Syntheses of four D- and L-hoxoses via diastereoselective and enantioselective dihydroxylation reactions

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