Intramolecular 1,8-hydrogen atom transfer reactions in disaccharide systems containing furanose units

Article

pubs.acs.org/joc

Intramolecular 1,8-Hydrogen Atom Transfer Reactions in

Disaccharide Systems Containing Furanose Units

Sabrina Guyenne, Elisa I. Leon, Angeles Martín,* Ines Perez-Martín, and Ernesto Suarez*

́

Instituto de Productos Naturales y Agrobiología del CSIC, Carretera de La Esperanza 3, 38206 La Laguna, Tenerife, Spain

S

* Supporting Information

ABSTRACT: A previously developed 1,8-hydrogen atom transfer

(HAT) reaction promoted by 6-O-yl alkoxyl radicals between the

two pyranose units in Hexp-(1→4)-Hexp disaccharides has been

extended to other systems containing at least a furanose ring in

their structures. In Penf-(1→3)-Penf (A) and Hexp-(1→3)-Penf

(B) disaccharides, the 1,8-HAT reaction and concomitant

cyclization to a 1,3,5-trioxocane ring are in competition with

radical β-scission of the C4−C5 bond and formation of

dehomologated products. The inﬂuence of the stereoelectronic β-oxygen eﬀect on the β-scission and consequently on the

1,8-HAT reaction has been studied using the four possible isomeric ^D-furanoses. D-xylo- and D-lyxo-derivatives aﬀorded

preferentially 1,8-HAT products, whereas ^D-arabino- and D-ribo-derivatives gave exclusively direct β-scission of the alkoxyl radical.

When the 6-O-yl radical is on a pyranose ring, as occurs in Penf-(1→4)-Hexp (C), it has been shown to provide the cyclized

products exclusively.

requires a well-deﬁned conformation of the glycosidic (Φ) and

aglyconic (Ψ) bonds, which, as expected, are highly dependent

on the stereochemistry of the four chiral centers involved in the

cyclization step (C5, C4, C1′, and C5′). In conclusion, we have

established that if, under oxidative conditions, a conformation-

ally stable boat−chair 1,3,5-trioxocane ring can be formed, the

abstraction would occur preferentially at C5′ (1,8-HAT),

whereas if this process is energetically disfavored, namely, a

1,3,5-trioxocane ring in boat−boat or crown ether conforma-

tion, the abstraction should take place mainly at C1′ (1,6-HAT)

to give an interglycosidic spiro ortho ester motif.¹²In both cases

the cyclization mechanism implicates an oxonium ion

intermediate formed by oxidation of the C-radical with an

excess of (diacetoxyiodo)benzene (DIB).^11aWe also found that

under reductive conditions a predominant inversion of the

conﬁguration at C5′ may take place and hence the trans-

formation of ^D-Hexp-(1→4)-D-Hexp disaccharides into more

valuable ^L-Hexp-(1→4)-D-Hexp systems can be accomplished

in good yields.

INTRODUCTION

■

Much attention has been devoted to free radical reactions in

carbohydrate chemistry in recent years.¹Although the vast

majority of the work reported in this area has been focused on

anomeric radicals of hexopyranose systems, the conformation,

lifetime, and reactivity of the C4 radical in pentofuranoses have

also been investigated in some detail.²The importance of these

radicals in the DNA damage through the metabolism of oxygen

and in the mode of action of certain DNA cleavage agents (e.g.,

iron bleomycin, (1,10-phen)₂Cu complex, and enediyne natural

products) has motivated these studies.³

These C4 radicals, in either aldofuranose or oligonucleotide

systems, have been usually generated by reductive fragmenta-

tion of 4-phenylseleno derivatives⁴or Norrish type 1

photochemical cleavage of ketones.⁵The homolytic rupture

of the inactive C4−H bond by intramolecular 1,5- and 1,6-

hydrogen atom transfer (HAT) reactions from aryl C-radicals,⁶

alkoxyl radicals,⁷N-radicals,⁸or Norrish−Yang photocyclization

of 1,2-diketones⁹have also been occasionally used, and a few

examples of these reactions can be found in the literature.

Over the past few years, we have been particularly interested

in intramolecular HAT reactions promoted by properly

positioned alkoxyl radicals as a method for the regioselective

functionalization of remote inactive carbons in the carbohy-

drate skeleton.^7,10In most cases, the reaction proceeded via

thermodynamically stable six- or seven-membered transition

states (TSs) to give tetrahydrofuran or tetrahydropyran rings,

respectively. Recently, we have described the stereochemical

and conformational factors that control a novel 1,8-HAT

reaction between the two pyranose units in Hexp-(1→4)-Hexp

disaccharide systems when promoted by a primary 6-O-yl

radical (Scheme 1).¹¹The results show that the process

RESULTS AND DISCUSSION

■

Since in the results we have published, until now, the hydrogen

donor and acceptor have always been located in hexopyranose

moieties, a logical extension of these studies would be to

include furanose residues in the disaccharide. Three principal

structural arrangements, Penf-(1→3)-Penf (A), Hexp-(1→3)-

Penf (B), and Penf-(1→4)-Hexp (C), are outlined in Scheme 2.

Additionally, examples of related Penp-(1→4)-Hexp (e.g., 41)

Received: June 4, 2012

Published: August 1, 2012

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Scheme 1. 1,8-HAT versus 1,6-HAT in Hexp-(1→4)-Hexp Disaccharide Systems

o

and Hexf-(1→4)-Hexp (e.g., 58) systems have also been

rings adopt a constrained east E conformation (P = 90°),

which leaves the Hα−C4′ (pseudoaxial), the Hβ−C1′

(pseudoequatorial), and the 5-O-yl radical on a pseudoequa-

torial side chain in a global disposition very similar to that

found in our earlier α-^D-Hexp-(1→4)-D-Hexp models. In the

second one the arabino rings adopt an opposite west E_o

conformation (P = 270°) with the Hα−C4′ (pseudoequato-

rial), the Hβ−C1′ (pseudoaxial), and the 5-O-yl radical on a

pseudoaxial side chain. The energies of the staggered

conformations exo-syn, non-exo, and exo-anti around the

glycosidic torsion angle were calculated by performing a

coordinated scan of Φ and Ψ dihedrals.¹⁸Since it is generally

accepted that a narrow range of distances of approximately

2.5−3.0 Å are required for the abstraction to take place,¹⁹the

distances between the oxygen at C5 and the extractable

hydrogens were also calculated as indicative of HAT reaction

feasibility.

The results of this study highlight the clear inﬂuence of the

furanose ring conformation on the 1,6- and 1,8-HAT TSs. In

the Araf E_o-(1→3)-Araf E_omodel, the distances between the 5-

O-yl radical and the extractable hydrogens (H1′ and H4′) are

excessively long (4.9−7.0 Å) and HAT reactions are clearly

unfavorable. Notwithstanding, in the Araf^oE-(1→3)-Araf^oE

model, the global minimum was found to be an exo-syn

conformer with an ideal distance O5−H4′ of 2.9 Å (see Table

1S of the Supporting Information for details).

The intuitive extrapolation of these results suggests that 1,8-

HAT should be favored with restricted or stabilized furanose

ring conformers at the east side of the pseudorotational

itinerary with phase angle values of about 90° and disfavored

with conformers at the opposite west side (P = 270°).

The easy dehomologation of 5-O-yl radicals by β-scission

poses a diﬃcult problem, but an example previously described

from this laboratory encourages us to think that intramolecular

HAT could eﬀectively compete with the dehomologation

reaction. The reaction of diol 1²⁰with the DIB/I₂system

aﬀorded exclusively 2,6-anhydro-β-^D-ribo-hex-2-ulose (2,6-

anhydro-β-^D-psicose) derivative 3 in high yield via an evident

1,5-HAT reaction, while no products coming from β-scission

could be detected in the reaction mixture (Scheme 3).⁷

Notwithstanding, under the same conditions the selectively

monosilyl-protected 2²¹gave only the mixture of dehomolo-

gated anomeric acetates 4.²²

included in this study.

Scheme 2. Furanose Disaccharide Arrangements

At ﬁrst sight, the diﬀerences between the 1,8-HAT reaction

in the hexopyranose disaccharides and these three systems may

seem trivial. Upon close examination, however, four important

diﬀerences arise: (a) There is an increased conformational

ﬂexibility of the aldofuranosyl ring in solution as compared to

the well-deﬁned chair conformation of the aldopyranosyl ring.

(b) A greater ﬂexibility of the glycosidic (Φ) bond is expected

in these tetrahydrofuran systems, where the electronic eﬀects

tend to be less pronounced.¹³(c) Easy dehomologation of 5-O-

yl radicals by β-scission with loss of formaldehyde has been

described in furanose rings, and under oxidative¹⁴and

reductive¹⁵conditions, the homologous reaction in pyranose

systems has not been observed. (d) An additional concern

comes from the stability of the ﬁnal 1,3,5-trioxocane ring, which

in the case of furanoses (2,6,10-trioxabicyclo[5.2.1]decane

system) could be more prone to hydrolyze.¹⁶The ﬁrst two

diﬀerences may play a critical role in the nine-membered TS,

and in general, these drawbacks may transform the process into

a much more diﬃcult task.

To illustrate the eﬀect that the furanose ring conformation

could have on the 1,8-HAT reaction, we prepared two

theoretical models of methyl 2,3,5-tri-O-methyl-α-^D-Araf-(1→

3)-2-O-methyl-α-^D-Araf (arrangement A) using molecular

mechanics (Figure 1).¹⁷In the ﬁrst one both arabinofuranose

To arrive at a reasonable explanation of the factors governing

these diﬀerences, the conformation of the furanose ring was

determined by pseudorotational analysis of NMR ring coupling

constants (³J_H,H).²³Due probably to the restrictions imposed

by the [3.3.0]bicycle, the furanose ring conformations in 1 and

2 are very similar, with the most populated conformers at phase

angles of P = 292° (¹T_o) and P = 276° (E_o), respectively (see

Table 2S of the Supporting Information for details).²⁴In these

northern conformations, the furanose side chain at C4 and the

Figure 1. Minimized exo-syn conformers of α-D-Arap^oE-(1→3)-α-D-

Arap^oE and α-D-ArapE_o-(1→3)-α-D-ArapE_odisaccharides. The dis-

tances between 5O and H4′ are shown by arrows.

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methods and X-ray crystallographic analysis and therefore could

be a good candidate to test our 1,8-HAT reaction.

Scheme 3. HAT versus Dehomologation in Ribose

Derivatives

Keeping the above considerations in mind, a series of

disaccharides belonging to each one of the above-mentioned

arrangements were synthesized and are outlined in Table 1.

a

Table 1. Synthesis of Disaccharides

hydrogen at C1 lie in a syn-1,3-pseudodiaxial relationship

favoring the 1,5-abstraction whereas the tether at C1 and the

hydrogen at C4 are in a disfavored syn-1,3-pseudodiequatorial

orientation. The distances C1′−O−H4 and C5−O−H1 on the

minimum energy conformers were then calculated by perform-

ing a coordinated scan of H1−C1−C1′−O and H4−C4−C5−

O dihedrals.¹⁷As shown in Table 2S, the 1,5-HAT reaction can

only be performed from the 5-O-yl radical (d = 2.5 Å), being

impossible from the 1′-O-yl radical (d = 4.5−4.7 Å), thereby

conﬁrming the experimental results.

In comparative terms, the reaction was also studied with

more ﬂexible 2,3-di-O-methylribose derivatives 9 and 10. The

preparation of these compounds was carried out as outlined in

Scheme 3. Protection of the 5-OH group in benzyl ^D-

ribofuranoside (5) as a tert-butyldimethylsilyl ether and

subsequent dimethylation gave saccharide 6 as an anomeric

mixture of isomers. The C-glycosidation of the deprotected

anomeric alcohol 7 with trimethylsulfoxonium ylide following

a

Glycosylations by the trichloroacetimidate method were performed

with peracetylated donors (2.3 equiv), acceptors (1 equiv), (TMS)-

OTf (0.025 equiv), and 3 Å molecular sieves (50 wt %) in anhydrous

b

CH₂Cl₂at 0 °C. Isolated yield after chromatographic puriﬁcation.

the Frec

́

hou et al.²⁵protocol aﬀorded after acetylation a

c

Reagents and conditions: (a) acetate (1 equiv), K₂CO₃(3 equiv) in

MeOH at rt, then Amberlyst 15 H⁺; (b) alcohol (1 equiv), NaH (6

chromatographically separable mixture of isomers 8. The major

α-isomer was deprotected consecutively with K₂CO₃and TBAF

to give the diol 10²⁶and the intermediate alcohol 9. When the

radical reaction was applied to diol 10, a complex mixture of

inseparable acetates was obtained upon β-fragmentation and we

were unable to detect the formation of any HAT product in the

reaction mixture. Monosilylated 9 also aﬀorded only β-

fragmented products, including a 1-O-acetyl-^D-ribofuranose

mixture of anomers 11 and a small amount of unexpected

disaccharide structures 12 promoted by intermolecular

glycosidation via a ribofuranosylium cation intermediate. The

preferred conformations of 9 and 10 calculated analogously

indicate that distances are too large for the 1,5-HAT reaction to

take place (Table 2S, Supporting Information).

Considerable attention has been focused on conformational

analysis of aldofuranosides because of their biological

importance, and the most important structural features of

these compounds have been published.²⁷A quick survey of the

literature reveals that methyl α-^D-arabinofuranoside exists

preferentially in a conformation of the eastern region of the

pseudorotational itinerary (E₄) as determined by computational

d

equiv), MeI (7.5 equiv) in DMF at 0 °C. Reagents and conditions: n-

pentenyl glycoside (1 equiv), acceptor (1 equiv), N-iodosuccinimide

(NIS) (1.3 equiv), (TMS)OTf (0.3 equiv) in dry CH₂Cl₂at 0 °C →

rt. TCA = trichloroacetimidyl.

The glycosyl donors α-^D-Araf 24,²⁸α-L-Araf 29,²⁹α-L-Rhap

32,³⁰α-D-Manf 37,³¹and α-D-Lyxp 40³²were prepared

according to the literature procedures. The incorporation of

acetyl protecting groups in all trichloroacetimidate derivatives

serves to ensure the control of the glycosylation stereo-

chemistry by neighboring C2 group participation.³³

The preparation of monosaccharide alcohols α-D-Araf 14, β-

D-Ribf 16, β-D-Xylf 18, and α-D-Lyxf 23 used as glycosyl

acceptors was carried out according to well-established

experimental procedures as described in Scheme 4. Protection

of the 5-OH group as a tert-butyldiphenylsilyl ether in 13³⁴and

15³⁵aﬀorded methyl α-D-arabinofuranoside (14) and methyl β-

D-ribofuranoside (16), respectively, in excellent yield. Methyl β-

D-xylofuranoside derivative (18) was obtained in two steps

from β-^D-ribofuranoside 16 involving initial Dess−Martin

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Scheme 4. Preparation of Glycosyl Donors

Scheme 5. HAT Reactions of Arrangement A Disaccharide

Models under Oxidative Conditions

periodinane oxidation to ketone 17 and subsequent reduction

with sodium borohydride to aﬀord the 3-β-isomeric alcohol 18

preferentially. The synthesis of α-^D-lyxofuranoside derivative 23

began with the known methyl α-^D-lyxofuranoside (19),³⁶which

was partially protected by 3,5-di-O-silylation using (i-

Pr₂SiCl)₂O in pyridine to give compound 20 in 81% yield.

The latter was in turn methylated with the MeI/Ag₂O system

to aﬀord 21; probably due to the highly congested β-face of the

ring, the reaction was very slow and the yield was only 41%

(84% brsm) after 5 days. The 1,1,3,3-tetraisopropyldisiloxane-

1,3-diyl group of 21 was removed by TBAF to give the diol 22

in 99% yield. The usual tert-butyldiphenylsilylation of 22 gave

the desired 5-masked product 23 in 99% yield.

dehomologated acetates 43 in moderate yield could be detected

(Scheme 5).

Recently, it was claimed that, under reductive conditions in

ribo- and xylofuranose derivatives where the neighboring

hydroxyl group at C3 is protected, the β-fragmentation is

prevented and the 5-O-yl radical is simply quenched by the

stannane.^15dAlthough this is in apparent contradiction with a

previous ﬁnding by Robins et al.^15ain protected ribonucleosides

where, under similar conditions, the β-scission occurs

exclusively, we decided to prepare α-^D-Araf-(1→3)-β-D-Ribf

derivative 44 to check this possibility. Again, only β-fragmented

products, the acetate 45 together with a small amount of

aldehyde 46, were obtained (Scheme 5). There is no evidence

for the formation of any 1,8-HAT product within the limits of

¹H NMR detection. A pseudorotational study showed α-D-

ArafE₄-(1→3)-β-D-RibfE₂conformations for 44 and seems to

conﬁrm the results. The β-^D-ribofuranose moiety adopts

preferentially a west E₂conformation, and the calculated C5−

O−H4′ distance (3.5 Å) in the global exo-syn minimum is

unfavorable for the 1,8-HAT.

After these unsuccessful eﬀorts, we decided to try a diﬀerent

approach to avoid the dehomologation reaction by destabiliza-

tion of the C4 radical intermediate. The fragmentation of the

C4−C5 bond should be favored by a trans disposition of the

oxygen substituent at C3 (as in preceding models) due to a

stereoelectronic β-oxygen eﬀect. Consequently, a cis disposition

of this substituent on the β-face of the ring may prevent the β-

fragmentation.^14a

The known methyl 6-O-(tert-butyldiphenylsilyl)-2,3-di-O-

methyl-α-^D-glucopyranoside (34) also used as a glycosyl

acceptor was prepared by a previously described method.^11a

The required disaccharides 25, 27, 30, 33, 35, and 41 were

prepared by the trichloroacetimidate method using a catalytic

amount of (TMS)OTf as a Lewis acid;^33aas expected an

exclusive 1,2-trans relative disposition of the glycosidic bond

and the 2-acetyl group was always observed (Table 1). The n-

pentenyl glycoside 37³¹was activated with N-iodosuccinimide

(NIS)/(TMS)OTf and used as a glycosyl acceptor for the

synthesis of α-^D-Manf-(1→4)-α-D-Glcp disaccharide 38.^33bIn

most of the prepared disaccharides, 25, 27, 30, 35, and 38, and

to favor the HAT reaction by the electrophilic alkoxyl radical,

the electron-withdrawing acetyl protecting groups (EWGs)

were substituted by methyl ethers.^10bThe models 26, 28, 31,

36, and 39 thus obtained were desilylated with TBAF, and the

free primary alcohols were then ready for the generation of the

alkoxyl radicals under oxidative conditions.

3

Pseudorotational analysis of ring J_H,Hcoupling constants of

α-^D-Araf-(1→3)-α-D-Araf derivative 42, our ﬁrst disaccharide

model (Scheme 5), indicated that both furanose rings adopt a

preferential population of E₄conformations.³⁷Analogously to

the Araf^oE-(1→3)-Araf^oE theoretical model previously studied,

the global minimum was found to be an exo-syn conformer with

an ideal distance C5−O−H4′ of 2.7 Å for the 1,8-HAT to take

place. Unfortunately, 42 failed to undergo the desired 1,8-HAT

reaction upon treatment with the DIB/I₂system under a variety

of diﬀerently modiﬁed conditions. The β-fragmentation

reaction is faster, and only an inseparable mixture of isomeric

The stereochemistry of such a disaccharide should follow the

pattern established in our previous research on Hexp-(1→4)-

Hexp models to accommodate the ﬁnal 1,3,5-trioxocane ring in

a stable boat−chair conformation.¹¹The synthesis of a Penf-

(1→3)-Penf disaccharide model with a 3β-aglyconic bond

would require an α-^L-sugar as a glycosyl donor to have a stable

transition state for the 1,8-HAT reaction. Therefore, α-^L-Araf-

(1→3)-α-^D-Lyxf disaccharide 47 was prepared and irradiated

under the DIB/I₂conditions. To our delight, the desired 1,3,5-

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trioxocane derivative 48 was obtained, along with a small

amount of dehomologated acetates 49 as an inseparable 9:1

mixture of diastereomers. Products arising from 1,6-HAT of the

anomeric H1′ were not isolated. We are aware of only one

previous example in the literature of the 2,6,10-

trioxabicyclo[5.2.1]decane system present in the structure of

compound 48 and are unaware of any examples in the

carbohydrate ﬁeld.¹⁶As expected, 48 was very sensitive to acid

decomposition, but it could be puriﬁed by rapid column

chromatography on neutral alumina, albeit in low recovery yield

(22%). The regioselectivity of the process was assured by NMR

spectroscopy; namely, the hydrogens at C5′ appear now as

doublets (δ_H3.40 and 3.45 ppm) with a strong correlation

observed between the C4′ signal (δ_C108.1 ppm) and protons

at C5 (δ_H3.85 and 4.36 ppm, dd) in the 2D HMBC

experiment.

which gives us some idea on the hydrolysis mechanism.

Reasonable evidence for the assignment of the C1′ R

stereochemistry to the acetal 57 was obtained from the

NOESY experiment, which showed signiﬁcant cross-peaks

correlating the axial H1′ with H4 and the axial H6. As described

in the Experimental Section, a small amount of methyl 2,3-di-

O-methyl-α-^D-glucopyranoside, one of the ﬁnal hydrolyzed

monosaccharides, was also obtained.

In this section we have included the related disaccharide α-^D-

Manf-(1→4)-α-^D-Glcp 58 (Scheme 7). The reaction proceeded

analogously to that of 53 to give the trioxocane 59 in similar

yield. The only side product detected was the methylenedioxy

60 generated by 1,7-HAT of one hydrogen of the methoxyl

group at C3 through a conformational equilibrium between

glucopyranose ⁴C₁and ¹C₄ring chairs. The structure and

conformation of 60 were conﬁrmed by analysis of the vicinal

1

³J_H,Hcoupling constants in the H NMR spectrum together

Next the reaction of α-^L-Rhap-(1→3)-β-D-Xylf derivative 50,

an arrangement B model, was examined (Scheme 6).

with DEPT and 2D HSQC and HMBC experiments. Of

particular relevance is the HMBC connectivity of C6 (δ_C64.1

ppm) with the protons at the methylenedioxy bridge (δ_H4.66

and 4.81 ppm, d).

Scheme 6. HAT Reaction of the Arrangement B

Disaccharide Model under Oxidative Conditions

Finally, we carried out the reaction with α-^D-Lyxp-(1→4)-α-

D-Glcp derivative 41, where the hydrogen donor is a pentose in

pyranose form (Scheme 8). Surprisingly, the major product was

the orthoacetate 61 as a sole isomer, resulting from initial 1,8-

HAT and subsequent neighboring participation of the acetate

group after oxidation of the C-radical intermediate. The minor

product was the spiro ortho ester 62, obtained as a mixture of

isomers and evidently formed by a competitive 1,6-HAT.

Although compound 61 could be puriﬁed by silica gel column

chromatography, it is unstable and in the presence of a catalytic

amount of acid undergoes a partial hydrolysis to give in

quantitative yield the dialdose derivative 63. As a global result

of the intramolecular HAT reaction, a regio- and stereoselective

oxidative functionalization at C5′ has been produced with a

concomitant ester shift.³⁸

Compound 50 was designed with ^D-xylofuranose to minimize

the stabilizing β-oxygen eﬀect, assessing its inﬂuence as a

general strategy to avoid the dehomologation reaction. ^D-

Xylose and ^D-lyxose are the only two pentofuranoses which

have a cis relationship between the hydroxyl substituent at C3

and the adjacent side chain.

Likewise, when 50 was subjected to similar reaction

conditions, the same trend was also followed and led to the

formation of 1,3,5-trioxocane derivative 51 and a mixture of

dehomologated acetates 52. The yield of 51 can be slightly

improved by running the reaction at low temperature (0 °C).

The NMR characteristics of 51 clearly indicate that oxidation

has taken place at C5′. Accordingly, the methyl at C5′ appears

now as a singlet at δ_H1.40 ppm, and the HMBC correlations of

C5 proton signals at δ_H4.02 and 4.09 ppm with the C5′ carbon

atom (δ_C101.4 ppm) conﬁrm the new connectivity of both

sugar rings.

This methodology was also applied to α-^D-Araf-(1→4)-α-D-

Glcp 53, a disaccharide belonging to the arrangement C type

(Scheme 7). As expected, no dehomologated products were

produced by β-scission of this 6-O-pyranosyl radical, and as a

consequence, the cyclized product 54 was formed in

signiﬁcantly better yield (55%) than those in the other models

previously obtained.

For comparative purposes the reaction was also applied to

disaccharide analogue 55, where the hydroxyl groups at the

furanose ring are acetylated. Two products, 56 and 57, coming

from the 1,8-HAT reaction are now formed in lower yield due

to the EWG inﬂuence of the neighboring acetyl groups.

Interestingly, we were able to isolate the acetal 57, clearly an

intermediate in the hydrolysis of the 1,3,5-trioxocane ring,

For comparative purposes, a number of models belonging to

arrangements B and C were also studied under reductive

conditions. With this aim, the phthalimide derivatives 64, 70,

74, and 78 were prepared from the corresponding alcohols 50,

53, 55, and 58 by reaction with N-hydroxyphthalimide via

Mitsunobu condensation (Schemes 9 and 10).³⁹

The reaction of α-L-Rhap-(1→3)-β-D-Xylf phthalimide 64

with n-Bu₃SnH/AIBN aﬀorded three compounds (Scheme 9).

Two minor products resulted from 1,8-HAT reactions, the β-^D-

Gulp-(1→3)-β-^D-Xylf 65 (26%) formed by hydrogen abstrac-

tion at C5′ and subsequent radical quenching with inversion of

conﬁguration and alcohol 50 (19%), which could arise either by

abstraction and retention of the conﬁguration at C5′ or simply

by reduction of the 6-O-yl radical prior to the abstraction or

very probably by a combination of both mechanisms.

Unfortunately, as happened under oxidizing conditions, the

third and most abundant product was the dehomologated α-^L-

Rhap-(1→3)-α-^L-Threof disaccharide 66 (49%). Repetition of

this reaction with n-Bu₃SnD showed, after exhaustive analysis of

the isotopic distribution, the complete monodeuteration for the

β-scission product 69 and also for the inverted alcohol 67.

Moreover, 50% deuterium labeling was found in compound 68,

the reduction of the O-radical being responsible for the

unlabeled molecules. We can therefore conclude that in this

model the global process occurs in low yield but predominantly

with inversion of conﬁguration (inversion:retention ratio

3.8:1).

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Scheme 7. HAT Reactions of Arrangement C Disaccharide Models under Oxidative Conditions

deuteration at C4′ in compound 72, while 75% deuterium

labeling was found in the alcohol 73. These results permit us to

establish that the abstraction at C4′ occurs in a 63% yield with

an inversion:retention ratio of approximately 1.4:1.

Scheme 8. HAT Reaction of the α-D-Lyxp-(1→4)-α-D-Glcp

Model under Oxidative Conditions

For the related 6-O-phthalimide 74 with the peracetylated ^D-

arabino moiety, the reaction gave preferentially the inverted

product 75, and the use of n-Bu₃SnD as a reagent showed a

lower abstraction yield at C4′ in comparison with that of

substrate 70 but an improved inversion:retention ratio, 2.6:1.

This higher inversion:retention ratio of acetylated α-^D-Ara 74

versus methylated α-^D-Ara 70 could be explained with the

increase in electronegativity of the β-oxygenated substituent as

observed in the pyranose series between peracetylated and

permethylated β-maltose.^11b

Finally, when the reductive HAT was performed with the

phthalimide 78, the inverted product 79 was generated in lower

yield and the alcohol precursor derivative 80 was then the

major isomer with a 48% yield. Repetition of the experiment

with n-Bu₃SnD/AIBN originated a mixture of compounds 81

(29%), with complete deuteration at C4′, and 82 (49%), with a

70% labeling at C4′. Thus, the deuterium was only

incorporated at position 4′, with no deuterium detected at

other sites within NMR limits, unlike the experiment under

oxidative conditions where abstraction at the methoxyl group at

C3 was also observed (Scheme 7). 1,8-HAT occurs in this

model with a 63% yield with an inversion:retention ratio of

approximately 1:1.2, slightly favoring the retained product.

The reduction of β-D-Araf-(1→4)-β-D-Glcp phthalimide 70

by treatment with n-Bu₃SnH/AIBN aﬀorded exclusively

compounds by hydrogen abstraction at C4′: the β-^L-Xylf-(1→

4)-β-^D-Glcp derivative 71 (46%) formed by inversion to

generate a β-^L-xylofuranose moiety and the alcohol 53 (41%)

with retention of conﬁguration at this carbon (Scheme 10).

The experiment using n-Bu₃SnD conﬁrmed a complete

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Scheme 9. HAT Reaction of the Arrangement B Disaccharide Model under Reductive Conditions

Scheme 10. HAT Reactions of Arrangement C Disaccharide Models under Reductive Conditions

The HAT reactions in these models proceeded with excellent

regioselectivity, and only 1,8-abstraction was generally

observed. The possible competitive 1,6-abstraction of the H1′

was only detected in alcohol 41 and may be attributable to

reactivity diﬀerences between the secondary H5′ and the

tertiary H1′. Furthermore, a 1,7-HAT is involved in the

functionalization of the methoxyl group at C3, which results in

the formation of a small amount of 60 during the reaction of

alcohol 58.

We found that the sensitive 2,6,10-trioxabicyclo[5.2.1]decane

ring system present in 48, 54, 56, and 59 may be susceptible to

partial hydrolysis either under the reaction conditions or during

the puriﬁcation process by chromatography, and at least in one

case we have managed to isolate intermediate 57.

Under reductive conditions the HAT reaction proceeded

analogously; the same competitive β-fragmentation was

observed by n-Bu₃SnH/AIBN treatment of D-xylofuranose

phthalimide 64. The observed inversion:retention ratio at C4′

in ^D-arabinofuranose 70 is modest (1.4:1) and increased

signiﬁcantly in triacetylated phthalimide 74; an analogous result

CONCLUSIONS

■

On the basis of the experimental evidence presented, the

previously developed 1,8-HAT reaction between the two

pyranose units in Hexp-(1→4)-Hexp systems can be extended

to other disaccharides containing at least a furanose ring in their

structures. Some limitations have been observed: when the 5-O-

yl radical is generated on ^D-arabinofuranose or D-ribofuranose

rings such as in 42 and 44, no HAT products can be detected.

Instead, the 5-O-yl radicals underwent faster β-scission to give

exclusively dehomologated products. This may be explained by

the stabilizing β-oxygen eﬀect on the C4−O bond breaking,

providing an impetus for the β-fragmentation to occur.

Notwithstanding, if the alkoxyl radical is part of 3β-isomeric

D-lyxofuranose 47 or D-xylofuranose 50 moieties, 1,8-HAT

reaction occurs preferentially in moderate to low yield in

competition with the β-scission. No dehomologation products

were observed with 6-O-yl radicals in pyranose systems, and the

yields of the 1,8-HAT products increased signiﬁcantly. See, for

example, arrangement C models 53 and 58 in Scheme 7.

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Oxidative HAT of 2. A solution of alcohol 2 (51 mg, 0.16 mmol)

in dry CH₂Cl₂(6.3 mL) containing DIB (56.7 mg, 0.176 mmol), I₂

(20.3 mg, 0.08 mmol), and powdered molecular sieves 3 Å (52 mg)

was stirred under nitrogen at 32 °C for 3 h while being irradiated with

two 80 W tungsten-ﬁlament lamps. An excess of solid Na₂S₂O₃was

then added and stirring continued until complete disappearance of the

iodine color. The reaction mixture was then ﬁltered and concentrated

under reduced pressure. Silica gel column chromatography of the

reaction residue (hexanes−EtOAc, 90:10 → 70:30) aﬀorded the

known²²1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-O-isopropyli-

dene-β-^D-ribofuranose (4β) (12.6 mg, 0.036 mmol, 23%), 1-O-

acetyl-5-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-α-^D-ribofura-

nose (4α) (10.4 mg, 0.03 mmol, 18.7%), and unreacted starting

material 2 (12.7 mg, 0.04 mmol, 25%). Attempts to increase the yield

of 4 by varying the reaction times and the number of equivalents of

DIB were unsuccessful.

was already observed for peracetylated hexopyranose sys-

tems.^11b

These results allow us to conclude that the principal

drawback of these reactions is the β-fragmentation; the adverse

entropic eﬀects caused by the furanose ring ﬂexibility and by

the decrease in the anomeric eﬀects may have a negative

inﬂuence on the competition with the dehomologation but do

not seem to be critical.

EXPERIMENTAL SECTION

■

General Experimental Methods. Melting points were measured

on a hot-stage apparatus. Optical rotations were recorded on a

polarimeter at a wavelength of 589 nm at ambient temperature in

CHCl₃solutions. IR spectra were recorded on an FT-IR

1

spectrophotometer in a ﬁlm. H and ¹³C NMR spectra were obtained

Benzyl 5-O-(tert-Butyldimethylsilyl)-2,3-di-O-methyl-β-^D-ri-

bofuranoside (6β) and Benzyl 5-O-(tert-Butyldimethylsilyl)-

2,3-di-O-methyl-α-^D-ribofuranoside (6α). To a solution of benzyl

D-ribofuranoside (5) (0.92 g, 3.8 mmol) in dry DMF (30.7 mL) were

added imidazole (388 mg, 5.7 mmol) and tert-butyldimethylsilyl

chloride [(TBDMS)Cl] (689 mg, 4.563 mmol) under nitrogen at 0

°C, and the mixture was stirred at that temperature for 1 h. EtOH was

then added, and the reaction mixture was concentrated under reduced

pressure. The residue was then coevaporated with toluene and puriﬁed

by column chromatography (hexanes−EtOAc, 9:1 → 7:3) to give the

diol intermediate (1.09 g, 3.076 mmol, 80%) as a colorless oil. This

material was used in the next reaction without separation of isomers.

To a solution of benzyl 5-O-(tert-butyldimethylsilyl)-^D-ribofuranoside

(1089 mg, 3.076 mmol) in dry DMF (36.6 mL) cooled to 0 °C was

added NaH, 60% dispersion in mineral oil (492 mg, 12.3 mmol), and

the mixture was stirred at this temperature under nitrogen until all

hydrogen evolution had ceased. Then an excess of methyl iodide (957

μL, 15.3 mmol) was added and stirring continued at room temperature

for 2 h. Excess reagent was destroyed by addition of MeOH, and the

mixture was concentrated under high vacuum. Column chromatog-

raphy (hexanes−EtOAc, 90:10 → 80:20) of the residue aﬀorded 6β

(841 mg, 2.2 mmol, 72%) and 6α (312 mg, 0.82 mmol, 26%). Data for

compound 6β: colorless oil; [α]_D−49.8 (c 0.41, CHCl₃); IR 2929,

from 400 or 500 MHz spectrometers. The chemical shifts are given in

parts per million (ppm) relative to TMS at δ 0.00 ppm or to residual

CDCl₃at δ 7.26 ppm for proton spectra and relative to CDCl₃at δ

77.00 ppm for carbon spectra, unless otherwise noted. ¹³C DEPT and

2D COSY, HSQC, and HMBC experiments were performed routinely

for all new compounds. Low- and high-resolution mass spectra were

recorded with TOF analyzer mass spectrometers by using electrospray

ioniazation (ESI+) or electron impact (EI) at 70 eV, as speciﬁed in

each case. Reaction progress was monitored by thin-layer chromatog-

raphy (TLC) carried out on 0.25 mm coated commercial silica gel

plates impregnated with a ﬂuorescent indicator (254 nm) visualized by

UV light and/or submersion in standard vanillin TLC stains followed

by heating on a hot plate until development of color. Flash column

chromatography was performed on Merck silica gel 60 PF (0.063−0.2

mm), unless otherwise indicated. Circular layers of 1 mm of Merck

silica gel 60 PF₂₅₄were used on a Chromatotron for centrifugally

assisted chromatography. All reactions were performed in single-neck

round-bottom ﬂasks ﬁtted with rubber septa under a positive pressure

of nitrogen with magnetic stirring, unless otherwise noted.

Commercially available reagents and solvents were analytical grade

or were puriﬁed by standard procedures prior to use.

2,5-Anhydro-3,4-O-isopropylidene-^D-altritol (1). We have

detected some coupling constant errors in the data described

previously for this compound.⁷The corrected data are as follows:

¹H NMR (400 MHz, CDCl₃) δ_H1.32 (3H, s), 1.49 (3H, s), 3.61 (1H,

dd, J = 11.7, 6.6 Hz), 3.65 (1H, dd, J = 11.7, 4.1 Hz), 3.85 (1H, dd, J =

12.0, 5.1 Hz), 3.89 (1H, dd, J = 11.7, 6.0 Hz), 4.12 (1H, ddd, J = 6.0,

4.7, 4.7 Hz), 4.18 (1H, ddd, J = 6.3, 4.1, 1.6 Hz), 4.67 (1H, dd, J = 6.0,

1.6 Hz), 4.79 (1H, dd, J = 6.3, 4.4 Hz).

1

1464, 1254, 1133, 1099 cm⁻¹; H NMR (500 MHz, CDCl₃) δ_H0.07

(3H, s), 0.08 (3H, s), 0.90 (9H, s), 3.42 (3H, s), 3.47 (3H, s), 3.72

(1H, dd, J = 11.0, 5.0 Hz), 3.78 (1H, dd, J = 11.0, 4.7 Hz), 3.80 (1H,

dd, J = 4.7, 1.6 Hz), 3.93 (1H, dd, J = 6.6, 4.7 Hz), 4.09 (1H, ddd, J =

6.3, 4.7, 4.7 Hz), 4.50 (1H, d, J = 11.7 Hz), 4.78 (1H, d, J = 12.0 Hz),

5.10 (1H, d, J = 1.6 Hz), 7.33 (5H, m); ¹³C NMR (125.7 MHz,

CDCl₃) δ_C−5.43 (CH₃), −5.35 (CH₃), 18.3 (C), 25.9 (3 × CH₃),

58.2 (CH₃), 58.3 (CH₃), 64.2 (CH₂), 69.3 (CH₂), 80.2 (CH), 81.9

(CH), 82.4 (CH), 103.6 (CH), 127.7 (CH), 127.9 (2 × CH), 128.3 (2

× CH), 137.6 (C); MS (ESI⁺) m/z (rel intens) 405 (M⁺+ Na);

HRMS (ESI⁺) m/z calcd for C₂₀H₃₄NaO₅Si 405.2073, found

405.2075. Anal. Calcd for C₂₀H₃₄O₅Si: C, 62.79; H, 8.96. Found: C,

63.03; H, 8.67. Data for compound 6α: colorless oil; [α]_D+97.1 (c

2,5-Anhydro-6-O-(tert-butyldimethylsilyl)-3,4-O-isopropyli-

dene-^D-altritol (2). A solution of trimethylsulfoxonium iodide (3.256

g, 14.8 mmol) and potassium tert-butoxide (1.329 g, 11.8 mmol) in

dry DMSO (13.8 mL) was stirred at 0 °C under nitrogen for 30 min.

5-O-(tert-Butyldimethylsilyl)-2,3-O-isopropylidene-^D-ribofuranose⁴⁰(3

g, 9.87 mmol) in dry DMSO (6.7 mL) was then added and the

mixture stirred at room temperature for 2 h. An aqueous saturated

solution of NH₄Cl was added and the mixture extracted with Et₂O.

The organic layer was concentrated under reduced pressure and the

residue puriﬁed by silica gel column chromatography (hexanes−

EtOAc, 90:20 → 70:30) to give 2 (1355 mg, 4.6 mmol, 47%) as a

colorless oil: [α]_D−16.0 (c 0.412, CHCl₃); IR 3468, 2933, 1463, 1258,

1

0.52, CHCl₃); IR 2928, 1464, 1254, 1111, 1046 cm⁻¹; H NMR (500

MHz, CDCl₃) δ_H0.05 (3H, s), 0.07 (3H, s), 0.89 (9H, s), 3.43 (3H,

s), 3.44 (3H, s), 3.61 (1H, dd, J = 11.0, 5.0 Hz), 3.67 (1H, dd, J = 6.6,

4.4 Hz), 3.71 (1H, dd, J = 10.7, 3.5 Hz), 3.78 (1H, dd, J = 6.6, 2.2 Hz),

4.16 (1H, ddd, J = 4.7, 3.5, 2.5 Hz), 4.68 (1H, d, J = 12.6 Hz), 4.83

(1H, d, J = 12.6 Hz), 5.06 (1H, d, J = 4.4 Hz), 7.31 (5H, m); ¹³C

NMR (125.7 MHz, CDCl₃) δ_C−5.5 (CH₃), −5.4 (CH₃), 18.2 (C),

25.8 (3 × CH₃), 58.5 (CH₃), 58.6 (CH₃), 63.8 (CH₂), 68.6 (CH₂),

78.4 (CH), 80.8 (CH), 83.1 (CH), 98.8 (CH), 127.4 (CH), 128.1 (2

× CH), 128.2 (2 × CH), 138.0 (C); MS (ESI⁺) m/z (rel intens) 405

(M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for C₂₀H₃₄NaO₅Si

405.2073, found 405.2076. Anal. Calcd for C₂₀H₃₄O₅Si: C, 62.79; H,

8.96. Found: C, 62.79; H, 8.84.

5-O-(tert-Butyldimethylsilyl)-2,3-di-O-methyl-^D-ribofuranose

(7). A solution of 6β,α (2.19 gr, 5.73 mmol) in EtOAc (64 mL)

containing Pd/C (10%) hydrogenation catalyst (219 mg) was

deoxygenated and stirred under hydrogen at room temperature and

atmospheric pressure for 6 h. The mixture was then ﬁltered through

1

1083 cm⁻¹; H NMR (500 MHz, CDCl₃) δ_H0.057 (3H, s), 0.060

(3H, s), 0.89 (9H, s), 1.34 (3H, s), 1.51 (3H, s), 3.70 (1H, dd, J =

11.0, 3.5 Hz), 3.74 (1H, dd, J = 11.0, 3.5 Hz), 3.83 (1H, dd, J = 11.7,

5.4 Hz), 3.87 (1H, dd, J = 12.0, 5.7 Hz), 4.15 (1H, ddd, J = 3.5, 3.5, 0.0

Hz), 4.21 (1H, ddd, J = 5.4, 5.4, 4.4 Hz), 4.79 (1H, dd, J = 6.0, 4.1

Hz), 4.83 (1H, dd, J = 6.3, 0.9 Hz); ¹³C NMR (100.6 MHz, CDCl₃)

δ_C−5.6 (CH₃), −5.5 (CH₃), 18.1 (C), 24.6 (CH₃), 25.8 (3 × CH₃),

26.1 (CH₃), 62.1 (CH₂), 64.9 (CH₂), 82.0 (CH), 82.2 (CH), 83.3

(CH), 84.2 (CH), 112.5 (C); MS (ESI⁺) m/z (rel intens) 341 (M⁺+

Na, 100); HRMS (ESI⁺) m/z calcd for C₁₅H₃₀NaO₅Si 341.1760, found

341.1760. Anal. Calcd for C₁₅H₃₀O₅Si: C, 56.57; H, 9.49. Found: C,

56.28; H, 9.49.

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Celite and concentrated under reduced pressure. The residue was

puriﬁed by silica gel column chromatography (hexanes−EtOAc, 75:25

→ 70:30) to give 7 (1.56 gr, 5.34 mmol, 93%) as an anomeric mixture:

colorless oil (ratio α:β = 63:37); IR 3443, 2931, 1471, 1256, 1130,

(ESI⁺) m/z calcd for C₁₄H₃₀NaO₅Si 329.1760, found 329.1762. Anal.

Calcd for C₁₄H₃₀O₅Si: C, 54.87; H, 9.87. Found: C, 54.74; H, 9.87.

Oxidative HAT of 9. A solution of alcohol 9 (63 mg, 0.206 mmol)

in dry CH₂Cl₂(8.1 mL) containing DIB (73 mg, 0.227 mmol), I₂(26

mg, 0.103 mmol), and powdered molecular sieves 3 Å (63 mg) was

stirred under nitrogen at 27 °C for 1 h while being irradiated with two

80 W tungsten-ﬁlament lamps. An excess of solid Na₂S₂O₃was then

added and stirring continued until complete disappearance of the

iodine color. The reaction mixture was then ﬁltered and concentrated

under reduced pressure. Silica gel column chromatography of the

reaction residue (hexanes−EtOAc, 90:10 → 50:50) aﬀorded 1-O-

acetyl-5-O-(tert-butyldimethylsilyl)-2,3-di-O-methyl-β-^D-ribofuranose

(11β) (12.8 mg, 0.038 mmol, 19%), 5-O-(tert-butyldimethylsilyl)-2,3-

di-O-methyl-β-^D-ribofuranosyl-(1→1)-2,5-anhydro-6-O-(tert-butyldi-

methylsilyl)-3,4-di-O-methyl-^D-altritol (12β) (5.2 mg, 0.009 mmol,

9%), 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-di-O-methyl-α-^D-ri-

bofuranose (11α) (9.9 mg, 0.03 mmol, 15%), and 5-O-(tert-

butyldimethylsilyl)-2,3-di-O-methyl-α-^D-ribofuranosyl-(1→1)-2,5-an-

hydro-6-O-(tert-butyldimethylsilyl)-3,4-di-O-methyl-^D-altritol (12α)

(4.5 mg, 0.008 mmol, 8%). Data for compound 11β: colorless oil;

[α]_D+3.0 (c 0.96, CHCl₃); IR 2933, 1747, 1465, 1373, 1232, 1133,

1

1046 cm⁻¹; H NMR (500 MHz, CDCl₃) δ_Hcomplex spectrum; ¹³C

NMR (125.7 MHz, CDCl₃) δ_Ccomplex spectrum; MS (ESI⁺) m/z

(rel intens) 315 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₁₃H₂₈NaO₅Si 315.1604, found 315.1604. Anal. Calcd for C₁₃H₂₈O₅Si:

C, 53.39; H, 9.65. Found: C, 53.41; H, 9.58.

1-O-Acetyl-2,5-anhydro-6-O-(tert-butyldimethylsilyl)-3,4-di-

O-methyl-^D-altritol (8α) and 1-O-Acetyl-2,5-anhydro-6-O-(tert-

butyldimethylsilyl)-3,4-di-O-methyl-^D-allitol (8β). A solution of

trimethylsulfoxonium iodide (1763 mg, 8.01 mmol) and potassium

tert-butoxide (719 mg, 6.41 mmol) in dry DMSO (7.5 mL) was stirred

at 0 °C under nitrogen for 30 min. Then 7 (1560 mg, 5.34 mmol)

dissolved in dry DMSO (3.7 mL) was added and the mixture stirred at

room temperature for 4 h. An aqueous saturated solution of NH₄Cl

was added and the mixture extracted with Et₂O. The organic layer was

dried over Na₂SO₄and concentrated under reduced pressure and the

residue puriﬁed by silica gel column chromatography (hexanes−

EtOAc, 90:10 → 65:35). The alcohols (773 mg, 2.53 mmol, 47%)

were acetylated with Ac₂O (4 mL) in pyridine (12 mL) for 16 h at

room temperature to give a mixture of acetates which was puriﬁed by

silica gel column chromatography (hexanes−EtOAc, 95:5 → 85:15) to

aﬀord 8α (667 mg, 1.92 mmol, 76%) and 8β (143 mg, 0.41 mmol,

16%) as colorless oils. Data for compound 8α: [α]_D+33.2 (c 0.91,

CHCl₃); IR 2929, 1731, 1463, 1371, 1258, 1131 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ_H0.06 (3H, s), 0.07 (3H, s), 0.90 (9H, s), 2.07 (3H,

s), 3.43 (3H, s), 3.49 (3H, s), 3.67 (1H, dd, J = 11.0, 3.5 Hz), 3.69

(1H, dd, J = 11.0, 3.8 Hz), 3.87 (1H, dd, J = 4.7, 4.7 Hz), 3.95 (1H, dd,

J = 5.0, 5.0 Hz), 4.05 (1H, ddd, J = 4.1, 4.1, 4.1 Hz), 4.22 (1H, dd, J =

10.7, 8.5 Hz), 4.26 (1H, ddd, J = 8.5, 5.4, 2.8 Hz), 4.35 (1H, dd, J =

10.7, 2.2 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C−5.5 (CH₃), −5.4

(CH₃), 18.2 (C), 20.9 (CH₃), 25.8 (3 × CH₃), 58.2 (CH₃), 59.5

(CH₃), 63.4 (CH₂), 64.1 (CH₂), 77.7 (CH), 80.4 (CH), 80.8 (CH),

81.6 (CH), 170.9 (C); MS (ESI⁺) m/z (rel intens) 371 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₁₆H₃₂NaO₆Si 371.1866, found

371.1865. Anal. Calcd for C₁₆H₃₂O₆Si: C, 55.14; H, 9.25. Found: C,

55.15; H, 9.07. Data for compound 8β: [α]_D−35.6 (c 0.50, CHCl₃);

1

1098 cm⁻¹; H NMR (400 MHz, CDCl₃) δ_H0.06 (3H, s), 0.07 (3H,

s), 0.91 (9H, s), 2.05 (3H, s), 3.44 (3H, s), 3.52 (3H, s), 3.70 (1H, dd,

J = 11.6, 3.8 Hz), 3.80 (1H, dd, J = 11.4, 3.5 Hz), 3.80 (1H, dd, J = 4.8,

1.0 Hz), 3.96 (1H, dd, J = 7.2, 4.7 Hz), 4.09 (1H, ddd, J = 7.0, 3.5, 3.5

Hz), 6.14 (1H, d, J = 1.1 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C

−5.5 (CH₃), −5.4 (CH₃), 18.3 (C), 21.2 (CH₃), 25.9 (3 × CH₃), 58.2

(CH₃), 58.3 (CH₃), 62.7 (CH₂), 78.4 (CH), 81.9 (CH), 82.6 (CH),

98.3 (CH), 169.7 (C); MS (ESI⁺) m/z (rel intens) 357 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₁₅H₃₀NaO₆Si 357.1709, found

357.1714. Anal. Calcd for C₁₅H₃₀O₆Si: C, 53.86; H, 9.04. Found: C,

53.83; H, 8.95. Data for compound 11α: colorless oil; [α]_D+44.7 (c

0.43, CHCl₃); IR 2929, 1747, 1465, 1378, 1241, 1111, 1011 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ_H0.06 (3H, s), 0.07 (3H, s), 0.90 (9H, s),

2.14 (3H, s), 3.44 (3H, s), 3.47 (3H, s), 3.63 (1H, dd, J = 11.0, 4.7

Hz), 3.70 (1H, dd, J = 11.0, 3.2 Hz), 3.86 (1H, dd, J = 6.3, 1.9 Hz),

3.88 (1H, dd, J = 6.3, 4.1 Hz), 4.28 (1H, ddd, J = 4.4, 2.8, 1.6 Hz), 6.34

(1H, d, J = 4.4 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C−5.6 (CH₃),

−5.4 (CH₃), 18.2 (C), 21.4 (CH₃), 25.8 (3 × CH₃), 58.5 (CH₃), 59.1

(CH₃), 63.6 (CH₂), 78.2 (CH), 80.6 (CH), 84.7 (CH), 94.3 (CH),

170.8 (C); MS (ESI⁺) m/z (rel intens) 357 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₁₅H₃₀NaO₆Si 357.1709, found 357.1710. Anal.

Calcd for C₁₅H₃₀O₆Si: C, 53.86; H, 9.04. Found: C, 54.11; H, 9.23.

Data for compound 12β: colorless oil; [α]_D−2.7 (c 0.3, CHCl₃); IR

2929, 1464, 1255, 1136, 1107 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ_H

0.060 (6H, s), 0.063 (3H, s), 0.067 (3H, s), 0.897 (9H, s), 0.899 (9H,

s), 3.40 (3H, s), 3.42 (3H, s) 3.47 (3H, s), 3.48 (3H, s), 3.64 (1H, dd,

J = 11.0, 8.5 Hz), 3.66−3.69 (3H, m), 3.73 (1H, dd, J = 10.7, 4.4 Hz),

3.80 (1H, dd, J = 4.7, 1.3 Hz), 3.84−3.91 (4H, m), 4.00−4.05 (2H,

m), 4.19 (1H, ddd, J = 8.5, 5.4, 3.2 Hz), 5.06 (1H, d, J = 0.9 Hz); ¹³C

NMR (100.6 MHz, CDCl₃) δ_C−5.09 (CH₃), −5.02 (CH₃), −4.98

(CH₃), −4.95 (CH₃), 18.66 (C), 18.72 (C), 26.3 (6 × CH₃), 58.5

(CH₃), 58.69 (CH₃), 58.65 (CH₃), 59.9 (CH₃), 63.9 (CH₂), 64.8

(CH₂), 67.7 (CH₂), 79.8 (CH), 80.7 (CH), 81.4 (CH), 81.7 (2 ×

CH), 82.0 (CH), 82.5 (CH), 105.3 (CH); MS (ESI⁺) m/z (rel intens)

603 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for C₂₇H₅₆NaO₉Si₂

603.3361, found 603.3369. Anal. Calcd for C₂₇H₅₆O₉Si₂: C, 55.83; H,

9.72. Found: C, 55.53; H, 9.87. Data for compound 12α: colorless oil;

[α]_D+33.5 (c 0.48, CHCl₃); IR 2929, 1471, 1257, 1136, 1078 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ_H0.05 (3H, s), 0.054 (3H, s), 0.06

(3H, s), 0.07 (3H, s), 0.89 (9H, s), 0.90 (9H, s), 3.40 (3H, s), 3.42

(3H, s), 3.47 (3H, s), 3.54 (3H, s), 3.62 (1H, dd, J = 10.7, 5.1 Hz),

3.65 (1H, dd, J = 11.4, 3.2 Hz), 3.68 (1H, dd, J = 6.6, 4.4 Hz), 3.71

(1H, dd, J = 10.7, 3.5 Hz), 3.73 (1H, dd, J = 10.7, 3.2 Hz), 3.76 (1H,

dd, J = 6.9, 2.8 Hz), 3.79 (1H, dd, J = 10.4, 7.9 Hz), 3.84 (1H, dd, J =

10.4, 5.7 Hz), 3.87 (1H, dd, J = 6.6, 4.1 Hz), 3.91 (1H, ddd, J = 6.6,

3.5, 3.5 Hz), 3.94 (1H, dd, J = 4.4, 4.4 Hz), 4.14 (1H, ddd, J = 5.1, 3.5,

2.6 Hz), 4.25 (1H, ddd, J = 7.6, 5.7, 4.1 Hz), 5.07 (1H, d, J = 4.4 Hz);

¹³C NMR (125.7 MHz, CDCl₃) δ_C−5.48 (CH₃), −5.47 (CH₃), −5.35

(CH₃), −5.30 (CH₃), 18.26 (C), 18.32 (C), 25.85 (3 × CH₃), 25.92

1

IR 2929, 1747, 1471, 1373, 1241, 1135 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ_H0.065 (3H, s), 0.07 (3H, s), 0.90 (9H, s), 2.08 (3H, s),

3.425 (3H, s), 3.431 (3H, s), 3.59 (1H, dd, J = 7.3, 5.4 Hz), 3.62 (1H,

dd, J = 11.0, 5.1 Hz), 3.68 (1H, dd, J = 11.0, 3.8 Hz), 3.80 (1H, dd, J =

5.4, 3.5 Hz), 4.03 (1H, dd, J = 11.4, 6.3 Hz), 4.04 (1H, ddd, J = 4.1,

2.8, 2.8 Hz), 4.11 (1H, ddd, J = 6.6, 6.6, 3.5 Hz), 4.30 (1H, dd, J =

11.4, 3.2 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C−5.6 (CH₃), −5.4

(CH₃), 18.2 (C), 20.8 (CH₃), 25.8 (3 × CH₃), 57.7 (CH₃), 58.0

(CH₃), 63.3 (CH₂), 65.0 (CH₂), 78.1 (CH), 79.3 (CH), 80.7 (CH),

82.6 (CH), 170.7 (C); MS (ESI⁺) m/z (rel intens) 371 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₁₆H₃₂NaO₆Si 371.1866, found

371.1868. Anal. Calcd for C₁₆H₃₂O₆Si: C, 55.14; H, 9.25. Found: C,

55.29; H, 9.04.

2,5-Anhydro-6-O-(tert-butyldimethylsilyl)-3,4-di-O-methyl-

D-altritol (9). To a solution of 8α (706 mg, 2.03 mmol) in MeOH (32

mL) was added K₂CO₃(280 mg, 2.03 mmol). The mixture was stirred

at room temperature under nitrogen for 2 h, neutralized with

Amberlist 15H⁺, ﬁltered, and concentrated under reduced pressure.

The residue was puriﬁed by silica gel column chromatography

(hexanes−EtOAc, 70:30 → 60:40) to give 9 (597 mg, 1.95 mmol,

96%) as a colorless oil: [α]_D+2.1 (c 1.16, CHCl₃); IR 3442, 2929,

1465, 1253, 1133 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ_H0.06 (3H, s),

0.07 (3H, s), 0.90 (9H, s), 3.44 (3H, s), 3.49 (3H, s), 3.64 (1H, dd, J =

11.0, 4.4 Hz), 3.66 (1H, dd, J = 11.0, 3.8 Hz), 3.74 (1H, dd, J = 11.7,

4.7 Hz), 3.79 (1H, dd, J = 11.7, 4.7 Hz), 3.87 (1H, dd, J = 5.4, 3.5 Hz),

4.06 (1H, dd, J = 5.4, 6.6 Hz), 4.11 (1H, ddd, J = 3.5, 3.5, 3.5 Hz), 4.19

(1H, ddd, J = 6.6, 4.7, 4.7 Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ_C

−5.6 (CH₃), −5.4 (CH₃), 18.2 (C), 25.8 (3 × CH₃), 58.1 (CH₃), 59.2

(CH₃), 62.0 (CH₂), 63.7 (CH₂), 79.3 (CH), 80.4 (CH), 80.8 (CH),

82.0 (CH), MS (ESI⁺) m/z (rel intens) 329 (M⁺+ Na, 100); HRMS

7379

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Article

(3 × CH₃), 58.3 (CH₃), 58.4 (CH₃), 58.6 (CH₃), 59.8 (CH₃), 63.1

(CH₂), 63.8 (CH₂), 66.0 (CH₂), 78.1 (CH), 78.6 (CH), 79.2 (CH),

80.4 (CH), 80.9 (CH), 81.4 (CH), 82.9 (CH), 101.2 (CH); MS

(ESI⁺) m/z (rel intens) 603 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₂₇H₅₆NaO₉Si₂603.3361, found 603.3373. Anal. Calcd for

C₂₇H₅₆O₉Si₂: C, 55.83; H, 9.72. Found: C, 55.98; H, 9.58.

MHz, CDCl₃) δ_C19.2 (C), 26.8 (3 × CH₃), 55.2 (CH₃), 58.4 (CH₃),

64.6 (CH₂), 70.9 (CH), 84.1 (CH), 84.6 (CH), 105.2 (CH), 127.6 (2

× CH), 127.7 (2 × CH), 129.6 (CH), 129.7 (CH), 133.38 (C),

133.42 (C), 135.61 (2 × CH), 135.62 (2 × CH); MS (ESI⁺) m/z (rel

intens) 439 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₂₃H₃₂NaO₅Si 439.1917, found 439.1920. Anal. Calcd for

C₂₃H₃₂O₅Si: C, 66.31; H, 7.74. Found: C, 66.00; H, 7.78.

2,5-Anhydro-3,4-di-O-methyl-^D-altritol (10). To a solution of 9

(200 mg, 0.653 mmol) in dry THF (16.8 mL) was added TBAF/THF

1 M (1.63 mL, 1.63 mmol), and the mixture was stirred at room

temperature for 2 h. The reaction was concentrated under reduced

pressure and the residue puriﬁed by silica gel column chromatography

(CHCl₃→ CHCl₃−MeOH, 95:5) to give 10 (114 mg, 0.59 mmol,

91%) as a colorless oil: [α]_D+2.1 (c 1.16, CHCl₃); IR 3412, 2936,

1456, 1144, 1067 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ_H3.46 (3H, s),

3.52 (3H, s), 3.60 (1H, dd, J = 12.3, 3.8 Hz), 3.77 (1H, dd, J = 12.0,

4.7 Hz), 3.82 (1H, dd, J = 12.0, 3.2 Hz), 3.83 (1H, dd, J = 5.7, 5.7 Hz),

3.84 (1H, dd, J = 11.7, 5.7 Hz), 3.99 (1H, dd, J = 5.1, 5.1 Hz), 4.09

(1H, ddd, J = 6.0, 3.5, 3.5 Hz), 4.18 (1H, ddd, J = 5.4, 5.4, 4.6 Hz); ¹³C

NMR (100.6 MHz, CDCl₃) δ_C58.5 (CH₃), 59.7 (CH₃), 61.8 (CH₂),

62.6 (CH₂), 80.2 (CH), 80.4 (CH), 80.9 (CH), 81.1 (CH); MS

(ESI⁺) m/z (rel intens) 215 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₈H₁₆NaO₅215.0895, found 215.0893. Anal. Calcd for C₈H₁₆O₅:

C, 49.99; H, 8.39. Found: C, 49.73; H, 8.56.

Methyl 5-O-(tert-Butyldiphenylsilyl)-2-O-methyl-β-^D-erythro-

pentofuranosid-3-ulose (17). To a solution of alcohol 16 (720 mg,

1.73 mmol) in dry CH₂Cl₂(40 mL) containing solid NaHCO₃(1.67

g, 19.91 mmol) was added Dess−Martin periodinane (1.10 g, 2.60

mmol) under nitrogen at 0 °C, and the mixture was stirred at room

temperature for 1 h. Then the reaction mixture was poured into a

saturated solution of NaHCO₃and Na₂S₂O₃and extracted with

CH₂Cl₂. The organic layers were dried over Na₂SO₄and concentrated

under reduced pressure. The residue was puriﬁed by column

chromatography (hexanes−EtOAc, 95:5) to give the ketone 17 (598

mg, 1.44 mmol, 83%) as a colorless oil: [α]_D+16.3 (c 0.560, CHCl₃);

1

IR 2933, 2858, 1773, 1465, 1428, 1113 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ_H1.04 (9H, s), 3.57 (3H, s), 3.59 (3H, s), 3.80 (1H, dd, J =

5.0, 1.1 Hz), 3.86 (1H, s), 3.87 (1H, s), 4.16 (1H, ddd, J = 3.2, 3.2, 1.1

Hz), 5.04 (1H, d, J = 5.0 Hz), 7.36−7.45 (6H, m), 7.65−7.74 (4H,

m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C19.2 (C), 26.7 (3 × CH₃),

55.9 (CH₃), 58.9 (CH₃), 63.8 (CH₂), 81.2 (CH), 83.6 (CH), 105.0

(CH), 127.68 (2 × CH), 127.74 (2 × CH), 129.7 (CH), 129.8 (CH),

133.86 (C), 133.89 (C), 135.6 (2 × CH), 135.7 (2 × CH), 210.0 (C);

MS (ESI⁺) m/z (rel intens) 437 (M⁺+ Na, 100); HRMS (ESI⁺) m/z

calcd for C₂₃H₃₀NaO₅Si 437.1760, found 437.1763. Anal. Calcd for

C₂₃H₃₀O₅Si: C, 66.63; H, 7.29. Found: C, 66.53; H, 7.19.

Oxidative HAT of 10. A solution of alcohol 10 (55 mg, 0.286

mmol) in dry CH₂Cl₂(11.3 mL) containing DIB (101.3 mg, 0.315

mmol), I₂(36.3 mg, 0.143 mmol), and powdered molecular sieves 3 Å

(55 mg) was stirred under nitrogen at 26 °C for 1 h while being

irradiated with two 80 W tungsten-ﬁlament lamps. An excess of solid

Na₂S₂O₃was then added and stirring continued until complete

disappearance of the iodine color. The reaction mixture was then

Methyl 5-O-(tert-Butyldiphenylsilyl)-2-O-methyl-β-^D-xylofur-

anoside (18). To a solution of ketone 17 (634 mg, 1.531 mmol) in

EtOH/H₂O (5.7 mL, 9:1) was added NaBH₄(104 mg, 2.756 mmol),

and the mixture was stirred at room temperature for 1 h. After this

time the mixture was cooled to 0 °C, solid NH₄Cl was added, and the

stirring was continued for 1 h. The mixture was then ﬁltered over

Celite and concentrated under reduced pressure. The residue was

puriﬁed by column chromatography (hexanes−EtOAc, 90:10) to give

in order of elution the alcohol 18 (446 mg, 1.072 mmol, 70%) and the

alcohol 16 (89 mg, 0.214 mmol, 14%) described previously. Data for

compound 18: [α]_D−35.1 (c 0.730, CHCl₃); IR 3509, 2933, 2858,

1

ﬁltered and concentrated under reduced pressure. TLC and H NMR

analyses clearly showed that this substrate aﬀorded a complex mixture

of fragmentation products that was not studied.

Methyl 5-O-(tert-Butyldiphenylsilyl)-2-O-methyl-α-^D-arabi-

nofuranoside (14). To a solution of methyl 2-O-methyl-α-^D-

arabinofuranoside (13)³⁴(357 mg, 2.0 mmol) in dry DMF (8.2

mL) were added imidazole (341 mg, 5.0 mmol) and tert-

butyldiphenylsilyl chloride [(TBDPS)Cl] (576 μL, 2.2 mmol) under

nitrogen at 0 °C, and the mixture was stirred at that temperature for 1

h. MeOH was then added and the reaction mixture concentrated

under reduced pressure. The residue was coevaporated with toluene

and puriﬁed by column chromatography (hexanes−EtOAc, 9:1 →

85:15) to give the alcohol 14 (826 mg, 1.99 mmol, 99%) as an oil:

[α]_D+43.1 (c 0.420, CHCl₃); IR 3446, 2936, 1430, 1195, 1046 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ_H1.07 (9H, s), 3.35 (3H, s), 3.37 (3H,

s), 3.68 (1H, dd, J = 2.5, 1.3 Hz), 3.72 (1H, dd, J = 10.4, 6.3 Hz), 3.85

(1H, dd, J = 10.4, 5.0 Hz), 4.07 (2H, m), 4.86 (1H, d, J = 1.3 Hz),

7.36−7.44 (6H, m), 7.67−7.69 (4H, m); ¹³C NMR (125.7 MHz,

CDCl₃) δ_C19.2 (C), 26.8 (3 × CH₃), 54.9 (CH₃), 57.5 (CH₃), 64.3

(CH₂), 76.4 (CH), 84.5 (CH), 90.2 (CH), 106.8 (CH), 127.68 (2 ×

CH), 127.70 (2 × CH), 129.7 (2 × CH), 133.3 (2 × C), 135.58 (2 ×

CH); 135.60 (2 × CH); MS (ESI⁺) m/z (rel intens) 439 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₂₃H₃₂NaO₅Si 439.1917, found

439.1914. Anal. Calcd for C₂₃H₃₂O₅Si: C, 66.31; H, 7.74. Found: C,

66.24; H, 7.53.

Methyl 5-O-(tert-Butyldiphenylsilyl)-2-O-methyl-β-^D-ribofur-

anoside (16). To a solution of methyl 2-O-methyl-β-^D-ribofuranoside

(15)³⁵(449 mg, 2.52 mmol) in dry DMF (10 mL) were added

imidazole (428 mg, 6.3 mmol) and (TBDPS)Cl (724 μL, 2.77 mmol)

under nitrogen at 0 °C, and the mixture was stirred at that temperature

for 0.5 h. Then MeOH was added, and the reaction mixture was

concentrated under reduced pressure. The residue was then

coevaporated with toluene and puriﬁed by column chromatography

(hexanes−EtOAc, 85:15) to give the alcohol 16 (970 mg, 2.33 mmol,

92%) as an oil: [α]_D−2.5 (c 0.440, CHCl₃); IR 3468, 2933, 1465,

1426, 1111, 1046 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ_H1.07 (9H, s),

2.48 (1H, br s), 3.35 (3H, s), 3.51 (3H, s), 3.65 (1H, dd, J = 5.4, 0.9

Hz), 3.74 (1H, dd, J = 11.0, 4.7 Hz), 3.83 (1H, dd, J = 11.0, 4.1 Hz),

3.99 (1H, ddd, J = 4.7, 4.7, 4.7 Hz), 4.31 (1H, dd, J = 5.4, 5.4 Hz), 4.91

(1H, s), 7.36−7.44 (6H, m), 7.69−7.71 (4H, m); ¹³C NMR (100.6

1

1465, 1428, 1111, 1050 cm⁻¹; H NMR (500 MHz, CDCl₃) δ_H1.06

(9H, s), 3.34 (3H, s), 3.44 (3H, s), 3.75 (1H, s), 3.88 (1H, dd, J =

10.7, 5.4 Hz), 4.04 (1H, dd, J = 10.7, 5.7 Hz), 4.24 (1H, d, J = 4.4 Hz),

4.31 (1H, ddd, J = 5.4, 5.4, 5.4 Hz), 4.90 (1H, s), 7.37−7.45 (6H, m),

7.70−7.73 (4H, m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C19.1 (C), 26.8

(3 × CH₃), 55.3 (CH₃), 57.6 (CH₃), 63.3 (CH₂), 74.2 (CH), 82.5

(CH), 89.2 (CH), 106.8 (CH), 127.7 (4 × CH), 129.7 (CH), 129.8

(CH), 133.09 (C), 133.14 (C), 135.6 (4 × CH); MS (ESI⁺) m/z (rel

intens) 439 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₂₃H₃₂NaO₅Si 439.1917, found 439.1916. Anal. Calcd for (%) for

C₂₃H₃₂O₅Si: C, 66.31; H, 7.74. Found: C, 66.03; H, 7.72.

Methyl 3,5-O-(Tetraisopropyldisiloxane-1,3-diyl)-α-^D-lyxo-

furanoside (20). To a solution of methyl α-^D-lyxofuranoside (19)³⁶

(960 mg, 5.85 mmol) in dry pyridine (17.4 mL) was added 1,3-

dichloro-1,1,3,3-tetraisopropyldisiloxane (1.94 mL, 6.1 mmol), and the

mixture was stirred at room temperature for 1.5 h. After this time

water was added and the mixture concentrated under reduced

pressure. The residue was puriﬁed by column chromatography

(hexanes−EtOAc, 100:0 → 98:2) to give compound 20 (1928 mg,

4.75 mmol, 81%) as a colorless oil: [α]_D+41.2 (c 0.427, CHCl₃); IR

3520, 2947, 2869, 1460, 1096, 1039 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ_H1.05 (28H, m), 2.90 (1H, d, J = 9.5 Hz, OH), 3.37 (3H, s),

3.89 (1H, dd, J = 10.1, 4.7 Hz), 3.92 (1H, dd, J = 10.4, 9.8 Hz), 4.10

(1H, ddd, J = 9.5, 5.4, 2.8 Hz), 4.13 (1H, ddd, J = 9.8, 4.7, 3.2 Hz),

4.43 (1H, dd, J = 5.4, 3.2 Hz), 4.79 (1H, d, J = 2.8 Hz); ¹³C NMR

(125.7 MHz, CDCl₃) δ_C12.4 (CH), 12.7 (CH), 12.8 (CH), 13.3

(CH), 16.95 (CH₃), 17.00 (CH₃), 17.16 (CH₃), 17.24 (CH₃), 17.27

(CH₃), 17.37 (2 × CH₃), 17.39 (CH₃), 55.6 (CH₃), 59.0 (CH₂), 71.2

(CH), 77.3 (CH), 79.5 (CH), 109.8 (CH); MS (ESI⁺) m/z (rel

intens) 429 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

7380

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Article

C₁₈H₃₈NaO₆Si₂429.2105, found 429.2102. Anal. Calcd for

C₁₈H₃₈O₆Si₂: C, 53.16; H, 9.42. Found: C, 53.22; H, 9.11.

pressure. The residue was puriﬁed by column chromatography

(hexanes−EtOAc mixtures).

Methyl 2-O-Methyl-3,5-O-(tetraisopropyldisiloxane-1,3-

diyl)-α-^D-lyxofuranoside (21). To a solution of 20 (1.89 g, 4.65

mmol) in dry acetone (24.2 mL) were added Ag₂O (4.31 g, 18.6

mmol) and methyl iodide (3.67 mL, 58.95 mmol) with stirring at

room temperature. After 5 days the mixture was ﬁltered over Celite

and concentrated under reduced pressure. The residue was puriﬁed by

column chromatography (hexanes−EtOAc, 100:0 → 95:5) to give 21

as a colorless oil (800 mg, 1.9 mmol, 41%, 84% brsm) and starting

material 20 (972 mg, 2.39 mmol, 51%). Data for compound 21: [α]_D

+54.8 (c 0.425, CHCl₃); IR 2944, 2869, 1467, 1094, 1054, 1037 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ_H1.05 (28H, m), 3.441 (3H, s), 3.443

(3H, s), 3.64 (1H, dd, J = 5.4, 4.1 Hz), 3.82 (1H, dd, J = 10.1, 4.7 Hz),

3.89 (1H, dd, J = 10.1, 10.1 Hz), 4.15 (1H, ddd, J = 10.1, 4.7, 2.2 Hz),

4.40 (1H, dd, J = 3.8, 2.2 Hz), 4.96 (1H, d, J = 5.4 Hz); ¹³C NMR

(125.7 MHz, CDCl₃) δ_C12.5 (CH), 12.6 (CH), 13.1 (CH), 13.4

(CH), 17.00 (CH₃), 17.01 (CH₃), 17.1 (CH₃), 17.2 (CH₃), 17.28

(CH₃), 17.33 (CH₃), 17.4 (CH₃), 17.5 (CH₃), 56.5 (CH₃), 58.7

(CH₃), 59.0 (CH₂), 70.1 (CH), 79.6 (CH), 86.6 (CH), 107.6 (CH);

MS (ESI⁺) m/z (rel intens) 443 (M⁺+ Na, 100); HRMS (ESI⁺) m/z

calcd for C₁₉H₄₀NaO₆Si₂443.2261, found 443.2263. Anal. Calcd for

C₁₉H₄₀O₆Si₂: C, 54.25; H, 9.58. Found: C, 54.25; H, 9.31.

Methyl 2,3,5-Tri-O-acetyl-α-^D-arabinofuranosyl-(1→3)-5-O-

(tert-butyldiphenylsilyl)-2-O-methyl-α-^D-arabinofuranoside

(25). Compound 25 was prepared from 24^28,29a(761 mg, 1.808

mmol) and 14 (327 mg, 0.786 mmol) following the general procedure.

The residue was puriﬁed by column chromatography (hexanes−

EtOAc, 85:15 → 75:25) to give the disaccharide 25 (503 mg, 0.747

mmol, 95%) as a colorless oil: [α]_D+87.4 (c 0.310, CHCl₃); IR 2933,

1757, 1745, 1428, 1369, 1228, 1113 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ_H1.06 (9H, s), 1.98 (3H, s), 2.04 (3H, s), 2.10 (3H, s), 3.38

(3H, s), 3.41 (3H, s), 3.80 (1H, dd, J = 3.5, 1.6 Hz), 3.84 (2H, br d, J =

3.8 Hz), 4.06−4.10 (2H, m), 4.13 (1H, dd, J = 11.7, 5.4 Hz), 4.25 (1H,

dd, J = 6.6, 3.5 Hz), 4.26 (1H, dd, J = 11.7, 3.5 Hz), 4.89 (1H, d, J =

1.6 Hz), 4.97 (1H, ddd, J = 5.1, 1.6, 0.6 Hz), 5.09 (1H, d, J = 1.6 Hz),

5.18 (1H, s), 7.35−7.44 (6H, m), 7.69−7.71 (4H, m); ¹³C NMR

(125.7 MHz, CDCl₃) δ_C19.3 (C), 20.63 (CH₃), 20.64 (CH₃), 20.71

(CH₃), 26.7 (3 × CH₃), 54.9 (CH₃), 57.6 (CH₃), 63.1 (CH₂), 63.2

(CH₂), 76.9 (CH), 79.7 (CH), 80.4 (CH), 81.4 (CH), 81.8 (CH),

90.1 (CH), 104.7 (CH), 106.9 (CH), 127.57 (2 × CH), 127.64 (2 ×

CH), 129.59 (CH), 129.66 (CH), 133.42 (C), 133.49 (C), 135.58 (2

× CH), 135.66 (2 × CH), 169.6 (C), 170.0 (C), 170.5 (C); MS

(ESI⁺) m/z (rel intens) 697 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₃₄H₄₆NaO₁₂Si 697.2656, found 697.2650. Anal. Calcd for

C₃₄H₄₆O₁₂Si: C, 60.52; H, 6.87. Found C, 60.23; H, 6.57.

Methyl 2-O-Methyl-α-^D-lyxofuranoside (22). To a solution of

compound 21 (1038 mg, 2.47 mmol) in dry THF (16.9 mL) was

added a 1 M solution of TBAF/THF (6.2 mL, 6.2 mmol), and the

mixture was stirred at room temperature for 1.5 h. The reaction

mixture was concentrated under reduced pressure and the residue

puriﬁed by column chromatography (hexanes−EtOAc, 50:50 →

0:100) to give diol 22 (434 mg, 2.44 mmol, 99%) as a colorless oil:

[α]_D+96.1 (c 0.31, CHCl₃); IR 3420, 2944, 2836, 1456, 1119, 1042

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ_H3.36 (3H, s), 3.48 (3H, s), 3.67

(1H, dd, J = 5.4, 1.6 Hz), 3.83 (1H, dd, J = 12.2, 3.8 Hz), 3.87 (1H, dd,

J = 12.3, 4.4 Hz), 4.10 (1H, ddd, J = 5.7, 4.4, 4.4 Hz), 4.47 (1H, dd, J =

5.4, 5.4 Hz), 4.90 (1H, d, J = 1.6 Hz); ¹³C NMR (125.7 MHz, CDCl₃)

δ_C55.2 (CH₃), 58.8 (CH₃), 61.4 (CH₂), 71.5 (CH), 79.1 (CH), 84.5

(CH), 105.3 (CH); MS (ESI⁺) m/z (rel intens) 201 (M⁺+ Na, 100);

HRMS (ESI⁺) m/z calcd for C₇H₁₄NaO₅201.0739, found 201.0734.

Anal. Calcd for C₇H₁₄O₅: C, 47.18; H, 7.92. Found: C, 47.42; H, 7.76.

Methyl 5-O-(tert-Butyldiphenylsilyl)-2-O-methyl-α-^D-lyxofur-

anoside (23). To a solution of diol 22 (402 mg, 2.26 mmol) in dry

DMF (9.2 mL) were added imidazole (384 mg, 5.6 mmol) and

(TBDPS)Cl (649 μL, 2.49 mmol) under nitrogen at 0 °C, and the

mixture was stirred at that temperature for 1 h. MeOH was then

added, and the reaction mixture was concentrated under reduced

pressure. The residue was then coevaporated with toluene and puriﬁed

by column chromatography (hexanes−EtOAc, 90:10 → 85:15) to give

the alcohol 23 (928 mg, 2.23 mmol, 99%) as an oil: [α]_D+52 (c 0.54,

CHCl₃); IR 3498, 2933, 2858, 1471, 1428, 1115, 1052 cm⁻¹; ¹H NMR

(400 MHz, CDCl₃) δ_H1.06 (9H, s), 3.39 (3H, s), 3.48 (3H, s), 3.73

(1H, dd, J = 5.1, 2.8 Hz), 3.90 (1H, dd, J = 10.7, 5.4 Hz), 4.03 (1H, dd,

J = 10.7, 5.4 Hz), 4.14 (1H, ddd, J = 5.4, 5.4, 4.0 Hz), 4.37 (1H, dd, J =

5.0, 4.0 Hz), 4.93 (1H, d, J = 2.8 Hz), 7.36−7.44 (6H, m), 7.39−7.73

(4H, m); ¹³C NMR (125.7 MHz, CDCl₃) δ_C19.2 (C), 26.7 (3 ×

CH₃), 55.5 (CH₃), 58.6 (CH₃), 62.4 (CH₂), 70.6 (CH), 80.6 (CH),

86.2 (CH), 106.6 (CH), 127.62 (2 × CH), 127.64 (2 × CH), 129.6 (2

× CH), 133.3 (C), 133.4 (C), 135.6 (2 × CH), 135.7 (2 × CH); MS

(ESI⁺) m/z (rel intens) 439 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₂₃H₃₂NaO₅Si 439.1917, found 439.1919. Anal. Calcd for

C₂₃H₃₂O₅Si: C, 66.31; H, 7.74. Found: C, 66.30; H, 7.63.

Methyl 2,3,5-Tri-O-methyl-α-^D-arabinofuranosyl-(1→3)-5-O-

(tert-butyldiphenylsilyl)-2-O-methyl-α-^D-arabinofuranoside

(26). To a solution of compound 25 (452 mg, 0.671 mmol) in MeOH

(32 mL) was added K₂CO₃(278 mg, 2 mmol), and the mixture was

stirred at room temperature for 2 h, then neutralized with Amberlyst

15 H⁺ion-exchange resin for 1 h, ﬁltered, and concentrated. To the

crude residue (550 mg) in dry DMF (8 mL) was added NaH, 60%

dispersion in mineral oil (161 mg, 4 mmol), and the mixture was

stirred at 0 °C under nitrogen until all hydrogen evolution had ceased.

Then an excess of methyl iodide (313 μL, 5 mmol) was added and

stirring continued at room temperature for 3 h. Excess reagent was

destroyed by addition of MeOH, and the mixture was concentrated

under high vacuum. Column chromatography (hexanes−EtOAc,

85:15) of the residue aﬀorded 26 (386.5 mg, 0.655 mmol, 98%) as

a colorless oil: [α]_D+100.0 (c 0.470, CHCl₃); IR 2929, 1428, 1188,

1

1112 cm⁻¹; H NMR (500 MHz, CDCl₃) (hydrogens at C5′a and

C5′b have very similar chemical shifts, and as a consequence, the

coupled hydrogen at C4′ appears as a complex signal by virtual

coupling; the data for hydrogens at C4′ and C5′ shown here have been

calculated by iterative simulation using DAISY) δ_H1.06 (9H, s), 3.32

(3H, s), 3.37 (3H, s), 3.38 (3H, s), 3.39 (3H, s), 3.40 (3H, s), 3.44

(2H, br d, J = 4.2 Hz), 3.63 (1H, dd, J = 6.9, 3.2 Hz), 3.75 (1H, dd, J =

3.2, 1.3 Hz), 3.76 (1H, dd, J = 3.5, 1.6 Hz), 3.85 (1H, dd, J = 11.3, 5.4

Hz, H-5′a), 3.86 (1H, dd, J = 11.3, 2.8 Hz, H-5′b), 3.91 (1H, ddd, J =

6.6, 4.1, 4.1 Hz), 4.09 (1H, ddd, J = 6.6, 4.4, 3.5 Hz, H-4′), 4.21 (1H,

dd, J = 6.6, 3.2 Hz), 4.88 (1H, d, J = 1.6 Hz), 5.12 (1H, br s), 7.34−

7.41 (6H, m), 7.70−7.72 (4H, m); ¹³C NMR (125.7 MHz, CDCl₃) δ_C

19.3 (C), 26.7 (3 × CH₃), 54.8 (CH₃), 57.5 (2 × CH₃), 58.0 (CH₃),

59.3 (CH₃), 63.5 (CH₂), 71.8 (CH₂), 79.5 (CH), 80.6 (CH), 82.3

(CH), 85.3 (CH), 90.0 (CH), 90.4 (CH), 104.8 (CH), 106.9 (CH),

127.5 (2 × CH), 127.6 (2 × CH), 129.48 (CH), 129.51 (CH), 133.66

(C), 133.69 (C), 135.66 (2 × CH), 135.70 (2 × CH); MS (ESI⁺) m/z

(rel intens) 613 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₃₁H₄₆NaO₉Si 613.2809, found 613.2819. Anal. Calcd for C₃₁H₄₆O₉Si:

C, 63.02; H, 7.85. Found C, 63.20; H, 7.65.

Methyl 2,3,5-Tri-O-methyl-α-^D-arabinofuranosyl-(1→3)-2-O-

methyl-α-^D-arabinofuranoside (42). To a solution of disaccharide

26 (338.5 mg, 0.574 mmol) in dry THF (14.7 mL) was added

dropwise a 1 M solution of Bu₄NF/THF (1.43 mL, 1.43 mmol), and

the mixture was stirred at room temperature for 4.5 h. The solvent was

then removed in vacuo and the residue puriﬁed by column

chromatography (hexanes−EtOAc, 1:1 → 0:1) to give the alcohol

42 (190 mg, 0.540 mmol, 94%) as a colorless oil: [α]_D+157.0 (c

General Procedure for the Glycosylations. To a stirred 0.12 M

solution of trichloroacetimidate (2.3 equiv) and alcohol acceptor (1

equiv) in dry CH₂Cl₂containing freshly activated powdered 3 Å

molecular sieves (50 wt % with respect to the acceptor) was added

dropwise at 0 °C a 0.2 M solution of (TMS)OTf/CH₂Cl₂(0.025

equiv), and the mixture was stirred at that temperature for ca. 2 h. The

reaction mixture was then poured into a saturated solution of

NaHCO₃and extracted with CH₂Cl₂. The organic layers were washed

with brine, dried over Na₂SO₄, and concentrated under reduced

1

1.120, CHCl₃); IR 3494, 2933, 2828, 1456, 1109, 1052 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ_H3.357 (3H, s), 3.360 (3H, s), 3.37 (6H,

7381

dx.doi.org/10.1021/jo301153u | J. Org. Chem. 2012, 77, 7371−7391

The Journal of Organic Chemistry

Article

s), 3.38 (3H, s), 3.50 (1H, dd, J = 10.4, 5.4 Hz), 3.55 (1H, dd, J = 10.7,

3.8 Hz), 3.56 (1H, dd, J = 6.6, 3.2 Hz), 3.73 (1H, dd, J = 12.3, 3.8 Hz),

3.74 (1H, dd, J = 3.2, 1.6 Hz), 3.74 (1H, dd, J = 3.5, 1.9 Hz), 3.82 (1H,

dd, J = 12.0, 3.2 Hz), 4.02 (2H, m), 4.06 (1H, dd, J = 6.6, 3.2 Hz), 4.84

(269 mg, 0.456 mmol) in dry THF (11.7 mL) was added dropwise a 1

M solution of Bu₄NF/THF (1.14 mL, 1.14 mmol), and the mixture

was stirred at room temperature for 2 h. The solvent was then

removed in vacuo and the residue puriﬁed by column chromatography

(hexanes−EtOAc, 10:90) to give the alcohol 44 (156 mg, 0.443 mmol,

97%) as a colorless oil: [α]_D+78.3 (c 0.650, CHCl₃); IR 3490, 2929,

1

(1H, d, J = 1.3 Hz), 5.10 (1H, br s); H NMR (500 MHz, C₆D₆+

D₂O) δ_H3.05 (3H, s), 3.07 (3H, s), 3.072 (3H, s), 3.13 (3H, s), 3.15

(3H, s), 3.40 (2H, m), 3.68 (1H, dd, J = 6.9, 3.2 Hz), 3.86 (1H, dd, J =

3.2, 1.3 Hz), 3.90 (2H, m), 3.96 (1H, dd, J = 3.2, 1.3 Hz), 4.28 (2H,

m), 4.43 (1H, dd, J = 6.6, 3.2 Hz), 4.88 (1H, br s), 5.30 (1H, br s);¹³C

NMR (125.7 MHz, CDCl₃) δ_C54.8 (CH₃), 57.51 (CH₃), 57.54

(CH₃), 58.0 (CH₃), 59.3 (CH₃), 62.0 (CH₂), 72.3 (CH₂), 80.2 (CH),

80.7 (CH), 82.0 (CH), 85.4 (CH), 89.7 (CH), 90.4 (CH), 105.4

(CH), 106.7 (CH); MS (ESI⁺) m/z (rel intens) 375 (M⁺+ Na, 100);

HRMS (ESI⁺) m/z calcd for C₁₅H₂₈NaO₉375.1631, found 375.1628.

Anal. Calcd for C₁₅H₂₈O₉: C, 51.13; H, 8.01. Found C, 51.48; H, 7.95.

Methyl 2,3,5-Tri-O-acetyl-α-^D-arabinofuranosyl-(1→3)-5-O-

(tert-butyldiphenylsilyl)-2-O-methyl-β-^D-ribofuranoside (27).

Compound 27 was prepared from 24^28,29a(327 mg, 0.768 mmol)

and 16 (139 mg, 0.334 mmol) following the general procedure. The

residue was puriﬁed by column chromatography (hexanes−EtOAc,

80:20) to give the disaccharide 27 (216 mg, 0.320 mmol, 96%) as a

colorless oil: [α]_D+49.0 (c 0.390, CHCl₃); IR 2933, 1747, 1430, 1371,

1228, 1044 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H1.07 (9H, s), 1.98

(3H, s), 2.04 (3H, s), 2.10 (3H, s), 3.36 (3H, s), 3.48 (3H, s), 3.68

(1H, dd, J = 11.4, 4.5 Hz), 3.72 (1H, dd, J = 4.8, 1.6 Hz), 3.84 (1H, dd,

J = 11.4, 3.4 Hz), 4.09−4.19 (3H, m), 4.29 (1H, dd, J = 11.4, 2.9 Hz),

4.48 (1H, dd, J = 6.6, 4.5 Hz), 4.93 (1H, d, J = 1.6 Hz), 4.96 (1H, d, J

= 4.8, 1.6 Hz), 5.13 (1H, d, J = 1.3 Hz), 5.15 (1H, s), 7.35−7.44 (6H,

m), 7.68−7.71 (4H, m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C19.2 (C),

20.6 (CH₃), 20.68 (CH₃), 20.70 (CH₃), 26.8 (3 × CH₃), 55.8 (CH₃),

58.4 (CH₃), 63.1 (CH₂), 63.9 (CH₂), 73.9 (CH), 76.9 (CH), 80.9

(CH), 81.1 (CH), 81.9 (CH), 82.2 (CH), 104.8 (CH), 106.0 (CH),

127.6 (2 × CH), 127.7 (2 × CH), 129.6 (CH), 129.7 (CH), 133.3

(C), 133.4 (C), 135.6 (4 × CH), 169.4 (C), 170.0 (C), 170.5 (C); MS

(ESI⁺) m/z (rel intens) 697 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₃₄H₄₆NaO₁₂Si 697.2656, found 697.2657. Anal. Calcd for

C₃₄H₄₆O₁₂Si: C, 60.52; H, 6.87. Found C, 60.30; H, 6.92.

1

2828, 1456, 1107, 1052 cm⁻¹; H NMR (500 MHz, CDCl₃) δ_H3.39

(3H, s), 3.397 (3H, s), 3.403 (3H, s), 3.41 (3H, s), 3.48 (3H, s), 3.53

(1H, dd, J = 10.7, 5.7 Hz), 3.57−3.61 (2H, m), 3.65 (1H, dd, J = 11.7,

4.1 Hz), 3.73 (1H, d, J = 5.1 Hz), 3.77 (1H, dd, J = 12.0, 3.5 Hz), 3.81

(1H, d, J = 2.8 Hz), 4.07 (1H, ddd, J = 6.0, 6.0, 3.5 Hz), 4.16 (1H, ddd,

J = 6.9, 3.8, 3.8 Hz), 4.38 (1H, dd, J = 6.9, 5.0 Hz), 4.90 (1H, s), 5.07

(1H, s); ¹³C NMR (100.6 MHz, CDCl₃) δ_C55.5 (CH₃), 57.5 (CH₃),

57.9 (CH₃), 58.3 (CH₃), 59.3 (CH₃), 63.2 (CH₂), 72.3 (CH₂), 74.3

(CH), 80.9 (CH), 82.4 (CH), 82.6 (CH), 85.5 (CH), 89.6 (CH),

105.0 (CH), 106.1 (CH); MS (ESI⁺) m/z (rel intens) 375 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₁₅H₂₈NaO₉375.1631, found

375.1629. Anal. Calcd for C₁₅H₂₈O₉: C, 51.13; H, 8.01. Found C,

51.08; H, 8.05.

Methyl 2,3,5-Tri-O-acetyl-α-^L-arabinofuranosyl-(1→3)-5-O-

(tert-butyldiphenylsilyl)-2-O-methyl-α-^D-lyxofuranoside (30).

Compound 30 was prepared from 29²⁹(850 mg, 2.02 mmol) and

23 (365 mg, 0.878 mmol) following the general procedure. The

residue was puriﬁed by column chromatography (hexanes−EtOAc,

85:15 → 75:25) to give the disaccharide 30 (587 mg, 0.871 mmol,

99%) as a colorless oil: [α]_D−38.7 (c 0.23, CHCl₃); IR 2936, 2858,

1758, 1747, 1734, 1430, 1373, 1228, 1046 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ_H1.05 (9H, s), 1.78 (3H, s), 2.05 (3H, s), 2.07 (3H, s), 3.40

(3H, s), 3.41 (3H, s), 3.70 (1H, dd, J = 3.8, 3.8 Hz), 3.86 (1H, dd, J =

11.0, 6.6 Hz), 3.93 (1H, dd, J = 10.7, 5.4 Hz), 4.05 (1H, ddd, J = 5.4,

3.8, 3.8 Hz), 4.08 (1H, dd, J = 11.7, 5.4 Hz), 4.20 (1H, ddd, J = 6.6,

5.7, 3.8 Hz), 4.27 (1H, dd, J = 11.7, 3.5 Hz), 4.42 (1H, dd, J = 4.1, 4.1

Hz), 4.87 (1H, ddd, J = 4.1, 0.9, 0.9 Hz), 4.95 (1H, d, J = 3.8 Hz), 5.08

(1H, d, J = 1.2 Hz), 5.30 (1H, br s), 7.34−7.42 (6H, m), 7.65−7.69

(4H, m); ¹³C NMR (125.7 MHz, CDCl₃) δ_C19.2 (C), 20.3 (CH₃),

20.7 (2 × CH₃), 26.8 (3 × CH₃), 55.8 (CH₃), 58.7 (CH₃), 62.7

(CH₂), 63.2 (CH₂), 73.4 (CH), 77.1 (CH), 79.9 (CH), 80.7 (CH),

81.2 (CH), 86.8 (CH), 105.1 (CH), 106.8 (CH), 127.67 (2 × CH),

127.68 (2 × CH), 129.69 (CH), 129.72 (CH), 133.5 (C), 133.8 (C),

135.5 (2 × CH), 135.6 (2 × CH), 169.1 (C), 170.0 (C), 170.4 (C);

MS (ESI⁺) m/z (rel intens) 697 (M⁺+ Na, 100); HRMS (ESI⁺) m/z

calcd for C₃₄H₄₆NaO₁₂Si 697.2656, found 697.2657. Anal. Calcd for

C₃₄H₄₆O₁₂Si: C, 60.52; H, 6.87. Found C, 60.41; H, 6.60.

Methyl 2,3,5-Tri-O-methyl-α-^D-arabinofuranosyl-(1→3)-5-O-

(tert-butyldiphenylsilyl)-2-O-methyl-β-^D-ribofuranoside (28).

To a solution of compound 27 (405 mg, 0.601 mmol) in MeOH

(28.5 mL) was added K₂CO₃(249 mg, 1.803 mmol), and the mixture

was stirred at room temperature for 2 h, then neutralized with

Amberlyst 15 H⁺ion-exchange resin for 1 h, ﬁltered, and concentrated.

To the crude residue in dry DMF (7.2 mL) was added NaH, 60%

dispersion in mineral oil (144 mg, 3.606 mmol), and the mixture was

stirred at 0 °C under nitrogen until all hydrogen evolution had ceased.

Then an excess of methyl iodide (281 μL, 4.507 mmol) was added and

stirring continued at room temperature for 3 h. Excess reagent was

destroyed by addition of MeOH, and the mixture was concentrated

under high vacuum. Column chromatography (hexanes−EtOAc,

80:20) of the residue aﬀorded 28 (269 mg, 0.456 mmol, 76%) as a

colorless oil: [α]_D+54.0 (c 0.715, CHCl₃); IR 2933, 2828, 1463, 1111,

Methyl 2,3,5-Tri-O-methyl-α-^L-arabinofuranosyl-(1→3)-5-O-

(tert-butyldiphenylsilyl)-2-O-methyl-α-^D-lyxofuranoside (31).

To a solution of compound 30 (550 mg, 0.816 mmol) in MeOH

(39 mL) was added K₂CO₃(338 mg, 2.45 mmol), and the mixture was

stirred at room temperature for 2 h, then neutralized with Amberlyst

15 H⁺ion-exchange resin for 1 h, ﬁltered, and concentrated. To the

crude residue (627 mg) in dry DMF (9.7 mL) was added NaH, 60%

dispersion in mineral oil (196 mg, 4.9 mmol), and the mixture was

stirred at 0 °C under nitrogen until all hydrogen evolution had ceased.

Then an excess of methyl iodide (381 μL, 6.12 mmol) was added and

stirring continued at room temperature for 3 h. Excess reagent was

destroyed by addition of MeOH, and the mixture was concentrated

under high vacuum. Column chromatography (hexanes−EtOAc,

85:15) of the residue aﬀorded 31 (459 mg, 0.778 mmol, 95%) as a

colorless oil: [α]_D−27.5 (c 0.335, CHCl₃); IR 2933, 1471, 1191, 1115,

1

1054 cm⁻¹; H NMR (500 MHz, CDCl₃) δ_H1.06 (9H, s), 3.33 (3H,

s), 3.35 (3H, s), 3.38 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 3.47 (1H, dd,

J = 10.7, 4.7 Hz), 3.50 (1H, dd, J = 10.7, 3.5 Hz), 3.64 (1H, dd, J = 7.2,

3.5 Hz), 3.71 (1H, dd, J = 11.4, 4.7 Hz), 3.75 (1H, dd, J = 4.7, 1.6 Hz),

3.80 (1H, dd, J = 3.5, 0.9 Hz), 3.82 (1H, dd, J = 11.4, 3.5 Hz), 3.99

(1H, ddd, J = 7.6, 4.4, 4.4 Hz), 4.16 (1H, ddd, J = 6.3, 4.4, 3.5 Hz),

4.46 (1H, dd, J = 6.3, 4.7 Hz), 4.94 (1H, d, J = 1.6 Hz), 5.08 (1H, s),

7.35−7.43 (6H, m), 7.70−7.72 (4H, m); ¹³C NMR (100.6 MHz,

CDCl₃) δ_C19.3 (C), 26.8 (3 × CH₃), 55.3 (CH₃), 57.5 (CH₃), 57.9

(CH₃), 58.1 (CH₃), 59.3 (CH₃), 64.4 (CH₂), 71.8 (CH₂), 73.5 (CH),

80.5 (CH), 82.4 (CH), 82.6 (CH), 85.3 (CH), 90.1 (CH), 104.8

(CH), 105.8 (CH), 127.60 (2 × CH), 127.64 (2 × CH), 129.5 (CH),

129.6 (CH), 133.6 (2 × C), 135.65 (2 × CH), 135.67 (2 × CH); MS

(ESI⁺) m/z (rel intens) 613 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₃₁H₄₆NaO₉Si 613.2809, found 613.2803. Anal. Calcd for

C₃₁H₄₆O₉Si: C, 63.02; H, 7.85. Found C, 63.39; H, 7.86.

1

1046 cm⁻¹; H NMR (500 MHz, CDCl₃) δ_H1.05 (9H, s), 3.27 (3H,

s), 3.32 (3H, s), 3.36 (3H, s), 3.39 (1H, dd, J = 10.7, 5.1 Hz), 3.402

(3H, s), 3.404 (3H, s), 3.41 (1H, dd, J = 10.4, 3.8 Hz), 3.53 (1H, dd, J

= 6.3, 2.5 Hz), 3.68 (1H, dd, J = 4.1, 4.1 Hz), 3.70 (1H, dd, J = 2.8, 0.9

Hz), 3.86 (1H, dd, J = 11.0, 6.6 Hz), 3.91 (1H, ddd, J = 6.6, 5.1, 3.8

Hz), 3.97 (1H, dd, J = 11.0, 4.4 Hz), 4.21 (1H, ddd, J = 6.9, 4.7, 4.7

Hz), 4.40 (1H, dd, J = 4.1, 4.1 Hz), 4.93 (1H, d, J = 3.8 Hz), 5.18 (1H,

br s), 7.34−7.42 (6H, m), 7.67−7.71 (4H, m); ¹³C NMR (125.7 MHz,

CDCl₃) δ_C19.3 (C), 26.9 (3 × CH₃), 55.7 (CH₃), 57.4 (CH₃), 57.7

(CH₃), 58.6 (CH₃), 59.2 (CH₃), 63.3 (CH₂), 72.2 (CH₂), 73.1 (CH),

80.4 (CH), 80.7 (CH), 85.3 (CH), 87.0 (CH), 89.6 (CH), 105.0

(CH), 106.7 (CH), 127.5 (2 × CH), 127.6 (2 × CH), 129.5 (2 ×

Methyl 2,3,5-Tri-O-methyl-α-^D-arabinofuranosyl-(1→3)-2-O-

methyl-β-^D-ribofuranoside (44). To a solution of disaccharide 28

7382

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CH), 133.9 (C), 134.1 (C), 135.6 (2 × CH), 135.7 (2 × CH); MS

(ESI⁺) m/z (rel intens) 613 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₃₁H₄₆NaO₉Si 613.2809, found 613.2808. Anal. Calcd for

C₃₁H₄₆O₉Si: C, 63.02; H, 7.85. Found C, 62.96; H, 7.72.

(CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.9 (CH₃), 55.7 (CH₃), 57.9 (CH₃),

62.0 (CH₂), 67.3 (CH), 68.8 (CH), 69.8 (CH), 70.9 (CH), 79.1

(CH), 80.5 (CH), 88.6 (CH), 96.4 (CH), 107.6 (CH), 169.8 (C),

169.9 (C), 170.1 (C); MS (ESI⁺) m/z (rel intens) 473 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₁₉H₃₀NaO₁₂473.1635, found

473.1639. Anal. Calcd for C₁₉H₃₀O₁₂: C, 50.66; H, 6.71. Found C,

50.58; H, 6.58.

Methyl 2,3,5-Tri-O-methyl-α-^L-arabinofuranosyl-(1→3)-2-O-

methyl-α-^D-lyxofuranoside (47). To a solution of disaccharide 31

(389 mg, 0.659 mmol) in dry THF (16.9 mL) was added dropwise a 1

M solution of Bu₄NF/THF (1.65 mL, 1.65 mmol), and the mixture

was stirred at room temperature for 3 h. The solvent was then

removed in vacuo and the residue puriﬁed by column chromatography

(hexanes−EtOAc, 1:1 → 0:1) to give the alcohol 47 (209 mg, 0.594

mmol, 90%) as a colorless oil: [α]_D−67 (c 0.215, CHCl₃); IR 3498,

2936, 2832, 1456, 1113, 1042 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H

3.10 (1H, br dd, J = 6.6, 6.6 Hz, OH), 3.38 (3H, s), 3.395 (3H, s),

3.399 (3H, s), 3.41 (3H, s), 3.45 (3H, s), 3.51 (2H, d, J = 5.7 Hz), 3.57

(1H, dd, J = 4.7, 1.8 Hz), 3.71 (1H, dd, J = 5.1, 2.5 Hz), 3.73 (1H, m),

3.80 (1H, m), 3.82 (1H, dd, J = 1.9, 0.6 Hz), 4.15 (1H, ddd, J = 5.4,

5.4, 5.4 Hz), 4.18 (1H, ddd, J = 7.3, 5.7, 4.1 Hz), 4.60 (1H, dd, J = 5.4,

5.4 Hz), 4.96 (1H, d, J = 2.5 Hz), 5.20 (1H, s); ¹³C NMR (125.7

MHz, CDCl₃) δ_C55.4 (CH₃), 57.5 (CH₃), 57.8 (CH₃), 58.6 (CH₃),

59.3 (CH₃), 61.0 (CH₂), 72.9 (CH₂), 74.0 (CH), 78.2 (CH), 82.2

(CH), 84.6 (CH), 85.2 (CH), 88.1 (CH), 104.9 (CH), 106.1 (CH);

MS (ESI⁺) m/z (rel intens) 375 (M⁺+ Na, 100); HRMS (ESI⁺) m/z

calcd for C₁₅H₂₈NaO₉375.1631, found 375.1628. Anal. Calcd for

C₁₅H₂₈O₉: C, 51.13; H, 8.01. Found C, 51.29; H, 7.86.

Methyl 2,3,4-Tri-O-acetyl-α-^L-rhamnopyranosyl-(1→3)-5-O-

(tert-butyldiphenylsilyl)-2-O-methyl-β-^D-xylofuranoside (33).

Compound 33 was prepared from 32³⁰(959 mg, 2.215 mmol) and

18 (384 mg, 0.923 mmol) following the general procedure. The

residue was puriﬁed by column chromatography (hexanes−EtOAc,

85:15) to give the disaccharide 33 (590 mg, 0.857 mmol, 93%) as a

colorless oil: [α]_D−67.2 (c 0.360, CHCl₃); IR 2936, 2858, 1751, 1432,

1371, 1224, 1052 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H1.07 (9H, s),

1.13 (3H, d, J = 6.1 Hz), 1.91 (3H, s), 2.00 (3H, s), 2.15 (3H, s), 3.33

(3H, s), 3.41 (3H, s), 3.75 (1H, dd, J = 1.6, 1.6 Hz), 3.82 (1H, dd, J =

10.6, 5.0 Hz), 3.97 (1H, dddd, J = 9.5, 6.1, 6.1, 6.1 Hz), 4.10 (1H, dd, J

= 10.6, 6.6 Hz), 4.23−4.28 (2H, m), 4.82 (1H, d, J = 1.6 Hz), 4.92

(1H, d, J = 1.6 Hz), 5.04 (1H, dd, J = 9.8, 9.8 Hz), 5.24 (1H, dd, J =

3.5, 1.6 Hz), 5.30 (1H, dd, J = 10.1, 3.4 Hz), 7.36−7.42 (6H, m),

7.69−7.72 (4H, m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C17.6 (CH₃),

19.2 (C), 20.7 (2 × CH₃), 20.9 (CH₃), 27.0 (3 × CH₃), 55.5 (CH₃),

57.8 (CH₃), 62.1 (CH₂), 66.9 (CH), 68.9 (CH), 69.9 (CH), 71.1

(CH), 76.5 (CH), 80.9 (CH), 87.2 (CH), 95.3 (CH), 107.3 (CH),

127.7 (4 × CH), 129.6 (CH), 129.7 (CH), 133.4 (C), 133.6 (C),

135.5 (4 × CH), 169.54 (C), 169.96 (C), 170.05 (C); MS (ESI⁺) m/z

(rel intens) 711 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₃₅H₄₈NaO₁₂Si 711.2813, found 711.2819. Anal. Calcd for

C₃₅H₄₈O₁₂Si: C, 61.03; H, 7.02. Found C, 61.12; H, 7.03.

Methyl 2,3,5-Tri-O-acetyl-α-^D-arabinofuranosyl-(1→4)-6-O-

(tert-butyldiphenylsilyl)-2,3-di-O-methyl-α-^D-glucopyranoside

(35). Compound 35 was prepared from 24^28,29a(425 mg, 0.98 mmol)

and 34^11a(101 mg, 0.22 mmol) following the general procedure. The

residue was puriﬁed by column chromatography (hexanes−EtOAc,

7:3) to give the disaccharide 35 (160 mg, 0.22 mmol, 99%) as a

colorless oil: [α]_D+83.6 (c 0.420, CHCl₃); IR 2933, 2855, 1745, 1369,

1223, 1043 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H1.05 (9H, s), 1.96

(3H, s), 1.97 (3H, s), 2.07 (3H, s), 3.19 (1H, dd, J = 9.5, 3.7 Hz), 3.43

(3H, s), 3.52 (3H, s), 3.54−3.59 (2H, m), 3.55 (3H, s), 3.68 (1H, m),

3.79 (1H, dd, J = 11.1, 6.1 Hz), 3.83 (1H, m), 3.86 (1H, dd, J = 11.1,

2.1 Hz), 3.96 (1H, dd, J = 11.9, 5.0 Hz), 4.07 (1H, dd, J = 4.0, 11.9

Hz), 4.84 (1H, d, J = 3.7 Hz), 4.92 (1H, ddd, J = 4.8, 1.6, 0.5 Hz), 5.07

(1H, dd, J = 1.6, 0.5 Hz), 5.45 (1H, s), 7.33−7.42 (6H, m), 7.68−7.70

(4H, m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C19.2 (C), 20.59 (CH₃),

20.62 (CH₃), 20.7 (CH₃), 26.7 (3 × CH₃), 54.8 (CH₃), 58.9 (CH₃),

60.9 (CH₃), 63.0 (CH₂), 63.2 (CH₂), 70.8 (CH), 73.8 (CH), 76.9

(CH), 80.7 (CH), 81.0 (CH), 82.3 (CH), 83.6 (CH), 97.0 (CH),

106.3 (CH), 127.5 (2 × CH), 127.6 (2 × CH), 129.6 (2 × CH),

133.56 (C), 133.64 (C), 135.6 (2 × CH), 135.7 (2 × CH), 169.3 (C),

169.9 (C), 170.4 (C); MS (ESI⁺) m/z (rel intens) 741 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₃₆H₅₀NaO₁₃Si 741.2918, found

741.2938. Anal. Calcd for C₃₆H₅₀O₁₃Si: C, 60.15; H, 7.01. Found C,

59.98; H, 6.83.

Methyl 2,3,5-Tri-O-methyl-α-^D-arabinofuranosyl-(1→4)-6-O-

(tert-butyldiphenylsilyl)-2,3-di-O-methyl-α-^D-glucopyranoside

(36). To a solution of compound 35 (450 mg, 0.627 mmol) in MeOH

(30 mL) was added K₂CO₃(258 mg, 1.88 mmol), and the mixture was

stirred at room temperature for 2 h, then neutralized with Dowex (50

× 8) H⁺ion-exchange resin for 1 h, ﬁltered, and concentrated. To the

crude residue in dry DMF (7.5 mL) was added NaH, 55% dispersion

in mineral oil (164 mg, 3.76 mmol), and the mixture was stirred at 0

°C under nitrogen until all hydrogen evolution had ceased. Then an

excess of methyl iodide (293 μL, 4.70 mmol) was added and stirring

continued at this temperature for 3 h. Excess reagent was destroyed by

addition of MeOH, and the mixture was concentrated under high

vacuum. Column chromatography (hexanes−EtOAc, 70:30) of the

residue aﬀorded 36 (278 mg, 0.438 mmol, 70%) as a colorless oil:

[α]_D+98.2 (c 0.510, CHCl₃); IR 2931, 2827, 1363, 1112, 1045 cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ_H1.05 (9H, s), 3.18 (1H, dd, J = 10.6,

4.2 Hz), 3.20 (1H, dd, J = 9.5, 3.7 Hz), 3.23 (3H, s), 3.25 (1H, dd, J =

10.6, 4.5 Hz), 3.30 (3H, s), 3.40 (3H, s), 3.44 (3H, s), 3.45 (1H, dd, J

= 9.3, 9.3 Hz), 3.51 (3H, s), 3.54 (1H, dd, J = 6.1, 2.6 Hz), 3.568 (1H,

dd, J = 9.2, 9.2 Hz), 3.574 (3H, s), 3.67 (1H, dd, J = 2.6, 0.8 Hz),

3.68−3.74 (2H, m), 3.78 (1H, dd, J = 10.9, 7.2 Hz), 3.96 (1H, dd, J =

10.9, 1.6 Hz), 4.84 (1H, d, J = 3.7 Hz), 5.33 (1H, s), 7.33−7.42 (6H,

m), 7.68−7.73 (4H, m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C19.3 (C),

26.8 (3 × CH₃), 54.7 (CH₃), 57.5 (CH₃), 57.8 (CH₃), 58.6 (CH₃),

59.1 (CH₃), 60.8 (CH₃), 63.7 (CH₂), 71.2 (CH), 71.9 (CH₂), 74.7

(CH), 80.9 (CH), 82.5 (CH), 83.5 (CH), 85.5 (CH), 90.0 (CH), 96.7

(CH), 106.5 (CH), 127.5 (4 × CH), 129.4 (CH), 129.5 (CH), 133.8

(C), 133.9 (C), 135.68 (2 × CH), 135.71 (2 × CH); MS (ESI⁺) m/z

(rel intens) 657 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₃₃H₅₀NaO₁₀Si 657.3071, found 657.3062. Anal. Calcd for

C₃₃H₅₀O₁₀Si: C, 62.43; H, 7.94. Found C, 62.34; H, 7.96.

Methyl 2,3,5-Tri-O-acetyl-α-^D-arabinofuranosyl-(1→4)-2,3-

di-O-methyl-α-^D-glucopyranoside (55). To a solution of dis-

accharide 35 (224 mg, 0.31 mmol) in dry THF (9 mL) was added

dropwise a 1 M solution of Bu₄NF/THF (0.77 mL, 0.77 mmol), and

the mixture was stirred at room temperature for 24 h. The solvent was

then removed in vacuo and the residue puriﬁed by column

chromatography (hexanes−EtOAc, 30:70) to give the alcohol 55

(97.2 mg, 0.202 mmol, 65%) as a colorless oil: [α]_D+102.8 (c 0.140,

Methyl 2,3,4-Tri-O-acetyl-α-^L-rhamnopyranosyl-(1→3)-2-O-

methyl-β-^D-xylofuranoside (50). To a solution of disaccharide 33

(590 mg, 0.858 mmol) in dry THF (21.9 mL) was added dropwise a 1

M solution of Bu₄NF/THF (3.0 mL, 3.0 mmol), and the mixture was

stirred at room temperature for 5 h. The solvent was then removed in

vacuo and the residue puriﬁed by column chromatography (hexanes−

EtOAc, 40:60) to give the alcohol 50 (326 mg, 0.724 mmol, 84%) as a

colorless oil: [α]_D−75.3 (c 0.933, CHCl₃); IR 3494, 2936, 2832, 1749,

1373, 1226, 1048 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ_H1.23 (3H, d,

J = 6.3 Hz), 1.99 (3H, s), 2.05 (3H, s), 2.15 (3H, s), 3.40 (3H, s), 3.44

(3H, s), 3.78−3.83 (2H, m), 3.858 (1H, dddd, J = 10.1, 6.4, 6.4, 6.4

Hz), 3.860 (1H, dd, J = 3.5, 2.2 Hz), 4.31 (1H, ddd, J = 6.9, 6.9, 4.7

Hz), 4.33 (1H, dd, J = 6.9, 3.5 Hz), 4.85 (1H, d, J = 2.2 Hz), 4.94 (1H,

d, J = 1.9 Hz), 5.07 (1H, dd, J = 9.8, 9.8 Hz), 5.23 (1H, dd, J = 9.8, 3.5

1

Hz), 5.25 (1H, dd, J = 3.5, 1.9 Hz); H NMR (500 MHz, C₆D₆) δ_H

5.70 (1H, dd, J = 10.1, 3.5 Hz), 5.62 (1H, dd, J = 3.2, 1.9 Hz), 5.53

(1H, dd, J = 10.1, 10.1 Hz), 5.18 (1H, d, J = 1.9 Hz), 4.80 (1H, d, J =

1.9 Hz), 4.36 (1H, dd, J = 6.6, 3.8 Hz), 4.23 (1H, ddd, J = 6.3, 5.1, 5.1

Hz), 4.12 (1H, dddd, J = 9.8, 6.3, 6.3, 6.3 Hz), 3.96 (1H, dd, J = 3.8,

1.9 Hz), 3.85 (1H, dd, J = 11.7, 5.4 Hz), 3.80 (1H, dd, J = 11.7, 5.4),

3.12 (3H, s), 3.06(3H, s), 1.69 (3H, s), 1.66 (3H, s), 1.61, (3H, s),

1.24 (3H, d, J = 6.0 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C17.5

7383

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CHCl₃); IR 3450, 2966, 1750, 1228, 1039 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ_H2.10 (3H, s), 2.107 (3H, s), 2.108 (3H, s), 2.30 (1H, br s),

3.21 (1H, dd, J = 9.1, 3.5 Hz), 3.42 (3H, s), 3.51 (3H, s), 3.57 (3H, s),

3.57−3.67 (3H, m), 3.74−3.81 (2H, m), 4.19 (1H, dd, J = 11.4, 6.3

Hz), 4.31 (1H, ddd, J = 6.1, 4.5, 4.5 Hz), 4.37 (1H, dd, J = 11.4, 3.8

Hz), 4.82 (1H, d, J = 3.5 Hz), 5.01 (1H, dd, J = 4.6, 1.8 Hz), 5.17 (1H,

dd, J = 2.0, 0.8 Hz), 5.49 (1H, s); ¹³C NMR (100.6 MHz, CDCl₃) δ_C

20.62 (CH₃), 20.64 (CH₃), 20.7 (CH₃), 55.2 (CH₃), 59.0 (CH₃), 61.0

(CH₃), 61.7 (CH₂), 63.4 (CH₂), 70.0 (CH), 74.2 (CH), 77.0 (CH),

80.7 (CH), 81.1 (CH), 82.2 (CH), 83.2 (CH), 97.6 (CH), 107.0

(CH), 169.3 (C), 169.9 (C), 170.6 (C); MS (ESI⁺) m/z (rel intens)

503 (M⁺+ Na, 100); HRMS (ESI⁺) calcd for C₂₀H₃₂NaO₁₃503.1741,

found 503.1743. Anal. Calcd for C₂₀H₃₂O₁₃: C, 50.00; H, 6.71. Found

C, 50.22; H, 6.78.

Methyl 2,3,5-Tri-O-methyl-α-^D-arabinofuranosyl-(1→4)-2,3-

di-O-methyl-α-^D-glucopyranoside (53). To a solution of com-

pound 36 (280 mg, 0.442 mmol) in dry THF (11.4 mL) was added a 1

M solution of TBAF/THF (1.11 mL, 1.11 mmol), and the mixture was

stirred at room temperature for 6 h. The reaction mixture was

concentrated under reduced pressure and the residue puriﬁed by

column chromatography (EtOAc) to give the alcohol 53 (174 mg,

0.439 mmol, 99%) as a colorless oil: [α]_D+160.8 (c 0.375, CHCl₃); IR

3468, 2926, 2830, 1459, 1096, 1051 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ_H3.23 (1H, dd, J = 9.3, 3.7 Hz), 3.387 (3H, s), 3.391 (3H,

s), 3.395 (3H, s), 3.43 (3H, s), 3.488 (3H, s), 3.489 (1H, dd, J = 10.6,

5.8 Hz), 3.53 (1H, dd, J = 10.6, 4.8 Hz), 3.54−3.59 (2H, m), 3.57 (1H,

dd, J = 9.3, 9.3 Hz), 3.58 (3H, s), 3.65 (1H, dd, J = 9.8, 9.1 Hz), 3.72

(1H, br d, J = 12.7 Hz), 3.75 (1H, dd, J = 2.9, 1.3 Hz), 3.84 (1H, br d,

J = 12.2 Hz), 4.12 (1H, ddd, J = 6.1, 6.1, 4.5 Hz), 4.82 (1H, d, J = 3.7

Hz), 5.41 (1H, s); ¹³C NMR (100.6 MHz, CDCl₃) δ_C55.1 (CH₃),

57.6 (CH₃), 58.0 (CH₃), 58.7 (CH₃), 59.3 (CH₃), 60.9 (CH₃), 61.7

(CH₂), 70.4 (CH), 72.6 (CH₂), 74.8 (CH), 81.3 (CH), 82.4 (CH),

83.1 (CH), 85.7 (CH), 89.6 (CH), 97.4 (CH), 107.2 (CH); MS

(ESI⁺) m/z (rel intens) 419 (M⁺+ Na, 100). HRMS (ESI⁺) m/z calcd

for C₁₇H₃₂NaO₁₀419.1893, found 419.1886. Anal. Calcd for

C₁₇H₃₂O₁₀: C, 51.51; H, 8.14. Found C, 51.44; H, 8.29.

Dowex (50 × 8) H⁺ion-exchange resin for 1 h, ﬁltered, and

concentrated. To the crude residue in dry acetone (8.3 mL) were

added Ag₂O (1.53 g, 6.62 mmol) and methyl iodide (412 μL, 6.62

mmol), and the mixture was stirred at room temperature under

nitrogen for 24 h. Then the reaction mixture was ﬁltered through

Celite and concentrated under reduced pressure. Column chromatog-

raphy (hexanes−EtOAc, 70:30) of the residue aﬀorded the title

compound 39 (368 mg, 0.543 mmol, 65%) as a colorless oil: [α]_D

1

+78.7 (c 0.240, CHCl₃); IR 2931, 1107, 1064 cm⁻¹; H NMR (400

MHz, CDCl₃) δ_H1.03 (9H, s), 2.99 (1H, dd, J = 10.6, 6.1 Hz), 3.02

(3H, s), 3.17 (1H, dd, J = 9.6, 3.7 Hz), 3.27−3.39 (3H, m), 3.33 (3H,

s), 3.42−3.58 (3H, m), 3.44 (3H, s), 3.46 (3H, s), 3.47 (3H, s), 3.50

(3H, s), 3.55 (3H, s), 3.66−3.73 (3H, m), 3.89 (1H, dd, J = 9.5, 0 Hz),

4.84 (1H, d, J = 3.7 Hz), 5.30 (1H, d, J = 4.0 Hz), 7.35−7.43 (6H, m),

7.69−7.72 (4H, m);¹³C NMR (100.6 MHz, CDCl₃) δ_C19.2 (C), 26.7

(3 × CH₃), 54.9 (CH₃), 57.9 (CH₃), 58.5 (CH₃), 58.7 (CH₃), 58.8

(CH₃), 59.9 (CH₃), 60.8 (CH₃), 64.0 (CH₂), 71.8 (CH), 72.8 (CH₂),

74.8 (CH), 77.2 (CH), 77.9 (CH), 79.8 (CH), 82.3 (CH), 83.4 (CH),

87.0 (CH), 96.9 (CH), 105.9 (CH), 127.6 (4 × CH), 129.5 (2 × CH),

133.6 (2 × C), 135.6 (2 × CH), 135.7 (2 × CH); MS (ESI⁺) m/z (rel

intens) 701 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₃₅H₅₄NaO₁₁Si, 701.3333, found 701.3334. Anal. Calcd for

C₃₅H₅₄O₁₁Si: C, 61.92; H, 8.02. Found: C, 61.80; H, 7.92.

Methyl 2,3,5,6-Tetra-O-methyl-α-^D-mannofuranosyl-(1→4)-

2,3-di-O-methyl-α-^D-glucopyranoside (58). To a solution of

compound 39 (217 mg, 0.320 mmol) in dry THF (30 mL) was

added a 1 M solution of TBAF/THF (0.96 mL, 0.960 mmol), and the

mixture was stirred at room temperature for 2 h. The reaction mixture

was concentrated under reduced pressure and the residue puriﬁed by

column chromatography (EtOAc) to give the alcohol 58 (108 mg,

0.245 mmol, 77%) as a colorless oil: [α]_D+103.6 (c 0.110, CHCl₃); IR

1

3684, 3512, 2932, 1102 cm⁻¹; H NMR (400 MHz, CDCl₃) δ_H2.99

(1H, br s), 3.19 (1H, dd, J = 9.5, 3.7 Hz), 3.35 (3H, s), 3.37 (3H, s),

3.38 (3H, s), 3.44 (3H, s), 3.46 (3H, s), 3.48−3.58 (4H, m), 3.50 (3H,

s), 3.55 (3H, s), 3.62−3.65 (3H, m), 3.70 (1H, dd, J = 3.7 Hz), 3.81

(1H, dd, J = 12.4, 2.9 Hz), 3.88 (1H, dd, J = 3.4, 3.4 Hz), 4.10 (1H, dd,

J = 9.0, 3.2 Hz), 4.77 (1H, d, J = 3.4 Hz), 5.41 (1H, d, J = 4.0 Hz); ¹³C

NMR (100.6 MHz, CDCl₃) δ_C54.9 (CH₃), 57.0 (CH₃), 58.6 (2 ×

CH₃), 59.2 (CH₃), 60.1 (CH₃), 60.7 (CH₂), 60.7 (CH₃), 69.7 (CH₂),

70.4 (CH), 74.5 (CH), 76.9 (CH), 77.8 (CH), 79.7 (CH), 82.1 (CH),

83.1 (CH), 87.2 (CH), 97.4 (CH), 107.0 (CH); MS (ESI⁺) m/z (rel

intens) 463 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₁₉H₃₆NaO₁₁, 463.2155, found 463.2153. Anal. Calcd for

C₁₉H₃₆O₁₁: C, 51.81; H, 8.24. Found: C, 52.02; H, 8.07.

Methyl 2,3,5,6-Tetra-O-acetyl-α-^D-mannofuranosyl-(1→4)-6-

O-(tert-butyldiphenylsilyl)-2,3-di-O-methyl-α-^D-glucopyrano-

side (38). To a solution of 37³¹(1.77 g, 4.25 mmol) and 34^11a(1.90

g, 4.25 mmol) in dry CH₂Cl₂(6 mL) were added N-iodosuccinimide

(1.24 g, 5.51 mmol) and, at 0 °C, (TMS)OTf (230 μL, 1.27 mmol),

and the mixture was stirred at room temperature for 1 h. Then the

reaction mixture was poured into a saturated solution of NaHCO₃and

extracted with CH₂Cl₂. The organic layers were washed with brine,

dried over Na₂SO₄, and concentrated under reduced pressure. The

residue was puriﬁed column chromatography (hexanes−EtOAc, 8:2)

to give the disaccharide 38 (2.02 g, 2.55 mmol, 60%) as an amorphous

Methyl 2,3,4-Tri-O-acetyl-α-^D-lyxopyranosyl-(1→4)-2,3-di-O-

methyl-α-^D-glucopyranoside (41). Compound 41 was prepared

from 40³²(664 mg, 1.584 mmol) and 34^11a(331 mg, 0.720 mmol)

following the general procedure. The residue was puriﬁed by column

chromatography (hexanes−EtOAc, 1:1) to give the alcohol 41 (554

mg, 1.154 mmol, 73%) as a colorless oil: [α]_D+160.0 (c 0.03, CHCl₃);

1

solid: [α]_D+89.6 (c 0.240, CHCl₃); IR 2933, 1755, 1229 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ_H1.03 (9H, s), 1.83 (3H, s), 1.90 (3H, s),

2.00 (3H), 2.02 (3H, s), 3.15 (1H, dd, J = 9.7, 3.6 Hz), 3.33 (1H, dd, J

= 10.1, 8.7 Hz), 3.46 (3H, s), 3.48−3.55 (2H, m), 3.49 (3H, s), 3.51

(3H, s), 3.60 (1H, dd, J = 8.6, 4.4 Hz), 3.67 (1H, m), 3.75 (1H, dd, J =

10.9, 6.9 Hz), 3.84 (1H, dd, J = 11.1, 1.6 Hz), 4.30 (1H, dd, J = 12.0,

2.5 Hz), 4.83 (1H, d, J = 3.4 Hz), 5.0 (1H, dd, J = 4.9, 3.3 Hz), 5.09

(1H, dd, J = 6.5, 2.0 Hz), 5.29 (1H, dd, J = 4.6, 4.6 Hz), 5.40 (1H, d, J

= 3.4 Hz), 7.35−7.44 (6H, m), 7.67−7.71 (4H, m); ¹³C NMR (100.6

MHz, CDCl₃) δ_C19.1 (C), 20.2 (2 × CH₃), 20.5 (CH₃), 20.6 (CH₃),

26.6 (3 × CH₃), 54.9 (CH₃), 58.8 (CH₃), 60.9 (CH₃), 62.7 (CH₂),

63.7 (CH₂), 68.1 (CH), 70.6 (CH), 71.4 (CH), 75.7 (CH), 75.9 (2 ×

CH), 82.1 (CH), 83.2 (CH), 96.9 (CH), 105.6 (CH), 127.7 (4 ×

CH), 129.6 (2 × CH), 133.4 (2 × C), 135.5 (2 × CH), 135.7 (2 ×

CH), 169.2 (C), 169.4 (2 × C), 170.3 (C); MS (ESI⁺) m/z (rel

intens) 813 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₃₉H₅₄NaO₁₅Si, 813.3130, found 813.3109. Anal. Calcd for

C₃₉H₅₄O₁₅Si: C, 59.22; H, 6.88. Found: C, 59.36; H, 6.86.

1

IR 3530, 2933, 1753, 1123 cm⁻¹; H NMR (400 MHz, CDCl₃) δ_H

2.01 (3H, s), 2.03 (6H, s), 2.37 (1H, br s), 3.15 (1H, dd, J = 9.1, 3.3

Hz), 3.37 (3H, s), 3.45 (3H, s), 3.49−3.57 (4H, m), 3.55 (3H, s),

3.69−3.83 (2H, m), 3.88 (1H, dd, J = 11.8, 4.1 Hz), 4.77 (1H, d, J =

3.4 Hz), 5.00 (1H, m), 5.11 (2H, br s), 5.27 (1H, d, J = 5.3 Hz); ¹³C

NMR (100.6 MHz, CDCl₃) δ_C20.5 (CH₃), 20.6 (CH₃), 20.7 (CH₃),

55.1 (CH₃), 58.8 (CH₃), 61.0 (CH₃), 61.7 (2 × CH₂), 67.3 (CH),

68.2 (CH), 69.2 (CH), 69.9 (CH), 75.6 (CH), 82.2 (CH), 83.0 (CH),

97.3 (CH), 99.0 (CH), 169.5 (C), 169.6 (C), 169.8 (C); MS (ESI⁺)

m/z (rel intens) 503 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₂₀H₃₂NaO₁₃, 503.1741, found 503.1741. Anal. Calcd for C₂₀H₃₂O₁₃:

C, 50.00; H, 6.71. Found: C, 50.13; H, 7.01.

General Procedure for the Oxidative HAT Reactions. A 0.025

M solution of the alcohol (1 equiv) in dry CH₂Cl₂containing DIB

(1.1−2.5 equiv) and I₂(0.5−1.2 equiv) under nitrogen was irradiated

with two 80 W tungsten-ﬁlament lamps at room temperature for the

speciﬁed time. The reaction mixture was then poured into 10%

aqueous Na₂S₂O₃, extracted with CH₂Cl₂, dried over Na₂SO₄, and

concentrated. The residue was puriﬁed by silica gel column

chromatography (hexanes−EtOAc mixtures).

Methyl 2,3,5,6-Tetra-O-methyl-α-^D-mannofuranosyl-(1→4)-

6-O-(tert-butyldiphenylsilyl)-2,3-di-O-methyl-α-^D-glucopyra-

noside (39). To a solution of compound 38 (654 mg, 0.828 mmol) in

MeOH (27 mL) was added K₂CO₃(457 mg, 3.31 mmol), and the

mixture was stirred at room temperature for 3 h, then neutralized with

7384

dx.doi.org/10.1021/jo301153u | J. Org. Chem. 2012, 77, 7371−7391

The Journal of Organic Chemistry

Article

Oxidative HAT of 42. Method A at Room Temperature. The

reaction proceeded from 42 (46 mg, 0.131 mmol) containing DIB (72

mg, 0.223 mmol) and I₂(33 mg, 0.130 mmol) following the general

procedure by irradiation for 2 h. Chromatotron chromatography of the

reaction residue (hexanes−EtOAc, 6:4) gave 43 as an inseparable

mixture of isomers (27 mg, 0.071 mmol, dr 6:1, 54%): colorless oil; IR

2936, 2828, 1757, 1749, 1456, 1117, 1055 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) (major isomer) δ_H2.09 (3H, s), 3.38 (3H, s), 3.39 (6H, s),

3.42 (3H, s), 3.45 (3H, s), 3.51 (1H, dd, J = 10.7, 4.7 Hz), 3.56 (1H,

dd, J = 10.7, 3.5 Hz), 3.64 (1H, dd, J = 6.9, 3.2 Hz), 3.70 (1H, dd, J =

2.8, 2.8 Hz), 3.78 (1H, d, J = 3.2 Hz), 4.06 (1H, ddd, J = 6.9, 4.7, 5.5

Hz), 4.13 (1H, dd, J = 2.8, 2.8 Hz), 5.04 (1H, d, J = 2.8 Hz), 5.09 (1H,

s), 6.20 (1H, d, J = 2.2 Hz); ¹³C NMR (125.7 MHz, CDCl₃) (major

isomer) δ_C21.1 (CH₃), 56.4 (CH₃), 57.6 (CH₃), 58.0 (CH₃), 58.1

(CH₃), 59.3 (CH₃), 71.8 (CH₂), 80.9 (CH), 83.2 (CH), 85.1 (CH),

87.6 (CH), 89.9 (CH), 100.0 (CH), 105.6 (CH), 108.5 (CH), 169.6

(C); MS (ESI⁺) m/z (rel intens) 403 (M⁺+ Na, 100); HRMS (ESI⁺)

m/z calcd for C₁₆H₂₈NaO₁₀403.1580, found 403.1584. Anal. Calcd for

C₁₆H₂₈O₁₀: C, 50.52; H, 7.42. Found C, 50.46; H, 7.34.

Oxidative HAT of 44. Method A at Room Temperature. The

reaction proceeded from alcohol 44 (44 mg, 0.125 mmol) containing

DIB (68 mg, 0.212 mmol) and I₂(32 mg, 0.125 mmol) following the

general procedure by irradiation for 1.5 h. After this time another

portion of DIB (20 mg, 0.062 mmol) was added, and irradiation was

continued for an additional 0.5 h. Chromatotron chromatography of

the residue (hexanes−EtOAc, 50:50) gave in order of elution methyl

2,3,5-tri-O-methyl-α-^D-arabinofuranosyl-(1→3)-2-O-methyl-β-D-ribo-

pentodialdo-1,4-furanose (46) (3.5 mg, 0.01 mmol, 8%) and methyl

(4R)-2,3,5-tri-O-methyl-α-^D-arabinofuranosyl-(1→3)-4-O-acetyl-2-O-

methyl-β-^D-erythro-tetrodialdo-1,4-furanose (45) (30.3 mg, 0.08 mmol,

64%), both as colorless oils. Data for compound 46: [α]_D+79.1 (c

0.230, CHCl₃); IR 2933, 2828, 1736, 1454, 1107, 1050 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ_H3.39 (6H, s), 3.40 (3H, s), 3.41 (3H, s),

3.48 (3H, s), 3.52 (1H, dd, J = 10.9, 5.0 Hz), 3.58 (1H, dd, J = 10.9,

3.4 Hz), 3.63 (1H, dd, J = 7.2, 3.2 Hz), 3.71 (1H, d, J = 4.8 Hz), 3.81

(1H, d, J = 3.2 Hz), 4.07 (1H, ddd, J = 8.2, 5.0, 3.4 Hz), 4.38 (1H, dd,

J = 6.6, 1.9 Hz), 4.58 (1H, dd, J = 6.6, 4.8 Hz), 4.99 (1H, s), 5.05 (1H,

s), 9.62 (1H, d, J = 1.9 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C55.5

(CH₃), 57.5 (CH₃), 58.0 (CH₃), 58.6 (CH₃), 59.3 (CH₃), 71.9 (CH₂),

74.9 (CH), 80.6 (CH), 82.0 (CH), 85.1 (CH), 85.3 (CH), 89.9 (CH),

105.1 (CH), 106.5 (CH), 199.4 (CH); MS (ESI⁺) m/z (rel intens)

373 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for C₁₅H₂₆NaO₉

373.1475, found 373.1478. Anal. Calcd for C₁₅H₂₆O₉: C, 51.42; H,

7.48. Found C, 51.44; H, 7.43. Data for compound 45: [α]_D+81.5 (c

0.390, CHCl₃); IR 2933, 2832, 1747, 1456, 1232, 1113, 1055 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ_H2.08 (3H, s), 3.398 (3H, s), 3.403 (3H,

s), 3.41 (6H, s), 3.46 (3H, s), 3.53 (1H, dd, J = 10.7, 5.4 Hz), 3.59

(1H, dd, J = 11.0, 3.2 Hz), 3.62 (1H, dd, J = 7.3, 3.2 Hz), 4.09 (1H,

ddd, J = 7.3, 5.4, 3.2 Hz), 4.37 (1H, dd, J = 4.7, 2.2 Hz), 5.04 (1H, d, J

= 3.2 Hz), 5.12 (1H, s), 6.16 (1H, d, J = 2.2 Hz); ¹³C NMR (100.6

MHz, CDCl₃) δ_C21.1 (CH₃), 56.1 (CH₃), 57.5 (CH₃), 58.0 (CH₃),

58.5 (CH₃), 59.3 (CH₃), 72.1 (CH₂), 77.7 (CH), 80.6 (CH), 82.9

(CH), 85.4 (CH), 90.0 (CH), 99.9 (CH), 105.8 (CH), 107.8 (CH),

169.7 (C); MS (ESI⁺) m/z (rel intens) 403 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₁₆H₂₈NaO₁₀403.1580, found 403.1576. Anal.

Calcd for C₁₆H₂₈O₁₀: C, 50.52; H, 7.42. Found C, 50.35; H, 7.38.

Method B at 0 °C. The reaction proceeded from alcohol 44 (44 mg,

0.125 mmol) containing DIB (68 mg, 0.212 mmol) and I₂(32 mg,

0.125 mmol) following the general procedure by irradiation for 2 h.

After this time another three portions of DIB (40 mg, 0.125 mmol)

were added every 2 h, and irradiation was continued for 7.5 h in total.

Chromatotron chromatography of the residue (hexanes−EtOAc,

50:50) gave in order of elution aldehyde 46 (1 mg, 0.003 mmol,

2%) and acetate 45 (24.2 mg, 0.06 mmol, 51%).

subjected to puriﬁcation by rapid alumina (Merck 90 active neutral)

column chromatography (hexanes−EtOAc, 6:3 → 0:1) to give 48 (8.7

mg, 0.025 mmol, 22%) and 49 as an inseparable mixture of isomers

(6.3 mg, 0.016 mmol, β/α 9:1, 14%). Data for compound 48: colorless

oil, [α]_D+61 (c 0.39, CHCl₃); IR 2929, 2828, 1456, 1146, 1111, 1046

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H3.36 (3H, s), 3.40 (1H, d, J =

10.1 Hz), 3.42 (3H, s), 3.43 (3H, s), 3.44 (3H, s), 3.45 (1H, d, J = 10.2

Hz), 3.48 (3H, s), 3.71 (1H, dd, J = 5.0, 1.9 Hz), 3.80 (1H, d, J = 1.2

Hz), 3.85 (1H, dd, J = 12.9, 1.9 Hz), 3.92 (1H, d, J = 1.6 Hz), 4.19

(1H, ddd, J = 7.3, 5.4, 1.9 Hz), 4.34 (1H, dd, J = 5.4, 5.4 Hz), 4.36

(1H, dd, J = 13.2, 7.3 Hz), 4.86 (1H, d, J = 2.2 Hz), 5.15 (1H, s); ¹³C

NMR (125.7 MHz, CDCl₃) δ_C55.2 (CH₃), 57.4 (CH₃), 58.78 (CH₃),

58.84 (CH₃), 59.7 (CH₃), 64.2 (CH₂), 74.1 (CH), 75.8 (CH₂), 79.9

(CH), 84.0 (CH), 86.8 (CH), 89.7 (CH), 103.3 (CH), 104.7 (CH),

108.1 (C), MS (ESI⁺) m/z (rel intens) 373 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₁₅H₂₆NaO₉373.1475, found 373.1474. Anal.

Calcd for C₁₅H₂₆O₉: C, 51.42; H, 7.48. Found C, 51.30; H, 7.38. Data

for compound 49 (contaminated with 10% α-epimer): colorless oil, IR

2936, 2832, 1747, 1234, 1115, 1057, 1013 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) (β-isomer) δ_H2.07 (3H, s), 3.38 (3H, s), 3.39 (3H, s), 3.40

(3H, s), 3.41 (6H, s), 3.45 (3H, s), 3.53 (1H, dd, J = 10.7, 5.0 Hz),

3.59 (1H, dd, J = 10.7, 3.2 Hz), 3.62 (1H, dd, J = 7.3, 3.2 Hz), 3.81

(1H, dd, J = 3.2, 1.0 Hz), 3.85 (1H, dd, J = 4.7, 2.8 Hz), 4.09 (1H, ddd,

J = 6.9, 5.0, 3.2 Hz), 4.37 (1H, dd, J = 4.7, 2.2 Hz), 5.03 (1H, d, J = 3.2

Hz), 5.11 (1H, br s), 6.15 (1H, d, J = 2.2 Hz); ¹³C NMR (125.7 MHz,

CDCl₃) (β-isomer) δ_C21.1 (CH₃), 56.1 (CH₃), 57.5 (CH₃), 58.0

(CH₃), 58.5 (CH₃), 59.3 (CH₃), 72.0 (CH₂), 77.7 (CH), 80.6 (CH),

82.9 (CH), 85.3 (CH), 90.0 (CH), 99.9 (CH), 105.8 (CH), 107.8

(CH), 169.7 (C); MS (ESI⁺) m/z (rel intens) 403 (M⁺+ Na, 100);

HRMS (ESI⁺) m/z calcd for C₁₆H₂₈NaO₁₀403.1580, found 403.1575.

Anal. Calcd for C₁₆H₂₈O₁₀: C, 50.52; H, 7.42. Found C, 50.86; H, 7.34.

Oxidative HAT of 50. Method A at Room Temperature. The

reaction proceeded from 5 (42 mg, 0.093 mmol) containing DIB (51

mg, 0.159 mmol) and I₂(24 mg, 0.093 mmol) following the general

procedure by irradiation for 0.75 h. Column chromatography of the

residue (hexanes−EtOAc, 70:30) gave in order of elution methyl

(4R)-2,3,4-tri-O-acetyl-α-^L-rhamnopyranosyl-(1→3)-4-O-acetyl-2-O-

methyl-β-^D-erythro-tetrodialdo-1,4-furanose (52β) (7.5 mg, 0.016

mmol, 17%), methyl (4S)-2,3,4-tri-O-acetyl-α-^L-rhamnopyranosyl-

(1→3)-4-O-acetyl-2-O-methyl-β-^D-erythro-tetrodialdo-1,4-furanose

(52α) (9 mg, 0.019 mmol, 20%), and methyl 5′,5-anhydro-(2′,3′,4′-

tri-O-acetyl-6′-deoxy-α-^L-lyxo-hexos-5′-ulopyranosyl)-(1→3)-2-O-

methyl-β-^D-xylofuranoside (51) (9 mg, 0.020 mmol, 22%) as colorless

oils. Data for compound 52β: [α]_D−42.0 (c 0.560, CHCl₃); IR 2936,

2851, 1747, 1373, 1226, 1054 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H

1.18 (3H, d, J = 6.4 Hz), 1.98 (3H, s), 2.05 (3H, s), 2.15 (3H, s), 2.16

(3H, s), 3.43 (3H, s), 3.44 (3H, s), 3.84 (1H, dddd, J = 9.8, 6.4, 6.4,

6.4 Hz), 3.93 (1H, dd, J = 7.2, 3.4 Hz), 4.15 (1H, dd, J = 7.2, 4.5 Hz),

4.87 (1H, d, J = 3.4 Hz), 4.94 (1H, d, J = 1.6 Hz), 5.06 (1H, dd, J =

10.1, 10.1 Hz), 5.21 (1H, dd, J = 10.3, 3.4 Hz), 5.29 (1H, dd, J = 3.4,

1.9 Hz), 6.24 (1H, d, J = 4.8 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C

17.3 (CH₃), 20.7 (CH₃), 20.8 (CH₃), 20.9 (CH₃), 21.2 (CH₃), 56.0

(CH₃), 58.5 (CH₃), 67.3 (CH), 68.8 (CH), 69.7 (CH), 70.7 (CH),

80.1 (CH), 86.7 (CH), 94.6 (CH), 97.8 (CH), 108.0 (CH), 170.0 (2

× C), 170.1 (C), 170.2 (C); MS (ESI⁺) m/z (rel intens) 501 (M⁺+

Na, 100); HRMS (ESI⁺) m/z calcd for C₂₀H₃₀NaO₁₃501.1584, found

501.1587. Anal. Calcd for C₂₀H₃₀O₁₃: C, 50.21; H, 6.32. Found C,

50.23; H, 6.36. Data for compound 52α: [α]_D−93.6 (c 0.405,

CHCl₃); IR 2936, 2847, 1749, 1371, 1226, 1052 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ_H1.20 (3H, d, J = 6.3 Hz), 1.98 (3H, s), 2.05 (3H, s),

2.10 (3H, s), 2.15 (3H, s), 3.42 (3H, s), 3.47 (3H, s), 3.70 (1H, dd, J =

2.8, 2.8 Hz), 3.93 (1H, dddd, J = 9.8, 6.3, 6.3, 6.3 Hz), 4.12 (1H, dd, J

= 2.8, 2.8 Hz), 4.87 (1H, d, J = 1.6 Hz), 5.071 (1H, dd, J = 9.8, 9.8

Hz), 5.074 (1H, d, J = 2.8 Hz), 5.24 (1H, dd, J = 3.5, 1.9 Hz), 5.27

(1H, dd, J = 9.8, 3.5 Hz), 6.21 (1H, d, J = 2.2 Hz); ¹³C NMR (125.7

MHz, CDCl₃) δ_C17.2 (CH₃), 20.7 (CH₃), 20.8 (CH₃), 20.9 (CH₃),

21.1 (CH₃), 56.3 (CH₃), 58.2 (CH₃), 67.2 (CH), 68.8 (CH), 69.8

(CH), 70.9 (CH), 84.1 (CH), 87.4 (CH), 97.2 (CH), 99.7 (CH),

108.8 (CH), 169.6 (C), 169.8 (C), 170.0 (C), 170.1 (C); MS (ESI⁺)

m/z (rel intens) 501 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

Oxidative HAT of 47. The reaction proceeded from 47 (40 mg,

0.114 mmol) containing DIB (40.4 mg, 0.125 mmol), I₂(14.5 mg,

0.057 mmol), and powdered 3 Å molecular sieves following the

general procedure by irradiation for 7 h at 40 °C. After this time

another portion of DIB (7.5 mg, 0.023 mmol) was added, and

irradiation was continue for a further 8 h. The residue (56 mg) was

7385

dx.doi.org/10.1021/jo301153u | J. Org. Chem. 2012, 77, 7371−7391

The Journal of Organic Chemistry

Article

C₂₀H₃₀NaO₁₃501.1584, found 501.1585. Anal. Calcd for C₂₀H₃₀O₁₃:

C, 50.21; H, 6.32. Found C, 50.44; H, 6.21. Data for compound 51:

[α]_D−18.6 (c 0.333, CHCl₃); IR 2929, 2847, 1751, 1373, 1226, 1057

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ_H1.40 (3H, s), 1.97 (3H, s), 2.10

(3H, s), 2.15 (3H, s), 3.41 (3H, s), 3.42 (3H, s), 3.91 (1H, dd, J = 4.4,

2.2 Hz), 4.02 (1H, dd, J = 13.2, 4.7 Hz), 4.09 (1H, dd, J = 13.3, 7.6

Hz), 4.10 (1H, dd, J = 5.0, 4.4 Hz), 4.45 (1H, ddd, J = 7.6, 5.0, 5.0

Hz), 4.83 (1H, d, J = 2.2 Hz), 4.90 (1H, d, J = 1.3 Hz), 5.34 (1H, d, J

= 10.7 Hz), 5.43 (1H, dd, J = 3.2, 1.3 Hz), 5.71 (1H, dd, J = 10.7, 3.5

Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ_C20.6 (CH₃), 20.79 (CH₃),

20.82 (CH₃), 21.1 (CH₃), 55.0 (CH₃), 58.1 (CH₃), 62.6 (CH₂), 66.0

(CH), 70.1 (CH), 71.2 (CH), 77.3 (CH), 81.6 (CH), 89.3 (CH), 97.9

(CH), 101.4 (C), 107.0 (CH), 169.5 (C), 169.9 (C), 170.4 (C); MS

(ESI⁺) m/z (rel intens) 471 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₁₉H₂₈NaO₁₂471.1478, found 471.1483. Anal. Calcd for

C₁₉H₂₈O₁₂: C, 50.89; H, 6.29. Found C, 50.66; H, 6.22.

Method B at 0 °C. The reaction proceeded from 5 (40 mg, 0.089

mmol) containing DIB (49 mg, 0.151 mmol) and I₂(23 mg, 0.089

mmol) following the general procedure by irradiation at 0 °C for 3 h.

After this time another portion of DIB (49 mg, 0.151 mmol) was

added, and irradiation was continued for an additional 1 h.

Chromatotron chromatography of the residue (hexanes−EtOAc,

75:25) gave in order of elution 52β (4.6 mg, 0.010 mmol, 11%),

52α (5.6 mg, 0.012 mmol, 13%), and 51 (11.3 mg, 0.025 mmol, 28%),

all identical as previously described.

Oxidative HAT of 53. The reaction proceeded from 53 (30 mg,

0.076 mmol) containing DIB (49 mg, 0.193 mmol) and I₂(19.3 mg,

0.076 mmol) following the general procedure by irradiation for 5 h.

Chromatotron chromatography of the residue (hexanes−EtOAc,

30:70) gave methyl 4′,6-anhydro-(2′,3′,5′-tri-O-acetyl-α-^D-threo-pen-

tos-4′-ulofuranosyl)-(1→4)-2,3-di-O-methyl-α-^D-glucopyranoside

(54) (16.6 mg, 0.042 mmol, 55%) as a colorless oil: [α]_D+71.2 (c

0.170, CHCl₃); IR 2936, 2828, 1452, 1106, 1052 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ_H3.14 (1H, dd, J = 9.5, 3.7 Hz), 3.34 (3H, s), 3.41

(3H, s), 3.42 (3H, s), 3.45 (1H, d, J = 10.9 Hz), 3.49 (3H, s), 3.500

(3H, s), 3.503 (1H, m), 3.51 (1H, d, J = 10.9 Hz), 3.59 (3H, s), 3.64

(1H, m), 3.67 (1H, dd, J = 9.5, 9.5 Hz), 3.75 (1H, dd, J = 11.7, 8.2

Hz), 3.79 (1H, dd, J = 5.8, 2.9 Hz), 3.85 (1H, d, J = 2.9 Hz), 3.93 (1H,

dd, J = 11.7, 9.8 Hz), 4.73 (1H, d, J = 3.7 Hz), 5.22 (1H, s); ¹³C NMR

(100.6 MHz, CDCl₃) δ_C54.9 (CH₃), 57.6 (CH₃), 59.0 (CH₃), 59.1

(CH₃), 59.6 (CH₃), 61.2 (CH₃), 65.1 (CH₂), 66.5 (CH), 71.9 (CH),

77.3 (CH), 81.0 (CH), 81.4 (CH), 87.7 (CH), 90.5 (CH), 97.5 (CH),

104.2 (CH), 106.0 (C); MS (70 eV, EI) m/z (rel intens) 394 (M⁺,

<1), 363 (10), 277 (7), 145 (15), 101 (100); HRMS (EI) m/z calcd

for C₁₇H₃₀O₁₀394.1839, found 394.1836. Anal. Calcd for C₁₇H₃₀O₁₀:

C, 51.77; H, 7.67. Found C, 51.62; H, 7.58.

for compound 57: crystalline solid; mp 159.4−160.9 °C (from n-

hexane−EtOAc); [α]_D+80.0 (c 0.100, CHCl₃); IR 2933, 2832, 1751,

1338, 1219, 1054 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ_H2.09 (3H, s),

2.16 (3H, s), 2.17 (3H, s), 3.20 (1H, dd, J = 9.5, 3.8 Hz), 3.28 (1H, dd,

J = 9.5, 9.5 Hz), 3.42 (3H, s), 3.47 (1H, dd, J = 10.4, 10.4 Hz), 3.52

(3H, s), 3.54 (3H, s), 3.58 (1H, dd, J = 9.5, 9.5 Hz), 3.66 (1H, ddd, J =

10.1, 10.1, 5.0 Hz), 4.15 (1H, dd, J = 10.4, 5.1 Hz), 4.71 (1H, d, J = 5.7

Hz), 4.80 (1H, d, J = 3.8 Hz), 4.84 (1H, d, J = 17.3 Hz), 4.88 (1H, d, J

= 17.3 Hz), 5.47 (1H, dd, J = 5.7, 3.8 Hz), 5.50 (1H, dd, J = 3.8 Hz);

¹³C NMR (125.7 MHz, CDCl₃) δ_C20.36 (CH₃), 20.39 (CH₃), 20.5

(CH₃), 55.4 (CH₃), 59.4 (CH₃), 60.7 (CH₃), 61.8 (CH), 66.7 (CH₂),

68.8 (CH₂), 70.2 (CH), 73.9 (CH), 79.5 (CH), 81.2 (CH), 81.8

(CH), 98.1 (CH), 98.5 (CH), 169.5 (C), 169.78 (C), 169.80 (C),

197.5 (C); MS (ESI⁺) m/z (rel intens) 501 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₂₀H₃₀NaO₁₃501.1584, found 501.1583. Anal.

Calcd for C₂₀H₃₀O₁₃: C, 50.21; H, 6.32. Found C, 50.02; H, 6.21.

Oxidative HAT of 58. The reaction proceeded from 58 (108 mg,

0.245 mmol) containing DIB (118 mg, 0.366 mmol) and I₂(74 mg,

0.291 mmol) following the general procedure by irradiation for 3 h.

Column chromatography of the reaction residue (hexanes−EtOAc,

30:70) gave methyl 4′,6-anhydro-(2′,3′,5′,6′-tetra-O-methyl-α-^D-lyxo-

pentos-4′-ulofuranosyl)-(1→4)-2,3-di-O-methyl-α-^D-glucopyranoside

(59) (57.3 mg, 0.131 mmol, 53%) and methyl 2,3,5,6-tetra-O-methyl-

α-^D-mannofuranosyl-(1→4)-2-O-methyl-3,6-O-methylidene-α-D-glu-

copyranoside (60) (13 mg, 0.030 mmol, 12%), both as colorless oils.

Data for compound 59: [α]_D+91.4 (c 0.140, CHCl₃); IR 2933, 1106

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H3.10 (1H, dd, J = 9.4, 3.6 Hz),

3.15−3.56 (5H, m), 3.33 (3H, s), 3.35 (3H, s), 3.42 (6H, s), 3.47 (3H,

s), 3.54 (3H, s), 3.55 (3H, s), 3.69 (1H, dd, J = 12.2, 3.4 Hz), 3.72

(1H, dd, J = 12.0, 1.8 Hz), 3.82 (1H, d, J = 5.3 Hz), 4.04 (1H, d, J =

5.3 Hz), 4.12 (1H, dd, J = 12.4, 10.1 Hz), 4.71 (1H, d, J = 3.7 Hz),

5.19 (1H, s); ¹³C NMR (100.6 MHz, CDCl₃) δ_C55.0 (CH₃), 58.6

(CH₃), 58.9 (2 × CH₃), 59.6 (CH₃), 60.7 (CH₃), 61.1 (CH₃), 65.5

(CH₂), 67.4 (CH), 73.6 (CH₂), 78.9 (CH), 81.0 (CH), 81.5 (CH),

82.4 (CH), 82.8 (CH), 90.5 (CH), 97.5 (CH), 103.7 (CH), 107.7

(C); MS (ESI⁺) m/z (rel intens) 461 (M⁺+ Na, 100); HRMS (ESI⁺)

m/z calcd for C₁₉H₃₄NaO₁₁, 461.1999, found 461.1998. Anal. Calcd

for C₁₉H₃₄O₁₁: C, 52.05; H, 7.82. Found: C, 52.29; H, 7.73. Data for

compound 60: [α]_D+61.4 (c 0.070, CHCl₃); IR 2932, 1044 cm⁻¹; ¹H

NMR (400 MHz, CDCl₃) δ_H3.29 (1H, dd, J = 9.7, 3.6 Hz), 3.36 (1H,

dd, J = 10.3, 2.6 Hz), 3.40−3.63 (3H, m), 3.40 (3H, s), 3.44 (3H, s),

3.49 (6H, s), 3.54 (3H, s), 3.58 (3H, s), 3.79 (1H, dd, J = 4.8, 2.9 Hz),

3.88 (1H, dd, J = 10.7, 1.2 Hz), 3.93 (1H, dd, J = 4.8, 2.1 Hz), 3.96

(1H, dd, J = 10.1, 10.1 Hz), 4.05 (1H, dd, J = 10.7, 1.7 Hz), 4.10−4.15

(2H, m), 4.66 (1H, d, J = 7.4 Hz), 4.81 (1H, d, J = 7.4 Hz), 4.87 (1H,

d, J = 3.4 Hz), 5.46 (1H, d, J = 2.9 Hz); ¹³C NMR (100.6 MHz,

CDCl₃) δ_C55.3 (CH₃), 56.6 (CH₃), 58.5 (CH₃), 58.7 (CH₃), 60.3

(CH₃), 60.9 (CH₃), 64.1 (CH₂), 65.0 (CH₂), 69.3 (CH), 71.7 (CH),

76.6 (2 × CH), 80.3 (CH), 82.1 (CH), 83.5 (CH), 89.5 (CH), 94.8

(CH₂), 97.7 (CH), 105.6 (CH); MS (ESI⁺) m/z (rel intens) 461 (M⁺

+ Na, 100); HRMS (ESI⁺) m/z calcd for C₁₉H₃₄NaO₁₁, 461.1999,

found 461.1999. Anal. Calcd for C₁₉H₃₄O₁₁: C, 52.05; H, 7.82. Found:

C, 52.01; H, 7.84.

Oxidative HAT of 55. The reaction proceeded from 55 (54 mg,

0.112 mmol) containing DIB (62 mg, 0.191 mmol) and I₂(29 mg,

0.112 mmol) following the general procedure by irradiation for 2 h.

After this time another portion of DIB (18 mg, 0.056 mmol) was

added, and irradiation was continued for an additional 1.5 h. Column

chromatography of the reaction residue (hexanes−EtOAc, 50:50) gave

methyl 4′,6-anhydro-(2′,3′,5′-tri-O-acetyl-α-^D-threo-pentos-4′-ulofura-

nosyl)-(1→4)-2,3-di-O-methyl-α-^D-glucopyranoside (56) (5.1 mg,

0.011 mmol, 9%), methyl (1′R)-4,6-O-(2′,3′,5′-tri-O-acetyl-α-^D-threo-

pentos-4′-ulosylidene)-2,3-di-O-methyl-α-^D-glucopyranoside (57)

(10.7 mg, 0.022 mmol, 20%), and methyl 2,3-di-O-methyl-α-^D-

glucopyranoside⁴¹(3 mg, 0.014 mmol, 12%). Data for compound

Oxidative HAT of 41. The reaction proceeded from 41 (50.6 mg,

0.105 mmol) in dry CH₂Cl₂(2.1 mL) containing DIB (68 mg, 0.211

mmol) and I₂(32 mg, 0.126 mmol) following the general procedure

by irradiation for 3 h. Column chromatography of the residue

(hexanes−EtOAc, 6:4) gave the orthoacetate 61 (26 mg, 0.054 mmol,

51%) and methyl 4,6-O-(2,3,4-tri-O-acetyl-α-^D-lyxopyranosylidene)-

2,3-di-O-methyl-α-^D-glucopyranoside (62) (13 mg, 0.027 mmol, β/α

3.6:1, 26%), both as colorless oils. Data for compound 61: unstable for

complete characterization; ¹H NMR (400 MHz, CDCl₃) δ_H1.54 (3H,

s), 2.07 (3H, s), 2.11 (3H, s), 3.16 (1H, dd, J = 9.8, 3.4 Hz), 3.40 (3H,

s), 3.50 (3H, s), 3.56 (3H, s), 3.60 (1H, dd, J = 9.5, 9.5 Hz), 3.67 (1H,

dd, J = 8.7, 2.9 Hz), 3.76 (1H, dd, J = 9.7, 2.8 Hz), 3.82 (1H, dd, J =

8.6, 4.6 Hz), 3.83 (1H, ddd, J = 9.3, 9.3, 4.0 Hz), 4.46 (1H, dd, J = 7.0,

6.0 Hz), 4.75 (1H, d, J = 3.4 Hz), 5.30 (1H, dd, J = 3.0, 3.0 Hz), 5.38

(1H, d, J = 2.9 Hz), 5.80 (1H, d, J = 7.1 Hz), 5.82 (1H, dd, J = 5.8, 3.2

Hz);¹³C NMR (100.6 MHz, CDCl₃) δ_C20.2 (CH₃), 20.7 (CH₃), 20.9

(CH₃), 55.2 (CH₃), 58.9 (CH₃), 60.9 (CH₃), 66.1 (CH₂) 66.2 (CH),

1

56: unstable oil; H NMR (500 MHz, CDCl₃) δ_H2.10 (3H, s), 2.12

(3H, s), 2.16 (3H, s), 3.14 (1H, dd, J = 9.5, 3.5 Hz), 3.40 (3H, s), 3.51

(3H, s), 3.52 (1H, dd, J = 9.1, 9.1 Hz), 3.57−3.62 (2H, m), 3.61 (3H,

s), 3.76 (1H, dd, J = 12.3, 3.8 Hz), 3.95 (1H, dd, J = 12.3, 9.8 Hz),

4.12 (1H, d, J = 11.7 Hz), 4.36 (1H, d, J = 11.7 Hz), 4.75 (1H, d, J =

3.8 Hz), 5.11 (1H, d, J = 1.9 Hz), 5.20 (1H, d, J = 1.9 Hz), 5.22 (1H,

s); ¹³C NMR (100.6 MHz, CDCl₃) δ_C20.68 (CH₃), 20.70 (CH₃),

20.74 (CH₃), 55.3 (CH₃), 59.2 (CH₃), 61.4 (CH₃), 63.2 (CH₂), 65.4

(CH₂), 66.4 (CH), 78.3 (CH), 78.8 (CH), 80.8 (CH), 81.5 (CH),

81.7 (CH), 97.7 (CH), 98.7 (C), 104.9 (CH), 169.7 (C), 170.0 (C),

170.6 (C); MS (ESI⁺) m/z (rel intens) 501 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₂₀H₃₀NaO₁₃501.1584, found 501.1590. Data

7386

dx.doi.org/10.1021/jo301153u | J. Org. Chem. 2012, 77, 7371−7391

The Journal of Organic Chemistry

Article

68.3 (CH), 70.0 (CH), 76.0 (CH), 76.8 (CH), 81.9 (CH), 83.0 (CH),

95.4 (CH), 97.3 (CH), 97.4 (CH), 122.3 (C), 169.6 (C), 169.7 (C).

Data for compound 62 (mixture of isomers): IR 2932, 1757, 1222

618.1793. Anal. Calcd for C₂₇H₃₃NO₁₄: C, 54.45; H, 5.59; N, 2.35.

Found: C, 54.25; H, 5.65; N, 2.17.

Methyl 2,3,5-Tri-O-methyl-α-^D-arabinofuranosyl-(1→4)-2,3-

di-O-methyl-6-O-phthalimido-α-^D-glucopyranoside (70). The

reaction proceeded from alcohol 53 (160 mg, 0.404 mmol) following

the general procedure by stirring at 0 °C for 3 h. The residue obtained

was puriﬁed by column chromatography (hexanes−Et₂O, 30:70) to

give N-phthalimide 70 (196 mg, 0.362 mmol, 90%) as a colorless oil:

[α]_D+108.4 (c 0.694, CHCl₃); IR 2933, 2829, 1791, 1733, 1374, 1107,

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ_H2.01, (3H, s), 2.02 (3H, s),

2.04 (3H, s), 2.09 (3H, s), 2.12 (3H, s), 2.15 (3H, s), 3.15 (1H, dd, J =

9.4, 3.6 Hz), 3.22 (1H, dd, J = 9.6, 4.5 Hz), 3.41 (3H, s), 3.42 (3H, s),

3.45−4.13 (14H, m), 3.51 (6H, s), 3.52 (3H, s), 3.53 (3H, s), 4.76

(1H, d, J = 3.5 Hz), 4.80 (1H, d, J = 3.6 Hz), 5.04 (1H, ddd, J = 10.2,

10.2, 6.0 Hz), 5.14 (2H, d, J = 9.7 Hz), 5.23 (1H, m), 5.33−5.36 (2H,

m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C20.63 (4 × CH₃), 20.7 (CH₃),

20.8 (CH₃), 55.37 (CH₃), 55.45 (CH₃), 59.4 (CH₃), 59.5 (CH₃), 61.0

(CH₃), 61.2 (2 × CH₂), 61.5 (2 × CH₂), 61.6 (CH₃), 66.6 (2 × CH),

69.0 (CH), 69.1 (CH), 69.4 (2 × CH), 70.5 (CH), 70.7 (CH), 74.4

(CH), 74.5 (CH), 79.4 (CH), 79.6 (CH), 81.1 (CH), 81.2 (CH), 98.7

(2 × CH), 108.5 (C), 109.2 (C), 169.3 (2 × C), 169.8 (2 × C), 169.9

(2 × C); MS (ESI⁺) m/z (rel intens) 501 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₂₀H₃₀NaO₁₃, 501.1584, found 501.1590. Anal.

Calcd for C₂₀H₃₀O₁₃: C, 50.21; H, 6.32. Found: C, 50.18; H, 6.37.

Methyl (5′S)-2′,3′,5′-Tri-O-acetyl-α-^D-lyxo-pentos-5′-ulopyr-

anosyl-(1→4)-2,3-di-O-methyl-α-^D-glucopyranoside (63). A sol-

ution of compound 61 (10 mg, 0.021 mmol) in CHCl₃(10 mL) was

treated with a catalytic amount of HCl and stirred at room

temperature for 24 h. The reaction mixture was poured into aqueous

saturated NaHCO₃and extracted with CHCl₃. The organic layer was

evaporated to give compound 63 (10.3 mg, 0.021 mmol, quant) as a

colorless oil: [α]_D+94.9 (c 0.920, CHCl₃); IR 3477, 2931, 1751, 1223

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H2.02 (3H, s), 2.09 (3H, s), 2.13

(3H, s), 2.63 (2H, br s), 3.20 (1H, dd, J = 9.5, 3.4 Hz), 3.42 (3H, s),

3.50 (1H, m), 3.51 (3H, s), 3.55−3.63 (2H, m), 3.58 (3H, s), 3.71

(1H, dd, J = 9.8, 9.8 Hz), 3.83 (1H, d, J = 2.4 Hz), 4.81 (1H, d, J = 3.4

Hz), 5.06 (1H, d, J = 7.7 Hz), 5.14 (1H, dd, J = 9.5, 7.7 Hz), 5.27−

5.32 (3H, m);¹³C NMR (100.6 MHz, CDCl₃) δ_C20.6 (CH₃), 20.76

(CH₃), 20.79 (CH₃), 55.3 (CH₃), 58.9 (CH₃), 61.2 (CH₃), 61.6

(CH₂), 67.8 (CH), 69.3 (CH), 69.9 (CH), 71.0 (CH), 75.7 (CH),

82.4 (CH), 83.1 (CH), 91.9 (CH), 97.5 (CH), 98.6 (CH), 169.7 (2 ×

C), 170.5 (C); MS (ESI⁺) m/z (rel intens) 519 (M⁺+ Na, 100);

HRMS (ESI⁺) m/z calcd for C₂₀H₃₂NaO₁₄, 519.1690, found 519.1689.

Anal. Calcd for C₂₀H₃₂O₁₄: C, 48.39; H, 6.50. Found: C, 48.54; H,

6.83.

1

1039 cm⁻¹; H NMR (400 MHz, CDCl₃) δ_H3.239 (1H, dd, J = 9.5,

3.4 Hz), 3.244 (3H, s), 3.31 (3H, s), 3.408 (3H, s), 3.411 (1H, dd, J =

10.9, 5.6 Hz), 3.45 (1H, dd, J = 10.6, 4.5 Hz), 3.49 (3H, s), 3.50 (3H,

s), 3.51 (1H, dd, J = 5.8, 2.1 Hz), 3.58 (3H, s), 3.59 (1H, dd, J = 9.5,

9.5 Hz), 3.61 (1H, dd, J = 10.3, 8.8 Hz), 3.72 (1H, dd, J = 2.4, 0.8 Hz),

3.98 (1H, m), 4.08 (1H, ddd, J = 5.8, 5.8, 4.5 Hz), 4.38 (1H, dd, J =

11.4, 6.9 Hz), 4.53 (1H, dd, J = 11.4, 1.6 Hz), 4.82 (1H, d, J = 3.2 Hz),

5.36 (1H, s), 7.72 (2H, m), 7.82 (2H, m); ¹³C NMR (100.6 MHz,

CDCl₃) δ_H55.6 (CH₃), 57.5 (CH₃), 57.8 (CH₃), 58.7 (CH₃), 59.1

(CH₃), 60.8 (CH₃), 69.2 (CH), 72.6 (CH₂), 74.9 (CH), 77.9 (CH₂),

81.1 (CH), 82.0 (CH), 82.9 (CH), 85.8 (CH), 89.7 (CH), 97.3 (CH),

106.9 (CH), 123.4 (2 × CH), 129.1 (2 × C), 134.2 (2 × CH), 163.2

(2 × C); MS (ESI⁺) m/z (rel intens) 564 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₂₅H₃₅NNaO₁₂564.2057, found 564.2053. Anal.

Calcd for C₂₅H₃₅NO₁₂: C, 55.45; H, 6.51; N, 2.59. Found C, 55.20; H,

6.48; N, 2.87.

Methyl 2,3,5-Tri-O-acetyl-α-^D-arabinofuranosyl-(1→4)-2,3-

di-O-methyl-6-O-phthalimido-α-^D-glucopyranoside (74). The

reaction proceeded from alcohol 55 (61.6 mg, 0.128 mmol) following

the general procedure by stirring at 0 °C for 1 h. The residue obtained

was puriﬁed by column chromatography (hexanes−EtOAc, 50:50) to

give N-phthalimide 74 (60.7 mg, 0.097 mmol, 76%) as a white

amorphous solid: [α]_D+64.0 (c 0.100, CHCl₃); IR 2929, 2847, 1792,

1

1732, 1369, 1224, 1042 cm⁻¹; H NMR (400 MHz, CDCl₃) δ_H2.05

(3H, s), 2.08 (3H, s), 2.10 (3H, s), 3.25 (1H, dd, J = 9.5, 3.4 Hz), 3.47

(3H, s), 3.51 (3H, s), 3.57 (3H, s), 3.62 (1H, dd, J = 9.5, 8.7 Hz), 3.78

(1H, dd, J = 10.1, 8.7 Hz), 3.93 (1H, ddd, J = 10.1, 5.6, 1.6 Hz), 4.17

(1H, m), 4.31−4.36 (2H, m), 4.40 (1H, dd, J = 11.1, 5.6 Hz), 4.46

(1H, dd, J = 11.1, 1.9 Hz), 4.80 (1H, d, J = 3.4 Hz), 5.00 (1H, ddd, J =

4.8, 1.9, 0.8 Hz), 5.17 (1H, dd, J = 1.9, 0.8 Hz), 5.52 (1H, s), 7.75 (2H,

m), 7.83 (2H, m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C20.6 (3 × CH₃),

55.6 (CH₃), 58.9 (CH₃), 60.8 (CH₃), 63.3 (CH₂), 68.9 (CH), 73.9

(CH), 77.0 (CH), 77.1 (CH₂), 80.96, (CH), 80.99 (CH), 81.7 (CH),

83.0 (CH), 97.4 (CH), 106.6 (CH), 123.4 (2 × CH), 128.9 (2 × C),

134.4 (2 × CH), 163.1 (2 × C), 169.3 (C), 170.1 (C), 170.5 (C); MS

(ESI⁺) m/z (rel intens) 648 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₂₈H₃₅NaNO₁₅648.1904, found 648.1896. Anal. Calcd for

C₂₈H₃₅NO₁₅: C, 53.76; H, 5.64; N, 2.24. Found C, 53.59; H, 5.47;

N, 2.58.

General Procedure for the Synthesis of N-Hydroxyphthali-

mides. DEAD (2.5 equiv) was added dropwise to a stirred 0.09 M

solution of the alcohol (1 equiv) in dry THF containing N-

hydroxyphthalimide (2.5 equiv) and PPh₃(2.5 equiv) under nitrogen

at 0 °C, and the stirring continued at this temperature for the time

speciﬁed. Then the solvent was removed, and the reaction was

quenched with water and extracted with EtOAc. The combined

extracts were dried over Na₂SO₄and evaporated. The residue obtained

was puriﬁed by column chromatography.

Methyl 2,3,4-Tri-O-acetyl-α-^L-rhamnopyranosyl-(1→3)-2-O-

methyl-5-O-phthalimido-β-^D-xylofuranoside (64). The reaction

prceeded from alcohol 50 (260 mg, 0.578 mmol) following the general

procedure by stirring at 0 °C for 1.5 h. The residue obtained was

puriﬁed by column chromatography (hexanes−EtOAc, 70:30) to give

compound 64 (269 mg, 0.452 mmol, 78%) as a white foam: [α]_D

−100.0 (c 0.415, CHCl₃); IR 2940, 2832, 1790, 1744, 1731, 1371,

1226, 1046 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H1.24 (3H, d, J = 6.4

Hz), 1.97 (3H, s), 2.04 (3H, s), 2.15 (3H, s), 3.35 (3H, s), 3.39 (3H,

s), 3.74 (1H, dd, J = 1.6, 1.6 Hz), 3.96 (1H, dddd, J = 9.8, 6.4, 6.4, 6.4

Hz), 4.42 (1H, dd, J = 11.1, 7.2 Hz), 4.45 (1H, d, J = 6.4, 2.1 Hz), 4.54

(1H, dd, J = 11.1, 5.0 Hz), 4.68 (1H, ddd, J = 6.6, 6.6, 5.0 Hz), 4.84

(1H, d, J = 1.3 Hz), 4.92 (1H, d, J = 1.6 Hz), 5.07 (1H, dd, J = 9.8, 9.8

Hz), 5.21 (1H, dd, J = 9.8, 3.4 Hz), 5.24 (1H, dd, J = 3.4, 1.9 Hz), 7.76

(2H, m), 7.85 (2H, m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C17.4

(CH₃), 20.6 (CH₃), 20.8 (CH₃), 20.9 (CH₃), 55.4 (CH₃), 57.7 (CH₃),

67.3 (CH), 68.9 (CH), 69.8 (CH), 70.8 (CH), 76.7 (CH₂), 77.75

(CH), 77.80 (CH), 87.8 (CH), 95.8 (CH), 107.5 (CH), 123.5 (2 ×

CH), 129.0 (2 × C), 134.5 (2 × CH), 163.4 (2 × C), 169.7 (C), 170.0

(C), 170.1 (C); MS (ESI⁺) m/z (rel intens) 618 (M⁺+ Na, 100);

HRMS (ESI⁺) m/z calcd for C₂₇H₃₃NNaO₁₄618.1799, found

Methyl 2,3,5,6-Tetra-O-methyl-α-^D-mannofuranosyl-(1→4)-

2,3-di-O-methyl-6-O-phthalimido-α-^D-glucopyranoside (78).

The reaction proceeded from alcohol 58 (227 mg, 0.516 mmol)

following the general procedure by stirring at 0 °C for 1 h. The residue

obtained was puriﬁed by column chromatography (Et₂O) to give N-

phthalimide 78 (254 mg, 0.434 mmol, 84%) as a white crystalline

solid: mp 117.2−117.9 °C (from n-hexane−EtOAc); [α]_D+127.1 (c

0.070, CHCl₃); IR 1932, 1790, 1738, 1102 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ_H3.16 (1H, dd, J = 9.3, 3.4 Hz), 3.21 (3H, s), 3.33 (3H, s),

3.35 (1H, m), 3.38 (3H, s), 3.41 (3H, s), 3.42 (3H, s), 3.45 (3H, s),

3.47−3.58 (4H, m), 3.51 (3H, s), 3.66 (1H, dd, J = 4.1, 4.1 Hz), 3.83

(1H, dd, J = 3.2, 3.2 Hz), 3.88 (1H, ddd, J = 8.2, 8.2, 0 Hz), 3.97 (1H,

dd, J = 8.7, 3.2 Hz), 4.30 (1H, dd, J = 11.7, 6.9 Hz), 4.39 (1H, d, J =

3.4 Hz), 4.69 (1H, d, J = 3.4 Hz), 5.33 (1H, d, J = 4.0 Hz), 7.67 (2H,

m), 7.75 (2H, m); ¹³C NMR (100.6 MHz, CDCl₃) δ_C55.4 (CH₃),

57.2 (CH₃), 58.5 (CH₃), 58.6 (CH₃), 59.0 (CH₃), 59.9 (CH₃), 60.6

(CH₃), 69.2 (CH), 70.7 (CH₂), 74.9 (CH), 76.9 (CH), 77.1 (CH₂),

77.6 (CH), 79.7 (CH), 81.5 (CH), 82.8 (CH), 87.4 (CH), 97.2 (CH),

106.6 (CH), 123.2 (2 × CH), 128.9 (2 × C), 134.2 (2 × CH), 163.1

(2 × C); MS (ESI⁺) m/z (rel intens) 608 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₂₇H₃₉NNaO₁₃, 608.2319, found 608.2322. Anal.

7387

dx.doi.org/10.1021/jo301153u | J. Org. Chem. 2012, 77, 7371−7391

The Journal of Organic Chemistry

Article

Calcd for C₂₇H₃₉NO₁₃: C, 55.38; H, 6.71; N, 2.39. Found: C, 55.56;

H, 6.43; N, 2.44.

169.90 (C), 170.0 (C); MS (ESI⁺) m/z (rel intens) 444 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₁₈H₂₇²HNaO₁₁444.1592, found

444.1599. Data for compound 68: H NMR (400 MHz, CDCl₃) δ_H

1

General Procedure for the Reductive HAT Reactions with n-

Bu₃SnH or n-Bu₃SnD. A 0.013 M solution of phthalimide (1 equiv)

in dry benzene containing n-Bu₃SnH or n-Bu₃SnD (1 equiv) and

AIBN (0.1 equiv) was heated at reﬂux temperature for 1.5 h. After this

time another portion of n-Bu₃SnH or n-Bu₃SnD (1 equiv) and AIBN

(0.1 equiv) were added, and heating at reﬂux was continued for an

additional 1 h. After being cooled to room temperature, the reaction

mixture was concentrated under reduced pressure. The residue was

dissolved in CH₃CN and washed with n-hexane, and the combined

more polar extracts were concentrated under reduced pressure. The

residue was puriﬁed by chromatography.

1.22 (3H, s), 1.23 (3H, d, J = 6.1 Hz), 1.99 (3H, s), 2.05 (3H, s), 2.15

(3H, s), 3.40 (3H, s), 3.44 (3H, s), 3.78−3.89 (3.25H, m), 4.31 (1H,

ddd, J = 6.9, 6.9, 4.5 Hz), 4.33 (1H, dd, J = 6.9, 3.7 Hz), 4.85 (1H, d, J

= 1.9 Hz), 4.94 (1H, d, J = 1.9 Hz), 5.063 (1H, d, J = 9.5 Hz), 5.065

(1H, dd, J = 9.8, 9.8 Hz), 5.22 (1H, dd, J = 9.8, 3.4 Hz), 5.25 (1H, dd,

J = 3.4, 1.9 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C17.369 (CH₃),

17.502 (CH₃), 20.7 (CH₃), 20.8 (CH₃), 20.9 (CH₃), 55.7 (CH₃), 57.9

(CH₃), 61.666 (CH, t, J_CD= 21.9 Hz), 61.996 (CH₂), 67.3 (CH), 68.8

(CH), 69.8 (CH), 70.814 (CH), 70.870 (CH), 79.1 (CH), 80.447

(CH), 80.511 (CH), 88.6 (CH), 96.4 (CH), 107.6 (CH), 169.8 (C),

169.9 (C), 170.1 (C); MS (ESI⁺) m/z (rel intens) 474 (M⁺+ Na,

100), 473 (28); HRMS (ESI⁺) m/z calcd for C₁₉H₂₉²HNaO₁₂

474.1698, found 474.1705; calcd for C₁₉H₃₀NaO₁₂473.1635, found

Reductive HAT of 64. Method A with n-Bu₃SnH. The reaction

proceeded from phthalimide 64 (70 mg, 0.118 mmol) following the

general procedure. The residue was puriﬁed by column chromatog-

raphy (hexanes−EtOAc, 75:25 → 40:60) to give in order of elution

methyl 2,3,4-tri-O-acetyl-α-^L-rhamnopyranosyl-(1→3)-2-O-methyl-α-

L-threofuranoside (66) (18.4 mg, 0.044 mmol, 49%), the alcohol 50

(10.1 mg, 0.022 mmol, 19%), previously described, and methyl 2,3,4-

tri-O-acetyl-6-deoxy-β-^D-gulopyranosyl-(1→3)-2-O-methyl-β-D-xylo-

furanoside (65) (14 mg, 0.031 mmol, 26%) as colorless oils. Data for

compound 66: [α]_D−88.8 (c 0.125, CHCl₃); IR 2929, 2828, 1747,

1373, 1230, 1055 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H1.21 (3H, d,

J = 6.3 Hz), 1.98 (3H, s), 2.04 (3H, s), 2.15 (3H, s), 3.37 (3H, s), 3.39

(3H, s), 3.74 (1H, dd, J = 2.9, 1.3 Hz), 3.78−3.85 (2H, m), 4.11−4.17

(2H, m), 4.82 (1H, d, J = 1.3 Hz), 4.85 (1H, d, J = 1.3 Hz), 5.06 (1H,

dd, J = 9.8, 9.8 Hz), 5.25 (1H, dd, J = 3.4, 1.9 Hz), 5.26 (1H, dd, J =

9.3, 3.4 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C17.3 (CH₃), 20.67

(CH₃), 20.74 (CH₃), 20.9 (CH₃), 54.8 (CH₃), 57.8 (CH₃), 67.0

(CH), 68.8 (CH), 69.382 (CH₂), 69.9 (CH), 71.0 (CH), 81.353

(CH), 89.6 (CH), 97.4 (CH), 106.9 (CH), 169.88 (C), 169.91 (C),

170.0 (C); MS (ESI⁺) m/z (rel intens) 443 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₁₈H₂₈NaO₁₁443.1529, found 443.1526. Anal.

Calcd for C₁₈H₂₈O₁₁: C, 51.42; H, 6.71. Found C, 51.28; H, 6.63. Data

for compound 65: [α]_D−51.0 (c 0.100, CHCl₃); IR 3498, 2936, 2832,

1745, 1228, 1048 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H1.17 (3H, d,

J = 6.6 Hz), 2.01 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 3.37 (3H, s), 3.43

(3H, s), 3.70 (1H, dd, J = 12.2, 4.5 Hz), 3.78 (1H, dd, J = 3.4, 1.9 Hz),

3.80 (1H, dd, J = 11.7, 5.8 Hz), 4.12 (1H, dddd, J = 6.6, 6.6, 6.6, 1.6

Hz), 4.28 (1H, dd, J = 6.6, 3.4 Hz), 4.31 (1H, ddd, J = 6.4, 6.4, 4.2

Hz), 4.82 (1H, d, J = 1.9 Hz), 4.83 (1H, dd, J = 3.7, 1.9 Hz), 4.84 (1H,

d, J = 8.5 Hz), 5.01 (1H, dd, J = 8.5, 3.4 Hz), 5.33 (1H, dd, J = 3.7, 3.7

Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C15.733 (CH₃), 20.5 (CH₃),

20.69 (CH₃), 20.72 (CH₃), 55.4 (CH₃), 57.8 (CH₃), 61.6 (CH₂), 67.9

(CH), 68.4 (CH), 69.0 (CH), 70.182 (CH), 80.8 (CH), 82.5 (CH),

89.3 (CH), 98.4 (CH), 106.9 (CH), 168.9 (C), 169.4 (C), 169.8 (C);

MS (ESI⁺) m/z (rel intens) 473 (M⁺+ Na, 100); HRMS (ESI⁺) m/z

calcd for C₁₉H₃₀NaO₁₂473.1635, found 473.1643. Anal. Calcd for

C₁₉H₃₀O₁₂: C, 50.66; H, 6.71. Found C, 50.79; H, 6.63.

1

473.1644. Data for compound 67: H NMR (400 MHz, CDCl₃) δ_H

1.16 (3H, s), 2.01 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 3.38 (3H, s),

3.43 (3H, s), 3.70 (1H, dd, J = 11.9, 4.0 Hz), 3.78 (1H, dd, J = 3.4, 2.1

Hz), 3.81 (1H, dd, J = 11.7, 5.8 Hz), 4.28 (1H, dd, J = 6.6, 3.4 Hz),

4.31 (1H, ddd, J = 6.6, 6.6, 4.5 Hz), 4.82 (1H, d, J = 1.9 Hz), 4.83 (1H,

d, J = 4.0 Hz), 4.84 (1H, d, J = 8.5 Hz), 5.01 (1H, dd, J = 8.5, 3.4 Hz),

5.33 (1H, dd, J = 3.7, 3.7 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C

15.634 (CH₃), 20.5 (CH₃), 20.70 (CH₃), 20.73 (CH₃), 55.4 (CH₃),

57.8 (CH₃), 61.6 (CH₂), 67.9 (CH), 68.4 (CH), 70.133 (CH), 80.8

(CH), 82.5 (CH), 89.3 (CH), 98.4 (CH), 106.9 (CH), 168.9 (C),

169.4 (C), 169.8 (C); MS (ESI⁺) m/z (rel intens) 474 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₁₉H₂₉²HNaO₁₂474.1698, found

474.1705.

Reductive HAT of 70. Method A with n-Bu₃SnH. The reaction

proceeded from phthalimide 70 (50 mg, 0.092 mmol) following the

general procedure. The residue was puriﬁed by Chromatotron

chromatography (CHCl₃−MeOH, 99:1) to give methyl 2,3,5-tri-O-

methyl-β-^L-xylofuranosyl-(1→4)-2,3-di-O-methyl-α-D-glucopyranoside

(71) (16.9 mg, 0.043 mmol, 46%) as a colorless oil and the precursor

alcohol 53 (14.8 mg, 0.037 mmol, 41%). Data for compound 71: [α]_D

+145.4 (c 0.240, CHCl₃); IR 3505, 2933, 2832, 1456, 1100, 1050

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ_H3.22 (1H, dd, J = 9.7, 3.8 Hz),

3.40 (6H, s), 3.45 (3H, s), 3.49 (3H, s), 3.55 (1H, ddd, J = 10.1, 3.2,

3.2 Hz), 3.56 (1H, dd, J = 9.5, 9.5 Hz), 3.60 (3H, s), 3.61 (1H, dd, J =

10.1, 6.9 Hz), 3.65 (1H, dd, J = 9.5, 9.5 Hz), 3.66 (1H, dd, J = 10.1, 4.7

Hz), 3.70 (1H, dd, J = 4.7, 2.2 Hz), 3.72 (1H, dd, J = 12.3, 3.8 Hz),

3.77 (1H, dd, J = 1.9, 1.9 Hz), 3.88 (1H, dd, J = 12.3, 2.8 Hz), 4.29

(1H, ddd, J = 6.9, 4.7, 4.7 Hz), 4.81 (1H, d, J = 3.8 Hz), 5.41 (1H, d, J

= 1.3 Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ_C55.1 (CH₃), 57.6

(CH₃), 58.1 (CH₃), 58.8 (CH₃), 59.1 (CH₃), 60.9 (CH₃), 62.3 (CH₂),

70.3 (CH), 70.738 (CH₂), 76.0 (CH), 80.1 (CH), 82.4 (CH), 83.023

(CH), 83.2 (CH), 87.2 (CH), 97.5 (CH), 107.2 (CH); MS (ESI⁺) m/

z (rel intens) 419 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd for

C₁₇H₃₂NaO₁₀419.1893, found 419.1892. Anal. Calcd for C₁₇H₃₂O₁₀:

C, 51.51; H, 8.14. Found C, 51.69; H, 8.23.

Method B with n-Bu₃SnD. The reaction proceeded from

phthalimide 64 (80 mg, 0.134 mmol) following the general procedure.

The residue was puriﬁed by column chromatography (hexanes−

EtOAc, 75:25 → 40:60) to give in order of elution methyl 2,3,4-tri-O-

acetyl-α-^L-rhamnopyranosyl-(1→3)-2-O-methyl-α-L-(4-²H)-

Method B with n-Bu₃SnD. The reaction proceeded from

phthalimide 70 (50 mg, 0.092 mmol) following the general procedure.

The residue was puriﬁed by Chromatotron chromatography (CHCl₃−

MeOH, 99:1) to give methyl 2,3,5-tri-O-methyl-β-^L-(4-²H)-

xylofuranosyl-(1→4)-2,3-di-O-methyl-α-^D-glucopyranoside (72) (13.6

mg, 0.034 mmol, 37%) and methyl 2,3,5-tri-O-methyl-α-^D-[4-²H]-

arabinofuranosyl-(1→4)-2,3-di-O-methyl-α-^D-glucopyranoside (73)

2

threofuranoside (69) (15.7 mg, 0.037 mmol, 28%, H-4a:²H-4b ratio

70:30), methyl 2′,3′,4′-tri-O-acetyl-α-^L-[5′-²H]rhamnopyranosyl-(1→

3)-2-O-methyl-β-^D-xylofuranoside (68) (9.5 mg, 0.021 mmol, 8%,

¹H:²H ratio 1:1), and methyl 2,3,4-tri-O-acetyl-6-deoxy-β-D-(5-²H)-

gulopyranosyl-(1→3)-2-O-methyl-β-^D-xylofuranoside (67) (9 mg, 0.02

1

(12.7 mg, 0.032 mmol, 35%, H:²H ratio 25:75). Data for compound

1

72: H NMR (400 MHz, CDCl₃) δ_H3.22 (1H, dd, J = 9.3, 3.7 Hz),

1

mmol, 15%) as colorless oils. Data for compound 69: H NMR (400

3.40 (6H, s), 3.45 (3H, s), 3.50 (3H, s), 3.55 (1H, ddd, J = 9.8, 3.2, 3.2

Hz), 3.56 (1H, dd, J = 9.3, 9.3 Hz), 3.596 (1H, d, J = 10.3 Hz), 3.602

(3H, s), 3.65 (1H, dd, J = 9.3, 9.3 Hz), 3.66 (1H, d, J = 10.3 Hz), 3.70

(1H, d, J = 2.2 Hz), 3.72 (1H, dd, J = 12.2, 3.4 Hz), 3.77 (1H, dd, J =

2.4, 1.6 Hz), 3.89 (1H, dd, J = 12.4, 2.7 Hz), 4.81 (1H, d, J = 3.7 Hz),

5.42 (1H, d, J = 1.3 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C55.1

(CH₃), 57.6 (CH₃), 58.1 (CH₃), 58.8 (CH₃), 59.1 (CH₃), 60.9 (CH₃),

62.3 (CH₂), 70.3 (CH), 70.667 (CH₂), 76.0 (CH), 82.4 (CH), 82.940

(CH), 83.2 (CH), 87.2 (CH), 97.5 (CH), 107.2 (CH); MS (ESI⁺) m/

z (rel intens) 420 (M⁺+ Na, 100). HRMS (ESI⁺) calcd for

MHz, CDCl₃) δ_H1.21 (3H, d, J = 6.4 Hz), 1.98 (3H, s), 2.04 (3H, s),

2.15 (3H, s), 3.37 (3H, s), 3.39 (3H, s), 3.74 (1H, dd, J = 3.2, 1.3 Hz),

3.77−3.79 (1H, m), 3.81 (1H, dddd, J = 9.8, 6.4, 6.4, 6.4 Hz), 4.11−

4.14 (1H, m), 4.82 (1H, d, J = 1.3 Hz), 4.85 (1H, d, J = 1.1 Hz), 5.05

(1H, dd, J = 9.8, 9.8 Hz), 5.25 (1H, dd, J = 3.4, 1.9 Hz), 5.27 (1H, dd,

J = 9.3, 3.7 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C17.3 (CH₃), 20.66

(CH₃), 20.73 (CH₃), 20.9 (CH₃), 54.8 (CH₃), 57.8 (CH₃), 67.0

(CH), 68.8 (CH), 69.073 (CH, t, J_CD= 23.3 Hz), 69.9 (CH), 71.0

(CH), 81.283 (CH), 89.6 (CH), 97.4 (CH), 106.9 (CH), 169.88 (C),

7388

dx.doi.org/10.1021/jo301153u | J. Org. Chem. 2012, 77, 7371−7391

The Journal of Organic Chemistry

Article

C₁₇H₃₁²HNaO₁₀420.1956, found 420.1956. Data for compound 73:

¹H NMR (only the deuterated compound is described) (400 MHz,

CDCl₃) δ_H3.23 (1H, dd, J = 9.3, 3.4 Hz), 3.39 (3H, s), 3.396 (3H, s),

3.400 (3H, s), 3.44 (3H, s), 3.491 (1H, d, J = 10.3 Hz), 3.494 (3H, s),

3.53 (1H, d, J = 10.3 Hz), 3.55−3.59 (2H, m), 3.58 (1H, dd, J = 9.3,

9.3 Hz), 3.59 (3H, s), 3.66 (1H, dd, J = 9.3, 9.3 Hz), 3.72 (1H, dd, J =

12.7, 2.4 Hz), 3.76 (1H, dd, J = 2.9, 1.1 Hz), 3.84 (1H, dd, J = 12.7, 3.2

Hz), 4.83 (1H, d, J = 3.4 Hz), 5.41 (1H, s); ¹³C NMR (100.6 MHz,

CDCl₃) δ_C55.1 (CH₃), 57.7 (CH₃), 58.0 (CH₃), 58.7 (CH₃), 59.3

(CH₃), 60.9 (CH₃), 61.7 (CH₂), 70.4 (CH), 72.556 (CH₂), 72.626

(CH₂), 74.8 (CH), 81.3 (CH), 82.4 (CH), 83.1 (CH), 85.650 (CH),

85.699 (CH), 89.6 (CH), 97.4 (CH), 107.2 (CH); MS (ESI⁺) m/z

(rel intens) 420 (M⁺+ Na, 100), 419 (17); HRMS (ESI⁺) m/z calcd

for C₁₇H₃₁²HNaO₁₀420.1956, found 420.1961; calcd for

C₁₇H₃₂NaO₁₀419.1893, found 419.1897.

+ Na, 100), 503 (27); HRMS (ESI⁺) m/z calcd for C₂₀H₃₁²HNaO₁₃

504.1803, found 504.1798; calcd for C₂₀H₃₂O₁₃Na 503.1741, found

503.1742.

Reductive HAT of 78. Method A with n-Bu₃SnH. The reaction

proceeded from phthalimide 78 (82 mg, 0.140 mmol) following the

general procedure, except that the addition of the second portion of

reagents was omitted, and the reaction was heated at reﬂux

temperature for 4 h. The residue was puriﬁed by column

chromatography on silica gel 60 PF (0.063−0.2 mm) with 10% KF

(hexanes−EtOAc, 10:90 → 0:100) to give an inseparable mixture of

alcohols (50.3 mg, 0.114 mmol, 82%, 1.4:1). Acetylation of the mixture

of alcohols (50.3 mg, 0.114 mmol) in dry pyridine (3.3 mL)

containing Ac₂O (1.1 mL) at room temperature for 2 h gave after

Chromatotron chromatography (hexanes−EtOAc, 1:1) methyl 2,3,5,6-

tetra-O-methyl-α-^D-mannofuranosyl-(1→4)-6-O-acetyl-2,3-di-O-meth-

yl-α-^D-glucopyranoside (80) (30.3 mg, 0.063 mmol, 55%) and methyl

2,3,5,6-tetra-O-methyl-α-^D-talofuranosyl-(1→4)-6-O-acetyl-2,3-di-O-

methyl-α-^D-glucopyranoside (79) (24.8 mg, 0.051 mmol, 45%), both

as colorless oils. Data for compound 80: [α]_D+148.2 (c 0.110,

CHCl₃); IR 2931, 1743, 1038 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H

2.06 (3H, s), 3.20 (1H, dd, J = 9.3, 3.4 Hz), 3.36−3.61 (4H, m), 3.36

(3H, s), 3.39 (3H, s), 3.44 (3H, s), 3.48 (3H, s), 3.49 (3H, s), 3.53

(3H, s), 3.58 (3H, s), 3.67−3.74 (3H, m), 3.91 (1H, dd, J = 4.5, 3.4

Hz), 4.04 (1H, dd, J = 8.7, 3.4 Hz), 4.17 (1H, dd, J = 11.9, 6.6 Hz),

4.37 (1H, dd, J = 12.0, 2.2 Hz), 4.80 (1H, d, J = 3.4 Hz), 5.36 (1H, d, J

= 3.7 Hz); ¹³C NMR (100.6 MHz, CDCl₃) δ_C20.8 (CH₃), 55.0

(CH₃), 57.5 (CH₃), 58.7 (CH₃), 58.8 (CH₃), 59.1 (CH₃), 60.2 (CH₃),

61.0 (CH₃), 63.5 (CH₂), 68.0 (CH), 71.2 (CH₂), 75.7 (CH), 77.1

(CH), 78.0 (CH), 79.8 (CH), 82.0 (CH), 83.1 (CH), 87.5 (CH), 97.2

(CH), 106.9 (CH), 170.6 (C); MS (ESI⁺) m/z (rel intens) 505 (M⁺+

Na, 100); HRMS (ESI⁺) m/z calcd for C₂₁H₃₈NaO₁₂, 505.2261, found

505.2256. Anal. Calcd for C₂₁H₃₈O₁₂: C, 52.27; H, 7.94. Found: C,

52.32; H, 8.02. Data for compound 79: [α]_D+21.3 (c 0.530, CHCl₃);

IR 2930, 1743, 1056 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ_H2.07 (3H,

s), 3.21 (1H, dd, J = 9.4, 3.6 Hz), 3.37−3.59 (5H, m), 3.35 (3H, s),

3.40 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 3.49 (3H, s), 3.50 (3H, s),

3.61 (3H, s), 3.37−3.74 (2H, m), 3.91 (1H, dd, J = 7.7, 4.5 Hz), 4.02

(1H, dd, J = 7.7, 3.4 Hz), 4.24 (1H, dd, J = 12.0, 6.2 Hz), 4.58 (1H, dd,

J = 11.9, 1.85 Hz), 4.81 (1H, d, J = 3.7 Hz), 5.34 (1H, br s); ¹³C NMR

(100.6 MHz, CDCl₃) δ_C20.9 (CH₃), 55.0 (CH₃), 57.9 (CH₃), 58.0

(CH₃), 58.8 (2 × CH₃), 59.0 (CH₃), 61.1 (CH₃), 63.8 (CH₂), 68.4

(CH), 72.2 (CH₂), 76.5 (CH), 78.5 (CH), 79.0 (CH), 80.6 (CH),

82.1 (2 × CH), 83.2 (CH), 97.1 (CH), 105.7 (CH), 170.7 (C); MS

(ESI⁺) m/z (rel intens) 505 (M⁺+ Na, 100); HRMS (ESI⁺) m/z calcd

for C₂₁H₃₈NaO₁₂, 505.2261, found 505.2263. Anal. Calcd for

C₂₁H₃₈O₁₂: C, 52.27; H, 7.94. Found: C, 52.44; H, 8.14.

Reductive HAT of 74. Method A with n-Bu₃SnH. The reaction

proceeded from phthalimide 74 (31.5 mg, 0.050 mmol) following the

general procedure. The residue was puriﬁed by Chromatotron

chromatography (CHCl₃−MeOH, 100:0.2) to give methyl 2,3,5-tri-

O-acetyl-β-^L-xylofuranosyl-(1→4)-2,3-di-O-methyl-α-D-glucopyrano-

side (75) (9.7 mg, 0.020 mmol, 40%) as a colorless oil and the

precursor alcohol 55 (4.8 mg, 0.010 mmol, 20%). Data for compound

75: [α]_D+95.0 (c 0.360, CHCl₃); IR 3524, 2929, 2840, 1745, 1228,

1

1048 cm⁻¹; H NMR (500 MHz, CDCl₃) δ_H2.09 (3H, s), 2.10 (3H,

s), 2.11 (3H, s), 3.20 (1H, dd, J = 9.5, 3.5 Hz), 3.41 (3H, s), 3.50 (3H,

s), 3.54−3.57 (2H, m), 3.56 (3H, s), 3.63 (1H, dd, J = 9.5, 9.5 Hz),

3.76 (1H, dd, J = 12.3, 2.8 Hz), 3.90 (1H, dd, J = 12.3, 3.5 Hz), 4.25

(1H, dd, J = 11.7, 7.3 Hz), 4.31 (1H, dd, J = 11.7, 4.7 Hz), 4.51 (1H,

ddd, J = 7.3, 4.7, 4.7 Hz), 4.81 (1H, d, J = 3.5 Hz), 5.16 (1H, dd, J =

1.6, 1.6 Hz), 5.26 (1H, dd, J = 4.7, 1.9 Hz), 5.44 (1H, d, J = 0.9 Hz);

¹³C NMR (125.7 MHz, CDCl₃) δ_C20.61 (CH₃), 20.62 (CH₃), 20.7

(CH₃), 55.2 (CH₃), 59.0 (CH₃), 61.1 (CH₃), 61.6 (CH₂), 61.992

(CH₂), 70.2 (CH), 74.328 (CH), 75.7 (CH), 78.3 (CH), 79.6 (CH),

82.3 (CH), 83.1 (CH), 97.6 (CH), 107.4 (CH), 168.9 (C), 169.5 (C),

170.6 (C); MS (ESI⁺) m/z (rel intens) 503 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₂₀H₃₂NaO₁₃503.1741, found 503.1745. Anal.

Calcd for C₂₀H₃₂O₁₃: C, 55.00; H, 6.71. Found C, 49.91; H, 6.57.

Method B with n-Bu₃SnD. The reaction proceeded from

phthalimide 74 (27 mg, 0.043 mmol) following the general procedure.

The residue was puriﬁed by Chromatotron chromatography (CHCl₃−

MeOH, 100:0.2) to give methyl 2,3,5-tri-O-acetyl-β-^L-(4-²H)-

xylofuranosyl-(1→4)-2,3-di-O-methyl-α-^D-glucopyranoside (76) (8.2

mg, 0.017 mmol, 40%) and methyl 2,3,5-tri-O-acetyl-α-^D-[5-²H]-

arabinofuranosyl-(1→4)-6-O-phthalimido-2,3-di-O-methyl-α-^D-gluco-

pyranoside (77) (4.6 mg, 0.010 mmol, 22%, ¹H:²H ratio 30:70). Data

for compound 76: ¹H NMR (500 MHz, CDCl₃) δ_H2.09 (3H, s), 2.10

(3H, s), 2.11 (3H, s), 3.20 (1H, dd, J = 9.5, 3.5 Hz), 3.41 (3H, s), 3.50

(3H, s), 3.54−3.57 (2H, m), 3.56 (3H, s), 3.63 (1H, dd, J = 9.5, 9.5

Hz), 3.77 (1H, dd, J = 12.3, 2.8 Hz), 3.90 (1H, dd, J = 12.3, 3.2 Hz),

4.25 (1H, d, J = 11.7 Hz), 4.31 (1H, d, J = 11.7 Hz), 4.81 (1H, d, J =

3.5 Hz), 5.17 (1H, dd, J = 1.6, 1.6 Hz), 5.26 (1H, d, J = 2.2 Hz), 5.44

(1H, d, J = 1.3 Hz); ¹³C NMR (125.7 MHz, CDCl₃) δ_C20.61 (CH₃),

20.63 (CH₃), 20.7 (CH₃), 55.2 (CH₃), 59.0 (CH₃), 61.1 (CH₃), 61.6

(CH₂), 61.934 (CH₂), 70.2 (CH), 74.263 (CH), 75.7 (CH), 79.6

(CH), 82.3 (CH), 83.1 (CH), 97.6 (CH), 107.4 (CH), 168.9 (C),

169.5 (C), 170.6 (C); MS (ESI⁺) m/z (rel intens) 504 (M⁺+ Na,

100); HRMS (ESI⁺) m/z calcd for C₂₀H₃₁²HNaO₁₃504.1803, found

Method B with n-Bu₃SnD. The reaction proceeded from

phthalimide 78 (30.7 mg, 0.052 mmol) following the general

procedure, except that the addition of the second portion of reagents

was omitted, and the reaction was heated at reﬂux temperature for 4 h.

The residue was puriﬁed by column chromatography on silica gel 60

PF (0.063−0.2 mm) with 10% KF (hexanes−EtOAc, 10:90 → 0:100)

to give an inseparable mixture of methyl 2,3,5,6-tetra-O-methyl-α-^D-

[4-²H]mannofuranosyl-(1→4)-2,3-di-O-methyl-α-D-glucopyranoside

1

(82) (11.2 mg, 0.025 mmol, 49%, H:²H ratio 30:70) and methyl

2,3,5,6-tetra-O-methyl-α-^D-(4-²H)talofuranosyl-(1→4)-2,3-di-O-meth-

1

yl-α-^D-glucopyranoside (81) (6.8 mg, 0.015 mmol, 29%). H NMR

1

504.1803. Data for compound 77: H NMR (500 MHz, CDCl₃) δ_H

(only deuterated compounds are described) (400 MHz, CDCl₃) δ_H

3.23 (1H, dd, J = 7.6, 3.7 Hz), 3.25 (1H, dd, J = 7.7, 3.7 Hz), 3.35 (3H,

s), 3.38 (3H, s), 3.39 (3H, s), 3.40 (3H, s), 3.41 (3H, s), 3.42−3.56

(8H, m), 3.43 (3H, s), 3.48 (6H, s), 3.49 (6H, s), 3.50 (3H, s), 3.53

(3H, s), 3.57 (3H, s), 3.60 (3H, s), 3.61−3.68 (6H, m), 3.72 (1H, dd, J

= 7.7, 4.5 Hz), 3.74 (1H, dd, J = 7.2, 2.6 Hz), 3.84 (1H, dd, J = 12.4,

2.9 Hz), 3.87 (1H, d, J = 4.5 Hz, 3′-H inv), 3.91 (1H, d, J = 4.8 Hz, 3′-

H ret), 3.98 (1H, dd, J = 12.6, 2.5 Hz), 4.82 (2H, d, J = 3.7 Hz), 5.43

(1H, d, J = 4.0 Hz), 5.50 (1H, br s); ¹³C NMR (100.6 MHz, CDCl₃)

δ_C55.0 (CH₃), 55.1 (CH₃), 57.1 (CH₃), 57.7 (CH₃), 58.1 (CH₃), 58.7

(3 × CH₃), 59.0 (CH₃), 59.2 (CH₃), 59.4 (CH₃), 60.2 (CH₃), 60.7 (2

× CH₂), 60.8 (CH₃), 60.9 (CH₃), 69.7 (CH₂), 70.6 (CH), 70.7 (CH),

72.7 (CH₂), 74.5 (CH), 74.6 (CH), 76.9 (CH), 78.1 (CH), 78.2

2.10 (3H, s), 2.105 (3H, s), 2.107 (3H, s), 3.20 (1H, dd, J = 9.1, 3.8

Hz), 3.42 (3H, s), 3.51 (3H, s), 3.57 (3H, s), 3.58−3.67 (3H, m), 3.76

(1H, dd, J = 12.3, 2.2 Hz), 3.79 (1H, dd, J = 12.3, 3.5 Hz), 4.189 (1H,

d, J = 11.7 Hz), 4.192 (1H, dd, J = 11.4, 6.3 Hz), 4.31 (1H, ddd, J =

6.3, 4.7, 4.7 Hz), 4.364 (1H, d, J = 11.7 Hz), 4.368 (1H, dd, J = 11.4,

4.4 Hz), 4.82 (1H, d, J = 3.8 Hz), 5.006 (1H, dd, J = 1.9 Hz), 5.010

(1H, dd, J = 4.4, 1.8 Hz), 5.18 (1H, dd, J = 1.9, 0.9 Hz), 5.49 (1H, s);

¹³C NMR (125.7 MHz, CDCl₃) δ_C20.61 (CH₃), 20.64 (2 × CH₃),

55.2 (CH₃), 59.0 (CH₃), 61.0 (CH₃), 61.7 (CH₂), 63.346 (CH₂),

63.411 (CH₂), 70.0 (CH), 74.2 (CH), 76.974 (CH), 77.0 (CH), 80.7

(CH), 81.1 (CH), 82.2 (CH), 83.2 (CH), 97.6 (CH), 107.0 (CH),

169.3 (C), 169.9 (C), 170.5 (C); MS (ESI⁺) m/z (rel intens) 504 (M⁺

7389

dx.doi.org/10.1021/jo301153u | J. Org. Chem. 2012, 77, 7371−7391

The Journal of Organic Chemistry

Article

(CH), 79.7 (CH), 79.8 (CH), 81.7 (CH), 82.2 (CH), 82.3 (CH), 83.2

(CH), 83.6 (CH), 87.2 (2 × CH), 97.5 (2 × CH), 105.2 (CH), 107.1

(CH); MS (ESI⁺) m/z (rel intens) 464 (M⁺+ Na, 100); HRMS

(ESI⁺) m/z calcd for C₁₉H₃₅²HNaO₁₁, 464.2218, found 464.2211.

(10) (a) Boto, A.; Hernan

́

dez, D.; Hernan

́

dez, R.; Suar

́

ez, E. J. Org.

Chem. 2006, 71, 1938−1948. (b) Martín, A.; Quintanal, L. M.; Suar

E. Tetrahedron Lett. 2007, 48, 5507−5511. (c) Francisco, C. G.; Freire,

R.; Herrera, A. J.; Perez-Martín, I.; Suarez, E. Tetrahedron 2007, 63,

8910−8920.

(11) (a) Francisco, C. G.; Herrera, A. J.; Kennedy, A. R.; Martín, A.;

Melian, D.; Perez-Martín, I.; Quintanal, L. M.; Suar

ez, E. Chem.Eur.

J. 2008, 14, 10369−10381. (b) Martín, A.; Perez-Martín, I.; Quintanal,

L. M.; Suarez, E. J. Org. Chem. 2008, 73, 7710−7720.

́

ez,

́

ASSOCIATED CONTENT

■

́

S

* Supporting Information

́

¹H and ¹³C NMR spectra for all new compounds and molecular

modeling calculations (Figures S1−S3 and Tables S1−S3).

This material is available free of charge via the Internet at

http://pubs.acs.org.

́

(12) For other syntheses of this type of compound, see: (a) La Cruz,

T. E.; Rychnovsky, S. D. Synlett 2004, 2013−2015. (b) Nicolaou, K.

C.; Mitchell, H. J.; Fylaktakidou, K. C.; Suzuki, H.; Rodriguez, R. M.

Angew. Chem., Int. Ed. 2000, 39, 1089−1093. (c) Deslongchamps, P.;

Dory, Y. L.; Li, S. Tetrahedron 2000, 56, 3533−3538. (d) Nicolaou, K.

C.; Fylaktakidou, K. C.; Mitchell, H. J.; Delft, F. L.; Rodriguez, R. M.;

Conley, S. R.; Jin, Z. Chem.Eur. J. 2000, 6, 3166−3185.

(e) Ashworth, P.; Belagali, S. L.; Casson, S.; Marczak, A.; Kocienski,

P. Tetrahedron 1991, 47, 9939−9946.

AUTHOR INFORMATION

Corresponding Author

*E-mail: angelesmartin@ipna.csic.es (A.M.); esuarez@ipna.csic.

es (E.S.).

■

Notes

(13) The stereoelectronic stabilizing anomeric and β-oxygen eﬀects

of cyclic α-oxygenated radicals have been extensively studied in

glycopyranose systems. In ﬂexible ﬁve-membered glycofuranoses, these

stereoelectronic eﬀects tend to be signiﬁcantly less pronounced.

(a) Buckmelter, A. J.; Rychnovsky, S. D. Utilization of α-Oxygenated

Radicals in Synthesis. In Radicals in Organic Synthesis; Renaud, P., Sibi,

M., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 334−

349. (b) Giese, B. Angew. Chem., Int. Ed. Engl. 1989, 28, 969−980.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

This work was supported by the Research Programs

SolSubC200801000192 of the Gobierno de Canarias and

■

́

CTQ2010-18244 of the Ministerio de Ciencia e Innovacion,

coﬁnanced by the Fondo Europeo de Desarrollo Regional

(FEDER). I.P.-M. thanks the Spanish Ministerio de Ciencia e

Innovacion for the Research Program PIE 200930I138. S.G.

́

thanks the Gobierno de Canarias for a postdoctoral contract.

́ ́ ́

(14) (a) Boto, A.; Hernandez, D.; Hernandez, R.; Suarez, E. J. Org.

Chem. 2003, 68, 5310−5319. For an analogous radical decarbox-

ylation of aldofuranuronic acids, see: (b) Dhavale, D. D.; Tagliavini, E.;

Trombini, C.; Umani-Ronchi, A. Tetrahedron Lett. 1988, 29, 6163−

6166.

REFERENCES

(15) (a) Robins, M. J.; Guo, Z.; Samano, M. C.; Wnuk, S. F. J. Am.

■

Chem. Soc. 1999, 121, 1425−1433. (b) Huang, Q.; Herdewijn, P. J.

(1) (a) Pearce, A. J.; Mallet, J.-M.; Sinay, P. Radicals in Carbohydrate

̈

́

Org. Chem. 2011, 76, 3742−3753. (c) Sanchez-Eleuterio, A.; Quintero,

Chemistry. In Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.;

Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 538−577.

(b) Praly, J.-P. Adv. Carbohydr. Chem. Biochem. 2001, 56, 65−151.

L.; Sartillo-Piscil, F. J. Org. Chem. 2011, 76, 5466−5471.

(d) Hernandez-García, L.; Quintero, L.; Sanchez, M.; Sartillo-Piscil,

F. J. Org. Chem. 2007, 72, 8196−8201.

́

́ ́

(c) Perez-Martín, I.; Suarez, E. Radicals and Carbohydrates. In

(16) To our knowledge only a single example of this 2,6,10-

trioxabicyclo[5.2.1]decane system has been previously synthesized

with unspeciﬁed yield; see: Rio, G.; Rio, M.-J. J. Chem. Soc., Chem.

Commun. 1982, 72−74.

Encyclopedia of Radicals in Chemistry, Biology and Materials;

Chatgilialoglu, C., Studer, A., Eds.; John Wiley & Sons Ltd.:

Chichester, U.K., 2012; Vol. 2, pp 1131−1174.

(2) (a) Giese, B.; Dussy, A.; Meggers, E.; Petretta, M.; Schwitter, U. J.

Am. Chem. Soc. 1997, 119, 11130−11131. (b) Strittmatter, H.; Dussy,

A.; Schwitter, U.; Giese, B. Angew. Chem., Int. Ed. 1999, 38, 135−137.

For reviews, see: (c) Gimisis, T.; Chatgilialoglu, C. Oxidatively

Formed Sugar Radicals in Nucleic Acids. In Encyclopedia of Radicals in

Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.;

John Wiley & Sons Ltd.: Chichester, U.K., 2012; Vol. 3, pp 1347−

1370. (d) Chatgilialoglu, C. Reactivity of Nucleic Acid Sugar Radicals.

In Radical and Radical Ion Reactivity in Nucleic Acid Chemistry;

Greenberg, M. M., Ed.; John Wiley & Sons: Hoboken, NJ, 2009; pp

99−133. (e) von Sonntag, C. Free-Radical-Induced DNA Damage and

Its Repair; Springer-Verlag: Berlin, 2006. (f) Pogozelski, W. K.; Tullius,

T. D. Chem. Rev. 1998, 98, 1089−1108.

(3) Kerwin, S. M. DNA Damage Due to Diradical-Generating

Cyclizations. In Radical and Radical Ion Reactivity in Nucleic Acid

Chemistry; Greenberg, M. M., Ed.; John Wiley & Sons: Hoboken, NJ,

2009; pp 389−419.

(4) Xi, Z.; Rong, J.; Chattopadhyaya, J. Tetrahedron 1994, 50, 5255−

5272.

(5) Peukert, S.; Batra, R.; Giese, B. Tetrahedron Lett. 1997, 38, 3507−

3510.

(6) Sakaguchi, N.; Hirano, S.; Matsuda, A.; Shuto, S. Org. Lett. 2006,

8, 3291−3294.

(7) Francisco, C. G.; Herrera, A. J.; Suar

7439−7445.

(8) Francisco, C. G.; Herrera, A. J.; Suar

1012−1017.

(9) Herrera, A. J.; Rondon

(17) MacroModel, version 9.7, and the AMBER* force ﬁeld with the

GB/SA solvent model for CHCl , Schrodinger, LLC, New York, NY,

̈

3

2009. The minimum for each conformational isomer was calculated by

performing a coordinate scan calculation of Φ and Ψ dihedrals from

−180° to +180° in increments of 5°.

(18) For deﬁnitions of these staggered conformations and glycosidic

bond torsion angles (Φ = H1′−C1′−O−C4; Ψ = C1′−O−C4−H4),

́

see: Jimenez-Barbero, J.; Espinosa, J. F.; Asensio, J. L.; Canada, F. J.;

̃

Poveda, A. Adv. Carbohydr. Chem. Biochem. 2000, 56, 235−284.

(19) (a) Feray, L.; Kuznetsov, N.; Renaud, P. Hydrogen Atom

Abstraction. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,

Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 246−278.

(b) Dorigo, A. E.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 2195−

2197. (c) Dorigo, A. E.; Houk, K. N. J. Org. Chem. 1988, 53, 1650−

1664. (d) Dorigo, A. E.; McCarrick, M. A.; Loncharich, R. J.; Houk, K.

N. J. Am. Chem. Soc. 1990, 112, 7508−7514.

(20) (a) Fleet, G. W. J.; Seymour, L. C. Tetrahedron Lett. 1987, 28,

̀

3015−3018. (b) Ahmed, F. M. S.; David, S.; Vatele, J.-M. Carbohydr.

Res. 1986, 155, 19−31. (c) Montgomery, J. A.; Hewson, K.; Laseter, A.

G. Carbohydr. Res. 1973, 27, 303−308.

(21) (a) Vamshikrishna, K.; Srihari, P. Tetrahedron 2012, 68, 1540−

1546. (b) Kaliappan, K. P.; Subrahmanyam, A. V. Org. Lett. 2007, 9,

1121−1124.

́

ez, E. J. Org. Chem. 2002, 67,

(22) (a) Wilcox, C. S.; Otoski, R. M. Tetrahedron Lett. 1986, 27,

1011−1014. (b) De Voss, J. J.; Hangeland, J. J.; Townsend, G. A. J.

Org. Chem. 1994, 59, 2715−2723.

́

ez, E. J. Org. Chem. 2003, 68,

(23) Program Matlab GUI as described in the following: Hendrickx,

́

, M.; Suar

́

ez, E. J. Org. Chem. 2008, 73,

3384−3391.

P. M. S.; Martins, J. C. Chem. Cent. J. 2008, 2, 20. The ³J_H1,H2, ³J_H2,H3

,

7390

dx.doi.org/10.1021/jo301153u | J. Org. Chem. 2012, 77, 7371−7391

The Journal of Organic Chemistry

Article

3

and J_H3,H4constants were obtained by iterative simulation of the

Radicals and Hydrogen Atom Migrations. In Encyclopedia of Radicals in

Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.;

John Wiley & Sons Ltd.: Chichester, U.K., 2012; Vol. 1, pp 125−146.

(39) (a) Mitsunobu, O. Synthesis 1981, 1−28. (b) Grochowski, E.;

Jurczak, J. Synthesis 1976, 682−684.

spectra using DAISY as implemented in TOPSPIN, version 2.1, for

Bruker. For a description of the pseudorotation concept, see:

(a) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94,

8205−8212. (b) Houseknecht, J. B.; Altona, C.; Hadad, C. M.;

Lowary, T. L. J. Org. Chem. 2002, 67, 4647−4651.

(24) Similar conformations have been observed in the solid state of

2′,3′-O-isopropylideneribofuranose derivatives by X-ray crystallo-

́

graphic analysis: Jenkinson, S. F.; Wang, C.; Pino-Gonzalez, M.-S.;

(40) Kaskar, B.; Heise, G. L.; Michalak, R. S.; Vishnuvajjala, B. R.

Synthesis 1990, 1031−1032.

(41) (a) Nicoll-Griffith, D. A.; Weiler, L. Tetrahedron 1991, 47,

2733−2750. (b) Jakab, Z.; Mandi, A.; Borbas, A.; Benyei, A.;

Komaromi, I.; Lazar, L.; Antus, S.; Liptak, A. Carbohydr. Res. 2009,

344, 2444−2453.

Fleet, G. W. J.; Watkin, D. J. Acta Crystallogr. 2009, E65, o263. Best,

D.; Jenkinson, S. F.; Booth, K. V.; Fleet, G. W. J.; Watkin, D. J. Acta

Crystallogr. 2007, E63, o2165−o2167. Viswamitra, M. A.; Gautham, N.

Proc.Indian Acad. Sci., Chem. Sci. 1984, 93, 261−269.

́

(25) Frechou, C.; Dheilly, L.; Beaupere, D.; Uzan, R.; Demailly, G.

Tetrahedron Lett. 1992, 33, 5067−5070.

(26) Kamada, M.; Satoh, T.; Kakuchi, T.; Yokota, K. Tetrahedron:

Asymmetry 1999, 10, 3667−3669.

(27) For conformational preferences of methyl aldopentofuranosides,

see: (a) Taha, H. A.; Castillo, N.; Roy, P.-N.; Lowary, T. L. J. Chem.

Theory Comput. 2009, 5, 430−438. (b) Houseknecht, J. B.; Lowary, T.

L.; Hadad, C. M. J. Phys. Chem. A 2003, 107, 372−378. (c) House-

knecht, J. B.; Lowary, T. L.; Hadad, C. M. J. Phys. Chem. A 2003, 107,

5763−5777. (d) D’Souza, F. W.; Ayers, J. D.; McCarren, P. R.;

Lowary, T. L. J. Am. Chem. Soc. 2000, 122, 1251−1260. (e) Cloran, F.;

Zhu, Y.; Osborn, J.; Carmichael, I.; Serianni, A. S. J. Am. Chem. Soc.

2000, 122, 6435−6448. For X-ray analysis of aldopentofuranosides,

see: (f) Nacario, R. C.; Lowary, T. L.; McDonald, R. Acta Crystallogr.,

Sect. E 2007, E63, o498−o500. (g) Evdokimov, A.; Gilboa, A. J.;

Koetzle, T. F.; Klooster, W. T.; Schultz, A. J.; Mason, S. A.; Albinati,

A.; Frolow, F. Acta Crystallogr., Sect. B 2001, B57, 213−220.

(h) Gordon, M. T.; Lowary, T. L.; Hadad, C. M. J. Am. Chem. Soc.

1999, 121, 9682−9692. (i) Evdokimov, A. G.; Kalb (Gilboa), A. J.;

Koetzle, T. F.; Klooster, W. T.; Martin, J. M. L. J. Phys. Chem. A 1999,

103, 744−753. (j) Podlasek, C. A.; Stripe, W. A.; Carmichael, I.;

Shang, M.; Basu, B.; Serianni, A. S. J. Am. Chem. Soc. 1996, 118, 1413−

1425.

(28) Gurjar, M. K.; Reddy, L. K.; Hotha, S. J. Org. Chem. 2001, 66,

4657−4660.

(29) (a) Su, Y.; Xie, J.; Wang, Y.; Hu, X.; Lin, X. Eur. J. Med. Chem.

2010, 45, 2713−2718. (b) Deng, S.; Yu, B.; Hui, Y.; Yu, H.; Han, X.

Carbohydr. Res. 1999, 317, 53−62.

(30) (a) Wang, J.; Li, J.; Tuttle, D.; Takemoto, J. Y.; Chang, C.-W. T.

Org. Lett. 2002, 4, 3997−4000. (b) van Steijn, A. M. P.; Kamerling, J.

P.; Vliegenthart, J. F. G. Carbohydr. Res. 1991, 211, 261−277.

(31) Velty, R.; Benvegnu, T.; Gelin, M.; Privat, E.; Plusquellec, D.

Carbohydr. Res. 1997, 299, 7−14.

(32) Parhi, A. K.; Mootoo, D. R.; Franck, R. W. Tetrahedron 2008,

64, 9821−9827.

(33) For reviews on disaccharide synthesis using these method-

ologies, see: (a) Schmidt, R. R.; Jung, K.-H. Oligosaccharide Synthesis

with Trichloroacetimidates. In Preparative Carbohydrate Chemistry;

Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 283−312.

(b) Fraser-Reid, B.; Madsen, R. Oligosaccharide Synthesis by n-

Pentenyl Glycosides. In Preparative Carbohydrate Chemistry;

Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 339−356.

(34) Gotfredsen, C. H.; Jacobsen, J. P.; Wengel, J. Bioorg. Med. Chem.

1996, 4, 1217−1225.

(35) Parmentier, G.; Schmitt, G.; Dolle, F.; Luu, B. Tetrahedron

1994, 50, 5361−5368.

(36) Dangerfield, E. M.; Gulab, S. A.; Plunkett, C. H.; Timmer, M. S.

M.; Stocker, B. L. Carbohydr. Res. 2010, 345, 1360−1365.

(37) This is in reasonable agreement with computational and X-ray

crystallographic reported data for monosaccharide methyl α-^D-

arabinofuranoside rings; see refs 21b and 24.

(38) For a review on radical rearrangement of esters under reductive

conditions, see: (a) Crich, D. Radical Rearrangement of Esters. In

Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-VCH:

Weinheim, Germany, 2001; Vol. 2, pp 188−206. (b) Sasaki, K.;

Cumpstey, I.; Crich, D. Radical Rearrangements: Ester-Substituted

7391

dx.doi.org/10.1021/jo301153u | J. Org. Chem. 2012, 77, 7371−7391

Article Doi

Intramolecular 1,8-hydrogen atom transfer reactions in disaccharide systems containing furanose units

DOI: 10.1021/jo301153u

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