Synthesis and Structural Revision of Glyphaeaside C

and sporadic occurrences in various plants.

Letter

Synthesis and Structural Revision of Glyphaeaside C

Brendan J. Byatt,* Atsushi Kato, and Stephen G. Pyne*

Cite This: https://doi.org/10.1021/acs.orglett.1c01248

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sı Supporting Information

ABSTRACT: The iminosugar core of natural glyphaeaside C, originally assigned as a derivative of the piperidine natural product 1-

deoxynojirimycin (DNJ), has been revised as a derivative of 2,5-dideoxy-2,5-imino-L-mannitol (L-DMDP) by the total synthesis of its

enantiomer. This revised L-DMDP-derived conﬁguration is the ﬁrst of its kind to be observed in nature. The prepared iminosugars

displayed the nanomolar inhibition of bovine liver β-glucosidase and β-galactosidase.

he glyphaeaside alkaloids are a family of ten iminosugars

that were isolated from the roots of Glyphaea brevis that

The glyphaeasides were classiﬁed into types A, B, and C

according to the conﬁguration of their identiﬁed piperidine

iminosugar core. Glyphaeaside C, the only one of its type, was

assigned as either the 1-deoxynojirimycin (DNJ) derivative 1

have polyhydroxylated phenylalkyl side-chains unique among

the carbohydrate-like class of natural products (Figure 1). Such

C-alkylated iminosugars have been found sparingly in nature,

(

Figure 1) or its enantiomer by analyzing the 1D and 2D NMR

spectroscopic data, speciﬁcally referencing the large coupling

constants (J₂_,₃= J₃_,₄= 6.7 Hz and J₄_,₅= 7.5 Hz) and H2/H4

and H3/H5 ROESY correlations to characterize the two pairs

of 1,3-trans-diaxial protons in the six-membered ring. Although

the side-chain conﬁguration was not determined, the small

J₁_e_q_,₂_a_xcoupling constant (2.5 Hz) suggested a pseudoanomeric

α-conﬁguration at C1.

being largely limited to the broussonetine family of alkaloids

−5

While glyphaeaside C was the most potent inhibitor of

almond β-glucosidase and snail β-mannosidase out of the

isolated compounds, all glyphaeaside alkaloids displayed at

least some inhibition of both enzymes seemingly independent

of their core conﬁgurations. Additionally, glyphaeaside C

showed only a mild inhibition of rice α-glucosidase in contrast

to similar α-1-C-alkylated derivatives of DNJ, and the A-type

glyphaeasidesα-1-C-alkylated derivatives of 1-deoxyfucono-

jirimycin (DFJ)also lacked the substantial bovine kidney α-

L-fucosidase inhibition that is characteristic of similar DFJ

derivatives. These structure−activity relationships led to a

hypothesis that the side-chain functionalization of the

glyphaeasides is the primary determinant of their glycosidase

inhibition potency and speciﬁcity rather than their iminosugar

core conﬁguration.

Received: April 13, 2021

Figure 1. Proposed general structures of glyphaeaside C and related

iminosugars.

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

However, upon our analysis of the NMR spectroscopic data

of glyphaeaside C, it was noticed that the ring proton coupling

Scheme 1. (a) Retrosynthesis of syn-8′,9′-Diols 2a and 2b,

(b) Synthesis of Pyrrolidine Fragment 6a, and (c) Synthesis

of Oxazolidinones 11a and 11b

constants matched those of 2,5-dideoxy-2,5-imino-D-mannitol

(

D-DMDP, J₂_,₃= J₄_,₅= 7.7 Hz and J₃_,₄= 7.1 Hz) more closely

than those of DNJ (J₂= 8.5 Hz, J₃_,₄= 9.0 Hz, and J₄_,₅= 9.1

Hz). Furthermore, the C NMR data suggested that C2 (δ_C

6.0) was adjacent to the nitrogen, rather than C1 (δ 70.1).

These observations led us to hypothesize that glyphaeaside C

is in fact a D-DMDP derivative of general structure 2 (Figure

10,11

This alternative structure would also be consistent with

the observed ROESY correlations found between the ring

protons and might explain, at least in part, the unexpected

aﬃnity of glyphaeaside C toward almond β-glucosidase. A

comparison of the ¹³C NMR ring-carbon chemical shifts of

glyphaeaside C with those of other reported iminosugars that

were also measured in CD OD revealed a near-perfect

correlation with L-DMDP derivative 4 in contrast to DNJ

derivative 3 as an example (Table 1).

Table 1. Selected ¹³C NMR Spectroscopic Data of

Glyphaeaside C and Structurally Related Iminosugars in

CD OD

glyphaeaside C

5.3 (1)

0.4 (2)

2.8 (3)

9.5 (4)

9.5 (5)

8.6 (6)

70.1

66.0

75.1

76.7

64.8

58.6

69.7 (1′)

66.0 (5)

75.1 (4)

76.7 (3)

64.8 (2)

58.6 (CH OH)

Chemical shifts (CD OD) are reported in parts per million as per

their publication. Carbon atom associated with resonance.

To resolve the observed spectroscopic irregularities and the

uncertain side-chain conﬁguration of glyphaeaside C, a total

synthesis of general structure 2 was attempted. The natural

product was observed to have a negative speciﬁc rotation,

13,14

suggesting an L-conﬁguration.

However, considering that

almost all naturally occurring pyrrolidine iminosugars have a D-

conﬁguration, and synthetic L-DMDP showed diminished β-

glucosidase inhibition and elevated α-glucosidase inhibition

relative to those of the natural enantiomer, the D-DMDP

conﬁguration was pursued. The relative H NMR chemical

shifts of the benzylic methylene (H10′) protons of glyphaea-

side C (2) matched well with those of the 1,2-dihydroxy-3-(4-

hydroxyphenyl)propane moiety of syn-conﬁgured diolmycin

B2 and not well with those of the anti-conﬁgured diolmycin

B1, reducing the four possible stereoisomers of 2 down to two:

syn-8′,9′-diols 2a and 2b (Scheme 1a). We planned to utilize

complementary Sharpless asymmetric dihydroxylation (ADH)

reactions to access both syn-diols from the common precursor

potential lack of stereochemical control that is otherwise

aﬀorded by the chiral allylborane reagent.

Vinylpyrrolidine 9 was prepared from commercially available

2,3,5-tri-O-benzyl-β-D-arabinofuranose (8) in a 28% yield over

16,17

seven steps using reported procedures (Scheme 1b).

Subsequent epoxidation with m-CPBA aﬀorded epoxides 10a

and 10b in 57% and 29% yields, respectively. The desired

isomer 10a was formed as the major product, albeit only in a

moderate excess, and the two epoxides were easily separated by

column chromatographyan advantage over methods that

aﬀord inseparable mixtures of alcohol products from the

reaction of RM (R = allyl; M = ZnBr, MgBr) with related 2-

(

E)-5, which was in turn prepared via the cross metathesis

CM) of pyrrolidine 6a and O-protected allylphenol 7. We

decided to prepare 6a via an epoxide ring-opening approach

rather than a carbonyl addition approach, such as the Brown

allylation of a 2-pyrrolidinecarboxaldehyde derivative used in

18,19

pyrrolidinecarboxaldehydes.

Epoxide 10a was then sub-

Carriera’s synthesis of (+)-broussonetine H, to avoid the

jected to a ring-opening reaction using the Gilman reagent

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 2. Preparation and Isolation of the Four Diastereomers of General Structure 2

Measured using the H NMR integration of H10′. Yield relative to 6a. Measured using the HPLC trace of the 2a/2b reaction mixture prior to

the syn/anti-diol separation.

formed at −40 °C from CuBr·DMS and hept-6-en-1-

ylmagnesium bromide to aﬀord alcohol 6a in an 84% yield.

A small quantity of 6a was treated with NaH to aﬀord the

oxazolidinone 11a, and 1D NOESY analysis enabled the

veriﬁcation of the stereochemical conﬁguration at C1 through

an observed H1/H7a correlation (Scheme 1c). The reaction

of the minor epoxide 10b under the same conditions as those

of 10a (Scheme 1b) aﬀorded a mixture of 6b and the

corresponding oxazolidinone 11b, suggesting that the

associated alkoxide intermediate undergoes cyclization faster

than the (R)-epimer due to the formation of the more

favorable trans-1,7a-oxazolidinone ring. The 6b/11b mixture

was completely converted to 11b using NaH, and the C1

conﬁguration was similarly determined through an observed

H1/H7 1D NOESY correlation (Scheme 1c).

conversion of 6a and favored the formation of the more

thermodynamically stable (E)-5 alkene. The puriﬁcation of 5

necessitated open-air oxidation and an additional column

over silica gel to remove visible ruthenium impurities that have

been reported as, and were found to be, detrimental to the

subsequent OsO -catalyzed dihydroxylation of alkenes.

Separate ADH reactions of alkene mixture 5 with AD-mix-α

and AD-mix-β aﬀorded syn/anti-8′,9′-diol mixtures 13a/13a′

and 13b/13b′ in 87% (dr 4.8:1) and 90% (dr 3.4:1) yields,

respectively, with the syn/anti-diol ratios reﬂecting the (E/Z)-

composition of the starting material (Scheme 2). The 8′,9′-diol

conﬁgurations of 13a and 13b were assigned according to the

ADH “Sharpless mnemonic”, with the (4-(benzyloxy)phenyl)-

methyl C9′ moiety considered the “R ” substituent. Due to

the near-insolubility of the hydrophobic alkene substrate in the

With pyrrolidine 6a in hand, the complementary CM

standard 1:1 H O/t-BuOH solvent system, a ternary 2:2:1

component was prepared via the BBr -mediated O-demethy-

H O/t-BuOH/THF solvent system was used for these ADH

lation of commercially available 4-allylanisole (12), followed

reactions instead. The global deprotection of 13a/13a′ and

by the benzylation of the resulting allylphenol to aﬀord 7 in a

4% yield (Scheme 2). Although second-generation Grubbs

catalysts have seen frequent use in the CM reactions of

13b/13b′ under hydrogenolysis conditions (H /PdCl ) and

elution through a plug of RP-18 silica aﬀorded syn/anti-8′,9′-

diol mixtures 2a/2a′ and 2b/2b′, respectively. These diol

mixtures were then separated by semipreparative RP-HPLC,

aﬀording 2a and 2a′ from the ﬁrst mixture and 2b and 2b′

from the second. The aqueous component of the mobile phase

was buﬀered with TFA (pH 2.4) to replicate the conditions

,16,22

alkylated iminosugars,

their propensity to catalyze the

double-bond migration of allylbenzenes prompted the use of

Grubbs’ ﬁrst-generation catalyst. The reaction of 6a and

excess 7 in the presence of 10 mol % catalyst aﬀorded

inseparable mixtures of (E/Z)-5 in 66−76% yields and (E/Z)-

ratios of 3.4:1−4.8:1; longer reaction times increased the

used to isolate the natural product. Signals characteristic of

the TFA counterion were observed in the F NMR (δ =

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

The Supporting Information is available free of charge at

Letter

−

76.8 to −77.0 ppm) and negative-ion ESI-MS (m/z: 113,

and particularly those with the D-DMDP conﬁguration

((+)-broussonetine E, IC₅₀= 0.0020 μM). While not tested

49) spectra of all ﬁnal products, and as such their isolated

yields and all measurements dependent thereof were calculated

as TFA salts.

against this speciﬁc enzyme, natural glyphaeaside C displayed

only mild inhibition of Aspergiullus oryzae β-galactosidase (82%

at 1000 μM), providing further evidence of its L-DMDP-

conﬁguration. Regarding almond β-glucosidase inhibition, 2b

was also the strongest inhibitor, though it was 5.1× less potent

than natural glyphaeaside C (IC₅₀= 0.15 μM). The diﬀerence

between the synthesized compounds and the targeted natural

product is further exempliﬁed by their inhibition of snail β-

mannosidase, speciﬁcally that the synthesized compounds were

weaker by approximately an order of magnitude.

The H and ¹³C NMR spectroscopic data of 2a and 2b in

CD OD matched perfectly with those reported for natural

glyphaeaside C in the same solvent (Δδ = 0.00−0.01 ppm

and Δδ = 0.0−0.1 ppm). While the diastereoisomers 2a and

b were identical by RP-HPLC and NMR analysis in CD OD,

they were identiﬁed as diﬀerent diastereomers, each with a

high diastereomeric purity (>98%), from their NMR analysis

in C D N (see Figures S78 and S79). Thus, a re-examination

of NMR proﬁle of the natural product using C D N may be

In conclusion, a comparison of the NMR spectroscopic data

of glyphaeaside C with similar reported compounds led to the

determination that the originally proposed structure 1 was

incorrect and more likely a stereoisomer of general structure 2.

As part of a total synthesis investigation, the 5-C-hydroxyalkyl

moiety of 2 was accessed via the ring-opening of epoxide 10a, a

novel synthesis route that should ﬁnd future useful applications

in azasugar synthesis. The four 8′,9′-diol diastereomers of 2

were prepared utilizing the complementary ADH reactions of

(E/Z)-5 and the eventual separation by semipreparative HPLC

after global deprotection. The biological activity proﬁles of the

prepared compounds are relatively conserved with respect to

their side-chain conﬁgurations and consistent with similar D-

DMDP-derived alkaloids. However, they are notably diﬀerent

from the natural product, which is now believed to possess the

L-DMDP conﬁguration. A comparison of speciﬁc rotation data

suggests that natural glyphaeaside C is the enantiomer of 2a,

although further studies, such as a reisolation of the natural

product, are needed to unambiguously conﬁrm this assertion.

necessary to determine its absolute 8′,9′-diol conﬁguration.

All four ﬁnal products displayed positive speciﬁc rotations,

the ﬁrst indication that the natural product did, in fact, have a

L-arabinose conﬁguration. Although none of the speciﬁc

rotations perfectly matched the magnitude of the natural

product ([α] −0.8 (c 1.18, MeOH)), that of 2a ([α] +3.0

(

c 0.46, MeOH)) was much closer in magnitude than that of

b {[α] +19.9 (c 0.42, MeOH)}, which would posit that the

structure of natural glyphaeaside C is ent-2a. While some

naturally occurring L-arabino-iminosugars have been observed,

this revised structure would represent the ﬁrst example of an L-

DMDP derivative to be found in nature and is certainly

opposite to that found in the broussonetines (Figure 1, for

example).

The four ﬁnal products were tested against a panel of

glycosidases to ascertain their corresponding inhibitory eﬀects

(Table 2). In general, glycosidase inhibition was independent

Table 2. Concentrations of Glyphaeaside C Stereoisomers

Giving a 50% Inhibition of the Selected Glycosidases

ASSOCIATED CONTENT

sı Supporting Information

■

IC₅₀(μM)

https://pubs.acs.org/doi/10.1021/acs.orglett.1c01248.

enzyme

natural

2a′

2b′

α-glucosidase

rice

β-glucosidase

almond

bovine liver

human lysosome

β-galactosidase

bovine liver

A. oryzae

Experimental procedures and characterization data

13%

21.3%

5.7%

3.0%

4.2%

(PDF)

FAIR data, including the primary NMR FID ﬁles, for

compounds 2a, 2a′, 2b, 2b′, (E/Z)-5, 6a, 6b , 7, 9, 10a,

0.15

0.92

0.037

0.77

0.019

195

0.99

0.060

0.82

0.038

0b, 11a, 11b, 13a, 13a′, 13b, and 13b′ (ZIP)

0.031

0.020

0.043

0.019

AUTHOR INFORMATION

Corresponding Authors

■

82%

β-mannosidase

snail

Stephen G. Pyne − School of Chemistry and Molecular

Bioscience, University of Wollongong, Wollongong, New South

Wales 2522, Australia; orcid.org/0000-0003-0462-0277;

Email: spyne@uow.edu.au

4.5

See the Supporting Information for complete assay data. Inhibition

percet at 1000 μM. Inhibition percent at 100 μM. Not tested.

Brendan J. Byatt − School of Chemistry and Molecular

Bioscience, University of Wollongong, Wollongong, New South

Wales 2522, Australia; Email: bbyatt@uow.edu.au

of the side-chain conﬁguration; in cases where the IC₅₀was

determined (compounds that showed >50% inhibition at a 100

μM inhibitor concentration), the enzyme that experienced the

greatest variation of inhibition was human lysosomal β-

glucosidase, where the IC₅₀values of 2a (33 μM) and 2b

Author

Atsushi Kato − Department of Hospital Pharmacy, University

of Toyama, Toyama 2630, Japan; orcid.org/0000-0001-

(

195 μM) diﬀered by a factor of 5.9. Concerning mammalian

β-glucosidase activity, the compounds showed a far greater

inhibitory activity toward bovine liver, where 2b was the

strongest inhibitor (IC = 0.019 μM) and showed an increase

8022-196X

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c01248

in potency of four orders of magnitude compared to that of

human lysosomal. All compounds displayed the nanomolar

inhibition of bovine liver β-galactosidase (IC₅₀= 0.019−0.043

μM), a trait shared with many of the broussonetine alkaloids

Notes

The authors declare no competing ﬁnancial interest.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Moreno-Clavijo, E.; Robina, I.; Goti, A. Cycloadditions of Sugar-

Letter

ACKNOWLEDGMENTS

■

We thank the Australian Research Council (DP 130101968)

and the University of Wollongong for ﬁnancially supporting

this project.

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