Synthesis of branched iminosugars through a hypervalent iodine(III)-mediated radical-polar crossover reaction

Article

pubs.acs.org/joc

Synthesis of Branched Iminosugars through a Hypervalent

Iodine(III)-Mediated Radical-Polar Crossover Reaction

Andres G. Santana, Nieves R. Paz, Cosme G. Francisco, Ernesto Suarez, and Concepcion C. Gonzalez*

́

Instituto de Productos Naturales y Agrobiología del CSIC, Avenida Astrofísico Francisco Sanchez 3, 38206 La Laguna, Tenerife, Spain

S

* Supporting Information

ABSTRACT: The synthesis of a novel type of branched iminosugars is described. This synthetic strategy is based on two key

reactions: ﬁrst, an aldol reaction with formaldehyde in order to introduce selectively the hydroxymethyl branch, and second, a

tandem β-fragmentation-intramolecular cyclization reaction. The combination of both reactions aﬀorded a battery of compounds

exhibiting a great structural complexity, with the concomitant formation of a quaternary center, starting from readily available

aldoses. With this approach we have demonstrated the usefulness of the fragmentation of anomeric alkoxyl radicals (ARF)

promoted by the PhIO/I₂system for the preparation of new compounds with potential interest for both medicinal and synthetic

chemists.

In this context, we have reported a methodology for the

synthesis of several polyhydroxylated nitrogen heterocycles.^12,13

The versatility of this procedure became clear after the synthesis

of several iminosugar skeletons, prepared both in the furanose

and the pyranose form. The relevance of these polyhydroxylated

alkaloids, structurally related to cyclic carbohydrates, stems from

the fact that they can bind speciﬁcally to the active sites of the

glycosidases, by mimicking either the corresponding substrate or

its transition state, thus inhibiting the enzymatic catalysis.¹⁴

Another tandem β-fragmentation−cyclization process that has

also been studied in our laboratory involves the conversion of

aldoses into ketoses.¹⁵This methodology, which represents

an eﬀective alternative to the alkaline isomerization of Lobry de

Bruyn-Alberda van Ekestein,¹⁶uses as starting material readily

available aldoses to which a hydroxymethyl branch has been

introduced at position C−2 by means of an aldol reaction with

formaldehyde.¹⁷

With this consideration in mind, we envisaged a combination

of both strategies in order to prepare novel iminosugars

exhibiting a hydroxymethyl group at the anomeric position.¹⁸

The resulting iminoketoses¹⁹would represent an intermediate

state between iminoaldoses and imino-C-glycosides, and also,

they could be considered as interesting synthons, giving rise

quickly to homoiminosugars by regioselective reduction, among

other modiﬁcations.²⁰

1. INTRODUCTION

Radical-polar crossover reactions,¹also called radical-ionic

cascades, are radical-initiated processes that, however, do not

terminate homolytically, but heterolytically. For these trans-

formations to take place, radical initiators are not needed.

Instead, the reagents employed have the ability to give or accept an

electron. The radical intermediates thus generated become ionic,

either by oxidation or reduction, resulting in the respective cations

or anions that evolve from this point on in a heterolytic manner.

Samarium iodide is the most common reagent for these reactions

to end in an anionic form, by converting the radical intermediate

into a nucleophile.^2,3On the other side, the radical species can be

generated by oxidation of the substrate by transferring one

electron to a metal center, such as Mn^III/Cu^II,⁴Ce^IV,⁵and Fe^III.⁶

Most recently, nonmetallic systems such as hypervalent iodine

reagents, and especially iodoso-derivatives, have also been used,

traditionally, for the radical coupling between phenolic aromatics.⁷

In this regard, our research group has been devoted to the

development of new synthetic strategies based on alkoxyl radicals,

mainly in the carbohydrate ﬁeld. One of our main ﬁndings is the

β-fragmentation of anomeric alkoxyl radicals⁸that relies upon

the formation, in a ﬁrst step, of an anomeric alkoxyl radical by the

action of acetylhypoiodite, generated in situ by the hypervalent

iodine(III) reagent and iodine. This radical then undergoes,

under mild conditions, a β-fragmentation of the C1−C2 bond.

The evolution of this reaction has been shown to depend on the

nature of the protecting group at C−2,⁹and in the case of electron

donating groups, such as ethers, the C−2 radical intermediate is

oxidized (by an excess of reagent) to give an oxonium ion that can

be trapped intra- or intermolecularly by diﬀerent nucleophiles,

thus making the whole process a radical-polar crossover reaction

(Scheme 1).^10,11

A careful search in the literature showed that there are many

references related to the synthesis of iminosugars²¹and imino-

C-glycosides,²²but as far as we know, there are no synthetic

references to this type of ketose.

Received: May 17, 2013

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Scheme 1. Anomeric Alkoxyl Radical Fragmentation (ARF): Mechanism and Applications

Scheme 2. Synthesis of Iminoketoses

Herein, we report the eﬃcient synthesis of several imino-

ketopentoses and iminoketohexoses from carbohydrates, by the

concatenation of the two methodologies presented above

(Scheme 2).

For the synthesis of precursors 16a and 16b, where the internal

nucleophile is located on a secondary position, 2,3:5,6-di-O-

isopropylidene-^D-mannofuranose was used as starting material

(Scheme 4). Initially, an analogous synthetic route as that

described in Scheme 3 was assayed for the preparation of

compounds 16a and 16b; however, the aldol reaction carried

out in the ﬁnal steps of the synthesis with more elaborated

intermediates proved to be very sluggish, and the desired product

was obtained in very low yield. In order to avoid this, we decided

to perform the aldol reaction in a ﬁrst step, as described in the

literature.²⁶Thus, when compound 9 was treated with

formaldehyde in methanol, under our optimized conditions,

the corresponding aldol product was obtained in 88% yield,

which was treated with benzoyl chloride to aﬀord the dibenzoate

10. Deprotection of the 5,6-O-isopropylidene and further

protection of the primary alcohol as TBS ether aﬀorded the

silyl derivative 11 in 95% yield. The substitution of the secondary

alcohol by the azide moiety was accomplished in a two-step

procedure: ﬁrst was the activation of the alcohol as a triﬂate ester,

and then the nucleophilic substitution with sodium azide

aﬀorded the desired ^L-gulo azide 13 in good yield. The deprotec-

tion of both benzoate esters and the selective protection of the

primary alcohol as TBS ether or pivalate ester aﬀorded compounds

15a and 15b in good yields after the two steps. Finally, hydro-

genation of the azide and in situ protection as BOC carbamate led

to compounds 16a and 16b.

2. RESULTS AND DISCUSSION

In order to test the viability of our synthetic approach, a battery of

substrates showing diﬀerent stereochemistry, protecting groups

and substitution pattern was prepared, starting with 5-amino-5-

deoxy-^D-ribo derivatives 4a and 4b, which were synthesized from

the readily available azide 1 (Scheme 3).²³Aldol reaction with

aqueous formaldehyde and methanol in the presence of excess

potassium carbonate aﬀorded the corresponding aldol 2²⁴in

good yield, as an anomeric mixture. It should be noted here that

a careful control of the pH is necessary to obtain the desired

products rapidly and in good yields, since cross-Cannizzaro side

reactions may compete under longer reaction times.²⁵The

selective protection of the new primary alcohol, either with

TBSCl or PivCl, provided the silyl derivative 3a and the pivalate

3b, respectively. Hydrogenation of the azides and in situ

protection of the resulting free amines with di-tert-butyl-

dicarbonate aﬀorded ^D-ribo compounds 4a and 4b in good

yields. Lyxose derivatives 8a and 8b, presenting the opposite

stereochemistry at positions C−2 and C−3, were synthesized

from 5-azido-5-deoxy-^D-lyxose (5)¹²following a similar protocol

(Scheme 3).

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Scheme 3. Synthesis of Substrates for the Pentofuranose Series

Scheme 4. Synthesis of Substrates for the Hexofuranose Series (I)

In order to prepare the precursors 23a, 23b and 29, epoxide

17,¹³also derived from D-mannose, was used as a common

starting material (Scheme 5). On the one hand, treatment of 17

with neat TBAF·2HF²⁷provided ﬂuorohydrin 18 as a colorless

oil in 91% yield; on the other, the deoxygenated compound 24

was obtained, also in very good yield, by the reductive opening of

the epoxide with LiAlH₄. Activation of the resulting secondary

alcohols as triﬂate esters and subsequent displacement with

sodium azide yielded the azides 19 and 25, which were afterward

treated with CAN to remove the anomeric PMB protecting

group. From this point on, the synthetic scheme used was similar

to the ﬁrst one. Aldol reaction, selective protection of the

resulting diols and hydrogenation of the azide with in situ

formation of the carbamate, furnished compounds 23a, 23b and

29 in good yields.

Mitsunobu conditions. Nucleophilic opening with sodium azide

and protection of the resulting secondary alcohol as TBS-ether

using TBSOTf aﬀorded compound 32 in good yield.

Methanolysis of both benzoates and selective protection of the

primary alcohol led to the silylated compound 34a and the

pivalate 34b, which were hydrogenated and selectively protected

to obtain compounds 35a and 35b, respectively, in good yields

(Scheme 6).

With the aim of demonstrating the synthetic usefulness of our

methodology toward the preparation of potential glycosidase

inhibitors and structurally related derivatives, the hemiacetalic

precursors 4, 8, 16, 23, 29 and 35 were submitted to photolysis

upon treatment with iodosylbenzene²⁸and I₂, as oxidizing system,

under the conditions speciﬁed in Table 1.

When the reaction was performed with the silylated ^D-ribo-

derivative 4a, we were pleased to ﬁnd that the expected cyclic

iminoketose 36 was obtained in 61% yield as a single compound

Finally, compounds 35a and 35b, both presenting the internal

nucleophile at the primary, yet more distant C−6 position, were

synthesized in order to widen the scope of this methodology.

The synthesis started from epoxide 30, easily prepared from

dibenzoate 11 by treatment, with Ph₃P and DEAD under

1

(entry 1). The H and ¹³C NMR spectra of this compound

showed at room temperature a mixture of conformers due to

the restricted rotation of the nitrogen−carbon bond of the

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Scheme 5. Synthesis of Substrates for the Hexofuranose Series (II)

Scheme 6. Synthesis of the Substrates for the Hexopyranose Series

carbamate group. However, when these were recorded at 70 °C,

sharp well-resolved spectra were obtained in accordance with the

proposed structure.

compound 38 was obtained in a low yield, despite the reaction

mixture was allowed to react for a longer time (entry 3). The

slowdown in the nucleophilic capture results in an increased

lifetime on the intermediates, which leads to partial decom-

position of the substrate. Similarly to what happened with the

D-ribose analogue 4b, a better result was obtained when pivalate

8b was used as starting material in the photolysis (entry 4).

Compound 16a, which is characterized for having two bulky

tert-butyldimethylsilyl groups, aﬀorded, after 4 h of reaction, the

doubly branched iminoketose 40 in a moderate 46% yield along

with a minor compound identiﬁed as the alcohol 40a (entry 5).

2D experiments showed that the free alcohol in 40a was located

in C−1, thus alleviating the steric congestion of the protected

cyclized product. Once again, when the reaction was carried out

with pivalate 16b, the corresponding iminoketose 41 was

obtained in a slightly higher yield (58%) and in a shorter reaction

time (entry 6). It should be noted here that, in this case, no other

cyclized compound was isolated, highlighting the higher robust-

ness of pivalate in comparison to TBS-ether under these reaction

conditions.

Next, the reaction with pivalate 4b was carried out. The

introduction of an ester group, as in this case, would allow us

to evaluate the inﬂuence of the protecting group of the

hydroxymethyl branch during the cyclization step. In this speciﬁc

case, the corresponding iminoketose 37 was obtained with an

improved yield of 71% and also as a single isomer (entry 2). It is

worth mentioning that these compounds have been formed

after four consecutive reaction steps: formation of the anomeric

alkoxyl radical (A), scission of the C1−C2 bond with

concomitant formation of the formate group (B), oxidation of

the C2−radical to the corresponding tertiary oxycarbenium (C),

and ﬁnally, nucleophilic capture of this cationic intermediate by

the carbamate group (Scheme 7). This result would translate into

an approximate 90% average yield for each individual step.

In order to evaluate the stereoelectronic requirements aﬀecting

this reaction, compound 8a, derived from D-lyxose, was reacted

under the same reaction conditions. The corresponding cyclized

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The fragmentation reaction on the ﬂuorinated compound 23a

led to the formation of the iminoketohexose 42, albeit in low

yield. In this case a diﬀerent iminosugar 42a, proceeding from

a double fragmentation pathway, was identiﬁed as the major

product, producing a combined yield for the cyclization reaction

of 72%. Once iminoketose 42 is formed, the deprotection of the

silyl group can take place in the reaction medium, generating

a primary alcohol which, under these oxidizing conditions,

a

Table 1. Conversion of C−2 Branched Aminoaldoses into Iminoketoses

E

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Table 1. continued

a

Reaction conditions: All reactions were performed in dry DCM or DCE (40 mL/mmol) under irradiation with two 80 W tungsten-ﬁlament lamps

b

c

at room temperature, containing PhIO (2−2.5 equiv) and I₂(0.5−1.2 equiv). Isolated yield after chromatography. NaHCO₃100% w/w was added.

d

The reaction was carried out at 80 °C.

Scheme 7. Mechanism of the Tandem ARF-Cyclization Reaction

Scheme 8. Plausible Mechanism for the Synthesis of Compound 42a

undergoes a second fragmentation to generate an acyliminium

cation that is ﬁnally trapped by water (Scheme 8).²⁹A thorough

study of the NMR spectra of this compound indicated that its

open form is prevalent in solution instead of the aminal form.

According to the previous examples where the pivalate

derivatives aﬀorded the corresponding cyclized products in better

yields, a similar trend for compound 23b was expected. However,

we were disappointed to ﬁnd a very complex reaction mixture,

where the cyclized compound 43 was isolated as a major compound

but in a lower yield (39%), along with another trace compound

identiﬁed as the free amine (43a, 8%). These unexpected results

give an idea of the inﬂuence that a single ﬂuorine atom can exert on

the reactivity and stability of neighboring functional groups.

The photolysis of the 6-deoxyfuranose 29 furnished the

iminoketose 44 in a moderate yield after 2 h of reaction. This

time, no other side products derived from partial deprotection

were detected. Surprisingly, compound 44 was obtained in a

lower yield than compound 41, despite the fact that the

carbamate group in the 6-deoxy substrate is less hindered than on

the other, where the bulky TBS-ether group ﬂanks the carbamate.

These results show that the reaction outcome is not inﬂuenced

by the steric encumbrance of the nucleophile as much as by the

electronic eﬀects induced by vicinal groups.

Next, compounds 35a and 35b were synthesized in order to

exploit this procedure toward preparing iminoketohexoses in the

pyranose form. However, the desired iminoketohexose was not

obtained as a product of the photolysis of the hemiacetal 35a;

instead, the major product identiﬁed in the reaction mixture was

compound 45, which comes from the deprotection of the silyl

group and further fragmentation, following a mechanism similar to

that explained in Scheme 8. It should be noted that this reaction,

despite presenting the nucleophilic carbamate in a primary position,

needs about 20 h to be completed. Such long reaction times cause

the decomposition of the intermediate in the reaction media.

Similarly to what happened to compound 42a, NMR spectra of 45

also showed that this structure preferred to adopt the open

carbonyl form rather than the hemiaminal form. Interestingly, the

photolysis of compound 35b aﬀorded the expected iminoketose 46

in 46% yield. The successful formation of this homologated

iminosugar broadens the scope of this methodology toward the

synthesis of novel iminoketoses, also in the pyranose form, and

gives an idea of the versatility of this combined process.

F

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3. CONCLUSION

Article

The residue was puriﬁed by column chromatography (hexanes−EtOAc,

70:30 → 1:1) to yield compound 2 (830 mg, 3.39 mmol, 85%) as a

colorless oil: IR 3610, 2996, 2103, 1373, 1244 cm⁻¹. NMR showed

In summary, we have presented here the ﬁrst approach to the

synthesis of polyhydroxylated iminoketoses by using tandem

β-fragmentation−intramolecular cyclization, promoted by the

readily available and nontoxic iodosylbenzene, as a key step.

These compounds present a well-deﬁned quaternary center, and

in general, they are obtained under mild conditions, with short

reaction times and moderate to good overall yields. Moreover,

simple modiﬁcations on these polyfunctionalized scaﬀolds may

lead to more elaborated synthetic derivatives, also possessing

interesting pharmacological features. Biological evaluation assays

against a set of commercial glycosidases are currently under study

and will be reported in due course.

1

a mixture of anomers in a 2:1 ratio. Major isomer: H NMR δ_H1.37

(3H, s), 1.44 (3H, s), 3.29 (1H, dd, J = 6.0, 12.6 Hz), 3.53 (1H, dd, J =

8.1, 12.6 Hz), 3.79 (1H, d, J = 12.0 Hz), 3.86 (1H, d, J = 12.0 Hz), 4.24

(1H, ddd, J = 1.2, 6.0, 8.1 Hz), 4.45 (1H, d, J = 1.2 Hz), 5.42 (1H, s); ¹³C

NMR δ_C27.4 (CH₃), 27.8 (CH₃), 52.1 (CH₂), 63.1 (CH₂), 80.5 (CH),

84.9 (CH), 93.3 (C), 104.6 (CH), 113.8 (C). Minor isomer: ¹H NMR

δ_H1.42 (3H, s), 1.54 (3H, s), 3.40 (1H, dd, J = 5.0, 13.0 Hz), 3.46 (1H,

dd, J = 4.8, 13.0 Hz), 3.77 (2H, s), 4.26 (1H, ddd, J = 2.1, 4.8, 5.0 Hz),

4.45 (1H, d, J = 2.1 Hz), 5.18 (1H, s); ¹³C NMR δ_C26.9 (CH₃), 27.0

(CH₃), 53.3 (CH₂), 62.9 (CH₂), 83.3 (CH), 84.5 (CH), 91.2 (C), 97.8

(CH), 115.3 (C); MS (EI-TOF) m/z (rel intensity) 230 [(M − CH₃)⁺,

20], 131 (19), 96 (46), 91 (25), 59 (100); HRMS (EI-TOF) m/z

[M − CH₃]⁺Calcd for C₈H₁₂N₃O₅230.0777, found 230.0777. Anal.

Calcd for C₉H₁₅N₃O₅: C, 44.08; H, 6.17; N, 17.13. Found: C, 44.32; H,

6.19; N, 17.06.

5-Azido-2-C-(tert-butyldimethyl)silyloxymethyl-5-deoxy-2,3-O-

isopropylidene-^D-ribofuranose (3a). To a solution of diol 2 (565 mg,

2.30 mmol) in dry DMF (5.8 mL, 2.5 mL/mmol) at 0 °C and under

nitrogen were added imidazole (313 mg, 4.60 mmol) and then TBSCl

(380 mg, 2.50 mmol), and the mixture was stirred for 4 h. It was poured

into an ice/water mixture and extracted several times with diethyl ether.

The organic phase was dried over sodium sulfate and concentrated

under a vacuum. The resulting crude was puriﬁed by column chromato-

graphy (hexanes−EtOAc, 95:5 → 85:15) to obtain compound 3a

(600 mg, 1.67 mmol, 73%) as a colorless oil: IR 3600, 3500, 2931, 2103,

1256 cm⁻¹. NMR showed a mixture of anomers in a 5:1 ratio. Major

4. EXPERIMENTAL SECTION

General Methods. Optical rotations were measured with a

polarimeter at the sodium line at ambient temperature in CHCl₃

solutions. IR spectra were recorded CCl₄unless otherwise stated, with

an FTIR instrument. NMR spectra were recorded with a 400 MHz

1

spectrometer for H, 100.6 MHz for ¹³C, and 376.5 MHz for ¹⁹F in

CDCl₃unless otherwise stated, in the presence of TMS as internal

standard. Structures were elucidated by COSY, DEPT, HSQC and

NOESY experiments. Mass spectra were recorded with a spectrometer

by using EI-TOF (70 eV) or by using electrospray ionization (ESI⁺-

TOF), as speciﬁed in each case. Elemental analyses were performed with

an analyzer using a CHN method. Merck silica gel 60 PF (0.063−0.2

mm) was used for column chromatography. Circular layers of 1 mm of

Merck silica gel 60 PF₂₅₄were used on a Chromatotron for centrifugally

assisted chromatography. Commercially available reagents and solvents

were analytical grade or were puriﬁed by standard procedures prior to

use. All reactions involving air- or moisture-sensitive materials were

carried out under a nitrogen atmosphere. The spray reagents for TLC

analysis were conducted with 0.5% vanillin in H₂SO₄−EtOH (1:4) and

further heating until development of color.

5-Azido-5-deoxy-2,3-O-isopropylidene-^D-ribofuranose (1). So-

dium methoxide (254 mg, 4.70 mmol) was added to a solution of the

5-azido-1-O-benzoyl-5-deoxy-2,3-O-isopropylidene-β-^D-ribofuranose²³

(1.50 g, 4.70 mmol) in dry methanol (50 mL, 10 mL/mmol) under

nitrogen and in an ice/water bath. The reaction was stirred until

reaching room temperature (1h), and then the solvent was removed

under reduced pressure. The resulting extract was dissolved in EtOAc

and washed with brine; the organic phase was dried over anhydrous

sodium sulfate and evaporated under a vacuum. The residue was puriﬁed

by column chromatography (hexanes−EtOAc, 80:20) to yield 1 (986 mg,

4.59 mmol, 97%) as a colorless oil: IR 3611, 3462, 2991, 2103, 1271 cm⁻¹.

NMR showed a mixture of anomers in a 2:1 ratio. Major isomer: ¹H NMR

δ_H1.30 (3H, s), 1.46 (3H, s), 3.37 (1H, dd, J = 5.8, 12.7 Hz), 3.55 (1H, dd,

J = 7.3, 12.7 Hz), 4.30 (1H, ddd, J = 1.1, 5.8, 7.3 Hz), 4.61 (1H, d, J = 5.9

Hz), 4.63 (1H, dd, J = 1.1, 5.9 Hz), 5.45 (1H, s); ¹³C NMR δ_C24.8 (CH₃),

26.4 (CH₃), 53.9 (CH₂), 82.1 (CH), 85.4 (CH), 86.0 (CH), 103.3 (CH),

112.7 (C). Minor isomer: ¹H NMR δ_H1.37 (3H, s), 1.55 (3H, s), 3.39

(1H, dd, J = 3.7, 12.7 Hz), 3.51 (1H, dd, J = 4.0, 12.7 Hz), 4.23 (1H, ddd,

J = 2.6, 3.7, 4.0 Hz), 4.63 (1H, dd, J = 2.6, 6.7 Hz), 4.66 (1H, dd, J = 4.0, 6.7

Hz), 5.40 (1H, d, J = 4.0 Hz); ¹³C NMR δ_C24.7 (CH₃), 26.1 (CH₃), 53.0

(CH₂), 79.5 (CH), 79.6 (CH), 81.6 (CH), 96.9 (CH), 114.6 (C); MS

(EI-TOF) m/z (rel intensity) 200 [(M − CH₃)⁺, 21], 159 (27), 101 (9),

59 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for C₇H₁₀N₃O₄

200.0671, found 200.0664. Anal. Calcd for C₈H₁₃N₃O₄: C, 44.65; H, 6.09;

N, 19.53. Found: C, 44.91; H, 6.35; N, 19.22.

1

isomer: H NMR (500 MHz) δ_H0.077 (3H, s), 0.080 (3H, s), 0.89

(9H, s), 1.42 (3H, s), 1.54 (3H, s), 3.34 (1H, dd, J = 6.0, 12.9 Hz), 3.38

(1H, dd, J = 6.0, 12.9 Hz), 3.71 (1H, d, J = 10.6 Hz), 3.74 (1H, d, J = 10.6

Hz), 4.20 (1H, ddd, J = 1.9, 6.0, 6.0 Hz), 4.52 (1H, d, J = 1.9 Hz), 5.12

(1H, s); ¹³C NMR (125.7 MHz) δ_C−5.7 (CH₃), −5.6 (CH₃), 18.3 (C),

25.8 (3 × CH₃), 27.1 (CH₃), 27.3 (CH₃.), 51.6 (CH₂), 63.1 (CH₂), 80.4

(CH), 83.6 (CH), 90.7 (C), 97.7 (CH), 114.7 (C). Minor isomer:

¹H NMR (500 MHz) δ_H0.09 (3H, s), 0.10 (3H, s), 0.90 (9H, s), 1.38

(3H, s), 1.45 (3H, s), 3.30 (1H, dd, J = 6.8, 12.8 Hz), 3.53 (1H, dd, J =

6.8, 12.8 Hz), 3.80 (1H, d, J = 10.8 Hz), 3.93 (1H, d, J = 10.8 Hz), 4.21

(1H, ddd, J = 1.5, 6.8, 6.8 Hz), 4.48 (1H, d, J = 1.5 Hz), 5.35 (1H, s);

¹³C NMR (125.7 MHz) δ_C−5.7 (CH₃), −5.6 (CH₃), 18.2 (C), 25.7

(3 × CH₃), 27.7 (CH₃), 27.8 (CH₃), 53.2 (CH₂), 63.5 (CH₂), 84.2

(CH), 84.5 (CH), 93.0 (C), 105.4 (CH), 113.9 (C); MS (EI-TOF) m/z

(rel intensity) 344 [(M − CH₃)⁺, 5], 302 (1), 171 (7), 159 (15),

75 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for C₁₄H₂₆N₃O₅Si

344.1642, found 344.1634. Anal. Calcd for C₁₅H₂₉N₃O₅Si: C, 50.12; H,

8.13; N, 11.69. Found: C, 50.34; H, 8.17; N, 11.62.

5-(tert-Butoxycarbonyl)amino-2-C-(tert-butyldimethyl)-

silyloxymethyl-5-deoxy-2,3-O-isopropylidene-^D-ribofuranose (4a).

To a solution of azide 3a (170 mg, 0.47 mmol) in EtOAc (7.0 mL, 15

mL/mmol) were added di-tert-butyl dicarbonate (155 mg, 0.71 mmol)

and 10% Pd/C (17 mg, 10% w/w). Three vacuum/hydrogen cycles were

performed, and the mixture was stirred under hydrogen atmosphere for

1 h. The reaction mixture was then ﬁltered over a Celite pad and washed

twice with ethyl acetate, and the combinated ﬁltrates were evaporated.

The crude was puriﬁed by column chromatography (hexanes−EtOAc,

85:15 → 70:30) to yield compound 4a (195 mg, 0.45 mmol, 96%) as a

colorless oil: IR 3458, 3373, 2932, 1719, 1504, 1252, 1170, 1103 cm⁻¹.

NMR showed a mixture of anomers in a 5:3 ratio. Major isomer:

¹H NMR (500 MHz, DMSO-d₆) δ_H0.037 (3H, s), 0.041 (3H, s), 0.87

(9H, s), 1.32 (3H, s), 1.37 (9H, s), 1.43 (3H, s), 2.93−3.05 (1H, m),

3.12−3.21 (1H, m), 3.56 (1H, d, J = 11.0 Hz), 3.67 (1H, d, J = 11.0 Hz),

3.89 (1H, ddd, J = 0.9, 5.4, 9.1 Hz), 4.39 (1H, d, J = 0.9 Hz), 5.11 (1H, d,

J = 4.1 Hz), 6.64 (1H, d, J = 4.1 Hz), 6.83 (1H, dd, J = 6.0, 6.0 Hz); ¹³C

NMR (125.7 MHz, DMSO-d₆) δ_C−5.7 (CH₃), −5.6 (CH₃), 18.0 (C),

25.8 (3x CH₃), 26.9 (CH₃), 27.5 (CH₃), 28.1 (3x CH₃), 43.2 (CH₂),

62.5 (CH₂), 81.9 (C), 83.8 (CH), 84.0 (CH), 94.3 (C), 103.2 (CH),

112.3 (C), 155.5 (C). Minor isomer: ¹H NMR (500 MHz, DMSO-d₆)

δ_H0.06 (6H, s), 0.86 (9H, s), 1.28 (3H, s), 1.31 (9H, s), 1.39 (3H, s),

2.93−3.05 (1H, m), 3.12−3.21 (1H, m), 3.71 (1H, d, J = 11.7 Hz),

5-Azido-5-deoxy-2-C-hydroxymethyl-2,3-O-isopropylidene-^D-ri-

bofuranose (2). Potassium carbonate (860 mg, 100% w/w) was added

to a 35% aqueous solution of formaldehyde (8.0 mL, 2 mL/mmol), and

the mixture was stirred until a clear solution was observed. A solution of

compound 1 (860 mg, 4.0 mmol) in dry methanol (18 mL, 4.5 mL/

mmol) was then added dropwise while heating at 80 °C. After 2 h, the

solvent was removed under a vacuum, and the residue was extracted

twice with EtOAc and washed with brine. The organic phase was

dried over anhydrous sodium sulfate and concentrated under a vacuum.

G

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3.74 (1H, d, J = 11.7 Hz), 3.93 (1H, ddd, J = 2.4, 6.8, 6.8 Hz), 4.28 (1H, d,

J = 2.4 Hz), 4.92 (1H, d, J = 7.3 Hz), 5.83 (1H, d, J = 7.0 Hz), 6.88 (1H,

dd, J = 5.8, 5.8 Hz); ¹³C NMR (125.7 MHz, DMSO-d₆) δ_C−5.6 (CH₃),

−5.4 (CH₃), 17.9 (C), 25.7 (3 × CH₃), 27.3 (CH₃), 27.7 (CH₃), 28.0

(3 × CH₃), 41.5 (CH₂), 63.7 (CH₂), 77.8 (C), 79.5 (CH), 82.7 (CH),

90.9 (C), 96.6 (CH), 113.7 (C), 155.6 (C); MS (EI-TOF) m/z (rel

intensity) 418 [(M − CH₃)⁺, 1], 376 (1), 304 (78), 57 (100); HRMS

(EI-TOF) m/z [M − CH₃]⁺Calcd for C₁₉H₃₆NO₇Si 418.2261, found

418.2246. Anal. Calcd for C₂₀H₃₉NO₇Si: C, 55.40; H, 9.07; N, 3.23.

Found: C, 55.40; H, 9.06; N, 3.22.

5-Azido-5-deoxy-2,3-O-isopropylidene-2-C-pivaloyloxymethyl-^D-

ribofuranose (3b). To a solution of compound 2 (146 mg, 0.60 mmol)

in dry pyridine (3 mL, 5 mL/mmol) were added, under nitrogen and at

0 °C, DMAP (14 mg, 0.11 mmol, 10% w/w) and pivaloyl chloride (88 μL,

0.72 mmol), and then the mixture was allowed to warm up to room

temperature and stirred for 24 h. The reaction was poured into 10%

aqueous HCl and extracted twice with EtOAc. The organic phase was

washed with sodium bicarbonate and brine, dried over sodium sulfate

and concentrated under a vacuum. The crude was puriﬁed by column

chromatography (hexanes−EtOAc, 90:10 → 80:20) to yield compound

3b (150 mg, 0.46 mmol, 76%) as a white solid: IR 3609, 3449, 2974, 2937,

2103, 1734, 1381, 1280 cm⁻¹. NMR showed a mixture of anomers in a 2:1

ratio. Major isomer: ¹H NMR δ_H1.21 (9H, s), 1.46 (3H, s), 1.56 (3H, s),

3.43 (1H, dd, J = 4.5, 13.0 Hz), 3.48 (1H, dd, J = 4.5, 13.0 Hz), 3.85 (1H, d,

J = 8.0 Hz), 4.20 (1H, d, J = 12.0 Hz), 4.26 (1H, ddd, J = 2.4, 4.5, 4.5 Hz),

4.32 (1H, d, J = 12.0 Hz), 4.48 (1H, d, J = 2.4 Hz), 5.19 (1H, d, J = 8.0 Hz);

¹³C NMR δ_C27.0 (3 × CH₃), 27.2 (CH₃), 27.3 (CH₃), 38.8 (C), 52.4

(CH₂), 64.0 (CH₂), 80.5 (CH), 83.6 (CH), 89.7 (C), 98.2 (CH), 115.7

(C), 177.9 (C). Minor isomer: ¹H NMR δ_H1.20 (9H, s), 1.42 (3H, s),

1.46 (3H, s), 3.33 (1H, dd, J = 5.8, 12.7 Hz), 3.57 (1H, dd, J = 7.6, 12.7

Hz), 4.00 (1H, bs), 4.25 (1H, d, J = 12.2 Hz), 4.26 (1H, ddd, J = 1.3, 5.8,

7.6 Hz), 4.41 (1H, d, J = 1.3 Hz), 4.44 (1H, d, J = 12.2 Hz), 5.41 (1H, bs);

¹³C NMR δ_C27.1 (3 × CH₃), 27.6 (CH₃), 28.0 (CH₃), 38.8 (C), 53.7

(CH₂), 63.7 (CH₂), 84.5 (CH), 85.1 (CH), 92.8 (C), 104.0 (CH), 114.1

(C), 178.3 (C); MS (EI-TOF) m/z (rel intensity) 314 [(M − CH₃)⁺, 8],

215 (6), 96 (47), 57 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for

C₁₃H₂₀N₃O₆314.1352, found 314.1352. Anal. Calcd for C₁₄H₂₃N₃O₆: C,

51.06; H, 7.04; N, 12.76. Found: C, 51.35; H, 7.13; N, 12.63.

under a vacuum. The residue was puriﬁed by column chromatography

(hexanes−EtOAc, 90:10 → 70:30) to yield 5 (467 mg, 2.17 mmol, 93%)

as a colorless oil: IR 3611, 2992, 2949, 2101, 1373, 1270 cm⁻¹. NMR

showed a mixture of anomers in a 5:1 ratio. Major isomer: ¹H NMR δ_H

1.32 (3H, s), 1.46 (3H, s), 2.71 (1H, bs), 3.52 (1H, dd, J = 4.8, 12.2 Hz),

3.57 (1H, dd, J = 6.6, 12.2 Hz), 4.30 (1H, ddd, J = 3.7, 4.8, 6.6 Hz), 4.63

(1H, d, J = 5.8 Hz), 4.75 (1H, dd, J = 3.7, 5.8 Hz), 5.41 (1H, s); ¹³C

NMR δ_C24.7 (CH₃), 25.9 (CH₃), 49.9 (CH₂), 78.8 (CH), 79.7 (CH),

1

85.5 (CH), 101.2 (CH), 112.9 (C). Minor isomer: H NMR δ_H1.38

(3H, s), 1.54 (3H, s), 2.71 (1H, bs), 3.55−3.62 (2H, m), 3.68 (1H, ddd,

J = 3.7, 6.5, 6.5 Hz), 4.55 (1H, dd, J = 3.7, 6.1 Hz), 4.69 (1H, dd, J = 3.4,

6.1 Hz), 5.04 (1H, d, J = 3.7 Hz); ¹³C NMR δ_C24.9 (CH₃), 25.7 (CH₃),

49.4 (CH₂), 74.4 (CH), 78.7 (CH), 79.3 (CH), 97.0 (CH), 113.6 (C);

MS (EI-TOF) m/z (rel intensity) 200 [(M − CH₃)⁺, 71], 159 (17),

135 (17), 59 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for

C₇H₁₀N₃O₄200.0671, found 200.0671. Anal. Calcd for C₈H₁₃N₃O₄:

C, 44.65; H, 6.09; N, 19.53. Found: C, 44.35; H, 5.94; N, 19.28.

5-Azido-5-deoxy-2-C-hydroxymethyl-2,3-O-isopropylidene-^D-lyxo-

furanose (6). Potassium carbonate (573 mg, 100% w/w) was added to

a 35% aqueous solution of formaldehyde (5.0 mL, 2 mL/mmol), and the

mixture was stirred until a clear solution was observed. A solution of

compound 5 (573 mg, 2.66 mmol) in dry methanol (13 mL, 5 mL/mmol)

was then added dropwise while heating at 80 °C. After 2 h, the solvent

was removed under a vacuum, and the residue was extracted twice with

EtOAc and washed with brine. The organic phase was dried over

anhydrous sodium sulfate and concentrated under a vacuum. The residue

was puriﬁed by column chromatography (hexanes−EtOAc, 70:30 → 1:1)

to yield compound 6 (470 mg, 1.92 mmol, 72%) as a colorless oil: IR

3565, 3421, 2990, 2103, 1271 cm⁻¹. NMR showed a mixture of anomers

in a 2:1 ratio. Major isomer: ¹H NMR (500 MHz) δ_H1.41 (3H, s), 1.47

(3H, s), 3.24 (1H, bs), 3.54 (1H, dd, J = 5.2, 12.7 Hz), 3.59 (1H, dd, J =

7.6, 12.7 Hz), 3.84 (1H, d, J = 11.9 Hz), 3.99 (1H, d, J = 11.9 Hz), 4.32

(1H, ddd, J = 3.1, 5.2, 7.6 Hz), 4.61 (1H, d, J = 3.1 Hz), 5.41 (1H, s); ¹³C

NMR (125.7 MHz) δ_C27.4 (CH₃), 27.5 (CH₃), 49.8 (CH₂), 63.4 (CH₂),

79.5 (CH), 82.9 (CH), 94.0 (C), 103.7 (CH), 114.2 (C). Minor isomer:

¹H NMR (500 MHz) δ_H1.47 (3H, s), 1.57 (3H, s), 3.52−3.61 (2H, m),

3.73 (1H, ddd, J = 3.3, 6.3, 6.7 Hz), 3.77 (1H, d, J = 11.5 Hz), 3.81 (1H, d,

J = 11.5 Hz), 4.59 (1H, d, J = 3.3 Hz), 4.92 (1H, d, J = 6.7 Hz); ¹³C NMR

(125.7 MHz) δ_C26.9 (CH₃), 27.1 (CH₃), 49.4 (CH₂), 62.7 (CH₂), 74.5

(CH), 81.9 (CH), 89.7 (C), 97.5 (CH), 114.4 (C); MS (EI-TOF) m/z

(rel intensity) 230 [(M − CH₃)⁺, 61], 110 (32), 96 (100), 71 (45), 59

(100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for C₈H₁₂N₃O₅

230.0777, found 230.0777. Anal. Calcd for C₉H₁₅N₃O₅: C, 44.08; H,

6.17; N, 17.13. Found: C, 44.30; H, 6.34; N, 16.87.

5-(tert-Butoxycarbonyl)amino-5-deoxy-2,3-O-isopropylidene-2-

C-pivaloyloxymethyl-^D-ribofuranose (4b). To a solution of azide 3b

(240 mg, 0.73 mmol) in EtOAc (11.0 mL, 15 mL/mmol) were added di-

tert-butyl dicarbonate (238 mg, 1.1 mmol) and 10% Pd/C (24 mg, 10%

w/w). Three vacuum/hydrogen cycles were performed, and the mixture

was stirred under hydrogen atmosphere for 2 h. The reaction mixture

was then ﬁltered over a Celite pad and washed twice with ethyl acetate,

and the combined ﬁltrates were evaporated. The crude was puriﬁed

by column chromatography (hexanes−EtOAc, 90:10 → 70:30) to yield

compound 4b (282 mg, 0.70 mmol, 96%) as a colorless oil: IR 3459,

3373, 2980, 2937, 1731, 1718, 1510, 1247, 1158 cm⁻¹. NMR showed a

5-Azido-2-C-(tert-butyldimethyl)silyloxymethyl-5-deoxy-2,3-O-

isopropylidene-^D-lyxofuranose (7a). To a solution of diol 6 (500 mg,

2.04 mmol) in dry DMF (5.0 mL, 2.5 mL/mmol) at 0 °C and under

nitrogen, were added imidazole (280 mg, 4.08 mmol), DMAP (25 mg,

0.2 mmol), and TBSCl (355 mg, 2.35 mmol), and the mixture was

stirred for 2 h at room temperature and then poured into an ice/water

mixture and extracted several times with diethyl ether. The organic

phase was dried over sodium sulfate and concentrated under a vacuum.

The resulting crude was puriﬁed by column chromatography (hexanes−

EtOAc, 95:5 → 85:15) to obtain compound 7a (530 mg, 1.48 mmol,

72%) as a colorless oil: IR 3608, 3524, 2989, 2104, 1256 cm⁻¹. NMR

showed a mixture of anomers in a 4:1 ratio. Major isomer: ¹H NMR δ_H

0.08 (3H, s), 0.09 (3H, s), 0.90 (9H, s), 1.43 (3H, s), 1.54 (3H, s), 3.53

(1H, dd, J = 6.6, 12.5 Hz), 3.58 (1H, dd, J = 6.6, 12.5 Hz), 3.67 (1H, ddd,

J = 2.9, 6.6, 6.6 Hz), 3.74 (2H, s), 4.58 (1H, d, J = 2.9 Hz), 4.80 (1H, bs),

5.01 (1H, bs); ¹³C NMR δ_C−5.3 (CH₃), −5.2 (CH₃), 18.5 (C), 26.1

(3 × CH₃), 27.2 (CH₃), 27.3 (CH₃), 49.8 (CH₂), 63.5 (CH₂), 75.0

(CH), 83.0 (CH), 89.2 (C), 97.6 (CH), 114.3 (C). Minor isomer: ¹H

NMR δ_H0.13 (6H, s), 0.91 (9H, s), 1.38 (3H, s), 1.47 (3H, s), 3.52−

3.57 (1H, m), 3.60 (1H, dd, J = 6.4, 12.7 Hz), 3.83 (1H, d, J = 10.6 Hz),

4.08 (1H, d, J = 10.6 Hz), 4.21 (1H, ddd, J = 2.9, 6.4, 6.4 Hz), 4.56 (1H,

d, J = 2.9 Hz), 4.80 (1H, bs), 5.29 (1H, bs); ¹³C NMR δ_C−5.3 (CH₃),

−5.2 (CH₃), 18.5 (C), 26.1 (3 × CH₃), 27.8 (2 × CH₃), 50.0 (CH₂),

64.4 (CH₂), 79.2 (CH), 83.6 (CH), 93.5 (C), 104.9 (CH), 114.6 (C);

MS (EI-TOF) m/z (rel intensity) 344 [(M − CH₃)⁺, 4], 226 (2),

183 (15), 75 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for

1

mixture of anomers in a 2:1 ratio (only major one is described): H

NMR (500 MHz, DMSO-d₆) δ_H1.15 (9H, s), 1.35 (3H, s), 1.36 (9H, s),

1.37 (3H, s), 3.02 (1H, ddd, J = 5.4, 5.4, 13.8 Hz), 3.14 (1H, ddd, J = 6.9,

9.6, 13.8 Hz), 3.76 (1H, bs), 3.92 (1H, dd, J = 5.3, 9.6 Hz), 4.14 (1H, d,

J = 12.2 Hz), 4.22 (1H, d, J = 12.2 Hz), 4.47 (1H, s), 5.19 (1H, d, J = 3.8

Hz), 6.84−6.89 (1H, m); ¹³C NMR (125.7 MHz, DMSO-d₆) δ_C26.8

(3 × CH₃), 27.6 (CH₃), 27.7 (CH₃), 28.1 (3 × CH₃), 38.2 (C), 43.1

(CH₂), 63.9 (CH₂), 77.9 (C), 84.1 (CH), 84.2 (CH), 92.4 (C), 102.8

(CH), 112.6 (C), 155.6 (C), 177.3 (C); MS (EI-TOF) m/z (rel

intensity) 388 [(M − CH₃)⁺, 1], 312 (7), 245 (10), 199 (24), 57 (100);

HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for C₁₈H₃₀NO₈388.1971,

found 388.1965. Anal. Calcd for C₁₉H₃₃NO₈: C, 56.56; H, 8.24; N, 3.47.

Found: C, 56.41; H, 8.41; N, 3.36.

5-Azido-5-deoxy-2,3-O-isopropylidene-^D-lyxofuranose (5). Sodium

methoxide (157 mg, 2.91 mmol) was added to a solution of 5-azido-1-O-

benzoyl-5-deoxy-2,3-O-isopropylidene-α-^D-lyxofuranose¹²(740 mg,

2.32 mmol) in dry methanol (25 mL, 10 mL/mmol) under nitrogen

and in an ice/water bath. The reaction was stirred at room temperature

for 1.5 h. Then, the solvent was removed under reduced pressure. The

resulting extract was dissolved in EtOAc and washed with brine; the

organic phase was dried over anhydrous sodium sulfate and removed

H

dx.doi.org/10.1021/jo401041s | J. Org. Chem. XXXX, XXX, XXX−XXX

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C₁₄H₂₆N₃O₅Si, 344.1642, found 344.1641. Anal. Calcd for

C₁₅H₂₉N₃O₅Si: C, 50.12; H, 8.13; N, 11.69. Found: C, 50.13; H, 7.95;

N, 11.65.

compound 8b (230 mg, 0.57 mmol, 66%) as a colorless oil: IR 3596,

2986, 1737, 1705, 1408, 1240 cm⁻¹. NMR showed a mixture of anomers

1

in a 6:1 ratio (only major anomer described): H NMR (500 MHz,

5-(tert-Butoxycarbonyl)amino-2-C-(tert-butyldimethyl)-

silyloxymethyl-5-deoxy-2,3-O-isopropylidene-^D-lyxofuranose (8a).

To a solution of azide 7a (210 mg, 0.59 mmol) in EtOAc (9.0 mL,

15 mL/mmol) were added di-tert-butyl dicarbonate (167 mg, 0.77 mmol)

and 10% Pd/C (21 mg, 10% w/w). Three vacuum/hydrogen cycles were

performed, and the mixture was stirred under hydrogen atmosphere

for 3 h. The reaction mixture was then ﬁltered over a Celite pad, washed

twice with ethyl acetate, and the combinated ﬁltrates were evaporated.

The crude was puriﬁed by column chromatography (hexanes−EtOAc,

80:20 → 70:30) to yield compound 8a (230 mg, 0.53 mmol, 90%) as an

oil: IR 3459, 2954, 2931, 2858, 1718, 1370 cm⁻¹. NMR showed a mixture

of anomers in a 2:1 ratio. Major isomer: ¹H NMR (500 MHz, DMSO-d₆)

δ_H0.057 (3H, s), 0.061 (3H, s), 0.88 (9H, s), 1.34 (3H, s), 1.370 (9H, s),

1.42 (3H, s), 3.13−3.24 (2H, m), 3.69 (1H, d, J = 11.5 Hz), 3.76 (1H, d,

J = 11.5 Hz), 4.04−4.07 (1H, m), 4.45 (1H, d, J = 3.1 Hz), 5.03 (1H, d, J =

4.4 Hz), 5.73 (1H, d, J = 4.4 Hz), 6.83 (1H, bs); ¹³C NMR δ_C−5.7 (CH₃),

−5.6 (CH₃), 18.1 (C), 25.8 (3× CH₃), 26.8(CH₃), 27.0 (CH₃), 28.3 (3×

CH₃), 39.7 (CH₂), 63.1 (CH₂), 74.8 (CH), 79.3 (C), 82.9 (CH), 89.1

DMSO-d₆) δ_H1.15 (9H, s), 1.36 (12H, s), 1.40 (3H, s), 3.11−3.23 (2H,

m), 4.08 (1H, ddd, J = 3.3, 5.9, 8.0 Hz), 4.12 (1H, d, J = 12.2 Hz), 4.29

(1H, d, J = 12.2 Hz), 4.46 (1H, d, J = 3.3 Hz), 5.09 (1H, d, J = 4.0 Hz),

6.50 (1H, d, J = 4.0 Hz), 6.85 (1H, dd, J = 5.2, 5.2 Hz); ¹³C NMR (125.7

MHz, DMSO-d₆) δ_C26.8 (3 × CH₃), 27.5 (CH₃), 27.6 (CH₃), 28.2 (3 ×

CH₃), 38.2 (CH₂), 38.7 (C), 63.1 (CH₂), 77.7 (CH), 80.6 (C), 82.1

(CH), 93.1 (C), 101.4 (CH), 112.8 (C), 155.5 (C), 177.2 (C); MS

(EI-TOF) m/z (rel intensity) 403 (M⁺, 1), 372 (1), 286 (4), 231 (3), 85

(15), 57 (100); HRMS (EI-TOF) m/z [M]⁺Calcd for C₁₉H₃₃NO₈

403.2206, found 403.2190. Anal. Calcd for C₁₉H₃₃NO₈: C, 56.56; H,

8.24; N, 3.47. Found: C, 56.66; H, 8.35; N, 3.50.

2-C-Hydroxymethyl-2,3:5,6-di-O-isopropylidene-^D-mannofura-

nose (9a).²⁶Potassium carbonate (750 mg) was added to a 35%

aqueous solution of formaldehyde (7.5 mL, 1.5 mL/mmol), and the

mixture was stirred until a clear solution was observed. A solution of

compound 9 (1.30 g, 5.00 mmol) in dry methanol (10 mL, 2 mL/mmol)

was then added dropwise while heating at 80 °C. After 20 h, the solvent

was removed under a vacuum, and the residue was extracted twice

with EtOAc and washed with brine. The organic phase was dried over

anhydrous sodium sulfate and concentrated under a vacuum. The

residue was puriﬁed by column chromatography (hexanes−EtOAc,

70:30 → 1:1) to yield compound 9a (1.27 g, 4.39 mmol, 88%) as an oil:

IR 3615, 3419, 2989, 2937, 1456, 1371 cm⁻¹. NMR showed a mixture

of anomers in a 2:1 ratio. Major isomer: ¹H NMR δ_H1.38 (3H, s), 1.42

(3H, s), 1.45 (3H, s), 1.47 (3H, s), 2.60 (1H, bs), 3.16 (1H, bs), 3.86

(1H, d, J = 11.9 Hz), 3.99 (1H, d, J = 11.9 Hz), 4.04 (1H, dd, J = 4.7, 8.7

Hz), 4.10 (1H, dd, J = 6.1, 8.7 Hz), 4.16 (1H, dd, J = 3.0, 7.7 Hz), 4.40

(1H, ddd, J = 4.7, 6.1, 7.7 Hz), 4.67 (1H, d, J = 3.0 Hz), 5.38 (1H, s); ¹³C

NMR δ_C25.1 (CH₃), 26.9 (CH₃), 27.3 (2 × CH₃), 63.6 (CH₂), 66.6

(CH₂), 73.1 (CH), 81.1 (CH), 82.8 (CH), 93.7 (C), 103.8 (CH), 109.2

(C), 113.8 (C). Minor isomer: ¹H NMR δ_H1.37 (3H, s), 1.44 (3H, s),

1.49 (3H, s), 1.56 (3H, s), 1.87 (1H, bs), 3.51 (1H, dd, J = 2.9, 8.2 Hz),

3.77 (1H, d, J = 11.7 Hz), 3.81 (1H, d, J = 11.7 Hz), 3.87 (1H, d, J = 11.0

Hz), 4.05 (1H, dd, J = 4.3, 8.8 Hz), 4.11 (1H, dd, J = 6.1, 8.9 Hz), 4.38

(1H, ddd, J = 4.3, 6.1, 8.3 Hz), 4.65 (1H, d, J = 2.8 Hz), 4.89 (1H, d, J =

11.0 Hz); ¹³C NMR δ_C25.2 (CH₃), 26.8 (CH₃), 26.97 (CH₃), 27.02

(CH₃), 62.8 (CH₂), 67.1 (CH₂), 72.9 (CH), 76.4 (CH), 81.9 (CH),

89.5 (C), 97.6 (CH), 109.4 (C), 114.1 (C); MS (EI-TOF) m/z (rel

intensity) 275 [(M − CH₃)⁺, 35], 217 (14), 199 (22), 101 (100);

HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for C₁₂H₁₉O₇275.1131,

found 275.1134. Anal. Calcd for C₁₃H₂₂O₇: C, 53.78; H, 7.64. Found: C,

53.78; H, 7.68.

1

(C), 97.0 (CH), 113.7 (C), 155.9 (C). Minor isomer: H NMR (500

MHz, DMSO-d₆) δ_H0.04 (6H, s), 0.86 (9H, s), 1.33 (3H, s), 1.36 (9H, s),

1.40 (3H, s), 3.13−3.20 (2H, m), 3.51−3.54 (1H, m), 3.66 (2H, s), 4.39

(1H, d, J = 3.1 Hz), 4.75 (1H, d, J = 9.6 Hz), 5.25 (1H, bs), 5.73 (1H, d, J =

9.6 Hz); ¹³C NMR δ_C−5.7 (CH₃), −5.6 (CH₃), 18.1 (C), 25.7 (3 ×

CH₃), 27.0 (CH₃), 27.4 (CH₃), 28.3 (3 × CH₃), 39.8 (CH₂), 63.9 (CH₂),

79.0 (CH), 79.3 (C), 83.6 (CH), 93.2 (C), 104.4 (CH), 114.0 (C), 155.9

(C); MS (EI-TOF) m/z (rel intensity) 418 [(M − CH₃)⁺, 1], 360 (1),

302 (25), 276 (23), 199 (31), 75 (60), 57 (100); HRMS (EI-TOF) m/z

[M − CH₃]⁺Calcd for C₁₉H₃₆NO₇Si 418.2261, found 418.2252. Anal.

Calcd for C₂₀H₃₉NO₇Si: C, 55.40; H, 9.07; N, 3.23. Found: C, 55.25; H,

9.00; N, 3.27.

5-Azido-5-deoxy-2,3-O-isopropylidene-2-C-pivaloyloxymethyl-^D-

lyxofuranose (7b). To a solution of compound 6 (294 mg, 1.20 mmol)

in dry pyridine (6 mL, 5 mL/mmol) were added, under nitrogen and

at 0 °C, DMAP (30 mg, 10% w/w) and pivaloyl chloride (0.2 mL, 1.68

mmol), and then the mixture was warmed at 40 °C and stirred for 24 h.

The reaction was poured into 10% aqueous HCl and extracted twice

with EtOAc. The organic phase was washed with sodium bicarbonate

and brine, dried over sodium sulfate and concentrated under a vacuum.

The crude was puriﬁed by column chromatography (hexanes−EtOAc,

90:10 → 80:20) to yield compound 7b (290 mg, 0.88 mmol, 73%) as a

white solid: IR 3446, 2981, 2104, 1736, 1647 cm⁻¹. NMR showed

1

a mixture of anomers in a 3:2 ratio. Major isomer: H NMR δ_H1.22

(9H, s), 1.43 (3H, s), 1.46 (3H, s), 3.22 (1H, bs), 3.52 (1H, dd, J = 5.4,

12.7 Hz), 3.60 (1H, dd, J = 4.2, 12.7 Hz), 4.28 (1H, ddd, J = 3.1, 4.2, 5.4

Hz), 4.29 (1H, d, J = 12.2 Hz), 4.46 (1H, d, J = 12.2 Hz), 4.50 (1H, d, J =

3.1 Hz), 5.35 (1H, s); ¹³C NMR δ_C27.1 (3 × CH₃), 27.5 (CH₃), 27.8

(CH₃), 38.8 (C), 49.6 (CH₂), 63.3 (CH₂), 78.8 (CH), 82.7 (CH), 93.4

(C), 102.6 (CH), 114.5 (C), 178.3 (C). Minor isomer: ¹H NMR δ_H1.21

(9H, s), 1.46 (3H, s), 1.55 (3H, s), 3.54 (1H, dd, J = 6.4, 12.3 Hz), 3.58

(1H, dd, J = 5.9, 12.3 Hz), 3.68 (1H, ddd, J = 3.0, 5.9, 6.4 Hz), 3.88 (1H,

d, J = 12.0 Hz), 4.20 (1H, d, J = 11.7 Hz), 4.26 (1H, d, J = 11.7 Hz), 4.52

(1H, d, J = 3.0 Hz), 4.93 (1H, d, J = 12.0 Hz); ¹³C NMR δ_C26.78 (CH₃),

26.84 (CH₃), 27.1 (3 × CH₃), 38.9 (C), 49.2 (CH₂), 63.6 (CH₂), 74.4

(CH), 82.3 (CH), 87.5 (C), 97.7 (CH), 114.7 (C), 177.7 (C); MS

(EI-TOF) m/z (rel intensity) 314 [(M − CH₃)⁺, 9], 215 (2), 139 (2), 96

(75), 57 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for

C₁₃H₂₀N₃O₆314.1352, found 314.1354. Anal. Calcd for C₁₄H₂₃N₃O₆:

C, 51.06; H, 7.04; N, 12.76. Found: C, 51.19; H, 7.37; N, 13.07.

5-(tert-Butoxycarbonyl)amino-5-deoxy-2,3-O-isopropylidene-2-

C-pivaloyloxymethyl-^D-lyxofuranose (8b). To a solution of azide 7b

(284 mg, 0.86 mmol) in EtOAc (12.0 mL, 15 mL/mmol) were added di-

tert-butyl dicarbonate (375 mg, 1.72 mmol) and 10% Pd/C (50 mg, 20%

w/w). Three vacuum/hydrogen cycles were performed, and the mixture

was stirred under hydrogen atmosphere for 3 h. The reaction mixture

was then ﬁltered over a Celite pad and washed twice with ethyl acetate,

and the combinated ﬁltrates were evaporated. The crude was puriﬁed

by column chromatography (hexanes−EtOAc, 90:10 → 70:30) to yield

1-O-Benzoyl-2-C-benzoyloxymethyl-2,3:5,6-di-O-isopropylidene-

D-mannofuranose (10). To a solution of compound 9a (900 mg, 3.10

mmol) in dry pyridine (10 mL, 3 mL/mmol) was added, under nitrogen

and at 0 °C, DMAP (40 mg, 0.31 mmol) and benzoyl chloride (1.08 mL,

9.3 mmol), and the mixture was stirred for 13 h and allowed to reach

room temperature. The reaction was poured into aqueous HCl and

extracted with EtOAc. The organic phase was washed with sodium

bicarbonate and brine, dried over sodium sulfate and concentrated

under a vacuum. The residue was puriﬁed by column chromatography

(hexanes−EtOAc, 90:10) to aﬀord 10 (1.29 g, 2.59 mmol, 84%) as an

oil: IR 2990, 2938, 2884, 1731, 1266 cm⁻¹. NMR showed a mixture of

1

anomers in a 5:2 ratio. Major isomer: H NMR δ_H1.38 (3H, s), 1.45

(3H, s), 1.48 (3H, s), 1.56 (3H, s), 4.04 (1H, dd, J = 4.0, 9.0 Hz), 4.13

(1H, dd, J = 6.1, 9.0 Hz), 4.15 (1H, dd, J = 3.3, 8.3 Hz), 4.48 (1H, ddd,

J = 4.0, 6.1, 8.3 Hz), 4.72 (1H, d, J = 11.9 Hz), 4.78 (1H, d, J = 11.9 Hz),

4.88 (1H, d, J = 3.3 Hz), 6.54 (1H, s), 7.34−7.48 (6H, m), 7.91−8.00

(4H, m); ¹³C NMR δ_C25.1 (CH₃), 27.0 (CH₃), 27.4 (CH₃), 27.5

(CH₃), 63.7 (CH₂), 67.0 (CH₂), 72.6 (CH), 82.6 (CH), 82.9 (CH),

93.4 (C), 101.7 (CH), 109.6 (C), 115.2 (C), 128.4 (2 × CH), 128.5 (2 ×

CH), 129.2 (C), 129.4 (C), 129.6 (2 × CH), 129.7 (2 × CH), 133.3

(CH), 133.6 (CH), 164.7 (C), 166.1 (C). Minor isomer: ¹H NMR δ_H

1.40 (3H, s), 1.43 (3H, s), 1.44 (3H, s), 1.45 (3H, s), 4.11−4.18 (3H,

m), 4.55 (1H, ddd, J = 4.9, 6.0, 7.7 Hz), 4.70 (1H, d, J = 11.7 Hz), 4.74

(1H, d, J = 11.7 Hz), 4.80 (1H, d, J = 4.0 Hz), 6.22 (1H, s), 7.51−7.61

(6H, m), 8.04−8.12 (4H, m); ¹³C NMR δ_C25.3 (CH₃), 26.2 (CH₃),

I

dx.doi.org/10.1021/jo401041s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

26.3 (CH₃), 26.9 (CH₃), 64.4 (CH₂), 66.7 (CH₂), 73.4 (CH), 79.8

(CH), 81.4 (CH), 89.8 (C), 99.0 (CH), 109.4 (C), 115.1 (C), 128.5

(2 × CH), 128.6 (2 × CH), 129.2 (C), 129.4 (C), 129.7 (2 × CH),

129.9 (2 × CH), 133.4 (CH), 133.5 (CH), 164.9 (C), 166.0 (C); MS

(EI-TOF) m/z (rel intensity) 483 [(M − CH₃)⁺, 22], 425 (10), 272

(11), 114 (50), 105 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd

for C₂₆H₂₇O₉483.1655, found 483.1652. Anal. Calcd for C₂₇H₃₀O₉: C,

65.05; H, 6.07. Found: C, 65.12; H, 6.27.

557 [(M − CH₃)⁺, 6], 393 (20), 335 (5), 185 (16), 105 (100); HRMS

(EI-TOF) m/z [M − CH₃]⁺Calcd for C₂₉H₃₇O₉Si 557.2207, found

557.2208. Anal. Calcd for C₃₀H₄₀O₉Si: C, 62.91; H, 7.04. Found: C,

62.92; H, 7.00.

5-Azido-1-O-benzoyl-2-C-benzoyloxymethyl-6-O-(tert-

butyldimethyl)silyl-5-deoxy-2,3-O-isopropylidene-^L-gulofuranose

(13). To a solution of alcohol 12 (1.00 g, 1.75 mmol) in dry DCM

(7 mL, 4 mL/mmol) were added, under nitrogen and at −15 °C,

pyridine (0.54 mL, 7.00 mmol) and then triﬂic anhydride dropwise

(0.53 mL, 3.15 mmol), and the mixture was stirred for 30 min at this

temperature. The reaction was puriﬁed by ﬂash chromatography

(DCM) aﬀording the corresponding triﬂate (1.17 g, 1.66 mmol,

95%), which was dissolved in dry DMF (8 mL, 4.5 mL/mmol). Sodium

azide (340 mg, 5.25 mmol) was added in one portion under nitrogen,

and the mixture was stirred at room temperature for 12 h. The reaction

was poured into ice and extracted with ether. The organic phase was

dried over sodium sulfate and concentrated under a vacuum. The crude

was puriﬁed by column chromatography (hexanes−EtOAc, 90:10 →

85:15) to yield compound 13 (750 mg, 1.25 mmol, 71% after two steps)

as a colorless oil: IR 3068, 2929, 2857, 2102, 1730, 1270 cm⁻¹. NMR

showed a mixture of anomers in a 5:1 ratio. Major isomer: ¹H NMR δ_H

0.10 (6H, s), 0.91 (9H, s), 1.45 (3H, s), 1.57 (3H, s), 3.78 (1H, ddd, J =

3.7, 4.8, 8.6 Hz), 3.88 (1H, dd, J = 4.8, 10.9 Hz), 3.92 (1H, dd, J = 3.7,

10.9 Hz), 4.37 (1H, dd, J = 2.9, 8.6 Hz), 4.67 (1H, d, J = 12.2 Hz), 4.74

(1H, d, J = 2.9 Hz), 4.77 (1H, d, J = 12.2 Hz), 6.65 (1H, s), 7.32−7.49

(6H, m), 7.90−8.00 (4H, m); ¹³C NMR δ_C−5.6 (CH₃), −5.5 (CH₃),

18.2 (C), 25.8 (3 × CH₃), 27.5 (2 × CH₃), 62.2 (CH), 63.2 (CH₂), 63.6

(CH₂), 81.6 (CH), 82.5 (CH), 93.6 (C), 101.0 (CH), 115.2 (C), 128.4

(4 × CH), 129.2 (C), 129.3 (C), 129.65 (2 × CH), 129.72 (2 × CH),

133.3 (CH), 133.5 (CH), 164.5 (C), 166.1 (C). Minor isomer:

¹H NMR δ_H0.06 (3H, s), 0.08 (3H, s), 0.86 (9H, s), 1.40 (3H, s), 1.42

(3H, s), 3.84−3.94 (3H, m), 4.33 (1H, dd, J = 4.4, 8.5 Hz), 4.67−4.77

(2H, m), 4.70 (1H, d, J = 4.4 Hz), 6.31 (1H, s), 7.50−7.62 (6H, m),

8.04−8.14 (4H, m); ¹³C NMR δ_C−5.7 (CH₃), −5.6 (CH₃), 18.1 (C),

25.7 (3x CH₃), 26.1 (CH₃), 26.2 (CH₃), 63.3 (CH), 64.4 (CH₂), 63.7

(CH₂), 78.9 (CH), 81.4 (CH), 90.1 (C), 98.9 (CH), 115.2 (C), 128.4

(2 × CH), 128.6 (2 × CH), 129.1 (C), 129.4 (C), 129.7 (2 × CH),

129.9 (2 × CH), 133.2 (CH), 133.4 (CH), 164.9 (C), 165.9 (C); MS

(EI-TOF) m/z (rel intensity) 582 [(M − CH₃)⁺, 2], 540 (1), 390 (7),

240 (19), 179 (57), 105 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺

Calcd for C₂₉H₃₆N₃O₈Si 582.2272, found 582.2256. Anal. Calcd for

C₃₀H₃₉N₃O₈Si: C, 60.28; H, 6.58; N, 7.03. Found: C, 60.30; H, 6.55;

N, 6.89.

5-Azido-6-O-(tert-butyldimethyl)silyl-2-C-(tert-butyldimethyl)-

silyloxymethyl-5-deoxy-2,3-O-isopropylidene-^L-gulofuranose (15a).

Sodium methoxide (54 mg, 1.01 mmol) was added to a solution of azide

13 (300 mg, 0.50 mmol) in dry methanol (5 mL, 10 mL/mmol) under

nitrogen and in an ice/water bath. The reaction was stirred at room

temperature for 2 h, and then the solvent was removed under reduced

pressure. The resulting residue was dissolved in EtOAc and washed

with brine; the organic phase was dried over anhydrous sodium sulfate

and evaporated under a vacuum. The residue was puriﬁed by column

chromatography (hexanes−EtOAc, 90:10 → 70:30) to yield diol 14

(187 mg, 0.48 mmol, 96%) as a colorless oil. To a solution of diol 14

(85 mg, 0.22 mmol) in dry DMF (1.5 mL, 7 mL/mmol) at 0 °C and

under nitrogen were added imidazole (37 mg, 0.55 mmol) and TBSCl

(40 mg, 0.24 mmol), and the mixture was stirred for 2 h at room

temperature. It was then poured into an ice/water mixture and extracted

several times with diethyl ether. The organic phase was dried over

sodium sulfate and concentrated under a vacuum. The resulting crude

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

obtain compound 15a (97 mg, 0.19 mmol, 88%) as a colorless oil: IR

3528, 2952, 2859, 2103, 1469, 1381, 1255, 1109 cm⁻¹. NMR showed a

mixture of anomers in a 4:1 ratio (only the major anomer is described):

¹H NMR δ_H0.07 (6H, s), 0.086 (3H, s), 0.090 (3H, s), 0.87 (9H, s), 0.90

1-O-Benzoyl-2-C-benzoyloxymethyl-2,3-O-isopropylidene-^D-

mannofuranose (11). Compound 10 (1.20 g, 2.41 mmol) was

dissolved in 80% aqueous acetic acid (25 mL, 10 mL/mmol) and

stirred for 20 h at room temperature. The solvent was evaporated under

a vacuum, and the residue thus obtained was extracted with EtOAc and

sodium bicarbonate; the organic phase was washed with brine, dried

over sodium sulfate and concentrated under a vacuum. The crude was

puriﬁed by column chromatography (hexanes−EtOAc, 85:15 → 1:1 →

0:100) to aﬀord diol 11 (1.01 g, 2.21 mmol, 92%) as a white solid: IR

3443, 2990, 1731, 1271 cm⁻¹. NMR showed a mixture of anomers in

a 5:1 ratio. Major isomer: ¹H NMR δ_H1.47 (3H, s), 1.56 (3H, s), 2.34

(2H, bs), 3.72 (1H, dd, J = 5.6, 11.7 Hz), 3.88 (1H, dd, J = 3.2, 11.7 Hz),

4.12 (1H, ddd, J = 3.2, 5.6, 8.2 Hz), 4.26 (1H, dd, J = 3.2, 8.3 Hz), 4.70

(1H, d, J = 12.0 Hz), 4.78 (1H, d, J = 12.0 Hz), 4.93 (1H, d, J = 3.2 Hz),

6.58 (1H, s), 7.34−7.49 (6H, m), 7.91−7.99 (4H, m); ¹³C NMR δ_C

27.52 (CH₃), 27.54 (CH₃), 63.7 (CH₂), 64.0 (CH₂), 69.6 (CH), 81.6

(CH), 83.1 (CH), 93.2 (C), 101.4 (CH), 115.2 (C), 128.4 (2 × CH),

128.5 (2 × CH), 129.1 (C), 129.3 (C), 129.6 (2 × CH), 129.7 (2 ×

CH), 133.3 (CH), 133.6 (CH), 164.7 (C), 166.1 (C). Minor isomer: ¹H

NMR δ_H1.42 (3H, s), 1.43 (3H, s), 2.35 (2H, bs), 3.81 (1H, dd, J = 5.3,

11.6 Hz), 3.94 (1H, dd, J = 2.8, 11.6 Hz), 4.09−4.15 (1H, m), 4.23−4.29

(1H, m), 4.67 (1H, d, J = 11.9 Hz), 4.73 (1H, d, J = 11.9 Hz), 4.90 (1H,

d, J = 4.5 Hz), 6.26 (1H, s), 7.51−7.62 (6H, m), 8.05−8.10 (4H, m); ¹³C

NMR δ_C26.2 (CH₃), 26.3 (CH₃), 63.8 (CH₂), 64.4 (CH₂), 70.5 (CH),

77.2 (CH), 79.4 (CH), 90.2 (C), 98.8 (CH), 115.6 (C), 128.5 (2 ×

CH), 128.6 (2 × CH), 129.1 (C), 129.3 (C), 129.7 (2 × CH), 129.8

(2 × CH), 133.5 (2 × CH), 164.9 (C), 166.0 (C); MS (EI-TOF) m/z

(rel intensity) 443 [(M − CH₃)⁺, 10], 321 (3), 295 (4), 114 (36), 105

(100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for C₂₃H₂₃O₉

443.1342, found 443.1340. Anal. Calcd for C₂₄H₂₆O₉: C, 62.88; H,

5.72. Found: C, 62.84; H, 5.83.

1-O-Benzoyl-2-C-benzoyloxymethyl-6-O-(tert-butyldimethyl)silyl-

2,3-O-isopropylidene-^D-mannofuranose (12). To a solution of diol 11

(700 mg, 1.53 mmol) in dry DMF (4.0 mL, 2.5 mL/mmol) at 0 °C and

under nitrogen were added imidazole (260 mg, 3.83 mmol) and TBSCl

(277 mg, 1.84 mmol), and the mixture was stirred for 1.5 h at room

temperature. Then, it was poured into an ice/water mixture and

extracted several times with diethyl ether. The organic phase was dried

over sodium sulfate and concentrated under a vacuum. The resulting

crude was puriﬁed by column chromatography (hexanes−EtOAc,

90:10 → 80:20) to obtain compound 12 (834 mg, 1.46 mmol, 95%) as a

colorless oil: IR 3565, 3065, 2954, 2930, 2883, 1731, 1270 cm⁻¹. NMR

showed a mixture of anomers in a 5:1 ratio. Major isomer: ¹H NMR δ_H

−0.06 (3H, s), 0.00 (3H, s), 0.77 (9H, s), 1.47 (3H, s), 1.55 (3H, s), 2.73

(1H, bs), 3.77 (1H, dd, J = 3.7, 10.3 Hz), 3.84 (1H, dd, J = 3.2, 10.3 Hz),

4.01−4.09 (1H, m), 4.23 (1H, dd, J = 2.9, 8.7 Hz), 4.72 (1H, d, J = 11.9

Hz), 4.78 (1H, d, J = 11.9 Hz,), 4.95 (1H, d, J = 2.9 Hz), 6.56 (1H, s),

7.31−7.47 (6H, m), 7.89−8.00 (4H, m); ¹³C NMR δ_C−5.8 (CH₃),

−5.5 (CH₃), 18.1 (C), 25.6 (4 × CH₃), 25.8 (CH₃), 63.6 (CH₂), 63.7

(CH₂), 68.7 (CH), 81.0 (CH), 83.1 (CH), 93.1 (C), 101.4 (CH), 114.9

(C), 128.3 (4 × CH), 129.2 (C), 129.4 (C), 129.59 (2 × CH), 129.63

(2 × CH), 133.2 (CH), 133.4 (CH), 164.6 (C), 166.1 (C). Minor

1

isomer: H NMR δ_H0.077 (3H, s), 0.082 (3H, s), 0.89 (9H, s), 1.44

(3H, s), 1.45 (3H, s), 3.83 (1H, dd, J = 4.5, 10.3 Hz), 3.91 (1H, dd, J =

2.9, 10.3 Hz), 4.15 (1H, d, J = 4.0 Hz), 4.14−4.19 (1H, m), 4.68 (1H, d,

J = 11.9 Hz), 4.74 (1H, d, J = 11.9 Hz), 4.90 (1H, d, J = 4.0 Hz), 6.25

(1H, s), 7.49−7.60 (6H, m), 8.04−8.11 (4H, m); ¹³C NMR δ_C−5.5

(2 × CH₃), 18.2 (C), 26.2 (CH₃), 26.3 (CH₃), 27.5 (3 × CH₃), 63.9

(CH₂), 64.5 (CH₂), 69.8 (CH), 78.8 (CH), 81.8 (CH), 89.7 (C),

98.6 (CH), 115.1 (C), 128.3 (2 × CH), 128.5 (2 × CH), 129.2 (C),

129.4 (C), 129.7 (2 × CH), 129.8 (2 × CH), 133.31 (CH),

133.32 (CH), 164.8 (C), 165.9 (C); MS (EI-TOF) m/z (rel intensity)

(9H, s), 1.41 (3H, s), 1.53 (3H, s), 3.62 (1H, ddd, J = 3.4, 4.5, 9.0 Hz),

3.69 (1H, dd, J = 2.7, 9.0 Hz), 3.72 (2H, s), 3.79 (1H, d, J = 12.2 Hz),

3.85 (1H, d, J = 4.5 H), 3.86 (1H, d, J = 3.4 Hz), 4.56 (1H, d, J = 2.7 Hz),

4.99 (1H, d, J = 12.2 Hz); ¹³C NMR δ_C−5.7 (2 × CH₃), −5.6 (CH₃),

−5.5 (CH₃), 18.17 (C), 18.23 (C), 25.8 (6 × CH₃), 26.9 (CH₃),

J

dx.doi.org/10.1021/jo401041s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

27.0 (CH₃), 62.4 (CH), 63.0 (CH₂), 63.3 (CH₂), 75.3 (CH), 82.5

(CH), 89.1 (C), 96.8 (CH), 113.7 (C); MS (ESI-TOF) m/z (rel

intensity) 526 [(M + Na)⁺, 100]; HRMS (ESI-TOF) m/z [M + Na]⁺

Calcd for C₂₂H₄₅N₃O₆Si₂Na 526.2745, found 526.2740.

NMR showed a mixture of anomers in a 3:2 ratio (only the major anomer

is described): ¹H NMR (500 MHz, 70 °C) δ_H0.06 (3H, s), 0.07 (3H, s),

0.91 (9H, s), 1.23 (9H, s), 1.42 (3H, s), 1.45 (9H, s), 1.50 (3H, s), 2.64

(1H, bs), 3.72 (1H, dd, J = 6.0, 10.7 Hz), 3.77 (1H, dd, J = 4.1, 10.7 Hz),

3.82 (1H, dd, J = 3.5, 10.4 Hz), 3.97−4.07 (1H, m), 4.30 (1H, d, J = 12.0

Hz), 4.49 (1H, d, J = 12.0 Hz), 4.50 (1H, d, J = 3.5 Hz), 4.79−4.86 (1H,

m), 4.87 (1H, d, J = 11.7 Hz); ¹³C NMR (125.7 MHz, 70 °C) δ_C−5.4

(2 × CH₃), 18.3 (C), 26.0 (3 × CH₃), 27.00 (CH₃), 27.02 (CH₃), 27.3

(3 × CH₃), 28.5 (3 × CH₃), 39.0 (C), 51.9 (CH), 63.2 (CH₂), 64.0

(CH₂), 74.7 (CH), 79.5 (C), 83.2 (CH), 88.2 (C), 97.4 (CH), 114.5

(C), 155.7 (C), 177.7 (C); MS (ESI-TOF) m/z (rel intensity) 570

[(M + Na)⁺, 100]; HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for

C₂₆H₄₉NO₉SiNa 570.3074, found 570.3076.

5-(tert-Butoxycarbonyl)amino-6-O-(tert-butyldimethyl)silyl-2-C-

(tert-butyldimethyl)silyloxymethyl-5-deoxy-2,3-O-isopropylidene-^L-

gulofuranose (16a). To a solution of azide 15a (90 mg, 0.18 mmol) in

EtOAc (3.0 mL, 15 mL/mmol) were added di-tert-butyl dicarbonate

(58 mg, 0.27 mmol) and 10% Pd/C (18 mg, 20% w/w). Three vacuum/

hydrogen cycles were performed, and the mixture was stirred under

hydrogen atmosphere for 13 h. The reaction mixture was then ﬁltered

over a Celite pad, washed twice with ethyl acetate, and the combinated

ﬁltrates were evaporated. The crude was puriﬁed by column chromato-

graphy (hexanes−EtOAc, 90:10) to yield compound 16a (67 mg,

0.116 mmol, 65%) as a foam: IR 3611, 3523, 3456, 2955, 2858, 1718,

1498, 1254, 1108 cm⁻¹. NMR showed a mixture of anomers in a 2:1 ratio

(only the major anomer is described): ¹H NMR (500 MHz, DMSO-d₆)

δ_H0.01 (3H, s), 0.03 (3H, s), 0.04 (3H, s), 0.05 (3H, s), 0.85 (9H, s),

0.87 (9H, s), 1.33 (3H, s), 1.36 (9H, s), 1.38 (3H, s), 3.57−3.65 (2H,

m), 3.66 (1H, d, J = 11.7 Hz), 3.73 (1H, d, J = 11.7 Hz), 3.82 (1H, dddd,

J = 5.3, 9.1, 9.1, 13.5 Hz), 3.97 (1H, dd, J = 2.6, 9.1 Hz), 4.41 (1H, d, J =

2.6 Hz), 5.03 (1H, d, J = 3.8 Hz), 6.37 (1H, d, J = 3.8 Hz), 6.46 (1H, d,

J = 9.1 Hz); ¹³C NMR (125.7 MHz, 70 °C) δ_C−5.6 (CH₃), −5.5 (CH₃),

−5.4 (2 × CH₃), 18.28 (C), 18.30 (C), 25.9 (3 × CH₃), 26.0 (3 × CH₃),

27.0 (CH₃), 27.1 (CH₃), 28.5 (3 × CH₃), 51.9 (CH), 63.1 (CH₂), 63.5

(CH₂), 74.7 (CH), 79.1 (C), 83.3 (CH), 89.5 (C), 96.8 (CH), 113.7

(C), 155.6 (C); MS (ESI-TOF) m/z (rel intensity) 600 [(M + Na)⁺,

100]; HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for C₂₇H₅₅NO₈Si₂Na

600.3364, found 600.3358.

p-Methoxybenzyl 6-Deoxy-6-ﬂuoro-2,3-O-isopropylidene-α-^D-

mannofuranoside (18). Freshly prepared TBAF·2HF²⁷(1530 mg,

5.09 mmol) was added dropwise to a ﬂask containing epoxide 17¹³

(820 mg, 2.55 mmol), and then the mixture was heated under nitrogen

at 95 °C, for 60 h. Once cooled, the reaction mixture was poured into

water and extracted with EtOAc. The organic phase was washed with

brine, dried over sodium sulfate and concentrated under a vacuum.

The crude was puriﬁed by column chromatography (hexanes−EtOAc,

80:20) to yield ﬂuorohydrin 18 (790 mg, 2.31 mmol, 91%) as a colorless

oil: [α]_D+78.4 (c 0.51); IR (CHCl₃) 3507, 3020, 1613, 1514, 1250,

1082 cm⁻¹; ¹⁹F NMR δ_F−234.1 (1F, s); ¹H NMR δ_H1.32 (3H, s), 1.47

(3H, s), 3.80 (3H, s), 4.01 (1H, dd, J = 3.8, 8.3 Hz), 4.16 (1H, dddd, J =

2.8, 5.0, 8.3 Hz, ³J_FH= 23.3 Hz), 4.41 (1H, d, J = 11.4 Hz), 4.56 (1H, ddd,

J = 5.0, 9.7 Hz, ²J_FH= 47.4 Hz), 4.57 (1H, d, J = 11.4 Hz), 4.64 (1H, d, J =

5.8 Hz), 4.65 (1H, ddd, J = 2.8, 9.7 Hz, ²J_FH= 47.5 Hz), 4.86 (1H, dd, J =

3.8, 5.8 Hz), 5.09 (1H, s), 6.85−6.90 (2H, m), 7.21−7.26 (2H, m); ¹³C

NMR δ_C24.6 (CH₃), 25.9 (CH₃), 55.3 (CH₃), 68.8 (CH₂), 69.3 (CH, d,

²J_FC= 18.4 Hz), 77.9 (CH, d, ³J_FC= 6.4 Hz), 80.0 (CH), 84.8 (CH₂, d,

5-Azido-6-O-(tert-butyldimethyl)silyl-5-deoxy-2,3-O-isopropyli-

dene-2-C-pivaloyloxymethyl-^L-gulofuranose (15b). To a solution of

diol 14 (128 mg, 0.33 mmol) in dry pyridine (2 mL, 6 mL/mmol) were

added, under nitrogen and at 0 °C, DMAP (13 mg, 10% w/w) and

pivaloyl chloride (61 μL, 0.495 mmol), and then the mixture was warmed

to room temperature and stirred for 5 h. The reaction was poured into

10% aqueous HCl and extracted twice with EtOAc. The organic phase

was washed with sodium bicarbonate and brine, dried over sodium sulfate

and concentrated under a vacuum. The crude was puriﬁed by column

chromatography (hexanes−EtOAc, 90:10) to yield compound 15b

(108 mg, 0.23 mmol, 70%) as a colorless oil: IR 3526, 3457, 2956, 2932,

2859, 2104, 1737, 1462, 1255, 1125 cm⁻¹. NMR showed a mixture of

¹J_FC= 169.5 Hz), 84.9 (CH), 105.1 (CH), 112.8 (C), 113.9 (2 × CH),

129.3 (C), 129.8 (2 × CH), 159.5 (C); MS (EI-TOF) m/z (rel

intensity) 342 (M⁺, 5), 327 [(M − CH₃)⁺, 6], 221 (19), 163 (38), 121

(100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for C₁₇H₂₃FO₆

342.1479, found 342.1477. Anal. Calcd for C₁₇H₂₃FO₆: C, 59.64; H,

6.77. Found: C, 59.80; H, 6.74.

p-Methoxybenzyl 5-Azido-5,6-dideoxy-6-ﬂuoro-2,3-O-isopropyli-

dene-β-^L-gulofuranoside (19). To a solution of alcohol 18 (660 mg,

1.93 mmol) in dry DCM (15.0 mL, 8 mL/mmol) were added at −20 °C

and under N₂, pyridine (0.6 mL, 7.74 mmol) and triﬂic anhydride

(0.58 mL, 3.47 mmol), and the reaction was stirred at this temperature

for 1 h before being poured into a cold 10% aqueous HCl solution and

extracted with DCM. The organic phase was dried over anhydrous

sodium sulfate and concentrated under a vacuum. The residue was used

in the next step without further puriﬁcation. Thus, to a solution of the

resulting triﬂate in DMF (9.5 mL, 5.0 mL/mmol) was added sodium

azide (627 mg, 9.65 mmol), and the reaction was heated at 40 °C for

15 h. The reaction was poured into ice/water and extracted with EtOAc.

The organic layer was dried and concentrated under a vacuum. The

residue was puriﬁed by column chromatography (hexanes−EtOAc,

90:10) to aﬀord the title compound 19 (611 mg, 1.66 mmol, 86%) as a

colorless oil: [α]_D+75.7 (c 0.59); IR 2939, 2099, 1613, 1514, 1251, 1085

cm⁻¹; ¹⁹F NMR δ_F−230.6 (1F, s); ¹H NMR δ_H1.27 (3H, s), 1.45 (3H,

s), 3.79 (3H, s), 3.90 (1H, dddd, J = 2.5, 4.1, 9.0 Hz, ³J_FH= 26.6 Hz), 4.21

(1H, dd, J = 3.5, 9.0 Hz), 4.44 (1H, d, J = 11.3 Hz), 4.627 (1H, dd, J = 2.5

Hz, ²J_FH= 47.0 Hz), 4.629 (1H, dd, J = 4.1 Hz, ²J_FH= 47.2 Hz), 4.64 (1H,

d, J = 11.3 Hz), 4.65 (1H, d, J = 5.9 Hz), 4.71 (1H, dd, J = 3.5, 5.9 Hz),

5.11 (1H, s), 6.86−6.91 (2H, m), 7.24−7.29 (2H, m); ¹³C NMR δ_C24.6

1

anomers in a 5:3 ratio. Major isomer: H NMR δ_H0.08 (3H, s), 0.09

(3H, s), 0.90 (9H, s), 1.21 (9H, s), 1.42 (3H, s), 1.46 (3H, s), 3.15 (1H,

bs), 3.64 (1H, ddd, J = 3.3, 5.1, 9.3 Hz), 3.82 (1H, dd, J = 5.1, 10.9 Hz),

3.88 (1H, dd, J = 3.3, 10.9 Hz), 4.26 (1H, dd, J = 3.0, 9.3 Hz), 4.29 (1H, d,

J = 12.4 Hz), 4.45 (1H, d, J = 12.4 Hz), 4.47 (1H, d, J = 3.0 Hz), 5.38 (1H,

s); ¹³C NMR δ_C−5.5 (2 × CH₃), 18.2 (C), 25.8 (3 × CH₃), 27.2 (3 ×

CH₃), 27.6 (CH₃), 27.8 (CH₃), 38.8 (C), 62.4 (CH), 63.2 (CH₂), 63.3

(CH₂), 79.3 (CH), 82.4 (CH), 93.6 (C), 102.3 (CH), 114.4 (C), 178.2

1

(C). Minor isomer: H NMR δ_H0.077 (3H, s), 0.081 (3H, s), 0.89

(9H, s), 1.20 (9H, s), 1.45 (3H, s), 1.55 (3H, s), 3.61−3.66 (1H, m), 3.72

(1H, dd, J = 3.0, 8.8 Hz), 3.82−3.88 (2H, m), 4.20 (1H, d, J = 11.6 Hz),

4.24 (1H, d, J = 11.6 Hz), 4.51 (1H, d, J = 3.0 Hz), 4.92 (1H, d, J = 9.6

Hz); ¹³C NMR δ_C−5.68 (CH₃), −5.66 (CH₃), 18.2 (C), 25.8 (3 ×

CH₃), 26.87 (CH₃), 26.89 (CH₃), 27.2 (3 × CH₃), 38.8 (C), 62.1

(CH), 63.2 (CH₂), 63.5 (CH₂), 75.1 (CH), 82.4 (CH), 87.7 (C), 97.2

(CH), 114.4 (C), 177.7 (C); MS (ESI-TOF) m/z (rel intensity) 496

[(M + Na)⁺, 100]; HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for

C₂₁H₃₉N₃O₇SiNa 496.2455, found 496.2449.

5-(tert-Butoxycarbonyl)amino-6-O-(tert-butyldimethyl)silyl-5-

deoxy-2,3-O-isopropylidene-2-C-pivaloyloxymethyl-^L-gulofuranose

(16b). To a solution of azide 15b (95 mg, 0.20 mmol) in EtOAc (3.0 mL,

15 mL/mmol) were added di-tert-butyl dicarbonate (66 mg, 0.3 mmol)

and 10% Pd/C (20 mg, 20% w/w). Three vacuum/hydrogen cycles were

performed, and the mixture was stirred under hydrogen atmosphere for

12 h. The reaction mixture was then ﬁltered over a Celite pad, washed

twice with ethyl acetate, and the combinated ﬁltrates were evaporated.

The crude was puriﬁed by column chromatography (hexanes−EtOAc,

90:10 → 80:20) to yield compound 16b (48 mg, 0.09 mmol, 44%) as

an oil: IR 3613, 3454, 2957, 2859, 1733, 1500, 1254, 1154 cm⁻¹.

2

(CH₃), 25.9 (CH₃), 55.2 (CH₃), 61.0 (CH, d, J_FC= 17.6 Hz), 68.7

3

1

(CH₂), 78.5 (CH, d, J_FC= 6.4 Hz), 79.4 (CH), 82.7 (CH₂, d, J_FC

=

172.3 Hz), 85.3 (CH), 104.6 (CH), 112.9 (C), 113.9 (2 × CH), 128.9

(C), 129.9 (2 × CH), 159.4 (C); MS (ESI-TOF) m/z (rel intensity) 390

[(M + Na)⁺, 100]; HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for

C₁₇H₂₂FN₃O₅Na 390.1441, found 390.1444. Anal. Calcd for

C₁₇H₂₂FN₃O₅: C, 55.58; H, 6.04; N, 11.44. Found: C, 55.88; H, 6.06;

N, 11.07.

5-Azido-5,6-dideoxy-6-ﬂuoro-2,3-O-isopropylidene-^L-gulofura-

nose (20). To a solution of 19 (570 mg, 1.55 mmol) in a 9:1 mixture

of CH₃CN/H₂O (15.5 mL, 10 mL/mmol) was added, at 0 °C,

K

dx.doi.org/10.1021/jo401041s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

CAN (1.70 g, 3.10 mmol), and the resulting suspension was stirred at

that temperature for 2 h and then was poured into an aqueous sodium

bicarbonate solution and extracted with EtOAc. The organic phase

was dried over sodium sulfate and concentrated under a vacuum. The

residue was puriﬁed by column chromatography (hexanes−EtOAc,

85:15) to aﬀord compound 20 (314 mg, 1.27 mmol, 82%) as a colorless

oil: IR 3599, 2992, 2102, 1378, 1269, 1088 cm⁻¹. NMR showed a

mixture of anomers in a 6:1 ratio (only the major anomer is described):

7:2 ratio. Major isomer: ¹⁹F NMR δ_F−232.7 (0.2F, s), −231.2 (0.8F, s);

¹H NMR (500 MHz, 70 °C) δ_H0.118 (3H, s), 0.120 (3H, s), 0.91 (9H,

s), 1.42 (3H, s), 1.45 (9H, s), 1.54 (3H, s), 3.72 (1H, dd, J = 3.0, 6.8 Hz),

3.75 (2H, s), 4.11−4.20 (1H, m), 4.52 (1H, dd, J = 1.0 Hz, ²J_FH= 47.3

Hz), 4.53 (1H, dd, J = 4.7 Hz, ²J_FH= 47.0 Hz), 4.60 (1H, d, J = 3.0 Hz),

4.88 (1H, bs), 4.97 (1H, d, J = 6.3 Hz); ¹³C NMR δ_C−5.60 (CH₃),

−5.58 (CH₃), 18.2 (C), 25.8 (3 × CH₃), 26.8 (CH₃), 27.0 (CH₃), 28.5

2

(3 × CH₃), 50.8 (CH, d, J_FC= 20.1 Hz), 63.6 (CH₂), 74.2 (CH, d,

1

¹⁹F NMR δ_F−230.2 (1F, s); H NMR δ_H1.31 (3H, s), 1.46 (3H, s),

³J_FC= 5.3 Hz), 80.1 (C), 82.8 (CH₂, d, ¹J_FC= 170.6 Hz), 83.1 (CH), 89.5

(C), 97.2 (CH), 114.1 (C), 155.6 (C). Minor isomer: ¹⁹F NMR δ_F

2.79 (1H, bs), 3.89 (1H, dddd, J = 2.9, 4.4, 9.1 Hz, ³J_FH= 25.4 Hz), 4.30

(1H, dd, J = 3.5, 9.1 Hz), 4.64 (1H, dd, J = 4.5 Hz, ²J_FH= 47.2 Hz), 4.65

(1H, dd, J = 2.9 Hz, ²J_FH= 46.7 Hz), 4.66 (1H, d, J = 5.9 Hz), 4.74 (1H,

dd, J = 3.5, 5.9 Hz), 5.44 (1H, s); ¹³C NMR δ_C24.6 (CH₃), 25.9 (CH₃),

61.2 (CH, d, ²J_FC= 18.4 Hz), 78.8 (CH, d, ³J_FC= 7.1 Hz), 79.3 (CH),

82.7 (CH₂, d, ¹J_FC= 172.3 Hz), 85.7 (CH), 101.0 (CH), 113.0 (C); MS

(EI-TOF) m/z (rel intensity) 232 [(M − CH₃)⁺, 44], 159 (24), 73 (31),

59 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for C₈H₁₁FN₃O₄

232.0734, found 232.0726. Anal. Calcd for C₉H₁₄FN₃O₄: C, 43.72; H,

5.71; N, 17.00. Found: C, 43.64; H, 5.68; N, 17.29.

1

−229.8 (0.4F, s), −228.9 (0.6F, s); H NMR (500 MHz, 70 °C) δ_H

0.125 (3H, s), 0.131 (3H, s), 0.93 (9H, s), 1.37 (3H, s), 1.38 (3H, s),

1.47 (9H, s), 3.61 (1H, d, J = 9.8 Hz), 3.67 (1H, d, J = 9.8 Hz), 4.11−4.20

(1H, m), 4.18−4.24 (1H, m), 4.56−4.63 (2H, m), 4.61 (1H, d, J = 8.5

Hz), 5.30 (1H, bs); ¹³C NMR δ_C−5.7 (CH₃), −5.5 (CH₃), 18.4 (C),

25.9 (3 × CH₃), 26.6 (CH₃), 27.2 (CH₃), 28.4 (3 × CH₃), 51.8 (CH, d,

²J_FC= 22.3 Hz), 67.5 (CH₂), 78.4 (CH, d, ³J_FC= 4.2 Hz), 79.6 (C), 80.8

(CH₂, d, ¹J_FC= 170.6 Hz), 83.6 (CH), 93.5 (C), 104.4 (CH), 114.3 (C),

155.3 (C); MS (ESI-TOF) m/z (rel intensity) 488 [(M + Na)⁺, 100];

HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for C₂₁H₄₀FNO₇SiNa

488.2456, found 488.2445. Anal. Calcd for C₂₁H₄₀FNO₇Si: C, 54.17; H,

8.66; N, 3.01. Found: C, 54.21; H, 8.43; N, 3.11.

5-Azido-2-C-(tert-butyldimethyl)silyloxymethyl-5,6-dideoxy-6-ﬂuo-

ro-2,3-O-isopropylidene-^L-gulofuranose (22a). Potassium carbonate

(500 mg, 200% w/w) was added to a 35% aqueous solution of

formaldehyde (1.3 mL, 2 mL/mmol), and the mixture was stirred until

a clear solution was observed. A solution of compound 20 (250 mg, 1.01

mmol) in dry methanol (2 mL, 2 mL/mmol) was then added dropwise

while heating at 80 °C. After 2 h, the solvent was removed under a

vacuum, and the residue was extracted twice with EtOAc and washed

with brine. The organic phase was dried over anhydrous sodium sulfate

and concentrated under a vacuum. The residue was puriﬁed by rotatory

chromatography (hexanes−EtOAc, 80:20 → 60:40) to yield compound

21 (224 mg, 0.81 mmol, 80%) as a colorless oil. To a solution of diol 21

(110 mg, 0.4 mmol) in dry DMF (2 mL, 5 mL/mmol) at 0 °C and under

nitrogen were added imidazole (60 mg, 0.88 mmol) and then TBSCl

(72 mg, 0.48 mmol), and the mixture was stirred for 4 h. It was poured

into an ice/water mixture and extracted several times with diethyl ether.

The organic phase was dried over sodium sulfate and concentrated

under a vacuum. The resulting crude was puriﬁed by column chromato-

graphy (hexanes−EtOAc, 90:10) to obtain compound 22a (118 mg,

0.30 mmol, 75%) as a colorless oil: IR (CHCl₃) 3500, 2932, 2104, 1258,

1106 cm⁻¹. NMR showed a mixture of anomers in a 3:2 ratio. Major

isomer: ¹⁹F NMR δ_F−230.0 (1F, s); ¹H NMR δ_H0.08 (6H, s), 0.88 (9H,

s), 1.41 (3H, s), 1.53 (3H, s), 3.71 (1H, dd, J = 2.8, 8.6 Hz), 3.73 (1H, d,

J = 10.3 Hz), 3.75 (1H, d, J = 10.3 Hz), 3.84 (1H, d, J = 12.1 Hz), 3.86−

3.97 (1H, m), 4.58 (1H, d, J = 2.8 Hz), 4.57−4.71 (2H, m), 5.02 (1H, d,

J = 12.1 Hz); ¹³C NMR δ_C−5.65 (2 × CH₃), 18.1 (C), 25.7 (3 × CH₃),

26.7 (CH₃), 26.9 (CH₃), 61.0 (CH, d, ²J_FC= 17.7 Hz), 63.1 (CH₂), 75.0

(CH, d, ³J_FC= 7.1 Hz), 82.3 (CH), 82.8 (CH₂, d, ¹J_FC= 172.3 Hz), 88.9

(C), 97.1 (CH), 114.0 (C). Minor isomer: ¹⁹F NMR δ_F−230.1 (1F, s);

¹H NMR δ_H0.12 (3H, s), 0.13 (3H, s), 0.91 (9H, s), 1.38 (3H, s), 1.47

5-Azido-5,6-dideoxy-6-ﬂuoro-2,3-O-isopropylidene-2-C-pivaloy-

loxymethyl-^L-gulofuranose (22b). To a solution of compound 21

(110 mg, 0.4 mmol) in dry pyridine (2 mL, 5 mL/mmol) were added,

under nitrogen and at 0 °C, DMAP (11 mg, 10% w/w) and pivaloyl

chloride (100 μL, 0.81 mmol), and then the mixture was warmed to

room temperature and stirred for 10 h. The reaction was poured into

10% aqueous HCl and extracted twice with DCM. The organic phase was

washed with sodium bicarbonate and brine, dried over sodium sulfate

and concentrated under a vacuum. The crude was puriﬁed by column

chromatography (hexanes−EtOAc, 90:10 → 1:1) to yield compound

22b (75 mg, 0.21 mmol, 53%) as a colorless oil: IR (CHCl₃) 3597, 3516,

3354, 2983, 2104, 1731, 1279, 1151, 1123 cm⁻¹. NMR showed a mixture

of anomers in a 3:2 ratio. Major isomer: ¹⁹F NMR δ_F−230.5 (1F, s);

¹H NMR δ_H1.21 (9H, s), 1.46 (3H, s), 1.56 (3H, s), 3.73 (1H, dd, J = 2.9,

8.5 Hz), 3.84−3.96 (2H, m), 4.19 (1H, d, J = 11.7 Hz), 4.30 (1H, d, J =

11.7 Hz), 4.53 (1H, dd, J = 0.8, 2.9 Hz), 4.63 (2H, dd, J = 3.6 Hz, ²J_FH

=

47.0 Hz), 4.95 (1H, d, J = 11.1 Hz); ¹³C NMR δ_C26.6 (CH₃), 26.8

2

(CH₃), 27.1 (3 × CH₃), 38.9 (C), 60.8 (CH, d, J_FC= 18.4 Hz), 63.5

3

1

(CH₂), 74.9 (CH, d, J_FC= 7.1 Hz), 82.1 (CH), 82.7 (CH₂, d, J_FC

=

172.3 Hz), 87.5 (C), 97.6 (CH), 114.7 (C), 177.7 (C). Minor isomer:

¹⁹F NMR δ_F−230.0 (1F, s); ¹H NMR δ_H1.22 (9H, s), 1.42 (3H, s), 1.48

(3H, s), 3.07 (1H, bs), 3.84−3.96 (1H, m), 4.310 (1H, dd, J = 0.5, 6.1

Hz), 4.311 (1H, d, J = 12.2 Hz), 4.45 (1H, d, J = 12.2 Hz), 4.50 (1H, d, J =

2.9 Hz), 4.62 (2H, dd, J = 7.2 Hz, ²J_FH= 47.2 Hz), 5.40 (1H, s); ¹³C NMR

δ_C27.1 (3 × CH₃), 27.5 (CH₃), 27.6 (CH₃), 38.8 (C), 61.0 (CH, d,

²J_FC= 19.1 Hz), 63.2 (CH₂), 79.1 (CH, d, ³J_FC= 7.1 Hz), 82.3 (CH), 82.6

(CH₂, d, ¹J_FC= 172.3 Hz), 93.6 (C), 102.4 (CH), 114.7 (C), 178.1 (C);

MS (ESI-TOF) m/z (rel intensity) 384 [(M + Na)⁺, 100)]; HRMS

(ESI-TOF) m/z [M + Na]⁺Calcd for C₁₅H₂₄FN₃O₆Na 384.1547, found

384.1550.

5-(tert-Butoxycarbonyl)amino-5,6-dideoxy-6-ﬂuoro-2,3-O-iso-

propylidene-2-C-pivaloyloxymethyl-^L-gulofuranose (23b). To a

solution of azide 22b (108 mg, 0.30 mmol) in EtOAc (4.5 mL, 15

mL/mmol) were added di-tert-butyl dicarbonate (98 mg, 0.45 mmol),

DIPEA (51 μL, 0.30 mmol) and 10% Pd/C (21 mg, 20% w/w). Three

vacuum/hydrogen cycles were performed, and the mixture was stirred

under hydrogen atmosphere for 15 h. The reaction mixture was then

ﬁltered over a Celite pad, washed twice with ethyl acetate, and

the combined ﬁltrates were evaporated. The crude was puriﬁed by

rotatory chromatography (hexanes−EtOAc 80:20) to yield compound

23b (95 mg, 0.22 mmol, 73%) as a colorless oil: IR (CHCl₃) 2983, 1725,

1504, 1369, 1281 cm⁻¹. ¹H and ¹³C NMR spectra were too complex to

be described due to the mixture of anomers and rotamers. However

when both of them were attempted to be registered at a higher temp-

erature, the product decomposed before reaching the coalescence

temperature. MS (ESI-TOF) m/z (rel intensity) 458 [(M + Na)⁺, 100];

HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for C₂₀H₃₄FNO₈Na

(3H, s), 3.83 (1H, d, J = 10.7 Hz), 3.86−3.97 (1H, m), 4.06 (1H, d, J =

10.7 Hz), 4.24 (1H, dd, J = 2.8, 8.8 Hz), 4.56 (1H, d, J = 2.8 Hz), 4.57−

4.71 (2H, m), 5.34 (1H, d, J = 6.0 Hz); ¹³C NMR δ_C−5.7 (CH₃), −5.6

(CH₃), 18.1 (C), 25.7 (3 × CH₃), 27.3 (CH₃), 27.4 (CH₃), 61.2 (CH, d,

²J_FC= 18.4 Hz), 63.8 (CH₂), 79.2 (CH, d, ³J_FC= 7.1 Hz), 82.8 (CH₂, d,

¹J_FC= 172.3 Hz), 82.9 (CH), 93.4 (C), 104.3 (CH), 114.3 (C); MS

(ESI-TOF) m/z (rel intensity) 414 [(M + Na)⁺, 100)]; HRMS (ESI-

TOF) m/z [M + Na]⁺Calcd for C₁₆H₃₀FN₃O₅SiNa 414.1836, found

414.1832.

5-(tert-Butoxycarbonyl)amino-2-C-(tert-butyldimethyl)-

silyloxymethyl-5,6-dideoxy-6-ﬂuoro-2,3-O-isopropylidene-^L-gulofura-

nose (23a). To a solution of azide 22a (110 mg, 0.28 mmol) in EtOAc

(4.2 mL, 15 mL/mmol) were added di-tert-butyl dicarbonate (74 mg,

0.34 mmol), DIPEA (49 μL, 0.28 mmol) and 10% Pd/C (22 mg, 20%

w/w). Three vacuum/hydrogen cycles were performed, and the mixture

was stirred under hydrogen atmosphere for 15 h. The reaction mixture

was then ﬁltered over a Celite pad, washed twice with ethyl acetate,

and the combined ﬁltrates were evaporated. The crude was puriﬁed

by column chromatography (hexanes−EtOAc, 90:10 → 80:20) to yield

compound 23a (115 mg, 0.25 mmol, 88%) as a colorless oil: IR (CHCl₃)

3442, 1708, 1502, 1369 cm⁻¹. NMR showed a mixture of anomers in a

L

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458.2166, found 458.2170. Anal. Calcd for C₂₀H₃₄FNO₈: C, 55.16; H,

7.87; N, 3.22. Found: C, 55.26; H, 7.63; N, 3.34.

214 [(M − CH₃)⁺, 37], 159 (61), 212 (15), 73 (89), 59 (100); HRMS

(EI-TOF) m/z [M − CH₃]⁺Calcd for C₈H₁₂N₃O₄214.0828, found

214.0823. Anal. Calcd for C₉H₁₅N₃O₄: C, 47.16; H, 6.60; N, 18.33.

Found: C, 47.11; H, 6.67; N, 18.28.

p-Methoxybenzyl 6-Deoxy-2,3-O-isopropylidene-α-^D-mannofura-

noside (24). To a solution of epoxide 17 (740 mg, 2.3 mmol) in dry

ether (23 mL, 10 mL/mmol) was added lithium aluminum hydride

(220 mg, 5.75 mmol), and the reaction mixture was heated at reﬂux for

3 h. Once cooled, the excess of hydride was destroyed by a dropwise

addition of an aqueous sodium sulfate solution till the eﬀervescence

ceased, and then stirring was continued for 30 min. The mixture was

ﬁltrated, and the ﬁltrate was extracted with EtOAc and saturated

ammonium chloride. The organic phase was dried over sodium sulfate

and concentrated under a vacuum. The residue was puriﬁed by column

chromatography (hexanes−EtOAc, 70:30) to yield alcohol 24 (700 mg,

2.16 mmol, 94%) as a colorless oil: [α]_D+78.7 (c 0.55); IR 3607, 2982,

2937, 1613, 1514, 1250 cm⁻¹; ¹H NMR δ_H1.31 (3H, s), 1.34 (3H, d, J =

6.4 Hz), 1.47 (3H, s), 3.77 (1H, ddd, J = 0.5, 3.8, 7.3 Hz), 3.80 (3H, s),

4.09 (1H, dddd, J = 6.4, 6.4, 6.4, 7.3 Hz), 4.42 (1H, d, J = 11.7 Hz), 4.59

(1H, d, J = 11.7 Hz), 4.62 (1H, d, J = 6.0 Hz), 4.85 (1H, dd, J = 3.8,

6.0 Hz), 5.10 (1H, s), 6.85−6.89 (2H, m), 7.23−7.27 (1H, m); ¹³C

NMR δ_C20.4 (CH₃), 24.5 (CH₃), 25.9 (CH₃), 55.2 (CH₃), 66.5 (CH),

68.6 (CH₂), 80.0 (CH), 83.2 (CH), 85.0 (CH), 104.9 (CH), 112.6 (C),

113.8 (2 × CH), 129.4 (C), 129.7 (2 × CH), 159.3 (C); MS (EI-TOF)

m/z (rel intensity) 324 (M⁺, 2), 309 (3), 203 (7), 157 (4), 145 (28), 121

(100); HRMS (EI-TOF) m/z [M]⁺Calcd for C₁₇H₂₄O₆324.1573,

found 324.1572. Anal. Calcd for C₁₇H₂₄O₆: C, 62.95; H, 7.46. Found: C,

62.82; H, 7.62.

p-Methoxybenzyl 5-Azido-5,6-dideoxy-2,3-O-isopropylidene-β-^L-

gulofuranoside (25). To a solution of alcohol 24 (600 mg, 1.85

mmol) in dry DCM (15.0 mL, 8 mL/mmol) were added at −20 °C and

under N₂, pyridine (0.57 mL, 7.4 mmol) and triﬂic anhydride (0.62 mL,

3.47 mmol), and the reaction was stirred at this temperature for 45 min

before pouring into a cold aqueous HCl solution and extracted with

DCM. The organic phase was dried over anhydrous sodium sulfate and

concentrated under a vacuum. Next, to a solution of the resulting residue

in DMF (10 mL, 5.0 mL/mmol) was added sodium azide (601 mg,

9.25 mmol), and the reaction was stirred at room temperature for 16 h.

The solvent was removed under a vacuum, and the residue was solved in

water and extracted with EtOAc. The organic layer was washed with

brine, dried over sodium sulfate and concentrated under a vacuum. The

residue was puriﬁed by rotatory chromatography (hexanes−EtOAc,

98:2) to aﬀord the title compound 25 (440 mg, 1.26 mmol, 68%) as a

colorless oil: [α]_D+51.3 (c 0.32); IR (CHCl₃) 2997, 2940, 2093, 1612,

1514, 1250 cm⁻¹; ¹H NMR δ_H1.26 (3H, d, J = 6.4 Hz), 1.28 (3H, s),

1.44 (3H, s), 3.79 (3H, s), 3.82 (1H, dddd, J = 6.4, 6.4, 6.4, 9.3 Hz), 3.89

(1H, dd, J = 3.1, 9.3 Hz), 4.44 (1H, d, J = 11.4 Hz), 4.61 (1H, d, J = 5.9

Hz), 4.63 (1H, dd, J = 3.1, 5.9 Hz), 4.64 (1H, d, J = 11.4 Hz), 5.08

(1H, s), 6.85−6.90 (2H, m), 7.25−7.30 (2H, m); ¹³C NMR δ_C16.0

(CH₃), 24.8 (CH₃), 26.0 (CH₃), 55.2 (CH₃), 57.1 (CH), 68.6 (CH₂),

79.7 (CH), 83.5 (CH), 85.2 (CH), 104.9 (CH), 112.6 (C), 113.9 (2 ×

CH), 129.1 (C), 129.9 (2 × CH), 159.4 (C); MS (EI-TOF) m/z (rel

intensity) 349 (M⁺, 16), 334 (6), 246 (7), 142 (11), 121 (100); HRMS

(EI-TOF) m/z [M]⁺Calcd for C₁₇H₂₃N₃O₅349.1638, found 349.1640.

Anal. Calcd for C₁₇H₂₃N₃O₅: C, 58.44; H, 6.64; N, 12.03. Found: C,

58.62; H, 6.63; N, 12.12.

5-Azido-5,6-dideoxy-2,3-O-isopropylidene-2-C-pivaloyloxyme-

thyl-^L-gulofuranose (28). Potassium carbonate (370 mg, 200% w/w) was

added to a 35% aqueous solution of formaldehyde (1.6 mL, 2 mL/

mmol), and the mixture was stirred until a clear solution was observed.

A solution of compound 26 (185 mg, 0.81 mmol) in dry methanol

(3.5 mL, 4.5 mL/mmol) was then added dropwise while heating at

80 °C. After 2 h, the solvent was removed under a vacuum, and the

residue was extracted twice with EtOAc and washed with brine. The

organic phase was dried over anhydrous sodium sulfate and

concentrated under a vacuum. The residue was puriﬁed by rotatory

chromatography (hexanes−EtOAc, 80:20 → 60:40) to yield compound

27 (173 mg, 0.67 mmol, 83%) as a colorless oil. NMR showed a mixture

of anomers in a 3:1 ratio. To a solution of compound 27 (160 mg, 0.618

mmol) in dry pyridine (3 mL, 5 mL/mmol) were added, under nitrogen

and at 0 °C, DMAP (16 mg, 10% w/w) and pivaloyl chloride (1.84 mL,

1.50 mmol), and then the mixture was warmed to room temperature and

stirred for 38 h. The reaction was poured into 10% aqueous HCl and

extracted twice with EtOAc. The organic phase was washed with sodium

bicarbonate and brine, dried over sodium sulfate and concentrated

under a vacuum. The crude was puriﬁed by column chromatography

(hexanes−EtOAc, 95:5 → 85:15) to yield compound 28 (95 mg, 0.277

mmol, 45%) as a colorless oil: IR (CHCl₃) 3692, 3596, 2096, 1728,

1382, 1155, 1091 cm⁻¹. NMR showed a mixture of anomers in a 9:2 ratio

1

(major anomer is only described): H NMR δ_H1.23 (9H, s), 1.28

(3H, d, J = 6.7 Hz), 1.42 (3H, s), 1.48 (3H, s), 2.90 (1H, bs), 3.78−3.87

(1H, m), 4.01 (1H, dd, J = 3.0, 9.3 Hz), 4.30 (1H, d, J = 12.2 Hz), 4.44

(1H, d, J = 3.0 Hz), 4.45 (1H, d, J = 12.2 Hz), 5.38 (1H, d, J = 1.8 Hz);

¹³C NMR δ_C15.9 (CH₃), 27.2 (3 × CH₃), 27.6 (CH₃), 27.8 (CH₃), 38.9

(C), 57.1 (CH), 63.3 (CH₂), 82.6 (CH), 83.8 (CH), 93.4 (C), 102.5

(CH), 114.4 (C), 178.2 (C); MS (EI-TOF) m/z (rel intensity) 328

[(M − CH₃)⁺, 3], 215 (5), 110 (63), 57 (100); HRMS (EI-TOF) m/z

[M − CH₃]⁺Calcd for C₁₄H₂₂N₃O₆328.1509, found 328.1516. Anal.

Calcd for C₁₅H₂₅N₃O₆: C, 52.47; H, 7.34; N, 12.24. Found: C, 52.19; H,

7.20; N, 12.35.

5-(tert-Butoxycarbonyl)amino-5,6-dideoxy-2,3-O-isopropylidene-

2-C-pivaloyloxymethyl-^L-gulofuranose (29). To a solution of azide 28

(157 mg, 0.457 mmol) in EtOAc (7.0 mL, 15 mL/mmol) were added

di-tert-butyl dicarbonate (120 mg, 0.548 mmol) and 10% Pd/C (30 mg,

20% w/w). Three vacuum/hydrogen cycles were performed, and the

mixture was stirred under hydrogen atmosphere for 2.5 h. The reaction

mixture was then ﬁltered over a Celite pad, washed twice with ethyl

acetate, and the combined ﬁltrates were evaporated. The crude was

puriﬁed by column chromatography (hexanes−EtOAc, 90:10 → 70:30)

to yield compound 29 (120 mg, 0.288 mmol, 63%) as a colorless oil: IR

(CHCl₃) 3443, 1725, 1680, 1415, 1369, 1160 cm⁻¹. ¹H and ¹³C NMR

spectra were too complex to be described due to the mixture of anomers

and rotamers. However when both of them were attempted to be

registered at a higher temperature, the product decomposed before

reaching the coalescence temperature. MS (ESI-TOF) m/z (rel intensity)

440 [(M + Na)⁺, 100]; HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for

C₂₀H₃₅NO₈Na 440.2260, found 440.2274. Anal. Calcd for C₂₀H₃₅NO₈: C,

57.54; H, 8.45; N, 3.35. Found: C, 57.73; H, 8.31; N, 3.38.

5,6-Anhydro-1-O-benzoyl-2-C-benzoyloxymethyl-2,3-O-isopro-

pylidene-^D-mannofuranose (30). To a solution of diol 11 (2.0 g,

4.37 mmol) in dry toluene (17 mL, 4 mL/mmol) were added, under

nitrogen, triphenylphosphine (1.26 g, 4.80 mmol) and diethylazodi-

carboxilate (DEAD) dropwise (790 μL, 5.02 mmol). Then, the reaction

was heated at reﬂux for 2 h, and the solvent was removed under a

vacuum. The residue was puriﬁed by column chromatography

(hexanes−EtOAc, 95:5 → 75:25) to yield epoxide 30 (1.83 g, 4.16

mmol, 95%) as a colorless oil: IR 3065, 2994, 2939, 1737, 1376, 1277

cm⁻¹. NMR showed a mixture of anomers in a 5:1 ratio. Major isomer:

¹H NMR δ_H1.49 (3H, s), 1.59 (3H, s), 2.80 (1H, dd, J = 2.4, 5.0 Hz),

5-Azido-5,6-dideoxy-2,3-O-isopropylidene-^L-gulofuranose (26).

To a solution of 25 (370 mg, 1.06 mmol) in DCM (10 mL, 10 mL/

mmol) was added, at 0 °C, triﬂuoroacetic acid (1.0 mL, 10% v/v), and the

resulting mixture was stirred at that temperature for 2 h. The reaction was

poured into an aqueous sodium bicarbonate solution and extracted with

DCM. The organic phase was dried over sodium sulfate and concentrated

under a vacuum. The residue was puriﬁed by rotatory chromatography

(C₆H₆−EtOAc, 90:10) to aﬀord the compound 26 (195 mg, 0.85 mmol,

80%) as a colorless oil: IR (CHCl₃) 3596, 3361, 3020, 2991, 2943, 2093,

1381, 1215, 1090 cm⁻¹. NMR showed a mixture of anomers in a 10:1 ratio

1

(only the major anomer is described): H NMR δ_H1.285 (3H, d,

J = 6.5 Hz), 1.287 (3H, s), 1.44 (3H, s), 3.53 (1H, bs), 3.79 (1H, dddd,

J = 6.5, 6.5, 6.5, 9.4 Hz), 3.98 (1H, dd, J = 3.5, 9.4 Hz), 4.60 (1H, d, J = 5.9

Hz), 4.67 (1H, dd, J = 3.5, 5.9 Hz), 5.40 (1H, s); ¹³C NMR δ_C15.8 (CH₃),

24.7 (CH₃), 26.0 (CH₃), 57.3 (CH), 79.6 (CH), 83.4 (CH),

85.6 (CH), 101.1 (CH), 112.7 (C); MS (EI-TOF) m/z (rel intensity)

2.93 (1H, dd, J = 4.0, 5.0 Hz), 3.39 (1H, ddd, J = 2.4, 4.0, 6.5 Hz), 3.88

(1H, dd, J = 3.1, 6.5 Hz), 4.71 (1H, d, J = 12.2 Hz), 4.79 (1H, d, J = 12.2

Hz), 4.92 (1H, d, J = 3.1 Hz), 6.59 (1H, s), 7.34−7.44 (4H, mz),

M

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7.51−7.58 (2H, m), 7.90−7.99 (4H, m); ¹³C NMR δ_C27.48 (CH₃),

27.52 (CH₃), 46.6 (CH₂), 48.3 (CH), 63.6 (CH₂), 83.0 (CH), 83.1

(CH), 93.4 (C), 101.4 (CH), 115.3 (C), 128.4 (2 × CH), 128.5 (2 ×

CH), 129.1 (C), 129.3 (C), 129.6 (2 × CH), 129.7 (2 × CH), 133.3

(CH), 133.6 (CH), 164.7 (C), 166.1 (C). Minor isomer: ¹H NMR δ_H

1.44 (3H, s), 1.46 (3H, s), 2.86 (1H, dd, J = 2.6, 5.0 Hz), 2.98 (1H, dd,

J = 3.7, 5.0 Hz), 3.49 (1H, ddd, J = 2.6, 3.7, 6.6 Hz), 3.88 (1H, dd, J = 4.8,

6.6 Hz), 4.69 (1H, d, J = 11.9 Hz), 4.74 (1H, d, J = 11.9 Hz), 4.88 (1H, d,

J = 4.8 Hz), 6.29 (1H, s), 7.39−7.49 (4H, mz), 7.56−7.63 (2H, m),

8.04−8.12 (4H, m); ¹³C NMR δ_C26.1 (2 × CH₃), 46.4 (CH₂), 49.1

(CH), 64.4 (CH₂), 80.9 (CH), 81.8 (CH), 90.1 (C), 98.9 (CH), 115.5

(C), 128.5 (2 × CH), 128.6 (2 × CH), 129.2 (C), 129.4 (C), 129.7 (2 ×

CH), 129.9 (2 × CH), 133.4 (CH), 133.5 (CH), 164.9 (C), 166.0 (C);

MS (EI-TOF) m/z (rel intensity) 425 [(M − CH₃)⁺, 6], 214 (12), 113

(31), 105 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Cacld for

C₂₃H₂₁O₈425.1236, found 425.1229. Anal. Calcd for C₂₄H₂₄O₈: C,

65.45; H, 5.49. Found: C, 65.22; H, 5.84.

101.4 (CH), 114.6 (C), 128.40 (2 × CH), 128.42 (2 × CH), 129.3 (C),

129.4 (C), 129.6 (2 × CH), 129.7 (2 × CH), 133.2 (CH), 133.5 (CH),

164.7 (C), 166.1 (C); MS (ESI-TOF) m/z (rel intensity) 620

[(M + Na)⁺, 100]; HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for

C₃₀H₃₉N₃O₈SiNa 620.2404, found 620.2413. Anal. Calcd for

C₃₀H₃₉N₃O₈Si: C, 60.28; H, 6.58; N, 7.03. Found: C, 60.25; H, 6.53;

N, 6.99.

6-Azido-5-O-(tert-butyldimethyl)silyl-2-C-(tert-butyldimethyl)-

silyloxymethyl-6-deoxy-2,3-O-isopropylidene-^D-mannofuranose

(34a). Sodium methoxide (54 mg, 1.0 mmol) was added to a solution of

azide 32 (300 mg, 0.50 mmol) in dry methanol (7.5 mL, 15 mL/mmol)

under nitrogen and in an ice/water bath. The reaction was stirred at

room temperature for 5 h, and then the solvent was removed under

reduced pressure. The residue was puriﬁed by column chromatography

(hexanes−EtOAc, 80:20 → 70:30) to yield diol 33 (175 mg, 0.45 mmol,

90%) as a colorless oil. To a solution of diol 33 (84 mg, 0.216 mmol) in

dry DCM (1.5 mL, 6 mL/mmol) at 0 °C and under nitrogen were added

diisopropylethylamine (75 μL, 0.434 mmol) and then TBSOTf (75 μL,

0.326 mmol), and the mixture was stirred for 24 h at room temperature.

It was poured into a brine solution and extracted several times with

DCM. Theorganic phase was dried over sodium sulfate and concentrated

under a vacuum. The resulting crude was puriﬁed by column chromato-

graphy (hexanes−EtOAc, 90:10 → 80:20) to obtain compound 34a

(70 mg, 0.139 mmol, 64%) as a colorless oil: IR 3520, 2931, 2859, 2103,

1469, 1254 cm⁻¹. NMR showed a mixture of anomers in a 4:1 ratio (only

the major anomer is described): ¹H NMR δ_H0.08 (3H, s), 0.09 (3H, s),

0.10 (3H, s), 0.13 (3H, s), 0.895 (9H, s), 0.904 (9H, s), 1.41 (3H, s), 1.51

(3H, s), 3.29 (1H, dd, J = 4.2, 12.7 Hz), 3.56 (1H, dd, J = 2.5, 12.7 Hz),

3.59 (1H, dd, J = 2.9, 8.9 Hz), 3.72 (1H, d, J = 10.6 Hz), 3.74 (1H, d, J =

10.6 Hz), 3.86 (1H, d, J = 11.6 Hz), 4.08 (1H, ddd, J = 2.5, 4.2, 8.9 Hz),

4.58 (1H, d, J = 2.9 Hz), 4.95 (1H, d, J = 11.6 Hz); ¹³C NMR δ_C−5.63

(CH₃), −5.61 (CH₃), −5.3 (CH₃), −4.2 (CH₃), 18.0 (C), 18.2 (C),

25.71 (3 × CH₃), 25.73 (3 × CH₃), 26.3 (CH₃), 26.9 (CH₃), 54.7 (CH₂),

63.3 (CH₂), 69.4 (CH), 75.9 (CH), 82.0 (CH), 88.6 (C), 97.2 (CH),

113.1 (C); MS (EI-TOF) m/z (rel intensity) 488 [(M − CH₃)⁺, 1], 446

[(M − C₄H₉)⁺, 1], 331 (1), 285 (1), 169 (4), 117 (10), 73 (100); HRMS

(EI-TOF) m/z [M − CH₃]⁺Calcd for C₂₁H₄₂N₃O₆Si₂488.2612, found

488.2610. Anal. Calcd for C₂₂H₄₅N₃O₆Si₂: C, 52.45; H, 9.00; N, 8.34.

Found: C, 52.60; H, 9.11; N, 8.00.

5-O-(tert-Butyldimethyl)silyl-2-C-(tert-butyldimethyl)-

silyloxymethyl-6-(tert-butoxycarbonyl)amino-6-deoxy-2,3-O-iso-

propylidene-^D-mannofuranose (35a). To a solution of compound 34a

(65 mg, 0.129 mmol) in EtOAc (2.0 mL, 15 mL/mmol) were added

di-tert-butyl dicarbonate (37 mg, 0.168 mmol) and 10% Pd/C (13 mg,

20% w/w). Three vacuum/hydrogen cycles were performed, and the

mixture was stirred under hydrogen atmosphere for 20 h. The reaction

mixture was then ﬁltered over a Celite pad, washed twice with ethyl

acetate, and the combined ﬁltrates were evaporated. The crude was

puriﬁed by column chromatography (hexanes−EtOAc, 90:10 → 80:20)

to yield compound 35a (70 mg, 0.121 mmol, 94%) as a colorless oil:

IR 3520, 3460, 2955, 2931, 2858, 1720, 1505, 1252, 1174 cm⁻¹. NMR

showed a mixture of anomers in a 3:1 ratio (only the major anomer is

described): ¹H NMR (500 MHz, 70 °C) δ_H0.09 (6H, s), 0.10 (3H, s),

0.12 (3H, s), 0.89 (9H, s), 0.91 (9H, s), 1.41 (3H, s), 1.44 (9H, s), 1.51

(3H, s), 3.29 (1H, dd, J = 4.6, 9.8 Hz), 3.40 (1H, dd, J = 4.1, 9.8 Hz), 3.41

(1H, dd, J = 3.1, 8.5 Hz), 3.70 (1H, d, J = 12.0 Hz), 3.73 (1H, d, J = 10.4

Hz), 3.75 (1H, d, J = 10.4 Hz), 4.02 (1H, ddd, J = 4.1, 4.6, 8.5 Hz), 4.57

(1H, d, J = 3.1 Hz), 4.77, (1H, bs), 4.90 (1H, d, J = 12.0 Hz); ¹³C NMR

(125.7 MHz, 70 °C) δ_C−5.61 (CH₃), −5.59 (CH₃), −5.1 (CH₃), −4.4

(CH₃), 18.1 (C), 18.2 (C), 25.8 (6 × CH₃), 26.6 (CH₃), 27.0 (CH₃),

28.5 (3 × CH₃), 45.1 (CH₂), 63.6 (CH₂), 68.7 (CH), 78.0 (CH), 78.9

(C), 82.5 (CH), 88.8 (C), 97.6 (CH), 113.2 (C), 156.0 (C); MS (ESI-

TOF) m/z (rel intensity) 600 [(M + Na)⁺, 100]; HRMS (ESI-TOF)

m/z [M + Na]⁺Calcd for C₂₇H₅₅NO₈Si₂Na 600.3364, found 600.3372.

6-Azido-5-O-(tert-butyldimethyl)silyl-6-deoxy-2,3-O-isopropyli-

dene-2-C-pivaloyloxymethyl-^D-mannofuranose (34b). To a solution

of diol 33 (80 mg, 0.20 mmol) in dry pyridine (1.0 mL, 5 mL/mmol)

were added, under nitrogen and at 0 °C, DMAP (catalytic amount) and

pivaloyl chloride (32 μL, 0.260 mmol), and then the mixture was

warmed to room temperature and stirred for 24 h. The reaction was

6-Azido-1-O-benzoyl-2-C-benzoyloxymethyl-6-deoxy-2,3-O-iso-

propylidene-^D-mannofuranose (31). To a solution of epoxide 30

(1.82 g, 4.14 mmol) in dry DMF (20 mL, 5 mL/mmol), under nitrogen,

were added sodium azide (1.88 g, 28.95 mmol) and ammonium chloride

(222 mg, 4.14 mmol), and the mixture was stirred at 80 °C for 4 h. The

solvent was removed under a vacuum, and the residue was extracted with

EtOAc and water. The organic phase was dried over anhydrous sodium

sulfate and concentrated under a vacuum. The crude was puriﬁed by

column chromatography (hexanes−EtOAc, 80:20) to aﬀord compound

31 (1.59 g, 3.29 mmol, 79%) as a colorless oil: IR 3612, 3506, 3068,

2992, 2939, 2104, 1733, 1271, 1108 cm⁻¹. NMR showed a mixture of

1

anomers in a 5:1 ratio. Major isomer: H NMR δ_H1.48 (3H, s), 1.56

(3H, s), 2.60 (1H, d, J = 5.0 Hz), 3.48 (1H, dd, J = 6.0, 12.9 Hz), 3.60

(1H, dd, J = 3.4, 12.8 Hz), 4.16−4.24 (1H, m), 4.21 (1H, dd, J = 2.7, 6.9

Hz), 4.70 (1H, d, J = 12.2 Hz), 4.80 (1H, d, J = 12.2 Hz), 4.93 (1H, d, J =

2.7 Hz), 6.57 (1H, s), 7.35−7.44 (4H, m), 7.52−7.58 (2H, m), 7.91−

7.99 (4H, m); ¹³C NMR δ_C27.6 (2 × CH₃), 54.1 (CH₂), 63.6 (CH₂),

68.9 (CH), 81.8 (CH), 82.8 (CH), 93.3 (C), 101.4 (CH), 115.4 (C),

128.46 (2 × CH), 128.51 (2 × CH), 129.1 (C), 129.3 (C), 129.65 (2 ×

CH), 129.72 (2 × CH), 133.3 (CH), 133.6 (CH), 164.6 (C), 166.1 (C).

Minor isomer: ¹H NMR δ_H1.42 (3H, s), 1.43 (3H, s), 2.68 (1H, d, J =

4.8 Hz), 3.52 (1H, dd, J = 6.4, 13.0 Hz), 3.67 (1H, dd, J = 2.9, 13.0 Hz),

4.16−4.24 (1H, m), 4.37 (1H, dddd, J = 2.9, 4.8, 6.4, 9.0 Hz), 4.68 (1H,

d, J = 11.9 Hz), 4.73 (1H, d, J = 11.9 Hz), 4.91 (1H, d, J = 5.0 Hz), 6.28

(1H, s), 7.44−7.50 (4H, m), 7.57−7.63 (2H, m), 8.06−8.09 (4H, m);

¹³C NMR δ_C26.1 (CH₃), 26.3 (CH₃), 53.8 (CH₂), 64.5 (CH₂), 70.0

(CH), 79.8 (CH), 81.5 (CH), 90.4 (C), 98.9 (CH), 116.0 (C), 128.5

(2 × CH), 128.6 (2 × CH), 129.1 (C), 129.4 (C), 129.77 (2 × CH),

129.83 (2 × CH), 133.50 (CH), 133.52 (CH), 164.8 (C), 166.0 (C);

MS (ESI-TOF) m/z (rel intensity) 506 [(M + Na)⁺, 100]; HRMS

(ESI-TOF) m/z [M + Na]⁺Calcd for C₂₄H₂₅N₃O₈Na 506.1539, found

506.1531. Anal. Calcd for C₂₄H₂₅N₃O₈: C, 59.62; H, 5.21; N, 8.69.

Found: C, 59.35; H, 5.47; N, 8.98.

6-Azido-1-O-benzoyl-2-C-benzoyloxymethyl-5-O-(tert-

butyldimethyl)silyl-6-deoxy-2,3-O-isopropylidene-^D-mannofura-

nose (32). To a solution of alcohol 31 (215 mg, 0.445 mmol) in dry

DCM (3 mL, 7 mL/mmol) at 0 °C and under nitrogen, was added

diisopropylethylamine (155 μL, 0.89 mmol) and tert-butyldimethylsilyl

triﬂate (153 μL, 0.668 mmol), and the mixture was stirred for 12 h.

Then, it was poured into a saturated aqueous ammonium chloride

solution and extracted with DCM. The organic phase was dried over

sodium sulfate, concentrated under a vacuum and puriﬁed by column

chromatography (hexanes−EtOAc, 90:10 → 80:20) to yield compound

32 (226 mg, 0.379 mmol, 85%) as a colorless oil: IR 2932, 2858, 2104,

1734, 1270, 1106 cm⁻¹. NMR showed a mixture of anomers in a 5:1 ratio

(only the major anomer is described): ¹H NMR δ_H0.15 (3H, s), 0.16

(3H, s), 0.92 (9H, s), 1.43 (3H, s), 1.53 (3H, s), 3.34 (1H, dd, J = 4.0,

13.0 Hz), 3.57 (1H, dd, J = 2.6, 13.0 Hz), 4.19 (1H, ddd, J = 2.6, 4.0, 8.8

Hz), 4.31 (1H, dd, J = 2.9, 8.8 Hz), 4.71 (1H, d, J = 11.9 Hz), 4.78 (1H,

d, J = 11.9 Hz), 4.79 (1H, d, J = 2.9 Hz), 6.54 (1H, s), 7.34−7.43 (4H,

m), 7.50−7.56 (2H, m), 7.91−7.98 (4H, m); ¹³C NMR δ_C−5.2 (CH₃),

−4.3 (CH₃), 18.0 (C), 25.7 (3 × CH₃), 27.2 (CH₃), 27.4 (CH₃),

54.6 (CH₂), 63.9 (CH₂), 69.1 (CH), 81.8 (CH), 82.3 (CH), 93.1 (C),

N

dx.doi.org/10.1021/jo401041s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

poured into 10% aqueous HCl and extracted twice with EtOAc. The

organic phase was washed with sodium bicarbonate and brine, dried over

sodium sulfate and concentrated under a vacuum. The crude was

puriﬁed by column chromatography (hexanes−EtOAc, 95:5 → 90:10)

to yield compound 34b (70 mg, 0.148 mmol, 74%) as a colorless oil: IR

3611, 3524, 2957, 2932, 2103, 1737, 1253, 1101 cm⁻¹. NMR showed a

mixture of anomers in a 4:1 ratio (only the major anomer is described):

¹H NMR δ_H0.10 (3H, s), 0.13 (3H, s), 0.89 (9H, s), 1.23 (9H, s), 1.46

(3H, s), 1.53 (3H, s), 3.31 (1H, dd, J = 3.9, 13.0 Hz), 3.56 (1H, dd, J =

2.5, 13.0 Hz), 3.61 (1H, dd, J = 2.8, 8.8 Hz), 3.87 (1H, d, J = 11.7 Hz),

4.10 (1H, ddd, J = 2.5, 3.8, 8.7 Hz), 4.21 (1H, d, J = 11.9 Hz), 4.28 (1H,

d, J = 11.9 Hz), 4.53 (1H, d, J = 2.8 Hz), 4.90 (1H, d, J = 11.6 Hz); ¹³C

NMR δ_C−5.3 (CH₃), −4.2 (CH₃), 18.0 (C), 25.7 (3 × CH₃), 26.3

(CH₃), 26.8 (CH₃), 27.1 (3 × CH₃), 38.9 (C), 54.6 (CH₂), 63.9 (CH₂),

69.2 (CH), 75.4 (CH), 81.8 (CH), 87.2 (C), 97.7 (CH), 113.9 (C),

177.8 (C); MS (EI-TOF) m/z (rel intensity) 458 [(M − CH₃)⁺, 2], 358

(13), 238 (12), 57 (100); HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for

C₂₀H₃₆N₃O₇Si 458.2323, found 458.2338. Anal. Calcd for

C₂₁H₃₉N₃O₇Si: C, 53.25; H, 8.30; N, 8.87. Found: C, 53.42; H, 8.19;

N, 8.72.

5-O-(tert-Butyldimethyl)silyl-6-(tert-butoxycarbonyl)amino-6-

deoxy-2,3-O-isopropylidene-2-C-pivaloyloxymethyl-^D-mannofura-

nose (35b). To a solution of azide 34b (70 mg, 0.148 mmol) in EtOAc

(2.0 mL, 15 mL/mmol) were added di-tert-butyl dicarbonate (48 mg,

0.22 mmol) and 10% Pd/C (14 mg, 20% w/w). Three vacuum/hydrogen

cycles were performed, and the mixture was stirred under hydrogen

atmosphere for 3 h. The reaction mixture was then ﬁltered over a Celite

pad, washed twice with ethyl acetate, and the combined ﬁltrates were

evaporated. The crude was puriﬁed by column chromatography

(hexanes−EtOAc, 90:10 → 80:20) to yield compound 35b (73 mg,

0.133 mmol, 90%) as a colorless oil: IR 3460, 2932, 1726, 1504, 1250 cm⁻¹.

NMR showed a mixture of anomers in a 2:1 ratio (only the major anomer is

described): ¹H NMR (500 MHz, 70 °C) δ_H0.09 (3H, s), 0.12 (3H, s), 0.88

(9H, s), 1.22 (9H, s), 1.43 (9H, s), 1.45 (3H, s), 1.53 (3H, s), 3.28 (1H,

ddd, J = 4.4, 4.8, 13.7 Hz), 3.407 (1H, ddd, J = 4.0, 7.1, 13.7 Hz), 3.411 (1H,

dd, J = 3.1, 8.5 Hz), 4.02 (1H, ddd, J = 4.0, 4.8, 8.5 Hz), 4.21 (1H, d, J = 12.0

Hz), 4.26 (1H, d, J = 12.0 Hz), 4.49 (1H, d, J = 3.1 Hz), 4.76 (1H, bs), 4.84

(1H, s); ¹³C NMR (125.7 MHz, 70 °C) δ_C−5.1 (CH₃), −4.4 (CH₃), 18.1

(C), 25.8 (3 × CH₃), 26.6 (CH₃), 26.9 (CH₃), 27.2 (3 × CH₃), 28.5 (3 ×

CH₃), 38.9 (C), 45.0 (CH₂), 64.0 (CH₂), 68.6 (CH), 77.6 (CH), 79.0 (C),

82.3 (CH), 87.5 (C), 98.0 (CH), 113.9 (C), 155.9 (C), 177.7 (C); MS

(ESI-TOF) m/z (rel intensity) 570 [(M + Na)⁺, 100]; HRMS (ESI-TOF)

m/z [M + Na]⁺Calcd for C₂₆H₄₉NO₉SiNa 570.3074, found 570.3073.

General Procedure for the Synthesis of Iminosugars 36−46. A

solution of the corresponding hemiacetal (1 mmol) in dry DCM or

DCE (40 mL) containing PhIO (2.0−2.5 equiv) and iodine (0.5−1.2

equiv) was irradiated with 80 W tungsten-ﬁlament lamps at room

temperature for 1−20 h. The reaction mixture was then poured into

aqueous sodium thiosulfate and extracted with DCM. The organic phase

was dried and concentrated in vacuo. Column chromatography of the

residue (hexanes−EtOAc mixtures) aﬀorded the desired cyclic imino-

compounds.

5-(tert-Butoxycarbonyl)amino-1-O-(tert-butyldimethyl)silyl-5-

deoxy-4-O-formyl-2,3-O-isopropylidene-α-^D-ribulofuranose (36).

Following the general procedure [DCM, PhIO (2.2 equiv), I₂(1.2

equiv)], compound 4a (53 mg, 0.12 mmol) aﬀorded, after 1 h, the

iminosugar 36 (32 mg, 0.07 mmol, 61%) as a colorless oil: [α]_D−21.7

(c 0.18); IR 2980, 2931, 2858, 1737, 1715, 1367, 1254 cm⁻¹; ¹H NMR

(500 MHz, 70 °C) δ_H0.07 (3H, s), 0.08 (3H, s), 0.91 (9H, s), 1.39 (3H,

s), 1.46 (9H, s), 1.49 (3H, s), 3.53 (1H, dd, J = 8.2, 9.8 Hz), 3.75 (1H, d,

J = 10.7 Hz), 3.88 (1H, dd, J = 8.2, 9.8 Hz), 4.12−4.56 (1H, bs), 4.61

(1H, d, J = 3.9 Hz), 5.17 (1H, ddd, J = 3.9, 8.2, 8.2 Hz), 8.06 (1H, s); ¹³C

NMR (125.7 MHz, 70 °C) δ_C−5.5 (2 × CH₃), 18.2 (C), 25.8 (3 ×

CH₃), 26.7 (CH₃), 27.4 (CH₃), 28.4 (3x CH₃), 48.6 (CH₂), 63.9 (CH₂),

68.5 (CH), 80.4 (C), 82.6 (CH), 99.9 (C), 113.7 (C), 137.7 (C), 159.8

(CH); MS (EI-TOF) m/z (rel intensity) 431 (M⁺, 1), 318 (100), 216

(58), 186 (23); HRMS (EI-TOF) m/z [M]⁺Calcd for C₂₀H₃₇NO₇Si

431.2339, found 431.2355. Anal. Calcd for C₂₀H₃₇NO₇Si: C, 55.66; H,

8.64; N, 3.25. Found: C, 55.59; H, 8.45; N, 3.20.

5-(tert-Butoxycarbonyl)amino-5-deoxy-4-O-formyl-2,3-O-isopro-

pylidene-1-O-pivaloyl-α-^D-ribulofuranose (37). Following the general

procedure [DCM, PhIO (2.2 equiv), I₂(1.2 equiv)], compound 4b

(57 mg, 0.14 mmol) aﬀorded, after 2 h, the iminosugar 37 (40 mg,

0.10 mmol, 71%) as a colorless oil: [α]_D−43.1 (c 0.10); IR 2980, 1738,

1705, 1394, 1173 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆, 75 °C) δ_H1.17

(9H, s), 1.38 (3H, s), 1.406 (9H, s), 1.414 (3H, s), 3.41 (1H, dd, J = 9.8,

9.8 Hz), 3.83 (1H, dd, J = 7.9, 9.8 Hz), 4.32 (1H, d, J = 11.3 Hz), 4.68

(1H, d, J = 11.3 Hz), 4.72 (1H, d, J = 3.9 Hz), 5.10 (1H, ddd, J = 3.9, 7.9,

9.8 Hz), 8.24 (1H, s); ¹³C NMR (125.7 MHz, DMSO-d₆, 75 °C) δ_C26.3

(CH₃), 26.7 (3 × CH₃), 27.0 (CH₃), 27.8 (3 × CH₃), 38.1 (C), 47.6

(CH₂), 62.5 (CH₂), 67.0 (CH), 79.9 (C), 81.3 (CH), 96.9 (C), 112.9

(C), 152.2 (C), 161.3 (CH), 176.4 (C); MS (EI-TOF) m/z (rel

intensity) 386 [(M − CH₃)⁺, 1], 286 (25), 255 (36), 186 (99), 57 (100);

HRMS (EI-TOF) m/z [M − CH₃]⁺Calcd for C₁₈H₂₈NO₈386.1815,

found 386.1810. Anal. Calcd for C₁₉H₃₁NO₈: C, 56.85; H, 7.78; N, 3.49.

Found: C, 57.06; H, 8.17; N, 3.31.

5-(tert-Butoxycarbonyl)amino-1-O-(tert-butyldimethyl)silyl-5-

deoxy-4-O-formyl-2,3-O-isopropylidene-β-^D-xylulofuranose (38).

Following the general procedure [DCM, PhIO (2.2 equiv), I₂(1.2 equiv)],

compound 8a (44 mg, 0.10 mmol) aﬀorded, after 5 h, the compound 38

(15 mg, 0.04 mmol, 35%) as a colorless oil: [α]_D+13.8 (c 0.174); IR

2931, 2857, 1737, 1702, 1370, 1216 cm⁻¹; ¹H NMR (500 MHz, 70 °C)

δ_H0.10 (6H, s), 0.93 (9H, s), 1.41 (3H, s), 1.43 (3H, s), 1.49 (9H, s), 3.55

(1H, d, J = 12.7 Hz), 3.86−3.94 (1H, m), 3.96 (1H, dd, J = 4.5, 12.7 Hz),

4.32 (1H, d, J = 10.7 Hz), 4.63 (1H, s), 5.23 (1H, d, J = 4.5 Hz), 8.01 (1H,

s); ¹³C NMR (125.7 MHz, 70 °C) δ_C−5.5 (CH₃), −5.3 (CH₃), 18.4 (C),

25.9 (3 × CH₃), 27.0 (CH₃), 27.7 (CH₃), 28.5 (3 × CH₃), 52.4 (CH₂),

63.7 (CH₂), 72.0 (CH), 80.5 (C), 84.4 (CH), 101.1 (C), 112.9 (C),

153.6 (C), 159.5 (CH); MS (EI-TOF) m/z (rel intensity) 431 (M⁺, 1),

416 (1), 318 (41), 216 (31), 170 (31), 57 (100); HRMS (EI-TOF) m/z

[M]⁺Calcd for C₂₀H₃₇NO₇Si 431.2339, found 431.233. Anal. Calcd

for C₂₀H₃₇NO₇Si: C, 55.66; H, 8.64; N, 3.25. Found: C, 55.73; H, 8.70;

N, 3.27.

5-(tert-Butoxycarbonyl)amino-5-deoxy-4-O-formyl-2,3-O-isopro-

pylidene-1-O-pivaloyl-β-^D-xylulofuranose (39). Following the general

procedure [DCE, PhIO (2.5 equiv), I₂(1.1 equiv)], compound 8b

(200 mg, 0.50 mmol) aﬀorded, after 2 h, the iminosugar 39 (115 mg,

0.29 mmol, 58%) as a colorless oil: [α]_D+35.6 (c 0.89); IR 2981, 2936,

1736, 1704, 1394, 1159 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆, 70 °C)

δ_H1.17 (9H, s), 1.37 (3H, s), 1.38 (3H, s), 1.42 (9H, s), 3.51 (1H, d, J =

12.8 Hz), 3.87 (1H, dd, J = 4.7, 12.8 Hz), 4.35 (1H, d, J = 11.6 Hz), 4.52

(1H, s), 4.67 (1H, d, J = 11.6 Hz), 5.13 (1H, d, J = 4.7 Hz), 8.21 (1H, s);

¹³C NMR (125.7 MHz, 70 °C) δ_C27.17 (CH₃), 27.23 (3 × CH₃), 27.3

(CH₃), 28.4 (3 × CH₃), 38.9 (C), 52.1 (CH₂), 63.5 (CH₂), 71.6 (CH),

81.1 (C), 84.8 (CH), 98.7 (C), 113.0 (C), 153.4 (C), 159.3 (CH), 177.5

(C); MS (EI-TOF) m/z (rel intensity) 401 (M⁺, 1), 355 (3), 230 (37),

128 (100), 57 (100); HRMS (EI-TOF) m/z [M]⁺Calcd for C₁₉H₃₁NO₈

401.2050, found 401.2053. Anal. Calcd for C₁₉H₃₁NO₈: C, 56.85; H,

7.78; N, 3.49. Found: C, 56.92; H, 7.75; N, 3.70.

5-(tert-Butoxycarbonyl)amino-1,6-di-O-(tert-butyldimethyl)silyl-

5-deoxy-4-O-formyl-2,3-O-isopropylidene-α-^L-sorbofuranose (40)

and 5-(tert-Butoxycarbonyl)amino-6-O-(tert-butyldimethyl)silyl-5-

deoxy-4-O-formyl-2,3-O-isopropylidene-α-^L-sorbofuranose (40a).

Following the general procedure [DCM, PhIO (2.0 equiv), I₂(1.2 equiv)],

compound 16a (50 mg, 0.09 mmol) aﬀorded after 4 h, the iminosugar 40

(23 mg, 0.04 mmol, 46%) along with other minor cyclized compounds, of

which 40a (4 mg, 0.009 mmol, 10%) could be characterized. Compound

40. Colorless oil: [α]_D+56.2 (c 0.4); IR 2955, 2930, 2858, 1739, 1703,

1471, 1255, 1161, 1090 cm⁻¹; ¹H NMR (500 MHz, 70 °C) δ_H0.04 (3H,

s), 0.06 (3H, s), 0.081 (3H, s), 0.084 (3H, s), 0.88 (9H, s), 0.92 (9H, s),

1.39 (3H, s), 1.43 (3H, s), 1.48 (9H, s), 3.64 (1H, dd, J = 9.1, 9.3 Hz),

3.78 (1H, d, J = 10.7 Hz), 4.16 (1H, dd, J = 4.6, 9.3 Hz), 4.28 (1H, ddd, J =

4.6, 5.0, 9.1 Hz), 4.30 (1H, d, J = 10.7 Hz), 4.52 (1H, d, J = 1.0 Hz), 5.49

(1H, ddd, J = 0.7, 1.0, 5.0 Hz), 8.04 (1H, s); ¹³C NMR (125.7 MHz,

70 °C) δ_C−5.52 (CH₃), −5.47 (CH₃), −5.3 (CH₃), −5.2 (CH₃), 18.2

(C), 18.4 (C), 25.9 (3 × CH₃), 26.0 (3 × CH₃), 26.9 (CH₃), 27.7 (CH₃),

28.5 (3 × CH₃), 60.0 (CH₂), 61.6 (CH), 63.9 (CH₂), 72.4 (CH), 80.6

(C), 82.4 (CH), 102.4 (C), 112.6 (C), 154.4 (C), 159.4 (CH); MS (ESI-

TOF) m/z (rel intensity) 576 [(M + H)⁺, 100], 598 [(M + Na)⁺, 44].

O

dx.doi.org/10.1021/jo401041s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

HRMS (ESI-TOF) m/z [M + H]⁺Calcd for C₂₇H₅₄NO₈Si₂576.3388,

found 576.3381. Compound 40a. Colorless oil: [α]_D+14.5 (c 0.1); ¹H

NMR (500 MHz) δ_H0.15 (6H, s), 0.95 (9H, s), 1.38 (3H, s), 1.42 (3H,

s), 1.49 (9H, s), 3.73 (1H, d, J = 10.2 Hz), 3.75−3.81 (1H, m), 4.11 (1H,

dd, J = 4.0, 11.2 Hz), 4.19 (1H, ddd, J = 4.0, 4.2, 8.7 Hz), 4.34 (1H, d, J =

10.2 Hz), 4.36 (1H, d, J = 7.0 Hz), 4.49 (1H, d, J = 10.2 Hz), 4.84 (1H, dd,

J = 4.2, 10.2 Hz), 8.05 (1H, s); ¹³C NMR (125.7 MHz) δ_C−5.5 (CH₃),

−5.4 (CH₃), 18.4 (C), 25.9 (3 × CH₃), 26.5 (CH₃), 27.4 (CH₃), 28.4

(3 × CH₃), 60.9 (CH₂), 61.4 (CH), 65.3 (CH₂), 70.3 (CH), 81.2 (C),

87.6 (CH), 101.4 (C), 112.5 (C), 159.5 (C), 160.4 (CH); MS (EI-TOF)

m/z (rel intensity) 462 [(M + H)⁺, 1], 446 (1), 334 (16), 304 (44), 246

(26), 57 (100). HRMS (EI-TOF) m/z [M + H]⁺Calcd for C₂₁H₄₀NO₈Si

462.2523, found 462.2509.

5-(tert-Butoxycarbonyl)amino-6-O-(tert-butyldimethyl)silyl-5-

deoxy-4-O-formyl-2,3-O-isopropylidene-1-O-pivaloyl-α-^L-sorbofura-

nose (41). Following the general procedure [DCM, PhIO (2.2 equiv), I₂

(1.2 equiv)], compound 16b (27 mg, 0.05 mmol) aﬀorded, after 2 h,

compound 41 (16 mg, 0.029 mmol, 58%) as a colorless oil: [α]_D+58.2

(c 0.29); IR 2957, 2931, 2858, 1736, 1706, 1479, 1367, 1255 cm⁻¹;

¹H NMR (500 MHz, 70 °C) δ_H0.04 (3H, s), 0.07 (3H, s), 0.89 (9H, s),

1.23 (9H, s), 1.43 (3H, s), 1.44 (3H, s), 1.49 (9H, s), 3.66 (1H, dd, J =

9.3, 9.3 Hz), 4.18 (1H, dd, J = 4.3, 9.3 Hz), 4.29 (1H, d, J = 12.0 Hz),

4.27−4.31 (1H, m), 4.40 (1H, s), 4.85 (1H, d, J = 12.0 Hz), 5.51 (1H, d,

J = 4.7 Hz), 8.04 (1H, s); ¹³C NMR (125.7 MHz, 70 °C) δ_C−5.5 (CH₃),

−5.4 (CH₃), 18.2 (C), 25.9 (3 × CH₃), 27.1 (CH₃), 27.3 (3 × CH₃),

27.7 (CH₃), 28.4 (3 × CH₃), 38.9 (C), 59.9 (CH₂), 61.5 (CH), 64.0

(CH₂), 72.2 (CH), 81.2 (C), 82.8 (CH), 100.3 (C), 112.9 (C.), 154.0

(C), 159.3 (CH), 177.6 (C); MS (ESI-TOF) m/z (rel intensity) 568

[(M + Na)⁺, 100]; HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for

C₂₆H₄₇NO₉SiNa 568.2918, found 568.2911. Anal. Calcd for

C₂₆H₄₇NO₉Si: C, 57.22; H, 8.68; N, 2.57. Found: C, 57.08; H, 8.66;

N, 2.70.

(rel intensity) 358 [(M + Na)⁺, 100]; HRMS (ESI-TOF) m/z

[M + Na]⁺Calcd for C₁₄H₂₂FNO₇Na 358.1278, found 358.1277.

5-(tert-Butoxycarbonyl)amino-5,6-dideoxy-6-ﬂuoro-4-O-formyl-

2,3-O-isopropylidene-1-O-pivaloyl-α-^L-sorbofuranose (43) and 5-

Amino-5,6-dideoxy-6-ﬂuoro-4-O-formyl-2,3-O-isopropylidene-1-O-

pivaloyl-α-^L-sorbofuranose (43a). Following the general procedure

[DCE, PhIO (2.5 equiv), I₂(0.5 equiv)], compound 23b (47 mg, 0.108

mmol) aﬀorded, after 1 h, the ﬂuorinated iminosugars 43 (18 mg, 0.042

mmol, 39%) and 43a (3 mg, 0.009 mmol, 8%). Compound 43.

Colorless oil: [α]_D+76.2 (c 1.09); IR 2985, 1730, 1699, 1480, 1377,

1

1151, 1016 cm⁻¹; H NMR (500 MHz, 70 °C) δ_H1.24 (9H, s), 1.44

(3H, s), 1.45 (3H, s), 1.50 (9H, s), 4.34 (1H, d, J = 12.0 Hz), 4.46 (1H, d,

J = 1.6 Hz), 4.46−4.52 (1H, m), 4.54 (1H, ddd, J = 7.7, 8.8 Hz, ²J_FH

45.4 Hz), 4.81 (1H, d, J = 12.0 Hz), 4.85 (1H, ddd, J = 3.8, 8.8 Hz, ²J_FH

=

54.2 Hz), 5.41 (1H, ddd, J = 1.3, 1.6, 5.5 Hz), 8.08 (1H, s); ¹³C NMR δ_C

27.0 (CH₃), 27.2 (3 × CH₃), 27.7 (CH₃), 28.2 (3 × CH₃), 38.8 (C), 59.0

(CH, d, ²J_FC= 24.7 Hz), 63.5 (CH₂), 71.5 (CH), 79.5 (CH₂, d, ¹J_FC

=

173.7 Hz), 81.9 (C), 82.4 (CH), 99.7 (C), 113.2 (C), 155.4 (C), 159.3

(CH), 177.7 (C); EM (ESI-TOF) m/z (rel intensity) 456 [(M + Na)⁺,

100]; HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for C₂₀H₃₂FNO₈Na

456.2010, found 456.2011. Anal. Calcd for C₂₀H₃₂FNO₈: C, 55.42; H,

7.44; N, 3.23. Found: C, 55.50; H, 7.66; N, 3.36. Compound 43a.

Colorless oil: [α]_D+50.8 (c 0.25); IR 3353, 2989, 1731, 1677, 1480,

1

1375, 1149, 1112 cm⁻¹; ¹⁹F NMR δ_F−227.8 (1F, s); H NMR (500

MHz) δ_H1.25 (9H, s), 1.421 (3H, s), 1.425 (3H, s), 4.29 (1H, d, J = 12.0

Hz), 4.42−4.47 (1H, m), 4.490 (1H, d, J = 12.0 Hz), 4.491 (1H, s), 4.52

(1H, d, J = 4.7 Hz), 4.66 (1H, ddd, J = 8.7, 8.7 Hz, ²J_FH= 45.7 Hz), 5.20

(1H, ddd, J = 4.7, 8.7 Hz, ²J_FH= 46.3 Hz), 8.13 (1H, s); ¹³C NMR δ_C

26.6 (CH₃), 27.2 (3 × CH₃), 27.5 (CH₃), 38.9 (C), 59.7 (CH, d, ²J_FC

=

24.4 Hz), 64.3 (CH₂), 70.9 (CH, d, ³J_FC= 2.1 Hz), 79.8 (CH₂, d, ¹J_FC

166.3 Hz), 85.1 (CH), 98.6 (C), 114.1 (C), 163.4 (CH), 177.8 (C); MS

(ESI-TOF) m/z (rel intensity) 356 [(M + Na)⁺, 100]; HRMS (ESI-

TOF) m/z [M + Na]⁺Calcd for C₁₅H₂₄FNO₆Na 356.1485, found

356.1488.

5-(tert-Butoxycarbonyl)amino-1-(tert-butyldimethyl)silyl-5,6-di-

deoxy-6-ﬂuoro-4-O-formyl-2,3-O-isopropylidene-α-^L-sorbofuranose

(42) and 4-(tert-Butoxycarbonyl)amino-4,5-dideoxy-5-ﬂuoro-3-O-

formyl-1,2-O-isopropylidene-^L-xylonic acid (42a). To a solution of

23a (38 mg, 0.081 mmol) in dry DCE (4 mL, 50 mL/mmol) were added

PhIO (45 mg, 0.204 mmol), I₂(10 mg, 0.04 mmol) and NaHCO₃

(40 mg, 100% w/w), and the resulting suspension was irradiated with

two 80 W tungsten-ﬁlament lamps at room temperature for 1.5 h. Then,

the reaction mixture was poured into aqueous sodium thiosulfate and

extracted with DCM. The organic phase was dried over sodium sulfate,

concentrated under a vacuum and puriﬁed by rotatory chromatography

(hexanes−EtOAc, 90:10 → 70:30) to aﬀord the ﬂuorinated iminosugars

42 (9.5 mg, 0.021 mmol, 25%) and 42a (13 mg, 0.038 mmol, 47%).

Compound 42. Colorless oil: [α]_D+96.2 (c 0.55); IR (CHCl₃) 2955,

2935, 1731, 1711, 1696, 1385, 1370, 1164, 1149 cm⁻¹; ¹H NMR (500

MHz, 70 °C) δ_H0.09 (6H, s), 0.93 (9H, s), 1.41 (3H, s), 1.44 (3H, s),

1.49 (9H, s), 3.82 (1H, d, J = 10.7 Hz), 4.24 (1H, d, J = 10.7 Hz), 4.46−

4.51 (1H, m), 4.51 (1H, ddd, J = 8.5, 8.5 Hz, ²J_FH= 45.1 Hz), 4.58 (1H,

d, J = 1.3 Hz), 4.81 (1H, ddd, J = 3.8, 8.5 Hz, ²J_FH= 41.0 Hz), 5.53 (1H,

dd, J = 1.3, 5.0 Hz), 8.07 (1H, s); ¹³C NMR (125.7 MHz, 70 °C) δ_C−5.5

(CH₃), −5.2 (CH₃), 18.4 (C), 26.0 (3 × CH₃), 27.0 (CH₃), 27.8 (CH₃),

28.4 (3 × CH₃), 59.4 (CH, d, ²J_FC= 25.4 Hz), 63.9 (CH₂), 72.2 (CH),

79.8 (CH₂, d, ¹J_FC= 169.5 Hz), 81.3 (C), 83.0 (CH), 101.8 (C), 113.1

(C), 156.2 (C), 159.2 (CH); MS (ESI-TOF) m/z (rel intensity) 486

[(M + Na)⁺, 100]; HRMS (ESI-TOF) m/z [M + Na]⁺Calcd for

C₂₁H₃₈FNO₇SiNa 486.2299, found 486.2299. Anal. Calcd for

C₂₁H₃₈FNO₇Si: C, 54.40; H, 8.26; N, 3.02. Found: C, 54.37; H, 8.46;

N, 3.12. Compound 42a. Colorless oil: [α]_D+6.3 (c 0.65); IR (CHCl₃)

3438, 2985, 1797, 1736, 1713, 1503, 1272, 1157 cm⁻¹; ¹⁹F NMR δ_F

−231.0 (1F, s); ¹H NMR (500 MHz) δ_H1.43 (9H, s), 1.56 (3H, s), 1.66

(3H, s), 4.34 (1H, ddddd, J = 3.5, 4.3, 6.0, 9.2 Hz, ³J_FH= 25.5 Hz), 4.42

(1H, ddd, J = 4.3, 9.9 Hz, ²J_FH= 47.0 Hz), 4.56 (1H, ddd, J = 3.5, 9.9 Hz,

²J_FH= 46.2 Hz), 4.67 (1H, d, J = 3.5 Hz), 4.98 (1H, d, J = 9.2 Hz), 5.57

5-(tert-Butoxycarbonyl)amino-5,6-dideoxy-4-O-formyl-2,3-O-iso-

propylidene-1-O-pivaloyl-α-^L-sorbofuranose (44). Following the

general procedure [DCE, PhIO (2.5 equiv), I₂(1.1 equiv)], compound

29 (30 mg, 0.072 mmol) was stirred at 80 °C for 2.5 h to aﬀord

iminosugar 44 (15 mg, 0.036 mmol, 50%) as a colorless oil: [α]_D+57.5

1

(c 0.57); IR (CHCl₃) 2985, 1729, 1701, 1458, 1373, 1156 cm⁻¹; H

NMR (500 MHz, 70 °C) δ_H1.24 (9H, s), 1.28 (3H, d, J = 6.3 Hz), 1.42

(3H, s), 1.43 (3H, s), 1.50 (9H, s), 4.31 (1H, dddd, J = 6.0, 6.3, 6.3, 6.3

Hz), 4.32 (1H, d, J = 12.0 Hz), 4.38 (1H, d, J = 1.3 Hz), 4.83 (1H, d, J =

12.0 Hz), 5.34 (1H, ddd, J = 1.3, 1.3, 6.0 Hz), 8.08 (1H, dd, J = 0.8, 1.3

Hz); ¹³C NMR δ_C14.3 (CH₃), 27.0 (CH₃), 27.2 (3 × CH₃), 27.6

(CH₃), 28.3 (3 × CH₃), 38.8 (C), 56.1 (CH), 63.7 (CH₂), 73.5 (CH),

81.0 (C), 82.2 (CH), 99.6 (C), 112.8 (C), 154.1 (C), 159.6 (CH), 177.8

(C); EM (ESI-TOF) m/z (rel intensity) 438 [(M + Na)⁺, 100]; HRMS

(ESI-TOF) m/z [M + Na]⁺Calcd for C₂₀H₃₃NO₈Na 438.2104, found

438.2112. Anal. Calcd for C₂₀H₃₃NO₈: C, 57.82; H, 8.01; N, 3.37.

Found: C, 57.87; H, 8.34; N, 3.39.

5-(tert-Butoxycarbonyl)amino-4-(tert-butyldimethyl)silyl-5-

deoxy-3-O-formyl-1,2-O-isopropylidene-^D-arabinonic acid (45). Fol-

lowing the general procedure [DCM, PhIO (2.0 equiv), I₂(1.2 equiv)],

compound 35a (35 mg, 0.06 mmol) aﬀorded, after 20 h, compound 45

(9.5 mg, 0.02 mmol, 33%) as a colorless oil: IR 3440, 2985, 1796, 1736,

1

1712, 1498 cm⁻¹; H NMR (500 MHz, 70 °C) δ_H0.14 (3H, s), 0.17

(3H, s), 0.93 (9H, s), 1.46 (9H, s), 1.56 (3H, s), 1.65 (3H, s), 3.16 (1H,

ddd, J = 4.1, 6.3, 14.5 Hz), 3.41 (1H, ddd, J = 4.1, 5.7, 14.5 Hz), 4.02 (1H,

ddd, J = 4.1, 4.1, 7.9 Hz), 4.78 (1H, d, J = 2.2 Hz), 4.76 (1H, dd, J = 5.7,

6.3 Hz), 5.36 (1H, dd, J = 2.2, 7.9 Hz), 8.03 (1H, s); ¹³C NMR (125.7

MHz, 70 °C) δ_C−5.0 (CH₃), −4.4 (CH₃), 18.1 (C), 25.8 (3 × CH₃),

26.6 (CH₃), 26.9 (CH₃), 28.5 (3 × CH₃), 42.7 (CH₂), 69.6 (CH), 71.4

(CH), 73.7 (CH), 79.0 (C), 111.5 (C), 155.8 (C), 159.1 (CH), 170.1

(C); EM (ESI-TOF) m/z (rel intensity) 470 [(M + Na)⁺, 100]; HRMS

(ESI-TOF) m/z [M + Na]⁺Calcd for C₂₀H₃₇NO₈SiNa 470.2186, found

470.2185.

(1H, dd, J = 3.5, 6.0 Hz), 8.09 (1H, s); ¹³C NMR (125.7 MHz) δ_C26.5

(CH₃), 26.7 (CH₃), 28.2 (3 × CH₃), 50.9 (CH, d, ²J_FC= 21.2 Hz), 69.4

(CH, d, ³J_FC= 3.2 Hz), 73.3 (CH), 80.4 (C), 82.6 (CH₂, d, ¹J_FC= 172.7

Hz), 112.0 (C), 155.1 (C), 159.4 (CH), 169.3 (C); EM (ESI-TOF) m/z

6-(tert-Butoxycarbonyl)amino-5-O-(tert-butyldimethyl)silyl-6-

deoxy-4-O-formyl-2,3-O-isopropylidene-1-O-pivaloyl-β-^D-fructopyra-

nose (46). Following the general procedure [DCM, PhIO (2.0 equiv),

P

dx.doi.org/10.1021/jo401041s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

I₂(1.2 equiv)], compound 35b (27 mg, 0.05 mmol) aﬀorded, after 4 h,

the compound 46 (12 mg, 0.02 mmol, 46%) as a colorless oil: [α]_D+5.1

(c 0.57); IR 2958, 2932, 2859, 1736, 1697, 1368, 1255, 1163, 1099 cm⁻¹;

¹H NMR (500 MHz, 70 °C) δ_H0.10 (3H, s), 0.12 (3H, s), 0.89 (9H, s),

1.18 (9H, s), 1.26 (3H, s), 1.45 (3H, s), 1.48 (9H, s), 3.22 (1H, dd, J =

9.6, 13.2 Hz), 3.91 (1H, dd, J = 4.5, 13.2 Hz), 4.27 (1H, d, J = 3.1 Hz),

4.25−4.30 (1H, m), 4.35 (1H, d, J = 11.7 Hz), 4.76 (1H, d, J = 11.7 Hz),

5.41 (1H, dd, J = 3.1, 3.1 Hz), 8.07 (1H, s); ¹³C NMR (125.7 MHz,

70 °C) δ_C−4.92 (CH₃),−4.87 (CH₃), 18.1 (C), 25.8 (3 × CH₃), 26.6

(CH₃), 27.3 (3 × CH₃), 27.6 (CH₃), 28.4 (3 × CH₃), 38.9 (C), 44.9

(CH), 62.0 (CH₂), 64.3 (CH), 70.3 (CH), 77.3 (CH), 80.9 (C), 90.2

(C), 110.0 (C), 154.8 (C), 159.4 (CH), 177.4 (C); MS (EI-TOF) m/z

(rel intensity) 474 [(M − CH₃− C₄H₈)⁺, 1], 458 (2), 444 (1), 373 (1),

314 (4), 129 (10), 57 (100); HRMS (EI-TOF) m/z [M − CH₃−

C₄H₈]⁺Calcd for C₂₁H₃₆NO₉Si 474.2159, found 474.2164. Anal. Calcd

for C₂₆H₄₇NO₉Si: C, 57.22; H, 8.68; N, 2.57. Found: C, 57.06; H, 8.99;

N, 2.46.

́ ́

2006, 47, 35−38. (f) Gonzalez, C. C.; Kennedy, A. R.; Leon, E. I.;

Riesco-Fagundo, C.; Suarez, E. Chem.Eur. J. 2003, 9, 5800−5809.

́

(9) Francisco, C. G.; Martin, C. G.; Suar

́

ez, E. J. Org. Chem. 1998, 63,

ez, E. J. Am. Chem. Soc. 1993,

́

ez, E. J. Org. Chem. 1998, 63,

8092−8093.

(10) de Armas, P.; Francisco, C. G.; Suar

́

115, 8865−8866.

(11) Francisco, C. G.; Martín, C. G.; Suar

2099−2109.

(12) Francisco, C. G.; Freire, R.; Gonzal

Fagundo, C.; Suarez, E. J. Org. Chem. 2001, 66, 1861−1866.

(13) Paz, N. R.; Santana, A. G.; Francisco, C. G.; Suarez, E.; Gonzalez,

́

ez, C. C.; Leon, E. I.; Riesco-

́

C. C. Org. Lett. 2012, 14, 3388−3391.

(14) Asano, N.; Nash, R. J.; Molyneuxc, R. J.; Fleet, G. W. J.

Tetrahedron: Asymmetry 2000, 11, 1645−1680.

́

(15) Armas, P.; Francisco, C. G.; Suarez, E. Tetrahedron Lett. 1993, 34,

7331−7334.

(16) Speck, J. C. Adv. Carbohydr. Chem. Biochem. 1958, 13, 63−103.

(17) Ho, P.-T. Can. J. Chem. 1979, 57, 381−383, 384−386.

(18) For other types of hydroxymethyl-branched iminosugars, see:

(a) Soengas, R. G.; Simone, M. I.; Hunter, S.; Nash, R. J.; Evinson, E. L.;

Fleet, G. W. J. Eur. J. Org. Chem. 2012, 2394−3402. (b) Li, H.; Zhang, Y.;

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H and ¹³C NMR spectra for all new compounds. This material is

available free of charge via Internet at http://pubs.acs.org.

Favre, S.; Vogel, P.; Sollogoub, M.; Bler

110−114.

́

iot, Y. Carbohydr. Res. 2012, 356,

(19) Although we have not found the term “iminoketose” described in

the literature, we are using it here to refer to those compounds where the

endocyclic oxygen of the corresponding ketoses has been replaced by a

nitrogen atom, by analogy with the iminoaldoses.

AUTHOR INFORMATION

■

Corresponding Author

*E-mail: ccgm@ipna.csic.es.

Notes

(20) (a) Kim, H.; Lim, W.; Im, D.; Kim, D.; Rhee, Y. H. Angew. Chem.,

Int. Ed. 2012, 51, 12055−12058. (b) Mordini, A.; Valacchi, M.; Epiroti,

F.; Reginato, G.; Cicchi, S.; Goti, A. Synlett 2011, 235−240. (c) Levin, V.

V.; Kozlov, M. A.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.;

Tartakovsky, V. A. Russ. Chem. Bull. 2009, 58, 484−486. (d) Assiego, C.;

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

Pino-Gonzal

2611−2613.

́ ́

ez, M. S.; Lopez-Herrera, F. J. Tetrahedron Lett. 2004, 45,

■

This work was supported by the Gobierno de Canarias (Research

Program ProID20100088) and the investigation program no.

CTQ2007-67492/BQU of the Ministerio de Educacion y

Ciencia (Spain) coﬁnanced with the Fondo Europeo de

Desarrollo Regional (FEDER). A.G.S. thanks the I3P-CSIC

Program for a fellowship.

(21) (a) Iminosugars: From Synthesis to Therapeutic Applications;

Compain, P., Martin, O. R., Eds.; Wiley-VCH: Weinheim, 2007.

́

(b) Iminosugars as Glycosidase Inhibitors. Nojirimycin and Beyond; Stutz,

̈

A. E., Ed.; Wiley-VCH: Weinheim, 1999. For recent references, see:

(c) Rajender, A.; Rao, J. P.; Rao, B. V. Eur. J. Org. Chem. 2013, 1749−

1757 and references cited therein. (d) Horne, G.; Wilson, F. X.; Tinsley,

J.; Williams, D. H.; Storer, R. Drug Discovery Today 2011, 16, 107−118.

(22) (a) San

́

chez-Fernan

́

dez, E. M.; Rísquez-Cuadro, R.; Chasseraud,

dez, J. M.

REFERENCES

■

M.; Ahidouch, A.; Mellet, C. O.; Ouadid-Ahidouch, H.; Fernan

́

(1) (a) Murphy, J. A. The Radical-Polar Crossover Reaction. In

Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:

Weinheim, 2001; Vol. 1, pp 298−315.

(2) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104,

3371−3403.

́

(3) For other examples with Zn, see: Perez-Luna, A.; Botuha, C.;

Ferreira, F.; Chemla, F. Chem.Eur. J. 2008, 8784−8788.

(4) (a) Mitasev, B.; Porco, J. A., Jr. Org. Lett. 2009, 11, 2285−2288 and

references cited therein. (b) Snider, B. B. In Transition Metals for Organic

Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,

2004; pp 483−490.

(5) (a) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862−1891.

(b) Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc. Rev. 1997, 26, 127−

132.

G. Chem. Commun. 2010, 46, 5328−5330. (b) Copain, P.; Chagnault,

V.; Martin, O. R. Tetrahedron: Asymmetry 2009, 20, 672−711.

(c) Moreno-Clavijo, E.; Carmona, A. T.; Moreno-Vargas, A. V.;

Robina, I. Tetrahedron Lett. 2007, 48, 159−162. (d) Dondoni, A.; Nuzzi,

A. J. Org. Chem. 2006, 71, 7574−7582. (e) Dhavale, D. D.; Matin, M. M.

ARKIVOC 2005, No. iii, 110−132.

(23) Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J. Am. Chem.

Soc. 1998, 120, 3007−3018.

(24) Simone, M. I.; Edwards, A. A.; Tranter, G. E.; Fleet, G. W. J.

Tetrahedron: Asymmetry 2008, 19, 2887−2894.

(25) We have observed that a careful control of the pH of the reaction

is necessary, since as result of disproportionation of formaldehyde, small

amounts of formic acid are continuously generated, which could

neutralize the medium and favor the cross-Cannizzaro reaction. See:

Schaffer, R. J. Am. Chem. Soc. 1959, 81, 5452−5454.

(6) Taniguchi, T.; Zaimoku, H.; Ishibashi, H. Chem.Eur. J. 2011, 17,

4307−4312 and references cited therein.

(26) Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5103−5106.

(27) Landini, D.; Molinari, H.; Penso, M.; Rampoldi, A. Synthesis 1988,

953−955.

(7) Zhadankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523−2584.

́

(8) For a review, see: (a) Suarez, E.; Rodríguez, M. S. β-Fragmentation

of Alkoxyl Radicals: Synthetic Applications. In Radicals in Organic

Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;

Vol. 2, pp 440−454. For selected references on β-fragmentation of

(28) Saltzman, H.; Sharefkin, J. G. Org. Synth. 1977, 5, 658−659.

́ ́ ́

(29) Boto, A.; Hernandez, D.; Hernandez, R.; Montoya, A.; Suarez, E.

Eur. J. Org. Chem. 2007, 325−334.

anomeric alkoxyl radicals: (b) Hernan

Suarez, E. Org. Lett. 2013, 15, 250−253. (c) Francisco, C. G.; Gonzal

C. C.; Kennedy, A. R.; Paz, N. R.; Suar

ez, E. Chem.Eur. J. 2008, 14,

6907−6912. (d) Alonso-Cruz, C. R.; Kennedy, A. R.; Rodríguez, M. S.;

Suarez, E. J. Org. Chem. 2008, 73, 4116−4122. (e) Francisco, C. G.;

Gonzalez, C. C.; Kennedy, A. R.; Paz, N. R.; Suarez, E. Tetrahedron Lett.

́

dez-Guerra, D.; Rodríguez, M. S.;

́

ez,

́

Q

dx.doi.org/10.1021/jo401041s | J. Org. Chem. XXXX, XXX, XXX−XXX

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Synthesis of branched iminosugars through a hypervalent iodine(III)-mediated radical-polar crossover reaction

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