Glycal Metallanitrenes for 2-Amino Sugar Synthesis: Amidoglycosylation of Gulal-, Allal-, Glucal-, and Galactal 3-Carbamates

Article

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Cite This: J. Org. Chem. XXXX, XXX, XXX −XXX

Glycal Metallanitrenes for 2‑Amino Sugar Synthesis:

Amidoglycosylation of Gulal‑, Allal‑, Glucal‑, and Galactal

3‑Carbamates

́

Simran Buttar, Julia Caine, Evelyne Gone, Renee Harris, Jennifer Gillman, Roxanne Atienza, Ritu Gupta,

Kimberly M. Sogi, Lauren Jain, Nadia C. Abascal, Yetta Levine, Lindsay M. Repka,

and Christian M. Rojas*

Department of Chemistry, Barnard College, 3009 Broadway, New York, New York 10027, United States

S

* Supporting Information

ABSTRACT: The rhodium(II)-catalyzed oxidative cyclization of glycal 3-carbamates with in situ incorporation of an alcohol

nucleophile at the anomeric position provides access to a range of 2-amino sugars having 1,2-trans-2,3-cis stereochemistry, a

structural motif present in compounds of medicinal and biological signiﬁcance such as the streptothricin group of antibiotics

and the Chitinase inhibitor allosamidin. All of the diastereomeric ^D-glycal 3-carbamates have been investigated, revealing signif-

icant diﬀerences in anomeric stereoselectivity depending on substrate stereochemistry and protecting groups. In addition, some

substrates were prone to forming C3-oxidized dihydropyranone byproducts under the reaction conditions. Allal- and gulal

3-carbamates provided uniformly high stereo- and chemoselectivity, while for glucal substrates, acyclic, electron-withdrawing

protecting groups at the 4O and 6O positions were required. Galactal 3-carbamates have been the most challenging substrates;

formation of their amidoglycosylation products is most eﬀective with an electron-withdrawing 6O-Ts substituent and a sterically

demanding 4O-TBS group. These results suggest a mechanism whereby conformational and electronic factors determine the

partitioning of an intermediate acyl nitrenoid between alkene addition, leading to amidoglycosylation, and C3−H insertion,

providing the dihydropyranone byproduct. Along the amidoglycosylation pathway, high anomeric selectivity results when a

glycosyl aziridine intermediate is favored over an aziridine-opened oxocarbenium donor.

INTRODUCTION

■

The biological¹and medicinal²signiﬁcance of 2-amino sugars

has stimulated the development of methods for their chem-

ical synthesis.³Examples shown in Figure 1 include the

streptothricin antibiotics (1)⁴and the Chitinase inhibitor

allosamidin (2),⁵as well as 2-amino sugar building blocks

such as 3⁶and 4⁷equipped with functionality useful for

glycodiversiﬁcation of bioactive compounds.⁸Glycals are

attractive starting materials⁹for accessing 2-amino sugars as

they provide a reactive enol ether alkene for incorporation of

nitrogen functionality at C2 and introduction of substituents

at the anomeric position.¹⁰An oxidative amino- or amido-

alkoxylation can accomplish both substitutions simultaneously,

constituting an overall amidoglycosylation reaction (5 → 6,

eq 1).

Two stereochemical elements require consideration in such

a process. First is the relative C1/C2 stereochemistry of pro-

duct 6 set in the double-bond addition. One strategy for

controlling this stereochemistry involves initial formation of a

transient glycosyl aziridine, which undergoes S_N2 ring opening

by an acceptor to give 1,2-trans stereochemistry. Glycosyl

Received: April 10, 2018

A

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Figure 1. Bioactive natural products and building blocks containing 2-amino sugars.

aziridines have been generated from glycals by direct nitrene-

or nitrenoid-mediated nitrogen atom transfer¹¹and by azide

cycloaddition, followed by loss of nitrogen from the resulting

triazoline.^10hThe second stereochemical element is glycal face

selectivity for nitrogen incorporation. The stereocenter at the

allylic C3 site of the glycal substrate (5) is particularly inﬂu-

ential, with intermolecular addition of nitrogen to the double

bond typically occurring trans to the C3 substituent. For exam-

ple, intermolecular nitrenoid additions to glycals reported by

Murakami gave 2,3-trans products.^11fAccess to the 2,3-cis

motif in 2-amino sugar synthesis necessary for preparation of

compounds such as 1 and 2 therefore requires diﬀerent strat-

egies.^10c,f,gDanishefsky and co-workers developed an ingenious

glycal sulfonamidoglycosylation approach, where the aziridine

was generated via trans-diaxial halosulfonamidation, followed

by internal displacement of halide from the 2-halo-1-

sulfonamido sugar.^10c

An alternative strategy takes advantage of the glycal C3

hydroxyl group as a directing element for intramolecular instal-

lation of nitrogen at the C2 position, establishing the 2,3-cis

arrangement. For example, Nicolaou and co-workers devel-

oped an IBX-mediated oxidative cyclization of glycal-derived

N-aryl carbamates that proceeds via N-centered radicals.¹²

Donohoe’s tethered aminohydroxylation approach is concep-

tually related, and has been applied to 3-amino sugar syn-

thesis.¹³Cardona and Goti have also recently reported a

related osmium-catalyzed approach from glycals that can aﬀord

a route to either 2- or 3-amino sugars.¹⁴

aziridination.¹⁵While amidoglycosylation occurred photo-

chemically with high 1,2-trans stereoselectivity, the intermedi-

acy of a free nitrene led to limited eﬃciency.¹⁶The azido-

formate (10) was also a substrate for an amidohalogenation−

glycosylation sequence promoted by iron(II) chloride, bromide,

or iodide,¹⁷likely via an N-centered radical intermediate.¹⁸

Our most versatile approach for nitrene-mediated amido-

glycosylation, and the subject of this article, has adapted the

Du Bois conditions for C−H insertion of carbamate-derived

rhodium acyl nitrenoids¹⁹to intramolecular CC insertion

within glycal 3-carbamate frameworks (Scheme 1).²⁰Under

typical Du Bois conditions with diacetoxyiodobenzene as the

oxidant,²¹acetate outcompetes the glycosyl acceptor as the

nucleophile unless we use very large amounts (>20 equiv) of

the acceptor. Fortunately, the use of iodosobenzene (PhIO)²²

as an alternative acetate-free iodine(III) source has remedied

this shortcoming.

Our initial studies with allal-²⁰and glucal²³3-carbamates

identiﬁed the inﬂuence of substrate stereochemistry on the

reaction outcome (Scheme 1, substrates 12 and 13). Allal

3-carbamates with 4O,6O acetonide or benzylidene protecting

groups gave clean amidoglycosylation (12a or 12e → 16) with

excellent 1,2-trans anomeric stereocontrol and no C3-oxidation

byproducts (20). However, glucal 3-carbamates 13a and 13d

with similar cyclic 4O,6O protection resulted in anomeric mix-

tures of 17 along with dihydropyranone byproducts 20. Upon

further investigation with substrates 13, we found that non-

polar solvents and acyclic 4O,6O protection produced 17 with

high 1,2-trans stereoselectivity and that acyclic, electron-

withdrawing protecting groups (Ac or Ts) also gave high

chemoselectivity for 17 over byproduct 20.²⁴

Our contribution has been to use alkene insertion reactions

of glycal 3-carbamoyl nitrenes and nitrenoids (7) as a means

for 2-amino sugar synthesis (eq 2). The intramolecular process

In this article, we report new experiments with gulal- and

galactal 3-carbamates (11 and 14, Scheme 1) as well as an allal

3-carbamate (12b) with acyclic 4O,6O protection. Moreover,

in additional new examples with all the ^D-glycal carbamates

11−14, we now demonstrate a variety of alcohol nucleophiles

that introduce structural diversity and provide functional

handles for further elaboration or subsequent cleavage of the

anomeric group to unveil the free reducing sugar. These results

support a mechanistic model wherein anomeric selectivity

establishes the otherwise elusive 2,3-cis stereo array and leads

to a presumed glycosyl aziridine intermediate (e.g., 8), though

this has proved too labile to isolate. We expected that, as long

as the aziridine was maintained, in situ glycosylation would occur

with inversion, leading to oxazolidinone-protected 2-amino

glycoside products bearing the 1,2-trans relationship as in 9.

In our initial foray in this area we used allal 3-azidoformate

10 (eq 3) to generate the acyl nitrene for intramolecular

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Scheme 1. One-Pot Amidoglycosylation with D-Glycal 3-Carbamates 11−14, Giving Amino Sugar Derivatives 15−18 and

Formation of Dihydropyranone Byproducts 19 and 20

depends on the feasibility of a glycosyl aziridine intermediate

and chemoselectivity arises from partitioning of an acyl

nitrenoid intermediate between CC addition and C−H

insertion. Our studies now span the dirhodium(II)-catalyzed

amidoglycosylation chemistry of all the diastereomeric ^D-glycal

3-carbamates (Scheme 1) and provide a robust basis for fur-

ther application of this methodology to the synthesis of stereo-

chemically diverse, oxazolidinone-containing 2-amino sugar

building blocks.

ester was trapped by O−S bond cleavage with the thiophilic

nucleophile diethylamine, providing 4,6-di-O-acetyl-^D-gulal

(24c) in good yield. To prepare gulals with other protecting

groups, we carried out methanolysis of 21 to provide diol

22,^25,27which was converted to either the isopropylidene

(23a) or the dibenzyl (23b) derivative. The oxidation−rearrange-

ment sequence²⁸provided gulals 24a and 24b having the

α-oriented C3 hydroxyl.

We treated gulals 24 with trichloroacetylisocyanate to intro-

duce the primary 3O-carbamoyl group. The classic Kocovsky

conditions, using neutral alumina to cleave the trichloroacetyl

carbamate intermediate,²⁹were ideal for the diacetyl-protected

system, giving primary carbamate 11c in high yield. Alter-

natively, substrates with base-stable protecting groups (24a

and 24b) were subjected to methanolysis to aﬀord the respec-

tive gulal 3-carbamates 11a and 11b. Additionally, to com-

plement our earlier studies with allal 3-carbamates bearing

cyclic 4O,6O protection (acetonide, benzylidene),^20,24we pre-

pared dibenzyl-protected allal carbamate 12b via the same

route as for 11b but starting with tri-O-acetyl-D-glucal and

proceeding via Mislow−Evans rearrangement of 25³⁰to 26³¹

(Scheme 2b).

The galactal 3-carbamates 14a, 14b, and 14d were prepared

in high yields from the corresponding 4O,6O-protected

D-galactals 27a,³²27b,³³and 27d,³⁴as shown in Scheme 3.

In preparing other, diﬀerently protected galactal 3-carbamates

14 (Scheme 4), we used a route similar to Nicolaou’s approach

to N-aryl-3-carbamoyl glycals^12bthat we also employed in

preparing 4O,6O-protected glucal 3-carbamates.²⁴In the pres-

ence of catalytic DBU, silylene-protected 27d reacted with 2,4-

dimethoxybenzyl isocyanate, to introduce the N-protected

carbamate in 28. Desilylation, followed by protection of the

resulting diol 29 provided derivatives 31, bearing protecting

groups with varying electronic and steric properties. During the

RESULTS

■

Synthesis of Gulal-, Allal-, and Galactal 3-Carba-

mates. In extending our amidoglycosylation chemistry to gulal

and galactal substrates, we were mindful of the strong inﬂuence

of 4O,6O protection on stereo- and chemoselectivity in

reactions of glucal 3-carbamates.²⁴We therefore sought to

compare 4O,6O groups having a range of electronic, steric, and

conformational properties: (1) acyclic, electron-withdrawing

(Ac, ClAc, Ts); (2) acyclic, electron-rich (Bn); (3) sterically

demanding (TBS); and (3) cyclic (acetonide, benzylidene,

di-tert-butylsilylene).

We adapted Danishefsky’s application²⁵of the Mislow−

Evans²⁶rearrangement to prepare gulal- and allal 3-carbamates

from galactal and glucal starting materials, respectively. Ferrier

rearrangement of tri-O-acetyl-^D-galactal provided α-thiophenyl

pseudoglycal 21^25,27en route to variously protected gulals

(Scheme 2a). Danishefsky and co-workers have described

oxidation of sulfur in 21 with m-CPBA, followed by the allylic

sulfoxide to sulfenate rearrangement²⁵and, with other sub-

strates, use of DMDO for the rearrangement-triggering oxi-

dation.^10dWe found DMDO to be the more generally eﬃcient

oxidant for our syntheses of gulal- and allal 3-carbamates.

Oxidation of thioether 21 with DMDO led to [2,3] rearrange-

ment of the allylic sulfoxide, and the resulting C3 sulfenate

C

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Scheme 2. Synthesis of (a) Gulal 3-Carbamates and (b) a Conformationally Flexible Allal 3-Carbamate

chemo- and stereoselective amidoglycosylations favored the con-

formation having a pseudoaxial 3O-carbamoyl group. For exam-

ple, conformational changes in the glucal 3-carbamate framework

(13) occurred upon introduction of acyclic, electron-with-

drawing 4O and 6O groups, as in 13c and 13f, two substrates

with increased selectivity. In these glucals, the conformational

diﬀerences were best reﬂected in the J_H4,H5values (Table 1).

Smaller values of J_H4,H5(cf. 13c and 13f versus 13a and 13d)

indicated a shift in conformational weighting away from the

13-(⁴H₅) arrangement toward the inverted 13-(⁵H₄) form, hav-

ing the pseudoaxial carbamate.^36,37As summarized in Table 1,

Scheme 3. Synthesis of Acetonide-, Benzyl-, and Silylene-

Protected Galactal 3-Carbamates

removal of the 2,4-dimethoxybenzyl (DMB) group with DDQ

in aqueous chloroform, starting material was consumed in about

1 h, generally accompanied by formation of two more polar

products, the desired primary carbamate 14 and a transient

bisaminal byproduct 32.³⁵With continued vigorous stirring of

the biphasic reaction mixture, hydrolysis of 32 to 14 occurred

over 2−4 h.

Conformations of Glycal 3-Carbamates. Our initial stud-

ies with glucal 3-carbamates^23,24and conformationally locked

allal 3-carbamates^20,24suggested that substrates undergoing

1

similar H NMR coupling constant analysis was used to eval-

uate an analogous eﬀect with gulal-, galactal-, and conforma-

tionally unconstrained allal 3-carbamates.³⁸

In the gulal 3-carbamates (11), we focused on J_H3,H4since

4

H3 and H4 are trans-diequatorial in the H₅conformer but

5

diaxial in the inverted H₄arrangement. As shown in Table 1,

the gulal carbamates all exhibited small J_H3,H4values, consistent

with a predominant 11-(⁴H₅) conformation. Additionally,

Scheme 4. Preparation of Variously Protected Galactal 3-carbamates

D

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a

Table 1. Conformational Analysis of D-Glycal 3-carbamates

a

b

All J values determined in CDCl₃unless otherwise indicated; nd = not determined; the highlighted J values are discussed in the text. In DMSO-

c

d

e

f

4

d₆. In C₆D₆. Also observed J_H3,H5= 1.4 Hz. Also observed J_H3,H5= 1.2 Hz. Also observed J_H3,H5= 1.2 Hz.

we observed four-bond coupling between H2 and H4 for

gulals 11, in accord with their W relationship in the H₅con-

found in 12a and 12e. We did not observe W-coupling between

4

H2 and H4 in allals 12, also consistent with conformer 12-(⁴H₅)

former.^37b,39Finally, we compared the J_H2,H3values of the gulal

3-carbamates to allal 3-carbamates 12a and 12e locked in the

⁴H₅conformation, since the gulal 3-carbamate conformer

11-(⁴H₅) should have a similar H2/H3 relationship. In fact,

the J_H2,H3values for gulals 11 and allals 12 showed good agree-

ment. In all respects, the NMR data support a predominant

⁴H₅conformation 11-(⁴H₅) for the gulal 3-carbamates, ori-

enting the 3O-carbamoyl group pseudo axial. This conforma-

tion is stabilized by the “allylic eﬀect”, i.e., the vinylogous

anomeric preference for having the C3−O bond pseudoaxial,

and by the antiperiplanar relationship of C3−O and C4−O

dipoles.⁴⁰

rather than 12-(⁵H₄).

In galactal 3-carbamates 14, the vicinal coupling constants

among H3, H4, and H5 are of equatorial-axial type in both

14-(⁴H₅) and 14-(⁵H₄). Therefore, we focused on the J_H2,H3

values, which for most of the galactal derivatives 14 were sim-

ilar to those of ⁴H₅-locked glucal 3-carbamates 13a and 13d. In

addition, the galactal conformer 14-(⁴H₅) has a W relationship

between H2 and H4, but the inverted form 14-(⁵H₄) does not.

For all but one of galactal 3-carbamates 14, we detected such a

four-bond W-coupling, J_H2,H4. These results indicate a preferred

conformation 14-(⁴H₅) for almost all the galactal 3-carbamates.

The exception was 6O-Ts,4O-TBS-protected galactal 3-carbamate

14j, where the J_H2,H4W-coupling disappeared and the J_H2,H3

value was the largest among the galactals studied, suggesting a

conformational shift toward the 14j-(⁵H₄) arrangement with

the carbamate group in a pseudoaxial position. Indeed, galactal

3-carbamate 14j turned out to be the most chemoselective in

amidoglycosylation reactions (vide infra).

For dibenzyl-protected allal 3-carbamate 12b, J_H4,H5and

J_H2,H3were diagnostic of conformation. These coupling con-

stants were nearly identical for the acyclic-protected dibenzyl

4

system 12b and the H₅-locked acetonide- and benzylidene-

protected allal 3-carbamates 12a and 12e. In particular, the

J_H4,H5value for 12b indicated a trans-diaxial relationship as also

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Amidoglycosylation Reactions of All Glycal Diaster-

eomers with 4-Penten-1-ol. Having synthesized the full

range of diastereomeric glycal 3-carbamates 11−14 (Gly,

Table 2), we applied uniform conditions (1.8 equiv of PhIO,

0.1 equiv of Rh₂(OAc)₄, 4 Å molecular sieves, ∼0.1 M glycal

carbamate in CH₂Cl₂) for the oxidative cyclization process

using 4-penten-1-ol (5 equiv) as the nucleophile (glycosyl

acceptor a, Scheme 1 and Table 2). This alcohol nucleophile

provides synthetically versatile n-pentenyl glycoside⁴¹products

and allowed us to compare selectivities with our prior studies

on allal- and glucal 3-carbamates.^23,24For each reaction, we

measured chemo- and stereoselectivity from the NMR spectra

of the crude reaction mixture. Because we isolated and

characterized a number of the possible dihydropyranone

byproducts 19 and 20 (DHP, Table 2) in our new work

with galactal 3-carbamates (vide infra) and in prior studies

with glucal 3-carbamates,²⁴we could easily identify any DHP

in NMR spectra of the crude reaction mixtures. Meanwhile, the

anomeric ratios for the AG products (15−18, Table 2) were

determined by integration of the H1 resonances when these

did not overlap with other signals in ¹H NMR spectra.

with the NOESY and ring-opening studies on 15ca and 15aa,

conﬁrmed 1,2-trans amidoglycosylation selectivity for all three

gulal 3-carbamate substrates studied.

In the allal series, we observed high 1,2-trans anomeric

stereoselectivity as well as excellent chemoselectivity (Table 2,

entries 4−6). Notably, the more conformationally ﬂexible

dibenzyl-protected allal 3-carbamate 12b was highly 1,2-trans

selective, analogous to the benzylidene- and acetonide-protected

allals 12a and 12e, and gave only the merest trace of DHP 20b.

As in the gulal-derived case, J_H1,H2was not a conclusive indica-

tor of anomeric stereochemistry in the ring-fused product

16ba, so we prepared oxazolidinone-opened 36 by hydrolysis

of Boc-protected derivative 35 (Scheme 5). The trans-diaxial

J_H1,H2value in 36 (8.3 Hz) conﬁrmed the β-anomeric conﬁg-

uration.

For the glucal carbamates 13 there was a pronounced

dependence of stereo- and chemoselectivity on the 4O and 6O

protecting groups. Conformationally locked substrates 13a and

13d provided low anomer selectivity and signiﬁcant formation

of corresponding dihydropyranones 20 (Table 2, entries 7 and 8).

Switching to acyclic protection in 4,6-di-O-benzyl substrate

13b (entry 9) resulted in a dramatic increase in 1,2-trans selec-

tivity but gave the same amount of dihydropyranone byproduct.

A less polar solvent further increased anomeric selectivity from

13b, but again without inhibiting formation of byproduct 20b

(entry 10). In the glucal-derived oxazolidinone-containing

2-mannosamine products 17, the 1,2-trans α-anomeric pro-

ducts have a distinguishing H1 singlet (J_H1,H2≈ 0 Hz) in contrast

to an H1 doublet (J_H1,H2= 2−3 Hz) for the minor β anomers.^23,24

Ultimately, we achieved high anomer selectivity and

chemoselectivity in the glucal 3-carbamate series 13 by using

acyclic, electron-withdrawing Ac and Ts groups at 4O and 6O.

For best results, these groups were required at both positions

(compare entries 11 and 12 versus entries 14 and 16). Con-

formationally restricted carbonate 13k gave low selectivity

despite the electron-withdrawing character of the protecting

group (entry 15), suggesting that both electronic and con-

formational factors are required for high stereo- and chemo-

selection.

1

To complement the H NMR integration data, and as an

1

alternative when H NMR signal overlap made it diﬃcult to

measure the anomeric ratio, we also used integration of the

well-separated C1 (δ 105−95) and C2 (δ 55−50) signals of

the anomers.⁴²

Amidoglycosylation in the gulal series to give 2-gulosamine

derivatives (15) was 1,2-trans-selective, and no C3-oxidation

byproducts formed (Table 2, entries 1−3). There was some

variation in anomeric selectivity, depending on the nature of

the protecting groups. Higher stereoselectivity occurred with

the acetonide protection in 11a and with electron-withdrawing,

acyclic protection in diacetyl gulal 3-carbamate 11c (entries 1

and 3), while the dibenzyl-protected 11b gave lower anomer

selectivity (entry 2). Because we had NMR data for all three

dihydropyranones 19a, 19b, and 19c from our galactal

3-carbamate studies (vide infra), we would have been able to

detect even traces of these compounds had they formed in the

reactions of gulal carbamates 11, but they did not.

The oxazolidinone ring fusion in our amidoglycosylation

products aﬀects the pyranose ring conformation, making cou-

pling constant analysis of stereochemistry ambiguous. We there-

fore took care in establishing the anomeric stereochemistry of

2-amidogulose products 15, beginning with NOESY studies of

both anomers of diacetyl-protected products 15ca. A NOESY

correlation between H1 and H5 was present for the major

anomer, but not for the minor anomer, implying that the major

anomer was the β diastereomer (1,2-trans product 15ca-β,

Figure 2). The characteristic H1/H5 NOESY cross peak also

appeared with the major acetonide-protected product 15aa,

again indicating the 1,2-trans stereochemistry. Because the

minor diastereomer of 15aa was not isolated in suﬃcient quan-

tity for NOESY analysis, we further characterized the major

product by N-Boc protection to 33 (Scheme 5) and subse-

quent oxazolidinone opening⁴³to give 34, having a J_H1,H2value

(8.6 Hz), consistent with the β-anomeric stereochemistry.

For dibenzyl-protected 15ba, we compared spectral data

with 15ca and 15aa (Figure 2). Both anomers of 15ba were

isolated, and there was a good match in the relative positions

of resonances for H1 (major product had the upﬁeld signal),

C1 (major product had the downﬁeld signal), C2 (major

product had the downﬁeld signal), and J_H1,H2(major product

had the larger coupling constant). This analysis, in conjunction

Galactal 3-carbamates 14 have proved the most diﬃcult to

harness for dirhodium(II)-catalyzed amidoglycosylation. With

either the acetonide- or silylene-protected carbamates (14a

and 14d), we isolated only the corresponding dihydropyr-

anones 19, in addition to unreacted starting material (Table 2,

entries 17 and 18). It was with dibenzyl-protected 14b that we

obtained the ﬁrst hint that galactal 3-carbamate amidoglyco-

sylation was feasible under these conditions (entry 19). We

isolated a small quantity of a single anomer of product 18ba,

along with dihydropyranone 19b as the main product.

The diacetyl-protected 14c was a more promising galactal 3-

carbamate for amidoglycosylation. Under our standard

conditions, about equal amounts of amidoglycosylation and

C3−H oxidation occurred (Table 2, entry 20), and we

detected only a single anomer of the 2-amidotalose product

18ca. NOESY analysis of 18ca (Figure 3) showed diagnostic

contacts between the NH and H1 protons and between H5

and H1′a on the n-pentenyl chain. There was no cross-peak

1

between H1 and H5. Finally, the anomeric H resonance

appeared as a singlet (J_H1,H2≈ 0 Hz), consistent with an

α-glycoside conformation as shown in Figure 3 with near-

orthogonal placement of H1 and H2 and reminiscent to the

J_H1,H2≈ 0 Hz observed in the α-2-amidomannosides 17

derived from glucal 3-carbamates 13.

F

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a

Table 2. Amidoglycosylation of Glycal 3-Carbamates with 4-Penten-1-ol Acceptor

G

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Table 2. continued

a

Typical reaction conditions: 1.8 equiv of PhIO, 0.1 equiv of Rh₂(OAc)₄, 5 equiv of 4-penten-1-ol, 4 Å molecular sieves (300 wt %), ∼0.1 M glycal

b

carbamate in CH₂Cl₂. Crude reaction mixtures were analyzed by ¹H and/or ¹³C NMR to measure conversion, anomer ratio, and dihydropyranone

c

d

e

f

formation. Isolated yield after chromatography. Average of two runs. Data in entries 5 and 7−16 are from ref 24. Solvent was hexanes/CH₂Cl₂

g

(1/1). The anomers were inseparable by chromatography; the yield of the α component was calculated from the relative integration of α and β

h

i

j

anomer H NMR signals in the puriﬁed mixture. 19a/14a = 2.2:1. 19d/14d = 3.6:1. Range from H and ¹³C NMR analysis over four runs.

1

k

l

Remaining starting material 14b (10−15%) also detected. Some 14c remained: 18ca/19c/14c = 38:52:10. Starting material 14h (∼10%) also

remained. Some 14i remained: 18ia/19i/14i = 52:34:14.

m

Figure 2. Stereochemistry determination in β-2-aminogulose oxazolidinones.

1

Scheme 5. Oxazolidinone Opening To Conﬁrm Stereochemistry of 2-Gulosamine and 2-Allosamine Derivatives by H NMR

We sought to increase the electron-withdrawing power of

the 4O and 6O protecting groups in galactal 3-carbamates 14

as a means to improve chemoselectivity. However, the divi-

dends were limited, as chloroacetyl protection, incorporating

either two ClAc groups (14g) or one along with a 6O tosyl

(14h), gave only small increases in chemoselectivity (Table 2,

entries 21 and 22). Interestingly, steric perturbation as in bis-

silyl-protected 14i (entry 23) increased chemoselectivity by

the same extent as the electron-withdrawing protecting groups

in 14g and 14h. Ultimately, combination of a bulky silyl ether

Figure 3. NOESY correlations in α-2-amidotalose derivative 18ca

prepared from galactal 3-carbamate 14c.

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Table 3. Amidoglycosylation of D-Glycal 3-Carbamates with Other Glycosyl Acceptor Alcohols

a

Crude reaction mixtures were analyzed by ¹H NMR to measure anomer ratios and to detect formation of dihydropyranones 19 and 20 and any

b

remaining starting material. Yields are of products after chromatography on silica gel. 17ﬀ/20f/13f = 14:1:12; starting material 13f (47%)

recovered. 17fg/20f/13f = 11:1:21; starting material 13f (53%) recovered. Using 3.1 equiv of PhIO. 17fh/20f/13f = 18:1:1. Data in entries

8−10 are from ref 24. 17fk/20f/13f = 12:1:6. 18jd/19j/14j = 16:3:1. 18jh/19j/14j = 5:2:1.

c

d

e

f

g

h

i

at 4O and an electron-withdrawing sulfonyl group at 6O led to

the most chemoselective and high-yielding galactal substrate

14j, providing amidoglycosylation product 18ja as a single 1,2-

trans anomer in 55% yield and with 5.6:1 chemoselectivity

(entry 24) as compared to the initial galactals 14a and 14d

(entries 17 and 18), which provided only the unwanted DHP

products 19 and none of the AG products at all.

Reactions of Selective Glycal 3-Carbamates with

Other Glycosyl Acceptors. Having identiﬁed selectivity-

inducing protecting groups for each of the four diastereomeric

D-glycal 3-carbamate frameworks 11−14, we used these

substrates to explore the addition of other glycosyl acceptor

alcohols (Table 3). Gratifyingly, the metallanitrene-mediated

chemistry was compatible with a range of alcohol nucleophiles,

enabling incorporation of varied anomeric functionality, includ-

ing groups such as alkynyl, alkenyl, and chloroalkyl, that are

amenable to further elaboration. Other anomeric substituents

(e.g., benzyl, 2-(trimethylsilyl)ethyl) that can serve as tempo-

rary masking groups for revealing C1-OH free reducing sugars

could also be introduced via the amidoglycosylation reactions

of 11−14.

Allylic alcohols were well tolerated as glycosyl acceptors, with

gulal substrate 11c giving β-allyl glycoside 15cb and gulosamine

geranyl glycoside 15cc in high yield and good anomeric

stereoselectivity (Table 3, entries 1 and 2). With benzylidene-

protected allal 12e, formation of a 2-(trimethylsilyl)ethyl

glycoside gave only the 1,2-trans product, allosamine oxazolidi-

none 16ed (entry 3). This glycosyl group is a known protecting

group for the anomeric oxygen, cleavable via ﬂuoride-induced

elimination.⁴⁴Incorporation of an internal alkyne in the

glycosyl acceptor was achieved, providing 2-pentynyl glycoside

16ee with good anomeric stereocontrol (entry 4). Dihydropyr-

anone byproduct formation from C3−H oxidation was not

observed for these gulal- or allal 3-carbamate substrates 11c

and 12e.

Terminal alkyne-containing alcohols gave lower yields when

used as acceptors in reactions with glucal 3-carbamate 13f

(Table 3, entries 5 and 6), though stereo- and chemoselectivity

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remained high. Using propargyl alcohol, 2-mannosamine

derivative 17ﬀ formed exclusively as the α (1,2-trans) product,

while 4-pentynyl glycoside 17fg was also generated as a single

anomer. In both cases, there was little dihydropyranone

formation, with the low yields resulting instead from

incomplete consumption of the glycal carbamate (13f). On

the other hand, we observed good eﬃciency with benzyl

alcohol as the acceptor, leading to selective formation of 17fh

(entry 7). Several examples from our preliminary report²⁴

(entries 8−10) further demonstrate the reaction scope for

glucal substrates, including direct access to disaccharide 17fj.

Best yields resulted with excess acceptor alcohol (5 equiv),

perhaps because of a need to activate the insoluble, oligomeric

iodosobenzene oxidant.⁴⁵A ﬁnal example in the glucal series

(entry 11) demonstrated installation of a diglyme-type linker

with a primary halide functionality in product 17fk. Electro-

phile-containing anomeric groups are of utility for attachment

of carbohydrate units to molecules of biological and medicinal

interest.⁴⁶

Although the galactal 3-carbamate series (14) was the most

prone to unwanted dihydropyranone formation by C3-

oxidation, the optimally protected substrate 14j provided

talosamine derivatives 18j bearing the all-cis C2−C5 stereo-

array (Table 3, entries 12 and 13). Even with our most

selective protecting group combination, formation of dihy-

dropyranone 19j was not completely suppressed. Nevertheless,

amidoglycosylation products 18jd and 18jh, bearing a C6

tosylate for possible further functionalization as well as readily

cleavable anomeric protecting groups, were prepared in

synthetically useful yields. When using benzyl alcohol as the

nucleophile (entries 7 and 13), we obtained highest

conversions and best yields by increasing the amount of

iodosobenzene, possibly because some of the oxidant is

consumed by direct reaction with the benzyl alcohol.

byproduct formation, meanwhile, also originates from the

metallanitrene intermediate 7, as supported by our previous

studies that utilized an alternative N-tosyloxycarbamate nitrene

precursor (which obviates the need for a hypervalent iodine

oxidant) and gave the same distribution of amidoglycosylation

and C3−H oxidation products with rhodium catalysis as

compared to the standard primary carbamate using PhIO.⁵¹

Control experiments with glucal 3-carbamates 13a and 13d

indicated no amidoglycosylation or dihydropyranone forma-

tion in the absence of dirhodium(II) catalyst.^24,51With the

acetonide-protected allal 3-carbamate 12a, a low yield (16%)

of amidoglycosylation was obtained in the absence of catalyst.²⁰

As our current studies have revealed, the allal carbamates are

the most favorable substrates, and the iminoiodinane inter-

mediate may be electrophilic enough to react directly with the

enol ether π bond.

Anomeric Stereoselectivity. In general, we attribute high

1,2-trans amidoglycosylation selectivity to S_N2 opening of a

glycosyl aziridine intermediate, whereas diminished anomeric

stereoselectivity results from a competitive oxocarbenium-

mediated S_N1 pathway. As discussed below, we have observed

that high 1,2-trans stereoselectivity correlates with conforma-

tional and electronic factors expected to favor a stereospeciﬁc

glycosyl aziridine donor over a less or perhaps diﬀerentially

selective (i.e., 1,2-cis selective) oxocarbenium electrophile.⁵²

Nitrogen-directed addition to a zwitterionic intermediate, for

example, could lead to the 1,2-cis product, as reported by

Padwa for a related indolyl carbamate system.^21a,b

A 1,2-trans-selective glycosyl aziridine donor (e.g., 8,

Scheme 6) is best accommodated when the C3−O bond is

pseudoaxial. If the sugar ring lacks the ﬂexibility to orient the

C3−O bond appropriately, keeping the N−anomeric contact

entails enough strain to disfavor the glycosyl aziridine. This

eﬀect became evident in reactions of glucal substrates 13. With

4,6-O-isopropylidene (13a) or di-tert-butylsilylene (13d)

protecting groups, we obtained low anomeric selectivity

(Table 2, entries 7 and 8). In these cases, the system is con-

formationally ﬁxed, and inspection of molecular models reveals

that, upon C2 amidation from glucal nitrenoid 38 (Scheme 7),

the corresponding glycosyl aziridine 39 suﬀers from eclipsing

interactions along the C3−C4 bond. This torsional strain is

released in aziridine-opened zwitterion 40, which we predict is

the preferred intermediate for 13a and 13d given the dimin-

ished 1,2-trans selectivity. By contrast, conformationally ﬂexible

glucal 3-carbamates, such as the 4,6-di-O-benzyl-protected 13b,

gave much better stereoselectivity (Table 2, entries 9 and 10).

Here, ring inversion better enables the covalent aziridine donor

39′ (intermediates numbered with a prime have the pseudoaxial

C3−O bond), favoring it over an oxocarbenium glycosyl

donor, particularly in less polar solvent mixtures (e.g., hexanes/

CH₂Cl₂as in Table 2, entry 10). Electron-withdrawing pro-

tecting groups as in 13c and 13f should further disfavor a C1

cation versus the glycosyl aziridine, while they also promote an

increased propensity in glucal substrates 13 for the conforma-

DISCUSSION

■

General Mechanistic Considerations. Consistent with

the work of Du Bois,⁴⁷Dauban and Dodd,⁴⁸and Che⁴⁹among

others on reactions of carbamates and sulfamates with

iodine(III) oxidants in the presence of dirhodium(II) catalysts,

the amidoglycosylation of glycal 3-carbamates likely involves a

rhodium-complexed nitrene 7, generated from iminoiodinane

37 (Scheme 6). Addition of the metallanitrene to the glycal

Scheme 6. Mechanistic Proposal for Amidoglycosylation via

an Acyl Metallanitrene

5

tionally inverted H₄arrangement, akin to that shown for the

derived nitrenoid 38′ (cf. Table 1 and Scheme 7). These elec-

tronic and conformational factors are consistent with the high

1,2-trans anomer selectivity observed with 13c and 13f (Table 2,

entries 11 and 12, and Table 3, entries 5−11).

Allal-derived systems 12 are highly stereoselective (Table 2,

entries 4−6, and Table 3, entries 3 and 4) and appear to enable

a glycosyl aziridine intermediate particularly well. In the case of

conformationally rigid acetonide- (12a) and benzylidene-protected

π bond provides a glycosyl aziridine (e.g., 8 in the 3-β series),

possibly with the metal still complexed at nitrogen (not

shown).⁵⁰As long as the N−anomeric contact is present, the

acceptor adds in S_N2 fashion, leading to the 1,2-trans

amidoglycosylation (AG) product. Dihydropyranone (DHP)

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Scheme 7. Inﬂuence of Conformational Flexibility on Glucal-Derived 2-Amido Glycosyl Donors

(12e) allal 3-carbamates, the C3−O bond is ﬁxed in the

pseudoaxial position. Even when the conformational lock is

opened, as in dibenzyl-protected allal 3-carbamate 12b, the

glycosyl aziridine donor (41′, Figure 4) is favorable because

a glycosyl aziridine donor 43′ (Figure 4), a species that should

be at least as favorable as the corresponding aziridine formed in

the glucal series (cf. 39′, Scheme 7).

In our model, an energetically favorable glycosyl aziridine is

the key to high anomeric stereoselectivity, but this interme-

diate need not arise in a concerted fashion. Instead, a zwitterion

could form ﬁrst, closing to the aziridine prior to glycosylation.

Initial glycal C2 amidation could therefore occur from a con-

former with the 3O-carbamoyl nitrenoid in either the

pseudoaxial (direct aziridination) or pseudoequatorial position

(stepwise aziridine formation). For example, benzyl-protected

glucal 13b, which our NMR measurements showed favors the

⁴H₅conformer, nevertheless gave high 1,2-trans stereocontrol.

This could arise either through the minor conformer 38b′ as

shown in Scheme 7 or, alternatively, by a conformational change

following C2−N bond formation to enable aziridine closure as

indicated in Scheme 8 (38b → 40b → 39b′). In short, while it

may be optimal to have the pseudoaxial C3−O bond in the

ground state (e.g., gulal- and allal 3-carbamates), this is not

necessary for good anomeric selectivity.

Figure 4. Allal-, gulal-, and galactal-derived glycosyl aziridine donors.

with the C4 and C5 substituents in the equatorial positions the

C3−O bond is pseudoaxial, leading to highly 1,2-trans-

selective glycosylation.

The situation is somewhat less propitious in the gulal

3-carbamate series (11). Although our NMR studies on 11

4

Chemoselectivity. Literature precedent suggests two

mechanistic options for conversion of acyl nitrenoid 7 to the

dihydropyranone (DHP, Scheme 9). Nitrene insertion into the

activated (vinylogously α-ethereal)⁵⁴C3−H bond could pro-

duce a four-membered cyclic carbamate (44) which frag-

ments,⁵⁵extruding either isocyanic acid to give the carbonyl

directly or carbon dioxide to reach an imine that would readily

hydrolyze to the dihydropyranone product. This is the mech-

anism that Du Bois has suggested for the formation of ketones

encountered in some C−H insertion attempts from secondary

alcohol-derived carbamates.⁵⁶A mechanistic alternative is hydride

transfer to the rhodium acyl nitrenoid (7 → 45), followed by

regeneration of the catalyst and formation of the carbonyl.

Doyle has reported a related ketone-forming reaction of rho-

dium carbenoids, proposed to occur by hydride transfer to the

acyl carbenoid carbonyl.⁵⁷Studies from Clark’s group, mean-

while, have suggested hydride transfer to the carbenoid carbon

or to the rhodium center.⁵⁸Several other groups have noted the

formation of carbonyl byproducts in reactions of nitrenoids

derived from primary carbamates, including cases where deuterium

substitution was used to curtail the unwanted oxidation.^18b,59

showed that the H₅conformation is favored in the ground

state (see Table 1), this places the C4 substituent axial in addi-

tion to the pseudoaxial C3 carbamoyl group. Even if alkene

insertion from a pseudoaxial acyl nitrenoid leads directly to the

glycosyl aziridine (42′, Figure 4), this intermediate may be

more prone to opening prior to nucleophilic addition, eroding

1,2-trans selectivity. Comparing 11b (dibenzyl) and 11c

(diacetyl) gulal 3-carbamates (Table 2, entries 2 and 3), we

obtained higher stereoselectivity with the more electron-

withdrawing acetyl groups, which would destabilize an

oxocarbenium donor relative to the glycosyl aziridine. The

acetonide-protected substrate 11a (Table 2, entry 1) gave

anomer selectivity comparable to the diacetyl-protected 11c,

presumably reﬂecting an intermediate 42′ that accommodates

the acetonide ring in a chair conformation while avoiding a 1,3-

diaxial interaction between an acetonide methyl and the C4−

C3 bond in the pyranose ring. This acetonide chair confor-

mation was evident in the starting gulal 11a, as the acetonide

methyls had well-separated ¹³C NMR chemical shifts (δ 29.2

and 18.4).⁵³Finally, the high 1,2-trans stereoselectivity with

galactal 3-carbamates 14 probably reﬂects the intermediacy of

Scheme 8. Stepwise Aziridine Formation from a Conformationally Flexible Glucal Precursor

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Both the direct insertion and hydride-transfer possibilities of

Scheme 9 can be viewed as part of the same mechanistic

chemoselective galactal substrate 14j (R⁶= Ts, R⁴= TBS) did

not show this long-range W coupling, suggesting a shift toward

the ⁵H₄conformation, which could be displayed in the nitrenoid

46′ as well. The promotion of amidoglycosylation relative to

C3−H oxidation with 14j reﬂects both the more optimal

geometry in 46′ for nitrenoid addition to the alkene and the

stereoelectronic deactivation of a now pseudoequatorial C3−H

bond.⁶²

Scheme 9. Possible Mechanisms for C3−H Oxidation via

Metallanitrene 7

Another possible inﬂuence on chemoselectivity, particularly

in the galactal case, is positioning of the rhodium-complexed

nitrene through rotations about the C3−O and O−C(O)

bonds. Along the path toward alkene amidation from 46

(Figure 5), nonbonding interactions arise between the axial

group at C4 and the nitrenoid, and subsequent C2−N bond

formation develops a 1,3-diaxial interaction. On the other

hand, if the nitrenoid moiety is turned away from the axial C4

substituent (as in rotamer 46-rot), it should favorably engage

the pseudoaxial C3−H bond to aﬀord the dihydropyranone

product.

continuum, involving buildup of positive charge at C3.

Rhodium nitrenoids are electrophilic, favoring reaction at

electron-rich C−H bonds in an insertion process that develops

positive character at carbon in the transition state.⁴⁷In our sub-

strates, the glycal C3 position is particularly prone to oxidation

because a C3 cation or partial positive charge is well accom-

modated, especially in stereoelectronically favorable cases (vide

infra). Accordingly, electron-withdrawing protecting groups

deactivate the C3−H bond toward oxidation,⁶⁰as for our

glucal- and galactal substrates (13 and 14), where the most

chemoselective systems have electron-withdrawing groups

(e.g., Ac, Ts) at one or both of the 4O and 6O positions.

A vinylogous anomeric eﬀect⁶¹likely contributes to the

particular susceptibility of a pseudoaxial C3−H bond toward

oxidation. Although they relate to the glycal 3-carbamates and

not the rhodium acyl nitrenoids themselves, our NMR

conformational studies suggest that both the allal- and gulal

3-carbamate systems, which disfavor C3 carbonyl formation,

prefer a ⁴H₅conformation with the 3O-carbamoyl group

pseudo axial (11-(⁴H₅) and 12-(⁴H₅), Table 1), placing the

C3−H bond in the stereoelectronically deactivated pseudoe-

quatorial position. In the glucal 3-carbamates, the conforma-

tion varied, depending on 4O,6O protection, and substrates

The diﬃculty of CC addition for the galactal 3-carbamate-

derived rhodium nitrenoids would therefore arise from both an

increased propensity for C3−H insertion and an impediment

4

to CC insertion from the preferred H₅conformation (46).

Meanwhile, the inverted ⁵H₄galactal arrangement (46′),

having the pseudoequatorial C3−H bond and placing the C4

substituent out of the way of CC addition, would favor

amidoglycosylation versus C3 oxidation, as fulﬁlled, albeit

imperfectly, by galactal 3-carbamate 14j. Studies are continuing

in our group to emphasize this reaction channel for the

galactals, including through catalyst control of chemoselectivity

by varying the metal and ligands.^63,64

CONCLUSIONS

■

Amidoglycosylation studies using the full range of diastereo-

meric ^D-glycal 3-carbamates and dirhodium(II) acetate

catalysis have revealed the profound eﬀect of glycal stereo-

chemistry on stereo- and chemoselectivity. The allals gave

excellent anomeric stereocontrol with either cyclic or dibenzyl

4O,6O protection and without any appreciable formation of

C3-oxidized dihydropyranone byproducts. The gulals showed

somewhat lower stereoselectivity with benzyl protecting

groups, but good 1,2-trans anomer control in the diacetyl-

and acetonide-protected cases, coupled with excellent chemo-

selectivity as dihydropyranones were not formed. Glucal

4

having the largest deviation away from the H₅conformer

(which has the pseudoaxial C3−H; see 13c and 13f, Table 1)

gave the smallest amount of dihydropyranones 20c and 20f in

amidoglycosylation studies (Table 2, entries 11 and 12). There

is synergy at work: a pseudoaxial 3O-carbamoyl group makes

amidoglycosylation easier and dihydropyranone formation

harder.

4

3-carbamates locked in a H₅conformation (pseudoequatorial

3O-carbamoyl group) gave low anomeric selectivities and led

to considerable formation of dihydropyranone byproducts.

However, conformationally ﬂexible glucal systems gave high

stereoselectivity, and both stereo- and chemoselectivity

improved with electron-withdrawing 4O,6O protection. The

use of electron-withdrawing protecting groups also helped

favor amidoglycosylation versus C3 oxidation with galactal

3-carbamates, but the tendency toward dihydropyranone

formation was particularly strong. Ultimately, the combination

of an electron-withdrawing C6-OTs group and a bulky C4-

OTBS substituent gave best results for the galactal 3-carbamate

case, an outcome tied to the system’s conformational

preference.

By contrast, the galactal 3-carbamates 14, which gave large

4

amounts of dihydropyranones, for the most part favor the H₅

conformation having the pseudoequatorial 3O-carbamoyl

group and the pseudoaxial C3 hydrogen, as characterized by

4

a long-range J_H2,H4(see Table 1 and depicted for the

corresponding nitrenoid 46 in Figure 5). However, the most

We interpret these results in terms of a rhodium acyl

nitrenoid intermediate that can lead to either CC addition

or C3−H oxidation. Positioning of the acyl nitrenoid for

alkene addition is aided by a pseudoaxial orientation, and high

1,2-trans selectivity implies a glycosyl aziridine donor. When an

Figure 5. Metallanitrene positioning in galactal 3-carbamate.

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IR (thin ﬁlm) 1739 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.64−7.52

(m, 2H), 7.37−7.23 (m, 3H), 6.23 (dd, J = 10.0, 3.3 Hz, 1H), 6.11

(ddd, J = 9.9, 5.3, 1.6 Hz, 1H); 5.86 (dd, J = 3.1, 1.7 Hz, 1H), 5.14

(dd, J = 5.3, 2.5 Hz, 1H), 4.71 (ddd, J = 6.3, 6.3, 2.5 Hz, 1H), 4.35−

4.20 (m, 2H), 2.09 (s, 3H), 2.04 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 170.6 (s), 170.3 (s), 134.6 (s), 131.7 (o), 131.3 (o), 128.9 (o),

127.6 (o), 124.4 (o), 83.4 (o), 67.2 (o), 63.3 (o), 62.6 (t), 20.8 (o),

20.7 (o); HRMS (FAB) m/z calcd for C₁₆H₁₉O₅S (M + H)⁺

323.0953, found 323.0941.

Thiophenyl 2,3-Dideoxy-α-^D-threo-hex-2-enopyranoside

(22).^25,27,28bThe diacetate 21 (3.89 g, 12.1 mmol) was dissolved in

MeOH/CH₂Cl₂(28 mL/15 mL) at room temperature. Potassium

carbonate (1.67 g, 12.1 mmol) was added and the mixture was well

stirred during 30 min. Saturated aq NH₄Cl (20 mL) was added, and

the mixture was extracted with CH₂Cl₂(3 × 20 mL). The combined

organic layers were dried (MgSO₄), ﬁltered, and concentrated. The

crude was puriﬁed by chromatography (SiO₂, 60% EtOAc/hexanes),

yielding diol 22 (2.63 g, 92%) as a ﬂuﬀy, white solid: mp 108−110 °C;

R_f= 0.22 (50% EtOAc/hexanes); IR (thin ﬁlm) 3280 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 7.60−7.46 (m, 2H), 7.38−7.21 (m, 3H), 6.16−

6.03 (m, 2H), 5.80 (s, 1H), 4.36 (ddd, J = 5.4, 5.4, 2.1 Hz, 1H),

4.07−3.78 (m, 3H), 2.57 (d, J = 8.7 Hz, 1H), 2.55 (t, J = 5.5 Hz, 1H);

¹³C NMR (75 MHz, CDCl₃) δ 134.6 (s), 131.9 (o), 129.3 (o),

aziridine intermediate is too strained, a zwitterionic oxocarbe-

nium intermediate competes, lowering anomeric selectivity.

The extent of C3−H oxidation, giving dihydropyranone

byproducts, depends on inductive and stereoelectronic factors

and can be curtailed by using appropriate protecting groups.

Metallanitrene-mediated alkene insertion from glycal

3-carbamates provides a tandem amidoglycosylation process

amenable to synthesis of 2-amino sugars having 1,2-trans-2,3-

cis stereochemistry. Using this methodology we have prepared

β-2-amidogulo-, β-2-amidoallo-, α-2-amidomanno-, and α-2-

amidotalopyranosides that include functionality (e.g., alkynyl,

alkenyl, primary chloride, tosyl) for further synthetic elaborat-

ion. These compounds are potential building blocks for carbo-

hydrate chemistry, including glycodiversiﬁcation. In addition,

our studies have outlined general aspects of the reactivity of

rhodium acyl nitrenoids, ﬁndings that have applicability

beyond the realm of 2-amino sugar synthesis.

EXPERIMENTAL SECTION

■

General Methods. ¹H NMR chemical shifts are reported in parts

per million (δ) relative to tetramethylsilane (TMS, δ 0.00), using as a

reference either added TMS or an appropriate signal for residual

solvent protons. ¹³C NMR chemical shifts are reported in parts per

million, using the center peak of the solvent signal as a reference

(δ 77.0 for CDCl₃). ¹³C NMR peak multiplicities, where reported,

were inferred using either DEPT 135 or edited HSQC experiments.

The designation “o” (for odd number of attached hydrogens) denotes

a CH or CH₃carbon. Where ¹H and ¹³C NMR peak assignments are

129.0 (o), 128.4 (o), 127.6 (o), 83.9 (o), 70.8 (o), 62.8 (o), 62.5 (t);

HRMS (EI) m/z calcd for C₁₂H₁₄O₃S (M⁺) 238.0664, found

238.0667.

Thiophenyl 4,6-O-Isopropylidene-2,3-dideoxy-α-^D-threo-hex-2-

enopyranoside (23a). To a solution of diol 22 (2.64 g, 11.1 mmol)

in CH₂Cl₂(55 mL) at room temperature was added 2,2-

dimethoxypropane (2.73 mL, 22.2 mmol) followed by pyridinium

p-toluenesulfonate (557 mg, 2.22 mmol). After 2 h, the reaction

mixture was concentrated and chromatographed directly (200 mL

SiO₂, 20% EtOAc/hexanes), aﬀording acetonide 23a (3.056 g, 99%)

as a yellow syrup. Alternatively, an aqueous workup of the reaction

mixture, using satd aq NaHCO₃, could be done prior to chroma-

tography, producing comparable results: R_f= 0.36 (20% EtOAc/

hexanes); IR (thin ﬁlm) 3053, 1583 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 7.58−7.47 (m, 2H), 7.36−7.18 (m, 3H), 6.22 (dd, J = 9.9,

3.6 Hz, 1H), 6.00 (ddd, J = 9.8, 5.3, 1.6 Hz, 1H), 5.97 (m, 1H), 4.26

(dd, J = 13.0, 3.4 Hz, 1H), 4.22−4.11 (m, 2H), 3.94 (dd, J = 13.0,

2.0 Hz, 1H), 1.52 (s, 3H), 1.46 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 135.4 (s), 130.8 (o), 130.6 (o), 128.9 (o), 127.0 (o), 125.6 (o), 98.8

(s), 83.6 (o), 62.6 (o),* 62.6 (t),* 60.8 (o), 28.8 (o), 19.2 (o), the

signals at δ 62.6 coincided but were diﬀerentiated in the DEPT 135

experiment; HRMS (FAB) m/z calcd for C₁₅H₁₇O₃S (M − H)⁺

277.0898, found 277.0904.⁶⁷

Thiophenyl 4,6-Di-O-benzyl-2,3-dideoxy-α-D-threo-hex-2-eno-

pyranoside (23b). To a suspension of sodium hydride (86.6 mg of

a 60% w/w suspension in oil, 2.17 mmol) in DMF (1 mL) at 0 °C

was added a solution of diol 22 (148 mg, 0.622 mmol) in DMF

(3 mL). The mixture was stirred for 15 min at 0 °C followed by

addition of benzyl bromide (0.18 mL, 1.5 mmol). The cold bath was

removed and stirring continued for 2 h at room temperature. The

reaction was quenched with satd aq NH₄Cl (8 mL) and the mixture

extracted with Et₂O (1 × 25 mL and 3 × 10 mL). The combined

organic layers were washed with brine (1 × 10 mL), dried (MgSO₄),

ﬁltered, and concentrated. The crude was chromatographed (40 mL

SiO₂, 10% EtOAc/hexanes) providing dibenzyl-protected α-thio-

phenyl pseudoglycal 23b as a white solid (179 mg, 69%). R_f= 0.63

(30% EtOAc/hexanes); mp 74−77 °C; R_f= 0.63 (30% EtOAc/

hexanes); IR (thin ﬁlm) 3059, 3030, 1582 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 7.62−7.53 (m, 2H), 7.38−7.15 (m, 13H), 6.16 (dd, J =

10.0, 3.1 Hz, 1H), 6.08 (ddd, J = 10.0, 5.0, 1.4 Hz, 1H), 5.85 (dd, J =

3.0, 1.4 Hz, 1H), 4.68−4.51 (m, 5H), 3.92−3.77 (m, 3H); ¹³C NMR

(75 MHz, CDCl₃) δ 138.3 (s), 138.2 (s), 135.0 (s), 131.8 (o), 130.3

(o), 128.7 (o), 128.29 (o), 128.26 (o), 127.7 (o), 127.61 (o),* 127.57

(o),* 127.5 (o), 127.2 (o), 126.1 (o), 83.8 (o), 73.3 (t), 70.8 (t), 70.0

(o), 69.4 (t), 67.7 (o), *these ¹³C NMR signals were best resolved by

processing the FID with no line broadening (lb = 0); HRMS (FAB)

m/z calcd for C₂₆H₂₇O₃S (M + H)⁺419.1681, found 419.1682.

given, these were made unambiguously by a combination of H/¹H

1

COSY, ¹H/¹³C HSQC, and ¹H/¹³C HMBC experiments. Atom

numbering for NMR peak assignments is shown on the structures

included on copies of spectra in the Supporting Information. Infrared

spectra were recorded on an FT-IR instrument, including using an

attenuated total reﬂection (ATR) accessory. Melting points were

obtained using a capillary melting point apparatus and are

uncorrected. High-resolution mass spectra (HRMS) were obtained

from the Columbia University Chemistry Department Mass

Spectrometry Facility either with a four-sector tandem JEOL system

or on a Waters Xevo G2-XS QTOF mass spectrometer.

Iodosobenzene (PhIO) was prepared according to the literature

procedure⁶⁵and was stored in the dark at −20 °C under nitrogen.

Solutions of dimethyldioxirane (DMDO) in acetone were prepared

according to the literature procedure.⁶⁶Oven-dried (135 °C) 4 Å

molecular sieves were further activated by ﬂame-drying under vacuum

(0.5 mmHg) just prior to use. Methylene chloride was either distilled

from CaH₂or used as received from Sigma-Aldrich (anhydrous, Sure

Seal). Anhydrous tetrahydrofuran (inhibitor-free, Sure Seal) was

purchased from Sigma-Aldrich. Other reagents were obtained

commercially and were used as received. Reactions were carried out

in oven- or ﬂame-dried glassware under an atmosphere of dry

nitrogen. The amidoglycosylation products were sometimes diﬃcult

to visualize on TLC. A useful system to char the TLC plates involved

preheating the eluted TLC plate, dipping the plate in a solution of

Coleman’s Permangante [KMnO₄(3 g), K₂CO₃(20 g), 5% NaOH

(5 mL), H₂O (300 mL)], and then gently warming the TLC plate.

Synthesis of Gulal 3-Carbamates 11. Thiophenyl 4,6-Di-O-

acetyl-2,3-dideoxy-α-^D-threo-hex-2-enopyranoside (21).^25,27Tri-O-

acetyl-^D-galactal (5.0 g, 18.4 mmol) was dissolved in CH₂Cl₂

(50 mL), and thiophenol (1.88 mL, 18.4 mmol) was added. The

solution was cooled to −20 °C, and SnCl₄(0.92 mL of a 1.0 M

solution in CH₂Cl₂, 0.92 mmol) was added dropwise over 5 min.

After 1 h at −20 °C, the reaction was quenched by addition of satd aq

NaHCO₃(30 mL), and the mixture was allowed to warm to room

temperature. The layers were separated, and the organic layer was

dried (MgSO₄), ﬁltered, and concentrated. The crude was chromato-

graphed (250 mL SiO₂, 10 → 15 → 25 → 40% EtOAc/hexanes),

aﬀording thiophenyl pseudoglycal 21 (3.9 g, 66%) as a white solid:

mp 87−90 °C (lit. 92−93 °C); R_f= 0.38 (30% EtOAc/hexanes);

M

DOI: 10.1021/acs.joc.8b00893

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The Journal of Organic Chemistry

Article

General Procedure for Oxidation and Rearrangement of

α-Thiophenyl Pseudoglycals to Gulal Derivatives Using

Dimethyldioxirane. A solution of the thiophenyl pseudoglycal

(∼2 mmol) in CH₂Cl₂(6 mL) was cooled to −78 °C and a solution

of DMDO (∼0.08 M in acetone) was added via glass pipet (steel

needles and cannula were avoided because they hastened decom-

position of the DMDO). Consumption of the starting material was

monitored by TLC and once the reaction was judged complete

(excess DMDO was typically required) the cold bath was removed

and the reaction mixture was allowed to warm to room temperature

and concentrated (rotary evaporator then high vacuum line for 15−

30 min). The crude was dissolved in THF (6 mL), diethylamine

(1.4 mL) was added, and the mixture was stirred for 1 h at room

temperature. The reaction mixture was concentrated, and the crude

was chromatographed (SiO₂, EtOAc/hexanes).

4,6-O-Isopropylidene-^D-gulal (24a). Prepared from 23a (573 mg,

2.06 mmol) via the general procedure using DMDO. Chromatog-

raphy (200 mL SiO₂, 60 → 65 → 70% EtOAc/hexanes) provided

acetonide-protected gulal 24a (240 mg, 63%). R_f= 0.27 (60% EtOAc/

hexanes); IR (thin ﬁlm) 3428, 1648 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 6.62 (d, J = 6.2 Hz, 1H), 5.00 (ddd, J = 6.5, 5.0, 1.5 Hz, 1H),

4.17−3.98 (m, 3H), 3.85 (dd, J = 5.1, 1.6 Hz, 1H), 3.72 (d, J = 1.5 Hz,

1H), 1.86 (br s, 1H), 1.51 (s, 3H), 1.42 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 146.8 (o), 99.3 (o), 98.6 (s), 68.1 (o), 64.5 (o), 62.9 (t),

62.1 (o), 29.3 (o), 18.5 (o); HRMS (FAB) m/z calcd for C₉H₁₅O₄

(M + H)⁺187.0970, found 187.0975.

SiO₂, 60 → 70% EtOAc/hexanes) gave acetonide-protected gulal

carbamate 11a (131 mg, 49%) as a white solid: mp 125−128 °C; R_f=

0.38 (60% EtOAc/hexanes); IR (thin ﬁlm) 3455, 3357, 3194, 1718,

1

1713, 1649, 1602 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 6.67 (d, J =

6.2 Hz, 1H, H1), 4.96 (ddd, J = 6.5, 5.1, 1.5 Hz, 1H, H2), 4.83 (dd,

J = 5.4, 2.0 Hz, 1H, H3), 4.68 (br s, 2H, NH₂), 4.14−4.01 (m, 3H,

H4, H6a,b), 3.67 (m, 1H, H5), 1.51 (s, 3H, C(CH₃)₂), 1.43 (s, 3H,

C(CH₃)₂); ¹³C NMR (75 MHz, CDCl₃) δ 155.7 (s, C(O)NH₂),

147.9 (o, C1), 98.8 (s, C(CH₃)₂), 96.1 (o, C2), 66.2 (o, C4), 65.1

(o, overlapping C3 and C5), 62.7 (t, C6), 29.2 (o, C(CH₃)₂), 18.4

(o, C(CH₃)₂); HRMS (ESI) m/z calcd for C₁₀H₁₅NO₅Na (M + Na)⁺

252.0848, found 252.0845.

3-O-Carbamoyl-4,6-di-O-benzyl-^D-gulal (11b). Prepared from

24b (213 mg, 0.653 mmol) via the general procedure for modiﬁed

Kocovsky carbamate synthesis. Chromatography (75 mL SiO₂, 35 →

40% EtOAc/hexanes) provided di-O-benzyl-protected gulal carba-

mate 11b (222 mg, 92%) as a white solid: mp 47−51 °C; R_f= 0.28

(35% EtOAc/hexanes); IR (thin ﬁlm) 3469, 3351, 3197, 3064, 3030,

1

1721, 1646, 1600 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 7.38−7.23

(m, 10H, ArH), 6.65 (d, J = 6.1 Hz, 1H, H1), 5.07 (dd, J = 5.3,

2.0 Hz, 1H, H3), 4.93 (ddd, J = 6.0, 5.4, 1.8 Hz, 1H, H2), 4.76 (d, J =

12.0 Hz, 1H, PhCH₂), 4.75 (br s, 2H, NH₂), 4.54 (d, J = 12.1 Hz, 1H,

PhCH₂), 4.45 (AB, J_AB= 12.0 Hz, Δν_AB= 24.4 Hz, 2H, PhCH₂), 3.99

(ddd, J = 6.2, 6.2, 1.0 Hz, 1H, H5), 3.72 (dd, J = 9.8, 6.7 Hz, 1H,

H6a), 3.66 (ddd, J = 1.8, 1.8, 1.8 Hz, 1H, H4), 3.49 (dd, J = 9.8,

5.7 Hz, 1H, H6b); ¹³C NMR (75 MHz, CDCl₃) δ 155.8 (s, C(O)NH₂),

148.0 (o, C1), 137.7 (s, C_i), 137.5 (s, C_i), 128.4 (o, C_Ar),* 128.3

(o, 2 × C_Ar),* 127.9 (o, 2 × C_Ar), 127.8 (o, C_Ar), 97.0 (o, C2), 73.5

(t, PhCH₂), 72.9 (o, C5), 72.1 (o, C4), 71.8 (t, PhCH₂), 68.9 (t, C6),

63.2 (o, C3), *these ¹³C NMR signals were best resolved by pro-

cessing the FID with no line broadening (lb = 0); HRMS (FAB) m/z

calcd for C₂₁H₂₂NO₅(M − H)⁺368.1498, found 368.1517.⁶⁷

4,6-Di-O-benzyl-^D-gulal (24b). Prepared from 23b (350 mg, 0.836

mmol) via the general procedure using DMDO. Chromatography

(200 mL SiO₂, 40% EtOAc/hexanes) provided dibenzyl-protected

gulal 24b (214 mg, 78%) as a light-yellow oil. R_f= 0.31 (40% EtOAc/

1

hexanes); IR (thin ﬁlm) 3406, 3063, 3031, 1643 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 7.38−7.22 (m, 10H), 6.57 (d, J = 6.1 Hz, 1H),

4.95 (ddd, J = 6.5, 4.8, 1.7 Hz, 1H), 4.56 (AB, J_AB= 12.0 Hz, Δν_AB

=

3-O-Carbamoyl-4,6-di-O-acetyl-D-gulal (11c). In this case,

because of the acetyl protecting groups, we followed the approach

of Kocovsky^29aand Sugai^29bwith alumina-mediated hydrolysis of the

N-trichloroacetyl carbamate intermediate. The activity of neutral

alumina (Bio-Rad Neutral Alumina AG 7, 100−200 mesh, Activity

grade 1) was adjusted by adding 300 μL of water to 10 g of the

alumina and mixing thoroughly. The moistened alumina was stored in

a tightly capped vial. To a solution of diacetyl-protected gulal 24c

(260 mg, 1.13 mmol) in CH₂Cl₂(3.5 mL) at room temperature was

added trichloroacetyl isocyanate (200 μL, 1.69 mmol). After 25 min,

TLC indicated complete consumption of starting material, and

enough of the alumina, prepared as described above, was added to just

absorb all the solvent. After standing for 20 min, the alumina was

suspended in EtOAc and stirred 20 min. The mixture was ﬁltered

through a pad of Celite, and the ﬁltrate was concentrated. The crude

was chromatographed (150 mL SiO₂, 60% EtOAc/hexanes), aﬀording

primary carbamate 11c (287 mg, 93%) as a solid: mp 134−136 °C, R_f

= 0.22 (60% EtOAc/hexanes); IR (thin ﬁlm) 3472, 3449, 3357, 1745,

45.6 Hz, 2H), 4.51 (AB, J_AB= 12.0 Hz, Δν_AB= 29.1 Hz, 2H), 4.09

(ddd, J = 6.9, 5.4, 1.5 Hz, 1H), 4.01 (ddd, J = 4.9, 4.9, 2.6 Hz, 1H),

3.77 (dd, J = 9.9, 7.0 Hz, 1H), 3.63−3.52 (m, 2H), 1.71 (br, 1H); ¹³C

NMR (75 MHz, CDCl₃) δ 146.6, 137.8, 137.7, 128.4, 128.0, 127.9,

127.8, 127.7, 100.5, 74.7, 73.4, 72.3, 68.9, 60.8; HRMS (FAB) m/z

calcd for C₂₀H₂₂O₄Na (M + Na)⁺349.1416, found 349.1403.

4,6-Di-O-acetyl-^D-gulal (24c.^25,27,28bPrepared from 21 (698.2 mg,

2.17 mmol) via the general procedure using DMDO. Chromatog-

raphy (200 mL SiO₂, 20 → 30 → 40 → 60 → 70 → 80% EtOAc/

hexanes) provided gulal 24c (404 mg, 81%) as a solid: mp 98−99 °C;

R_f= 0.29 (50% EtOAc/hexanes); IR (thin ﬁlm) 3437, 1734, 1712,

1645 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.60 (d, J = 6.2 Hz, 1H),

4.99 (ddd, J = 6.5, 4.9, 1.6 Hz, 1H), 4.92 (s, 1H), 4.30−4.21 (m, 3H),

3.97 (ddd, J = 4.9, 4.9, 2.4 Hz, 1H), 2.33 (br, 1H), 2.11 (s, 3H), 2.09

(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 170.7 (s), 170.3 (s), 146.5 (o),

100.2 (o), 69.8 (o), 69.4 (o), 62.7 (t), 61.1 (o), 20.83 (o), 20.77 (o);

HRMS (FAB) m/z calcd for C₁₀H₁₄O₆Na (M + Na)⁺253.0688,

found 253.0685.

1

1733, 1696, 1645, 1605 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 6.63

(d, J = 6.1 Hz, 1H, H1), 5.09 (m, 1H, H4), 5.05 (ddd, J = 5.7, 5.7,

1.4 Hz, 1H, H2), 4.86 (dd, J = 5.2, 2.4 Hz, 1H, H3), 4.79 (br s, 2H,

NH₂), 4.32−4.10 (m, 3H, H5, H6a,b), 2.11 (s, 3H, C(O)CH₃), 2.10

(s, 3H, C(O)CH₃); ¹³C NMR (75 MHz, CDCl₃) δ 170.6

(s, C(O)CH₃), 169.7 (s, C(O)CH₃), 155.2 (s, C(O)NH₂), 147.5

(o, C1), 97.7 (o, C2), 70.6 (o, C5), 66.3 (o, C4), 63.9 (o, C3), 62.5

(t, C6), 20.8 (o, C(O)CH₃), 20.7 (o, C(O)CH₃); HRMS (FAB) m/z

calcd for C₁₁H₁₅NO₇(M⁺) 273.0849, found 273.0847.

Synthesis of Allal 3-Carbamate 12b. Thiophenyl 4,6-Di-O-

benzyl-2,3-dideoxy-α-^D-erythro-hex-2-enopyranoside (25).³⁰To a

0 °C solution of the corresponding diol⁶⁸(488 mg, 2.05 mmol) in DMF

(6 mL) was added NaH (246 mg of a 60% w/w dispersion in oil,

6.15 mmol). After 15 min, benzyl bromide (0.56 mL, 4.68 mmol) was

added, and the mixture was allowed to warm to room temperature

and stirred 3 h. The reaction was quenched by addition of satd aq

NH₄Cl (8 mL) and extracted with Et₂O (1 × 25 mL, 3 × 10 mL).

The combined organic layers were washed with brine, dried

(MgSO₄), ﬁltered, and concentrated. Chromatography (150 mL

SiO₂) provided dibenzyl ether 25 (808 mg, 94%) as an oil: R_f= 0.64

General Procedure for Modiﬁed Kocovsky Carbamate

Synthesis Using Basic Methanolysis of the Intermediate

Trichloroacetyl Carbamate. To a 0 °C solution of the allylic

alcohol (∼0.6 mmol) in CH₂Cl₂(5 mL) was added trichloroacetyl

isocyanate (1.5 equiv). The solution was stirred at 0 °C during

10 min, and the ice bath was removed, allowing the mixture to warm

to room temperature. The starting alcohol was typically consumed

(TLC) within 20−30 min. The reaction mixture was recooled to 0 °C

and K₂CO₃(3 equiv, powdered) was added, followed immediately by

MeOH (5 mL). The mixture was stirred at 0 °C during 10 min and

then warmed to room temperature. Methanolysis to the desired

primary carbamate was typically complete within 2−3 h. The mixture

was poured into satd aq NH₄Cl (30 mL) and extracted with CH₂Cl₂

(3 × 25 mL). The combined organic layers were dried (MgSO₄),

ﬁltered, and concentrated. The crude was chromatographed (SiO₂,

EtOAc/hex), providing the primary carbamate product.

3-O-Carbamoyl-4,6-O-isopropylidene-^D-gulal (11a). Prepared

from 24a (216 mg, 1.16 mmol) via the general procedure for

modiﬁed Kocovsky carbamate synthesis. Chromatography (150 mL

N

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The Journal of Organic Chemistry

Article

1

(30% EtOAc/hexanes); H NMR (300 MHz, CDCl₃) δ 7.60−7.49

galactal carbamate 14b (222 mg, 98%) as a white solid: mp 78−81 °C;

R_f= 0.21 (40% EtOAc/hexanes); IR (thin ﬁlm) 3465, 3352, 3065,

3030, 1714, 1649, 1601 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.40−

7.20 (m, 10H, Ar-H), 6.43 (dd, J = 6.2, 1.4 Hz, 1H, H1), 5.39 (dddd,

J = 4.2, 2.8, 1.4, 1.4 Hz, 1H, H3), 4.83−4.68 (m, 3H, H2, NH₂), 4.65

(m, 2H), 7.40−7.17 (m, 13H), 6.08−5.93 (m, 2H), 5.77 (s, 1H), 4.57

(AB, J_AB= 12.1 Hz, Δν_AB= 41.6 Hz, 2H), 4.55 (AB, J_AB= 11.4 Hz,

Δν_AB= 44.4 Hz, 2H), 4.33 (ddd, J = 9.2, 3.6, 2.5 Hz, 1H), 4.25 (dd,

J = 9.3, 1.4 Hz, 1H), 3.85−3.69 (m, 2H); ¹³C NMR (75 MHz,

CDCl₃) δ 138.1 (s), 137.9 (s), 135.5 (s), 131.5 (o), 129.1 (o), 128.8

(o), 128.4 (o), 128.3 (o), 127.9 (o), 127.8 (o), 127.6 (o), 127.24 (o),

127.16 (o), 84.0 (o), 73.2 (t), 71.2 (t), 70.2 (o), 69.6 (o), 68.9 (t).

4,6-Di-O-benzyl-^D-allal (26).³¹Prepared from 25 (799 mg,

1.91 mmol) via the general rearrangement procedure using DMDO.

Chromatography (200 mL SiO₂, 35 → 40% EtOAc/hexanes)

provided allal 26 (383 mg, 62%): R_f= 0.33 (40% EtOAc/hexanes);

¹H NMR (300 MHz, CDCl₃) δ 7.40−7.20 (m, 10H), 6.46 (d, J =

5.9 Hz, 1H), 4.92 (dd, J = 5.8, 5.8 Hz, 1H), 4.61 (AB, J_AB= 11.5 Hz,

Δν_AB= 12.2 Hz, 2H), 4.60 (AB, J_AB= 12.2 Hz, Δν_AB= 23.9 Hz, 2H),

4.17 (dd, J = 5.1, 4.0 Hz, 1H), 4.08 (ddd, J = 10.2, 2.8, 2.8 Hz, 1H),

3.84−3.75 (m, 3H), 2.54 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃)

δ 146.6 (o), 137.9 (s), 137.4 (s), 128.5 (o), 128.3 (o), 128.1 (o),

127.9 (o), 127.8 (o), 127.7 (o), 100.0 (o), 74.1 (o), 73.5 (t), 72.12 (t),*

72.09 (o),* 68.5 (t), 59.8 (o), *these ¹³C NMR resonances were

resolved upon reprocessing the FID with lb = 0 and also in the DEPT

135 experiment.

(AB, J_AB= 11.9 Hz, Δν_AB= 70.1 Hz, 2H, −OCH₂Ph), 4.46 (AB, J_AB

=

11.9 Hz, Δν_AB= 24.0 Hz, 2H, −OCH₂Ph), 4.22 (m, 1H, H5), 4.03

(ddd, J = 3.9, 2.4, 1.4 Hz, 1H, H4), 3.64 (AB of ABX, J_AB= 10.1 Hz,

1

J_AX= 7.4 Hz, J_BX= 5.0 Hz, Δν_AB= 45.9 Hz 2H, H6); H NMR

(300 MHz, CDCl₃) of a more dilute sample (∼10 mg/mL) removed

the overlap of the H2 and NH2 resonances, revealing the H2 signal

(δ 4.75) as a ddd (J = 6.2, 3.1, 1.2 Hz); ¹³C NMR (75 MHz, CDCl₃)

δ 156.3 (s, OC(O)NH₂), 145.5 (o, C1), 137.9 (s, C_Ph), 137.8

(s, C_Ph), 128.35 (o, C_Ph),* 128.32 (o, C_Ph),* 128.1 (o, C_Ph), 127.80

(o, C_Ph),* 127.76 (o, C_Ph),* 127.7 (o, C_Ph), 98.9 (o, C2), 75.4

(o, C5), 73.7 (t, OCH₂Ph), 73.3 (t, OCH₂Ph), 70.5 (o, C4), 68.0

(t, C6), 66.5 (o, C3); *these ¹³C NMR signals were resolved by pro-

cessing the FID with lb = 0; HRMS (FAB) m/z calcd for C₂₁H₂₄NO₅

(M + H)⁺370.1654, found 370.1646. Anal. Calcd for C₂₁H₂₃NO₅: C,

68.28; H, 6.28; N, 3.79. Found C, 67.87; H, 6.58; N, 3.57. Selected

¹H NMR homonuclear decoupling results for 14b are in the

Supporting Information.

3O-Carbamoyl-4,6-O-di-tert-butylsilylene-^D-galactal (14d). Pre-

pared from 27d³⁴(217 mg, 0.757 mmol) via the general procedure

for modiﬁed Kocovsky carbamate synthesis. Chromatography (80 mL

SiO₂, 30 → 35 → 40% EtOAc/hexanes) provided galactal carbamate

14d (244 mg, 98%) as a viscous, clear, colorless oil that became a

white solid after full removal of solvent on the vacuum line: mp 125−

127 °C; R_f= 0.25 (30% EtOAc/hexanes); IR (thin ﬁlm) 3454, 3386,

3O-Carbamoyl-4,6-di-O-benzyl-^D-allal (12b). Prepared from

allylic alcohol 26 (383 mg, 1.17 mmol) via the general procedure

for modiﬁed Kocovsky carbamate synthesis (i.e., with MeOH, K₂CO₃

treatment). Chromatography (150 mL SiO₂, 30 → 40% EtOAc/

hexanes) gave dibenzyl-protected allal carbamate 12b (324 mg, 75%)

as a white solid: mp 118−119 °C; R_f= 0.29 (30% EtOAc/hexanes);

1

IR (thin ﬁlm) 3431, 3352, 3296, 3219, 1652, 1642, 1622 cm⁻¹; H

1

3341, 3197, 1716, 1652, 1598 cm⁻¹; H NMR (300 MHz, CDCl₃)

NMR (300 MHz, CDCl₃) δ 7.33−7.13 (m, 10H, ArH), 6.46 (d, J =

5.8 Hz, 1H, H1), 5.37 (dd, J = 6.0, 3.8 Hz, 1H, H3), 4.85 (dd, J = 5.9,

5.9 Hz, 1H, H2), 4.65 (br s, 2H, NH₂), 4.52 (AB, J_AB= 10.8 Hz,

δ 6.40 (dd, J = 6.4, 2.0 Hz, 1H, H1), 5.23 (m, 1H, H3), 4.80 (m, 1H,

H4), 4.74 (br s, 2H, NH₂), 4.66 (ddd, J = 6.4, 1.8, 1.8 Hz, 1H, H2),

4.26 (AB of ABX, J_AB= 12.6 Hz, J_AX= 2.0 Hz, J_BX= 1.7 Hz, Δν_AB

=

Δν_AB= 94.9 Hz, 2H, PhCH₂O), 4.52 (AB, J_AB= 12.1 Hz, Δν_AB

=

12.0 Hz, 2H, H6), 3.89 (apparent broadened s, 1H, H5), 1.05 (s, 9H,

Si[C(CH₃)₃]₂), 1.03 (s, 9H, Si[C(CH₃)₃]₂); ¹³C NMR (75 MHz,

CDCl₃) δ 156.4 (s, OC(O)NH₂), 145.6 (o, C1), 98.5 (o, C2), 73.2

(o, C5), 68.0 (o, C3), 67.3 (t, C6), 65.7 (o, C4), 27.6 (o,

Si[C(CH₃)₃]₂), 27.0 (o, Si[C(CH₃)₃]₂), 23.3 (s, Si[C(CH₃)₃]₂), 20.8

(s, Si[C(CH₃)₃]₂); HRMS (FAB) m/z calcd for C₁₅H₂₈NO₅Si

(M + H)⁺330.1737, found 330.1725. Selected ¹H NMR homonuclear

decoupling results for 14d are in the Supporting Information.

4,6-O-Di-tert-butylsilylene-3O-(N-2,4-dimethoxybenzyl)-

carbamoyl-^D-galactal (28). Di-tert-butylsilylene-protected galactal

27d³⁴(1.21 g, 4.22 mmol) was dissolved in CH₂Cl₂(5.0 mL) and 2,4-

dimethoxybenzyl isocyanate (0.78 mL, 4.7 mmol) was added,

followed by DBU (0.19 mL, 1.3 mmol). After 2 h at 25 °C, TLC

indicated complete consumption of starting material. The reaction

mixture was diluted with CH₂Cl₂and washed with 10% NaHCO₃

(30 mL). The aqueous layer was back-extracted with CH₂Cl₂(3 ×

30 mL), and the combined organic layers were washed with brine

(30 mL), dried (MgSO₄), ﬁltered, and concentrated. The crude was

chromatographed (5 → 10 → 15 → 20% EtOAc/hexanes, 60 mL

SiO₂), providing the dimethoxybenzyl carbamate 28 as a white,

crystalline solid (1.87 g, 92%): mp 121.5−123.5 °C; R_f= 0.25 (20%

EtOAc/hexanes); IR (thin ﬁlm) 3382, 1715, 1654, 1614, 1590 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 7.18 (d, J = 7.9 Hz, 1H), 6.58−6.33

(m, 3H), 5.35 (br t, J = 5.7 Hz, 1H), 5.23 (apparent br s, 1H), 4.76

(d, J = 2.9 Hz, 1H), 4.64 (d, J = 6.3 Hz, 1H), 4.33−4.17 (m, 4H),

3.89 (br s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 1.00 (s, 9H), 0.98 (s, 9H);

¹H NMR signals for a minor rotamer (∼15−20%) were observed as a

shoulder downﬁeld of the signal at δ 5.23, as a br peak at δ 5.03, as a

shoulder just downﬁeld of the δ 4.64 resonance, and as a br s at

δ 1.04; ¹³C NMR (75 MHz, CDCl₃) δ 160.4 (s), 158.4 (s), 155.9 (s),

145.3 (o), 130.1 (o), 119.2 (s), 103.7 (o), 98.9 (o), 98.5 (o), 73.2

(o), 67.6 (o), 67.3 (t), 65.8 (o), 55.4 (o), 55.2 (o), 40.4 (t), 27.6 (o),

27.0 (o), 23.2 (s), 20.8 (s); HRMS (FAB) m/z calcd for

C₂₄H₃₈NO₇Si (M + H)⁺480.2418, found 480.2435.

18.0 Hz, 2H, PhCH₂O), 4.03 (ddd, J = 10.7, 3.3, 2.5 Hz, 1H, H5),

3.81 (dd, J = 10.7, 3.8 Hz, 1H, H4), 3.78−3.66 (m, 2H, H6); ¹³C

NMR (75 MHz, CDCl₃) δ 156.4 (s, OC(O)NH₂), 148.0 (o, C1),

137.9 (s, C_Ph), 137.3 (s, C_Ph), 128.38 (o, C_Ph),* 128.37 (o, C_Ph),*

128.3 (o, C_Ph), 127.9 (o, C_Ph), 127.8 (o, C_Ph), 127.7 (o, C_Ph), 97.2

(o, C2), 73.6 (t, PhCH₂O), 73.1 (o, C5), 72.6 (o, C4), 72.0

(t, PhCH₂O), 68.5 (t, C6), 62.4 (o, C3), *these ¹³C NMR resonances

were resolved upon reprocessing the FID with lb = 0; HRMS (FAB)

m/z calcd for C₂₁H₂₂NO₅(M − H)⁺368.1498, found 368.1486.⁶⁷

Allal 3-carbamates 12a and 12e were prepared and characterized as

described in ref 20. Additional ¹H and ¹³C NMR spectra for

acetonide-protected allal 3-carbamate 12a were obtained in acetone-

d₆to aid in J-value analysis. The additional tabulated data and spectra

for 12a are included in the Supporting Information.

Synthesis of Galactal 3-Carbamates 14. 3O-Carbamoyl-4,6-

O-isopropylidene-^D-galactal (14a). Prepared from 27a³²(63.4 mg,

0.340 mmol) via the general procedure for modiﬁed Kocovsky

carbamate synthesis (i.e., MeOH, K₂CO₃treatment). Chromatog-

raphy (40 mL SiO₂, 60% EtOAc/hexanes) provided galactal

carbamate 14a (72.6 mg, 93%) as a white solid: mp 127−130 °C;

R_f= 0.19 (60% EtOAc/hexanes); IR (thin ﬁlm) 3457, 3361, 3200,

1718, 1710, 1702 (shoulder), 1656, 1605 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 6.50 (dd, J = 6.4, 2.1 Hz, 1H, H1), 5.37 (m, 1H, H3), 4.96

(br s, 2H, NH₂), 4.69 (ddd, J = 6.4, 1.7, 1.7 Hz, 1H, H2), 4.52

(apparent slightly br d, J = 4.9 Hz, 1H, H4), 4.03 (AB of ABX, J_AB

=

12.8 Hz, J_AX= 2.0 Hz, J_BX= 1.4 Hz, Δν_AB= 19.1 Hz, 2H, H6), 3.83

(apparent slightly br s, 1H, H5), 1.50 (s, 3H, CH₃), 1.48 (s, 3H,

CH₃); ¹³C NMR (75 MHz, CDCl₃) δ 156.2 (s, OC(O)NH₂), 145.5

(o, C1), 99.1 (s, C(CH₃)₂), 97.3 (o, C2), 67.7 (o, C5), 66.1 (o, C3),

62.98 (t, C6),* 62.96 (o, C4),* 29.4 (o, C(CH₃)₂), 18.5

(o, C(CH₃)₂), *these ¹³C NMR resonances were cleanly resolved

upon reprocessing the FID with lb = 0; HRMS (EI) m/z calcd for

C₉H₁₂NO₅(M-CH₃)⁺214.0715, found 214.0714.

3O-Carbamoyl-4,6-di-O-benzyl-^D-galactal (14b). Prepared from

27b³³(201 mg, 0.616 mmol) via the general procedure for modiﬁed

Kocovsky carbamate synthesis (i.e., MeOH, K₂CO₃treatment).

Chromatography (80 mL SiO₂, 45% EtOAc/hexanes) provided

3-O-(N-2,4-Dimethoxybenzyl)carbamoyl-^D-galactal (29). To a

0 °C solution of carbamate 28 (1.87 g, 3.89 mmol) in THF (25 mL)

in a plastic vial was added HF·pyr (18 drops from a plastic dropper).

O

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Article

The reaction mixture was stirred 5 min at 0 °C and at 25 °C until

TLC indicated complete conversion of starting material to a single

more polar product (1 h 15 min). The mixture was cooled to 0 °C,

neutralized by careful addition of satd aq NaHCO₃(40 mL), and

extracted with EtOAc (3 × 50 mL). The combined organic layers

were washed with H₂O (2 × 40 mL) and brine (40 mL), dried

(MgSO₄), ﬁltered, and concentrated. The crude diol product 29, a

white solid, could be puriﬁed by chromatography (90% EtOAc/

hexanes, SiO₂) but due to its high polarity was more conveniently

used directly in the next reaction without puriﬁcation: mp 118.5−

120.5 °C; R_f= 0.25 (90% EtOAc/hexanes); IR (thin ﬁlm) 3428,

3334, 1677, 1658, 1615, 1588 cm⁻¹; ¹H NMR (300 MHz, acetone-d₆)

δ 7.17 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 2.2 Hz, 1H), 6.46 (dd, J = 8.3,

2.3 Hz, 1H), 6.37 (dd, J = 6.3, 1.2 Hz, 1H), 6.34 (br, 1H), 5.25 (dd,

J = 2.0, 2.0 Hz, 1H), 4.59 (ddd, J = 6.4, 1.9, 1.9 Hz, 1H), 4.23

(apparent d, J = 6.0 Hz, 2H), 4.17 (br, 1H), 3.98 (br t, J = 5.8 Hz,

1H), 3.94−3.70 (m, 4H), 3.83 (s, 3H), 3.78 (s, 3H); ¹H NMR signal

for minor rotamer (∼10%) at δ 6.05; ¹³C NMR (75 MHz, acetone-d₆)

δ 161.4 (s), 159.2 (s), 156.9 (s), 146.0 (o), 130.1 (o), 120.4 (s),

105.0 (o), 100.3 (o), 99.1 (o), 78.4 (o), 68.3 (o), 64.4 (o), 61.8 (t),

55.8 (o), 55.7 (o), 40.3 (t); HRMS (FAB) m/z calcd for C₁₆H₂₁NO₇

(M⁺) 339.1318, found 339.1320.

4,6-Di-O-acetyl-3-O-(N-2,4-dimethoxybenzyl)carbamoyl-^D-gal-

actal (31c). The crude diol 29 (∼1.32 g, 3.87 mmol) was suspended

in CH₂Cl₂(25 mL), and pyridine (2.5 mL, 31 mmol), acetic

anhydride (1.46 mL, 15.5 mmol), and N,N-dimethyl-4-aminopyridine

(120 mg, 0.97 mmol) were added, in that order. After 2 h at 25 °C,

the reaction mixture was diluted with CH₂Cl₂(40 mL) and washed

with satd aq NaHCO₃(40 mL). The aqueous layer was back-

extracted with CH₂Cl₂, and the combined organic layers were dried

(MgSO₄), ﬁltered, and concentrated. The crude material was

chromatographed (60% EtOAc/hexanes, 100 mL SiO₂), providing

the diacetyl-protected 31c as a yellowish, viscous oil (1.48 g, 89% for

two steps from silylene-protected 28): R_f= 0.40 (60% EtOAc/

hexanes); IR (thin ﬁlm) 3378, 1745, 1724, 1649, 1614, 1590 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 7.18 (d, J = 7.9 Hz, 1H), 6.52−6.35

pyridine (1 mL) and p-toluenesulfonyl chloride (278 mg, 1.46 mmol)

and N,N-dimethyl-4-aminopyridine (30 mg, 0.24 mmol) were added.

The mixture was stirred 6 h at room temperature, diluted with

CH₂Cl₂(10 mL), and washed with satd aq NaHCO₃(15 mL). The

aqueous layer was back-extracted with EtOAc (10 mL), and the

combined organic layers were washed with brine (10 mL), dried

(MgSO₄), ﬁltered, and concentrated. The crude was chromatographed

(40 → 55 → 50 → 55 → 60 → 65% EtOAc/hexanes, 150 mL SiO₂),

yielding the 6O-tosyl derivative 30 (358 mg, 75%) as a pale yellow oil:

R_f= 0.40 (60% EtOAc/hexanes); IR (thin ﬁlm) 3400, 1707, 1647,

1

1614, 1590 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 7.79 (apparent d,

J = 8.3 Hz, 2H), 7.33 (apparent d, J = 8.1 Hz, 2H), 7.16 (d, J =

8.0 Hz, 1H), 6.49−6.40 (m, 2H), 6.31 (dd, J = 6.2, 1.2 Hz, 1H), 5.34

(t, J = 5.8 Hz, 1H), 5.27 (m, 1H), 4.68 (ddd, J = 6.2, 2.6, 1.1 Hz, 1H),

4.33−4.08 (m, 6H), 3.83 (s, 3H), 3.80 (s, 3H), 2.54 (br s, 1H), 2.44

(s, 3H); ¹H NMR signals for minor rotamer (∼15%) at δ 7.09 (br d,

J = 7.6 Hz), broad peak at δ 5.13, and a shoulder on the downﬁeld

side of the resonances at δ 6.31 and δ 4.68; ¹³C NMR (75 MHz,

CDCl₃) δ 160.7 (s), 158.5 (s), 155.7 (s), 145.03 (o), 144.96 (s),

132.7 (s), 130.3 (o), 129.8 (o), 128.0 (o), 118.6 (s), 103.9 (o), 98.9

(o), 98.6 (o), 73.9 (o), 67.7 (t), 66.5 (o), 64.0 (o), 55.4 (o), 55.3 (o),

40.8 (t), 21.6 (o); HRMS (FAB) m/z calcd for C₂₃H₂₇NO₉S (M⁺)

493.1407, found 493.1425.

4-O-Chloroacetyl-3-O-(N-2,4-dimethoxybenzyl)carbamoyl-6-O-

p-toluenesulfonyl-^D-galactal (31h). To a solution of alcohol 30

(108 mg, 0.219 mmol) in CH₂Cl₂(3 mL) were added, sequentially,

pyridine (71 μL, 0.88 mmol), chloracetic anhydride (78 mg,

0.44 mmol), and N,N-dimethyl-4-aminopyridine (6.6 mg,

0.055 mmol). The mixture was stirred at room temperature during

15 min, diluted with CH₂Cl₂(20 mL), and washed with satd aq

NaHCO₃(15 mL) and brine (35 mL). The organic layer was dried

(MgSO₄), ﬁltered, and concentrated. The crude was chromato-

graphed (50% EtOAc/hexanes, 60 mL SiO₂), yielding the

4O-chloroacetate ester 31h (89.7 mg, 74%) as a light yellow oil: R_f

= 0.46 (60% EtOAc/hexanes); IR (thin ﬁlm) 3407, 1768, 1720, 1648,

1614, 1591 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.76 (apparent d, J

= 8.3 Hz, 2H), 7.33 (apparent d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.9 Hz,

1H), 6.49−6.39 (m, 2H), 6.29 (d, J = 6.2 Hz, 1H), 5.41 (apparent s,

2H), 5.20 (t, J = 5.8 Hz, 1H), 4.75 (ddd, J = 6.0, 2.0, 2.0 Hz, 1H),

4.36−4.08 (m, 5H), 3.90 (apparent s, 2H), 3.83 (s, 3H), 3.80 (s, 3H),

(m, 3H), 5.55−5.38 (m, 2H), 5.20 (br t, J = 5.6 Hz, 1H), 4.77

(m, 1H), 4.39−4.13 (m, 5H), 3.82 (s, 3H), 3.79 (s, 3H), 2.08 (s, 3H),

1

2.06 (s, 3H); H NMR signals for minor rotamer (∼20%) at δ 7.11

(br d, J = 9.4 Hz), broad peak at δ 5.04, and a shoulder on the

downﬁeld side of the resonance at δ 4.77; ¹³C NMR (75 MHz,

CDCl₃) δ 170.6 (s), 169.9 (s), 160.5 (s), 158.4 (s), 155.3 (s),

145.0 (o), 130.2 (o), 118.8 (s), 103.7 (o), 99.4 (o), 98.5 (o),

72.8 (o), 64.5 (o), 63.9 (o), 61.9 (t), 55.3 (o), 55.2 (o), 40.5 (t), 20.7

(o), 20.6 (o); HRMS (FAB) m/z calcd for C₂₀H₂₅NO₉(M⁺)

423.1529, found 423.1544.

1

2.45 (s, 3H); H NMR signals for minor rotamer (∼15%) at δ 7.06

(br d, J = 7.0 Hz), 6.34 (d, J = 6.4 Hz), 5.00 (br s), and a downﬁeld

shoulder on the resonance at δ 4.75; ¹³C NMR (75 MHz, CDCl₃)

δ 166.2 (s), 160.6 (s), 158.5 (s), 155.1 (s), 145.2 (s), 144.8 (o), 132.5

(s), 130.2 (o), 129.9 (o), 128.0 (o), 118.8 (s), 103.8 (o), 99.2 (o),

98.6 (o), 72.0 (o), 66.44 (t), 66.36 (o), 63.2 (o), 56.05 (o),* 56.01

(o),* 40.7 (t), 40.4 (t), 21.6 (o); *these ¹³C NMR resonances were

resolved upon reprocessing the FID with lb = 0; HRMS (FAB) m/z

calcd for C₂₅H₂₈NO₁₀SCl (M⁺) 569.1122, found 569.1143.

4,6-Di-O-chloroacetyl-3-O-(N-2,4-dimethoxybenzyl)carbamoyl-

D-galactal (31g). Diol 29 (301 mg, 0.887 mmol) was suspended in

CH₂Cl₂(2 mL), and pyridine (574 μL, 0.561 mmol), chloroacetic

anhydride (607 mg, 3.55 mmol), and N,N-dimethyl-4-aminopyridine

(54.6 mg, 0.444 mmol) were added, in that order. The reaction

mixture was concentrated on the rotovap and for 1 h under high

vacuum (∼0.5 Torr). The crude material was chromatographed

directly (40 → 50 → 60% EtOAc/hexanes, 200 mL SiO₂), aﬀording

bis(chloroacetyl) ester 31g (315 mg, 72%) as a white foam: R_f= 0.50

(60% EtOAc/hexanes); IR (thin ﬁlm) 3409, 1764, 1724, 1654, 1648,

1615, 1590 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.18 (d, J = 8.0 Hz,

1H), 6.49−6.37 (m, 3H), 5.49 (m, 2H), 5.19 (t, J = 5.6 Hz, 1H), 4.80

4,6-Bis-O-tert-butyldimethylsilyl-3-O-(N-2,4-dimethoxybenzyl)-

carbamoyl-^D-galactal (31i). To a solution of diol 29 (125 mg, 0.368

mmol) in DMF (1 mL) were added, sequentially, imidazole (151 mg,

2.22 mmol) and tert-butyldimethylsilyl chloride (226 mg, 1.50 mmol).

After stirring at room temperature 5 h, additional imidazole (152 mg,

2.23 mmol) and tert-butyldimethylsilyl chloride (221 mg, 1.47 mmol)

were added. Stirring was continued for 72 h, and the reaction mixture

was diluted with CH₂Cl₂(20 mL) and washed with satd aq NaHCO₃

(15 mL) and brine (15 mL). The organic layer was dried (MgSO₄),

ﬁltered, and concentrated. The crude material was chromatographed

(10 → 15 → 20% EtOAc/hexanes, 120 mL SiO₂), yielding bis-

silylated 31i (121 mg, 58%) as a clear, colorless oil: R_f= 0.73 (40%

EtOAc/hexanes); IR (thin ﬁlm) 3459, 3365, 1722, 1715, 1650, 1644,

1615, 1591 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.17 (d, J = 7.9 Hz,

1H), 6.49−6.38 (m, 2H), 6.32 (dd, J = 6.1, 0.9 Hz, 1H), 5.27 (slightly

broadened apparent s, 1H), 5.14 (t, J = 5.8 Hz, 1H), 4.62 (dd, J = 5.9,

2.0 Hz, 1H), 4.27 (apparent d, J = 6.0 Hz, 2H), 4.16 (slightly

broadened apparent s, 1H), 3.94 (m, 1H), 3.88−3.72 (m, 2H), 3.81

(s, 3H), 3.80 (s, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.06 (apparent s,

(dd, J = 5.6, 2.6 Hz, 1H), 4.42−4.34 (m, 1H), 4.39 (AB of ABX, J_AB

=

10.9 Hz, J_AX= 7.5 Hz, J_BX= 4.1 Hz, Δν_AB= 53.1 Hz, 2H), 4.09

(apparent s, 2H), 4.00 (apparent s, 2H), 3.82 (s, 3H), 3.80 (s, 3H);

¹H NMR signals for minor rotamer (∼15%) appeared as broad peaks

at δ 7.09 and δ 5.02 as well as a shoulder on the downﬁeld side of the

resonance at δ 4.80; ¹³C NMR (75 MHz, CDCl₃) δ 167.0 (s), 166.5

(s), 160.7 (s), 158.5 (s), 155.2 (s), 145.0 (o), 130.3 (o), 118.8 (s),

103.8 (o), 99.3 (o), 98.6 (o), 72.2 (o), 66.5 (o), 63.4 (o), 63.1 (t),

55.4 (o), 55.3 (o), 40.7 (t), 40.6 (t), 40.5 (t); HRMS (FAB) m/z

calcd for C₂₀H₂₃NO₉³⁵Cl₂(M⁺) 491.0750, found 491.0744.

1

6H), 0.05 (s, 3H), 0.01 (s, 3H); H NMR signals for minor rotamer

3-O-(N-2,4-Dimethoxybenzyl)carbamoyl-6-O-p-toluenesulfonyl-

D-galactal (30). Diol 29 (329 mg, 0.969 mmol) was dissolved in

(∼15%) appeared as broadened peaks at δ 7.11, 4.86, and 4.78;

P

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¹³C NMR (75 MHz, CDCl₃) δ 160.5 (s), 158.5 (s), 155.9 (s), 144.6

(o), 130.2 (o), 119.1 (s), 103.7 (o), 99.3 (o), 98.5 (o), 78.1 (o),

67.1 (o), 64.8 (o), 60.8 (t), 55.4 (o), 55.2 (o), 40.8 (t), 25.9 (o),

25.8 (o), 18.3 (s), 18.2 (s), −4.8 (o), −4.9 (o), −5.2 (o), −5.3 (o);

HRMS (FAB) m/z calcd for C₂₈H₄₈NO₇Si₂(M − H)⁺566.2969,

found 566.2989.⁶⁷

3-O-Carbamoyl-4,6-di-O-chloroacetyl-^D-galactal (14g). Depro-

tection of N-(2,4-dimethoxybenzyl) carbamate 31g (313 mg,

0.433 mmol) was achieved using the general procedure in CHCl₃/

H₂O (7 mL/0.7 mL) during 3 h 30 min. Chromatography (50%

EtOAc/hexanes, 125 mL SiO₂) provided primary carbamate 14g

(99.2 mg, 93%) as a clear, colorless oil, which gave a white solid upon

standing in the freezer (−20 °C): mp 105−107.5 °C; R_f= 0.15 (40%

EtOAc/hexanes); IR (ATR) 3493, 3386, 1760 (shoulder), 1722,

4-O-tert-Butyldimethylsilyl-3-O-(N-2,4-dimethoxybenzyl)-

carbamoyl-6-O-p-toluenesulfonyl-^D-galactal (31j). To a solution of

alcohol 30 (192 mg, 0.389 mmol) in DMF (1 mL) was added

imidazole (158 mg, 2.23 mmol), followed by tert-butyldimethylsilyl

chloride (173 mg, 1.17 mmol). After stirring for 21 h at room

temperature, additional imidazole (158 mg, 2.23 mmol) and tert-

butyldimethylsilyl chloride (173 mg, 1.17 mmol) were added, and

stirring was continued for 3 days. The reaction mixture was diluted

with CH₂Cl₂(10 mL) and washed with satd aq NaHCO₃(10 mL)

and brine (10 mL). The aqueous layers were back-extracted with

CH₂Cl₂(10 mL), and the combined organic layers were dried

(MgSO₄), ﬁltered, and concentrated. The crude was chromato-

graphed (30 → 40% EtOAc/hexanes, 125 mL SiO₂), aﬀording silyl

ether 31j (183 mg, 77%) as a light yellow oil: R_f= 0.67 (60% EtOAc/

hexanes); IR (thin ﬁlm) 3456, 3407, 1731, 1715, 1699, 1645, 1614,

1591 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.77 (apparent d, J = 8.1

Hz, 2H), 7.29 (apparent d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.1 Hz, 1H),

6.51−6.38 (m, 2H), 6.11 (d, J = 6.0 Hz, 1H), 5.15 (apparent t, J = 4.2

Hz, 1H), 5.06 (t, J = 5.6 Hz, 1H), 4.74 (apparent t, J = 5.4 Hz, 1H),

4.44 (dd, J = 11.0, 8.7 Hz, 1H), 4.33−4.06 (m, 5H), 3.84 (s, 3H),

1

1652, 1594 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 6.45 (dd, J = 6.3,

1.5 Hz, 1H, H1), 5.51 (m, 2H, H3, H4, with H3 slightly upﬁeld of

H4), 4.81 (ddd, J = 6.3, 2.9, 1.3 Hz, 1H, H2), 4.73 (br s, 2H, NH₂),

4.40 (AB of ABX, J_AB= 9.7 Hz, J_AX= 7.0 Hz, J_BX= 3.7 Hz, Δν_AB

=

38.0 Hz, 2H, H6), 4.40 (m, 1H, H5), 4.15 (apparent s, 2H,

C(O)CH₂Cl), 4.12 (apparent s, 2H, C(O)CH₂Cl); ¹³C NMR (75

MHz, CDCl₃) δ 167.0 (s, C(O)CH₂Cl), 166.7 (s, C(O)CH₂Cl),

155.5 (s, C(O)NH₂), 145.3 (o, C1), 98.9 (o, C2), 72.1 (o, C5), 66.0

(o, C4), 64.3 (o, C3), 63.1 (t, C6), 40.6 (t, 2 × C(O)CH₂Cl); HRMS

(FAB) m/z calcd for C₁₁H₁₃NO₇³⁵Cl₂Na (M + Na)⁺363.9967, found

363.9979.

3-O-Carbamoyl-4O-chloroacetyl-6-O-p-toluenesulfonyl-^D-galac-

tal (14h). Oxidative removal of the N-(2,4-dimethoxybenzyl)

protecting group from carbamate 31h (129 mg, 0.226 mmol)

followed the general procedure in CHCl₃/H₂O (5 mL/0.5 mL)

during 4 h. Chromatography (50 → 55 → 60% EtOAc/hexanes,

60 mL SiO₂) yielded primary carbamate 14h (86.7 mg, 91%): R_f=

0.16 (40% EtOAc/hexanes); IR (ATR) 3491, 3388, 1765 (shoulder),

1725, 1652, 1598 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.79

(apparent d, J = 8.3 Hz, 2H, H_o), 7.37 (apparent d, J = 8.0 Hz, 2H,

H_m), 6.35 (dd, J = 6.3, 1.5 Hz, 1H, H1), 5.49−5.42 (m, 2H, H3, H4),

4.80 (br s, 2H, NH₂), 4.76 (ddd, J = 6.3, 2.9, 1.3 Hz, 1H, H2), 4.36

(dddd, J = 7.1, 5.3, 1.9, 1.2 Hz, 1H, H5), 4.22 (AB of ABX, J_AB= 10.5

Hz, J_AX= 7.1 Hz, J_BX= 5.1 Hz, Δν_AB= 25.8 Hz, 2H, H6), 4.06 (AB,

1

3.81 (s, 3H), 2.42 (s, 3H), 0.79 (s, 9H), 0.01 (apparent s, 6H); H

NMR signals for minor rotamer (∼15%) appeared as broadened

peaks at δ 7.07, 6.18, and 4.83; ¹³C NMR (75 MHz, CDCl₃) δ 160.6

(s), 158.6 (s), 155.5 (s), 144.7 (s), 144.3 (o), 133.1 (s), 130.4 (o),

129.8 (o), 128.0 (o), 119.0 (s), 103.9 (o), 99.2 (o), 98.6 (o), 74.8

(o), 67.1 (t), 66.4 (o), 64.4 (o), 55.4 (o), 55.3 (o), 40.6 (t), 25.6 (o),

21.6 (o), 17.9 (s), −5.1 (o), −5.3 (o); HRMS (FAB) m/z calcd for

C₂₉H₄₀NO₉SiS (M − H)⁺606.2193, found 606.2172.⁶⁷

General Procedure for Oxidative Removal of the N-2,4-

Dimethoxylbenzyl Protecting Group. To a solution of 2,4-

dimethoxybenzyl carbamate (1.0 equiv, ∼0.1−0.2 M) in CHCl₃/H₂O

(10/1) at 25 °C was added 2,3-dichloro-5,6-dicyanobenzoquinone

(3.0 equiv), and the heterogeneous mixture was stirred vigorously.

The reaction was monitored closely by TLC to ensure that a

transiently formed bisaminal 32 (not isolated, but the structure was

inferred by analogy to a fully characterized intermediate isolated

previously in the glucal series²⁴) was fully hydrolyzed to the desired

primary carbamate. Full conversion to the primary carbamate was

typically complete within 1−4 h. The reaction mixture was diluted

with CH₂Cl₂and washed twice with satd aq NaHCO₃. The organic

layer was dried (MgSO₄), ﬁltered, and concentrated, and the crude

product was chromatographed (SiO₂, EtOAc/hexanes), providing the

primary carbamate product.

J

_AB= 15.0 Hz, Δν_AB= 9.7 Hz, 2H, CH₂Cl), 2.46 (s, 3H, Ar-CH₃); ¹³

C

NMR (75 MHz, CDCl₃) δ 166.4 (s, OC(O)CH₂Cl), 155.5

(s, OC(O)NH₂), 145.3 (s), 145.1 (o, C1), 132.2 (s), 130.0

(o, C_m), 128.0 (o, C_o), 99.0 (o, C2), 72.0 (o, C5), 66.4 (t, C6),

65.8 (o, C4), 64.1 (o, C3), 40.5 (t, CH₂Cl), 21.7 (o, Ar-CH₃); HRMS

(FAB) m/z calcd for C₁₆H₁₈NO₈SClNa (M + Na)⁺442.0339, found

442.0365.

4,6-O-Bis-tert-butyldimethylsilyl-3-O-carbamoyl-6-O-p-toluene-

sulfonyl-^D-galactal (14i). The primary carbamate group of 14i was

revealed using the general procedure for DDQ deprotection of 2,4-

dimethoxybenzyl carbamate 31i (118 mg, 0.207 mmol). The

conversion occurred over 4 h 30 min, and chromatography (15 →

20 → 25% EtOAc/hexanes, 125 mL SiO₂) provided primary

carbamate 14i (49.3 mg, 57%) as a white solid: R_f= 0.37 (20%

EtOAc/hexanes); IR (thin ﬁlm) 3508, 3348, 3272, 3185, 1737, 1731,

1

1715, 1651, 1644, 1599 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 6.35

(dd, J = 6.2, 1.5 Hz, 1H, H1), 5.26 (dddd, J = 4.5, 3.0, 1.3, 1.3 Hz, 1H,

H3), 4.76 (br s, 2H, NH₂), 4.67 (ddd, J = 6.2, 3.2, 1.0 Hz, 1H, H2),

4.20 (ddd, J = 3.8, 2.6, 0.9 Hz, 1H, H4), 3.97 (dddd, J = 6.8, 5.7, 2.5,

3-O-Carbamoyl-4,6-di-O-acetyl-^D-galactal (14c). Prepared from

31c (1.48 g, 3.48 mmol) following the general procedure in CHCl₃/

H₂O (25 mL/2.5 mL) for 2 h, enabling hydrolysis of bisaminal

intermediate 32c. Using 40% EtOAc/hexanes and eluting twice, the

bisaminal 32c ran slightly below the ﬁnal product 14c on a SiO₂-

coated TLC plate. Chromatography (60% EtOAc/hexanes, 50 mL

SiO₂), provided 14c as a white crystalline solid (0.858 g, 90%): mp

86−88 °C; R_f= 0.63 (60% EtOAc/hexanes); IR (thin ﬁlm) 3475,

1.0 Hz, 1H, H5), 3.82 (AB of ABX, J_AB= 10.8 Hz, J_AX= 7.2 Hz, J_BX

=

5.8 Hz, Δν_AB= 14.1 Hz, 2H, H6), 0.91 (s, 9H, SiC(CH₃)₃), 0.90

(s, 9H, SiC(CH₃)₃), 0.10 (apparent s, 6H, SiCH₃), 0.07 (apparent s,

6H, SiCH₃); ¹³C NMR (75 MHz, CDCl₃) δ 156.4 (s, OC(O)NH₂),

145.0 (o, C1), 98.7 (o, C2), 78.2 (o, C5), 67.4 (o, C3), 64.9 (o, C4),

60.6 (t, C6), 25.9 (o, SiC(CH₃)₃), 25.8 (o, SiC(CH₃)₃), 18.3

(s, SiC(CH₃)₃), 18.2 (s, SiC(CH₃)₃), −4.7 (o, SiCH₃), −4.9

(o, SiCH₃), −5.2 (o, SiCH₃), −5.3 (o, SiCH₃); HRMS (FAB) m/z

calcd for C₁₉H₃₈NO₅Si₂(M − H)⁺416.2289, found 416.2315.⁶⁷

4O-tert-Butyldimethylsilyl-3-O-carbamoyl-6-O-p-toluenesulfon-

yl-^D-galactal (14j). Following the general procedure for DDQ-

mediated N-deprotection, 2,4-dimethoxybenzyl carbamate 31j

(153 mg, 0.251 mmol) was converted over 3 h to primary carbamate

14j, isolated after chromatography (20 → 30 → 40% EtOAc/hexanes,

120 mL SiO₂) as a clear, colorless oil (101 mg, 87%): R_f= 0.43 (40%

EtOAc/hexanes); IR (thin ﬁlm) 3490, 3388, 3280, 3206, 1728, 1646,

3370, 3198, 1745, 1730 (shoulder), 1652, 1603 cm⁻^{1 1}H NMR

;

(300 MHz, CDCl₃) δ 6.45 (d, J = 6.0 Hz, 1H, H1), 5.50−5.42

(m, 2H, H3, H4), 4.94 (br s, 2H, NH₂), 4.78 (ddd, J = 6.3, 2.1,

2.1 Hz, 1H, H2), 4.38−4.31 (m, 1H, H5), 4.32−4.18 (m, 2H, H6),

2.14 (s, 3H), 2.10 (s, 3H),; ¹³C NMR (75 MHz, CDCl₃) δ 170.6

(s, C(O)CH₃), 170.1 (s, C(O)CH₃), 155.8 (s, OC(O)NH₂), 145.2

(o, C1), 99.0 (o, C2), 72.7 (o, C5), 64.5 (o, C3), 64.2 (o, C4), 61.9

(t, C6), 20.73 (o, C(O)CH₃), 20.66 (o, C(O)CH₃); HRMS (FAB)

m/z calcd for C₁₁H₁₅NO₇Na (M + Na)⁺296.0746, found 296.0748.

Additional details on distinguishing the C3 and C4 resonances of 14c

by H/¹³C HMBC and on coupling constant analysis using H/¹³C

coupled HSQC with third-channel homonuclear ¹H decoupling are in

the Supporting Information.

1598 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 7.81 (apparent d, J =

1

8.4 Hz, 2H, H_o), 7.35 (apparent d, J = 8.1 Hz, 2H, H_m), 6.15 (dd, J =

6.1, 0.7 Hz, 1H, H1), 5.13 (apparent t, J = 4.6 Hz, 1H, H3), 4.78

Q

DOI: 10.1021/acs.joc.8b00893

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(dd, J = 6.0, 5.1 Hz, 1H, H2), 4.65 (br s, 2H, NH₂), 4.39 (AB of ABX,

provided anomers 15ba-β (35.4 mg, 55%) and 15ba-α (4.0 mg,

6%), both as colorless oils. Data for the major product 15ba-β: R_f=

0.41 (40% EtOAc/hexanes); IR (thin ﬁlm) 3317, 3064, 3031, 1765,

J_AB= 11.3 Hz, J_AX= 8.7 Hz, J_BX= 2.1 Hz, Δν_AB= 44.4 Hz, 2H, H6),

4.24−4.12 (m, 2H, H4, H5), 2.45 (s, 3H, Ar-CH₃), 0.83 (s, 9H,

SiC(CH₃)₃), 0.07 (s, 3H, SiCH₃), 0.04 (s, 3H, SiCH₃); ¹³C NMR

(75 MHz, CDCl₃) δ 155.9 (s, OC(O)NH₂), 144.8 (s), 144.5 (o, C1),

133.0 (s), 129.8 (o, C_m), 128.0 (o, C_o), 98.7 (o, C2), 74.7 (o, C5),

66.8 (t, C6), 66.2 (o, C4), 64.8 (o, C3), 25.5 (o, SiC(CH₃)₃), 21.6

(o, Ar-CH₃), 17.9 (s, SiC(CH₃)₃), −5.1 (o, SiCH₃), −5.3 (o, SiCH₃);

HRMS (FAB) m/z calcd for C₂₀H₃₁NO₇SiSNa (M + Na)⁺480.1488,

found 480.1511.

1

1640 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 7.40−7.22 (m, 10H,

Ar−H), 5.79 (dddd, J = 17.0, 10.3, 6.7, 6.7 Hz, 1H, H4′), 5.53 (br s,

1H, NH), 5.08−4.92 (m, 2H, H5′), 4.66 (dd, J = 6.5, 2.3 Hz, 1H,

H3), 4.59 (AB, J_AB= 11.9 Hz, Δν_AB= 30.5 Hz, 2H, OCH₂Ph), 4.50

(AB, J_AB= 11.9 Hz, Δν_AB= 12.7 Hz, 2H, OCH₂Ph), 4.37 (d, J =

7.5 Hz, 1H, H1), 3.98−3.85 (m, 2H, H5, H1′a), 3.79 (br apparent s,

1H, H4), 3.67 (AB of ABX, J_AB= 9.7 Hz, J_AX= 6.5 Hz, J_BX= 5.9 Hz,

Δν_AB= 16.4 Hz, 2H, H6), 3.55 (dd, J = 7.0, 7.0 Hz, 1H, H2), 3.46

(ddd, J = 9.5, 6.8, 6.8 Hz, 1H, H1′b), 2.10 (apparent q, J = 7.2 Hz,

2H, H3′), 1.69 (apparent pentet, J = 7.1 Hz, 2H, H2′); ¹³C NMR

(75 MHz, CDCl₃) δ 158.2 (s, OC(O)NH), 137.9 (o, C4′), 137.8

(s, C_i), 137.0 (s, C_i), 128.5 (o, C_Ar−H), 128.4 (o, C_Ar−H), 128.2

(o, C_Ar−H), 127.7 (o, C_Ar−H), 127.6 (o, C_Ar−H), 115.0 (t, C5′), 103.5

(o, C1), 76.1 (o, C3), 73.4 (t, OCH₂Ph), 73.23 (t, OCH₂Ph), 73.15

(o, C5), 70.1 (o, C4), 69.3 (t, C1′), 68.2 (t, C6), 53.4 (o, C2), 30.1

(t, C3′), 28.6 (t, C2′); HRMS (FAB) m/z calcd for C₂₆H₃₀NO₆

(M − H)⁺452.2073, found 452.2080.⁶⁷

General Procedure for Glycal Amidoglycosylation. The

primary carbamate (∼0.2 mmol), 4 Å molecular sieves (300 wt %

relative to the carbamate, stored in a 135 °C oven and ﬂame-dried

under vacuum just prior to use), Rh₂(OAc)₄(0.1 equiv), and PhIO

(1.8 equiv) were combined in a 10 mL round-bottom ﬂask. 4-Penten-

1-ol (5.0 equiv) was added, followed immediately by CH₂Cl₂

(2.0 mL). The mixture was well stirred, monitoring disappearance

of the starting carbamate by TLC. When starting material was

consumed (reaction times 3−18 h), the reaction mixture was ﬁltered

through a tightly packed pad of Celite, rinsing with EtOAc (75 mL).

The ﬁltrate was concentrated (rotary evaporator then high vacuum

overnight to remove excess 4-penten-1-ol). The crude was analyzed

by ¹H NMR and, in some cases, ¹³C NMR for determination of

the anomeric ratio, the ratio of amidoglycosylation product to

C3-oxidation byproduct, and any remaining starting material, as

reported in Table 2. The crude material was puriﬁed by chro-

matography (SiO₂, EtOAc/hexanes).

Data for the minor product 15ba-α: R_f= 0.26 (40% EtOAc/

1

hexanes); IR (thin ﬁlm) 3302, 3063, 3031, 1765, 1640 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 7.40−7.23 (m, 10H, Ar−H), 5.78 (dddd,

J = 17.0, 10.3, 6.7, 6.7 Hz, 1H, H4′), 5.08−4.90 (m, 3H, H5′, NH),

4.87 (d, J = 3.6 Hz, 1H, H1), 4.74 (dd, J = 7.8, 3.5 Hz, 1H, H3), 4.63

(AB, J_AB= 11.7 Hz, Δν_AB= 27.9 Hz, 2H, OCH₂Ph), 4.52 (AB, J_AB

=

12.0 Hz, Δν_AB= 12.4 Hz, 2H, OCH₂Ph), 4.24 (ddd, J = 5.6, 5.6,

3.5 Hz, 1H, H5), 3.98 (dd, J = 3.3, 3.3 Hz, 1H, H4), 3.91 (dd, J = 7.9,

3.6 Hz, 1H, H2), 3.78 (ddd, J = 9.5, 6.5, 6.5 Hz, 1H, H1′a), 3.64 (AB

of ABX, J_AB= 9.6 Hz, J_AX= 5.9 Hz, J_BX= 5.8 Hz, Δν_AB= 15.8 Hz, 2H,

H6), 3.39 (ddd, J = 9.4, 6.5, 6.5 Hz, 1H, H1′b), 2.09 (apparent q, J =

6.9 Hz, 2H, H3′), 1.66 (apparent pentet, J = 6.9 Hz, 2H, H2′); ¹³C

NMR (75 MHz, CDCl₃) δ 159.0 (s, OC(O)NH), 138.0 (o, C4′),

137.9 (s, C_i), 137.3 (s, C_i), 128.6 (o, C_Ar−H), 128.4 (o, C_Ar−H), 128.2

(o, C_Ar−H), 128.0 (o, C_Ar−H), 127.7 (o, C_Ar−H), 127.6 (o, C_Ar−H),

115.0 (t, C5′), 94.7 (o, C1), 74.0 (o, C3), 73.4 (two overlapping

resonances, 2t, 2 × OCH₂Ph), 71.7 (o, C4), 68.5 (t, C6), 68.2 (o, C5),

67.8 (t, C1′), 51.6 (o, C2), 30.2 (t, C3′), 28.6 (t, C2′); HRMS (FAB)

m/z calcd for C₂₆H₃₂NO₆(M + H)⁺454.2230, found 454.2245.

4-Pentenyl 2-Amino-2-N,3-O-carbonyl-2-deoxy-4,6-di-O-acetyl-

D-gulopyranosides (15ca). The reaction was carried out twice

(Run 1, 51.6 mg, 0.189 mmol of 11c; Run 2, 50.0 mg, 0.183 mmol

11c), using the general amidoglycosylation procedure. Chromatog-

raphy (50% EtOAc/hexanes) provided 15ca-β and 15ca-α separately

as oils. The yield of the major β anomer was 62% (run 1) and 69%

(run 2). Data for the major product 15ca-β: R_f= 0.35 (50% EtOAc/

Amidoglycosylation of Gulal 3-carbamates 11 with 4-

Penten-1-ol Acceptor. 4-Pentenyl 2-Amino-2-N,3-O-carbonyl-2-

deoxy-4,6-O-isopropylidene-^D-gulopyranosides (15aa). Starting

from primary carbamate 11a (50.1 mg, 0.219 mmol), following the

general amidoglycosylation procedure, and chromatography (45 →

50 → 55% EtOAc/hexanes) provided 15aa-β (45.2 mg, 66%) and a

few mixed fractions containing both 15aa-β and 15aa-α. Additional

chromatography gave a small amount of pure 15aa-α for full

characterization. Data for the major product 15aa-β: R_f= 0.57 (60%

1

EtOAc/hexanes); IR (thin ﬁlm) 3296, 3071, 1770, 1640 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 5.81 (dddd, J = 17.0, 10.3, 6.7, 6.7 Hz,

1H, H4′), 5.69 (s, 1H, NH), 5.12−4.91 (m, 2H, H5′), 4.53 (dd, J =

6.5, 1.2 Hz, 1H, H3), 4.35 (d, J = 7.8 Hz, 1H, H1), 4.18 (apparent s,

1H, H4), 4.14 (dd, J = 13.1, 2.4 Hz, 1H, H6a), 4.07−3.92 (m, 2H,

H6b, H1′a), 3.57 (dd, J = 7.4, 7.4 Hz, 1H, H2), 3.53 (m, 1H, H5),

3.44 (ddd, J = 9.4, 7.0, 7.0 Hz, 1H, H1′b), 2.12 (apparent q, J =

7.1 Hz, 2H, H3′), 1.72 (apparent pentet of d, J = 7.0, 2.1 Hz, 2H,

H2′), 1.49 (s, 3H, C(CH₃)₂); 1.44 (s, 3H, C(CH₃)₂); ¹³C NMR

(75 MHz, CDCl₃) δ 158.1 (s, OC(O)NH), 137.9 (o, C4′), 115.0

(t, C5′), 103.2 (o, C1), 99.0 (s, C(CH₃)₂), 78.2 (o, C3), 69.4

(t, C1′), 66.7 (o, C5), 63.7 (o, C4), 62.0 (t, C6), 52.7 (o, C2), 30.1

(t, C3′), 28.9 (o, C(CH₃)₂), 28.5 (t, C2′), 18.5 (o, C(CH₃)₂); HRMS

(FAB) m/z calcd for C₁₅H₂₄NO₆(M + H)⁺314.1604, found

314.1619. A NOESY study of the major product (see the Supporting

Information) indicated an NOE contact between H1 and H5,

consistent with the β-anomeric stereochemistry in 15aa-β.

1

hexanes); IR (thin ﬁlm) 3322, 1774, 1748, 1640 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 5.92 (br s, 1H, NH), 5.79 (dddd, J = 17.0, 10.3,

6.7, 6.7 Hz, 1H, H4′), 5.20 (apparent br s, 1H, H4), 5.08−4.93

(m, 2H, H5′a,b), 4.58 (dd, J = 6.5, 2.1 Hz, 1H, H3), 4.43 (d, J =

7.4 Hz, 1H, H1), 4.20 (AB of ABX, J_AB= 11.3 Hz, J_AX= 7.0 Hz, J_BX

=

6.0 Hz, Δν_AB= 19.3 Hz, 2H, H6a,b), 4.07 (ddd, J = 6.4, 6.4, 1.7 Hz,

1H, H5), 3.91 (ddd, J = 9.5, 6.6, 6.6 Hz, 1H, H1′a), 3.53 (dd, J = 7.0,

7.0 Hz, 1H, H2), 3.51 (ddd, J = 9.8, 6.8, 6.8 Hz, 1H, H1′b), 2.20−

2.05 (m, 2H, H3′a,b), 2.12 (s, 3H, C(O)CH₃), 2.05 (s, 3H,

C(O)CH₃), 1.71 (apparent pentet, J = 7.1 Hz, 2H, H2′a,b); ¹³C

NMR (75 MHz, CDCl₃) δ 170.4 (s, C(O)CH₃), 169.6

(s, C(O)CH₃), 157.7 (s, OC(O)NH), 137.7 (o, C4′), 115.1

(t, C5′), 103.6 (o, C1), 76.0 (o, C3), 70.5 (o, C5), 69.6 (t, C1′),

64.1 (o, C4), 61.4 (t, C6), 53.0 (o, C2), 30.0 (t, C3′), 28.6 (t, C2′),

20.6 (o, two overlapping signals, C(O)CH₃); HRMS (FAB) m/z

calcd for C₁₆H₂₄NO₈(M + H)⁺358.1502, found 358.1512.

Data for the minor product 15aa-α: R_f= 0.48 (60% EtOAc/

1

hexanes); IR (thin ﬁlm) 3310, 1767, 1745, 1641 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 5.80 (dddd, J = 17.0, 10.3, 6.7, 6.7 Hz, 1H),

5.15 (d, J = 3.3 Hz, 1H), 5.11−4.92 (m, 3H), 4.61 (dd, J = 7.9,

2.7 Hz, 1H), 4.24 (dd, J = 2.4, 2.4 Hz, 1H), 4.02 (AB of ABX, J_AB

=

12.9 Hz, J_AX= 2.2 Hz, J_BX= 2.0 Hz, Δν_AB= 43.0 Hz, 2H), 3.89 (dd,

J = 8.0, 3.4 Hz, 1H), 3.85 (m, 1H), 3.82 (ddd, J = 9.7, 6.5, 6.5 Hz,

1H), 3.48 (ddd, J = 9.7, 6.5, 6.5 Hz, 1H), 2.13 (apparent q, J = 7.1 Hz,

2H), 1.70 (apparent pentet, J = 6.9 Hz, 2H), 1.48 (s, 3H), 1.42

(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 158.8 (s), 138.0 (o), 115.0

(t), 98.9 (s), 95.1 (o), 74.4 (o), 68.2 (t), 63.7 (o), 63.5 (t), 61.4 (o),

50.8 (o), 30.1 (t), 29.1 (o), 28.5 (t), 18.7 (o); HRMS (FAB) m/z

calcd for C₁₅H₂₄NO₆(M + H)⁺314.1604, found 314.1606.

4-Pentenyl 2-Amino-2-N,3-O-carbonyl-2-deoxy-4,6-di-O-benzyl-

D-gulopyranosides (15ba). Reaction of primary carbamate 11b

(52.6 mg, 0.142 mmol), following the general amidoglycosylation

procedure, and chromatography (40 → 50% EtOAc/hexanes)

Data for the minor product 15ca-α: R_f= 0.20 (50% EtOAc/

hexanes); IR (thin ﬁlm) 3356, 1765 (shoulder), 1744 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 5.80 (dddd, J = 17.0, 10.2, 6.7, 6.7 Hz, 1H,

H4′), 5.30 (apparent t, J = 2.3 Hz, 1H, H4), 5.11−4.94 (m, 3H, NH,

H5′a,b), 4.90 (d, J = 4.3 Hz, 1H, H1), 4.60 (dd, J = 7.2, 2.7 Hz, 1H,

H3), 4.38 (ddd, J = 6.2, 6.2, 2.4 Hz, 1H, H5), 4.16 (AB of ABX, J_AB

=

11.5 Hz, J_AX= 6.9 Hz, J_BX= 5.6 Hz, Δν_AB= 19.9 Hz, 2H, H6a,b), 3.87

(dd, J = 7.2, 4.3 Hz, 1H, H2), 3.78 (ddd, J = 9.5, 6.5, 6.5 Hz, 1H, H1′),

R

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3.43 (ddd, J = 9.5, 6.4, 6.4 Hz, 1H, H1′b), 2.20−2.08 (m, 2H,

H3′a,b), 2.14 (s, 3H, C(O)CH₃), 2.07 (s, 3H, C(O)CH₃), 1.72

(apparent pentet, J = 6.9 Hz, 2H, H2′a,b); ¹³C NMR (75 MHz,

CDCl₃) δ 170.4 (s, C(O)CH₃), 169.4 (s, C(O)CH₃), 158.6

(s, OC(O)NH), 137.8 (o, C4′), 115.2 (t, C5′), 94.9 (o, C1), 73.2

(o, C3), 67.9 (t, C1′), 65.0 (o, C4), 64.2 (o, C5), 61.9 (t, C6), 50.5

(o, C2), 30.2 (t, C3′), 28.4 (t, C2′), 20.7 (o, two overlapping signals,

C(O)CH₃); HRMS (FAB) m/z calcd for C₁₆H₂₄NO₈(M + H)⁺

358.1502, found 358.1525. A comparative NOESY study of the diaste-

reomers was used to assign C-1 conﬁguration of 15ca anomers. The

NOESY spectrum of 15ca-β showed a correlation between H1 (δ 4.43)

and H5 (δ 4.07), while a NOESY cross peak was absent between the

corresponding 15ca-α resonances (H1 at δ 4.90 and H5 at δ 4.38).

The NOESY spectra are included in the Supporting Information.

Amidoglycosylation of Allal 3-Carbamates 12 with

4-Penten-1-ol Acceptor. 4-Pentenyl 2-Amino-2-N,3-O-carbonyl-

2-deoxy-4,6-O-isopropylidene-β-^D-allopyranoside (16aa). Starting

from allal carbamate 12a²⁰(77.9 mg, 0.340 mmol), the general

amidoglycosylation procedure, followed by chromatography (40 →

50 → 60% EtOAc/hexanes, 60 mL SiO₂), provided a single anomer

16aa-β (79.2 mg, 74%) as a clear oil. Data for the amidoglycosylation

product 16aa-β: R_f= 0.32 (65% EtOAc/hexanes); IR (thin ﬁlm)

3293, 1757, 1641 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.28 (s, 1H,

NH), 5.81 (dddd, J = 17.0, 10.3, 6.7, 6.7 Hz, 1H, H4′), 5.09−4.95

(m, 2H, H5′), 4.83 (dd, J = 7.3, 3.4 Hz, 1H, H3), 4.55 (d, J = 4.7 Hz,

1H, H1), 4.16 (dd, J = 9.8, 3.4 Hz, 1H, H4), 3.98 (dd, J = 9.5, 4.3 Hz,

1H, H6a), 3.90−3.67 (m, 4H, H2, H5, H6b, H1′a), 3.47 (ddd, J =

9.5, 6.5, 6.5 Hz, 1H, H1′b), 2.14 (apparent q, J = 7.1 Hz, 2H, H3′),

1.70 (apparent pentet, J = 7.0 Hz, 2H, H2′), 1.51 (s, 3H, C(CH₃)₂);

1.46 (s, 3H, C(CH₃)₂); ¹³C NMR (75 MHz, CDCl₃) δ 159.0

(s, OC(O)NH), 137.7 (o, C4′), 115.1 (t, C5′), 101.1 (o, C1), 100.2

(s, C(CH₃)₂), 73.9 (o, C3), 69.0 (t, C1′), 68.0 (o, C4), 63.5 (o, C5),

62.7 (t, C6), 55.7 (o, C2), 30.1 (t, C3′), 28.8 (o, C(CH₃)₂), 28.7

(t, C2′), 18.8 (o, C(CH₃)₂); HRMS (FAB) m/z calcd for C₁₅H₂₄NO₆

(M + H)⁺314.1604, found 314.1592.

amidoglycosylation procedure, followed by chromatography (50 →

60 → 70 → 80% EtOAc/hexanes), provided dihydropyranone 19a

(20.8 mg, 76%). Data for dihydropyranone 19a: R_f= 0.27 (60%

EtOAc/hexanes); IR (thin ﬁlm) 1664, 1599 cm⁻^{1 1}H NMR

;

(300 MHz, CDCl₃) δ 7.51 (d, J = 6.2 Hz, 1H), 5.53 (dd, J = 6.2,

1.2 Hz, 1H), 4.25−4.10 (m, 4H), 1.56 (s, 3H), 1.46 (s, 3H); ¹³C

NMR (75 MHz, CDCl₃) δ 186.6 (s), 164.1 (o), 105.3 (o), 99.1 (s),

73.0 (o), 68.9 (o), 61.4 (t), 29.1 (o), 18.4 (o); HRMS (FAB) m/z

calcd for C₉H₁₃O₄(M + H)⁺185.0814, found 185.0807.

1,5-Anhydro-2-deoxy-4,6-O-di-tert-butylsilylene-^D-threo-hex-1-

en-3-ulose (19d). Galactal carbamate 14d (50 mg, 0.15 mmol) was

subjected to the general amidoglycosylation procedure. The crude

material was chromatographed (30% EtOAc/hexanes), providing 19d

(21 mg, 49%). Data for dihydropyranone 19d: R_f= 0.53 (50%

EtOAc/hexanes); IR (thin ﬁlm) 1683, 1600 cm⁻^{1 1}H NMR

;

(300 MHz, CDCl₃) δ 7.43 (d, J = 6.1 Hz, 1H), 5.50 (dd, J = 6.1,

1.3 Hz, 1H), 4.41 (partially obscured AB of ABX, J_AB= 13.0 Hz, J_AX

=

1.9 Hz, J_BX= 1.6 Hz, Δν_AB= 17.1 Hz, 2H), 4.34 (m, 1H), 4.24

(m, 1H), 1.08 (s, 9H), 1.00 (s, 9H); ¹³C NMR (75 MHz, CDCl₃)

δ 187.9 (s), 163.2 (o), 105.0 (o), 78.4 (o), 72.7 (o), 65.5 (t), 27.4

(o), 26.7 (o), 23.3 (s), 20.7 (s); HRMS (FAB) m/z calcd for

C₁₄H₂₅O₄Si (M + H)⁺285.1522, found 285.1539.

4-Pentenyl 2-amino-2-N,3-O-carbonyl-2-deoxy-4,6-di-O-benzyl-

α-^D-talopyranoside (18ba) and 1,5-Anhydro-2-deoxy-4,6-di-O-

benzyl-^D-threo-hex-1-en-3-ulose (19b). Treatment of dibenzyl

galactal 3-carbamate 14b (50.4 mg, 0.137 mmol) under the general

amidoglycosylation reaction conditions during 4 h, followed by

chromatography (20 → 40% EtOAc/hexanes, 40 mL SiO₂) provided

18ba (8.6 mg, 14%) as a single anomer and dihydropyranone 19b

(38 mg, 61%). Data for amidoglycosylation product 18ba: R_f= 0.13 (50%

EtOAc/hexanes); IR (thin ﬁlm) 3317, 3064, 3031, 1762, 1639 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 7.38−7.25 (m, 10H), 5.77 (dddd, J =

17.0, 10.3, 6.7, 6.7 Hz, 1H), 5.22 (br s, 1H), 5.05−4.92 (m, 2H), 4.90

(d, J = 2.9 Hz, 1H), 4.89 (d, J = 10.8 Hz, 1H), 4.82 (dd, J = 8.3,

4.5 Hz, 1H), 4.48 (d, J = 11.3 Hz, 1H), 4.44 (AB, J_AB= 12.5 Hz, Δν_AB

=

15.9 Hz, 2H), 4.01−3.93 (m, 2H), 3.89 (dd, J = 8.3, 2.0 Hz, 1H), 3.73

(ddd, J = 9.5, 6.6, 6.6 Hz, 1H), 3.62−3.52 (m, 2H), 3.39 (ddd, J = 9.4,

6.6, 6.6 Hz, 1H), 2.07 (m, 2H), 1.64 (m, 2H); ¹³C NMR (75 MHz,

CDCl₃) δ 158.7, 137.83,* 137.82,* 137.3, 128.9, 128.41,* 128.38,*

128.0, 127.8, 127.7, 115.0, 97.0, 75.8, 73.7, 73.5, 71.0, 68.8, 68.6, 67.8,

54.5, 30.2, 28.6, *these ¹³C NMR signals resolved upon processing of

the FID with lb = 0; HRMS (FAB) m/z calcd for C₂₆H₃₂NO₆

(M + H)⁺454.2230, found 454.2202.

4-Pentenyl 2-Amino-2-N,3-O-carbonyl-2-deoxy-4,6-di-O-benzyl-

β-^D-allopyranoside (16ba). Starting from allal 3-carbamate 12b (44.7

mg, 0.121 mmol), the general amidoglycosylation procedure, followed

by chromatography (40 → 50 → 60 → 70% EtOAc/hexanes, 50 mL

SiO₂), provided 16ba-β (36.5 mg, 67%). A trace amount of

dihydropyranone 20b (not isolated) was identiﬁed in the crude

1

reaction mixture by comparison to H NMR data for 20b formed in

much larger amounts during reactions of 4,6-di-O-benzyl glucal

3-carbamate 13b (see Table 2, entries 9 and 10).^24,69Data for the

amidoglycosylation product 16ba-β: R_f= 0.28 (40% EtOAc/hexanes);

IR (thin ﬁlm) 3298, 3062, 3030, 1761, 1639 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 7.39−7.22 (m, 10H, ArH), 6.14 (br s, 1H,

NH), 5.76 (dddd, J = 17.0, 10.3, 6.7, 6.7 Hz, 1H, H4′), 5.07−4.92

Data for dihydropyranone 19b:^69aR_f= 0.43 (40% EtOAc/

1

hexanes); IR (thin ﬁlm) 3063, 3031, 1680, 1596 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 7.42−7.20 (m, 11H), 5.44 (dd, J = 6.0, 1.2 Hz,

1H), 4.59 (AB, J_AB= 11.9 Hz, Δν_AB= 72.3 Hz, 2H), 4.54 (AB, J_AB

=

11.7 Hz, Δν_AB= 20.8 Hz, 2H), 4.49 (apparent s, 1H), 3.92 (dd, J =

10.2, 7.1 Hz, 1H), 3.74 (dd, J = 10.2, 5.3 Hz, 1H), 3.69 (apparent s,

1H); ¹³C NMR (75 MHz, CDCl₃) δ 189.4 (s), 162.7 (o), 137.4 (s),

137.0 (s), 128.5 (o), 128.4 (o), 128.3 (o), 128.0 (o), 127.9 (o), 127.8

(o), 105.1 (o), 80.6 (o), 74.1 (o), 73.6 (t), 72.0 (t), 67.6 (t); HRMS

(FAB) m/z calcd for C₂₀H₂₁O₄(M + H)⁺325.1440, found 325.1426.

4-Pentenyl 2-Amino-2-N,3-O-carbonyl-2-deoxy-4,6-di-O-acetyl-

α-^D-talopyranoside (18ca) and 1,5-anhydro-2-deoxy-4,6-di-O-

acetyl-^D-threo-hex-1-en-3-ulose (19c). Starting from galactal

3-carbamate 14c (50 mg, 0.18 mmol), the general amidoglycosylation

procedure, followed by chromatography (60% EtOAc/hexanes),

provided 18ca (16.5 mg, 25%) and dihydropyranone 19c (19.1 mg,

46%). Data for amidoglycosylation product 18ca: R_f= 0.55 (90%

EtOAc/hexanes); IR (thin ﬁlm) 3346, 3077, 1770 (shoulder), 1749,

(m, 2H, H5′), 4.89 (dd, J = 7.7, 2.8 Hz, 1H, H3), 4.62 (AB, J_AB

=

11.2 Hz, Δν_AB= 43.1 Hz, 2H, OCH₂Ph), 4.55 (AB, J_AB= 12.1 Hz,

Δν_AB= 23.3 Hz, 2H, OCH₂Ph), 4.55 (d, J = 5.5 Hz, 1H, H1), 4.07−

3.93 (m, 2H, H4, H5), 3.86 (ddd, J = 9.4, 6.6, 6.6 Hz, 1H, H1′a),

3.75−3.60 (m, 3H, H2, H6), 3.40 (ddd, J = 9.4, 6.7, 6.7 Hz, 1H,

H1′b), 2.03 (apparent q, J = 6.9 Hz, 2H, H3′), 1.61 (apparent pentet,

J = 7.0 Hz, 2H, H2′); ¹³C NMR (75 MHz, CDCl₃) δ 159.0

(s, OC(O)NH), 137.91 (o, C4′),* 137.87 (s, C_Ph),* 137.3 (s, C_i),

128.4 (o, C_Ph), 128.3 (o, C_Ph), 127.9 (o, C_Ph), 127.71 (o, C_Ph), 127.66

(o, C_Ph), 114.9 (t, C5′), 100.8 (o, C1), 73.8 (o, C3), 73.3 (t, OCH₂Ph),

72.5 (o, C5), 71.9 (t, OCH₂Ph), 70.8 (o, C4), 69.3 (t, C6), 68.8 (t, C1′),

55.3 (o, C2), 30.0 (t, C3′), 28.6 (t, C2′); *these ¹³C resonances were

clearly resolved upon reprocessing the FID with lb = 0; HRMS (FAB)

m/z calcd for C₂₆H₃₂NO₆(M + H)⁺454.2230, found 454.2216.

For the amidoglycosylation reaction of allal 3-carbamate 12e with

4-penten-1-ol (Table 2, entry 5) and for the synthesis and

amidoglycosylation reactions of glucal 3-carbamates 13 with

4-penten-1-ol (Table 2, entries 7−16), see ref 24.

1

1640 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 5.80 (dddd, J = 16.9,

10.3, 6.6, 6.6 Hz, 1H, H4′), 5.78 (br s, 1H, NH), 5.45 (dd, J = 5.0,

1.7 Hz, 1H, H4), 5.10−4.95 (m, 2H, H5′), 4.90 (s, 1H, H1), 4.84

(dd, J = 7.7, 5.2 Hz, 1H, H3), 4.24−4.13 (m, 3H, H5, H6), 3.94 (d,

J = 7.8 Hz, 1H, H2), 3.75 (ddd, J = 9.5, 6.6, 6.6 Hz, 1H, H1′a), 3.46

(ddd, J = 9.6, 6.5, 6.5 Hz, 1H, H1′b), 2.16 (s, 3H, C(O)CH₃), 2.13

(m, 2H, H3′), 2.07 (s, 3H, C(O)CH₃), 1.70 (apparent pentet, J =

7.0 Hz, 2H, H2′); ¹³C NMR (75 MHz, CDCl₃) δ 170.5

(s, C(O)CH₃), 170.1 (s, C(O)CH₃), 158.7 (s, OC(O)NH), 137.6

Amidoglycosylation of Galactal 3-Carbamates 14 with

4-Penten-1-ol Acceptor. 1,5-Anhydro-2-deoxy-4,6-O-isopropyli-

dene-^D-threo-hex-1-en-3-ulose (19a). Beginning from acetonide-

protected galactal 3-carbamate 14a (34 mg, 0.15 mmol), the general

S

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(o, C4′), 115.2 (t, C5′), 96.7 (o, C1), 70.9 (o, C3), 67.8 (t, C1′),

65.1 (o, C5), 63.7 (o, C4), 62.6 (t, C6), 53.5 (o, C2), 30.2 (t, C3′),

28.4 (t, C2′), 20.7 (o, C(O)CH₃), 20.5 (o, C(O)CH₃); HRMS

(FAB) m/z calcd for C₁₆H₂₄NO₈(M + H)⁺358.1502, found

358.1523. Additional NMR data for 18ca obtained in C₆D₆solvent,

including ¹H homonuclear decoupling studies and details of a NOESY

study conﬁrming the α-anomeric stereochemistry of 18ca, can be

found in the Supporting Information.

Data for dihydropyranone 19h: R_f= 0.78 (60% EtOAc/hexanes);

1

IR (thin ﬁlm) 1772, 1686, 1597 cm⁻¹; H NMR (300 MHz, CDCl₃)

δ 7.79 (apparent d, J = 8.3 Hz, 2H), 7.38 (apparent d, J = 8.0 Hz,

2H), 7.29 (d, J = 6.1 Hz, 1H), 5.54 (d, J = 4.6 Hz, 1H), 5.50 (d, J =

6.2 Hz, 1H), 4.81 (ddd, J = 7.1, 4.3, 4.3 Hz, 1H), 4.30 (AB of ABX,

J

_AB= 11.4 Hz, J_AX= 7.3 Hz, J_BX= 3.9 Hz, Δν_AB= 18.2 Hz, 2H), 4.09

(AB, J_AB= 15.3 Hz, Δν_AB= 3.3 Hz, 2H), 2.47 (s, 3H); ¹³C NMR

(75 MHz, CDCl₃) δ 184.1 (s), 165.8 (s), 161.9 (o), 145.6 (s),

132.0 (s), 130.0 (o), 128.1 (o), 105.9 (o), 77.2 (o), 69.1 (o), 65.2 (t),

40.2 (t), 21.7 (o); HRMS (FAB) m/z calcd for C₁₅H₁₆O₇S³⁵Cl

(M + H)⁺375.0305, found 375.0320.

Data for dihydropyranone 19c:⁷⁰R_f= 0.66 (90% EtOAc/hexanes);

IR (thin ﬁlm) 1746, 1681, 1596 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 7.34 (d, J = 6.1 Hz, 1H), 5.56 (d, J = 4.5 Hz, 1H), 5.51 (dd, J = 6.0,

0.5 Hz, 1H), 4.78 (ddd, J = 7.3, 4.4, 4.4 Hz, 1H), 4.38 (AB of ABX,

4-Pentenyl 2-Amino-4,6-bis-O-tert-butyldimethylsilyl-2-N,3-O-

carbonyl-2-deoxy-α-^D-talopyranoside (18ia) and 1,5-Anhydro-2-

deoxy-4,6-bis-O-tert-butyldimethylsilyl-^D-threo-hex-1-en-3-ulose

(19i). Starting with galactal 3-carbamate 14i (71.9 mg, 0.172 mmol),

the general amidoglycosylation procedure and chromatography (5 →

15 → 25 → 40% EtOAc/hexanes, 60 mL SiO₂) provided 18ia (27.7

mg, 32%) as a single anomer and dihydropyranone 19i (14.8 mg,

23%). Data for amidoglycosylation product 18ia: R_f= 0.27 (20%

J

_AB= 12.3 Hz, J_AX= 7.5 Hz, J_BX= 4.0 Hz, Δν_AB= 22.4 Hz, 2H), 2.17

(s, 3H), 2.09 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 185.8, 170.4,

169.2, 161.9, 105.8, 77.9, 68.2, 60.6, 20.6, 20.5; HRMS (FAB) m/z

calcd for C₁₀H₁₃O₆(M + H)⁺229.0712, found 229.0714.

4-Pentenyl 2-amino-2-N,3-O-carbonyl-2-deoxy-4,6-di-O-chlor-

oacetyl-α-^D-talopyranoside (18ga) and 1,5-anhydro-2-deoxy-4,6-

di-O-chloroacetyl-^D-threo-hex-1-en-3-ulose (19g). Using the gen-

eral amidoglycosylation procedure, followed by chromatography

(45 → 50% EtOAc/hexanes, 60 mL SiO₂), galactal 3-carbamate

14g (101 mg, 0.295 mmol) provided amidoglycosylation product

18ga (49.1 mg, 39%) as a single anomer and dihydropyranone 19g

(18.6 mg, 21%), both as clear, colorless oils. Data for amidoglyco-

sylation product 18ga: R_f= 0.48 (60% EtOAc/hexanes); IR

EtOAc/hexanes); IR (thin ﬁlm) 3263, 1765 cm⁻^{1 1}H NMR

;

(300 MHz, CDCl₃) δ 5.81 (dddd, J = 17.0, 10.3, 6.7, 6.7 Hz, 1H),

5.63 (br s, 1H), 5.08−4.92 (m, 2H), 5.02 (d, J = 5.3 Hz, 1H), 4.66

(dd, J = 9.5, 4.1 Hz, 1H), 4.21 (dd, J = 4.0, 0.9 Hz, 1H), 3.88−3.76

(m, 2H), 3.76−3.65 (m, 3H), 3.45 (ddd, J = 9.7, 6.7, 6.7 Hz, 1H),

2.11 (apparent q, J = 7.2 Hz, 2H), 1.68 (apparent pentet, J = 7.1 Hz,

2H), 0.92 (s, 9H), 0.89 (s, 9H), 0.18 (s, 3H), 0.10 (s, 3H), 0.06 (two

overlapping s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 158.8 (s), 137.9

(o), 115.0 (t), 98.0 (o), 74.4 (o), 72.9 (o), 68.4 (t), 64.9 (o), 61.7 (t),

54.9 (o), 30.2 (t), 28.7 (t), 25.9 (o), 25.8 (o), 18.2 (s), 18.1 (s), −4.3

(o), −5.1 (o), −5.32 (o),* −5.34 (o)*; *these ¹³C NMR signals were

better resolved upon reprocessing of the FID with lb = 0; HRMS

(FAB) m/z calcd for C₂₄H₄₈NO₆Si₂(M + H)⁺502.3020, found

502.3015.

1

(thin ﬁlm) 3360, 1756 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 6.34

(br s, 1H), 5.80 (dddd, J = 17.0, 10.3, 6.7, 6.7 Hz, 1H), 5.50 (dd, J =

5.1, 2.7 Hz, 1H), 5.10−4.95 (m, 2H), 4.91 (apparent d, J = 1.3 Hz,

1H), 4.90 (dd, J = 7.8, 5.1 Hz, 1H), 4.43−4.21 (m, 3H), 4.18

(apparent s, 2H), 4.10 (apparent s, 2H), 3.97 (slightly br d, J =

7.8 Hz, 1H), 3.75 (ddd, J = 9.6, 6.6, 6.6 Hz, 1H), 3.48 (ddd, J = 9.6,

6.5, 6.5 Hz, 1H), 2.13 (apparent q, J = 7.1 Hz, 2H), 1.70 (apparent

pentet, J = 7.0 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 166.9 (s),

166.8 (s), 158.9 (s), 137.6 (o), 115.3 (t), 96.6 (o), 70.6 (o), 68.0 (t),

65.7 (o), 64.7 (o), 63.8 (t), 53.4 (o), 40.5 (t), 40.4 (t), 30.1 (t), 28.3

(t); HRMS (FAB) m/z calcd for C₁₆H₂₂NO₈³⁵Cl₂(M + H)⁺

426.0722, found 426.0719.

Data for dihydropyranone 19i: R_f= 0.68 (20% EtOAc/hexanes);

1

IR (ATR) 1686, 1599 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 7.30

(d, J = 6.0 Hz, 1H), 5.35 (dd, J = 6.0, 1.3 Hz, 1H), 4.25 (ddd, J = 6.5,

6.5, 2.4 Hz, 1H), 4.02 (dd, J = 2.5, 1.4 Hz, 1H), 3.94 (apparent d, J =

6.4 Hz, 2H), 0.90 (s, 9H), 0.87 (s, 9H), 0.12 (s, 3H), 0.08 (two

overlapping s, 6H), 0.07 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ

191.1 (s), 162.1 (o), 104.8 (o), 82.9 (o), 69.4 (o), 60.1 (t), 25.8 (o),

25.6 (o), 18.24 (s),* 18.22 (s),* −4.8 (o), −5.4 (o, 3C); *these ¹³C

NMR resonances were resolved upon reprocessing the FID with lb =

0; HRMS (FAB) m/z calcd for C₁₈H₃₇O₄Si₂(M + H)⁺373.2230,

found 373.2238.

4-Pentenyl 2-Amino-4-O-tert-butyldimethylsilyl-2-N,3-O-car-

bonyl-2-deoxy-6-O-p-toluenesulfonyl-α-^D-talopyranoside (18ja)

and 1,5-Anhydro-2-deoxy-4-O-tert-butyldimethylsilyl-6-O-p-tolue-

nesulfonyl-^D-threo-hex-1-en-3-ulose (19j). Using the general

procedure for amidoglycosylation, galactal 3-carbamate 14j

(52.1 mg, 0.114 mmol) gave, after chromatography (20 → 25 →

30 → 35 → 40% EtOAc/hexanes, 40 mL SiO₂) a single anomer of

18ja (34.0 mg, 55%) and dihydropyranone 19j (4.6 mg, 10%). Data

for amidoglycosylation product 18ja: R_f= 0.23 (40% EtOAc/

hexanes); IR (thin ﬁlm) 3271, 3153, 3075, 1763, 1640, 1598 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 7.78 (apparent d, J = 8.3 Hz, 2H),

Data for dihydropyranone 19g: R_f= 0.72 (60% EtOAc/hexanes);

IR (thin ﬁlm) 1761, 1686, 1597 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 7.36 (d, J = 6.1 Hz, 1H), 5.64 (d, J = 4.8 Hz, 1H), 5.55 (d, J =

6.1 Hz, 1H), 4.87 (ddd, J = 7.2, 4.4, 4.4 Hz, 1H), 4.53 (AB of ABX,

J

_AB= 12.3 Hz, J_AX= 7.3 Hz, J_BX= 3.9 Hz, Δν_AB= 42.6 Hz, 2H), 4.19

(apparent s, 2H), 4.10 (apparent s, 2H); ¹³C NMR (75 MHz, CDCl₃)

δ 184.4 (s), 166.8 (s), 165.9 (s), 161.9 (o), 105.8 (o), 77.2 (o),

69.3 (o), 61.9 (t), 40.4 (t), 40.3 (t); HRMS (FAB) m/z calcd for

C₁₀H₁₁O₆³⁵Cl₂(M + H)⁺296.9933, found 296.9940.

4-Pentenyl 2-Amino-2-N,3-O-carbonyl-2-deoxy-4-O-chloroace-

tyl-6-O-p-toluenesulfonyl-α-^D-talopyranoside (18ha) and 1,5-An-

hydro-2-deoxy-4-O-chloroacetyl-6-O-p-toluenesulfonyl-^D-threo-

hex-1-en-3-ulose (19h). The general procedure for amidoglycosyla-

tion was followed with galactal 3-carbamate 14h (82.7 mg,

0.197 mmol), providing, after chromatography (40 → 50 → 60%

EtOAc/hexanes, 60 mL SiO₂), a single anomer of amidoglycosylation

product 18ha (38 mg, 39%; weight and yield are corrected for ∼3 mg

of remaining starting carbamate 14h that coeluted with 18ha) and

dihydropyranone byproduct 19h (16.3 mg, 22%). Data for

amidoglycosylation product 18ha: R_f= 0.50 (60% EtOAc/hexanes);

IR (thin ﬁlm) 3376, 1762 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.77

(apparent d, J = 8.3 Hz, 2H), 7.34 (apparent d, J = 8.1 Hz, 2H), 6.31

(br s, 1H), 5.79 (dddd, J = 17.0, 10.3, 6.7, 6.7 Hz, 1H), 5.47 (dd, J =

5.0, 2.5 Hz, 1H), 5.09−4.95 (m, 2H), 4.86 (s, 1H), 4.85 (dd, J = 7.6,

5.1 Hz, 1H), 4.23 (ddd, J = 6.1, 6.1, 2.6 Hz, 1H), 4.08−4.20 (m, 2H),

4.07 (obscured AB, 2H), 3.93 (d, J = 7.7 Hz, 1H), 3.71 (ddd, J = 9.6,

6.6, 6.6 Hz, 1H), 3.42 (ddd, J = 9.6, 6.4, 6.4 Hz, 1H), 2.46 (s, 3H),

2.10 (apparent q, J = 7.1 Hz, 2H), 1.67 (apparent pentet, J = 7.0 Hz,

2H); ¹³C NMR (75 MHz, CDCl₃) δ 166.5 (s), 158.8 (s), 145.4 (s),

137.6 (o), 132.2 (s), 130.0 (o), 128.0 (o), 115.2 (t), 96.5 (o), 70.5

(o), 68.0 (t), 67.4 (t), 65.4 (o), 64.7 (o), 53.3 (o), 40.3 (t), 30.1 (t),

28.3 (t), 21.7 (o); HRMS (FAB) m/z calcd for C₂₁H₂₇NO₉S³⁵Cl

(M + H)⁺504.1095, found 504.1082.

7.34 (apparent d, J = 8.1 Hz, 2H), 5.90 (br s, 1H), 5.80 (dddd, J =

17.0, 10.3, 6.7, 6.7 Hz, 1H), 5.08−4.94 (m, 2H), 4.79 (d, J = 3.3 Hz,

1H), 4.65 (dd, J = 9.2, 3.6 Hz, 1H), 4.30 (dd, J = 3.9, 3.9 Hz, 1H),

4.21 (AB of ABX, J_AB= 10.5 Hz, J_AX= 7.7 Hz, J_BX= 4.3 Hz, Δν_AB

=

28.2 Hz, 2H), 4.07 (ddd, J = 7.8, 4.0, 4.0 Hz, 1H), 3.82 (ddd, J = 9.2,

3.3, 0.9 Hz, 1H), 3.71 (ddd, J = 9.7, 6.6, 6.6 Hz, 1H), 3.40 (ddd, J =

9.7, 6.4, 6.4 Hz, 1H), 2.45 (s, 3H), 2.09 (apparent q, J = 7.6 Hz, 2H),

1.65 (apparent pentet, J = 7.0 Hz, 2H), 0.86 (s, 9H), 0.14 (s, 3H),

0.04 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 158.6 (s), 145.0 (s),

137.7 (o), 132.7 (s), 129.9 (o), 128.0 (o), 115.1 (t), 97.4 (o),

74.3 (o), 70.3 (o), 69.4 (t), 68.4 (t), 64.7 (o), 54.5 (o), 30.1 (t), 28.6

(t), 25.6 (o), 21.6 (o), 17.9 (s), −4.6 (o), −5.1 (o); HRMS (FAB)

m/z calcd for C₂₅H₄₀NO₈SSi (M + H)⁺542.2244, found 542.2228.

Data for dihydropyranone 19j: R_f= 0.63 (40% EtOAc/hexanes);

IR (thin ﬁlm) 1682, 1599 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.80

T

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The Journal of Organic Chemistry

Article

(apparent d, J = 8.4 Hz, 2H), 7.37 (apparent d, J = 8.1 Hz, 2H), 7.21

(d, J = 6.0 Hz, 1H), 5.36 (dd, J = 6.1, 1.0 Hz, 1H), 4.51 (ddd, J = 7.6,

oxazolidinone 16ba-β (56.0 mg, 0.123 mmol) was converted to the

N-Boc derivative 35 (57.6 mg, 84%) as a clear, colorless oil: R_f= 0.35

(30% EtOAc/hexanes); IR (ATR) 1821, 1799, 1722 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 7.38−7.25 (m, 10H, ArH), 5.73 (dddd, J =

17.0, 10.3, 6.6, 6.6 Hz, 1H, H4′), 5.03−4.90 (m, 2H, H5′), 4.84−4.77

(m, 2H, H1, H3), 4.60 (AB, J_AB= 11.7 Hz, Δν_AB= 25.5 Hz, 2H,

OCH₂Ph), 4.54 (AB, J_AB= 12.0 Hz, Δν_AB= 24.4 Hz, 2H, OCH₂Ph),

4.27 (dd, J = 8.6, 1.8 Hz, 1H, H2), 4.24 (dd, J = 9.9, 2.8 Hz, 1H, H4),

4.06 (ddd, J = 10.1, 5.1, 2.3 Hz, 1H, H5), 3.81 (ddd, J = 9.5, 6.6,

6.6 Hz, 1H, H1′a), 3.61 (AB of ABX, J_AB= 10.5 Hz, J_AX= 5.4 Hz,

J_BX= 2.0 Hz, Δν_AB= 17.2 Hz, 2H, H6), 3.35 (ddd, J = 9.5, 6.6,

6.6 Hz, 1H, H1′b), 1.97 (apparent q, J = 7.2 Hz, 2H, H3′), 1.60−1.45

(m, 2H, H2′), 1.52 (s, 9H, C(CH₃)₃); ¹³C NMR (75 MHz, CDCl₃)

δ 151.1 (s), 149.0 (s), 137.93 (s, C_ArCH₂O), 137.88 (o, C4′), 137.3

(s, C_ArCH₂O), 128.5 (o, C_ArH), 128.4 (o, C_ArH), 128.0 (o, C_ArH),

127.91 (o, C_ArH),* 127.87 (o, C_ArH),* 127.7 (o, C_ArH) 114.9

(t, C5′), 96.7 (o, C1), 84.3 (s, C(CH₃)₃), 73.3 (t, OCH₂Ph), 72.0

(t, OCH₂Ph), 70.5 (o, C5), 70.3 (t, C6), 70.2 (o, C4), 69.6 (o, C3),

68.3 (t, C1′), 57.2 (o, C2), 30.0 (t, C3′), 28.5 (t, C2′), 27.9

(o, C(CH₃)₃); *these ¹³C NMR signals resolved upon processing of

the FID with lb = 0; HRMS (ESI) m/z calcd for C₃₁H₃₉NO₈Na

(M + Na)⁺576.2573, found 576.2569.

4-Pentenyl 2-Amino-2-N-tert-butoxycarbonyl-2-deoxy-4,6-di-O-

benzyl-β-^D-allopyranoside (36). Using the same procedure as for

33 → 34, the allosamine N-Boc oxazolidinone 35 (54 mg,

0.098 mmol) was hydrolyzed to allosamine C3 alcohol 36. The

product alcohol was close in R_fto the starting material, but could be

resolved on TLC using three elutions with 25% EtOAc/hexanes in

order to monitor the hydrolysis reaction. Chromatography (30%

EtOAc/hexanes, 30 mL SiO₂) provided product 36 (35 mg, 68%) as a

clear oil: R_f= 0.32 (30% EtOAc/hexanes); IR (ATR) 3446, 3381,

3066, 3031, 1708, 1641 cm⁻¹; ¹H NMR (300 MHz, acetone-d₆)

δ 7.40−7.20 (m, 10H, ArH), 5.84 (dddd, J = 17.1, 10.3, 6.8, 6.8 Hz,

1H, H4′), 5.66 (br d, J = 9.1 Hz, 1H, NH), 5.03 (dddd, J = 17.2, 1.8,

1.8, 1.8 Hz, 1H, H5′b), 4.93 (dddd, J = 10.2, 2.2, 1.1, 1.1 Hz, 1H,

H5′a), 4.62 (AB, J_AB= 11.6 Hz, Δν_AB= 55.4 Hz, 2H, OCH₂Ph), 4.62

(d, J = 8.0 Hz, 1H, H1), 4.58 (partially obscured AB, 2H, OCH₂Ph),

4.32 (apparent q, J = 2.8 Hz, 1H, H3), 4.23 (br s, 1H, OH), 3.96

(ddd, J = 9.4, 5.2, 2.0 Hz, 1H, H5), 3.84 (ddd, J = 9.6, 6.1, 6.1 Hz, 1H,

H1′a), 3.74 (AB of ABX, J_AB= 10.9 Hz, J_AX= 5.3 Hz, J_BX= 2.0 Hz,

Δν_AB= 35.4 Hz, 2H, H6), 3.59 (dd, J = 9.4, 2.4 Hz, 1H, H4), 3.57

(m, 1H, H2), 3.47 (ddd, J = 9.6, 6.6, 6.6 Hz, 1H, H1′b), 2.14

(apparent q, J = 7.2 Hz, 2H, H3′), 1.64 (apparent pentet, J = 7.0 Hz,

2H, H2′), 1.42 (s, 9H, C(CH₃)₃); ¹³C NMR (75 MHz, acetone-d₆) δ

156.0 (s, NHC(O)O), 140.0 (s, C_ArCH₂O), 139.6 (s, C_ArCH₂O),

139.5 (o, C4′), 129.12 (o, C_ArH),* 129.11 (o, C_ArH),* 128.8 (o,

C_ArH), 128.40 (o, C_ArH),* 128.39 (o, C_ArH),* 128.2 (o, C_ArH), 115.1

(t, C5′), 100.9 (o, C1), 78.9 (s, C(CH₃)₃), 76.5 (o, C4), 73.8

(t, OCH₂Ph), 73.4 (o, C5), 71.7 (t, OCH₂Ph), 70.8 (t, C6), 69.0

(t, C1′), 68.1 (o, C3), 54.7 (o, C2), 31.0 (t, C3′), 29.9 (t, C2′),^†28.7

(o, C(CH₃)₃), *these ¹³C NMR signals could be resolved upon

reprocessing of the FID with lb = 0, ^†this ¹³C NMR signal overlapped

with a solvent peak, but was detected in DEPT 135 and ¹H/¹³C

HSQC experiments; HRMS (ESI) m/z calcd for C₃₀H₄₁NO₇Na

(M + Na)⁺550.2781, found 550.2791.

4.5, 3.2 Hz, 1H), 4.31 (AB of ABX, J_AB= 10.8 Hz, J_AX= 7.7 Hz, J_BX

=

4.5 Hz, Δν_AB= 24.6 Hz, 2H), 4.03 (dd, J = 3.3, 1.0 Hz, 1H), 2.46

(s, 3H), 0.81 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 189.6, 161.3, 145.3, 132.3, 130.0, 128.0, 105.1, 79.6, 69.5,

66.1, 25.5, 21.7, 18.1, −4.8, −5.6; HRMS (FAB) m/z calcd for

C₁₉H₂₉O₆SSi (M + H)⁺413.1454, found 413.1451.

N-Boc Protection and Hydrolysis of 2-Gulosamine and

2-Allosamine Oxazolidinones. 4-Pentenyl 2-Amino-2-N-tert-

butoxycarbonyl-2-N,3-O-carbonyl-2-deoxy-4,6-O-isopropylidene-

β-^D-gulopyranoside (33). To a solution of oxazolidinone 15aa-β

(36.2 mg, 0.116 mmol) in THF (2 mL) were added N,N-

dimethyl-4-aminopyridine (70.5 mg, 0.578 mmol), Et₃N (80 μL,

0.58 mmol), and di-tert-butyl dicarbonate (135 μL, 0.588 mmol). The

mixture was stirred at 25 °C during 75 min then diluted with CH₂Cl₂

and washed with brine (1 × 15 mL). The aqueous layer was extracted

with CH₂Cl₂(2 × 5 mL), and the combined organic layers were dried

(MgSO₄), ﬁltered, and concentrated. The residue was chromato-

graphed (30 → 40% EtOAc/hexanes, 50 mL SiO₂), aﬀording N-

acylated product 33 (46.1 mg, 96%): R_f= 0.46 (45% EtOAc/

hexanes); IR (thin ﬁlm) 1828, 1735, 1640 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 5.79 (dddd, J = 17.0, 10.3, 6.7, 6.7 Hz, 1H), 5.18−4.91 (m,

2H), 4.47 (dd,

J = 6.0, 2.0 Hz, 1H), 4.46 (d, J =

7.5 Hz, 1H), 4.32 (dd, J = 7.2, 6.4 Hz, 1H), 3.20 (dd, J = 1.6, 1.6

Hz, 1H), 4.07 (AB of ABX, J_AB= 12.9 Hz, J_AX= 2.5 Hz, J_BX= 1.6 Hz,

Δν_AB= 34.1 Hz, 2H), 3.97 (ddd, J = 9.4, 6.8, 6.8 Hz, 1H), 3.56

(m, 1H), 3.40 (ddd, J = 9.4, 7.0, 7.0 Hz, 1H), 2.11 (apparent q, J =

7.2 Hz, 2H), 1.71 (apparent pentet, J = 7.2 Hz, 2H), 1.53 (s, 9H),

1.48 (s, 3H), 1.44 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 151.1 (s),

148.4 (s), 137.7 (o), 115.0 (t), 101.7 (o), 99.0 (s), 84.0 (s), 75.7 (o),

69.2 (t), 66.1 (o), 63.4 (o), 62.0 (t), 54.8 (o), 30.0 (t), 28.8 (o), 28.6

(t), 27.8 (o), 18.6 (o); HRMS (FAB) m/z calcd for C₂₀H₃₂NO₈

(M + H)⁺414.2128, found 414.2134.

4-Pentenyl 2-Amino-2-N-tert-butoxycarbonyl-2-deoxy-4,6-O-

isopropylidene-β-^D-gulopyranoside (34). N-Boc-protected oxazoli-

dinone 33 (41.1 mg, 0.0995 mmol) was dissolved in THF/H₂O

(1 mL/0.3 mL) and LiOH·H₂O (34.3 mg, 0.816 mmol) was added.

The mixture was well stirred during 90 min and poured into satd aq

NH₄Cl (20 mL). The mixture was extracted with CH₂Cl₂(3 ×

20 mL) and the combined organic layers were dried (MgSO₄),

ﬁltered, and concentrated. The crude product was chromatographed

(50% EtOAc/hexanes, 45 mL SiO₂), providing C3 alcohol 34 (35.5

mg, 92%): R_f= 0.24 (45% EtOAc/hexanes); IR (thin ﬁlm) 3448,

1

3079, 1718, 1697, 1641 cm⁻¹; H NMR (300 MHz, acetone-d₆) δ

5.84 (dddd, J = 17.1, 10.3, 6.8, 6.8 Hz, 1H), 5.57 (br d, J = 8.9 Hz,

1H), 5.02 (dddd, J = 17.2, 1.8, 1.8, 1.8 Hz, 1H), 4.92 (dddd, J = 10.2,

2.2, 1.1, 1.1 Hz, 1H), 4.68 (d, J = 4.2 Hz, 1H), 4.64 (d, J = 8.6 Hz,

1H), 4.10 (dd, J = 12.7, 2.1 Hz, 1H), 3.94 (dd, J = 3.1, 1.2 Hz, 1H),

3.90−3.72 (m, 4H), 3.64 (m, 1H), 3.42 (ddd, J = 9.5, 6.7, 6.7 Hz,

1H), 2.14 (m, 2H), 1.63 (m, 2H), 1.43 (s, 3H), 1.40 (s, 9H), 1.32

(s, 3H); ¹³C NMR (75 MHz, acetone-d₆) δ 156.3 (s), 139.5 (o),

115.0 (t), 100.1 (o), 98.7 (s), 78.8 (s), 71.2 (o), 70.3 (o), 68.6 (t),

66.1 (o), 63.6 (t), 51.9 (o), 31.0 (t), 29.9 (t),* 29.8 (o),* 28.7 (o),

19.2 (o), *the ¹³C NMR signals at δ 29.9 and 29.8 were obscured by

solvent peaks but detected in the DEPT 135 experiment; HRMS

(FAB) m/z calcd for C₁₉H₃₄NO₇(M + H)⁺388.2335, found

388.2328.

Because there was some overlap of the H1 resonance with one of

1

the benzyl methylene AB systems, we used H-coupled HSQC to

reﬁne the measurement of J_H1,H2. Details and spectra for the

determination of J_H1,H2= 8.3 0.1 Hz are included in the Supporting

Information.

1

Conﬁrmation of the J_H1,H2value for 34: From an edited H/¹³C

HSQC experiment, the ¹³C methine resonance at δ 101.1 was

1

correlated to the H doublet at δ 4.64 (J = 8.6 Hz). Additionally,

Amidoglycosylation of ^D-Glycal 3-Carbamates 11 (Gulal), 12

(Allal), 13 (Glucal), and 14 (Galactal) with Other Alcohol

Acceptors. Allyl 2-Amino-2-N,3-O-carbonyl-2-deoxy-4,6-di-O-ace-

tyl-β-^D-gulopyranoside (15cb-β) and the Minor Anomer (15cb-α).

The bis-acetyl-protected gulal 3-carbamate 11c (98.9 mg, 0.362 mmol)

was combined with allyl alcohol (5.1 equiv) under the general

amidoglycosylation conditions, and chromatography (55 → 60 → 65

→ 75% EtOAc/hexanes, 50 mL SiO₂) provided 15cb-β (96.8 mg,

81%) and 15cb-α (8.6 mg, 7%) separately, both as clear, colorless oils.

Data for the major anomer 15cb-β: R_f= 0.39 (60% EtOAc/hexanes);

deuterium exchange with a drop of added D₂O showed that the

1

nearby H doublet at δ 4.68 (J = 4.2 Hz) was the C3-OH, removing

any ambiguity from the assignment of the H1 signal at δ 4.64.

Assignment of the H1 resonance provided the corresponding J_H1,H2

=

8.6 Hz.

4-Pentenyl 2-Amino-2-N-tert-butoxycarbonyl-2-N,3-O-carbonyl-

2-deoxy-4,6-di-O-benzyl-β-^D-allopyranoside (35). Using the same

procedure as for 15aa-β → 33 and purifying the product 35 by

chromatography (30% EtOAc/hexanes, 60 mL SiO₂), the allosamine

U

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1

IR (ATR) 3316, 1769, 1740 cm⁻¹; H NMR (300 MHz, CDCl₃)

20.69 (o, H₃CC(O)O), 17.7 (o, C8′ or C10′), 16.4 (o, C8′ or C9′ or

C10′); HRMS (FAB) m/z calcd for C₂₁H₃₁NO₈Na (M + Na)⁺

448.1947, found 448.1945.

δ 5.92 (dddd, J = 17.1, 10.3, 6.7, 5.3 Hz, 1H, H2′), 5.87 (br s, 1H,

NH), 5.38−5.23 (m, 2H, H3′), 5.23 (apparent slightly br t, J =

1.8 Hz, 1H, H4), 4.62 (dd, J = 6.6, 2.2 Hz, 1H, H3), 4.52 (d, J =

7.4 Hz, 1H, H1), 4.40 (dddd, J = 12.5, 5.3, 1.3, 1.3 Hz, 1H, H1′a),

2-(Trimethylsilyl)ethyl 2-Amino-4,6-O-benzylidene-2-N,3-O-car-

bonyl-2-deoxy-β-^D-allopyranoside (16ed). Applying the general

amidogylcosylation procedure with allal 3-carbamate 12e (99.2 mg,

0.358 mmol) and 2-(trimethylsilyl)ethanol (250 μL, 1.74 mmol) as

the acceptor, followed by chromatography of the crude material (40%

EtOAc/hexanes, 50 mL SiO₂), provided 16ed (94.4 mg, 67%) as a

clear, colorless oil: R_f= 0.49 (60% EtOAc/hexanes); IR (ATR) 3293,

1757 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.55−7.45 (m, 2H, ArH),

7.41−7.31 (m, 3H, ArH), 6.27 (slightly br s, 1H, NH), 5.58 (s, 1H,

PhCH), 4.96 (dd, J = 7.4, 3.3 Hz, 1H, H3), 4.61 (d, J = 4.7 Hz, 1H,

H1), 4.40 (dd, J = 10.4, 4.9 Hz, 1H, H6eq), 4.13 (dd, J = 9.9, 3.4 Hz,

1H, H4), 3.99 (ddd, J = 10.1, 10.1, 4.9 Hz, 1H, H5), 3.93 (ddd, J =

10.6, 9.8, 6.5 Hz, 1H, H1′a), 3.79 (ddd, J = 7.3, 4.7, 0.5 Hz, 1H, H2),

3.72 (dd, J = 10.2, 10.2 Hz, 1H, H6ax), 3.55 (ddd, J = 10.6, 9.8,

6.3 Hz, 1H, H1′b) 0.96 (m, 2H, H2′), 0.04 (s, 9H, Si(CH₃)₃); ¹³C

NMR (75 MHz, CDCl₃) δ 159.0 (s, OC(O)NH), 136.7 (s, C_ArCH),

129.3 (o, C_ArH), 128.3 (o, C_ArH), 126.3 (o, C_ArH), 102.7 (o, PhCH),

100.5 (o, C1), 75.0 (o, C4), 73.4 (o, C3), 69.5 (t, C6), 67.2 (t, C1′)

62.6 (o, C5), 55.8 (o, C2), 18.2 (t, C2′), −1.4 (o, Si(CH₃)₃); HRMS

(FAB) m/z calcd for C₁₉H₂₆NO₆Si (M − H)⁺392.1529, found

392.1531.⁶⁷

2-Pentynyl 2-Amino-4,6-O-benzylidene-2-N,3-O-carbonyl-2-

deoxy-β-^D-allopyranoside (16ee). The general amidoglycosylation

procedure was followed, using allal 3-carbamate 12e (98.3 mg,

0.355 mmol) with 2-pentyn-1-ol (5.0 equiv) as the glycosyl acceptor.

Chromatography (50% EtOAc/hexanes, 50 mL SiO₂), yielded an

inseparable 13:1 β:α mixture of the internal alkyne-containing

product 16ee (94.7 mg, 74%) as a yellow-tinged white solid. The

yield of the major β product, corrected for the presence of the

α diasteromer, was 69%. NMR signals listed are for 16ee-β, unless

otherwise noted: R_f= 0.36 (60% EtOAc/hexanes); IR (ATR) 3274,

3169, 2227, 1761, 1747 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.55−

7.45 (m, 2H, ArH), 7.42−7.31 (m, 3H, ArH), 6.29 (slighly br s, 1H,

NH), 5.58 (s, 1H, PhCH), 4.98 (dd, J = 7.7, 3.3 Hz, 1H, H3), 4.83

(d, J = 4.1 Hz, 1H, H1), 4.40 (dd, J = 10.6, 4.7 Hz, 1H, H6eq), 4.37

(apparent dt, J = 15.1, 2.2 Hz, 1H, H1′a), 4.28 (apparent dt, J = 15.3,

2.1 Hz, 1H, H1′b), 4.19 (dd, J = 10.0, 3.4 Hz, 1H, H4), 4.05 (ddd, J =

10.0, 10.0, 5.0 Hz, 1H, H5), 3.91 (ddd, J = 7.8, 4.1, 0.6 Hz, 1H, H2),

3.73 (dd, J = 10.2, 10.2 Hz, 1H, H6ax), 2.26 (apparent qt, J = 7.5,

2.1 Hz, 2H, H4′), 1.16 (t, J = 7.5 Hz, 3H, H5′). Additional nono-

verlapping ¹H NMR signals detected for the 16ee-α anomer:

δ 6.58 (br s, 1H, NH), 5.97 (d, J = 2.3 Hz, 1H, H1), 5.61 (s, 1H,

PhCH), 5.05 (dd, J = 8.9, 3.1 Hz, 1H, H3), 3.69 (dd, J = 10.2,

10.2 Hz, H6ax), 2.40 (q, J = 7.5 Hz, 2H, H4′), 1.24 (t, J = 7.5 Hz, 3H,

H5′); ¹³C NMR (75 MHz, CDCl₃) δ 158.8 (s, OC(O)NH), 136.7

(s, C_ArCH), 129.3 (o, C_ArH), 128.3 (o, C_ArH), 126.3 (o, C_ArH), 102.6

(o, PhCH), 98.1 (o, C1), 89.9 (s, C2′ or C3′), 74.7 (o, C4), 73.6

(s, C2′ or C3′), 72.8 (o, C3), 69.5 (t, C6), 62.5 (o, C5), 56.3 (t, C1′),

55.2 (o, C2), 13.6 (o, C5′), 12.4 (t, H4′); HRMS (FAB) m/z calcd

for C₁₉H₂₂NO₆(M + H)⁺360.1447, found 360.1455.

4.23 (AB of ABX, J_AB= 11.4 Hz, J_AX= 7.1 Hz, J_BX= 5.8 Hz, Δν_AB

=

16.1 Hz, 2H, H6), 4.16−4.05 (m, 2H, H1′b, H5), 3.60 (dd, J = 7.0,

7.0 Hz, 1H, H2), 2.14 (s, 3H, H₃CC(O)O), 2.08 (s, 3H,

H₃CC(O)O); ¹³C NMR (75 MHz, CDCl₃) δ 170.4 (s, H₃CC(O)O),

169.5 (s, H₃CC(O)O), 157.6 (s, OC(O)NH), 132.9 (o, C2′), 118.9

(t, C3′), 102.3 (o, C1), 75.9 (o, C3), 70.6 (o, C5), 70.3 (t, C1′), 64.2

(o, C4), 61.4 (t, C6), 53.0 (o, C2), 20.64 (o, H₃CC(O)O), 20.60

(o, H₃CC(O)O); HRMS (FAB) m/z calcd for C₁₄H₂₀NO₈(M + H)⁺

330.1189, found 330.1183.

Data for the minor anomer 15cb-α: R_f= 0.22 (60% EtOAc/

hexanes); IR (ATR) 3332, 1768 (shoulder), 1742 cm⁻¹; H NMR

1

(300 MHz, CDCl₃) δ 5.89 (dddd, J = 17.1, 10.8, 6.1, 4.9 Hz, 1H,

H2′), 5.39−5.18 (m, 4H, H3′, H4, NH), 4.97 (d, J = 4.3 Hz, 1H,

H1), 4.62 (dd, J = 7.2, 2.8 Hz, 1H, H3), 4.41 (ddd, J = 6.7, 5.8,

2.4 Hz, 1H, H5), 4.28 (dddd, J = 13.0, 4.9, 1.5, 1.5 Hz, 1H, H1′a),

4.17 (AB of ABX, J_AB= 11.5 Hz, J_AX= 7.1 Hz, J_BX= 5.5 Hz, Δν_AB

=

21.6 Hz, 2H, H6), 4.02 (dddd, J = 13.0, 6.1, 1.3, 1.3 Hz, 1H, H1′b),

3.91 (dd, J = 7.2, 4.3 Hz, 1H, H2), 2.14 (s, 3H, H₃CC(O)O), 2.08

(s, 3H, H₃CC(O)O); ¹³C NMR (75 MHz, CDCl₃) δ 170.4

(s, H₃CC(O)O), 169.4 (s, H₃CC(O)O), 158.7 (s, OC(O)NH),

132.8 (o, C2′), 118.1 (t, C3′), 93.9 (o, C1), 73.2 (o, C3), 68.6

(t, C1′), 65.0 (o, C4), 64.4 (o, C5), 61.8 (t, C6), 50.5 (o, C2), 20.73

(o, H₃CC(O)O), 20.68 (o, H₃CC(O)O); HRMS (FAB) m/z calcd

for C₁₄H₂₀NO₈(M + H)⁺330.1189, found 330.1197.

Geranyl 2-Amino-2-N,3-O-carbonyl-2-deoxy-4,6-di-O-acetyl-β-^D-

gulopyranoside (15cc-β) and the Minor anomer (15cc-α). Under

the general amidoglycosylation conditions, gulal 3-carbamate 11c

(100.5 mg, 0.368 mmol) reacted with geraniol (5.0 equiv).

Chromatography (30 → 40 → 50 → 60% EtOAc/hexanes, 50 mL

SiO₂) separated the β anomer from α-enriched material, providing

15cc-β (135 mg, 86%) and 15cc-α (6.0 mg, 4%), both as clear,

colorless oils (NMR characterization indicated that the α anomer was

isolated as a ∼ 3:1 mixture with the β diastereomer under these

chromatography conditions). Data for the major anomer 15cc-β: R_f=

0.25 (40% EtOAc/hexanes); IR (ATR) 3321, 1769 (shoulder),

1743 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 5.62 (slightly br s, 1H, NH),

5.32 (broadened approx t, J = 7.2 Hz, 1H, H2′), 5.23 (br apparent t,

J = 1.8 Hz, 1H, H4), 5.08 (m, 1H, H6′), 4.60 (dd, J = 6.5, 2.2 Hz, 1H,

H3), 4.48 (d, J = 7.5 Hz, 1H, H1), 4.34 (apparent br dd, J = 11.8,

6.3 Hz, 1H, H1′a), 4.30−4.16 (m, 3H, H6, H1′b), 4.07 (ddd, J = 6.8,

6.0, 1.7 Hz, 1H, H5), 3.57 (dd, J = 7.0, 7.0 Hz, 1H, H2), 2.15−2.03

(m, 4H, H4′, H5′), 2.13 (s, 3H, H₃CC(O)O), 2.07 (s, 3H,

H₃CC(O)O), 1.69 (2 overlapping br s, 6H, H9′ and H8′ or H10′),

1.61 (br s, 3H, H8′ or H10′); ¹³C NMR (75 MHz, CDCl₃) δ 170.4

(s, H₃CC(O)O), 169.5 (s, H₃CC(O)O), 157.4 (s, OC(O)NH), 142.9

(s, C3′ or C7′), 131.9 (s, C3′ or C7′), 123.6 (o, C6′), 118.6 (o, C2′),

101.7 (o, C1), 75.9 (o, C3), 70.6 (o, C5), 65.4 (t, C1′), 64.2 (o, C4),

61.5 (t, C6), 53.0 (o, C2), 39.5 (t, C4′ or C5′), 26.3 (t, C4′or C5′),

25.6 (o, C8′ or C9′ or C10′), 20.6 (o, 2C, H₃CC(O)O), 17.7 (o, C8′

or C10′), 16.4 (o, C8′ or C9′ or C10′); HRMS (FAB) m/z calcd for

C₂₁H₃₀NO₈(M − H)⁺424.1971, found 424.1986.⁶⁷

Data for the minor anomer 15cc-α: R_f= 0.13 (40% EtOAc/

hexanes); IR (ATR) 3354, 1743 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

δ 5.30 (dd, J = 2.4, 2.4 Hz, 1H, H4), 5.28 (m, 1H, H2′), 5.07 (m, 1H,

H6′), 5.03 (br s, 1H, NH), 4.95 (d, J = 4.3 Hz, 1H, H1), 4.61 (dd, J =

7.3, 2.8 Hz, 1H, H3), 4.42 (ddd, J = 6.7, 5.9, 2.4 Hz, 1H, H5), 4.28−

4.03 (m, 4H, H6, H1′), 3.88 (dd, J = 7.3, 4.3 Hz, 1H, H2), 2.17−2.01

(m, 4H, H4′, H5′), 2.14 (s, 3H, H₃CC(O)O), 2.08 (s, 3H,

H₃CC(O)O), 1.69 (2 overlapping br s, 6H, H9′ and H8′ or H10′),

1.61 (br s, 3H, H8′ or H10′); ¹³C NMR (75 MHz, CDCl₃) δ 170.5

(s, H₃CC(O)O), 169.4 (s, H₃CC(O)O), 158.6 (s, OC(O)NH), 142.4

(s, C3′ or C7′), 131.9 (s, C3′ or C7′), 123.7 (o, C6′), 118.9 (o, C2′),

93.0 (o, C1), 73.1 (o, C3), 65.1 (o, C4), 64.3 (o, C5), 64.0 (t, C6 or

C1′), 62.0 (t, C6 or C1′), 50.5 (o, C2), 39.6 (t, C4′ or C5′), 26.3 (t,

C4′or C5′), 25.7 (o, C8′ or C9′ or C10′), 20.73 (o, H₃CC(O)O),

Propargyl 4-O-Acetyl-2-amino-2-N,3-O-carbonyl-2-deoxy-6-O-

p-toluenesulfonyl-α-^D-mannopyranoside (17ﬀ). With propargyl

alcohol (5.1 equiv) as the glycosyl acceptor, glucal 3-carbamate 13f

(102 mg, 0.267 mmol) was treated under the standard amidoglyco-

sylation conditions. Chromatography (55 → 65% EtOAc/hexanes,

90 mL SiO₂) provided 17ﬀ (52.4 mg, 45%) as a clear oil, as well as

recovered starting material 13f (48.5 mg, 47%). Data for 17ﬀ: R_f=

0.30 (65% EtOAc/hexanes); IR (ATR) 3375, 3285, 1760, 1598 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 7.78 (apparent d, J = 8.3 Hz, 2H,

ArH_o), 7.36 (apparent d, J = 8.0 Hz, 2H, ArH_m), 6.03 (slightly br s,

1H, NH), 5.06 (s, 1H, H1), 4.98 (dd, J = 9.9, 7.3 Hz, 1H, H4), 4.68

(dd, J = 7.4, 7.4 Hz, 1H, H3), 4.21 (AB of ABX, J_AB= 15.8 Hz, J_AX

=

2.4 Hz, J_BX= 2.3 Hz, Δν_AB= 6.8 Hz, 2H, H1′), 4.14−4.02 (m, 3H,

H2, H6), 3.97 (ddd, J = 9.8, 6.1, 3.7 Hz, 1H, H5), 2.50 (apparent t,

J = 2.4 Hz, 1H, H3′), 2.46 (s, 3H, Ar-CH₃), 2.08 (s, 3H,

H₃CC(O)O); ¹³C NMR (75 MHz, CDCl₃) δ 169.5 (s, H₃CC(O)O),

158.1 (s, OC(O)NH), 145.2 (s, Ar), 132.4 (s, Ar), 129.9

V

DOI: 10.1021/acs.joc.8b00893

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(o, Ar-meta), 128.0 (o, Ar-ortho), 94.6 (o, C1), 77.8 (s, C2′), 75.8

(C3′)*, 75.5 (o, C3), 68.4 (o, C4), 68.2 (t, C6), 66.2 (o, C5), 55.6

(o, C2), 54.7 (t, C1′), 21.7 (o, Ar-CH₃), 20.7 (o, H₃CC(O)O), *this

¹³C resonance gave a much diminished positive peak in the DEPT

135 spectrum and a negatively phased cross-peak in a phase-sensitive

HSQC experiment, presumably due to the large C_sp−H coupling

constant; HRMS (FAB) m/z calcd for C₁₉H₂₂NO₉S (M + H)⁺

440.1015, found 440.1010.

4-Pentynyl 4-O-Acetyl-2-amino-2-N,3O-carbonyl-2-deoxy-6-O-

p-toluenesulfonyl-α-^D-mannopyranoside (17fg). The glycal 3-

carbamate 13f (105 mg, 0.272 mmol) and 4-pentyn-1-ol (5.1

equiv) as the glycosyl acceptor were used in the general

amidoglycosylation procedure. Column chromatography (50 → 55

→ 60 → 65 → 70% EtOAc/hexanes, 90 mL SiO₂), followed by

preparative TLC (50% EtOAc/hexanes, 3 elutions), provided

4-pentynyl glycoside 17fg as single α anomer (20.1 mg, 16%) as a

brittle foam. Starting carbamate 13f (55.4 mg, 53%) was also

recovered during the chromatography. Data for 17fg: R_f= 0.36 (65%

EtOAc/hexanes); IR (ATR) 3374, 3291, 1761, 1598 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 7.78 (apparent d, J = 8.3 Hz, 2H), 7.36

(apparent d, J = 8.1 Hz, 2H), 6.09 (s, 1H), 4.97 (dd, J = 9.5, 7.1, 1H),

H₃CC(O)O); ¹³C NMR (75 MHz, CDCl₃) δ 169.5 (s, H₃CC(O)O),

158.2 (s, OC(O)NH), 145.1 (s, Ar), 132.5 (s, Ar), 129.9 (o, Ar-meta),

128.0 (Ar-ortho), 96.5 (o, C1), 75.7 (o, C3), 71.3 (t, OCH₂′), 70.6

(t, OCH₂′), 70.4 (t, OCH₂′), 70.0 (t, OCH₂′), 68.5 (o, C4), 68.3

(t, C6), 67.1 (t, OCH₂′), 65.8 (o, C5), 55.8 (o, C2), 42.8

(t, CH2′Cl), 21.6 (o, Ar-CH₃), 20.6 (o, H₃CC(O)O); HRMS (ESI)

m/z calcd for C₂₂H₃₀NO₁₁SClNa (M + Na)⁺574.1126, found 574.1116.

2-(Trimethylsilyl)ethyl 2-Amino-4-O-tert-butyldimethylsilyl-2-

N,3-O-carbonyl-2-deoxy-6-O-p-toluenesulfonyl-α-^D-talopyranoside

(18jd). The general amidoglycosylation procedure, with galactal 3-

carbamate 14j (74.9 mg, 0.164 mmol) and 2-(trimethylsilyl)ethanol

(4.9 equiv) as the acceptor, followed by chromatography (40 → 50%

EtOAc/hexanes, 75 mL SiO₂), provided 18jd (53.5 mg, 57%) as a

clear, colorless glass: R_f= 0.47 (50% EtOAc/hexanes); IR (thin ﬁlm)

3264, 1763, 1598 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.78

(apparent d, J = 8.3 Hz, 2H, ArH_o), 7.33 (apparent d, J = 8.0 Hz, 2H,

ArH_m), 5.65 (br s, 1H, NH), 4.83 (d, J = 3.6 Hz, 1H, H1), 4.63 (dd,

J = 9.2, 3.6 Hz, 1H, H3), 4.29 (dd, J = 3.8, 3.8 Hz, 1H, H4), 4.20 (AB

of ABX, J_AB= 10.4 Hz, J_AX= 7.5 Hz, J_BX= 4.6 Hz, Δν_AB= 24.2 Hz,

2H, H6), 4.06 (ddd, J = 7.3, 4.2, 4.2 Hz, 1H, H5), 3.82 (ddd, J = 10.1,

10.1, 6.4 Hz, 1H, H1′a), 3.79 (dd, J = 9.9, 3.3 Hz, 1H, H2), 3.50

(ddd, J = 10.0, 10.0, 6.5 Hz, 1H, H1′b), 2.44 (s, 3H, ArCH₃), 0.90

(m, 2H, H2′), 0.86 (s, 9H, SiC(CH₃)₃), 0.14 (s, 3H, Si^tBuCH₃), 0.04

(s, 3H, Si^tBuCH₃), 0.02 (s, 9H, Si(CH₃)₃); ¹³C NMR (75 MHz,

CDCl₃) δ 158.5 (s, OC(O)NH), 144.9 (s, Ar), 132.8 (s, Ar), 129.9

(o, Ar-meta), 128.0 (o, Ar-ortho), 96.9 (o, C1), 74.3 (o, C3), 70.3 (o, C5),

69.2 (t, C6), 66.6 (t, C1′), 64.8 (o, C4), 54.6 (o, C2), 25.7 (o,

SiC(CH₃)₃), 21.6 (o, ArCH₃), 18.02 (t, C2′), 17.97 (s, SiC(CH₃)₃), −1.4

(o, Si(CH₃)₃) −4.5 (o, Si^tBuCH₃), −5.1 (o, Si^tBuCH₃); HRMS (ESI)

m/z calcd for C₂₅H₄₃NO₈Si₂SNa (M + Na)⁺596.2145, found 596.2159.

Benzyl 2-Amino-4-O-tert-butyldimethylsilyl-2-N,3-O-carbonyl-2-

deoxy-6-O-p-toluenesulfonyl-α-^D-talopyranoside (18jh). The start-

ing galactal carbamate 14j (76.5 mg, 0.167 mmol) was treated under

the standard amidoglycosylation conditions with benzyl alcohol

(4.9 equiv) as the acceptor, but using 3.3 equiv iodosobenzene. The

additional iodosobenzene (beyond the typical 1.8 equiv) was

necessary to minimize unreacted starting carbamate. Chromatography

(50% EtOAc/hexanes, 75 mL SiO₂) provided benzyl glycoside 18jh

(47.6 mg, 51%) as a clear, colorless oil: R_f= 0.28 (50% EtOAc/

hexanes); IR (thin ﬁlm) 3264, 1763, 1598 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 7.80 (apparent d, J = 8.4 Hz, 2H, p-TolH_o), 7.40−7.23 (m,

7H, p-TolH_m, CH₂C₆H₅), 5.53 (br s, 1H, NH), 4.89 (d, J = 3.8 Hz,

1H, H1), 4.63 (dd, J = 9.2, 3.6 Hz, 1H, H3), 4.59 (AB, J_AB= 11.7 Hz,

Δν_AB= 69.8 Hz, 2H, CH₂C₆H₅), 4.26 (dd, J = 3.7, 3.7 Hz, 1H, H4),

4.84 (s, 1H), 4.67 (dd, J = 7.4, 7.4 Hz, 1H), 4.08 (AB of ABX, J_AB

=

10.7 Hz, J_AX= 4.0 Hz, J_BX= 3.5 Hz, Δν_AB= 18.1 Hz, 2H), 4.07 (m,

1H), 3.99 (ddd, J = 9.4, 6.2, 3.5 Hz, 1H), 3.80 (ddd, J = 10.0, 6.0,

6.0 Hz, 1H), 3.47 (ddd, J = 9.8, 5.9, 5.9 Hz, 1H), 2.46 (s, 3H), 2.28

(apparent td, J = 6.9, 2.6 Hz, 2H), 2.08 (s, 3H), 2.00 (apparent t, J =

2.6 Hz, 1H), 1.78 (apparent pentet, J = 6.6 Hz, 2H); ¹³C NMR (75 MHz,

CDCl₃) δ 169.5 (s), 158.3 (s), 145.2 (s), 132.4 (s), 129.9 (o), 128.0 (o),

96.2 (o), 83.1 (s), 75.7 (o), 69.3 (o), 68.34 (o)*, 68.31 (t)*, 66.2 (t),

65.7 (o), 55.7 (o), 27.8 (t), 21.7 (o), 20.7 (o), 15.1 (t), *these ¹³C

resonances distinguished by reprocessing the FID with lb = 0 and by

their opposite phases in the DEPT 135 spectrum; HRMS (ESI) m/z

calcd for C₂₁H₂₅NO₉SNa (M + Na)⁺490.1148, found 490.1144.

Benzyl 4-O-Acetyl-2-amino-2-N,3-O-carbonyl-2-deoxy-6-O-p-

toluenesulfonyl-α-^D-mannopyranoside (17fh). Reaction of glycal

carbamate 13f (61.1 mg, 0.159 mmol) and benzyl alcohol (5.2 equiv)

using the general amidoglycosylation conditions, but with 3.1 equiv

PhIO instead of the usual 1.8 equiv, gave a single α anomer of benzyl

glycoside 17fh (53.5 mg, 69%) as a glass, following chromatography

(90% Et₂O/pentane, 80 mL SiO₂): R_f= 0.22 (90% Et₂O/pentane);

1

IR (ATR) 3367, 1761, 1598 cm⁻¹; H NMR (300 MHz, CDCl₃) δ

7.79 (apparent d, J = 8.3 Hz, 2H, ArH_o), 7.42−7.27 (m, 7H, ArH_m,

CH₂C₆H₅), 6.13 (slightly br s, 1H, NH), 4.97 (dd, J = 9.5, 7.2 Hz, 1H,

H4), 4.92 (s, 1H, H1), 4.68 (dd, J = 7.4, 7.4 Hz, 1H, H3), 4.56 (AB,

J_AB= 11.4 Hz, Δν_AB= 63.7 Hz, 2H, CH₂C₆H₅), 4.12−3.97 (m, 4H,

H2, H5, H6), 2.45 (s, 3H, Ar-CH₃), 2.06 (s, 3H, H₃CC(O)O); ¹³C

NMR (75 MHz, CDCl₃) δ 169.6 (s, H₃CC(O)O), 158.3 (s,

OC(O)NH), 145.2 (s, Ar), 136.0 (s, Ar), 132.6 (s, Ar), 129.9 (o,

Ar), 128.6 (o, Ar), 128.5 (o, Ar), 128.3 (o, Ar-para’), 128.0 (o, Ar-

ortho), 95.2 (o, C1), 75.7 (o, C3), 69.6 (t, CH₂C₆H₅), 68.5 (o, C4),

68.3 (t, C6), 66.0 (o, C5), 55.8 (o, C2), 21.6 (o, Ar-CH₃), 20.6 (o,

H₃CC(O)O); HRMS (ESI) m/z calcd for C₂₃H₂₅NO₉SNa (M +

Na)⁺514.1148, found 514.1148.

4.20 (AB of ABX, J_AB= 10.2 Hz, J_AX= 7.4 Hz, J_BX= 3.8 Hz, Δν_AB

=

12.0 Hz, 2H, H6), 4.08 (ddd, J = 7.1, 4.0, 4.0 Hz, 1H, H5), 3.86 (ddd,

J = 9.2, 3.8, 0.9 Hz, 1H, H2), 2.43 (s, 3H, ArCH₃), 0.80 (s, 9H,

SiC(CH₃)₃), 0.10 (s, 3H, SiCH₃), 0.01 (s, 3H, SiCH₃); ¹³C NMR (75

MHz, CDCl₃) δ 158.3 (s, OC(O)NH), 145.0 (s, p-Tol or Ph), 136.5

(s, p-Tol or Ph), 132.8 (s, p-Tol or Ph), 129.9 (o, p-Tol-meta), 128.7

(o, Ph), 128.30 (o, Ph)*, 128.29 (o, Ph)*, 128.0 (o, p-Tol-ortho),

96.2 (o, C1), 74.1 (o, C3), 70.6 (o, C5), 70.3 (t, CH₂Ph), 69.4

(t, C6), 64.9 (o, C4), 54.5 (o, C2), 25.6 (o, SiC(CH₃)₃), 21.6

(o, ArCH₃), 17.9 (s, SiC(CH₃)₃), −4.5 (o, SiCH₃), −5.1 (o, SiCH₃),

*the ¹³C resonances at δ 128.30 and 128.29 were distinguished by

reprocessing the FID with lb = 0; HRMS (ESI) m/z calcd for

C₂₇H₃₇NO₈SiSNa (M + Na)⁺586.1907, found 586.1901.

For the amidoglycosylation reactions leading to 17ci and 17fj

(Table 3, entries 8−10), see ref 24.

2-[2-(2-Chloroethoxy)ethoxy]ethyl 4-O-Acetyl-2-amino-2-N,3-O-

carbonyl-2-deoxy-6-O-p-toluenesulfonyl-α-^D-mannopyranoside

(17fk). Using the general amidoglycosylation procedure, reaction of

glucal 3-carbamate 13f (66.4 mg, 0.172 mmol) and 2-[2-(2-

chloroethoxy)ethoxy]ethanol (5.0 equiv) followed by chromatog-

raphy (50 → 80 → 90 → 100% EtOAc/hexanes, 80 mL SiO₂) and

further puriﬁcation by preparative TLC (100% EtOAc, several

elutions) gave a single anomer of product 17fk (33.6 mg, 35%) as

a clear, colorless oil: R_f= 0.26 (90% EtOAc/hexanes); IR (ATR)

3301, 1761, 1598 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.77

(apparent d, J = 8.3 Hz, 2H, ArH_o), 7.36 (apparent d, J = 8.0 Hz, 2H,

ArH_m), 6.18 (br s, 1H, NH), 4.97 (dd, J = 9.1, 7.3 Hz, 1H, H4), 4.93

(s, 1H, H1), 4.68 (dd, J = 7.5, 7.5 Hz, 1H, H3), 4.13−3.99 (m, 4H,

H2, H5, H6), 3.83−3.73 (m, 3H, 2H of H1′-H5′, H6′a), 3.71−3.58

(m, 9H, 8H of H1′-H5′, H6′b), 2.45 (s, 3H, Ar−CH₃), 2.06 (s, 3H,

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.8b00893.

■

S

Additional NMR characterization data and copies of ¹H,

¹³C NMR, and 2-D NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: crojas@barnard.edu.

■

W

DOI: 10.1021/acs.joc.8b00893

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Carbohydrates and Glycoconjugates. Org. Biomol. Chem. 2016, 14,

11028−11047.

(9) Danishefsky, S. J.; Bilodeau, M. T. Glycals in Organic Synthesis:

The Evolution of Comprehensive Strategies for the Assembly of

Oligosaccharides and Glycoconjugates of Biological Consequence.

Angew. Chem., Int. Ed. Engl. 1996, 35, 1380−1419.

ORCID

Kimberly M. Sogi: 0000-0002-4011-2440

Christian M. Rojas: 0000-0001-7779-066X

Notes

The authors declare no competing ﬁnancial interest.

(10) (a) Lemieux, R. U.; Ratcliffe, R. M. The Azidonitration of Tri-

O-Acetyl-D-Galactal. Can. J. Chem. 1979, 57, 1244−1251. (b) Leblanc,

Y.; Fitzsimmons, B. J.; Springer, J. P.; Rokach, J. [4 + 2]

Cycloaddition Reaction of Dibenzyl Azodicarboxylate and Glycals. J.

Am. Chem. Soc. 1989, 111, 2995−3000. (c) Griffith, D. A.;

Danishefsky, S. J. Sulfonamidoglycosylation of Glycals. A Route to

Oligosaccharides with 2-Aminohexose Subunits. J. Am. Chem. Soc.

1990, 112, 5811−5819. (d) Griffith, D. A.; Danishefsky, S. J. Total

Synthesis of Allosamidin: An Application of the Sulfonamidoglyco-

sylation of Glycals. J. Am. Chem. Soc. 1991, 113, 5863−5864.

(e) Seeberger, P. H.; Roehrig, S.; Schell, P.; Wang, Y.; Christ, W. J.

Selective Formation of C-2 Azidodeoxy-D-Glucose Derivatives from

D-Glucal Precursors Using the Azidonitration Reaction. Carbohydr.

Res. 2000, 328, 61−69. (f) Liu, J.; Gin, D. Y. C2-Amidoglycosylation.

Scope and Mechanism of Nitrogen Transfer. J. Am. Chem. Soc. 2002,

124, 9789−9797. (g) Liu, J.; Di Bussolo, V.; Gin, D. Y. C2-

Acetamidomannosylation. Synthesis of 2-N-Acetylamino-2-Deoxy-α-

D-Mannopyranosides with Glucal Donors. Tetrahedron Lett. 2003, 44,

4015−4018. (h) Dahl, R. S.; Finney, N. S. A Surprising Dipolar

Cycloaddition Provides Ready Access to Aminoglycosides. J. Am.

Chem. Soc. 2004, 126, 8356−8357. (i) Schmidt, R. R.; Vankar, Y. D.

2-Nitroglycals as Powerful Glycosyl Donors: Application in the

Synthesis of Biologically Important Molecules. Acc. Chem. Res. 2008,

41, 1059−1073. (j) Mirabella, S.; Cardona, F.; Goti, A. From Glycals

to Aminosugars: A Challenging Test for New Stereoselective

Aminohydroxylation and Related Methodologies. Org. Biomol.

Chem. 2016, 14, 5186−5204.

(11) (a) Kozlowska-Gramsz, E.; Descotes, G. Addition des Nitrenes

sur les Ethers Vinyliques Cycliques. Application a la Synthese

d’Aminosucres. Tetrahedron Lett. 1981, 22, 563−566. (b) Du Bois, J.;

Tomooka, C. S.; Hong, J.; Carreira, E. M. Novel, Stereoselective

Synthesis of 2-Amino Saccharides. J. Am. Chem. Soc. 1997, 119,

3179−3180. (c) Guthikonda, K.; Wehn, P. M.; Caliando, B. J.; Du

Bois, J. Rh-Catalyzed Alkene Oxidation: A Highly Efficient and

Selective Process for Preparing N-Alkoxysulfonyl Aziridines. Tetrahe-

dron 2006, 62, 11331−11342. (d) Lorpitthaya, R.; Xie, Z.-Z.; Kuo, J.-

L.; Liu, X.-W. Stereocontrolled Intramolecular Aziridination of

Glycals: Ready Access to Aminoglycosides and Mechanistic Insights

from DFT Studies. Chem. - Eur. J. 2008, 14, 1561−1570.

(e) Lorpitthaya, R.; Xie, Z.-Z.; Sophy, K. B.; Kuo, J.-L.; Liu, X.-W.

Mechanistic Insights into the Substrate-Controlled Stereochemistry of

Glycals in One-Pot Rhodium-Catalyzed Aziridination and Aziridine

Ring Opening. Chem. - Eur. J. 2010, 16, 588−594. (f) Murakami, T.;

Sato, Y.; Yoshioka, K.; Tanaka, M. Convenient Stereocontrolled

Amidoglycosylation of Alcohols with Acetylated Glycals and

Trichloroethoxysulfonamide. Carbohydr. Res. 2016, 434, 121−131.

(g) Lu, D.-F.; Zhu, C.-L.; Jia, Z.-X.; Xu, H. Iron(II)-Catalyzed

Intermolecular Amino-Oxygenation of Olefins through the N−O

Bond Cleavage of Functionalized Hydroxylamines. J. Am. Chem. Soc.

2014, 136, 13186−13189.

ACKNOWLEDGMENTS

■

We are grateful to the National Institute of General Medical

Sciences of the National Institutes of Health (R15GM107832)

and the National Science Foundation (CHE-0957181) for

support of this research. We thank Aneta Turlik for additional

study and characterization of the reaction of 14b, Dr. John

Decatur (Columbia University) for NMR assistance, and

Dr. Yasuhiro Itagaki and Dr. Brandon Fowler (Columbia

University) for mass spectrometric analyses.

REFERENCES

■

(1) (a) Varki, A., Cummings, R. D., Esko, J. D., Freeze, H. H.,

Stanley, P., Bertozzi, C. R., Hart, G. W., Etzler, M. E., Eds. Essentials of

Glycobiology, 2nd ed.; Cold Spring Harbor Laboratory Press: Cold

́

Spring Harbor, 2009. (b) Galonic, D. P.; Gin, D. Y. Chemical

Glycosylation in the Synthesis of Glycoconjugate Antitumour

Vaccines. Nature 2007, 446, 1000−1007. (c) Seeberger, P. H.;

Werz, D. B. Synthesis and Medical Applications of Oligosaccharides.

Nature 2007, 446, 1046−1051.

(2) (a) Magano, J. Synthetic Approaches to the Neuraminidase

Inhibitors Zanamivir (Relenza) and Oseltamivir Phosphate (Tamiflu)

for the Treatment of Influenza. Chem. Rev. 2009, 109, 4398−4438.

(b) Silva, J. G.; Carvalho, I. New Insights into Aminoglycoside

Antibiotics and Derivatives. Curr. Med. Chem. 2007, 14, 1101−1119.

(c) Moscona, A. Neuraminidase Inhibitors for Influenza. N. Engl. J.

Med. 2005, 353, 1363−73. (d) Magnet, S.; Blanchard, J. S. Molecular

Insights into Aminoglycoside Action and Resistance. Chem. Rev. 2005,

105, 477−497.

(3) (a) Skarbek, K.; Milewska, M. J. Biosynthetic and Synthetic

Access to Amino Sugars. Carbohydr. Res. 2016, 434, 44−71.

(b) Adibekian, A.; Timmer, M. S. M.; Stallforth, P.; van Rijn, J.;

Werz, D. B.; Seeberger, P. H. Stereocontrolled Synthesis of Fully

Functionalized D-Glucosamine Monosaccharides via a Domino Nitro-

Michael/Henry Reaction. Chem. Commun. 2008, 3549−3551.

(c) Bongat, A. F. G.; Demchenko, A. V. Recent Trends in the

Synthesis of O-Glycosides of 2-Amino-2-Deoxysugars. Carbohydr. Res.

2007, 342, 374−406.

(4) (a) Kusumoto, S.; Kambayashi, Y.; Imaoka, S.; Shima, K.; Shiba,

T. Biosynthesis of Natural Products Containing β-Amino Acids. J.

Antibiot. 1982, 35, 925−927. (b) Gan, M.; Zheng, X.; Liu, Y.; Guan,

Y.; Xiao, C. Three New 12-Carbamoylated Streptothricins from

Streptomyces sp. I08A 1776. Bioorg. Med. Chem. Lett. 2012, 22, 6151−

6154.

(5) Berecibar, A.; Grandjean, C.; Siriwardena, A. Synthesis and

Biological Activity of Natural Aminocyclopentitol Glycosidase

Inhibitors: Mannostatins, Trehazolin, Allosamidins, and Their

Analogues. Chem. Rev. 1999, 99, 779−844.

(6) Yin, Z.; Comellas-Aragones, M.; Chowdhury, S.; Bentley, P.;

Kaczanowska, K.; BenMohamed, L.; Gildersleeve, J. C.; Finn, M. G.;

Huang, X. Boosting Immunity to Small Tumor-Associated Carbohy-

drates with Bacteriophage Qβ Capsids. ACS Chem. Biol. 2013, 8,

1253−1262.

(7) Peltier-Pain, P.; Marchillo, K.; Zhou, M.; Andes, D. R.; Thorson,

J. S. Natural Product Disaccharide Engineering through Tandem

Glycosyltransferase Catalysis Reversibility and Neoglycosylation. Org.

Lett. 2012, 14, 5086−5089.

(8) (a) Goff, R. D.; Thorson, J. S. Neoglycosylation and

Neoglycorandomization: Enabling Tools for the Discovery of Novel

Glycosylated Bioactive Probes and Early Stage Leads. MedChemComm

2014, 5, 1036−1047. (b) Chen, N.; Xie, J. N−O Linkage in

(12) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Vega, J. A.

Novel IBX-Mediated Processes for the Synthesis of Amino Sugars and

Libraries Thereof. Angew. Chem., Int. Ed. 2000, 39, 2525−2529.

(b) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt,

K. W.; Kranich, R.; Vega, J. A. Iodine(V) Reagents in Organic

Synthesis. Part 3. New Routes to Heterocyclic Compounds via o-

Iodoxybenzoic Acid-Mediated Cyclizations: Generality, Scope, and

Mechanism. J. Am. Chem. Soc. 2002, 124, 2233−2244.

(13) Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. The

Tethered Aminohydroxylation (TA) of Cyclic Allylic Carbamates. J.

Am. Chem. Soc. 2002, 124, 12934−12935.

X

DOI: 10.1021/acs.joc.8b00893

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(14) Mirabella, S.; Cardona, F.; Goti, A. Osmium-Catalyzed

Tethered Aminohydroxylation of Glycals: A Stereodirected Access

to 2- and 3-Aminosugars. Org. Lett. 2015, 17, 728−731.

Molecular Rearrangements in Organic Synthesis; Rojas, C. M., Ed.; John

Wiley & Sons: Hoboken, NJ, 2016; pp 569−625.

(27) Halcomb, R. L.; Boyer, S. H.; Wittman, M. D.; Olson, S. H.;

Denhart, D. J.; Liu, K. K. C.; Danishefsky, S. J. Studies Related to the

Carbohydrate Sectors of Esperamicin and Calicheamicin: Definition

of the Stability Limits of the Esperamicin Domain and Fashioning of a

Glycosyl Donor from the Calicheamicin Domain. J. Am. Chem. Soc.

1995, 117, 5720−5749.

(15) Kan, C.; Long, C. M.; Paul, M.; Ring, C. M.; Tully, S. E.; Rojas,

C. M. Photo Amidoglycosylation of an Allal Azidoformate. Synthesis

of β-2-Amido Allopyranosides. Org. Lett. 2001, 3, 381−384.

(16) For a triplet-mediated intermolecular reaction of azidoformate-

derived nitrenes with alkenes, including glycals, see: Scholz, S. O.;

Farney, E. P.; Kim, S.; Bates, D. M.; Yoon, T. P. Spin-Selective

Generation of Triplet Nitrenes: Olefin Aziridination via Visible Light

Photosensitization of Azidoformates. Angew. Chem., Int. Ed. 2016, 55,

2239−2242.

(28) For related studies, see: (a) de la Pradilla, R. F.; Lwoff, N.; del

́

Aguila, M. A; Tortosa, M.; Viso, A. [2,3]-Sigmatropic Rearrangements

of 3-Sulfinyl Dihydropyrans: Application to the Syntheses of the

Cores of ent-Dysiherbaine and Deoxymalayamicin A. J. Org. Chem.

2008, 73, 8929−8941. (b) Alberch, L.; Cheng, G.; Seo, S.-K.; Li, X.;

Boulineau, F. P.; Wei, A. Stereoelectronic Factors in the Stereo-

selective Epoxidation of Glycals and 4-Deoxypentenosides. J. Org.

Chem. 2011, 76, 2532−2547.

(17) Churchill, D. G.; Rojas, C. M. Iron(II)-Promoted Amidogly-

cosylation and Amidochlorination of an Allal C3-Azidoformate.

Tetrahedron Lett. 2002, 43, 7225−7228.

(18) (a) Bach, T.; Schlummer, B.; Harms, K. Intramolecular

Iron(II)-catalyzed Nitrogen Transfer Reactions of Unsaturated

Alkoxycarbonyl Azides: A Facile and Stereoselective Route to 4,5-

Disubstituted Oxazolidinones. Chem. - Eur. J. 2001, 7, 2581−2594.

(b) Shigeoka, D.; Kamon, T.; Yoshimitsu, T. Formal Synthesis of

(−)-Agelastatin A: An Iron(II)-Mediated Cyclization Strategy.

Beilstein J. Org. Chem. 2013, 9, 860−865. (c) Xiong, T.; Zhang, Q.

New Amination Strategies Based on Nitrogen-Centered Radical

Chemistry. Chem. Soc. Rev. 2016, 45, 3069−3087. (d) Jiang, H.; Lang,

K.; Lu, H.; Wojtas, L.; Zhang, X. P. Asymmetric Radical Bicyclization

of Allyl Azidoformates via Cobalt(II)-Based Metalloradical Catalysis.

J. Am. Chem. Soc. 2017, 139, 9164−9167. (e) Choi, G. J.; Knowles, R.

R. Catalytic Alkene Carboaminations Enabled by Oxidative Proton-

Coupled Electron Transfer. J. Am. Chem. Soc. 2015, 137, 9226−9229.

(19) Espino, C. G.; Du Bois, J. A Rh-Catalyzed C−H Insertion

Reaction for the Oxidative Conversion of Carbamates to Oxazolidi-

nones. Angew. Chem., Int. Ed. 2001, 40, 598−600.

(29) (a) Kocovsky, P. Carbamates: A Method of Synthesis and

Some Synthetic Applications. Tetrahedron Lett. 1986, 27, 5521−5524.

(b) Sugai and co-workers developed a similar approach and identified

the importance of properly activated alumina: Calveras, J.; Nagai, Y.;

Sultana, I.; Ueda, Y.; Higashi, T.; Shoji, M.; Sugai, T. New Chemo-

enzymatic Route toward N-Acetylneuraminic Acid Derivatives with

Alkyl Groups at C-7 Hydroxyl Group. Tetrahedron 2010, 66, 4284−

4291.

(30) (a) Levecque, P.; Gammon, D. W.; Jacobs, P.; De Vos, D.; Sels,

B. The Use of Ultrastable Y Zeolites in the Ferrier Rearrangement of

Acetylated and Benzylated Glycals. Green Chem. 2010, 12, 828−835.

(b) Reddy, B. V. S.; Divyavani, Ch.; Yadav, J. S. Highly Stereoselective

Synthesis of 2,3-Unsaturated Thioglycopyranosides Employing

Molecular Iodine. Synthesis 2010, 2010, 1617−1620.

(31) Kirschning, A.; Hary, U.; Plumeier, C.; Ries, M.; Rose, L.

Simple Oxidation of 3-O-Silylated Glycals: Application in Deblocking

3-O-Protected Glycals. J. Chem. Soc., Perkin Trans. 1 1999, 1, 519−

528.

(20) Levites-Agababa, E.; Menhaji, E.; Perlson, L. N.; Rojas, C. M.

Amidoglycosylation via Metal-Catalyzed Internal Nitrogen Atom

Delivery. Org. Lett. 2002, 4, 863−865.

̀

(32) Fernandez-Mayoralas, A.; Marra, A.; Trumtel, M.; Veyrieres, A.;

Sinay, P. Preparation of Pyranoid Glycal Derivatives from Phenyl

̈

(21) For other examples of intramolecular alkene amidoacetox-

ylation using carbamates under these conditions, see: (a) Padwa, A.;

Flick, A. C.; Leverett, C. A.; Stengel, T. Rhodium(II)-Catalyzed

Aziridination of Allyl-Substituted Sulfonamides and Carbamates. J.

Org. Chem. 2004, 69, 6377−6386. (b) Padwa, A.; Stengel, T.

Stereochemical Aspects of the Iodine(III)-Mediated Aziridination

Reaction of Some Cyclic Allylic Carbamates. Org. Lett. 2002, 4,

2137−2139. (c) Knapp, S.; Yu, Y. Synthesis of the Oxygenated

Pactamycin Core. Org. Lett. 2007, 9, 1359−1362. (d) Unsworth, W.

P.; Lamont, S. G.; Robertson, J. Substrate Scope and Stereocontrol in

the Rh(II)-Catalysed Oxyamination of Allylic Carbamates. Tetrahe-

dron 2014, 70, 7388−7394.

Thioglycosides and Glycosyl Phenyl Sulphones. Carbohydr. Res. 1989,

188, 81−95.

(33) Love, K. R.; Andrade, R. B.; Seeberger, P. H. Linear Synthesis

of a Protected H-Type II Pentasaccharide Using Glycosyl Phosphate

Building Blocks. J. Org. Chem. 2001, 66, 8165−8176.

(34) (a) Prepared as for the corresponding glucal compound:

Hoberg, J. O. Synthesis and Chemistry of 4,6-O-Di-(tert-butyl)-

silanediyl-D-Glucal. Carbohydr. Res. 1997, 300, 365−367. (b) Abdel-

Rahman, A. A.-H.; Winterfeld, G. A.; Takhi, M.; Schmidt, R. R.

Trichloroacetimidate as a Leaving Group in the Ferrier Rearrange-

ment: Highly Stereoselective Synthesis of Pseudogalactal Glycosides.

Eur. J. Org. Chem. 2002, 2002, 713−717.

(35) We observed the same phenomenon in our glucal 3-carbamate

studies where the corresponding 4,6-di-O-acetyl bisaminal was

isolated and fully characterized. See the Supporting Information of

ref 24.

(36) (a) Thiem, J.; Ossowski, P. Studies of Hexuronic Acid Ester

Glycals and the Synthesis of 2-Deoxy-β-Glycoside Precursors. J.

Carbohydr. Chem. 1984, 3, 287−313. (b) Roush, W. R.; Sebesta, D.

P.; Bennett, C. E. Stereoselective Synthesis of 2-Deoxy-β-Glycosides

from Glycal Precursors. 1. Stereochemistry of the Reaction D-glucal

Derivatives with Phenylsulfenyl Chloride and Phenylselenenyl

Chloride. Tetrahedron 1997, 53, 8825−8836.

̀

(22) Dauban, P.; Saniere, L.; Tarrade, A.; Dodd, R. H. Copper-

Catalyzed Nitrogen Transfer Mediated by Iodosylbenzene PhIO. J.

Am. Chem. Soc. 2001, 123, 7707−7708.

(23) Bodner, R.; Marcellino, B. K.; Severino, A.; Smenton, A. L.;

Rojas, C. M. α-N-Acetylmannosamine (ManNAc) Synthesis via

Rhodium(II)-Catalyzed Oxidative Cyclization of Glucal 3-Carba-

mates. J. Org. Chem. 2005, 70, 3988−3996.

(24) Gupta, R.; Sogi, K. M.; Bernard, S. E.; Decatur, J. D.; Rojas, C.

M. Protecting Group and Solvent Control of Stereo- and Chemo-

selectivity in Glucal 3-Carbamate Amidoglycosylation. Org. Lett. 2009,

11, 1527−1530.

(25) Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.; Golik, J.;

Vyas, D. A Route to Glycals in the Allal and Gulal Series: Synthesis of

the Thiosugar of Esperamicin A1. J. Org. Chem. 1990, 55, 1979−1981.

(26) (a) Braverman, S.; Stabinsky, Y. The Rearrangement of Allylic

Trichloromethanesulphenates. Chem. Commun. 1967, 270−271.

(b) Tang, R.; Mislow, K. Rates and Equilibria in the Interconversion

of Allylic Sulfoxides and Sulfenates. J. Am. Chem. Soc. 1970, 92,

2100−2104. (c) Evans, D. A.; Andrews, G. C. Allylic Sulfoxides.

Useful Intermediates in Organic Synthesis. Acc. Chem. Res. 1974, 7,

147−155. (d) Rojas, C. M. The Mislow−Evans Rearrangement. In

(37) (a) Hall, L. D.; Johnson, L. F. A Proton Magnetic Resonance

Study of D-Glucal Triacetate. Tetrahedron 1964, 20, 883−889.

(b) Chalmers, A. A.; Hall, R. H. Conformational Studies of D-Glycals

by ¹H Nuclear Magnetic Resonance Spectroscopy. J. Chem. Soc.,

Perkin Trans. 2 1974, 2, 728−732.

(38) Most of the J values listed in Table 1 were obtained by ﬁrst-

order analysis of ¹H NMR peak splittings at 300 MHz. For

complicated but still ﬁrst-order patterns, the rubric of Hoye was

useful: Hoye, T. R.; Zhao, H. A Method for Easily Determining

Coupling Constant Values: An Addendum to “A Practical Guide to

Y

DOI: 10.1021/acs.joc.8b00893

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

First-Order Multiplet Analysis in ¹H NMR Spectroscopy. J. Org.

Chem. 2002, 67, 4014−4016. In some cases we also used ¹H

homonuclear decoupling to help determine coupling constant values.

Those instances are noted in the Experimental Section, with the

decoupling results outlined in the Supporting Information. With

glycal 3-carbamates 13c, 13f, and 14c, key ¹H NMR resonances

showed second-order behavior due to chemical shift overlap,

including at 500 MHz. In these cases, we used coupled HSQC

experiments to determine the proton−proton coupling constants.

Coupled HSQC spectra of 14c are included in the Supporting

Information for this article, and see the Supporting Information of ref

24 for analysis of 13c and 13f. See also: Simova, S. Application of

HSQC to the Measurement of Homonuclear Coupling Constants,

J(H,H). Magn. Reson. Chem. 1998, 36, 505−510.

L.; Mazurais, M.; Dauban, P. Transition Metal-Catalyzed Iodine(III)-

Mediated Nitrene Transfer Reactions: Efficient Tools for Challenging

Syntheses. Chem. Commun. 2017, 53, 493−508.

(49) Lin, X.; Zhao, C.; Che, C.-M.; Ke, Z.; Phillips, D. L. A DFT

Study on the Mechanism of Rh₂^II,II-Catalyzed Intramolecular

Amidation of Carbamates. Chem. - Asian J. 2007, 2, 1101−1108.

(50) (a) Ciesielski, J.; Dequirez, G.; Retailleau, P.; Gandon, V.;

Dauban, P. Rhodium-Catalyzed Alkene Difunctionalization with

Nitrenes. Chem. - Eur. J. 2016, 22, 9338−9347. (b) Guasch, J.;

́

Díaz, Y.; Matheu, M. I.; Castillon, S. Rhodium-Catalyzed Regio- and

Stereoselective Oxyamination of Dienes via Tandem Aziridination/

Ring-Opening of Dienyl Carbamates. Chem. Commun. 2014, 50,

7344−7347.

(51) Hurlocker, B.; Abascal, N. C.; Repka, L. M.; Santizo-Deleon, E.;

Smenton, A. L.; Baranov, V.; Gupta, R.; Bernard, S. E.; Chowdhury,

S.; Rojas, C. M. Dihydropyranone Formation by Ipso C−H Activation

in a Glucal 3-Carbamate-Derived Rhodium Acyl Nitrenoid. J. Org.

Chem. 2011, 76, 2240−2244.

(39) Fetizon, M.; Khac, D. D.; Tho, N. D. An Approach to the

Synthesis of Optically Active Trichothecenes from Tri-O-Acetyl-D-

Glucal. Tetrahedron Lett. 1986, 27, 1777−1780.

(40) Ferrier, R. J.; Sankey, G. H. Unsaturated Carbohydrates. Part

VII. The Preference Shown by Allylic Ester Groupings on Pyranoid

Rings for the quasi-Axial Orientation. J. Chem. Soc. C 1966, 2345−

2349.

(52) (a) Yang, M. T.; Woerpel, K. A. The Effect of Electrostatic

Interactions on Conformational Equilibria of Multiply Substituted

Tetrahydropyran Oxocarbenium Ions. J. Org. Chem. 2009, 74, 545−

553. (b) Smith, D. M.; Woerpel, K. A. Electrostatic Interactions in

Cations and their Importance in Biology and Chemistry. Org. Biomol.

Chem. 2006, 4, 1195−1201.

(53) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I.

Configurational Assignment of Polyene Macrolide Antibiotics Using

the [¹³C]Acetonide Analysis. Acc. Chem. Res. 1998, 31, 9−17.

(54) Parker, K. A.; Chang, W. Regioselectivity of Rhodium Nitrene

Insertion. Syntheses of Protected Glycals of L-Daunosamine, D-

Saccharosamine, and L-Ristosamine. Org. Lett. 2005, 7, 1785−1788.

(55) Paquette, L. A.; Barton, T. J.; Horton, N. Reaction of

Diphenylcyclopropenone with Activated Isocyanates. A Facile Syn-

thesis of Selected Iminocyclopropenes. Tetrahedron Lett. 1967, 8,

5039−5042.

(56) (a) Du Bois, J. Rhodium-Catalyzed C−H Amination: Versatile

Methodology for the Selective Preparation of Amines and Amine

Derivatives. CHEMTRACTS−Org. Chem. 2005, 18, 1−13. (b) Espino,

C. G.; Du Bois, J. Rhodium(II)-Catalyzed Oxidative Amination. In

Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.;

Wiley-VCH: Weinheim, 2005; pp 379−416. See also footnote 17 of:

(c) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Expanding the

Substrate Scope for C−H Amination Reactions: Oxidative Cyclization

of Urea and Guanidine Derivatives. Org. Lett. 2006, 8, 1073−1076.

(57) Doyle, M. P.; Dyatkin, A. B.; Autry, C. L. A New Catalytic

Transformation of Diazo Esters: Hydride Abstraction in Dirhodium-

(II)-Catalysed Reactions. J. Chem. Soc., Perkin Trans. 1 1995, 1, 619−

621.

(41) (a) Fraser-Reid, B.; Madsen, R. Oligosaccharide Synthesis by n-

Pentenyl Glycosides. In Preparative Carbohydrate Chemistry;

Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 339−356.

(b) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.; Merritt, J.

R.; Rao, C. S.; Roberts, C.; Madsen, R. n-Pentenyl Glycosides in

Organic Chemistry: A Contemporary Example of Serendipity. Synlett

1992, 1992, 927−942.

(42) We expected similar ¹³C relaxation times for corresponding

nuclei in anomeric pairs of products 15−18, enabling their relative

1

integration. For example, H and ¹³C NMR integration results for

17ia agreed within 6%, even with a standard ¹³C NMR proton-gated

pulse sequence and delay time (d1 = 2 s). Integrals were also

consistent using an inverse-gated ¹³C NMR pulse sequence with a

longer delay time (d1 = 5 s). For a detailed study of standard, short-

delay ¹³C NMR for determining product ratios, see: Otte, D. A. L.;

Borchmann, D. E.; Lin, C.; Weck, M.; Woerpel, K. A. ¹³C NMR

Spectroscopy for the Quantitative Determination of Compound

Ratios and Polymer End Groups. Org. Lett. 2014, 16, 1566−1569.

(43) Ishizuka, T.; Kunieda, T. Mild and Selective Ring-Cleavage of

Cyclic Carbamates to Amino Alcohols. Tetrahedron Lett. 1987, 28,

4185−4188.

(44) Lipshutz, B. H.; Pegram, J. J.; Morey, M. C. Chemistry of β-

Trimethylsilylethanol. II. A New Method for Protection of an

Anomeric Center in Pyranosides. Tetrahedron Lett. 1981, 22, 4603−

4606.

(45) (a) Schardt, B. C.; Hill, C. L. Preparation of Iodobenzene

Dimethoxide. A New Synthesis of [¹⁸O]Iodosylbenzene and a

Reexamination of Its Infrared Spectrum. Inorg. Chem. 1983, 22,

1563−1565. (b) Moriarty, R. M.; Kosmeder, J. W.; Zhdankin, V. V.;

(58) Clark, J. S.; Dossetter, A. G.; Wong, Y.-S.; Townsend, R. J.;

Whittingham, W. G.; Russell, C. A. Anomalous Intramolecular C−H

Insertion Reactions of Rhodium Carbenoids: Factors Influencing the

Reaction Course and Mechanistic Implications. J. Org. Chem. 2004,

69, 3886−3898.

̂

Courillon, C.; Lacote, E.; Malacria, M.; Darses, B.; Dauban, P.

Iodosylbenzene. e-EROS Encyclopedia of Reagents for Organic Synthesis;

John Wiley & Sons, 2012.

(59) (a) Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.; Tantillo,

D. J.; Garg, N. K. Total Synthesis of Oxidized Welwitindolinones and

(−)-N-Methylwelwitindolinone C Isonitrile. J. Am. Chem. Soc. 2012,

134, 1396−1399. (b) Sato, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y.

An Expedient Route to a Potent Gastrin/CCK-B Receptor Antagonist

(+)-AG-041R. J. Org. Chem. 2009, 74, 7522−7524.

(60) For an example of site-selective C−H oxidation mediated by an

electron-withdrawing protecting group, see: Conrad, R. M.; Du Bois,

J. C−H Amination in Synthesis: An Approach to the Assembly of the

B/C/D Ring System of Aconitine. Org. Lett. 2007, 9, 5465−5468.

(61) (a) Curran, D. P.; Suh, Y.-G. Selective Mono-Claisen

Rearrangement of Carbohydrate Glycals. A Chemical Consequence

of the Vinylogous Anomeric Effect. Carbohydr. Res. 1987, 171, 161−

191. (b) Denmark, S. E.; Dappen, M. S.; Sear, N. L.; Jacobs, R. T. The

Vinylogous Anomeric Effect in 3-Alkyl-2-Chlorocyclohexanone

Oximes and Oxime Ethers. J. Am. Chem. Soc. 1990, 112, 3466−3474.

(46) Matsuda, A.; Doi, T.; Tanaka, H.; Takahashi, T. Parallel

Synthesis of Oligosaccharide Conjugated Enediynes onto Silyl-Linked

Solid-Support. Synlett 2001, 2001, 1101−1104.

(47) (a) Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du Bois, J. A

Mechanistic Analysis of the Rh-catalyzed Intramolecular C-H

Amination Reaction. Tetrahedron 2009, 65, 3042−3051. (b) Fiori,

K. W.; Du Bois, J. Catalytic Intermolecular Amination of C−H Bonds:

Method Development and Mechanistic Insights. J. Am. Chem. Soc.

2007, 129, 562−568.

(48) (a) Dauban, P.; Dodd, R. H. Iminoiodanes and C−N Bond

Formation in Organic Synthesis. Synlett 2003, 1571−1586.

(b) Dauban, P.; Lescot, C.; Diaz-Requejo, M. M.; Perez, P. J. Rh-,

Ag-, and Cu-Catalyzed C−N Bond Formation. In Innovative Catalysis

in Organic Synthesis: Oxidation, Hydrogenation, and C−X Bond

Forming Reactions; Andersson, P. G., Ed.; Wiley-VCH: Weinheim,

Germany, 2012; pp 257−277. (c) Darses, B.; Rodrigues, R.; Neuville,

Z

DOI: 10.1021/acs.joc.8b00893

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(62) (a) Sulikowski, G. A.; Lee, S. Kinetic Isotope Effects in the

Intramolecular Insertion of a Metal Carbene into a C-H Bond

Adjacent to Nitrogen. Tetrahedron Lett. 1999, 40, 8035−8038.

(b) Newhouse, T.; Baran, P. S. If C−H Bonds Could Talk: Selective

C−H Bond Oxidation. Angew. Chem., Int. Ed. 2011, 50, 3362−3374.

(63) Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C−H

Amination: Scope, Mechanism, and Applications. Chem. Rev. 2017,

117, 9247−9301.

Synthesis of 2-Deoxy-β-Glycosides. J. Org. Chem. 1998, 63, 2197−

2208.

(70) (a) Czernecki, S.; Vijayakumaran, K.; Ville, G. Convenient

Synthesis of Hex-1-enopyran-3-uloses: Selective Oxidation of Allylic

Alcohols Using Pyridinium Dichromate. J. Org. Chem. 1986, 51,

5472−5475. (b) Paulsen, H.; Bunsch, H. 1,4-Addition an Hex-1-

̈

enopyran-3-ulosen zu Oct-2-ulosonsauren. Chem. Ber. 1978, 111,

3484−3496.

(64) Examples of catalyst control of chemoselectivity in metal-

lanitrene/metalloradical reactions: Rhodium: (a) Hayes, C. J.; Beavis,

P. W.; Humphries, L. A. Rh(II)-Catalysed Room Temperature

Aziridination of Homoallyl-Carbamates. Chem. Commun. 2006,

4501−4502. (b) Zalatan, D. N.; Du Bois, J. A Chiral Rhodium

Carboxamidate Catalyst for Enantioselective C−H Amination. J. Am.

Chem. Soc. 2008, 130, 9220−9221. (c) Zhang, X.; Xu, H.; Zhao, C.

Mechanistic Investigation of Dirhodium-Catalyzed Intramolecular

Allylic C−H Amination versus Alkene Aziridination. J. Org. Chem.

2014, 79, 9799−9811. Cobalt: (d) Lu, H.; Jiang, H.; Hu, Y.; Wojtas,

L.; Zhang, X. P. Chemoselective Intramolecular Allylic C−H

Amination Versus CC Aziridination Through Co(II)-Based

Metalloradical Catalysis. Chem. Sci. 2011, 2, 2361−2366. Iron:

(e) Paradine, S. M.; White, M. C. Iron-Catalyzed Intramolecular

Allylic C−H Amination. J. Am. Chem. Soc. 2012, 134, 2036−2039.

(f) Hennessy, E. T.; Liu, R. Y.; Iovan, D. A.; Duncan, R. A.; Betley, T.

A. Iron-Mediated Intermolecular N-group Transfer Chemistry with

Olefinic Substrates. Chem. Sci. 2014, 5, 1526−1532. Silver:

(g) Alderson, J. M.; Corbin, J. R.; Schomaker, J. M. Tunable,

Chemo- and Site-Selective Nitrene Transfer Reactions through the

Rational Design of Silver(I) Catalysts. Acc. Chem. Res. 2017, 50,

2147−2158. Manganese: (h) Paradine, S. M.; Griffin, J. R.; Zhao, J.;

Petronico, A. L.; Miller, S. M.; White, M. C. A Manganese Catalyst for

Highly Reactive Yet Chemoselective Intramolecular C(sp³)−H

Amination. Nat. Chem. 2015, 7, 987−994. Iridium: (i) Hong, S.

Y.; Park, Y.; Hwang, Y.; Kim, Y. B.; Baik, M.-H.; Chang, S. Selective

Formation of γ-lactams via C−H Amidation Enabled by Tailored

Iridium Catalysts. Science 2018, 359, 1016−1021. (j) Conway, J. H.,

Jr.; Rovis, T. Regiodivergent Iridium(III)-Catalyzed Diamination of

Alkenyl Amides with Secondary Amines: Complementary Access to γ-

or δ-Lactams. J. Am. Chem. Soc. 2018, 140, 135−138.

(65) Saltzman, H.; Sharefkin, J. G. Iodosobenzene. In Organic

Syntheses; Baumgarten, H. E., Ed.; John Wiley & Sons: New York,

1973; Collect. Vol. 5, pp 658−659.

(66) (a) Murray, R. W.; Singh, M. Synthesis of Epoxides Using

Dimethyldioxirane: trans-Stilbene Oxide. In Organic Syntheses;

Freeman, J. P., Ed.; John Wiley & Sons: New York, 1998; Collect.

Vol. 9, p 288. (b) For a streamlined DMDO preparation, see also:

Taber, D. F.; DeMatteo, P. W.; Hassan, R. A. Simplified Preparation

of Dimethyldioxirane (DMDO). Org. Synth. 2013, 90, 350−357.

(67) We characterized [M − H]⁺ions in FAB HRMS analysis of

several products. Formation of [M − H]⁺ions has been noted in FAB

mass spectrometry of ether-containing compounds and of sugar

derivatives: (a) Baldwin, M. A.; Welham, K. J.; Toth, I.; Gibbons, W.

A. Hydride Abstraction in Fast Atom Bombardment. Org. Mass

Spectrom. 1988, 23, 697−699. (b) Zha, Q.; Bailey, M. D.; Bertrand,

M. J. The Observation of Predominant [M-H]⁺Ions in FAB Mass

Spectrometry of Derivatized Sugars. Can. J. Appl. Spectrosc. 1990, 35,

141−148.

(68) The diol was prepared from tri-O-acetyl-D-glucal via a Ferrier

rearrangement and de-acetylation as described in reference 15 and

analogous to the preparation of 22. Our experimental procedure for

this previously reported two-step process is included in the

Supporting Information. See additionally: Valverde, S.; García-

Ochoa, S.; Martín-Lomas, M. Alkylation and Acylation of Phenylthio

2,3-Dideoxyhex-2-enopyranosides at the Anomeric Centre by Polarity

Inversion. J. Chem. Soc., Chem. Commun. 1987, 383−384.

(69) For previous preparations of dihydropyranone 20b, see:

(a) Kirschning, A. Oxidation of Fully Protected Glycals by

Hypervalent Iodine Reagents. J. Org. Chem. 1995, 60, 1228−1232.

(b) Franck, R. W.; Marzabadi, C. H. Novel Bicyclic Donors for the

AA

DOI: 10.1021/acs.joc.8b00893

J. Org. Chem. XXXX, XXX, XXX−XXX

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Glycal Metallanitrenes for 2-Amino Sugar Synthesis: Amidoglycosylation of Gulal-, Allal-, Glucal-, and Galactal 3-Carbamates

DOI: 10.1021/acs.joc.8b00893

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