Tetrahedron Letters 55 (2014) 7222–7225

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Tetrahedron Letters

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A D-ribose-derived a-amino nitrile as a versatile intermediate for thecollective synthesis of piperidine-type iminosugar C-glycosides

http://dx.doi.org/10.1016/j.tetlet.2014.11.0240040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding authors.E-mail addresses: xiang-guo.hu@unsw.edu.au (X.-G. Hu), l.hunter@unsw.edu.au

(L. Hunter).

N

OHOH

HO

HO

1 (marketed drug):Gaucher's disease

N

OHOH

HO

HO

2 (marketed drug):Type II diabetes

3 (Phase II)hepatitis C

HN

OHOH

HO

NH

O

N

5: K i=0.469 pm against α-fucosidase

HN

OHOH

HO

7

4: K i=2.2 nm against glucocerebrosidase

N

OHHO

4

H

OH

Figure 1. Examples of N- and C-alkylated iminosugars.

Xiang-Guo Hu ⇑, A. Daryl Ariawan, Luke Hunter ⇑School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia

a r t i c l e i n f o

Article history:Received 12 August 2014Revised 28 October 2014Accepted 6 November 2014Available online 13 November 2014

Keywords:IminosugarIminocyclitolPolyhydroxylated alkaloidIminium saltAminonitrileRing-closing metathesis

a b s t r a c t

Iminosugar C-glycosides are valuable entities in medicinal chemistry. Herein we disclose a collective syn-thesis approach to such compounds, in a route that features a remarkably stable, fully characterised,ribose-derived iminium salt as a key intermediate. Addition of organometallic reagents to this key inter-mediate delivers a variety of iminosugar C-glycoside products in high yields and with excellentstereocontrol.

� 2014 Elsevier Ltd. All rights reserved.

:

H

OH

OEt

Iminosugars (e.g., 1–5, Fig. 1) are sugar mimics in which anitrogen replaces the ring oxygen of the corresponding monosac-charide.1 Because of their structural resemblance to the terminalsugar moiety of natural substrates, or to the activated intermediateof hydrolysis (i.e., the oxocarbenium ion), many iminosugars exhi-bit diverse glycosidase inhibitory activities.2 Hence, as a class theyhold significant potential for the treatment of diseases includingcancer, viral infection and diabetes.1

N-Alkylated piperidine derivatives (e.g., 1–3)3 are an importantsubset of medicinal iminosugars. Often the superior biologicalactivity of N-alkylated analogues relative to the parent iminosug-ars can be partly ascribed to their higher lipophilicity.1 Shiftingthe alkyl chain from the endocyclic nitrogen to the pseudoanomer-ic C1 position leads to piperidine-type iminosugar C-glycosides(e.g., 3–5).4 Such structures can retain the advantages ofN-alkylated analogues while bringing another benefit, that is, lock-ing a favourable conformation of the piperidine ring for achievingbetter ligand–enzyme interactions.5 In support of this notion,many synthetic iminosugar C-glycosides show promising biologi-cal activity. For example, compound 3 entered phase II clinicaltrials as an antiviral agent for the treatment of hepatitis C;6

compound 4 is a powerful pharmacological chaperone agent;7

and the fuconojirimycin derivative 5 is a sub-picomolar inhibitorof a-fucosidase.8

N-Alkylated iminosugars can be readily accessed via reductiveamination, but the synthesis of iminosugar C-glycosides posesgreater challenges.4,9 Iminosugar C-glycosides could potentiallybe synthesised by forging the C1AN or C5AN bonds throughreductive amination or nucleophilic substitution approaches, butthese methods would not be suitable for the rapid production ofdiverse libraries. Instead, a collective generation10 of iminosugar

NX

POOP

OP

R

N N

O

NO

N N CN

10 11

7 8 9

6

previouswork

this work

Scheme 1. Strategies for the synthesis of iminosugar C-glycosides 6.

X.-G. Hu et al. / Tetrahedron Letters 55 (2014) 7222–7225 7223

C-glycosides, based on an advanced intermediate such as an elec-trophilic cyclic imine derivative, is highly desirable (Scheme 1).Many groups have contributed to this area, employing as the keyintermediates imines 7,11–14 acyl iminium salts 815,16 or nitrones9.17 However, limitations still exist. Alkylation of imines 7 oftenproceeds in low yield due to inherent low reactivity of these neu-tral molecules;11b and conversely the instability of acyl iminiumsalts 8 and nitrones 9 has hampered their wider application. Forinstance, although nitrones 9 have been well documented asversatile intermediates in the synthesis of pyrrolidine-typeiminosugar C-glycosides,18 reports of their use in the synthesis ofpiperidine-type iminosugar C-glycosides are rare due to thepropensity of six-membered ring nitrones to dimerise or otherwisedecompose.17a,d,f

Another way to enhance the reactivity of imines is to convertthem into alkyl iminium salts (e.g., 10, Scheme 1),19 but such astrategy has not previously been documented in the context ofpiperidine iminosugar C-glycoside synthesis.20 We resolved toinvestigate this strategy, and we further envisaged that the alkyliminium salt 10 could in turn be obtained from a ribose-deriveda-amino nitrile 11. Amino nitriles are well known as precursorsof amino acids, but lesser known as stable iminium ion equiva-lents.21 The latter reactivity has been successfully harnessed byHusson in the so-called CN(R,S) strategy,22 but it is challenging toextend this methodology to iminosugar targets due to a lack of reg-ioselectivity in iminium formation and possible elimination sidereactions.23 Herein, we disclose the first example of a polyhydroxy-lated alkyl iminium salt for the collective synthesis of piperidine-type iminosugar C-glycosides.24 The allyl group was chosen asthe N-substituent in this work, as it can be easily removed ifdesired, or else subsequently functionalised to create further struc-tural diversity.

The first task was to procure the required a-amino nitrile(Scheme 2). This was achieved in three steps, starting from thecommercially available ribose derivative 12, in a sequence requir-ing only one chromatographic purification. Thus, selective tosyla-tion of 12 delivered compound 13,25 which underwentcyclisation with allylamine to afford the a-amino nitrile 14 in highyield after recrystallisation.26 Finally, silyl protection gave thedesired compound 15.27

OH

OO

OHOOH

OO

OTsO

12 13

75% 84%

(a) (b)

Scheme 2. Synthesis of a-amino nitrile 15. Reagents and conditions: (a) TsCl, pyridine, –78 �C to rt.

With the requisite precursor 15 in hand, the next task was toinvestigate its conversion into the corresponding alkyl iminiumsalt 16. Various Lewis acids were screened for their ability to effectthis transformation, and in each case, the process was continuouslymonitored by 1H NMR spectroscopy in CD2Cl2 at room temperature(see the Supporting information). Gratifyingly, both silver tetra-fluoroborate28 and silver trifluoromethanesulfonate were foundto generate quantitatively the desired iminium salt 16 from 15within one minute (Fig. 2). Other solvents were briefly investi-gated: it was found that the iminium salt 16 could also be gener-ated efficiently in chloroform and methanol, but not in acetonitrile.

At the outset of these studies, we recognised that the stabilityand reactivity of the iminium salt 16 would be pivotal to the suc-cess of the synthetic strategy. NMR studies revealed that 16 wassurprisingly stable: for example, it can be stored in CD2Cl2 solutionat 4 �C for three days without detectable decomposition; and it alsoappears to be unaffected when five molar equivalents of water areadded to the system. The stability of the iminium salt 16 thusallowed it to be fully characterised, providing the first reportedspectral data of such a complex polyhydroxylated iminium salt.

Attention was next turned to investigating the reactivity ofiminium salt 16 towards a variety of nucleophiles (Table 1).29 Inmarked contrast with its aforementioned stability, 16 was foundto exhibit high reactivity. For example, it reacted completely withmethylmagnesium iodide at low temperature within five minutes(Table 1, entries 1 and 2). This reaction delivered the desired imi-nosugar C-glycoside 17a as the sole product. The stereochemistryof 17a was unambiguously established by the observance of strongNOE correlations between H2 and H6a, as well as H2 and themethyl of the acetonide, indicating that the incoming nucleophilehad approached trans to the adjacent ring substituent.30 High ste-reocontrol was maintained even when the reaction was repeated atambient temperature (entry 3), and so for reasons of operationalsimplicity and environmental benefit, ambient temperature wasemployed for all subsequent reactions. A variety of Grignardreagents were successfully utilised (entries 4–9); the desired imi-nosugar C-glycosides 17b–g were formed in good yields and as asingle stereoisomer in each case, and in most instances, the prod-uct was obtained in analytically pure form without any need forchromatographic purification. Finally, phenyllithium and n-butyl-lithium were also investigated (entries 10 and 11), but none ofthe expected products were obtained in these cases.

The final goal of this study was to investigate deprotection and/orderivatisation of the N-allyl group. Deallylation of 17a was success-fully achieved under mild conditions by treatment with apalladium(0) catalyst (Scheme 3), and subsequent TBS/acetonidedeprotection then furnished the iminosugar C-glycoside 18.31 Com-pound 18 is a close structural analogue of the medicinally importantiminosugar, 5-methyl-1-deoxygalactonojirimycin (the iminosugarcore of 3),32 and in this work the potentially valuable analogue 18is obtained in six steps and 33% overall yield from commercial mate-rials. To further extend the utility of this strategy, some alternativemanipulations of the N-allyl group were investigated. Compound17e was cyclised by ring-closing metathesis to yield indolizidine19 (Scheme 3), which is a close structural analogue of intermediates

N

OHOO

CN N

OTBSOO

CN

14 15

76%

(c)

78 �C to rt; (b) allylamine, KCN, AcOH, MeOH, rt; (c) TBSOTf, 2,6-lutidine, CH2Cl2, –

3.03.54.04.55.05.56.06.57.07.58.08.5 ppm

3.77

33.

784

4.45

54.

466

4.47

94.

491

4.56

14.

564

4.56

94.

574

4.62

94.

640

4.65

34.

657

4.66

44.

668

4.67

54.

679

5.20

25.

210

5.35

75.

359

5.36

05.

701

5.73

05.

736

5.75

35.

937

5.94

95.

954

5.96

05.

965

5.97

75.

994

8.31

8

2.05

1.11

1.05

2.09

1.02

1.49

2.09

0.97

1.00

160 140 120 100 80 60 40 20 ppm

-5.3

4-5

.17

17.8

524

.84

25.4

026

.98

52.2

7

63.4

864

.95

72.1

272

.79

112.

44

125.

8812

7.65

172.

14N

OTBSOO

16

BF4

N

OTBSOO

16

BF4

Figure 2. Expansions from the 1H NMR (600 MHz) and 13C{1H} NMR (151 MHz) spectra of iminium salt 16 in CD2Cl2.

Table 1Synthesis of iminosugar C-glycosides

Entry Conditions AR Product (isolated yield)

1 CH3MgI, CH2Cl2, –78 �C ACH3 17a (quant.a)2 CH3MgI, CH2Cl2, 0 �C ACH3 17a (quant.a)3 CH3MgI, CH2Cl2, rt ACH3 17a (98%)

4 CH3(CH2)2CH2MgI, CH2Cl2, rt 17b (100%)

5 CH3(CH7)2CH2MgBr, CH2Cl2, rt 17c (81%)

6 PhMgBr, CH2Cl2, rt 17d (60%)

7 CH2CHMgBr, CH2Cl2, rt 17e (67%)

8 CH2CHCH2MgCl, CH2Cl2, rt 17f (72%)

9 PhCCMgBr, CH2Cl2, rt 17g (63%)

10 PhLi, rt 17d (0%)

11 CH3(CH2)2CH2Li, rt 17b (0%)

a Quantitative conversion by TLC analysis.

7224 X.-G. Hu et al. / Tetrahedron Letters 55 (2014) 7222–7225

used in the synthesis of the medicinal iminosugars, swainsonine33

and castanospermine.34 By analogy with this, the correspondingquinolizidine 20 could be obtained in a similar manner from 17f

(Scheme 3). In these sequences the N-allyl group can be viewed asa traceless protecting group, because it becomes incorporatedwithin the bicyclic target molecules.

N

OTBSOO

17a

(a) Pd(PPh3)4NDMBA, CH2Cl2

(b) 3 M HCl

75%

H.HClN

OHHOOH

18

N

OTBSOO

n=0: 17e

Grubbs IITi(OiPr)4, CH2Cl2

63−71%

N

OTBSOO

n=0: 19

n

n=1: 17f

n

n=1: 20

Scheme 3. Deprotection or further manipulations of the N-allyl group.NDMBA = N,N0-dimethylbarbituric acid.

X.-G. Hu et al. / Tetrahedron Letters 55 (2014) 7222–7225 7225

In conclusion, an efficient and highly stereoselective collectivesynthesis of iminosugar C-glycosides has been developed. Aribose-derived a-amino nitrile precursor 15 is rapidly convertedinto a remarkably stable polyhydroxylated iminium salt 16, whichin turn is readily functionalised by a variety of Grignard reagents tofurnish iminosugar C-glycosides (17a–g) in high yields. An allylmoiety was employed for N-protection throughout the sequence,and this N-allyl group was shown to be easily removable ifrequired, while also providing an option for further structuraldiversification through ring-closing metathesis. Application of thissynthetic strategy to other sugar precursors, and investigation ofthe glycosidase inhibition profile of the diverse iminosugars thusobtained, will be reported in due course.

Acknowledgements

X.G.H. acknowledges financial support from UNSW Australia(Science Faculty Research Grant). L.H. acknowledges support fromthe Australian Research Council (Discovery Early Career ResearcherAward).

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2014.11.024.

References and notes

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