General method for the synthesis of α- Or β-deoxyaminoglycosides bearing basic nitrogen

Kevin M. Hoang, Nicholas R. Lees, and Seth B. Herzon*

Article

General Method for the Synthesis of α- or β‑Deoxyaminoglycosides

Bearing Basic Nitrogen

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ABSTRACT: The introduction of glycosides bearing basic nitrogen is

challenging using conventional Lewis acid-promoted pathways owing

to competitive coordination of the amine to the Lewis acid promoter.

Additionally, because many aminoglycosides lack a C2 substituent,

diastereomeric mixtures of O-glycosides are often produced. Herein,

we present a method for the synthesis of α- or β- 2,3,6-trideoxy-3-

amino- and 2,4,6-trideoxy-4-amino O-glycosides from a common

precursor. Our strategy proceeds by the reductive lithiation of thiophenyl glycoside donors and trapping of the resulting anomeric

anions with 2-methyltetrahydropyranyl peroxides. We apply this strategy to the synthesis of α- and β-forosamine, pyrrolosamine,

acosamine, and ristosamine derivatives using primary and secondary peroxides as electrophiles. α-Linked products are obtained in

0−96% yield and with >50:1 selectivity. β-Linked products are obtained in 45−94% yield and with 1.7−>50:1 stereoselectivity.

Contrary to donors bearing an equatorial amine substituent, donors bearing an axial amine substituent favored β-products at low

temperatures. This work establishes a general strategy to synthesize O-glycosides bearing a basic nitrogen.

INTRODUCTION

■

Aminosugars bearing a basic nitrogen are found in

approximately 40% of glycosylated bacterial secondary

metabolites. In many instances, the aminoglycoside is

essential for biological activity. The vast majority of these

carbohydrates lack a C2 substituent, which makes stereo-

controlled glycosylations challenging, and the preparative-

scale separation of diastereomeric glycosylation products is

often not possible by ﬂash-column chromatography. Addition-

ally, competitive coordination of a basic amine to a Lewis acid

promoter renders many glycosylation reactions ineﬃcient. For

example, the β-glycoside 1 was prepared from the correspond-

ing α-glycosyl phosphinate with 2:3 α-to-β selectivity (57%

combined yield) using boron triﬂuoride diethyl etherate as

promoter (Figure 1a). The macrolide spinosyn A (2) was

obtained as a 3:2 mixture of α and β diastereomers (17%

combined yield) by a Koenigs−Knorr coupling. By strategic

use of a C2-directing group, the methymycin macrolactone

Figure 1. (a) Selected examples of O-glycosides containing basic

nitrogen. Yields and stereoselectivities in the glycosylation step are

shown. (b) Aminosugars bearing basic nitrogen are diﬃcult to install

via Lewis acid-mediated glycosylation reactions, but are stable toward

acidic hydrolysis. Introduction of an electron-withdrawing group

precursor 3 was obtained with high β-selectivity, but the yield

remained modest (43%). Glycosylation reactions employing

softer Lewis acids (e.g., gold) or electron-deﬁcient amino-

sugars (e.g., such as azide, carbamate, and sulfonamide

derivatives) have been employed to circumvent or decrease

(

EWG) facilitates Lewis acid-promoted glycosylation pathways, but

renders the products acid-labile.

the basicity of the amine substituent, but these strategies do

not provide a general approach to stereocontrol in the 2-deoxy

series. Finally, while glycosides bearing a basic nitrogen are

stable toward acidic hydrolysis owing to preferential N-

protonation, protection of the amine with electron-with-

drawing groups renders the glycosides acid-labile and prone

Received: October 26, 2020

Published: February 8, 2021

to anomerization (Figure 1b).

2021 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 2777−2783

777

Journal of the American Chemical Society

Supporting Information ).

Article

We recently reported a synthesis of 2-deoxyglycosides

wherein the conventional polarity of the donor and acceptor

is reversed. In this approach, reductive lithiation of thiophenyl

cient. The extent to which an amine might inﬂuence the rates

of epimerization was also not apparent.

glycosides 4 using lithium 4,4′-di-tert-butylbiphenylide

RESULTS AND DISCUSSION

■

(

LiDBB) forms the axial (α) anion 5α as the kinetic product

We recognized that the highly deoxygenated thiophenyl

glycoside 11α (Table 1), a precursor to forosamine (2,3,4,6-

tetradeoxy-4-dimethylamino-erythro-hexopyranose) derivatives,

represented a singularly challenging substrate for study. Both

α- and β-linked forosamine are found in natural products (for

Scheme 1a).

Addition of an alkyl (2-methyl)-

Scheme 1. Anomeric Anion Approach to Glycosides and

Aminoglycosides

example, the griseusin naphthoquinones, the spinosyn and

spiramycin macrolides, and the forazoline polyketides ), and

historically, the synthesis and stereocontrolled introduc-

,20

tion

of forosamine has been challenging. We developed a

synthesis of 11α from 3-deoxy-4,6-di-O-acetyl D-galactal that

proceeds in eight steps and 19% overall yield (see the

We found that reductive lithiation of 11α at −78 °C,

followed by addition of the MTHP monoperoxy acetal 12,

furnished the α-linked disaccharide 13α in 80% yield and

50:1 α-to-β selectivity (as determined by H NMR analysis of

the unpuriﬁed product mixture) using the conditions we

previously established (Table 1, entry 1). To our knowledge,

this constitutes the ﬁrst stereoselective synthesis of an α-forosyl

glycoside. Unfortunately, however, application of our prior

conditions to the synthesis of β-forosamine yielded no

observable β-disaccharide (entry 2). Considering the lower

inductive stabilization of the anion derived from 11α relative

to the mono- and dideoxyglycosides employed in our previous

study, we hypothesized that proton transfer from solvent was

competitive with isomerization. Upon decreasing the

equilibration time to 30 min, the β-disaccharide 13β was

produced with 1:2.5 β-to-α selectivity (46% combined yield,

entry 3). Conducting the equilibration at −30 °C for 60 min

increased the yield of product to 56%, but eroded the

selectivity (1:3.2 β-to-α, entry 4). Although changing the

solvent to exclusively tetrahydrofuran improved the selectivity,

the α-disaccharide 13α still predominated (73%, 1:1.5 β-to-α,

entry 5). Attempts to improve the selectivity by introducing

salt additives, or using other solvent systems, were unsuccessful

(

a) Reductive lithiation of thiophenyl glycosides 4 forms the axial

(α) anion 5α. Warming to −20 °C promotes equilibration to the

equatorial (β) anion 5β. The addition of alkyl MTHP peroxides 6 to

either anion provides the α- or β-linked products 7α and 7β,

respectively. (b) The stereoselectivity in the reductive lithiation of

amine-substituted thiophenyl glycosides 8 and their rates of

interconversion were unknown. Addition of 6 to either 9α or 9β

would provide the α- or β-aminoglycosides 10α or 10β, respectively.

(

entries 6−9). However, increasing the equilibration time to

tetrahydropyranyl (MTHP) peroxide 6 results in formal

alkoxenium ion transfer to provide the α-linked glycosides 7α.

An essential component of this approach is utilization of the

90 min provided the β-disaccharide 13β with 1:1 β-to-α

selectivity (46% combined yield; entry 10). On further

extending the equilibration time to 150 min, the β-disaccharide

13β was obtained with 3:1 β-to-α selectivity, although in only

10% yield (entry 11). These results support the notion that

proton abstraction from solvent by the more reactive α-anion

is competitive with isomerization. Consistent with this, 13β

was obtained with 4.7:1 β-to-α selectivity and in 46%

,10a,c,d

thermodynamically favored equilibration

of the axial (α)

anion to the more stable equatorial (β) anion 5β. Thus,

warming the α anion to −20 °C, followed by re-cooling to −78

C and peroxide addition, forms the β-linked products 7β.

Given the well-known compatibility of basic amines with

organolithium reagents, we reasoned that this method might

provide an entry to 2-deoxyaminoglycosides (Scheme 1b). In

particular, we sought to synthesize 4-amino-2,4,6-trideoxy and

-amino-2,3,6-trideoxy pyranoses, which are important classes

of carbohydrates present in anticancer drugs and natural

products such as the saccharomicins, doxorubicin, and

combined yield when THF-d was employed as solvent

(entry 12).

23,24

Alternatively, the β-disaccharide 13β was

formed with 5.3:1 β-to-α selectivity (69% combined yield)

when 10 equiv of the donor 11α was employed (entry 13).

These results constitute the most β-selective glycosylations

using a forosamine-derived donor to date. The best prior

example of which we are aware was reported in 2016 by Dai

and co-workers and proceeded in 71% yield and with 1:1 β-to-

α selectivity (2:1 ratio of donor and acceptor). Additionally,

these experiments underscore the higher basicity of the

tetradeoxygenated anomeric anions. More electron-deﬁcient

derivatives transformed with greater eﬃciency, as anticipated

(vide infra).

,14

daunomycin.

However, the incorporation of basic nitrogen

into the donors raises several interesting, but potentially

complicating, issues. While the reductive lithiation of all

oxygen-substituted thiophenyl glycosides reliably forms the

axial (α) anion as the kinetic product, we anticipated that the

amine might alter the preferred conformation of the anomeric

radical intermediate. In addition, formation of a stable chelate

might decrease the nucleophilicity of the organolithium

intermediate, rendering the C−O bond-forming step ineﬃ-

We then synthesized a series of 2,3,6-trideoxy-3-amino-

thioglycoside and 2,4,6-trideoxy-4-aminothioglycoside pronu-

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J. Am. Chem. Soc. 2021, 143, 2777−2783

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Table 1. Optimization of α- and β-Glycoside Synthesis Using the Forosamine Derivative 11α

entry

equiv 11α

solvent

T (°C)

t (min)

yield of 13 (%)

selectivity

1.5

2.0

10.0

THF−pentane

THF

>50:1 α:β

n.d.

−20

−30

−20

−30

1:2.5 β:α

1:3.2 β:α

1:1.5 β:α

1:4 β:α

1:10.8 β:α

1:3.9 β:α

1.8:1 β:α

1:1 β:α

THF

Et O

2-methyl-THF

THP

THF

THF-d₈

THF

150

3:1 β:α

4.7:1 β:α

5.3:1 β:α

−30

Temperature of α-to-β equilibration. Time of α-to-β equilibration. Combined yield of both diastereomers as determined by H NMR analysis

using 1,3,5-trimethoxybenzene as an internal standard, unless otherwise noted. Isolated yields following puriﬁcation by ﬂash-column

chromatography. n.d. = not detected. LiCl (5.0 equiv) was added prior to the reductive lithiation. The reductive lithiation and the reaction

temperature were conducted at −30 °C. THP = tetrahydropyran. The reductive lithiation was conducted using a solution of LiDBB in THF. Use

of LiDBB in THP led to recovery of starting material.

Table 2. Synthesis of α-Aminoglycosides^a^,^b

Stereoselectivities determined by H NMR analysis of the unpuriﬁed product mixtures. Isolated yields following puriﬁcation.

cleophiles present in natural products, including pyrrolos-

amine, acosamine, and ristosamine derivatives, and evaluated

their reactivities in this anionic glycosylation method.

Cognizant that there may be variability in the α-to-β

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equilibration, we ﬁrst evaluated the syntheses of α-amino-

glycosides. Overall, this approach to α-2,6-dideoxyaminoglyco-

sides proved general (Table 2). For example, reductive

lithiation of the pyrrolosamine derivative 14α, followed by

addition of the MTHP monoperoxy acetal 12, provided the α-

linked disaccharide 20α in 93% yield and with >50:1 α-to-β

selectivity. Alternatively, addition of the secondary MTHP

electrophile 19α to the α-anion derived from 14α furnished

the disaccharide 25α in 88% yield and with >50:1 α-to-β

selectivity. Coupling of the acosamine derivatives 16β−18α

with the MTHP electrophile 12 provided the α-disaccharides

Consistent with this, the β-linked disaccharide 20β was

obtained in 64% yield and with >50:1 β-to-α selectivity by

reductive lithiation of the pyrrolosamine derivative 14α,

equilibration (−20 °C, 1 h), and addition of the electrophile

12 (Table 3). Lithiation and thermal equilibration of the

acosamine derivative 16β in a 1:1 tetrahydrofuran−pentane

mixture, followed by the addition of 12, provided the

disaccharide 21β in 83% yield and with 3:1 β-to-α selectivity

(not shown). This result suggests that the position of the

amine (C4 for pyrrolosamine and C3 for acosamine)

inﬂuences the rate of equilibration.

21α−23α in 79−96% yield and with >50:1 selectivity for the

Consistent with previous studies,

higher rates of

α-anomer. These pronucleophiles also reacted eﬃciently with

the secondary MTHP electrophile 19α to furnish the α-

disaccharides 26α−28α in 78−92% yield and with >50:1 α-to-

β selectivities. Finally, we turned our attention to the

secondary amide 15α, which bears an acidic proton. Sequential

deprotonation (methyllithium, −78 °C), addition of LiDBB,

and introduction of either MTHP electrophile 12 or 19α

provided the α-disaccharides 24α and 29α in 60% and 80%

yields, respectively, and with >50:1 α-to-β selectivity in both

instances.

equilibration were observed when tetrahydrofuran was used

exclusively as solvent, and the disaccharide 21β was obtained

in 80% yield and with 16:1 β-to-α selectivity using the same

equilibration temperature and time. Alternatively, the dis-

accharide 26β was obtained in 45% yield and >50:1 β-to-α

selectivity following addition of the secondary electrophile

19α. The methoxymethyl ether derivative 17α was trans-

formed to the disaccharide 22β in 52% yield and with >50:1 β-

to-α selectivity. When subjecting the amide 15α to

deprotonation (methyllithium, −78 °C), reductive lithiation,

thermal equilibration, and addition of the MTHP electrophile

12, the β-disaccharide 24β was obtained in 56% yield and with

We then set out to develop a β-selective glycosylation

(

Table 3). The α- and β-diastereomers reported herein are

.6:1 β-to-α selectivity.

Unexpectedly, the L-ristosamine derivative 30β, which

Table 3. Synthesis of β-Aminoglycosides^a^,^b

contains an axial amine substituent, provided the β-

disaccharide 35β as the major product (87%, 2.8:1 β-to-α)

under nominally kinetic conditions (Table 4, entry 1). The

stereochemistry of 35β was conﬁrmed by observation of an

NOE correlation between H1 and H5. No signiﬁcant change in

diastereoselectivity was observed when the anion generated

from 30β was aged at −78 °C for 30 min prior to the addition

of the electrophile 12 or when the reductive lithiation was

carried out at warmer (−60 °C) or cooler (−100 °C)

temperatures (see Table S1 ). These data suggest that a mixture

of conﬁgurationally stable α- and β-anions are formed from

0β at −78 °C. One possible explanation for this is that the

axial amine in 30β renders the energies of the two anomeric

radical chair conformers, with the SOMO in an axial

orientation, comparable to one another (see 34α and 34β).

To test this, we synthesized the L-ristosamine derivative 30α,

which adopts the C conformation (conﬁrmed by nuclear

Overhauser eﬀect correlation between the C1 and C6

protons). Reductive lithiation of 30α at −78 °C, followed by

addition of the MTHP electrophile 12, provided the

disaccharide 35β in 83% yield and with 9:1 β-to-α selectivity

(

entry 2). These data suggest that the β, axial-conformer of the

radical derived from 30β and 30α is lower in energy than the

respective α, axial-conformer, but that some isomerization

between the two is occurring prior to anion formation.

Stereoselectivities determined by H NMR analysis of the unpuriﬁed

product mixtures. Combined yields of both diastereomers following

puriﬁcation.

On the basis of these observations, we synthesized the

ristosamine derivatives 31β−33β. We reasoned that the

products derived from 31β and 32β should show an increased

preference for the α-disaccharides, as the respective radicals

should favor the α, axial-conformer 34α due to the increased

steric bulk on the C4 oxygen. Consistent with this hypothesis,

reductive lithiation of 31β and trapping with the peroxide 12

provided the disaccharide 36β in 93% yield and with 1.7:1 β-

to-α selectivity. Although we expected the glycosylation with

32β to show an even further enhancement of α-selectivity due

to the bulky silyl protecting group, the product 37β was

formed with only marginally greater selectivity (2.0:1 β-to-α,

readily distinguished by H NMR spectroscopy. The anomeric

proton of the α-diastereomers is generally observed as a

doublet (J = 3.2−5.7 Hz) in the δ 4.75−5.59 ppm range. By

comparison, the anomeric proton of the β diastereomers is

generally observed as a doublet of doublets (J = 7.9−9.8, 2.0−

.4 Hz) in the δ 4.47−4.72 ppm range.

We anticipated that trideoxygenated donors would react

more eﬃciently than the forosamine donor 11α due to the

inductive stabilization deriving from the oxygen substituents.

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J. Am. Chem. Soc. 2021, 143, 2777−2783

Journal of the American Chemical Society

https://pubs.acs.org/10.1021/jacs.0c11262

Article

Table 4. Glycosylations Using the Ristosamine Derivatives 30α −33β

entry

R′

product

yield (%)

selectivity

30β

30α

31β

32β

33β

CH₃

TBS

CH₃

35β

36β

37β

2.8:1 β:α

9.1:1 β:α

1.7:1 β:α

2.0:1 β:α

6.4:1 β:α

38β

Stereoselectivities determined by H NMR analysis of the unpuriﬁed product mixtures. Combined yields of both diastereomers following

puriﬁcation.

4%). However, this observation may be due to solvent

Authors

eﬀects. Finally, we synthesized ristosamine derivative 33β,

with the expectation that the radical derived from 33β would

favor adopting the β, axial-conformation 34β, and thus, the

product derived from 33β should show an increased β-

preference. In line with our expectations, the glycosylation with

Kevin M. Hoang − Department of Chemistry, Yale University,

New Haven, Connecticut 06520, United States; orcid.org/

0000-0001-7180-7547

Nicholas R. Lees − Department of Chemistry, Yale University,

New Haven, Connecticut 06520, United States

3β yielded 38β in 86% yield and 6.4:1 β-to-α selectivity.

Complete contact information is available at:

These data suggest that by manipulating the conformation of

the thioglycoside pronucleophiles, β-selective glycosylation

reactions can be favored at −78 °C (e.g., without thermal

equilibration), a ﬁnding that has important implications for the

synthesis of oligosaccharides.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

CONCLUSION

■

Financial support from the National Institutes of Health (R35-

GM131913), the National Science Foundation (Graduate

Research Fellowship to K.M.H.), and Yale University is

gratefully acknowledged. We thank Dr. Fabian Menges for

HRMS analysis.

In conclusion, we have developed a synthesis of deoxyamino-

glycosides bearing basic amine residues. Both α- and β-

aminoglycosides are accessible in 45−96% yield. α-Linked

products are formed with >50:1 selectivity. While the

selectivities for β-linked products are variable, many products

are attainable with synthetically useful levels of selectivity. In

the course of these studies, we discovered that the

conformations of thioglycoside pronucleophiles can be utilized

to control the kinetic selectivity in the anion generation step,

which has important implications for the synthesis of

oligosaccharides. These ﬁndings constitute the ﬁrst general

strategy to synthesize α- or β-glycosides bearing a basic

nitrogen.

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AUTHOR INFORMATION

Corresponding Author

Seth B. Herzon − Department of Chemistry, Yale University,

New Haven, Connecticut 06520, United States; Department

of Pharmacology, Yale School of Medicine, New Haven,

Connecticut 06520, United States; orcid.org/0000-0001-

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