Intramolecular epoxide ring opening cyclisation reactions involving guanidines

Article abstract of DOI:10.1016/j.tet.2016.12.065

The cyclisation of N-allyl- and N-homoallylguanidines using DMDO leading to the formation of novel 5- and 6-membered guanidine heterocycles is reported. Several of the products formed displayed weak inhibition of glycosidase enzymes.

Full text of DOI:10.1016/j.tet.2016.12.065

Accepted Manuscript
Intramolecular epoxide ring opening cyclisation reactions involving guanidines
Zainab Al Shuhaib, Marcel Arndt, Mark Dennis, Daniel M. Evans, Iestyn Jones, Vera
Leitmann, Patrick J. Murphy, Dion Roberts, Richard Rowles, Yones K. Sadaghiani,
Andrew J. Thornhill, Robert J. Nash, Jackie Hollinshead, Barbara Bartholomew,
Graham J. Tizzard, Simon J. Coles
PII:
S0040-4020(16)31362-X
10.1016/j.tet.2016.12.065
TET 28357
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 October 2016
Revised Date: 20 December 2016
Accepted Date: 23 December 2016
Please cite this article as: Al Shuhaib Z, Arndt M, Dennis M, Evans DM, Jones I, Leitmann V, Murphy
PJ, Roberts D, Rowles R, Sadaghiani YK, Thornhill AJ, Nash RJ, Hollinshead J, Bartholomew B,
Tizzard GJ, Coles SJ, Intramolecular epoxide ring opening cyclisation reactions involving guanidines,
Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.065.
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ACCEPTED MANUSCRIPT
Intramolecular epoxide ring opening cyclisation reactions involving guanidines
Zainab Al Shuhaib, Marcel Arndt, Mark Dennis, Daniel M. Evans, Iestyn Jones, Vera Leitmann, Patrick J. Murphy,* Dion Roberts, Richard Rowles,
Yones K. Sadaghiani and Andrew J. Thornhill, Robert J. Nash, Jackie Hollinshead, Barbara Bartholomew, Graham J. Tizzard and Simon J. Coles

ACCEPTED MANUSCRIPT
Intramolecular epoxide ring opening cyclisation reactions involving guanidines
Zainab Al Shuhaib, Marcel Arndt, Mark Dennis, Daniel M. Evans, Iestyn Jones, Vera Leitmann, Patrick J.
Murphy,* Dion Roberts, Richard Rowles, Yones K. Sadaghiani, Andrew J. Thornhill
School of Chemistry, University of Wales, Bangor, Gwynedd, LL57 2UW
Robert J. Nash, Jackie Hollinshead, Barbara Bartholomew
PhytoQuest Limited, Plas Gogerddan, Aberystwyth, Ceredigion, SY23 3EB
Graham J. Tizzard and Simon J. Coles
UK National Crystallography Service, Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ
Abstract
The cyclisation of N-allyl- and N-homoallylguanidines using DMDO leading to the formation of novel 5- and 6-
membered guanidine heterocycles is reported. Several of the products formed displayed weak inhibition of
glycosidase enzymes.
Keywords: guanidines, epoxides, iodocyclisations, galactosidase inhibition, DMDO, epoxidation
Introduction
As part of a project directed towards the synthesis of marine natural products, we have previously reported
the intramolecular cyclisation of guanidine epoxides1 and the cyclisation of allyl and homoallyl substituted
guanidines using DMDO,1,2 I2/K2CO31-3 and under palladium catalysed conditions.4 We take this opportunity to
report our findings on the oxidative cyclisation reactions in full.
Epoxide ring opening using guanidines
Very few examples of epoxide ring opening processes utilising guanidines5 have been reported and our
preliminary investigations focused on the addition of guanidine to the simple epoxide 1. We treated 1 with
guanidine in t-BuOH at room temperature for 24 h to effect N-alkylation of guanidine, which we presumed to be
faster than the epoxide ring opening process. At this point, potassium t-butoxide was added to regenerate the free
guanidine from its salt, following which the reaction was heated at 60°C for a further 48 h to affect cyclisation to
give the 5-membered guanidine 2 (Scheme 1). In our previous work,1 we had reported efforts to purify 2 by column
chromatography and had succeeded in obtaining product of relatively high purity (> 95 %) though it was apparent
that it was contaminated with what appeared to be polymeric material. We also tried to purify 2 by derivatisation as
its t-butyldimethylsilyl ether 3. However this proved difficult as the compound was prone to hydrolysis on
chromatography which was thought to be promoted by the anchimeric assistance or the guanidinium group.6 We
were however able to purify 2 by HPLC and on examination of higher field NMR data, it was apparent that
significant quantities of a contaminant were present. Indeed re-examination of the crude reaction product indicated
a ca 9:1 ratio of 2 and what was though to be the isomeric 4. Compound 4 gave signals at δ 3.33 (2H, dd, J 3.1,
12.3, 2 x CH), 3.45, (2H, dd, J 2.7, 12.3 Hz, 2 x CH) and 4.38 (1H, tt, J 2.7, 3.1 Hz, CH) ppm and this 6-endo-tet
isomer 4 could possibly be formed by the attack of the guanidine on the CH2 of the epoxide after alkylation or
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more likely by initial epoxide opening by guanidine followed by the 6-exo-tet displacement of bromine.
Scheme 1: (a) (i) Guanidine hydrochloride, tBuOK, tBuOH, then epoxide 1 16 h, rt. (ii) tBuOK, 60°C, 24 h. (iii)
CF3CO2H, MeOH. (c) (i) 3 equiv. TBSCl, Imid., DMF, 16-24 h. (ii) NaBF4 (sat., aq.).
We wished to prepare 4 independently and thus reacted nitroguanidine 5 with 1,3-diaminopropan-2-ol 6 at
70°C in water to give 5-hydroxy-2-nitrimino-1,3-diazacyclohexane 7 in 27 % yield,7 which on hydrogenation in
aqueous acetic acid gave 4 as its acetate salt in 75% yield (Scheme 2). Spectroscopic data for the synthetic sample
of 4 corresponded exactly to the impurity found in the previous reactions.
Scheme 2: (a) Water, 70 °C, 2 h (b) (a) H2, 5 % Pd/C, 15% aqueous acetic acid 72 h.
Because of the problems with this impurity and problems associated with purification of the guanidine salts
in these reaction we turned our attention to the reaction of the protected guanidines 8a3 and 8b3 and their reaction
with the epoxidising agent DMDO.8 We had previously shown1 that the N-allyl-bis-Boc-guanidine 8a reacts with
o
DMDO in acetone at -20 C to give an intermediate epoxide 9a as evidenced by signals at δΗ 2.62 (1H, dd, J 2.4,
4.2 Hz, CH), 2.80 (1H, dd, J 4.2, 4.4 Hz, CH) and 3.14-3.22 (1H, m, CH) ppm. On continued stirring this
intermediate was consumed to give, on careful work up and chromatography, a 62% yield of the cyclic product 10a
the structure of which was confirmed by X-ray analysis.1 On attempted repeat of this reaction it was observed that a
second isomeric product was always formed in the reaction and, on isolation of this, X-ray crystallography2
confirmed the structure of the product as the rearranged product 11a isolated in 63% yield. A similar migration of a
Boc-group was reported in an N-Boc-protected 5-membered amide so this result is not suprising.9 More
conveniently, a complete conversion of 10a into 11a could be effected if a solution of the crude reaction mixture in
dichloromethane was stirred with silica gel overnight or by stirring in methanol containing a small amount (ca. 5
%) of water. A similar result was observed with the Z-protected guanidine 8b which was again treated with an
excess of DMDO in acetone at -20 oC and the reaction monitored by proton NMR. Epoxidation was found to occur
rapidly as evidenced by signals at δΗ 2.61 (1H, dd, J 2.8, 4.5 Hz, CH), 2.80 (1H, dd, J 4.4, 4.5 Hz, CH) and 3.16-
3.22 (1H, m, CH) ppm for epoxide 9b, but on continued stirring signals at δΗ 3.45 (1H, t, J 5.8 Hz, CH), 3.51 (1H,
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dd, J 5.1, 5.7 Hz, CH), 3.87 (1H, dd, J 3.0, 5.5 Hz, CH), 3.92 (1H, dd, J 2.8, 5.8 Hz, CH), and 4.03-4.11 (1H, m,
CH) ppm appeared which are evident of the structure 10b. However, after purification on silica gel, a new product
was formed in 64% yield, which had a considerably simpler spectrum with signals at δΗ 3.20 (1H, dd, J 10.2, 4.0
Hz, CH), 3.45-3.51 (1H, m, CH) and 3.87-3.95 (3H, m, CH, CH2) ppm and the two guanidine protons at δΗ (7.50-
9.60 (2H, br s, 2 x NH) which assigned the structure as 11b. Again it was possible to effect this rearrangement by
stirring the crude reaction product with silica gel in dichloromethane or by stirring in methanol containing a small
amount (ca. 5 %) of water. Finally, deprotection of 1a was accomplished by treatment with excess trifluoroacetic
acid in dichloromethane for 4 h to give guanidine 2 in 98 % yield (Scheme 3).
Scheme 3: (a) DMDO, acetone, -20 ˚C-rt, 3 days. (b) Silica gel, CH2Cl2
or MeOH/H2O (95:5), 16-24 h. (c) CF3CO2H, CH2Cl2, 0 ˚C-rt, 4 h.
We were interested in the mechanism of the Boc- and Cbz-group migration and in order to investigate this a
1:1 mixture of 8a and 8b was treated with DMDO at -20 °C and stirred at rt for 5 days at which point the formation
of a mixture of 10a and 10b was formed as indicated by 1H NMR. This mixture was then dissolved in a mixture of
methanol and water and stirred overnight at room temperature. Analysis of the product from this reaction by mass
spectrometry confirmed the presence of three different ions with m/z peaks at 316.1867 and 350.1710 Daltons
corresponding to the [M+H]+ ions for 11a and 11b as well as a mass at 384.1552 which correspond closely to the
[M+H]+ ion for 11c/11d. This observation suggest that the migration of the protecting groups is not exclusively
intramolecular and some evidence of intermolecular rearrangement is apparent. However, this may be happening in
the initial DMDO stage of the process (Scheme 4).
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Scheme 4: (a) DMDO, acetone, -20 ˚C-rt, 5 days. (b) MeOH/H2O (95:5), 16-24 h. R = Boc (a) or Cbz (b).
Following this work, we investigated the epoxidation of the dimethylallyl guanidine 8c3 and found that on
treatment with DMDO an epoxide 12a was formed after 16 hours which gave distinctive signals at δH 2.95 (1H,
dd, J 4.2, 7.4 Hz, CH), 3.24 (1H, ddd, J 4.4, 7.4, 14.3 Hz, CH), 3.98 (1H, ddd, J 4.2, 6.6, 14.3 Hz CH) ppm for the
three methine protons. This epoxide slowly underwent ring opening to give some evidence for the formation of the
5-membered guanidine 13a but this was transient and the rearranged 14a was formed after stirring for 7 days.
Attempted purification of this material was difficult as the product obtained was a gum which could not be
recrystallised and was also prone to decomposition on silica gel. A similar reaction of bis-Z protected 8d3 gave as a
stable product the epoxide 12b (δH 2.87 (1H, dd, J 4.1, 7.4 Hz, CH), 3.13 (1H, ddd, J 4.7, 7.4, 14.3 Hz, CH) and
3.88 (1H, ddd, J 4.1, 6.5, 14.3 Hz, CH) ppm) which on attempted recrystallisation from dichloromethane/petrol
deposited a precipitate of the cyclised and rearranged 5-membered guanidine 14b. Distinctive signals were
observed at δH 3.30 (1H, dd, J 10.3, 6.4 Hz, CH), 3.51 (1H, app t, J 10.3 Hz, CH) and 4.12 (1H, dd, J 10.3, 6.4 Hz,
CH) ppm for the three methyne protons with 2 guanidine NH signals at δH 8.19 (1H, br s, NH) and 8.93 (1H, br s,
NH) ppm. Conclusive proof of the 5-membered system was give in the carbon spectrum with the CH-N signal at
δC 61.3 ppm, whilst the quaternary C-O appeared at δC 84.3 ppm.¶ The slow rearrangement could be accelerated if
a solution of the crude reaction mixture in dichloromethane was stirred with silica gel overnight, to give an 87 %
yield of 14b. Hydrogenation of 14b over Pd/C gave 15 in 42 % yield after purification (Scheme 5).
Scheme 5: (a) DMDO, acetone, -20 ˚C-rt, 5 days. (b) Silica gel, CH2Cl2, 16 h.
(c) i) H2, 10% Pd/C, MeOH, 2 h; ii) HCl; iii) Ion exchange chromatography.
Following this the DMDO cyclisation of the homoallyl guanidine 8e3 was investigated and again this
underwent epoxidation and cyclisation to give the 6-membered guanidine 16 which on treatement with silica gel
gave 17 in 82% yield, the structure being determined by X-ray crystallography.2 Deprotection of this compound
with excess trifluoroacetic acid in chloroform for 24 h gave 18 in 66 % yield. The epoxidation reaction of the Boc-
protected guanidine 8f3 using DMDO under identical conditions was also performed, and on completion, the crude
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product 16 was dissolved in methanol/water. After stirring at rt for 4 days, purification by column chromatography
gave 19a in 72% yield. The structure of 19a was confirmed by X-ray crystallographic analysis (Figure 1). Finally,
epoxidation of the Cbz-protected guanidine 8g3 under identical conditions, followed by rearrangement in
methanol/water gave 19b in 79 %. This could be improved to give a 95 % yield by treatment of the crude reaction
mixture from the epoxidation step with TFA in MeOH for 24 h at rt (Scheme 6).
Scheme 6: (a) DMDO, acetone, -20 ˚C-rt, 24 h. (b) Silica gel, CH2Cl2, 24 h. (c) CF3CO2H,
CHCl3, rt, 24 h. (c) MeOH/H2O (95:5), 4 days. (d) MeOH/CF3CO2H (95:5), 24 h.
Figure 1: X-Ray structure of 19a.
We next investigated the epoxidation of the hydroxy-substituted allyl guanidines 204 and homoallyl
guanidine 24. Thus 20 was treated with an excess of DMDO at -20 oC in acetone and the mixture stirred to rt for 48
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h following which the reaction mixture was evaporated and the crude product dissolved in a methanol/water
mixture and the mixture stirred for 24 h. Analysis of the product 21 indicated a mixture of several isomeric
compounds relating to the migration of the Boc-protecting groups and this mixture was deprotected by treatment
with trifluoroacetic acid in dichloromethane for 24 h. On evaporation, the cyclised product 22 was obtained in 19%
overall yield for three steps after purification by HPLC. In a similar fashion homoallyl guanidine 24 (prepared by
hydrolysis of the acetate 234) was treated with DMDO to give cyclised guanidines 25, which in turn was
deprotected with trifluoroacetic acid in dichloromethane to give the guanidine 26 in 15% overall yield for three
steps after purification by HPLC (Scheme 7).
Scheme 7: (a) DMDO, acetone, -20 ˚C-rt, 24 h. (b) MeOH/H2O (95:5).
(c) CF3CO2H, CH2Cl2, rt, 24 h. (d) K2CO3, MeOH, 4 h.
Biological activity
We have reported previously1 that cyclic hydroxylated guanidines gave selective inhibition of b-
galactosidase and glycosidases are involved in many disease states and there are many opportunities for therapeutic
intervention both by inhibition and promotion of glycosidases.10 In addition, selectivity can be more important for
drug development that potency and so we here report the comparative activity of the synthesised compounds on a
range of glycosidases. The guanidines 3, 7, 15, 18, 22 and 26 were investigated for activity on a panel of
commercially available glycosidases from Sigma (α-glucosidases [yeast and Bacillus], β-glucosidase [almond], α-
galactosidase (Green coffee bean], β-galactosidase [bovine], α-mannosidase [Jack bean], hexosaminidases [bovine
kidney, Jack bean] and β-glucuronidase [bovine liver] at a top concentration of 0.14 mg/ml. 5 mM p-nitrophenyl-
substrates were used and the pH optima for the enzymes. Compound 3 showed no significant inhibition of any of
the glycosidases. Compounds 7, 15 and 18 showed some weak inhibition of the Bacillus α-glucosidase but with
less than 15% inhibition at the top concentration used (0.14 mg/mL in assay) with 18 also showing weak inhibition
(12%) of the β-glucosidase but more marked inhibition of the β-galactosidase (47%). Whilst 22 showed no
inhibition of most enzymes tested it showed a promotion of the bovine β-N-acetylglucosaminidase activity (18%)
which was also shown by 26 (22%) Both compounds also weakly promoted the Jack bean hexosaminidase (8.6 and
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17% respectively). Compound 26 also showed weak but unusual promotion of the α-mannosidase (23%) but had
some inhibition of the β-galactosidase (30%) Whilst this inhibition and promotion displayed by these compounds
is not strong, the selectivity is of interest, e.g. 7 and 15 mainly inhibiting the bacillus α-glucosidase. The promotion
of glycosidase activity, by 22 and 26 for example, of the bovine hexosaminidase, suggests improved folding or
stabilization of the glycosidase due to the molecule binding to it; improved glycosidase activity is of interest to
treat enzyme deficiencies (e.g. Tay Sachs disease) and improved folding and function may prevent deposition of
enzymes including hexosaminidase in neurodegenerative diseases.
Conclusions
The DMDO mediated cyclisation of allyl- and homo-allyl substituted guanidines is a useful and predictable
method for the synthesis of 5- and 6-membered guanidine heterocycles. We have prepared a range of these
heterocycles which displayed weak inhibition of glycosidase enzymes, however two compounds showed an
interesting promotion of glycosidase activity which might be of interest. We are continuing our synthetic work in
this area.
Acknowledgements
Thanks are given to the EPSRC for a studentship for AJT (GR/K81966), a fellowship to DE
(EP/J01821X/1) and to VASTox Wales and the ESF for a PhD studentship (IJ) and the EFS for an MSc studentship
(DE), the ERASMUS and SOCRATES schemes (HB, VL, YKS). We also thank the EPSRC National Mass
Spectrometry Facility at Swansea for their excellent work.
Experimental
All glassware used was washed with acetone and dried with N2 or in a vacuum oven. Reagents and starting
materials were purchased from commercial suppliers and used as supplied. Diethyl ether and tetrahydrofuran were
distilled from benzophenone and sodium wire, whilst dichloromethane was dried over CaH2 and freshly distilled.
DMF, chloroform and methanol were purchased as dry from Aldrich. Petrol refers to the fraction distilled between
boiling range of 40-60 ºC. Column chromatography and TLC chromatography was carried out using silica and
silica plates purchased from Fluorochem Ltd (particle size 35-70 µ) using HPLC grade acetic acid (AA)
chloroform (CFM), dichloromethane (DCM), diethyl ether (DE), ethyl acetate (EA), hexane (HX) and methanol
(ME). Compounds were visualised using UV, iodine or stained using polyphosphomolybdic acid (PMA) in EtOH
or vanillin in EtOH/H2SO4, with heating. IR spectra were recorded on a Perkin-Elmer 1600 series FTIR instrument
as thin films, Nujol mulls, or chloroform solution on NaCl plates with absorption frequencies reported in
wavenumbers (cm-1). Routine NMR samples were performed on a Bruker AC250, AC400 or on a Bruker Avance-
500 spectrometer. Chemical shifts for spectra are all reported in δ values (ppm) relative to the residual solvent peak
in each case. Electron Ionisation (EI) and Chemical Ionisation (CI) mass spectra were recorded on an Agilent Tech.
6890N spectrometer or an XCalibur MAT900 XLT spectrometer at the EPSRC Mass Spectrometry Service
(Swansea).
General conditions for epoxidation with DMDO8
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A finely divided sample of the guanidine in a 250 mL RBF was cooled (-20 °C), whereupon a freshly prepared
solution of DMDO8 (see SI) in acetone (100-150 mL) was added. The mixture was then stirred whilst slowly
warming to rt overnight and further stirred for the required time.
General condition for trifluoroacetic acid mediated Boc-deprotection.
The Boc-protected guanidine is dissolved in dichloromethane (5 mL) and cooled (0 °C) whereupon trifluoroacetic
acid (5 mL) was added slowly over 5 mins and the mixture stirred to rt for the indicated time. The reaction was
then evaporated and the residue repeatedly co-evaporated with chloroform to remove traces of trifluoroacetic acid.
(2-amino-4,5-dihydro-1H-imidazol-4-yl)methanol 2,2,2-trifluoroacetate 2 and 2-amino-1,4,5,6-
tetrahydropyrimidin-5-ol 2,2,2-trifluoroacetate 4
Potassium t-butoxide (1.80 g, 16.1 mmol, 1.1 eqv.) was added to a cooled (5 °C) solution of guanidine
hydrochloride (1.68 g, 17.5 mmol, 1.2 eq) in t-butanol (30 mL) and the mixture was stirred to rt over 1 h. 60
minutes. Epibromohydrin (1.26 ml, 14.6 mmol) was then added over 5 mins and the mixture was stirred at rt for 62
h. Further potassium tert-butoxide (1.80 g, 16.1 mmol, 1.1 eqv.) was then added and the mixture heated (60 °C) for
24 h. The resultant white slurry was then cooled (0 °C) and TFA (5 mL) in methanol (15 mL) was added slowly
over 10 mins and then mixture stirred to rt over 1 h. The reaction was evaporated onto silica gel (10 g) and purified
by chromatography (gradient elution, 0-100 % ME in CFM) to give a ca. 9:1 mixture (NMR) of 2 and 4 (1.87 g) as
their trifluoroacetate salts in 50% yield.
5-hydroxy-2-nitrimino-1, 3-diazacyclohexane 77
A solution of nitroguanidine 5 (1.50 g, 16.6 mmol) and 1,3-diaminopropan-2-ol 6 (2.30 g, 16.6 mmol) were
dissolved in water (60 mL) and the mixture heated at 70 °C for 2 h. The reaction mixture was cooled to rt and
stirred for 12 h, then cooled (0 °C) and the precipitate formed collected by filtration and washed with chilled water
(15 mL). The solid obtained was firstly air-dried then dried under vacuum (P2O5) to constant weight to give 7 (0.52
g, 27 % yield) as a white solid. Mp 230-233 °C (Lit7 233-233.5 °C); δH (500 MHz, D2O) 3.45 (2H, dd, J 3.1, 13.0,
2 x CH), 3.57, (2H, dd, J 2.6, 13.0 Hz, 2 x CH), 4.38 (1H, tt, J 2.6, 3.1 Hz, CH); δC (125 MHz, D2O) 44.3, 58.1,
153.6; MS(CI) 114.0 (100 %, [M+H-NO2]+) 160.0 (100%, [M+H+]); HRMS (EI) C4H8N4O3 [M+H+], found
160.0589, requires 160.0591.
2-amino-1,4,5,6-tetrahydropyrimidin-5-ol acetate 4
Palladium on charcoal (5 %, 0.6 g) was added to a solution of guanidine 7 (0.473 g, 2.97 mmol) in aqueous
acetic acid (15 % v/v, 50 mL) and the mixture stirred under H2 (balloon) for 72 h. The reaction was filtered through
a Celite© pad and then evaporated and the crude product purified by chromatography (5-15 % ME in CFM, then
15% - 20% ME in CFM with 0.1 % acetic acid) to give 4 as a white solid (0.388 g, 75% yield). Rf 0.20 (15% ME
in CFM with 0.1 % acetic acid); Mp 61-62 °C; δH (500 MHz, D2O) 1.92 (3H, s, Me), 3.33 (2H, dd, J 3.1, 12.3, 2 x
CH), 3.45, (2H, dd, J 2.7, 12.3 Hz, 2 x CH), 4.38 (1H, tt, J 2.7, 3.1 Hz, CH); νmax 3340, 2981, 2865, 1579; δC (125
MHz, D2O) 23.3, 43.9, 58.7, 153.6, 181.5; MS(CI) 116.1 (100 %, [M+H+]); HRMS(CI) C4H10N3O ([M+H+]),
found 116.0817, requires 116.0818.
tert-butyl 2-((tert-butoxycarbonyl)imino)-5-(hydroxymethyl)imidazolidine-1-carboxylate 10a
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Guanidine 8a3 (0.30 g, 1.00 mmol) was epoxidised using the standard conditions to give a crude product
(0.33 g) which was purification using rapid chromatography (gradient elution: 10-100 % EA in PE, then 10 % ME
in EA) to give 10a (196.0 mg, 62 % (71% based on recovered 8a), 11a (40.0 mg, 13%, 14% based on recovered
8a) and recovered 8a (40.0 mg). Recrystallisation (EA/PE or DCM/DE) gave crystals suitable for X-ray analysis1);
Mp. 130°C; δH (500 MHz, CDCl3) 1.42 (9H, s, t-Bu), 1.46 (9H, s, t-Bu), 3.63 (1H, br d, J 11.3 Hz, CH), 3.69-3.78
(3H, m, 3 x CH), 4.11-4.20 (1H, m, CH), 5.87 (2H, br s, NH, OH); δC (62.5 MHz, CDCl3) 28.1, 28.1, 48.8, 57.6,
62.3, 80.9, 83.6, 150.9, 152.9, 155.7; νmax 3346, 2983, 2975, 1753, 1743, 1600, 1141; MS(CI) 316.1 (100%,
[M+H+]); HRMS(CI) C14H26N3O5 ([M+H]+), found 316.1868, requires 316.1867.
tert-butyl-(4-(((tert-butoxycarbonyl)oxy)methyl)imidazolidin-2-ylidene)carbamate 11a.
Guanidine 10a3 and silica gel (ca. 1 g) in chloroform (20 mL) were stirred at rt for 72 h then filtered
through a Celite© pad which was washed with chloroform and ethyl acetate. Evaporation of the solvent gave a
crude compound which was recrystallised from chloroform by slow evaporation to give crystals of 11a (70.3 mg,
64% yield) suitable for X-ray analysis.2 Mp. 92-94 °C; δH (500 MHz, CDCl3) 1.44 (9H, s, t-Bu), 1.48 (9H, s, t-Bu),
3.40 (1H, dd, J 6.0, 9.7 Hz, CH), 3.73 (1H, dd, J 9.6, 9.7 Hz, CH), 4.07 (1H, dd, J 6.6, 10.9 Hz, CH), 4.10 (1H, dd,
J 5.5, 10.9 Hz, CH), 4.16 (1H, dddd, J 5.5, 6.0, 6.6, 9.67 Hz, CH), 6.67-8.86 (2H, br s, 2 x NH); δC (62.5 MHz,
CDCl3) 27.8, 28.4, 44.6, 52.9, 67.6, 78.8, 83.0, 153.2, 162.3, 164.4; vmax 3377, 2961, 1753, 1659, 1617, 1255;
MS(CI) 316.2 (100%, [M+H+]); HRMS(CI) C14H26N3O5 [M+H+], found 316.1871, requires 316.1867.
Benzyl (4-((((benzyloxy)carbonyl)oxy)methyl)imidazolidin-2-ylidene)carbamate 11b
Compound 8b3 (0.309 g, 0.84 mmol) was epoxidised under the general conditions for 5 days to give a crude
cyclised product (0.35 g) which was dissolved in dichloromethane (5 ml) and silica gel (1 g) was added and the
slurry stirred overnight. Evaporation of the dichloromethane and column chromatography of the residue (0-100%
EA in PE) gave 11b (0.208 g, 0.54 mmol, 64%) as a white solid. Mp 155-157 ˚C; Rf 0.46 (EtOAc); δH (500 MHz,
CDCl3), 3.20 (1H, dd, J 4.0, 10.2 Hz, CH), 3.45-3.51 (1H, m, CH), 3.87-3.95 (3H, m, CH, CH2), 4.94 (2H, s, CH2),
5.03 (2H, s, CH2), 7.10-7.30 (10H, m, 2 x Ph), 7.50-9.60 (2H, br s, 2 x NH); δC (125 MHz, CDCl3) 44.7, 52.5,
66.6, 68.3, 70.0, 127.9, 128.0, 128.5, 128.7, 135.1, 137.3, 154.8, 163.2, 165.3; vmax 3398, 3150, 3065, 3035, 2956,
1748, 1654, 1623, 1264; MS(CI) 384.2 (33 %, [M+H+]); HRMS(ES) C20H22N3O5 [M+H+], found 384.1558,
requires 384.1554.
(2-iminoimidazolidin-4-yl)methanol 2,2,2-trifluoroacetate 2
Guanidine 11a3 (134 mg, 0.425 mmol) was deprotected under the standard conditions to give 2 (96.0 mg)
as a gum in 98 % yield. δH (250 MHz, CD3OD) 3.50 (1H, dd, J 6.1, 9.8 Hz, CH), 3.54 (1H, dd, J 5.2, 11.4 Hz,
CH), 3.62 (1H, dd, J 4.5, 11.4 Hz, CH), 3.75 (1H, dd, J 9.8, 9.8 Hz CH), 4.07 (1H, dddd, J 4.5, 5.2, 6.1, 9.8 Hz,
CH); δC (125 MHz, CD3OD) 46.1, 58.1, 63.9, 161.4; νmax 3352, 2943, 1552; MS(CI) 116 (40 % [M+H+]);
HRMS(CI) C4H10N3O [M+H+], found 116.0825, requires 116.0818.
tert-Butyl (Z)-(5-((tert-butoxycarbonyl)oxy)-4,4-dimethyltetrahydropyrimidin-2(1H)-ylidene)carbamate 14a
Compound 8c3 (0.399 g, 1.22 mmol) was epoxidised under the general conditions and after 16 hours the
epoxide 12a was formed as evidenced by proton NMR (δH (500 MHz, CDCl3), 1.32 (3H, CH3), 1.33 (3H, CH3),
9

ACCEPTED MANUSCRIPT
1.49 (9H, s, tBu), 1.50 (9H, s, tBu), 2.95 (1H, dd, J 4.2, 7.4 Hz, CH), 3.24 (1H, ddd, J 4.4, 7.4, 14.3 Hz, CH), 3.98
(1H, ddd, J 4.2, 6.6, 14.3 Hz CH), 8.57 (1H, broad s, NH), 11.47 (1H, broad s, NH) ppm), which cyclised slowly to
give 14a as a oil in quantitative yield. After work up, attempted purification by column chromatography or
recrystallization led to considerable decomposition. δH (250 MHz, CDCl3) 1.21 (3H, CH3), 1.22 (3H, CH3), 1.49
(9H, s, tBu), 1.55 (9H, s, tBu), 3.83 (1H, dd, J 2.5, 12.8 Hz, CH), 3.86 (1H, dd, J 8.9, 12.8 Hz, CH), 4.22 (1H, dd, J
2.7, 8.5 Hz CH), 2 x NH not observed. δC (62.5 MHz, CDCl3) 20.9, 21.0, 27.8, 28.2, 43.3, 61.2, 79.9, 82.1, 82.8,
151.7, 160.2, 163.0; νmax 3346, 1748, 1656, 1611, 1368, 1315, 1251, 1143, 998; MS(CI) 188.1 (100 %), 232.1 (75
%), 288.2 (25 %), 244.2 (100 %, [M+H+]); HRMS(CI) C16H30N3O5 [M+H+], found 344.2178, requires 344.2180.
Benzyl (Z)-(5-(((benzyloxy)carbonyl)oxy)-4,4-dimethyltetrahydropyrimidin-2(1H)-ylidene)carbamate 14b
Compound 8d3 (0.42 g, 1.13 mmol) was epoxidised under the general conditions for 5 days to give the
crude epoxide 12b (0.46 g) as a white solid. δH (500 MHz, CDCl3) 1.21 (3H, CH3), 1.22 (3H, CH3), 2.87 (1H, dd, J
4.1, 7.4 Hz, CH), 3.13 (1H, ddd, J 4.7, 7.4, 14.3 Hz, CH) 3.88 (1H, ddd, J 4.1, 6.5, 14.3 Hz, CH), 5.04 (2H, s,
CH2), 5.07 (2H, s, CH2), 7.16-7.31 (10H, m, 2 x Ph), 8.46 (1H, broad dd, J 4.7, 6.5 Hz, NH), 11.66 (1H, broad s,
NH). The epoxide 12b (0.46 g) was dissolved in a minimum amount of dichloromethane (2-3 ml) and diluted with
PE (10-15 ml) and placed in a freezer. After 3 days a white amorphous precipitate of was obtained. Removal of the
supernatant liquid and drying of the solid gave 14b (100.0 mg, 23%) as a solid. The supernatant liquid was
evaporated and re-dissolved in dichloromethane (10 mL), whereupon silica gel (ca. 0.3 g) was added and the
mixture stirred for 48 h. After filtration and evaporation the crude product (0.36 g) was dissolved in
dichloromethane (3-4 mL) and diluted with petrol (20-25 mL) and on cooling for 2-3 days a further sample of 14b
(277.0 mg, 64%) was formed giving an overall yield of 87%. δH (500 MHz, CDCl3) 1.42 (3H, s, CH3), 1.45 (3H, s,
CH3), 3.30 (1H, dd, J 10.3, 6.4 Hz, CH), 3.51 (1H, t, J 10.3 Hz, CH) 4.12 (1H, dd, J 10.3, 6.4 Hz, CH) 5.07 (1H, d,
J 12.3 Hz, CH), 5.09 (1H, d, J 12.3 Hz, CH), 5.13 (2H, s, CH2), 7.27-7.43 (10H, m, 2 x Ph), 8.19 (1H, br s, NH),
8.93 (1H, br s, NH); δC (125 MHz, CDCl3) 20.7, 20.7, 42.8, 61.3, 66.5, 69.3, 84.3, 127.9, 128.0, 128.4, 128.4,
128.6, 128.7, 135.3, 137.3, 153.2, 163.4, 165.4; νmax 3383, 3074, 3037, 2985, 2928, 2857, 1741, 1654, 1624, 1270,
1253, 1107; MS (CI) 412 (100%, [M+H+]) HRMS (CI) C22H26N3O5 [M+H+], found 412.1869, requires 412.1867.
4-(2-hydroxypropan-2-yl)imidazolidin-2-iminium hydrogen carbonate 15
Guanidine 14b (52.6 mg, 0.128 mmol) was dissolved in methanol (3 mL), Pd/C (10 %, 120 mg) was added
and the mixture stirred under hydrogen gas (balloon) for 2 h. After filtration HCl (1M ca 2-3 drops) was added and
the mixture evaporated to give 15.HCl (17.2 mg, 0.096 mmol) as a gum in 75% yield. This was dissolved in a 1:1
mixture of EtOH/H20 (0.5 ml) and applied to a column of Amberlite CG400 (2 x 1 cm, OH- form, the resin having
previously been washed to neutrality with water) on eluting with water, three fractions (2 mL, 2 mL and 5 mL)
gave 15 (11.0 mg) in 42% yield as the hydrogen carbonate salt. δH (400 MHz, D2O) 1.16 (3H, s, CH3), 1.21 (3H, s,
CH3), 3.58 (1H, dd, J 10.1, 6.6 Hz, CH), 3.75 (1H, dd, J 10.1, 10.2 Hz CH), 3.98 (1H, dd, J 10.2, 6.6 Hz, CH); δC
(100 MHz, D2O) 23.3, 24.4, 43.9, 63.3, 71.4, 159.7, 165.1; νmax 3320, 3212, 2973, 2924, 2852, 1688, 1579, 1404,
1281, 1174, 1106, 1015, 950; MS (CI) 144.1 (100%, [M+H+]); HRMS (CI) C22H26N3O5 [M+H+], found 144.1127,
requires 144.1131.
tert-butyl (Z)-(4-(((tert-butoxycarbonyl)oxy)methyl)tetrahydropyrimidin-2(1H)-ylidene)carbamate 17
10

ACCEPTED MANUSCRIPT
Compound 8e3 (0.51 g, 1.63 mmol) was epoxidised under the general conditions for 3 days to give a crude
cyclised product (0.53 g) which was dissolved in dichloromethane (5 mL) and silica gel (2 g) added and the
mixture stirred for 16 h. The suspension was evaporated and compound purified by chromatography (0-10% ME in
EA) and the product obtained recrystallised (EA:PE 1:2) to give 17 (0.44 g, 1.33 mmol) in 82% yield as pale
yellow diamond shaped crystals. Rf 0.27 (10:90 ME:EA); Mp 160-161 oC; δH (500 MHz, CDCl3) 1.45 (9H, s, tBu),
t
1.47 (9H, s, Bu), 1.79-1.85 (1H, m, CH), 1.97-2.01 (1H, m, CH), 3.37 (1H, ddd, J 4.5, 8.1, 13.1, CH), 3.42-2.46
(1H, m, CH), 3.74-3.79 (1H, m, CH), 4.06 (1H, dd, J 6.6, 11.1, CH), 4.13 (1H, dd, J 5.7, 11.1), 6.90-10.3 (2H, br s,
2 x NH); δC (125 MHz, CDCl3) 22.4, 27.8, 28.3, 36.8, 47.9, 67.7, 80.0, 83.1, 153.1, 155.9, 159.2; νmax (Nujol mull)
3152, 2724, 1747, 1632, 1594, 1454, 1376, 1156; MS(CI) m/z 330.3 (100 %, [M+H]+); HRMS(ES) C15H27N3O5
[M+H+], found 330.2019, requires 330.2023.
(2-Iminohexahydropyrimidin-4-yl)methanol 2,2,2-trifluoroacetate 18
Compound 17 (38.2 mg was deprotected over 14 h using the standard method to give 18 (18.5 mg, 0.076
mmol in 66 % yield as a glass after chromatography (0-10 % ME in DCM). Rf 0.27 (20% ME in DCM); δH (500
MHz, CD3OD) 1.70-1.78 (1H, m, CH), 1.96-2.02 (1H, m, CH), 3.31 (1H, ddd, J 4.3, 9.3, 12.6, CH), 3.40 (1H, dt,
12.6, 5.0 Hz), 3.48-3.54 (2H, m, 2 x CH), 3.64-3.69 (1H, m, CH); δC (125 MHz, CD3OD) 23.3, 38.0, 52.0, 65.0,
2
116.1 (q, 1JCF 285 Hz), 155.9, 159.0 (q, JCF 41 Hz); νmax 3332, 3264, 3095, 2960, 2926, 2855, 1791, 1681, 1632,
1429, 1338, 1260, 1201, 1176, 1134, 1031, 835, 801, 712; MS(CI) 130.1 ([M+H+]); HRMS(ES) C5H12N3O
[M+H+], found 130.0975, requires 130.0975.
tert-Butyl(4-(((tert-butoxycarbonyl)oxy)methyl)-4-methyltetrahydropyrimidin-2(1H)-ylidene)carbamate 19a
Compound 8f 3 (0.330 g, 1.01 mmol) was epoxidised under the general conditions for 16 hrs to give a crude
cyclised product (0.35 g) on evaporation which was dissolved in dichloromethane, dried (MgSO4), filtered and
evaporated in vacuo. The resulting product was dissolved in methanol (5 mL) and water (0.1 mL) and stirred for 4
days, evaporated and purified column chromatography (20-100% EA in PE) to give 19a (0.250 g, 0.73 mmol in
72% yield as a white solid. The solid was dissolved in dichloromethane and hexane was added to the cloud point
whereupon cooling (-20 oC) gave crystals suitable for X-ray analysis (Figure 1). Rf 0.03 (EA); Mp 143-145°C; νmax
3261, 2978, 2931, 1745, 1714, 1644; δH (500 MHz; CDCl3) 1.35 (3H, s CH3), 1.46 (9H, s, 3 x CH3), 1.47 (9H, s, 3
x CH3), 1.71 (1H, ddd, J 5.5, 7.6, 13.4, CH), 1.93-2.00 (1H, m, CH), 3.37-3.48 (2H, m, CH2), 3.96 (1H, d, J 11.1
Hz, CH), 4.06 (1H, d, J 11.1 Hz, CH), 9.53 (2H, br s, 2 x NH); δC (125 MHz; CDCl3) 24.6, 27.8, 28.0, 35.7, 52.4,
70.6, 83.6, 85.2, 152.0, 153.1, 153.4; HRMS(ES) C16H30N3O5 [M+H+], found 344.2184, requires 344.2180.
Benzyl (4-((((benzyloxy)carbonyl)oxy)methyl)-4-methyltetrahydropyrimidin-2(1H)-ylidene)carbamate 19b
Compound 8f 3 (0.50 g, 1.26 mmol) was epoxidised under the general conditions for 16 hrs to give a crude
cyclised product (0.55 g) on evaporation which was dissolved in dichloromethane, dried (MgSO4), filtered and
o
evaporated in vacuo. The resulting product was dissolved in methanol (5 mL), cooled (0 C) and trifluoroacetic
acid (0.52 mL, 5 equiv.) was added drop wise. After warming to rt stirring was continuesd for 24 h and the mixture
then evaporated and the residue purified by chromatography (50-100 % EA in PE, followed by 2-4% ME in EA) to
give 19b (0.49 g, 1.19 mmol) as a colourless gum in 95% yield. Rf 0.16 (60:40 EA:PE); δH (500 MHz, CDCl3)
1.40 (3H, s, CH3), 1.77 (1H, ddd, J, 5.4, 7.5, 13.9, CH), 1.97-2.05 (1H, m, CH), 3.42-3.55 (2H, m, CH2), 4.08 (1H,
d, J 11.2 Hz, CH), 4.19 (1H, d, J 11.2 Hz, CH), 5.17 (2H, s, CH2), 5.24 (2H, s, CH2), 7.32-7.42 (10H, m, 2 x Ph),
11

ACCEPTED MANUSCRIPT
9.84 (2H, br s, NH); δC (125 MHz; CDCl3) 24.6, 27.9, 35.7, 52.2, 68.5, 70.5, 71.7, 128.3, 128.7, 128.8, 128.8,
128.8, 129.0, 134.8, 135.0, 152.3, 154.7, 155.3; νmax 3243, 3154, 3064, 3032, 2955, 2928, 2896, 1748, 1644, 1634,
1562, 1554; HRMS(ES) C22H26N3O5 ([M+H+]), found 412.1867, requires 412.1867.
+/- (R)-1-((S)-2-iminoimidazolidin-4-yl)ethane-1,2-diol 2,2,2-trifluoroacetate 22
Compound 204 (0.431 g 1.308 mmol) was epoxidised under the general conditions for 48 hrs to give crude
product (490 mg) which was dissolved in MeOH (5 mL) to which water (ca. 0.2 mL) was added and the mixture
stirred. After 24 h the reaction was evaporated to give crude 21 (451 mg) which was used in the next step without
further purification. Compound 21 (451 mg) was then deprotected using the standard method over 24 h.
Evaporation gave a gum (394 mg) which was purified by preparative HPLC (ACE 10 C18 250 x 21.8 mm column,
isocratic 95:5:0.1% water:acetonitrile:TFA, 15 mL/min, elution time 4.5 mins at 210 nm) to give 22 (66.0 mg, 0.25
mmol) as a white solid in 19% yield. Mp. 148-49 °C; δH (400 MHz, CD3OD) 3.54-3.64 (3H, m, 3 x CH), 3.78 (1H,
dd, J 9.8, 9.8 Hz, CH), 4.13 (1H, ddd, J 4.3, 7.0, 9.8 Hz, CH); δC (100 MHz, CD3OD) 46.5, 58.9, 64.5, 73.5, 161.5;
δC (125 MHz, D2O) 45.3, 57.0, 62.8, 72.5, 116.6 (CF3, q, 1JC-F 329 Hz), 160.1, 163.0 (C, q, 2JC-F 35 Hz). νmax 3332,
2976, 2921, 2855, 1738, 1638, 1614, 1361, 1277, 1253, 1158, 1102; MS(CI) 146.1 (100%, [M+H+]); HRMS(CI)
C5H12N3O2 [M+H+], found 146.0920, requires 146.0924.
tert-Butyl (((tert-butoxycarbonyl)amino)(((Z)-5-hydroxypent-3-en-1-yl)amino)methylene)-4-
azanecarboxylate 24
Acetate 234 (0.650 g, 1.68 mmol) was dissolved in dry methanol (10 ml), cooled (0 ˚C) and potassium
carbonate (204.0 mg, 1.48 mmol) was added and the mixture stirred for 7 h. The reaction was then filtered through
a silica plug, evaporated and the residue purified by chromatography (10-75% EA in PE) to give 24 (0.250 g, 0.728
mmols) in 43% yield as a gum. Rf 0.13 (25:75 EA:PE); δH (400 MHz, CDCl3) 1.45 (3H, s, tBu), 1.46 (3H, s, tBu),
2.33 (2H, app q, J 7.0 Hz, CH2), 2.63 (1H, br s, OH), 3.44 (2H, app q, J 6.2 Hz, CH2), 4.15 (2H, d, J 6.9 Hz, CH2),
5.43-5.50 (1H, m, CH), 5.76-5.82 (1H, m, CH), 8.25 (1H, br s, NH), 11.49 (1H, br s, NH); δC (100 MHz, CDCl3)
27.0, 28.1, 28.3, 40.4, 58.2, 79.5, 83.6, 128.2, 132.4, 153.6, 156.0, 163.5; νmax 2980, 2933, 1721, 1640, 1618, 1414,
1367, 1329, 1156, 1135; MS(ESI) 344.2 (100 %, [M+H+]); HRMS(CI) C16H30N3O5 [M+H+], found 344.2180,
requires 344.2180.
+/- (R)-1-((S)-2-Iminohexahydropyrimidin-4-yl)ethane-1,2-diol 2,2,2-trifluoroacetate 26.
Compound 24 (0.240 g, 0.700 mmol) was epoxidised under the general conditions for 48 hrs to give a crude
cyclised product (246 mg) which was dissolved in MeOH (5 mL) to which water (ca. 0.2 mL) was added and the
mixture stirred. After 24 h the reaction was evaporated to give crude 25 (215 mg) which was used in the next step
o
without further purification. Compound 25 (215 mg) was dissolved in DCM (5 mL), cooled (0 C) and
trifluoroacetic acid (5 mL) was added and the mixture stirred at rt for 48 h. Evaporation gave crude 26 (216 mg)
which was purified by preparative HPLC (ACE 10 C18 250 x 21.8 mm column, isocratic 95:5:0.1 %
water:acetonitrile:TFA, 15 mL/min, elution time 4.7 mins at 210 nm) to give 26 (29.0 mg, 0.106 mmol) as a gum
in 15 % yield. δH (400 MHz, CD3OD) 1.72-1.81 (1H, m, CH), 2.03-2.10 (1H, m, CH), 3.26-3.35 (1H, m, CH), 3.45
(1H, ddd, J 5.4, 5.4, 12.6 Hz, CH), 3.46-3.54 (1H, m, 2 x CH) 3.66 (1H, dd, J 4.1, 11.6 Hz, CH), 3.69 (1H, dd, J
4.0, 11.6 Hz, CH); δC (100 MHz, CD3OD) 24.2, 38.6, 52.7, 64.6, 74.6 (trifluoroacetate signals not observed); νmax
12

ACCEPTED MANUSCRIPT
3385, 2982, 2937, 1738, 1674, 1637, 1279, 1254, 1156, 912, 732; MS(CI) 160.1 (100%, [M+H+]); HRMS(CI)
C6H14N3O2 [M+H+], found 160.1078, requires 160.1081.
Glycosidase assays11
All enzymes and para-nitrophenyl substrates were purchased from Sigma β-galactosidase (bovine liver), α-
glucosidase (Bakers yeast), α-mannosidase (Jack bean), β-glucosidase (almond),
α-L-fucosidase (human placenta),
N-acetyl- -glucosaminidase (Bovine Kidney), Naringinase (Penicillium decumbens) and α-galactosidase (green
β
o
coffee beans). Compounds were assayed at 27 C in citric acid (0.1 M)/disodium hydrogen phosphate buffers (0.2
M) at the optimum pH for the enzyme. The incubation mixture consisted of enzyme solution (10 µl), an aqueous
solution of the substrate (10 µl) appropriate para-nitrophenyl substrate (50 µl of a 5 mM solution in buffer). The
reactions were stopped by addition of glycine (70 µl, 0.4 M at pH 10.4) during the exponential phase of the
reaction. Final absorbances were read at 405 nm using a Versamax microplate reader (Molecular Devices). Assays
were carried out in triplicate and the values given are means. Rat intestinal enzyme activities (Sigma rat intestine
powder) were also measured using appropriate substrates as above for the enzyme activity measured, the powder
(100 mg) was made up in PBS (2 mL) in ice and homogenised and then centrifuged. The supernatant was used as
the glycosidase activity source as above.
¶ We had previously2 assigned this as a 6-membered product.
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8) Mikula, H.; Svatunek, D.; Lumpi, D.; Glöcklhofer, F.; Hametner, C.; Fröhlich, Org. Process Res. Dev.
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