Exploring hydroamination-cycloaddition-fragmentation sequences to access polycyclicguanidines and vinyl-2-aminoimidazoles

Abstract

The intramolecular hydroamination of a guanidine on an eneyne unit affords a guanidine-substituted diene capable of reacting with dienophiles. These substrates undergo [4+2]-cycloaddition reactions to generate a series of complex cyclic- and spirocyclic-guanidines. Select substrates can further undergo a ring opening-elimination cascade that ultimately reveals a vinyl-2-aminoimidazole. As such this cascade reaction may find application in the synthesis of oroidin-type natural products and their analogues

Graphical abstract

1. Introduction

Marine sponges have been a prolific source of pyrrole-2-aminoimidazole alkaloids (PAIs).^1,2 Members of this family have been prized for their biological activities, especially as anti-tumors agents, anti-microbial or anti-biofilm agents.³ Besides their potential utility as therapeutics leads, the community has been fascinated with the genesis of the more structurally complex members of this family from the simple building blocks e.g. oroidin and hymenedin (Figure 1). Initial hypotheses suggested that these dimeric products were forged by electrocyclic reactions ([2+2] or [4+2] cycloadditions) of the vinyl-2-aminoimidazole fragment or from stepwise addition/isomerization sequences of the rapidly interconverting iminium ion tautomers of the 2-aminoimidazole core.⁴

Figure 1.

Biogenesis of complex pyrrole-2-aminoimidazole alkaloids form simple precursors.

However, Molinksi and Romo have recently shown that these cyclized and/or dimerized homologues arise from an enzymatic process. More specifically through the generation of a radical cation, via SET to an oxido-reductase.

We have previously demonstrated that propargylguanidines can be regiodivergently cyclized to the 5-exo product with Ag(I) or to the 6-endo product with Rh(II) catalysis (Scheme 1A).⁵ We became interested in extending the utility of this propargylguanidine hydroamination sequence to rapidly construct complex polycyclic guanidine scaffolds via the intermediacy of a guanidine-substituted diene, akin to the oroidin biosynthetic manifold. We envisioned that extension of the alkyne to an enyne would generate substrates at the same oxidation state as the vinyl-2-aminoimidazoles, albeit transposed (Scheme 1B). While the reactivity of many heteroatom substituted dienes have been studied, this represents an unknown class of guanidine-substituted dienes.

Scheme 1.

Applications of ene-ynes in the the guanidine hydroamination sequence.

Herein we explore the reactivity of these dienes to generate polycyclic guanidinium ion containing compounds and compounds that are structurally aligned with the PAIs. These complex structures arise from simple linear precursors via a cascade hydroamination-[4+2]-cycloaddition sequence.

2. Results and discussion

2.1 6-endo-selective hydroamination/[4+2] cycloaddition

We began by examining the hydraomination-[4+2]-cycloaddition cascade reaction with guanidine 1a (Scheme 2). Exposure of 1a to Rh(II) cleanly gave the 6-endo product 2a in 70% yield. This guanidine-substituted diene cleanly reacted with 4-phenyl-1,2,4-triazole-3,5-dione at room temperature to give 3a in 94% yield. Exploratory reactions showed that the diene 2a does not spontaneously react with electron poor dieneophiles (e.g. acrylates, quinones or fumarates) suggesting that the diacylated guanidine renders the diene relatively electron poor. The hydroamination-cycloaddition cascade can be carried out in a one-pot sequence to afford 3a in 74% isolated yield. Deprotection of the guanidine with trifluoroacetic acid followed by salt exchange gave 4a as a crystalline hydrochloride, the structure of which was confirmed by X-ray crystallography.

Scheme 2.

6-endo-selective hydroamination / [4+2]-cycloaddition sequence to access polyclicguanidines.

This reaction development permitted the synthesis of a focused library of these polycyclic guanidines (Scheme 3). Substitutions on the guanidine nitrogen (N1) are universally tolerated. As demonstrated, both cyclic and acyclic ene-ynes participate to give tetra- or tri-cyclic guanidines respecttively (e.g. 4b-4g). Other triazolinediones can be employed (4g). Substituents on the dihydroaminopyrimidine effectively control the approach of the dienophile to give the adducts 4h–i as single diastereomers.

Scheme 3.

Scope of the 6-endo-selective hydroamination / [4+2]-cycloaddition sequence.

2.2 5-exo-selective hydroamination/[4+2] cycloaddition

We then investigated the [4+2]-cycloaddition reaction on the 5-exo-dig derived dienes (Scheme 4). Interestingly hydroamination of 1c under Ag(I) conditions gave 7a in poor yield as the minor regiosiomer All other substrates in this series cyclize with >10:1 selectivity favoring the expected 5-exo-dig product. Reaction of 7a with 4-phenyl-1,2,4-triazole-3,5-dione proceeded cleanly to give the protected spirocyclic guanidine 8a. Deprotection of 8a with TFA for 30 min followed by salt exchange gave 9a in good yield, the structure of which was ultimately confirmed by X-ray crystallography. On working with this compound we ultimately observed that it decomposed when stored in solution, to give a compound that appeared to be an isomer of 9a as suggested by an identical mass (ultimately proven to be compound 10a in Scheme 6).

Scheme 4.

5-exo-selective hydroamination / [4+2]-cycloaddition sequence.

Scheme 6.

Scope of the [4+2]-Cycloaddition-fragmentation sequence to access vinyl-2-aminoimidazoles.

Insight into this decomposition was gained when studying the same reaction on substrate 1h (Scheme 5). Cyclization of 1h in the presence of Ag(I) gave 7b in good yield as a single regioisomer. Substitution at the alpha-position of the propargylguanidine favors the kinetically preferred 5-exo-dig product. Cycloaddition of the resultant diene gives 8b as a single diastereomer. Deprotection of 8b with TFA does not lead to the deprotected spirocycle but instead the allylic aminal fragments to reveal the vinyl-2-aminoimidazole 10b.

Scheme 5.

5-exo-selective hydroamination / [4+2]-cycloaddition-fragmentation sequence.

The structure of 10b was confirmed by X-ray crystallography and the spectral data were consistent with those of the isomer obtained from the decomposition of 9a. Presumably the more substituted 2-aminoimidazole ring in 8b fragments faster via stabilization of the intermediate N-acyliminium ion.

It was subsequently found that deprotection of the cycloadducts with 1:1 TFA:CH₂Cl₂ for >2 hours universally provides the ring-opened vinyl-2-aminoimidazoles 10a–i in good yield (Scheme 6).⁶

Having noted that the di-Boc-guanidine substituted dienes react with very reactive dienophiles, we also examined their participation in the acylnitroso Diels-Alder reaction (Scheme 7). Using Read de Alaniz’s conditions, we were able to generate the acylnitroso intermediate in-situ by oxidation of the N-hydroxycarbamate 11.⁷ This smoothly underwent cycloaddition with the dienes 2a,f,g to give the adducts 12a–c in moderate to good yield. These cycloadditions afford a single regio-isomer, confirmed in 12a by HMBC correlation of the C12 methine proton to the carbonyl of the benzylcarbamate. This is consistent with the more electron rich end of the diene reacting with the nitrogen of the acylnitroso system as previously demonstrated.^7b These intermediates can be deprotected without reduction of the internal alkene to give 13a–c.

Scheme 7.

[4+2]-Cycloaddition sequence with an acylnitroso-dienophile.

We also examined a hydroamination-Michael addition-[4+2]-cycloaddition sequence (Scheme 8). Reaction of the guanidine 14 with Ag(I) delivers the bicyclic guanidine substituted diene 15 in good yield. Reaction with 4-phenyl-1,2,4-triazole-3,5-dione gave the spirocycle 16. This example further serves to illustrate that guanidine substituted dienes that are only mono-acylated are competent dienes as well.

Scheme 8.

Hydroamination-Michael addition-[4+2]-cycloaddition sequence.

3. Conclusion

In conclusion, we have demonstrated that ene-yne containing di-Boc-guanidines generally undergo selective Rh(II)-mediated 6-endo-dig or Ag(I)-mediated 5-exo-dig hydroamination. The hydroamination products behave as electron poor dienes but can participate in [4+2]-cycloadditions with activated dienophiles. Cycloaddition of the 5-exo-dig products with a triazolinediones generates a spirocyclic allylic aminal which is prone to elimination to reveal a vinyl-2-aminoimidazole. As such, this sequence may find use in the preparation of PAI natural products or analogues. Given the successful reaction of monoacylsubstituted dienes, we are currently examining the ability of these more electron-rich systems to engage a wider variety of dieneophiles to access other complex and interesting structures.

4. Experimental section

4.1. General Experimental Considerations

Unless otherwise noted all starting materials were either known compounds or were obtained from commercial sources and used without purification. All reactions requiring anhydrous conditions were performed under a positive pressure of nitrogen using flame-dried glassware. Rhodium (II) octanoate, Silver nitrate, and Silver acetate were purchased from Sigma-Aldrich. Dichloromethane (CH₂Cl₂), acetonitrile (CH₃CN), toluene (C₆H₅CH₃), tetrahydrofuran (THF) and diethyl ether (Et₂O) were degassed with argon and passed through a solvent purification system (J.C. Meyer of Glass Contour) containing either alumina or molecular sieves. Flash chromatography was performed by CombiFlash R_f (TELEDYNE ISCO) or on Merk silica gel Kieselgel 60 (230–400 mesh) from EM science with the indicated solvent.

¹H NMR spectra were recorded on Varian Unity-300, Inova-400, or VXR-500 MHz spectrometers as indicated. The chemical shifts (δ) of proton resonances are reported relative to CDCl₃, DMSO-d₅, or CD₃OD using the following format: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, app = apparent), coupling constant(s) (J in Hz), integral].^{1,2 13}C NMR spectra were recorded at 75, 100, or 125 MHz. The chemical shifts of carbon resonances are reported relative to the deuterated solvent peak.

Infrared spectra were recorded on a Nicolet 380-FT IR spectrometer fitted with a SmartOrbit sample system. All absorptions are reported in cm-1 relative to polystyrene (1601 cm-1).

Mass spectra were obtained at the University of Utah CIF on a Micromass Quattro II (ESI/APCI) for LRMS or an LCT XE premier (ESI/APCI-TOF) for HRMS.

4.2 Synthetic Procedures and Characterization Data

4.2.1.General Procedure 1 for the guanylation of propargyl amines S-2a–i to form 1a–i

To a stirring solution of S-methyl-N,N′-diBocpseudothiourea (1.1 equiv), HgO (1.1 equiv), and triethylamine (3.0 equiv) in CH₂Cl₂ was added the appropriate propargyl amine (1.0 equiv). The reaction was stirred at room temperature until complete as judged by TLC. The reaction mixture was filtered through a short plug of Celite, concentrated, and purified by column chromatography to yield the propargylguanidine.

4.2.1.1. 1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-1-methyl-di-Boc-guanidine (1a)

The general procedure 1 was used to yield the propargylguanidine as a pale yellow solid (0.549 g, 71% yield). R_f = 0.45 (20% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 10.07 (s. 1H), 6.09 (s, 1H), 4.39 (s, 2H), 3.09 (s, 3H), 2.09 (m, 4H), 1.61 (m, 2H), 1.57 (m, 2H), 1.49 (s, 18H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.3, 153.6, 150.2, 137.4, 120.5, 87.5, 82.7, 79.3, 77.6, 36.4, 32.2, 28.9, 28.4, 28.3, 26.5, 22.5, 21.8 ppm; LRMS (ESI) Calculated for C₂₁H₃₄N₃O₄ m/z (M+H): 392.3, Obsd 392.4.

4.2.1.2. 1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-1-(cyclopropylmethyl)-di-Boc-guanidine (1b)

Prepared according to the general procedure 1, to give the propargylguanidine as white solid in 67% yield (0.573 g). R_f = 0.68 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 9.82 (s, 1H), 6.06 (s, 1H), 4.51 (s, 2H), 3.46 (s, 2H), 2.00 (m, 4H), 1.61 (m, 2H), 1.57 (m, 2H), 1.49 (s, 18H), 1.07 (m, 1H), 0.56 (m, 2H), 0.31 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 162.3, 154.6, 150.5, 135.1, 120.1, 86.8, 81.7, 80.6, 79.2, 52.1, 38.2, 29.0, 28.1, 28.0, 25.5, 22.1, 21.4, 8.9, 3.7 ppm; LRMS (ESI) Calculated for C₂₄H₃₈N₃O₄ m/z (M+H): 432.3, Obsd. 432.4.

4.2.1.3. 1-benzyl-1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-di-Boc-guanidine (1c)

Prepared according to the general procedure 1, to give the propargylguanidine as white solid in 71% yield (0.657 g). R_f = 0.55 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 9.91 (s, 1H), 7.33-7.26 (m, 5H), 6.07 (s, 1H), 4.83 (s, 2H), 4.21 (s, 2H), 2.08 (m, 4H), 1.62 (m, 2H), 1.57 (m, 2H), 1.50 (s, 18H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 155.4, 153.8, 150.7, 136.1, 135.6, 128.7, 128.5, 127.8, 120.3, 87.5, 82.3, 80.3, 79.8, 51.4, 38.7, 29.2, 28.3, 25.7, 22.4, 21.6 ppm; LRMS (ESI) Calculated for C₂₇H₃₈N₃O₄ m/z (M+H): 468.3, Obsd. 468.4.

4.2.1.4. 1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-1-(2,4-dimethoxybenzyl)-di-Boc-guanidine (1d)

Prepared according to the general procedure 1, to give the propargylguanidine as white solid in 83% yield (0.703 g). R_f = 0.71 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 9.97 (s, 1H), 7.33-7.27 (m, 5H), 5.27 (s, 1H), 5.22 (s, 1H), 4.83 (s, 2H), 4.24 (s, 2H), 1.86 (s, 3H), 1.51 (s, 9H), 1.49 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 162.4, 155.3, 150.6, 135.8, 128.6, 128.2, 127.7, 126.2, 122.4, 86.6, 82.4, 82.1, 79.6, 51.3, 38.4, 28.4, 28.3, 23.3 ppm; LRMS (ESI) Calculated for C₂₄H₃₄N₃O₄ m/z (M+H): 428.3, Obsd. 428.3.

4.2.1.5. 1-(3-(cyclohex-1-en-1-yl)prop-2-yn-1-yl)-1-(2,4-dimethoxybenzyl)-di-Boc-guanidine (1e)

Prepared according to the general procedure 1, to give the propargylguanidine as white solid in 68% yield (0.700 g). R_f = 0.56 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 9.44 (s, 1H), 7.22 (m, 1H), 6.46 (m, 2H), 6.07 (s, 1H), 4.59 (br, 2H), 4.25 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.08 (m, 4H), 1.62 (m, 2H), 1.57 (m, 2H), 1.51 (s, 9H), 1.50 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.3, 160.8, 158.1, 152.5, 150.2, 134.6, 131.4, 120.0, 115.4, 103.9, 98.2, 86.3, 81.1, 80.6, 78.4, 77.5, 59.8, 55.0, 54.9, 46.2, 28.8, 27.9, 27.8, 25.2, 21.9, 21.2 ppm; LRMS (ESI) Calculated for C₂₉H₄₂N₃O₆ m/z (M+H): 528.3, Obsd. 528.3.

4.2.1.6. 1-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(4-methylpent-4-en-2-yn-1-yl)-di-Boc-guanidine (1f)

Prepared according to the general procedure 1, to give the propargylguanidine as white solid in 81% yield (0.756 g). R_f = 0.48 (20% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 10.0 (s, 1H), 6.83-6.74 (m, 3H), 5.93 (s, 2H), 5.28 (s, 1H), 5.23 (s, 1H), 4.72 (s, 2H), 4.23 (s, 2H), 1.87 (s, 9H), 1.50 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 162.3, 155.1, 150.5, 147.9, 147.2, 129.3, 126.1, 122.3, 121.8, 108.1, 101.0, 86.5, 82.2, 82.0, 79.5, 51.0, 38.1, 28.1, 28.0, 23.2 ppm; LRMS (ESI) Calculated for C₂₅H₃₄N₃O₆ m/z (M+H): 472.2, Obsd. 472.4.

4.2.1.7. 1-(2,4-dimethoxybenzyl)-1-(4-methylpent-4-en-2-yn-1-yl)-di-Boc-guanidine (1g)

Prepared according to the general procedure 1, to give the propargylguanidine as white solid in 50% yield (0.483 g). R_f = 0.63 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 9.42 (s, 1H), 7.20 (m, 1H), 6.45 (m, 2H), 5.27 (s, 1H), 5.21 (s, 1H), 4.59 (s, 2H), 4.26 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 1.87 (s, 3H), 1.51 (s, 18H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.4, 160.9, 158.2, 150.4, 131.5, 126.2, 121.8, 115.4, 104.1, 98.4, 85.8, 82.7, 81.3, 78.7, 55.1, 46.5, 36.4, 28.0, 27.9, 23.2 ppm; LRMS (ESI) Calculated for C₂₆H₃₈N₃O₆ m/z (M+H): 488.3, Obsd. 488.5.

4.1.2.8. 1-(cyclopropylmethyl)-1-(5-methyl-1-phenylhex-5-en-3-yn-2-yl)-di-Boc-guanidine (1h)

Prepared according to the general procedure 1, to give the propargylguanidine as white solid in 22% yield (0.210 g). R_f = 0.50 (20% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 8.97 (s, 1H), 7.35-7.21 (m, 5H), 5.20 (s, 1H), 5.18 (s, 1H), 3.52 (m, 1H), 3.34 (dd, J = 14.7, 6.9 Hz, 1H), 3.27 (dd, J = 12.7, 4.9 Hz, 1H), 2.98 (dd, J = 12.7, 9.8 Hz, 1H), 1.80 (s, 3H), 1.51 (s, 9H), 1.49 (s, 9H), 1.24 (m, 1H), 0.59 (m, 2H), 0.35 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.9, 153.2, 150.8, 137.3, 129.9, 128.3, 126.9, 126.2, 122.1, 88.0, 85.7, 81.9, 79.3, 53.5, 51.5, 41.4, 28.3, 28.2, 23.3, 10.8, 5.7, 4.3 ppm; LRMS (ESI) Calculated for C₂₈H₄₀N₃O₄ m/z (M+H): 482.3, Obsd. 482.5.

4.1.2.9. 1-benzyl-1-(4-(cyclohex-1-en-1-yl)-1-phenylbut-3-yn-2-yl)-di-Boc-guanidine (1i)

Prepared according to the general procedure 1, to give the propargylguanidine as pale yellow solid in 78% yield (0.861 g). R_f = 0.51 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 7.36-7.18 (m, 10H), 5.94 (s, 1H), 4.97 (br, 1H), 4.62 (d, J = 16.7 Hz, 1H), 3.15 (dd, J = 12.7, 4.4 Hz, 1H), 2.76 (dd, J = 12.2, 9.8 Hz, 1H), 2.02 (m, 2H), 1.95 (m, 2H), 1.53 (m, 4H), 1.48 (s, 9H), 1.47 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.5, 154.3, 150.3, 138.4, 137.2, 128.6, 127.3, 127.1, 126.5, 126.3, 125.8, 122.3, 88.7, 84.8, 82.6, 78.9, 49.8, 46.3, 28.5, 28.3, 27.4, 24.7, 22.8, 21.7 ppm; LRMS (ESI) Calculated for C₃₄H₄₄N₃O₄ m/z (M+H): 558.3, Obsd. 558.5.

4.2.2.General Procedure 2 for the 6-endo cyclization of the Propargyl Guanidines 1a–g

To a stirring solution of the appropriate propargylguanidine (1.0 mmol) in CH₂Cl₂ (0.07 M) was added rhodium(II) octanoate dimer (10 mol%) and 4-nitrobenzoic acid (0.2 equiv). The reaction was stirred at room temperature until the reaction was complete by TLC. After completion, the reaction mixture was concentrated by rotary evaporation, and purified by column chromatography to yield 6-endo-dig cyclized guanidine.

4.2.2.1. tert-butyl (E)-2-((tert-butoxycarbonyl)imino)-6-(cyclohex-1-en-1-yl)-3-methyl-3,4-dihydropyrimidine-1(2H)-carboxylate (2a)

The general procedure 2 was used to yield 6-endo-dig cyclized guanidine as a white solid (6-endo-dig:5-exo-dig = >20:1), (0.274 g, total 70% yield). R_f = 0. 28 (60% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 6.35 (s. 1H), 5.61 (t, J = 5.2 Hz, 1H), 3.70 (d, J = 4.3 Hz, 2H), 3.05 (s, 3H), 2.16 (m, 4H), 1.69 (m, 2H), 1.60 (m, 2H), 1.54 (s, 9H), 1.41 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.4, 150.5, 149.6, 143.2, 132.4, 126.5, 110.0, 82.3, 78.7, 47.3, 37.7, 28.3, 28.1, 25.7, 25.6, 22.7, 22.3 ppm; LRMS (ESI) Calculated for C₂₁H₃₄N₃O₄ m/z (M+H): 392.3, Obsd. 392.3.

4.2.2.2. tert-butyl (E)-2-((tert-butoxycarbonyl)imino)-6-(cyclohex-1-en-1-yl)-3-(cyclopropylmethyl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2b)

Prepared according to the general procedure 2, to give 6-endo-dig cyclized guanidine as a white solid in 31% yield (6-endo-dig:5-exo-dig = >20:1), (0.134 g). R_f = 0.74 (40% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 6.37 (s, 1H), 5.64 (t, J = 5.1 Hz, 1H), 3.78 (d, J = 4.9 Hz, 1H), 3.33 (d, J = 6.8 Hz, 1H), 2.17 (m, 4H), 1.70 (m, 2H), 1.60 (m, 2H), 1.54 (s, 9H), 1.41 (s, 9H), 1.06 (m, 1H), 0.50 (m, 2H), 0.20 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5, 150.4, 149.5, 143.2, 132.2, 126.3, 110.3, 82.0, 78.4, 53.4, 44.4, 28.2, 27.9, 25.6, 25.5, 22.6, 22.1, 9.0, 3.4 ppm; LRMS (ESI) Calculated for C₂₄H₃₈N₃O₄ m/z (M+H): 432.3, Obsd. 432.4.

4.2.2.3. tert-butyl (E)-3-benzyl-2-((tert-butoxycarbonyl)imino)-6-(cyclohex-1-en-1-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2c)

Prepared according to the general procedure 2, to give 6-endo-dig cyclized guanidine as a white solid in 76% yield (6-endo-dig: 5-exo-dig = >20:1), (0.327 g). R_f = 0.25 (20% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.21 (m, 5H), 6.41 (s, 1H), 5.51 (t, J = 5.1 Hz, 1H), 4.70 (s, 2H), 3.55 (d, J = 4.1 Hz, 2H), 2.19 (m, 2H), 2.15 (m, 2H), 1.69 (m, 2H), 1.61 (m, 2H), 1.55 (s, 9H), 1.43 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5, 151.0, 149.6, 143.3, 136.2, 132.2, 128.6, 127.9, 127.5, 126.5, 110.5, 82.3, 78.7, 52.1, 43.6, 28.2, 28.0, 25.6, 25.5, 22.6, 22.1 ppm; LRMS (ESI) Calculated for C₂₇H₃₈N₃O₄ m/z (M+H): 468.3, Obsd. 468.4.

4.2.2.4. tert-butyl (E)-3-benzyl-2-((tert-butoxycarbonyl)imino)-6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2d)

Prepared according to the general procedure 2, to give 6-endo-dig cyclized guanidine as a white solid in 79% yield (6-endo-dig: 5-exo-dig = >20:1), (0.338 g). R_f = 0.57 (40% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.30-7.21 (m, 5H), 5.72 (s, 1H), 5.65 (t, J = 4.3 Hz, 1H), 5.07 (s, 1H), 4.71 (s, 2H), 3.58 (d, J = 3.4 Hz, 2H), 1.93 (s, 3H), 1.55 (s, 9H), 1.43 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.4, 150.9, 149.4, 142.9, 138.3, 136.1, 128.6, 127.8, 127.5, 115.1, 112.9, 82.9, 78.7, 52.1, 43.6, 28.2, 27.8, 20.0 ppm; LRMS (ESI) Calculated for C₂₄H₃₄N₃O₄ m/z (M+H): 428.3, Obsd. 428.3.

4.2.2.5. tert-butyl (E)-2-((tert-butoxycarbonyl)imino)-3-(2,4-dimethoxybenzyl)-6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2e)

Prepared according to the general procedure 2, to give 6-endo-dig cyclized guanidine as a pale yellow solid in 70% yield (6-endo-dig: 5-exo-dig = >20:1), (0.341 g). R_f = 0.41 (40% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.13 (m, 1H), 6.41 (m, 2H), 5.71 (s, 1H), 5.71 (s, 1H), 5.62 (t, J = 5.5 Hz, 1H), 5.05 (s, 1H), 4.64 (s, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.60 (d, J = 5.0 Hz, 2H), 1.91 (s, 3H), 1.54 (s, 9H), 1.43 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.5, 160.4, 158.6, 150.9, 149.5, 142.9, 138.4, 130.6, 116.6, 114.9, 113.3, 104.3, 98.3, 82.6, 78.4, 55.3, 55.2, 46.7, 43.4, 28.3, 27.9, 20.0 ppm; LRMS (ESI) Calculated for C₂₆H₃₈N₃O₆ m/z (M+H): 488.3, Obsd. 488.3.

4.2.2.6. tert-butyl (E)-3-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((tert-butoxycarbonyl)imino)-6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2f)

Prepared according to the general procedure 2, to give 6-endo-dig cyclized guanidine as a pale yellow solid in 76% yield (6-endo-dig: 5-exo-dig = 10:1), (0.358 g). R_f = 0.50 (40% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 6.74-6.70 (m, 3H), 5.92 (s, 2H), 5.71 (s, 1H), 5.67 (t, J = 5.0 Hz, 1H), 5.06 (s, 1H), 4.60 (s, 2H), 3.58 (d, J = 3.9 Hz, 2H), 1.93 (s, 3H), 1.55 (s, 9H), 1.43 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.3, 150.8, 149.3, 147.9, 147.1, 142.8, 138.3, 129.8, 121.4, 115.0, 112.9, 108.4, 108.2, 101.0, 82.8, 78.6, 51.8, 28.2, 27.8, 19.9 ppm; LRMS (ESI) Calculated for C₂₅H₃₄N₃O₆ m/z (M+H): 472.2, Obsd. 472.3.

4.2.2.7. tert-butyl (E)-3,4-dibenzyl-2-((tert-butoxycarbonyl)imino)-6-(cyclohex-1-en-1-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2g)

Prepared according to the general procedure 2, to give 6-endo-dig cyclized guanidine as a white solid in 96% yield (6-endo-dig: 5-exo-dig = >20:1), (0.535 g). R_f = 0.56 (40% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.07 (m, 10H), 6.44 (s, 1H), 5.32 (d, J = 6.9 Hz, 1H), 5.15 (d, J = 15.2 Hz, 1H), 4.12 (d, J = 15.2 Hz, 1H), 3.68 (m, 1H), 2.67 (m, 2H), 2.20 (m, 3H), 2.01 (m, 1H), 1.69 (m, 2H), 1.61 (m, 2H), 1.58 (s, 9H), 1.50 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.6, 150.8, 149.9, 142.1, 137.2, 136.3, 132.4, 129.4, 128.7, 128.5, 128.3, 127.7, 126.8, 126.7, 113.7, 82.3, 78.8, 56.3, 51.3, 39.5, 28.3, 28.1, 25.6, 25.5, 22.6, 22.2 ppm; LRMS (ESI) Calculated for C₃₄H₄₄N₃O₄ m/z (M+H): 558.3, Obsd 558.2.

4.2.2.8. tert-butyl (E)-4-benzyl-2-((tert-butoxycarbonyl)imino)-3-(cyclopropylmethyl)-6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2h)

Prepared according to the general procedure 2, to give 6-endo-dig cyclized guanidine as a white solid in 54% yield (6-endo-dig:5-exo-dig = 3:2), (0.260 g). R_f = 0.26 (20% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.32-7.15 (m, 5H), 5.70 (s, 1H), 5.58 (d, J = 6.9 Hz, 1H), 5.07 (t, J = 1.5 Hz, 1H), 4.01 (m, 1H), 3.47 (dd, J = 14.3, 7.1 Hz, 1H), 3.19 (dd, J = 14.3, 6.5 Hz, 1H), 3.00 (dd, J = 12.6, 5.4 Hz, 1H), 2.71 (dd, J = 12.6, 10.5 Hz, 1H), 1.89 (s, 3H), 1.56 (s, 9H), 1.49 (s, 9H), 1.05 (m, 1H), 0.55 (m, 2H), 0.23 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.8, 150.5, 149.9, 141.8, 138.7, 137.4, 129.5, 128.7, 127.0, 116.8, 115.3, 82.9, 78.9, 57.5, 53.5, 40.1, 28.4, 28.2, 20.1, 9.6, 4.2, 3.8 ppm; LRMS (ESI) Calculated for C₂₈H₄₀N₃O₄ m/z (M+H): 482.3, Obsd. 482.4.

4.2.2.9. tert-butyl (E)-3,4-dibenzyl-2-((tert-butoxycarbonyl)imino)-6-(prop-1-en-2-yl)-3,4-dihydropyrimidine-1(2H)-carboxylate (2i)

Prepared according to the general procedure 2, to give 6-endo-dig cyclized guanidine as a white solid in 70% yield (6-endo-dig:5-exo-dig = >20:1), (0.362 g). R_f = 0.60 (40% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.33-7.05 (m, 10H), 5.77 (s, 1H), 5.50 (d, J = 7.0 Hz, 1H), 5.18 (d, J = 15.1 Hz, 1H), 5.12 (s, 1H), 4.09 (d, J = 15.1 Hz, 1H), 3.74 (m, 1H), 2.71 (m, 2H), 1.91 (s, 3H), 1.60 (s, 9H), 1.53 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.6, 150.9, 149.8, 141.9, 138.6, 137.1, 136.3, 129.4, 128.6, 128.3, 127.8, 127.0, 116.7, 115.3, 83.0, 79.0, 56.4, 51.8, 39.5, 28.3, 28.1, 20.0 ppm; LRMS (ESI) Calculated for C₃₁H₄₀N₃O₄ m/z (M+H): 518.3, Obsd. 518.2.

4.2.3. General procedure 3 for the cycloaddition of the guanidine dienes 2a-i

To a stirring solution of the desired 6-endo-dig cyclic guanidine (diene, 1 equiv) in CH₂Cl₂ (0.07 M) was added the appropriate triazoledione (dienophile, 1.2 equiv). The reaction was stirred at room temperature until judged complete by TLC. After completion, the reaction mixture was concentrated by rotary evaporation, and purified by column chromatography to yield polycyclic guanidine.

4.2.3.1. tert-butyl (4aR,9aS,E)-2-((tert-butoxycarbonyl)imino)-3-methyl-6,8-dioxo-7-phenyl-3,4,4a,7,8,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-1(2H)-carboxylate (3a)

Prepared using the general procedure 3 to yield the polycyclic guanidine as a pale yellow solid, (0.160 g, 94% yield). R_f = 0.46 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.51-7.36 (m. 5H), 4.57 (m, 1H), 4.44 (m, 1H), 3.99 (dd, J =14.0, 3.0 Hz, 1H), 3.84 (dd, J =14.0, 7.5 Hz, 1H), 3.39 (m, 1H), 3.02 (s, 3H), 2.49 (m, 1H), 1.92 (m, 2H), 1.78 (m, 1H), 1.57 (m, 2H), 1.53 (s, 9H), 1.45 (s, 9H), 1.38 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.3, 154.5, 151.1, 149.5, 149.0, 134.3, 130.7, 129.1, 128.2, 125.3, 118.7, 82.9, 78.9, 55.2, 54.8, 50.1, 37.3, 30.8, 28.5, 28.2, 28.0, 26.6, 24.1 ppm; LRMS (ESI) Calculated for C₂₉H₃₉N₆O₆ m/z (M+H): 567.3, Obsd. 567.4.

4.2.3.2. tert-butyl (4aR,9aS,E)-2-((tert-butoxycarbonyl)imino)-3-(cyclopropylmethyl)-6,8-dioxo-7-phenyl-3,4,4a,7,8,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-1(2H)-carboxylate (3b)

Prepared according to the general procedure 3, to give the polycyclic guanidine as white solid in 35% yield (0.064 g). R_f = 0.45 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.49-7.34 (m, 5H), 4.60 (m, 1H), 4.43 (m, 1H), 4.35 (dd, J = 14.3, 1.5 Hz, 1H), 3.77 (dd, J = 14.3, 7.2 Hz, 1H), 3.46 (m, 1H), 3.42 (dd, J = 14.3, 7.8 Hz, 1H), 3.19 (dd, J = 14.3, 6.0 Hz, 1H), 2.45 (m, 1H), 1.89 (m, 2H), 1.72 (m, 1H), 1.54 (m, 1H), 1.49 (s, 9H), 1.45 (m, 1H), 1.42 (s, 9H), 1.33 (m, 1H), 1.05 (m, 1H), 0.52 (m, 1H), 0.45 (m, 1H), 0.21 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.6, 155.1, 151.6, 149.7, 149.3, 134.7, 130.9, 129.2, 128.4, 125.4, 119.4, 82.9, 79.0, 57.4, 54.8, 52.8, 47.1, 31.1, 28.6, 28.3, 28.1,27.0, 24.3, 9.2, 3.9, 3.2 ppm; LRMS (ESI) Calculated for C₃₂H₄₃N₆O₆ m/z (M+H): 607.3, Obsd. 607.3.

4.2.3.3 tert-butyl (4aR,9aS,E)-3-benzyl-2-((tert-butoxycarbonyl)imino)-6,8-dioxo-7-phenyl-3,4,4a,7,8,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-1(2H)-carboxylate (3c)

Prepared according to the general procedure 3, to give the polycyclic guanidine as white solid in 95% yield (0.183 g). R_f = 0.43 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.45-7.23 (m, 10H), 5.30 (d, J = 15.2 Hz, 1H), 4.55 (m, 1H), 4.40 (m, 1H), 4.06 (dd, J = 14.3, 1.6 Hz, 1H), 4.01 (d, J = 15.2 Hz, 1H), 3.75 (dd, J = 14.3, 7.3 Hz, 1H), 3.53 (m, 1H), 2.41 (m, 1H), 1.97 (m, 1H), 1.90 (m, 1H), 1.77 (m, 1H), 1.58 (m, 1H), 1.54 (s, 9H), 1.47 (s, 9H), 1.37 (m, 1H), 1.29 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.4, 154.3, 151.7, 149.6, 149.2, 136.5, 135.0, 130.8, 129.1, 128.5, 128.2, 128.1, 127.7, 125.2, 119.2, 83.0, 79.1, 56.4, 54.7, 51.6, 47.0, 30.9, 28.5, 28.3, 28.1, 27.0, 24.3 ppm; LRMS (ESI) Calculated for C₃₅H₄₃N₆O₆ m/z (M+H): 643.3, Obsd. 643.3.

4.2.3.4 tert-butyl (R,E)-2-benzyl-3-((tert-butoxycarbonyl)imino)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-carboxylate (3d)

Prepared according to general procedure 3, to the give polycyclic guanidine as white solid in 73% yield (0.132 g). R_f = 0.39 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.48-7.25 (m, 10H), 4.86 (d, J = 15.2 Hz, 1H), 4.60 (m, 1H), 4.46 (d, J = 15.2 Hz, 1H), 4.27 (d, J = 16.3 Hz, 1H), 3.99 (d, J = 16.3 Hz, 1H), 3.74 (m, 2H), 2.10 (s, 3H), 1.55 (s, 9H), 1.49 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.0, 153.3, 151.3, 149.2, 136.1, 130.8, 129.4, 128.9, 128.6, 128.5, 127.9, 127.5, 125.5, 122.3, 114.6, 83.6, 79.5, 54.6, 52.4, 47.3, 46.1, 28.4, 28.3, 15.7 ppm; LRMS (ESI) Calculated for C₃₂H₃₉N₆O₆ m/z (M+H): 603.3, Obsd. 603.4.

4.2.3.5. tert-butyl (R,E)-3-((tert-butoxycarbonyl)imino)-2-(2,4-dimethoxybenzyl)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-carboxylate (3e)

Prepared according to the general procedure 3, to give the polycyclic guanidine as pale yellow solid in 50% yield (0.099 g). R_f = 0.47 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.45-7.33 (m, 5H), 7.15 (m, 1H), 6.38 (m, 2H), 4.94 (d, J = 14.7 Hz, 1H), 4.55 (m, 1H), 4.22 (d, J = 16.5 Hz, 1H), 4.20 (d, J = 14.7 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.69 (m, 1H), 2.05 (s, 3H), 1.53 (s, 9H), 1.46 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.7, 159.8, 158.9, 153.0, 151.1, 151.0, 149.1, 131.2, 130.8, 129.2, 128.4, 127.0, 125.3, 122.2, 116.4, 104.2, 98.3, 83.0, 78.9, 55.3, 55.2, 54.9, 46.6, 46.5, 45.9, 28.3, 28.1, 15.5 ppm; LRMS (ESI) Calculated for C₃₄H₄₃N₆O₈ m/z (M+H): 663.3, Obsd. 663.4.

4.2.3.6. tert-butyl (R,E)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-((tert-butoxycarbonyl)imino)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-carboxylate (3f)

Prepared according to the general procedure 3, to give the polycyclic guanidine as pale yellow solid in 60% yield (0.116 g). R_f = 0.35 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.48-7.36 (m, 5H), 6.76 (s, 1H), 6.72 (m, 2H), 5.90 (m, 2H), 4.76 (d, J = 15.1 Hz, 1H), 4.60 (m, 1H), 4.60 (m, 1H), 4.34 (d, J = 15.1 Hz, 1H), 4.28 (d, J = 16.1 Hz, 1H), 4.02 (d, J = 16.1 Hz, 1H), 3.77 (dd, J = 13.7, 4.0 Hz, 1H), 3.69 (dd, J = 13.7, 7.4 Hz, 1H), 2.09 (s, 3H), 1.55 (s, 9H), 1.48 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.9, 153.3, 151.3, 151.2, 149.2, 148.1, 147.4, 130.8, 129.8, 129.4, 128.6, 127.5, 125.4, 122.2, 122.1, 108.9, 108.4, 101.2, 83.5, 79.4, 54.6, 52.2, 46.9, 46.1, 28.4, 28.2, 15.7 ppm; LRMS (ESI) Calculated for C₃₃H₃₉N₆O₈ m/z (M+H): 647.3, Obsd. 647.3.

4.2.3.7. tert-butyl (R,E)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-((tert-butoxycarbonyl)imino)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-carboxylate (3g)

Prepared according to the general procedure 3, to give the polycyclic guanidine as pale yellow solid in 61% yield (0.110 g). R_f = 0.29 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 6.74-6.71 (m, 3H), 5.92 (s, 2H), 4.74 (d, J = 15.1 Hz, 1H), 4.48 (m, 1H), 4.34 (d, J = 15.1 Hz, 1H), 4.18 (dd, J = 16.1, 2.0 Hz, 1H), 3.92 (dd, J = 16.1, 2.0 Hz, 1H), 3.68 (qd, J = 7.3, 5.4 Hz, 2H), 2.05 (d, J = 1.5 Hz, 3H), 1.54 (s, 9H), 1.47 (s, 9H), 1.23 (t, J = 7.3 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.8, 154.5, 152.3, 151.2, 149.2, 148.0, 147.3, 129.7, 127.5, 122.3, 122.0, 108.8, 108.3, 101.1, 83.3, 79.3, 54.4, 52.1, 46.9, 45.8, 34.5, 28.3, 28.2, 15.6, 13.4 ppm; LRMS (ESI) Calculated for C₂₉H₃₉N₆O₈ m/z (M+H): 599.3, Obsd. 599.4.

4.2.3.8. tert-butyl (4aR,9aS,E)-3,4-dibenzyl-2-((tert-butoxycarbonyl)imino)-6,8-dioxo-7-phenyl-3,4,4a,7,8,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-1(2H)-carboxylate (3h)

Prepared according to the general procedure 3, to give the polycyclic guanidine as white solid in 67% yield (0.147 g). R_f = 0.67 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.47-7.19 (m, 13H), 7.03 (m, 2H), 5.12 (d, J = 15.0 Hz, 1H), 4.66 (dd, J = 11.0, 2.3 Hz, 1H), 4.38 (s, 1H), 4.36 (m, 1H), 3.61 (m, 1H), 3.27 (dd, J = 13.2, 2.8 Hz, 1H), 2.90 (dd, J = 12.3, 12.3 Hz, 1H), 2.84 (d, J = 15.0 Hz, 1H), 2.33 (m, 1H), 1.89 (m, 1H), 1.83 (m, 1H), 1.73 (m, 1H), 1.56 (s, 9H), 1.51 (s, 9H), 1.49 (m, 1H), 1.27 (m, 1H), 1.16 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.3, 154.7, 151.9, 149.6, 149.3, 137.1, 136.7, 134.8, 130.7, 129.7, 129.1, 128.9, 128.5, 128.2, 128.1, 127.5, 127.1, 125.3, 119.5, 82.9, 79.0, 63.0, 59.3, 54.4, 52.1, 43.3, 30.6, 28.3, 28.2, 28.1, 26.8, 24.2 ppm; LRMS (ESI) Calculated for C₄₂H₄₉N₆O₆ m/z (M+H): 733.4, Obsd. 733.4.

4.2.3.9. tert-butyl (11aR,E)-1-benzyl-3-((tert-butoxycarbonyl)imino)-2-(cyclopropylmethyl)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-carboxylate (3i)

Prepared according to general procedure 3, to give the polycyclic guanidine as white solid in 83% yield (0.164 g). R_f = 0.10 (20% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.56-7.24 (m, 10H), 5.06 (dd, J = 10.4, 4.9 Hz, 1H), 4.55 (s, 1H), 4.40 (d, J = 16.6 Hz, 1H), 3.98 (d, J = 16.6 Hz, 1H), 3.68 (dd, J = 14.2, 6.3 Hz, 1H), 3.20 (dd, J = 13.2, 4.9 Hz, 1H), 2.99 (dd, J = 13.2, 10.3 Hz, 1H), 2.13 (s, 3H), 2.09 (dd, J = 14.2, 7.3 Hz, 1H), 1.60 (s, 9H), 1.56 (s, 9H), 0.78 (m, 1H), 0.50 (m, 1H), 0.36 (m, 1H), 0.05 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.1, 154.7, 151.9, 151.0, 149.6, 136.9, 130.8, 130.4, 129.5, 129.0, 128.7, 127.2, 125.7, 123.0, 83.2, 79.5, 63.1, 58.3, 53.2, 46.0, 43.7, 28.4, 28.3, 15.3, 9.5, 5.0, 2.1 ppm; LRMS (ESI) Calculated for C₃₆H₄₅N₆O₆ m/z (M+H): 657.3, Obsd. 657.3.

4.2.3.10. tert-butyl (11aR,E)-1,2-dibenzyl-3-((tert-butoxycarbonyl)imino)-5-methyl-8,10-dioxo-9-phenyl-2,3,6,9,10,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-4(1H)-carboxylate (3j)

Prepared according to general procedure 3, to give the polycyclic guanidine as white solid in 65% yield (0.135 g). R_f = 0.53 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.48-7.20 (m, 13H), 6.89 (m, 2H), 5.06 (d, J = 14.7 Hz, 1H), 4.42 (s, 1H), 4.41 (dd, J = 10.7, 3.9 Hz, 1H), 4.27 (d, J = 16.6 Hz, 1H), 3.83 (d, J = 16.6 Hz, 1H), 3.23 (dd, J = 13.7, 3.9 Hz, 1H), 3.00 (d, J = 14.7 Hz, 1H), 2.89 (dd, J = 13.7, 10.7 Hz, 1H), 2.13 (s, 3H), 1.58 (s, 9H), 1.52 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.8, 153.4, 151.9, 151.0, 149.6, 137.0, 136.4, 130.7, 129.9, 129.4, 129.0, 128.6, 128.5, 128.4, 127.8, 127.5, 127.3, 125.5, 123.0, 83.3, 79.6, 62.3, 58.6, 52.6, 45.9, 43.2, 28.4, 28.3, 15.3 ppm; LRMS (ESI) Calculated for C₃₉H₄₅N₆O₆ m/z (M+H): 693.3, Obsd. 693.4.

4.2.4 General procedure 4 for the deprotection and salt exchange of guanidines 3a–j

A 50 mL round-bottom flask was charged with the appropriate polycyclic guanidine (0.2 mmol). The CH₂Cl₂/TFA mixture (1:1, 4.0 mL) was added. The reaction mixture was stirred at room temperature for 2 hrs. The crude mixture was taken up in MeOH and 2 M HCl in ethyl ether was added. The mixture was again concentrated and the resulting solid triturated with ethyl ether. The solid was then collected to give the title compound.

4.2.4.1. (4aR,9aS)-2-imino-3-methyl-7-phenyl-1,2,3,4,4a,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-6,8(7H)-dione (4a)

Prepared according to the general procedure 4 to afford the HCl salt as a white powder (69 mg, 85%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.84 (s, 1H), 8.20 (s, 2H), 7.50-7.42 (m. 5H), 4.67 (s, 1H), 4.39 (d, J = 8.8 Hz, 1H), 4.29 (d, J = 7.3 Hz, 1H), 3.63 (t, J = 8.6 Hz, 1H), 3.07 (s, 4H), 2.17 (m, 1H), 1.81 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H), 1.34 (m, 1H), 1.20 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 153.9, 151.5, 149.1, 130.8, 128.8, 128.1, 126.0, 117.6, 114.2, 53.2, 49.1, 49.0, 37.3, 30.2, 26.8, 26.3, 23.5 ppm; HRMS (ESI) Calculated for C₁₉H₂₃N₆O₂ m/z (M+H): 367.1882, Obsd. 367.1890.

4.2.4.2. (4aR,9aS)-3-(cyclopropylmethyl)-2-imino-7-phenyl-1,2,3,4,4a,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-6,8(7H)-dione (4b)

Prepared according to the general procedure 4, to give the polycyclic guanidine as white solid in 66% yield (59 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.41 (s, 1H), 7.98 (s, 2H), 7.53-7.41 (m, 5H), 4.64 (m, 1H), 4.51 (dd, J = 12.4, 5.7 Hz, 1H), 4.42 (dd, J = 8.4, 2.0 Hz, 1H), 3.63 (t, J = 12.4 Hz, 1H), 3.39 (m, 2H), 2.94 (m, 1H), 2.17 (m, 1H), 1.91 (m, 1H), 1.80 (m, 2H), 1.55 (m, 1H), 1.37 (m, 1H), 1.24 (m, 1H), 1.04 (m, 1H), 0.54 (m, 1H), 0.31 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 156.1, 152.6, 151.3, 132.3, 130.2, 129.7, 127.5, 119.4, 117.0, 55.8, 55.5, 51.6, 49.7, 31.9, 28.3, 28.1, 25.3, 9.8, 4.2, 4.1 ppm; HRMS (ESI) Calculated for C₂₂H₂₈N₆O₂ m/z (M+H): 408.2274, Obsd. 408.2285.

4.2.4.3. (4aR,9aS)-3-benzyl-2-imino-7-phenyl-1,2,3,4,4a,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-6,8(7H)-dione (4c)

Prepared according to the general procedure 4, to give the polycyclic guanidine as white solid in 90% yield (79 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 11.00 (s, 1H), 8.53 (s, 2H), 7.49-7.34 (m, 10H), 4.82 (d, J = 16.2 Hz, 1H), 4.66 (d, J = 16.2 Hz, 1H), 4.63 (s, 1H), 4.40 (d, J = 10.4 Hz, 1H), 4.30 (dd, J = 12.2, 5.2 Hz, 1H), 3.56 (t, J = 11.9 Hz, 1H), 3.12 (m, 1H), 2.15 (m, 1H), 1.89 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H), 1.34 (m, 1H), 1.24 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 154.0, 151.5, 149.2, 134.5, 130.9, 128.9, 128.8, 128.2, 128.0, 127.4, 126.1, 117.7, 114.7, 53.3, 52.0, 49.2, 46.8, 30.2, 26.9, 26.4, 23.6 ppm; HRMS (ESI) Calculated for C₂₅H₂₇N₆O₂ m/z (M+H): 443.2195, Obsd. 443.2205.

4.2.4.4. (R)-2-benzyl-3-imino-5-methyl-9-phenyl-1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-8,10(9H)-dione (4d)

Prepared according to the general procedure 4, to give the polycyclic guanidine as white solid in 63% yield (55 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.38 (s, 2H), 7.49-7.32 (m, 10H), 4.70 (d, J = 15.9 Hz, 1H), 4.63 (m, 1H), 4.54 (d, J = 15.9 Hz, 1H), 4.22 (m, 2H), 3.94 (d, J = 15.3 Hz, 1H), 3.44 (t, J = 11.5 Hz, 1H), 1.88 (s, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 152.9, 151.2, 150.6, 134.2, 130.7, 128.6, 127.9, 127.8, 127.1, 125.8, 119.9, 106.9, 51.8, 48.6, 46.4, 44.8, 13.8 ppm; HRMS (ESI) Calculated for C₂₂H₂₄N₆O₂ m/z (M+H): 404.1961, Obsd. 404.1971.

4.2.4.5. (R)-2-(2,4-dimethoxybenzyl)-3-imino-5-methyl-9-phenyl-1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-8,10(9H)-dione (4e)

Prepared according to the general procedure 4, to give the polycyclic guanidine as white solid in 70% yield (70 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.87 (s, 1H), 8.34 (s, 2H), 7.48-7.42 (m, 5H), 7.24 (m, 1H), 6.60 (s, 1H), 6.51 (m, 1H), 4.60 (d, J = 15.2 Hz, 1H), 4.54 (m, 1H), 4.47 (d, J = 15.2 Hz, 1H), 4.32 (d, J = 7.8 Hz, 1H), 4.20 (d, J = 14.7 Hz, 1H), 3.92 (d, J = 14.7 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.36 (m, 1H), 1.88 (s, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 160.7, 159.8, 158.9, 153.0, 151.1, 151.0, 149.1, 131.2, 130.8, 129.2, 128.4, 127.0, 125.3, 122.2, 116.4, 104.2, 98.3, 83.0, 78.9, 55.3, 55.2, 54.9, 46.6, 46.5, 45.9, 28.3, 28.1, 15.5 ppm; HRMS (ESI) Calculated for C₂₄H₂₇N₆O₄ m/z (M+H): 463.2094, Obsd. 463.2099.

4.2.4.6. (R)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-imino-5-methyl-9-phenyl-1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-8,10(9H)-dione (4f)

Prepared according to the general procedure 4, to give the polycyclic guanidine as white solid in 88% yield (85 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.93 (s, 1H), 8.51 (s, 2H), 7.48-7.40 (m, 5H), 6.94-6.82 (m, 3H), 6.01 (s, 1H), 6.72 (m, 2H), 5.90 (m, 2H), 4.76 (d, J = 15.1 Hz, 1H), 4.60 (m, 1H), 4.60 (m, 1H), 4.34 (d, J = 15.1 Hz, 1H), 4.28 (d, J = 16.1 Hz, 1H), 4.02 (d, J = 16.1 Hz, 1H), 3.77 (dd, J = 13.7, 4.0 Hz, 1H), 3.69 (dd, J = 13.7, 7.4 Hz, 1H), 2.09 (s, 3H), 1.55 (s, 9H), 1.48 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 153.2, 151.1, 150.9, 147.7, 147.1, 131.0, 128.9, 128.2, 128.0, 126.1, 121.3, 120.1, 108.5, 108.1, 107.0, 101.2, 51.7, 48.8, 46.2, 45.0, 13.9 ppm; HRMS (ESI) Calculated for C₂₃H₂₃N₆O₄ m/z (M+H): 447.1781, Obsd. 447.1782.

4.2.4.7. (R)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-9-ethyl-3-imino-5-methyl-1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-8,10(9H)-dione (4g)

Prepared according to the general procedure 4, to give the polycyclic guanidine as white solid in 81% yield (70 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.88 (s, 1H), 8.46 (s, 2H), 6.93-6.82 (m, 3H), 6.02 (s, 2H), 4.68 (d, J = 16.1 Hz, 1H), 4.55 (d, J = 16.1 Hz, 1H), 4.51 (m, 1H), 4.20 (dd, J = 11.7, 4.9 Hz, 1H), 4.12 (d, J = 15.7 Hz, 1H), 3.81 (d, J = 15.7 Hz, 1H), 3.39 (m, 3H), 1.85 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 154.3, 151.9, 151.2, 147.7, 147.1, 128.0, 121.3, 120.3, 108.4, 108.1, 107.1, 101.2, 51.7, 48.6, 46.3, 44.8, 33.7, 13.9, 12.9 ppm; HRMS (ESI) Calculated for C₁₉H₂₃N₆O₄ m/z (M+H): 399.1781, Obsd. 399.1783.

4.2.4.8. (4aR,9aS)-3,4-dibenzyl-2-imino-7-phenyl-1,2,3,4,4a,9a,10,11,12,13-decahydro-6H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]cinnoline-6,8(7H)-dione (4h)

Prepared according to the general procedure 4, to give the polycyclic guanidine as white solid in 80% yield (91 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.54 (s, 2H), 7.51-7.14 (m, 15H), 5.00 (d, J = 16.6 Hz, 1H), 4.97 (s, 1H), 4.48 (s, 2H), 4.09 (d, J = 16.6 Hz, 1H), 3.44 (d, J = 12.7 Hz, 1H), 3.23 (d, J = 12.7 Hz, 1H), 2.94 (m, 1H), 2.27 (m, 1H), 1.83 (m, 2H), 1.78 (m, 1H), 1.55 (m, 1H), 1.32 (m, 1H), 1.02 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 165.7, 154.5, 149.7, 135.8, 135.4, 131.0, 130.3, 128.8, 128.6, 128.5, 128.2, 127.9, 127.1, 126.6, 126.2, 123.8, 117.1, 60.0, 59.5, 53.3, 50.7, 39.0, 31.0, 27.2, 26.7, 23.4 ppm; HRMS (ESI) Calculated for C₃₂H₃₃N₆O₂ m/z (M+H): 533.2665, Obsd. 533.2671.

4.2.4.9. (11aR)-1-benzyl-2-(cyclopropylmethyl)-3-imino-5-methyl-9-phenyl-1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-8,10(9H)-dione (4i)

Prepared according to the general procedure 4, to give the polycyclic guanidine as white solid in 72% yield (71 mg). ¹H NMR (500 MHz, CD₃OD) δ 7.57-7.29 (m, 10H), 4.97 (s, 2H), 4.30 (d, J = 15.9 Hz, 1H), 4.06 (d, J = 15.9 Hz, 1H), 3.55 (dd, J = 14.6, 6.2 Hz, 1H), 3.39 (d, J = 14.6, 3.8 Hz, 1H), 3.32 (d, J = 14.6, 3.8 Hz, 1H), 2.87 (dd, J = 14.6, 7.5 Hz, 1H), 1.82 (s, 3H), 1.03 (m, 1H), 0.64 (m, 1H), 0.56 (m, 1H), 0.31 (m, 1H), 0.21 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CD₃OD) δ 157.8, 155.9, 153.6, 137.1, 132.7, 131.6, 130.3, 130.1, 129.8, 128.7, 127.5, 121.2, 118.9, 61.2, 60.0, 54.2, 47.0, 40.2, 14.4, 10.1, 5.2, 3.3 ppm; HRMS (ESI) Calculated for C₂₆H₃₀N₆O₂ m/z (M+H): 458.2430, Obsd. 458.2436.

4.2.4.10. (11aR)-1,2-dibenzyl-3-imino-5-methyl-9-phenyl-1,2,3,4,6,11a-hexahydro-8H-pyrimido[5,4-c][1,2,4]triazolo[1,2-a]pyridazine-8,10(9H)-dione (4j)

Prepared according to general procedure 4, to give the polycyclic guanidine as white solid in 87% yield (92 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.39 (s, 2H), 7.53-7.13 (m, 15H), 5.03 (d, J = 16.5 Hz, 1H), 4.91 (s, 1H), 4.44 (q, J = 4.3 Hz, 1H), 4.37 (d, J = 16.5 Hz, 1H), 4.23 (d, J = 15.3 Hz, 1H), 4.04 (d, J = 15.3 Hz, 1H), 3.44 (dd, J = 14.3, 4.0 Hz, 1H), 3.28 (dd, J = 14.3, 4.6 Hz, 1H), 1.79 (s, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 155.7, 153.1, 151.9, 135.3, 135.2, 131.1, 130.5, 128.9, 128.5, 128.2, 127.9, 127.2, 126.8, 126.3, 119.2, 116.1, 59.1, 57.0, 50.1, 45.8, 37.4, 14.3 ppm; HRMS (ESI) Calculated for C₂₉H₂₉N₆O₂ m/z (M+H): 493.2352, Obsd. 493.2355.

4.2.5 General Procedure 5 for the cyclization of propargylguanidines using silver (I)

To a stirring solution of the preferred propargylguanidine (1.0 mmol) in CH₂Cl₂ (0.07 M) was added silver acetate (10 mol%) and acetic acid (3.0 equiv). After completion, the reaction mixture was concentrated by rotary evaporation, and purified by column chromatography to give 5-exo-dig cyclized guanidine.

4.2.5.1. tert-butyl (2E,5Z)-3-benzyl-2-((tert-butoxycarbonyl)imino)-5-(cyclohex-1-en-1-ylmethylene)imidazolidine-1-carboxylate (7a)

The general procedure 5 was used to give 5-exo-dig cyclized guanidine as a white solid in 85% yield (5-exo-dig:6-endo-dig = 2:3), (0.398 g). R_f = 0.50 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.34-7.26 (m, 5H), 5.75 (s, 1H), 5.49 (s, 1H), 4.58 (s, 2H), 3.70 (s, 2H), 2.22 (m, 2H), 2.13 (m, 2H), 1.63 (m, 4H), 1.54 (s, 9H), 1.47 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.2, 151.9, 149.3, 135.6, 134.1, 129.3, 128.8, 128.4, 127.9, 126.0, 120.3, 83.5, 79.2, 49.7, 48.4, 28.3, 28.1, 27.0, 25.8, 22.7, 22.2 ppm; LRMS (ESI) Calculated for C₂₇H₃₈N₃O₄ m/z (M+H): 468.3, Obsd. 468.3.

4.2.5.2. tert-butyl (2E,5Z)-3,4-dibenzyl-2-((tert-butoxycarbonyl)imino)-5-(cyclohex-1-en-1-ylmethylene)imidazolidine-1-carboxylate (7b)

Prepared according to the general procedure 5, to give the 5-exo-dig cyclized guanidine as a white solid in 85% yield (5-exo-dig:6-endo-dig = >20:1), (0.474 g). R_f = 0.50 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.35-7.01 (m, 10H), 5.52 (s, 1H), 5.07 (d, J = 15.1 Hz, 1H), 4.72 (s, 1H), 4.13 (d, J = 15.1 Hz, 1H), 3.63 (dd, J = 9.4, 4.2 Hz, 1H), 2.86 (dd, J = 13.0, 9.4 Hz, 1H), 2.41 (dd, J = 13.0, 9.4 Hz, 1H), 2.20 (m, 1H), 2.07 (m, 3H), 1.72 (m, 2H), 1.64 (m, 1H), 1.55 (s, 9H), 1.52 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.6, 152.1, 149.8, 136.2, 136.1, 134.1, 130.0, 129.7, 129.0, 128.5, 128.4, 128.1, 127.1, 122.3, 83.4, 79.4, 61.7, 46.9, 38.8, 28.4, 28.3, 26.9, 25.9, 22.9, 22.4 ppm; LRMS (ESI) Calculated for C₃₄H₄₄N₃O₄ m/z (M+H): 558.3, Obsd. 558.3.

4.2.5.3. tert-butyl (2E,5Z)-3-benzyl-2-((tert-butoxycarbonyl)imino)-5-(2-methylallylidene)imidazolidine-1-carboxylate (7c)

Prepared according to the general procedure 5, to give the 5-exo-dig cyclized guanidine as a white solid in 54% yield (5-exo-dig:6-endo-dig = 10:1), (0.231 g). R_f = 0.49 (40% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.35-7.27 (m, 5H), 5.60 (s, 1H), 5.00 (s, 2H), 4.60 (s, 2H), 3.72 (d, J = 1.0 Hz, 2H), 1.94 (s, 3H), 1.54 (s, 9H), 1.46 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.5, 152.1, 149.2, 140.3, 135.5, 128.9, 128.6, 128.5, 128.0, 119.1, 117.5, 84.2, 79.4, 49.6, 48.5, 28.4, 28.1, 21.2 ppm; LRMS (ESI) Calculated for C₂₄H₃₄N₃O₄ m/z (M+H): 428.3, Obsd. 428.3.

4.2.5.4. tert-butyl (2E,5Z)-3,4-dibenzyl-2-((tert-butoxycarbonyl)imino)-5-(2-methylallylidene)imidazolidine-1-carboxylate (7d)

Prepared according to the general procedure 5, to give the 5-exo-dig cyclized guanidine as a white solid in 90% yield (5-exo-dig:6-endo-dig = >20:1), (0.466 g). R_f = 0.47 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.36-7.00 (m, 10H), 5.07 (d, J = 15.1 Hz, 1H), 4.92 (s, 1H), 4.83 (s, 1H), 4.78 (s, 1H), 4.16 (d, J = 15.1 Hz, 1H), 3.66 (dd, J = 9.7, 4.6 Hz, 1H), 2.86 (dd, J = 13.1, 4.6 Hz, 1H), 2.46 (dd, J = 13.1, 9.7 Hz, 1H), 1.56 (s, 3H), 1.56 (s, 9H), 1.51 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.7, 152.0, 149.4, 140.0, 135.9, 135.8, 130.6, 129.9, 129.0, 128.5, 128.4, 128.1, 127.1, 83.8, 79.4, 61.5, 46.9, 38.8, 28.3, 28.2, 20.9 ppm; LRMS (ESI) Calculated for C₃₁H₄₀N₃O₄ m/z (M+H): 518.3, Obsd. 518.4.

4.2.5.5. tert-butyl (2E,5Z)-3-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((tert-butoxycarbonyl)imino)-5-(2-methylallylidene)imidazolidine-1-carboxylate (7e)

Prepared according to general procedure 5, to give the 5-exo-dig cyclized guanidine as a white solid in 80% yield (5-exo-dig:6-endo-dig = 10:1), (0.377 g). R_f = 0.45 (40% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 6.79-6.74 (m, 3H), 5.94 (s, 2H), 5.61 (s, 1H), 5.01 (s, 2H), 4.49 (s, 2H), 3.74 (s, 2H), 1.94 (s, 3H), 1.54 (s, 9H), 1.46 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.3, 151.8, 149.0, 148.0, 147.4, 140.0, 129.0, 128.3, 121.9, 118.9, 117.3, 108.9, 108.3, 101.1, 84.0, 79.2, 49.3, 48.1, 28.2, 28.0, 21.0 ppm; LRMS (ESI) Calculated for C₂₅H₃₄N₃O₆ m/z (M+H): 472.2, Obsd. 472.3.

4.2.5.6. tert-butyl (2E,5Z)-2-((tert-butoxycarbonyl)imino)-3-(2,4-dimethoxybenzyl)-5-(2-methylallylidene)imidazolidine-1-carboxylate (7f)

Prepared according to general procedure 5, to give the 5-exo-dig cyclized guanidine as a white solid in 60% yield (5-exo-dig:6-endo-dig = 9:1), (0.377 g). R_f = 0.39 (40% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.20 (m, 1H), 6.44 (m, 2H), 5.59 (s, 1H), 4.99 (s, 1H), 4.98 (s, 1H), 4.54 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.75 (s, 2H), 1.93 (s, 3H), 1.54 (s, 9H), 1.46 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.7, 159.2, 158.6, 151.7, 148.9, 140.0, 131.4, 128.8, 118.3, 116.8, 115.6, 104.3, 98.2, 83.5, 78.7, 55.1, 49.4, 42.4, 28.1, 28.0, 20.8 ppm; LRMS (ESI) Calculated for C₂₆H₃₈N₃O₆ m/z (M+H): 488.3, Obsd. 488.4.

4.2.5.7. tert-butyl (2E,5Z)-2-((tert-butoxycarbonyl)imino)-5-(cyclohex-1-en-1-ylmethylene)-3-methylimidazolidine-1-carboxylate (7g)

Prepared according to the general procedure 5, to give the 5-exo-dig cyclized guanidine as a white solid, (5-exo-dig:6-endo-dig = 1:1), (0.211 g, total 54% yield). R_f = 0.21 (60% ethyl acetate/N-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 5.76 (s. 1H), 5.58 (s, 1H), 3.90 (s, 2H), 2.97 (s, 3H), 2.20 (m, 2H), 2.14 (m, 2H), 1.63 (m, 4H), 1.51 (s, 9H), 1.46 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 158.9, 151.8, 149.2, 134.0, 129.1, 125.9, 119.9, 83.3, 78.9, 52.5,31.6, 28.1, 27.9, 26.8, 25.7, 22.6, 22.1 ppm; LRMS (ESI) Calculated for C₂₁H₃₄N₃O₄ m/z (M+H): 392.3, Obsd. 392.4.

4.2.5.8. tert-butyl (2E,5Z)-4-benzyl-2-((tert-butoxycarbonyl)imino)-3-(cyclopropylmethyl)-5-(2-methylallylidene)imidazolidine-1-carboxylate (7h)

Prepared according to the general procedure 5, to give the 5-exo-dig cyclized guanidine as a white solid in 79% yield (5-exo-dig:6-endo-dig = >20:1), (0.381 g). R_f = 0.16 (20% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.29 (m, 3H), 7.15 (m, 2H), 4.92 (s, 1H), 4.87 (s, 1H), 4.80 (s, 1H), 4.06 (dd, J = 9.8, 3.8 Hz, 1H), 3.70 (dd, J = 14.6, 6.6 Hz, 1H), 3.11 (dd, J = 13.0, 3.8 Hz, 1H), 3.00 (dd, J = 14.6, 7.5 Hz, 1H), 2.48 (dd, J = 13.0, 9.9 Hz, 1H), 1.88 (s, 3H), 1.54 (s, 9H), 1.51 (s, 9H), 1.03 (m, 1H), 0.64 (m, 1H), 0.56 (m, 1H), 0.30 (m, 1H), 0.26 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.7, 151.6, 149.4, 140.0, 135.9, 130.7, 129.2, 128.4, 127.1, 121.0, 117.4, 83.6, 79.1. 62.1, 47.7, 38.8, 28.2, 28.1, 20.8, 9.4, 4.8, 3.3 ppm; LRMS (ESI) Calculated for C₂₈H₄₀N₃O₄ m/z (M+H): 482.3, Obsd. 482.3.

4.2.6 General procedure 6 to form the cycloaddition of guanidine dienes 7a–h

To a stirring solution of the desired 5-exo-dig cyclic guanidine (diene, 1 equiv) in CH₂Cl₂ (0.07 M) was added the appropriate triazoledione (dienophile, 1.2 equiv). The reaction was stirred at room temperature until judged complete by TLC. After completion, the reaction mixture was concentrated by rotary evaporation, and purified by column chromatography to yield polycyclic guanidine.

4.2.6.1. tert-butyl (4R,10a′R,E)-1-benzyl-2-((tert-butoxycarbonyl)imino)-1′,3′-dioxo-2′-phenyl-2′,3′,8′,9′,10′,10a′-hexahydro-1′H,7′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]cinnoline]-3-carboxylate (8a)

Prepared according to the general procedure 6, to give the spirocyclic guanidine as white solid in 61% yield (0.118 g). R_f = 0.32 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.61-7.27 (m, 10H), 5.35 (s, 1H), 5.22 (d, J = 14.9 Hz, 1H), 4.40 (dd, J = 11.4, 3.5 Hz, 1H), 4.20 (d, J = 14.9 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.50 (d, J = 11.2 Hz, 1H), 2.46 (m, 1H), 2.40 (m, 1H), 2.14 (m, 1H), 1.96 (m, 1H), 1.90 (m, 1H), 1.60 (m, 1H), 1.49 (s, 9H), 1.42 (s, 9H), 1.37 (m, 1H), 1.30 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.1, 153.2, 151.6, 149.6, 148.7, 142.5, 135.6, 131.1, 129.2, 128.8, 128.7, 128.4, 127.8, 126.2, 115.8, 83.4, 78.5, 73.8, 56.8, 54.4, 49.9, 34.2, 31.1, 28.5, 28.2, 24.3 ppm; LRMS (ESI) Calculated for C₃₅H₄₃N₆O₆ m/z (M+H): 643.3, Obsd. 643.3.

4.2.6.2. tert-butyl (4R,5R,10a′R,E)-1,5-dibenzyl-2-((tert-butoxycarbonyl)imino)-1′,3′-dioxo-2′-phenyl-2′,3′,8′,9′,10′,10a′-hexahydro-1′H,7′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]cinnoline]-3-carboxylate (8b)

Prepared according to the general procedure 6, to give the spirocyclic guanidine as white solid in 94% yield (0.207 g). R_f = 0.54 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.59-7.35 (m, 5H), 7.23-7.14 (m, 8H), 6.95 (m, 2H), 5.49 (s, 1H), 4.95 (dd, J = 9.2, 5.2 Hz, 1H), 4.76 (d, J = 15.6 Hz, 1H), 4.68 (d, J = 15.6 Hz, 1H), 4.22 (dd, J = 11.6, 3.6 Hz, 1H), 2.96 (dd, J = 15.6, 5.2 Hz, 1H), 2.75 (dd, J = 15.6, 9.2 Hz, 1H), 2.30 (m, 1H), 2.20 (m, 1H), 2.00 (m, 1H), 1.69 (m, 1H), 1.61 (m, 1H), 1.49 (s, 9H), 1.40(s, 9H), 1.28 (m, 1H), 0.79 (m, 1H), 0.68 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.0, 152.9, 151.0, 149.8, 148.2, 141.4, 136.2, 135.8, 131.0, 129.1, 128.7, 128.4, 128.3, 128.2, 127.4, 126.8, 126.0, 112.2, 83.6, 78.5, 77.3, 63.7, 54.1, 48.8, 35.7, 34.2, 30.5, 28.5, 28.1, 26.8, 23.9 ppm; LRMS (ESI) Calculated for C₄₂H₄₉N₆O₆ m/z (M+H): 733.4, Obsd. 733.4.

4.2.6.3. tert-butyl (R,E)-1-benzyl-2-((tert-butoxycarbonyl)imino)-7′-methyl-1′,3′-dioxo-2′-phenyl-2′,3′-dihydro-1′H,8′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]pyridazine]-3-carboxylate (8c)

Prepared according to the general procedure 6, to give the spirocyclic guanidine as white solid in 56% yield (0.101 g). R_f = 0.16 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.58-7.26 (m, 10H), 5.45 (s, 1H), 5.14 (d, J = 14.9 Hz, 1H), 4.24 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 14.9 Hz, 1H), 3.99 (d, J = 16.8 Hz, 1H), 3.80 (d, J = 11.3 Hz, 1H), 3.47 (d, J = 11.3 Hz, 1H), 1.90 (s, 3H), 1.49 (s, 9H), 1.42 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.0, 152.7, 151.1, 150.0, 149.4, 135.4, 133.5, 130.9, 129.2, 128.7, 128.6, 128.4, 127.8, 126.0, 120.6, 83.3, 78.5, 73.7, 56.0, 49.6, 45.0, 28.4, 28.1, 19.9 ppm; LRMS (ESI) Calculated for C₃₂H₃₉N₆O₆ m/z (M+H): 603.3, Obsd. 603.4.

4.2.6.4. tert-butyl (4R,5R,E)-1,5-dibenzyl-2-((tert-butoxycarbonyl)imino)-7′-methyl-1′,3′-dioxo-2′-phenyl-2′,3′-dihydro-1′H,8′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]pyridazine]-3-carboxylate (8d)

Prepared according to the general procedure 6, to give the spirocyclic guanidine as pale yellow solid in 75% yield (0.156 g). R_f = 0.23 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.48-7.12 (m, 13H), 5.61 (s, 1H), 5.04 (d, J = 15.6 Hz, 1H), 4.88 (dd, J = 11.2, 4.9 Hz, 1H), 4.49 (d, J = 15.6 Hz, 1H), 3.88 (d, J = 16.6 Hz, 1H), 3.14 (dd, J = 14.7, 4.4 Hz, 1H), 2.80 (d, J = 16.6 Hz, 1H), 2.54 (dd, J = 14.7, 11.2 Hz, 1H), 1.77 (s, 3H), 1.50 (s, 9H), 1.36 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.0, 151.9, 149.7, 149.5, 149.1, 135.4, 135.3, 134.1, 130.8, 129.2, 128.8, 128.7, 128.4, 128.3, 128.2, 127.7, 126.8, 125.6, 117.3, 83.6, 78.9, 77.2, 62.0, 47.5, 43.9, 34.7, 28.5, 28.0, 20.1 ppm; LRMS (ESI) Calculated for C₃₉H₄₅N₆O₆ m/z (M+H): 693.3, Obsd. 693.4.

4.2.6.5. tert-butyl (R,E)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((tert-butoxycarbonyl)imino)-7′-methyl-1′,3′-dioxo-2′-phenyl-2′,3′-dihydro-1′H,8′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]pyridazine]-3-carboxylate (8e)

Prepared according to the general procedure 6, to give the spirocyclic guanidine as pale yellow solid in 87% yield (0.169 g). R_f = 0.17 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.58-7.34 (m, 5H), 6.83 (s, 1H), 6.74 (m, 2H), 5.92 (s, 2H), 5.46 (s, 1H), 5.01 (d, J = 14.6 Hz, 1H), 4.24 (d, J = 17.1 Hz, 1H), 4.13 (d, J = 14.6 Hz, 1H), 3.90 (d, J = 17.1 Hz, 1H), 3.78 (d, J = 11.4 Hz, 1H), 3.48 (d, J = 11.4 Hz, 1H), 1.90 (s, 3H), 1.49 (s, 9H), 1.42 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 158.9, 152.5, 151.0, 150.0, 149.3, 148.0, 147.3, 133.6, 130.9, 129.1, 129.0, 128.4, 125.9, 122.0, 120.5, 109.0, 108.2, 101.1, 83.2, 78.5, 73.6, 55.9, 49.3, 45.0, 28.4, 28.0, 20.0 ppm; LRMS (ESI) Calculated for C₃₃H₃₉N₆O₈ m/z (M+H): 647.3, Obsd. 647.4.

4.2.6.6. tert-butyl (R,E)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((tert-butoxycarbonyl)imino)-2′-ethyl-7′-methyl-1′,3′-dioxo-2′,3′-dihydro-1′H,8′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]pyridazine]-3-carboxylate (8f)

Prepared according to the general procedure 6, to give the spirocyclic guanidine as pale yellow solid in 91% yield (0.163 g). R_f = 0.17 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 6.84 (s, 1H), 6.76 (m, 2H), 5.94 (s, 2H), 5.41 (s, H), 4.98 (d, J = 14.7 Hz, 1H), 4.17 (d, J = 14.7 Hz, 1H), 4.14 (d, J = 17.1 Hz, 1H), 3.81 (d, J = 17.1 Hz, 1H), 3.72 (d, J = 11.2 Hz, 1H), 3.63 (qd, J = 7.3, 2.1 Hz, 2H), 3.42 (d, J = 11.2 Hz, 1H), 1.88 (s, 3H), 1.48 (s, 9H), 1.39 (s, 9H), 1.28 (t, J = 7.3 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.0, 152.2, 152.0, 151.4, 149.5, 148.1, 147.3, 133.4, 129.2, 122.1, 120.9, 109.1, 108.3, 101.2, 83.1, 78.6, 73.4, 55.8, 49.3, 45.0, 34.5, 28.5, 28.1, 20.0, 13.5 ppm; LRMS (ESI) Calculated for C₂₉H₃₉N₆O₈ m/z (M+H): 599.3, Obsd. 599.3.

4.2.6.7. tert-butyl (R,E)-2-((tert-butoxycarbonyl)imino)-1-(2,4-dimethoxybenzyl)-7′-methyl-1′,3′-dioxo-2′-phenyl-2′,3′-dihydro-1′H,8′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]pyridazine]-3-carboxylate (8g)

Prepared according to the general procedure 6, to give the spirocyclic guanidine as pale yellow solid in 97% yield (0.193 g). R_f = 0.13 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.57-7.25 (m, 6H), 6.41 (m, 2H), 5.44 (s, 1H), 4.85 (d, J = 14.5 Hz, 1H), 4.39 (d, J = 14.5 Hz, 1H), 4.21 (d, J = 16.9 Hz, 1H), 3.89 (d, J = 16.9 Hz, 1H), 3.87 (d, J = 11.3 Hz, 1H), 3.75 (s, 6H), 3.47 (d, J = 11.3 Hz, 1H), 1.88 (s, 3H), 1.48 (s, 9H), 1.40 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.6, 158.9, 158.7, 152.3, 150.7, 149.9, 149.4, 132.9, 131.5, 131.0, 129.0, 128.2, 125.8, 120.7, 115.6, 104.3, 98.2, 82.9, 78.1, 73.6, 55.7, 55.3, 55.2, 44.8, 43.2, 28.4, 27.9, 19.8 ppm; LRMS (ESI) Calculated for C₃₄H₄₃N₆O₈ m/z (M+H): 663.3, Obsd. 663.4.

4.2.6.8. tert-butyl (4R,10a′R,E)-2-((tert-butoxycarbonyl)imino)-1-methyl-1′,3′-dioxo-2′-phenyl-2′,3′,8′,9′,10′,10a′-hexahydro-1′H,7′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]cinnoline]-3-carboxylate (8h)

Prepared according to the general procedure 6, to give the spirocyclic guanidine as pale yellow solid in 76% yield (0.127 g). R_f = 0.13 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.59-7.33 (m, 5H), 5.43 (s, 1H), 4.42 (dd, J = 11.3, 3.4 Hz, 1H), 4.00 (d, J = 11.0 Hz, 1H), 3.82 (d, J = 11.0 Hz, 1H), 3.00 (s, 3H), 2.53 (m, 1H), 2.42 (m, 1H), 2.16 (m, 1H), 2.00 (m, 1H), 1.94 (m, 1H), 1.61 (m, 1H), 1.49 (m, 1H), 1.46 (s, 9H), 1.41 (s, 9H), 1.36 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 158.8, 153.1, 151.5, 149.3, 148.5, 142.6, 130.9, 129.0, 128.2, 126.0, 115.5, 83.0, 78.0, 73.6, 58.7, 54.2, 34.2, 32.2, 30.9, 28.3, 28.1, 28.0, 24.2 ppm; LRMS (ESI) Calculated for C₂₉H₃₉N₆O₆ m/z (M+H): 567.3, Obsd. 567.4.

4.2.6.9. tert-butyl (4R,5R,E)-5-benzyl-2-((tert-butoxycarbonyl)imino)-1-(cyclopropylmethyl)-7′-methyl-1′,3′-dioxo-2′-phenyl-2′,3′-dihydro-1′H,8′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]pyridazine]-3-carboxylate (8i)

Prepared according to general procedure 6, to give the spirocyclic guanidine as white solid in 88% yield (0.173 g). R_f = 0.30 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.51-7.13 (m, 10H), 5.57 (s, 1H), 5.24 (dd, J = 11.3, 4.3 Hz, 1H), 4.04 (dd, J = 14.6, 5.4 Hz, 1H), 3.92 (d, J = 16.6 Hz, 1H), 3.37 (dd, J = 14.6, 4.2 Hz, 1H), 2.88 (d, J = 16.6 Hz, 1H), 2.79 (dd, J = 14.6, 8.2 Hz, 1H), 2.67 (dd, J = 14.6, 11.3 Hz, 1H), 1.77 (s, 3H), 1.48 (s, 9H), 1.35 (s, 9H), 1.13 (m, 1H), 0.63 (m, 1H), 0.51 (m, 1H), 0.22 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.0, 151.8, 150.0, 149.8, 149.3, 135.9, 134.2, 131.0, 129.3, 129.0, 128.6, 128.4, 127.0, 125.8, 117.7, 83.4, 78.6, 77.2, 61.8, 48.0, 44.0, 34.8, 28.5, 28.1, 20.2, 8.5, 5.2, 2.5 ppm; LRMS (ESI) Calculated for C₃₆H₄₅N₆O₆ m/z (M+H): 657.3, Obsd. 657.4.

4.2.7. (4R,10a′R)-1-benzyl-2-imino-2′-phenyl-8′,9′,10′,10a′-tetrahydro-1′H,7′H-spiro[imidazolidine-4,5′-[1,2,4]triazolo[1,2-a]cinnoline]-1′,3′ (2′H)-dione (9a)

A 50 mL round-bottom flask was charged with the appropriate polycyclic guanidine (0.2 mmol). The CH₂Cl₂/TFA mixture (1:1, 4.0 mL) was added. The reaction mixture was stirred at room temperature for 2 hrs. The crude mixture was taken up in MeOH and 2 M HCl in ethyl ether was added. The mixture was again concentrated and the resulting solid triturated with ethyl ether. The solid was then collected to give the title compound as white solid in 50% yield (48 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 9.81 (s, 1H), 8.56 (s, 2H), 7.52-7.32 (m, 10H), 5.56 (s, 1H), 4.79 (d, J = 12.4 Hz, 1H), 4.56 (d, J = 12.4 Hz, 1H), 4.42 (m, 1H), 4.15 (s, 1H), 3.79 (s, 1H), 2.37 (m, 1H), 2.18 (m, 2H), 1.83 (m, 1H), 1.75 (m, 1H), 1.55 (m, 1H), 1.37 (m, 1H), 1.21 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 156.7, 152.0, 149.1, 140.8, 134.1, 130.4, 128.9, 128.4, 128.3, 127.8, 127.6, 126.0, 116.5, 72.6, 57.0, 53.7, 47.8, 32.7, 29.8, 27.3, 23.2 ppm; HRMS (ESI) Calculated for C₂₅H₂₇N₆O₂ m/z (M+H): 443.2195, Obsd. 443.2197.

4.2.8 General procedure 7 for the deprotection and fragmentation of 8a–i

A 50 mL round-bottom flask was charged with the appropriate polycyclic guanidine (0.2 mmol). The CH₂Cl₂/TFA mixture (1:1, 4.0 mL) was added. The reaction mixture was stirred at room temperature for 2 hrs. The crude mixture was taken up in MeOH and 2 M HCl in ethyl ether was added. The mixture was again concentrated and the resulting solid triturated with ethyl ether. The solid was then collected to give the title compound.

4.2.8.1. (R,Z)-1-(2-((2-amino-1-benzyl-1H-imidazol-4-yl)methylene)cyclohexyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10a)

Prepared according to the general procedure 7, to give the polycyclic guanidine as white solid in 50% yield (48 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 12.61 (s, 1H), 10.51 (s, 1H), 7.96 (s, 2H), 7.51-7.30 (m, 10H), 7.08 (s, 1H), 6.09 (s, 1H), 5.15 (d, J = 14.6 Hz, 1H), 5.10 (d, J = 14.6 Hz, 1H), 4.80 (s, 1H), 2.61 (m, 1H), 2.30 (m, 1H), 2.23 (m, 1H), 1.79 (m, 2H), 1.54 (m, 2H), 1.36 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 153.1, 152.8, 145.6, 140.1, 134.8, 131.3, 128.5, 127.8, 127.6, 127.3, 125.9, 121.7, 113.9, 113.1, 55.0, 47.4, 32.7, 29.2, 26.3, 20.2 ppm; HRMS (ESI) Calculated for C₂₅H₂₈N₆O₂ m/z (M+H): 443.2195, Obsd. 443.2197.

4.2.8.2. (R,Z)-1-(2-((2-amino-1,5-dibenzyl-1H-imidazol-4-yl)methylene)cyclohexyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10b)

Prepared according to the general procedure 7, to give the polycyclic guanidine as white solid in 85% yield (97 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 12.59 (s, 1H), 10.53 (s, 1H), 7.99 (s, 2H), 7.46-6.99 (m, 15H), 6.17 (s, 1H), 5.06 (d, J = 17.5 Hz, 1H), 4.99 (d, J = 17.5 Hz, 1H), 4.89 (s, 1H), 3.82 (d, J = 17.5 Hz, 1H), 3.78 (d, J = 17.5 Hz, 1H), 2.54 (m, 1H), 2.42 (m, 1H), 2.28 (m, 1H), 1.82 (m, 2H), 1.64 (m, 1H), 1.54 (s, 9H), 1.36 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 153.5, 153.2, 147.2, 142.5, 136.7, 134.7, 131.8, 128.7, 128.6, 128.5, 127.9, 127.8, 127.6, 126.6, 126.4, 126.1, 123.4, 119.3, 118.9, 55.4, 45.3, 33.0, 30.1, 27.8, 27.3, 20.5 ppm; HRMS (ESI) Calculated for C₃₂H₃₄N₆O₂ m/z (M+H): 533.2665, Obsd. 533.2669.

4.2.8.3. (Z)-1-(3-(2-amino-1-benzyl-1H-imidazol-4-yl)-2-methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10c)

Prepared according to the general procedure 7, to give the polycyclic guanidine as white solid in 80% yield (70 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 12.63 (s, 1H), 11.02 (s, 1H), 7.99 (s, 2H), 7.50-7.31 (m, 10H), 7.25 (s, 1H), 6.16, (s, 1H), 5.17 (s, 2H), 4.35 (s, 2H), 1.84 (s, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 152.6, 152.1, 145.8, 136.0, 135.2, 131.6, 128.8, 128.7, 128.0, 127.8, 127.5, 126.0, 122.0, 114.6, 114.5, 47.6, 47.2, 21.1 ppm; HRMS (ESI) Calculated for C₂₂H₂₃N₆O₂ m/z (M+H): 403.1882, Obsd. 403.1888.

4.2.8.4. (Z)-1-(3-(2-amino-1,5-dibenzyl-1H-imidazol-4-yl)-2-methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10d)

Prepared according to the general procedure 7, to give the polycyclic guanidine as white solid in 68% yield (72 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 12.73 (s, 1H), 11.05 (s, 1H), 7.96 (s, 2H), 7.52-7.02 (m, 15H), 6.30 (s, 1H), 5.05 (s, 2H), 4.12 (s, 2H), 3.82 (s, 2H), 1.83 (s, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 152.8, 152.3, 147.2, 136.7, 136.6, 134.8, 131.8, 128.9, 128.7, 128.6, 128.0, 127.9, 127.7, 126.7, 126.2, 126.1, 123.6, 119.4, 114.9, 47.2, 45.3, 28.0, 21.3 ppm; HRMS (ESI) Calculated for C₂₉H₂₉N₆O₂ m/z (M+H): 493.2352, Obsd. 493.2363.

4.2.8.5. (Z)-1-(3-(2-amino-1-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-imidazol-4-yl)-2-methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10e)

Prepared according to the general procedure 7, to give the polycyclic guanidine as pale yellow solid in 81% yield (78 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 12.40 (s, 1H), 10.91 (s, 1H), 7.85 (s, 2H), 7.30-7.18 (m, 5H), 7.09 (s, 1H), 6.87 (s, 1H), 6.76-6.69 (m, 2H), 5.95 (s, 1H), 5.80 (s, 2H), 4.87 (s, 2H), 4.16 (s, 2H), 1.63 (s, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 152.7, 152.3, 147.2, 145.7, 136.0, 131.7, 128.9, 128.8, 127.9, 126.1, 122.0, 121.8, 114.8, 114.4, 108.6, 108.4, 101.2, 47.5, 47.3, 21.2 ppm; HRMS (ESI) Calculated for C₂₃H₂₃N₆O₄ m/z (M+H): 447.1781, Obsd. 447.1785.

4.2.8.6. (Z)-1-(3-(2-amino-1-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-imidazol-4-yl)-2-methylallyl)-4-ethyl-1,2,4-triazolidine-3,5-dione (10f)

Prepared according to the general procedure 7, to give the polycyclic guanidine as white solid in 86% yield (75 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 12.58 (s, 1H), 10.63 (s, 1H), 8.01 (s, 2H), 7.24 (s, 1H), 7.05-6.88 (m, 3H), 6.09 (s, 1H), 6.00 (s, 2H), 5.05 (s, 2H), 4.24 (s, 2H), 3.42 (q, J = 7.3 Hz, 2H), 1.72 (s, 3H), 1.10 (t, J = 6.8 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 154.0, 153.6, 147.5, 147.2, 145.7, 136.2, 128.8, 122.0, 121.8, 114.5, 114.3, 108.6, 108.4, 101.2, 47.5, 47.1, 33.5, 21.1, 13.1 ppm; HRMS (ESI) Calculated for C₁₉H₂₃N₆O₄ m/z (M+H): 399.1781, Obsd. 399.1786.

4.2.8.7. (Z)-1-(3-(2-amino-1-(2,4-dimethoxybenzyl)-1H-imidazol-4-yl)-2-methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10g)

Prepared according to the general procedure 7, to give the polycyclic guanidine as pale yellow solid in 80% yield (80 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 12.63 (s, 1H), 11.07 (s, 1H), 7.88 (s, 2H), 7.48-7.23 (m, 6H), 6.96 (s, 1H), 6.56-6.50 (m, 2H), 6.14 (s, 1H), 4.97 (s, 2H), 4.33 (s, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 1.82 (s, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 160.9, 158.0, 152.7, 152.2, 145.8, 135.7, 131.6, 130.2, 128.8, 127.8, 126.1, 126.0, 121.5, 114.9, 114.8, 114.5, 104.6, 98.5, 55.5, 55.3, 47.2, 43.5, 21.2 ppm; HRMS (ESI) Calculated for C₂₄H₂₇N₆O₄ m/z (M+H): 463.2094, Obsd. 463.2094.

4.2.8.8. (R,Z)-1-(2-((2-amino-1-methyl-1H-imidazol-4-yl)methylene)cyclohexyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10h)

Prepared according to the general procedure 7, to give the polycyclic guanidine as white solid in 83% yield (67 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 12.57 (s, 1H), 10.59 (s, 1H), 7.77 (s, 2H), 7.46-7.37 (m, 5H), 7.02 (s, 1H), 6.09 (s, 1H), 4.81 (s, 1H), 3.43 (s, 3H), 2.63 (m, 1H), 2.37 (m, 1H), 2.23 (m, 1H), 1.82 (m, 2H), 1.53 (m, 2H), 1.37 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 153.1, 152.8, 145.8, 139.9, 131.4, 128.5, 127.6, 126.0, 121.1, 115.0, 113.0, 55.2, 32.8, 32.1, 29.4, 26.6, 20.3 ppm; HRMS (ESI) Calculated for C₁₉H₂₃N₆O₂ m/z (M+H): 367.1882, Obsd. 367.1880.

4.2.8.9. (Z)-1-(3-(2-amino-5-benzyl-1-(cyclopropylmethyl)-1H-imidazol-4-yl)-2-methylallyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (10i)

Prepared according to the general procedure 7, to give the polycyclic guanidine as white solid in 80% yield (79 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 12.53 (s, 1H), 10.96 (s, 1H), 7.76 (s, 2H), 7.50-7.19 (m, 10H), 6.28 (s, 1H), 4.49 (s, 2H), 4.00 (s, 2H), 3.66 (d, J = 4.2 Hz, 2H), 1.82 (s, 3H), 0.89 (m, 1H), 0.35 (m, 2H), 0.27 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 152.8, 152.2, 146.7, 137.0, 136.1, 131.7, 128.8, 128.7, 128.0, 127.8, 126.7, 126.1, 123.4, 119.0, 114.8, 47.3, 46.0, 27.8, 21.2, 10.0, 3.3 ppm; HRMS (ESI) Calculated for C₂₆H₃₀N₆O₂ m/z (M+H): 458.2430, Obsd. 458.2430.

4.2.9. General procedure 8 for the hetero cycloaddition of cyclic guanidines

To a stirring solution of the preferred cyclic guanidine (diene,1 equiv) and benzyl hydroxycarbamate 11 (dienophile, 1.2 equiv) in THF (0.07 M) was added CuCl (20 mol%) and pyridine (5 mol%). The reaction was stirred at room temperature open to the air until completed by TLC. Upon completion, the reaction was quenched with EDTA (0.5 M, pH 7.0), diluted with ethyl acetate and stirred for 30 min. The reaction was extracted with ethyl acetate three times and the combined organic layers were then dried over Na₂SO₄, filtered, and condensed by rotary evaporation. Purification was accomplished by flash chromatography to give the polycyclic guanidine.

4.2.9.1. 6-benzyl 1-(tert-butyl) (4aR,6aS,E)-2-((tert-butoxycarbonyl)imino)-3-methyl-3,4,4a,6a,7,8,9,10-octahydro-1H-benzo[c]pyrimido[4,5-e][1,2]oxazine-1,6(2H)-dicarboxylate (12a)

The general procedure 8 was used to give the polycyclic guanidine as pale yellow solid. (0.160 g, 72% yield). R_f = 0.52 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.31 (m. 5H), 5.25 (d, J = 12.7 Hz, 1H), 5.20 (d, J = 12.7 Hz, 1H), 4.80 (br, 1H), 3.59 (dd, J = 14.07, 7.3 Hz, 1H), 3.25 (d, J = 13.7 Hz, 1H), 3.16 (d, J = 14.2 Hz, 1H), 2.98 (s, 3H), 2.10 (m, 1H), 1.85 (m, 2H), 1.68 (m, 2H), 1.51 (s, 9H), 1.45 (m, 1H), 1.41 (s, 9H), 1.32 (m, 1H), 1.27 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.4, 154.2, 151.7, 149.2, 136.0, 134.0, 128.7, 128.6, 128.4, 128.2, 82.6, 78.6, 76.6, 67.7, 56.4, 49.9, 37.5, 32.2, 28.3, 28.1, 28.0, 26.3, 24.8 ppm; LRMS (ESI) Calculated for C₂₉H₄₁N₄O₇ m/z (M+H): 567.3, Obsd. 567.4.

4.2.9.2. 6-benzyl 1-(tert-butyl) (4aR,6aS,E)-2-((tert-butoxycarbonyl)imino)-3-(2,4-dimethoxybenzyl)-3,4,4a,6a,7,8,9,10-octahydro-1H-benzo[c]pyrimido[4,5-e][1,2]oxazine-1,6(2H)-dicarboxylate (12b)

Prepared according to the general procedure 8, to give the polycyclic guanidine as pale yellow solid in 51% yield (0.141 g). R_f = 0.33 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.31 (m, 5H), 7.13 (m, 1H), 6.39 (m, 2H), 5.17 (d, J = 14.2 Hz, 1H), 5.14 (d, J = 14.2 Hz, 1H), 5.05 (d, J = 14.7 Hz, 1H), 4.76 (br, 1H), 4.07 (d, J = 14.7 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 3.47 (dd, J = 14.7, 7.3 Hz, 1H), 3.32 (m, 1H), 3.22 (d, J = 14.7 Hz, 1H), 2.03 (m, 1H), 1.83 (m, 2H), 1.68 (m, 1H), 1.49 (s, 9H), 1.46 (m, 1H), 1.39 (s, 9H), 1.37 (m, 1H), 1.25 (m, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.6, 159.6, 159.0, 158.7, 154.4, 152.3, 149.5, 135.8, 130.5, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 117.0, 104.4, 98.5, 82.8, 79.0, 77.2, 67.6, 55.5, 55.4, 47.2, 46.2, 32.4, 28.5, 28.4, 28.3, 28.1, 26.6, 24.9 ppm; LRMS (ESI) Calculated for C₃₇H₄₉N₄O₉ m/z (M+H): 693.3, Obsd. 693.5.

4.2.9.3. 2-benzyl 5-(tert-butyl) (R,E)-7-(benzo[d][1,3]dioxol-5-ylmethyl)-6-((tert-butoxycarbonyl)imino)-4-methyl-6,7,8,8a-tetrahydro-2H-pyrimido[4,5-e][1,2]oxazine-2,5(3H)-dicarboxylate (12c)

Prepared according to the general procedure 8, to give the polycyclic guanidine as white solid in 61% yield (0.155 g). R_f = 0.38 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.33 (m, 5H), 6.74-6.67 (m, 3H), 5.90 (s, 2H), 5.22 (d, J = 12.2 Hz, 1H), 5.15 (d, J = 12.2 Hz, 1H), 4.81 (br, 1H), 4.68 (d, J = 15.2 Hz, 1H), 4.36 (d, J = 15.7 Hz, 1H), 4.33 (d, J = 15.2 Hz, 1H), 3.92 (d, J = 15.7 Hz, 1H), 3.38 (dd, J = 14.7, 7.3 Hz, 1H), 3.10 (d, J = 14.7 Hz, 1H), 1.95 (s, 3H), 1.52 (s, 9H), 1.43 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.9, 155.0, 151.8, 149.3, 148.0, 147.3, 135.8, 129.7, 128.7, 128.6, 128.3, 127.6, 123.9, 121.9, 108.9, 108.3, 101.1, 82.9, 79.3, 75.8, 68.1, 52.0, 48.3, 46.5, 28.3, 28.1, 14.8 ppm; LRMS (ESI) Calculated for C₃₃H₄₁N₄O₉ m/z (M+H): 637.3, Obsd. 637.4.

4.2.10 General procedure 9 for the deprotection and salt exchange of 12a–c

A 50 mL round-bottom flask was charged with the appropriate polycyclic guanidine (0.2 mmol). The CH₂Cl₂/TFA mixture (1:1, 4.0 mL) was added. The reaction mixture was stirred at room temperature for 2 hrs, then the solvent removed under reduced pressure. The crude mixture was taken up in MeOH and 2 M HCl in ethyl ether was added. The mixture was again concentrated and the resulting solid triturated with ethyl ether. The solid was then collected to give the title compound.

4.2.10.1. (4aR,6aS)-3-methyl-4,4a,6,6a,7,8,9,10-octahydro-1H-benzo[c]pyrimido[4,5-e][1,2]oxazin-2(3H)-imine (13a)

Prepared according to general procedure 9 (0.3 mmol scale), to give polycyclic guanidine as yellow solid in 95% yield (74 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.88 (s, 1H), 8.08 (s, 2H), 5.07 (s, 1H), 3.78 (s, 1H), 3.69 (s, 1H), 3.30 (d, J = 12.2 Hz, 1H), 3.01 (s, 3H), 2.92 (d, J = 12.2 Hz, 1H), 2.10 (m, 1H), 1.78 (m, 3H), 1.71 (m, 1H), 1.51 (m, 2H), 1.15 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 151.7, 119.5, 111.1, 66.3, 54.7, 47.4, 37.2, 30.2, 26.1, 25.9, 23.7 ppm; HRMS (ESI) Calculated for C₁₁H₁₉N₄O m/z (M+H): 223.1559, Obsd. 223.1561.

4.2.10.2. (4aR,6aS)-3-(2,4-dimethoxybenzyl)-4,4a,6,6a,7,8,9,10-octahydro-1H-benzo[c]pyrimido[4,5-e][1,2]oxazin-2(3H)-imine (13b)

Prepared according to the general procedure 9 (0.3 mmol scale), to give polycyclic guanidine as pale yellow solid in 89% yield (105 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.28 (s, 2H), 7.21 (m, 1H), 6.61-6.52 (m, 2H), 4.98 (m, 1H), 4.55 (d, J = 15.7 Hz, 1H), 4.47 (d, J = 15.7 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.55 (m, 1H), 3.15 (t, J = 10.7 Hz, 1H), 2.95 (m, 1H), 2.10 (m, 1H), 1.77 (m, 3H), 1.50 (m, 2H), 1.17 (m, 1H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 160.8, 158.3, 151.5, 130.4, 119.7, 113.7, 104.7, 98.6, 66.4, 55.6, 55.3, 54.7, 48.0, 45.0, 30.2, 26.2, 25.9, 23.8 ppm; HRMS (ESI) Calculated for C₁₉H₂₇N₄O₃ m/z (M+H): 359.2083, Obsd. 359.2092.

4.2.10.3. (R)-7-(benzo[d][1,3]dioxol-5-ylmethyl)-4-methyl-3,7,8,8a-tetrahydro-2H-pyrimido[4,5-e][1,2]oxazin-6(5H)-imine (13c)

Prepared according to general procedure 9 (0.3 mmol scale), to give polycyclic guanidine as yellow solid in 95% yield (96 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.40 (s, 2H), 6.94-6.82 (m, 3H), 6.01 (s, 2H), 4.97 (m, 1H), 4.59 (d, J = 16.1 Hz, 1H), 4.53 (d, J = 16.1 Hz, 1H), 3.77 (d, J = 15.7 Hz, 1H), 3.62 (m, 1H), 3.59 (d, J = 15.7 Hz, 1H), 3.13 (t, J = 10.3 Hz, 1H), 1.77 (s, 3H) ppm; ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 151.3, 147.6, 147.1, 127.9, 121.9, 121.5, 108.4, 108.3, 104.4, 101.2, 66.6, 51.9, 46.4, 45.4, 13.4 ppm; HRMS (ESI) Calculated for C₁₅H₁₉N₄O₃ m/z (M+H): 303.11457, Obsd. 303.1458.

4.2.11. N-((E)-amino((cyclopropylmethyl)(4-methylpent-4-en-2-yn-1-yl)amino)methylene)cinnamamide (14)

N-cyanocinnamamide (0.172 g, 1.0 mmol) was stirred in CH₂Cl₂ (10 mL). Chlorotrimethylsilane (0.152 mL, 1.2 mmol) and NEt₃ (0.209 mL, 1.5 mmol) were then added and the mixture stirred for 15 min. Secondary amine S-2k (0.149 g, 1.0 mmol) was then added. Upon completion (as judged by TLC on a basified reaction aliquot), the reaction mixture was washed 3 times with NaHCO₃ and then washed with a sat. brine solution. The combined organic layers were dried over Na₂SO₄, filtered and concentrated by rotary evaporation. Purification was accomplished by flash chromatography to yield the propagylguaniline as a pale yellow oil (0.209 g, 65% yield). R_f = 0.44 (60% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.66 (d, J = 16.2 Hz, 1H), 7.55 (m, 2H), 7.36-7.29 (m. 3H), 6.67 (d, J = 16.2 Hz, 1H), 5.29 (s, 1H), 5.24 (s, 1H), 4.50 (s, 2H), 3.46 (s, 2H), 1.86 (s, 3H), 1.08 (m, 1H), 0.59 (m, 2H), 0.34 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 177.8, 160.6, 139.9, 136.0, 129.2, 129.0, 128.7, 127.9, 126.1, 122.7, 86.1, 82.7, 51.4, 37.2, 23.4, 9.6, 4.0 ppm; LRMS (ESI) Calculated for C₂₀H₂₄N₃O m/z (M+H): 322.2, Obsd. 322.2.

4.2.12 (R,Z)-1-(cyclopropylmethyl)-3-(2-methylallylidene)-7-phenyl-2,3,6,7-tetrahydroimidazo[1,2-a]pyrimidin-5(1H)-one (15)

To a stirring solution of propargylguanidine 14 (0.5 mmol) in acetonitrile (5.0 mL) was added silver nitrate (0.05 mmol, 10 mol%). After completion, the reaction mixture was concentrated by rotary evaporation, and purified by column chromatography to yield the bicyclic guanidine as pale yellow solid in 83% yield (0.133 g). R_f = 0.43 (60% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.22 (m, 5H), 5.67 (s, 1H), 4.99 (s, 1H), 4.75 (s, 1H), 4.74 (dd, J = 10.8, 4.4 Hz, 1H), 4.13 (d, J = 11.9 Hz, 1H), 4.05 (d, J = 11.9 Hz, 1H), 3.33 (dd, J = 14.0, 6.5 Hz, 1H), 3.22 (dd, J = 14.0, 6.5 Hz, 1H), 2.84 (dd, J = 17.7, 4.4 Hz, 1H), 2.47 (dd, J = 17.7, 10.8 Hz, 1H), 1.83 (s, 3H), 1.01 (m, 1H), 0.59 (m, 2H), 0.26 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.3, 151.6, 143.5, 141.1, 128.6, 127.2, 126.5, 126.4, 116.1, 114.9, 56.4, 50.9, 49.1, 40.6, 22.0, 8.8, 3.7, 3.5 ppm; LRMS (ESI) Calculated for C₂₀H₂₄N₃O m/z (M+H): 322.2, Obsd. 322.2.

4.2.13. (3R,7R)-1-(cyclopropylmethyl)-7′-methyl-2′,7-diphenyl-1,2,2′,6,7-pentahydro-1′H,5H,8′H-spiro[imidazo[1,2-a]pyrimidine-3,5′-[1,2,4]triazolo[1,2-a]pyridazine]-1′,3′,5-trione (16)

To a stirring solution of the desired 5-exo-dig cyclic guanidine (diene, 1 equiv) in CH₂Cl₂ (0.07 M) was added the appropriate triazoledione (dienophile, 1.2 equiv). After completion, the reaction mixture was concentrated by rotary evaporation, and purified by column chromatography to give the polycyclic guanidine as white solid in 40% yield (0.060 g). R_f = 0.33 (40% ethyl acetate/n-hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.51-7.22 (m, 10H), 5.54 (d, J = 1.5 Hz, 1H), 4.78 (dd, J = 11.7, 4.9 Hz, 1H), 4.37 (d, J = 16.6 Hz, 1H), 4.17 (d, J = 9.8 Hz, 1H), 4.07 (d, J = 16.6 Hz, 1H), 3.73 (d, J = 9.8 Hz, 1H), 3.43 (dd, J = 14.9, 6.9 Hz, 1H), 3.16 (dd, J = 14.9, 6.9 Hz, 1H), 2.73 (dd, J = 16.6, 4.9 Hz, 1H), 2.40 (dd, J = 16.6, 11.7 Hz, 1H), 1.94 (s, 3H), 1.01 (m, 1H), 0.55 (m, 2H), 0.23 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.9, 151.1, 150.2, 149.4, 144.2, 132.5, 131.1, 129.4, 128.7, 128.5, 127.2, 126.5, 125.7, 119.7, 72.0, 57.0, 56.5, 49.8, 45.4, 40.2, 20.1, 8.8, 3.7, 3.6 ppm; HRMS (ESI) Calculated for C₂₈H₂₉N₆O₃ m/z (M+H): 497.2301, Obsd. 497.2309.