Synthesis of 4-Selenothreofuranose Derivatives via Pummerer-Type Reactions of trans-3,4-Dioxygenated Tetrahydroselenophenes Mediated by a Selenonium Intermediate

Abstract

Selenosugars are interesting targets of organic synthesis as they would possess potential biological activities. However, 4-selenotherofuranose derivatives, which have trans configuration for the two dihydroxy substituents at the 2,3-positions and a glycoside bond at the anomeric position, are not available in the current selenosugar library. In this study, racemic 4-selenothreofuranose derivatives were synthesized from trans-3,4-dioxygenated tetrahydroselenophenes in 77–99% yields with the α/β selectivity about 7:3 via oxidation and subsequent seleno-Pummerer rearrangement. The acetoxy group introduced at the anomeric position was then substituted with various nucleophiles, including activated 6-chloropurine, which afforded 4′-selenothreonucleoside derivatives, in the presence of BF₃·OEt₂ or TMSOTf. The stereochemistry of the selenosugar products was established by ¹H NMR spectroscopy as well as X-ray analysis. The similar α/β selectivity observed in the latter glycosylation reaction to that in the former seleno-Pummerer rearrangement suggested the mediation of a common selenonium intermediate (−Se⁺=C<). It was also suggested that an unexpected interaction between the ester protecting group at the 3-position of the selenofuranose ring and the anomeric carbon atom decreases the α/β selectivity.

Introduction

Selenosugars are intriguing carbohydrates which bring a biologically unique selenium atom substituting the oxygen atom or at any other positions of a sugar molecule. Various selenosugars have already been synthesized¹⁻⁶ during the course of an extensive research on thiosugars and their conjugates with a nucleobase, that is, thionucleosides.⁷⁻¹¹ Some representative examples are shown in Figure 1. Ogra and co-workers^12,13 characterized 1β-methylseleno-N-acetyl-d-galactosamine (1) as a major urinary selenium metabolite of rats fed with sodium selenite. Benzyl (Bn)-protected 1,4-anhydro-4-seleno-d-arabinitol (2) was synthesized by Pinto’s group¹⁴ and Se-alkylated to afford selenium congeners of ponkoranol, which exhibited high inhibitory activities against glucosidase enzymes.¹⁵ The same group also reported the synthesis of 4-seleno-d-galactitol derivative (3a) and investigated its functionalization applying Pummerer-like reactions.¹⁶ On the other hand, significant in vitro antioxidant activities of 1,4-anhydro-4-seleno-d-talitol (3b) and the related selenosugars were recently reported by Davies and Schiesser.¹⁷ In the meantime, Pinto and co-workers^18,19 succeeded in the stereoselective synthesis of a series of 4′-seleno-d-ribonucleosides (4) and applied the thymidine variant to the synthesis of oligonucleotides, which revealed a unique conformational shift arising from the introduced selenonucleoside. Thus, selenosugars and selenonucleosides are interesting targets of organic synthesis as they would possess potential biological activities, such as enzyme inhibitors,^14,15 antioxidants,^17,20 antibiotics,²¹⁻²³ and so forth.²⁴ However, 4-selenotherofuranose derivatives, which have trans configuration for the two dihydroxy substituents at the 2,3-positions such as 2 and 3a and a glycoside bond at the anomeric position, are not available in the current selenosugar library.

Figure 1.

Examples of selenosugars.

To access 4′-selenonucleoside derivatives, such as 4, Pummerer rearrangement²⁵⁻²⁷ is a useful synthetic tool. Indeed, the reaction has successfully been applied to the synthesis of various 4′-selenonucleosides via stereoselective introduction of a nucleobase into a tetrahydroselenophene skeleton.^18,28−30 The typical synthetic schemes are shown in Scheme 1 along with that employed in this study. Minakawa²⁹ synthesized 4′-selenouridine and 4′-selenocytidine applying the Pummerer-like reaction to a selenosugar substrate protected with tetraisopropyldisiloxan-1,3-diyl (TIPDS) and 2,4-dimethoxybenzoyl groups. The selenosugar was oxidized by iodosylbenzene, which generated a selenonium intermediate in the presence of 2,6-lutidine and trimethylsilyl trifluoromethanesufonate (TMSOTf), and reacted with a nucleobase (Scheme 1a). On the other hand, Jeong³¹ synthesized 4′-selenoribonucleoside derivatives applying a two-step strategy (Scheme 1b). The selenosugar substrate was first converted to a selenoribose derivative by seleno-Pummerer rearrangement, and then the acetoxy group introduced at the anomeric position was substituted with a nucleobase activated with N,O-bis(trimethylsilyl)acetamide (BSA) in the presence of TMSOTf. In these syntheses, the β anomers were dominantly obtained due to the intramolecular interaction between the anomeric carbon atom and the neighboring substituent during the selenonium intermediate.

Scheme 1. Synthesis of Selenonucleosides.

In our group, a water-soluble cyclic selenide, trans-3,4-dihydroxy-1-selenolane (DHS, 5), was developed and utilized as a redox reagent for oxidative folding of various proteins,³²⁻³⁴ a selenoenzyme model,³⁵⁻³⁷ a radical scavenger,³⁸⁻⁴⁰ and so forth⁴¹ with pertinent modifications. As another possible application of 5, we have planned its transformation to selenothreofuranose derivatives having a trans-2,3-dioxygenated configuration (Scheme 1c). Herein, we report that the seleno-Pummerer rearrangement of 5 with acid anhydrides affords 4-selenothreofuranose derivatives in good yields (77–99%). The acyloxy substituent introduced at the anomeric position can be further converted to other functional groups by the treatment with various nucleophiles, including an activated purine base, in the presence of a Lewis acid.

Results and Discussion

Se-Pummerer Rearrangement of 5

After protecting the hydroxy groups of racemic 5, the obtained 6a–f were oxidized to selenoxides 7a–f and were reacted with acid anhydrides to induce seleno-Pummerer rearrangement. The results are summarized in Table 1.

Table 1. Conversion of Protected DHS (6a–f) to 4-Selenothreofuranose Derivatives (8a–f) via Oxidation and Subsequent Seleno-Pummerer Rearrangement.

				condition
entry	substrate	X	R	(RCO)2O	solvent	temp/time	product	yield (%)	α/β ratioa
1	6a	Ac	Me	neat		100 °C/1 h	8a	79	56:44
2	6a	Ac	Me	1.2 eq	toluene	70 °C/2.5 h	8a	52	49:51
3	6b	Bz	Me	>10 eq	toluene	100 °C/2 h	8b	83	45:55
4	6c	Bn	Me	2 eq	toluene	90 °C/1.5 h	8c	94	68:32
5	6d	PMBb	Me	>10 eq	toluene	100 °C/2 h	8d	87	69:31
6	6e	TBS	Me	neat		100 °C/1 h	8e	88	70:30
7	6f	TIPDSc	Me	3 eq	toluene	90 °C /2 h	8f	98	81:19
8	6b	Bz	Ph	2 eq	toluene	90 °C/1.5 h	8b′	77	50:50
9	6c	Bn	Ph	2 eq	toluene	90 °C/1.5 h	8c′	99	75:25

^aRatios were determined by integration of the ¹H NMR peaks for 8. See the text for details.

^b4-Methoxybenzyl.

^cTetraisopropyldisiloxan-1,3-diyl (-Si(iPr)₂OSi(iPr)₂-).

In our initial attempt, selenide 6a (X = Ac) was oxidized by m-chloroperoxybenzoic acid (mCPBA). However, selenoxide 7a could not be isolated due to the reduction back to 6a. Therefore, acetic anhydride (Ac₂O) was added to the crude mixture without isolation of 7a. In this case, however, rearrangement product 8a was obtained in low yields (∼30%) probably due to an adverse effect of the coexisting byproducts from mCPBA. Indeed, when the oxidant was changed to hydrogen peroxide (H₂O₂), the reaction of the crude product 7a with Ac₂O afforded 8a in 79% yield (entry 1). The yield was decreased with the formation of the deacetylated products when the reaction was carried out in toluene (entry 2). Similar reaction conditions were applied for 6b–f to obtain the corresponding rearrangement products 8b–f in 83–98% yields (entries 3–7). Similarly, when benzoic anhydride (Bz₂O) was employed instead of Ac₂O, the expected products (8b′and 8c′) were obtained in good yields (entries 8 and 9). The results demonstrated that the DHS (5) can be efficiently converted to 4-selenothreofuranose derivatives applying the seleno-Pummerer rearrangement reaction. We also attempted to introduce a chloride or a nucleobase at the 2-position of 6 using thionyl chloride or activated uracil²⁸ instead of Ac₂O, but the desired products were not obtained.

Assignment of the α and β Anomers

Seleno-Pummerer rearrangement products 8a–f were obtained as a mixture of α and β anomers. These stereoisomers could not be separated by chromatography, but they exhibited different peaks in the NMR spectra. Indeed, their α/β ratios could be determined by integrating the clearly separated peaks in the ¹H NMR spectrum. For example, in the case of 8a (Table 1, entry 1), the major anomer showed the peaks at δ 6.03 (d, C¹H), 5.61 (dd, C²H), 5.37 (q, C³H), 3.25 (dd, C⁴H^A), and 3.14 (dd, C⁴H^B), while the corresponding peaks for the minor anomer appeared separately at δ 6.22 (d, C¹H), 5.50 (m, C²H), 5.24 (dd, C³H), 3.31 (dd, C⁴H^A), and 2.68 (dd, C⁴H^B). A downfield shift of C¹H and an upfield shift of C⁴H^B observed for the minor anomer were particularly remarkable. Similar spectral features were commonly detected for the other seleno-Pummerer rearrangement products (see Table S1). The ratios of the major and minor anomers thus determined were about 7:3 except for 8a (X = Ac), 8b (X = Bz), and 8b′ (X = Bz) having ester protections (Table 1, entries 1–3 and 8). It is also notable that in the case of a cyclic protecting group, that is, for 8f (X = TIPDS), the ratio was improved presumably due to the restriction of the conformational flexibility.

Assignments of the stereochemistry for the major and minor anomers were unambiguously established by isolation of the one isomer of 8b′ (X = Bz and R = Ph) by recrystallization. The single-crystal X-ray analysis revealed that the isolated isomer has all trans configuration for the three OBz substituents (Figure 2A). According to the formal nomenclature rule as well as a recent literature,⁴² this isomer, which has an upward substituent at the anomeric position, is hereafter called an α anomer. It should be noted that the assignment is opposite to those for d-glucopyranose and d-ribofuranose. The OBz substituents at the C² and C³ positions of the 4-selenothreofuranose ring resided in the axial directions. A similar diaxial structure is frequently observed for the derivatives of 5(43,44) as well as for 6b (Figure S1), suggesting a significant preference of the 4-selenothreofuranose skeleton to adopt a diaxial conformation. Another OBz substituent of 8b′ at the C¹ or anomeric position was tilted from the axial direction due to a twisted structure of the 4-selenothreofuranose ring. Since the α anomer of 8b′ showed in the ¹H NMR spectrum characteristic features (Figure 2B) similar to those observed for the major anomers of 8a–f and 8c′, it was confirmed that an α anomer was usually obtained as a major product of seleno-Pummerer rearrangement for 6 (see Table 1). Interestingly, the coupling constants observed for the C¹H proton (³J_H¹H²) were small (2.5–4.0 and 4.0–5.0 Hz for the α and β anomers of 8, respectively) (Table S1), suggesting a gauche form of the C¹H and C²H protons for both anomers. This is indeed consistent with a 2,3-diaxial conformation as observed for 8b′ in the solid state (Figure 2A). Thus, the 4-selenothreofuranose derivatives may maintain a similar 2,3-diaxial conformation in solution too for both anomers.

Figure 2.

Structural characterization of 8b′ (X = Bz and R = Ph). (A) Molecular structure for the α anomer of 8b′ determined by X-ray analysis. The ellipsoids are drawn with 50% probability. (B) ¹H NMR spectra for the isolated α anomer of 8b′ and the mixture of the α and β anomers in the regions of the CH protons (top) and the CH₂ protons (bottom).

Glycosylation of 4-Selenothreofuranose Derivatives

Subsequently, we substituted the acetoxy (OAc) group at the anomeric position of 8a–f to other functional groups, including a nucleobase analogue. As a pilot experiment, the reactions of 8c (X = Bn and R = Me) with methanol (MeOH) in the presence of an acid or a base were investigated (Table 2).

Table 2. Methanolysis and Glycosylation of 8c.

entry	acid or base	eq	condition	yield of 9c (%)a	yield of 10c (%)a
1	K2CO3	0.5	0 °C/1.5 h	48 (76:24)	0
2	BF3·OEt2	6	rt/18 h	88 (66:34)	7
3	BF3·OEt2	1.5	reflux/18 h	0	95 (72:28)
4	AlCl3	3	rt/18 h	66 (67:33)	0
5	TMSOTf	4	rt/18 h	56 (73:27)	17 (49:51)
6	TMSOTf	1	reflux/18 h	0	86 (54:46)

^aThe values in parentheses are the α/β ratios determined by integration of the ¹H NMR peaks.

When potassium carbonate was employed as a base in MeOH, methanolysis took place, producing hemiselenoacetal 9c in 48% yield (entry 1). In this reaction, a plausible diselenide byproduct, which would be formed by air oxidation of the ring-opened selenol isomer of 9c, was also obtained. The α/β anomeric ratio of 9c was 76:24, which was slightly augmented from that of the substrate’s starting anomeric composition. On the other hand, when boron trifluoride etherate (BF₃·OEt₂) was applied as a Lewis acid, the yield of 9c was significantly improved (entry 2), accompanied by formation of a small amount of glycoside 10c. Thus, the occurrence of glycosylation of 8c in addition to the methanolysis was suggested. Indeed, when the reaction was carried out at the reflux temperature, 10c was obtained almost quantitatively with the α/β ratio of 72:28 (entry 3). These anomers could be separated by column chromatography and clearly characterized by NMR. NOESY experiments for the major and minor anomers showed the cross peaks between C¹H and C³H protons and between C¹H and C²H protons, respectively, confirming the assignments of the major/minor products to the α/β anomers (Figures S57 and S62). Similarly, in applications of aluminum chloride (AlCl₃) and TMSOTf as a Lewis acid, methanolysis product 9c was obtained predominantly at room temperature, whereas at the reflux temperature, glycoside 10c was obtained in a good yield when TMSOTf was employed (entries 4–6). Thus, it was found that the OAc group at the anomeric position of 8c can be effectively substituted by a methoxy group using BF₃·OEt₂ or TMSOTf as a Lewis acid. It is likely, however, that the α/β selectivity of the glycosylation products would be decreased by the use of TMSOTf.

We subsequently investigated the scope of the glycosylation reaction of 8 with various nucleophiles using BF₃·OEt₂ (Scheme 2). In ethanol instead of MeOH, the corresponding ethoxide 11c was obtained in 84% yield. Allyltrimethylsilane (allylTMS) and anisole also worked as glycosyl acceptors to produce C-glycosides 12c, 12e, and 13c, although the yields were low to moderate. Similar C-glycosylation was previously reported for the corresponding threose derivative with a better yield (88% using SnBr₄),⁴⁵ suggesting the difficulty in the glycosylation of the 4-selenothreofuranose skeleton. Acetonitrile (MeCN) reacted with 8a (X = Ac) and 8b (X = Bz) at room temperature to afford glycosides 14a and 14b, respectively. The N-glycosylation also proceeded using TMSOTf but with an inverted α/β ratio. On the other hand, phenol and thioanisole did not work as a glycosyl acceptor in this transformation reaction.

Scheme 2. Scope of the Glycosylation of 8 with Various Acceptors.

TMSOTf (3 eq) was used instead of BF₃·OEt₂.

The anomeric mixture of 14a was recrystallized, and the molecular structure was determined by X-ray analysis. The results revealed that the crystals can be characterized as a 2:1 mixture of the α and β anomers, which were disordered in the crystal (Figure S2). Thus, it was reconfirmed that the α anomer was predominantly produced.

Synthesis of 4′-Selenothreonucleside Derivatives

Having been encouraged with the formation of N-glycosylated products in the presence of Lewis acids, we next investigated introduction of a nucleobase at the anomeric position of 8, which was obtained by seleno-Pummerer rearrangement (Table 1), according to Jeong’s procedure.³¹ However, all attempts were unsuccessful with 8b (X = Bz) having ester protecting groups, resulting in the formation of a complex mixture of unknown products with a recovery of a small amount of 8b (Table 3, entry 1). On the other hand, 4′-selenothreonucleoside derivatives 15 and 16 were obtained from 8c (X = Bn) and 8f (X = TIPDS), having ethereal protections, by the reaction with 6-chloropurine activated with BSA (entries 2–7).

Table 3. Synthesis of 4′-Selenothreonucleoside Derivatives.

entry	substrate	X	Lewis acid, eq	condition	yield of 15 (%)a	yield of 16 (%)a
1	8b	Bz	BF3·OEt2, 2	toluene/100 °C/18 h	0	0
2	8c	Bn	BF3·OEt2, 2	toluene/100 °C/1 h	3 (68:32)	10 (70:30)
3	8c	Bn	TMSOTf, 1	toluene/90 °C/18 h	27 (66:34)	36 (65:35)
4b	8c	Bn	TMSOTf, 1	toluene/90 °C/18 h	31 (62:38)	23 (61:39)
5	8c	Bn	TMSOTf, 1	MeCN/80 °C/3 h	3 (70:30)	19 (68:32)
6	8f	TIPDS	TMSOTf, 1	toluene/90 °C/18 h	11 (53:47)c	32 (34:66)c
7b	8f	TIPDS	TMSOTf, 1	toluene/90 °C/18 h	22 (52:48)c	25 (37:63)c

^aThe values in parentheses are the α/β ratios determined by integration of the ¹H NMR peaks.

^b6-Chloropurine 1.2 eq and BSA 2.0 eq were used.

^cThe yields and α/β ratios were determined based on the weights of the α and β anomers isolated by column chromatography.

When BF₃·OEt₂ was employed as a Lewis acid in toluene, the desired N-9 isomer (15c) and the N-7 isomer (16c) were obtained from 8c (X = Bn) in 3 and 10% yields, respectively (entry 2). Their α/β ratios were about 7:3 (vide infra for the assignments), which was the same as that of reactant 8c (see Table 1). In this reaction, a polymerized yellow viscous material was generated in a prolonged reaction. The yields of 15c and 16c were significantly improved by using TMSOTf instead of BF₃·OEt₂ (entry 3). The total yield (63%) was comparable with those reported for the syntheses of 4′-selenoribonucleoside derivatives (Scheme 1). Interestingly, the ratio of 15c to 16c was inverted when the amounts of 6-chloropurine and BSA were reduced to 1.2 and 2.0 eqs, respectively, while the total yield was slightly decreased (entry 4). The result suggested that the amount of the activated nucleobase can influence the ratio of the N-9 and N-7 adducts. We further investigated the reaction in MeCN according to the literature.⁷ However, the yields of 15c and 16c were decreased (entry 5), probably due to the occurrence of the reaction between 8c and MeCN (see Scheme 2).

When similar reaction conditions were applied for 8f with cyclic TIPDS protection, expected products 15f and 16f were obtained in slightly decreased yields (entries 6 and 7). In this case, however, the α and β anomers could be separated by silica gel column chromatography for both the products, and the molecular structures of the four stereoisomers (i.e., α-15f, β-15f, α-16f, and β-16f) were determined by X-ray analysis (Figure 3A).

Figure 3.

Structural characterization of 15f and 16f (X = TIPDS). (A) Molecular structure for the α and β anomers determined by X-ray analysis. The ellipsoids are drawn with 50% probability. Hydrogen atoms of β-16f were omitted for clarity. (B) ¹H NMR spectra for the isolated α and β anomers in the regions of the aromatic protons (left) and the furanose CH₂ protons (right).

In contrast to 8b′ (Figure 2A) and 14a (Figure S2), the two substituents on the C²′ and C³′ carbon atoms occupy equatorial positions of the furanose ring. This would be attributed to the conformational constraint by the cyclic TIPDS protection. Importantly, the comparison of their ¹H NMR spectra with each other revealed convenient clues for the assignments of stereochemistry for the 4′-selenothreofuranose derivatives. The first clue was regarding the assignment of the N-9 (15) and N-7 (16) isomers. In the ¹H NMR spectra for α- and β-15f (Figure 3B), the two aromatic protons of the 6-chloropurine were shifted toward upfield compared to α- and β-16f. The second clue was for the assignment of α and β anomers. The NMR peaks of the furanose CH₂ protons were more widely separated from each other for β-15f and β-16f than those for α-15f and α-16f. The latter feature was consonant with that observed for the α and β anomers of 8a–f (vide supra). Applying these clues (i.e., an upfield shift of the aromatic protons for the N-9 isomer and a wide separation of the ring CH₂ protons for the β isomer), we could easily assign the stereochemistry for the four stereoisomers of 15c and 16c.

Mechanistic Insights into the Stereoselectivity of the Seleno-Pummerer-Type Reactions

Formation of C- and N-glycosylation products (Scheme 2) suggested that the C–O covalent bond at the anomeric position of 8 was cleaved by the Lewis acid to generate a selenonium ion (−Se⁺=C<) as a possible intermediate. In addition, similar α/β ratios (∼7:3) were observed for the glycosylation for the substrates with ethereal protections (Scheme 2 and Tables 2 and 3) and the seleno-Pummerer rearrangement (Table 1), suggesting the same selenonium intermediate being involved in both reactions. Based on these considerations, a mechanism for the glycosylation was proposed as shown in Scheme 3.

Scheme 3. Proposed Mechanism for Glycosylation of 8.

Complex 17 between the Lewis acid and substrate 8 would produce selenonium ion 18 via elimination of an acetate anion from the anomeric position. The elimination process would compete with a nucleophilic attack of an alcohol molecule at the carbonyl C atom of the OAc group because a methanolysis product was obtained in the reaction of Table 2. However, the elimination would preferentially proceed at high temperatures or in the absence of alcohol. Selenonium 18 should be stabilized by the resonance with a canonical carbocation structure, which would accept an attack of a nucleophile predominantly from the α direction (i.e., the anti direction with respect to the OX substituent at the C² atom) due to the steric repulsion in the β attack (i.e., the syn attack with respect to the OX substituent at the C² atom). When TSMOTf was employed as a Lewis acid, a significant decrease in the α-attack selectivity was frequently observed (entries 5 and 6 in Table 2, 14b in Scheme 2, and entries 6 and 7 in Table 3). One possible explanation for this behavior may be the participation of a triflate anion, which would weakly interact to the cationic anomeric C atom preferentially from the α direction.

It is well established that when a nucleobase is introduced at the anomeric position of ribose in the presence of a Lewis acid, an acyloxy substituent at the 2-position strongly stabilizes the cationic anomeric C atom in the oxonium intermediate from the syn direction forming a cyclic structure, which sterically controls the attack of a nucleobase from the anti direction.^46,47 Such a neighboring group participation is well known in the corresponding thionium intermediates⁴⁸ and was applied for the stereoselective synthesis of thioribonucleosides^7,49 and selenoribonucleosides (Scheme 1a).²⁹ In our reactions of Table 1 and Scheme 2, the α/β selectivity obviously decreased for the substrates having ester protections against our expectation. This suggested that the contribution from the 2-acyloxy group is not effective in the 4-selenothreofuranose skeleton. To elucidate the reason for the decreased α/β selectivity, quantum chemical calculation was performed for selenonium ion 18.

The calculation was carried out at the B3LYP/6-31+G(d,p) level for 18′ (X = H) and 18″ (X = Ac). The obtained stable structures, as well as those for the sulfur analogues 19′ and 19″, are shown in Figure 4.

Figure 4.

Fully optimized structures obtained for selenonium ions 18′ and 18″ and thionium ions 19′ and 19″ at B3LYP/6-31+G(d,p).

In the optimized structures of 18′ and 19′ having two OH groups, the anomeric C atom adopts an sp²-hybridized planar structure. Comparison of the natural population analysis (NPA) charges of the C atoms indicated a less electrophilicity of 18′ than that of 19′. On the other hand, two stable structures A and B, which have a strong interaction between the anomeric C atom and the OAc group at the 2- or 3-position, respectively, were found for 18″ and 19″. The relative energy (ΔE) of structure B with respect to structure A for selenonium 18″ was significantly smaller than that for thionium 19″ (ΔΔE = −3.8 kcal/mol), suggesting a stronger interaction of the OAc group at the 3-position for 18″. This would be reflected by a shorter O–C¹ atomic distance observed for 18″B (1.51 Å) than that for 19″B (1.53 Å). The stronger interaction would hinder the α attack of a nucleophile at the anomeric C atom for 4-selenothreofuranose derivatives having ester protections, resulting in the diminishing α/β selectivity. For the case of 4-selenothreofuranose derivatives having ethereal protection, such interactions as predicted for 18″A and 18″B are not feasible; hence, the stereoselectivity of the nucleophilic attack would be simply controlled by the steric and/or conformational consequences derived from the protecting groups.

Conclusions

In this study, we have synthesized a series of 4-selenothreofuranose derivatives (8–14) starting from DHS (5) via seleno-Pummerer rearrangement and subsequent nucleophilic substitution reaction in the presence of BF₃·OEt₂ or TMSOTf. The both reactions would be mediated by selenonium 18 as a common intermediate. The most selenosugars were obtained as a ca. 7:3 mixture of α and β anomers. However, the α/β selectivity was decreased when the 2- and 3-positions were protected with ester functional groups because of the unexpected interaction between the carbonyl O atom of the protecting group at the 3-position and the anomeric C¹ atom. On the other hand, the α/β selectivity was slightly augmented when a cyclic protecting group, that is, TIPDS, was applied (Table 1, entry 7). We further succeeded in the synthesis of 4′-selenothreonucleoside derivatives (15cf and 16cf) by N-glycosylation of 8c (X = Bn) and 8f (X = TIPDS) with activated 6-chloropurine. The stereochemistry of all 4-selenothreose derivatives was unambiguously characterized by ¹H NMR spectroscopy as well as X-ray analysis.

Since selenosugars frequently exhibit greater biological activities than the corresponding sulfur analogues,^19,22−24 the 4-selenothreose derivatives synthesized in this study will be attractive as new-type building blocks for selenosugar-based drugs with versatile bioactivities. Their incorporation into threose nucleic acid, which is an artificial nucleic acid capable of carrying the genetic information,^42,50 will also be an intriguing challenge for developing novel variants of TNA.

Experimental Section

General Procedure

¹H (500 MHz), ¹³C (125.8 MHz), and ⁷⁷Se (95.4 MHz) NMR spectra were recorded on a Bruker AV-500 spectrometer at 298 K. High-resolution mass spectra (HRMS) were recorded on a JEOL JMS-T100LP mass spectrometer under atmospheric pressure chemical ionization (APCI+) conditions. MALDI-TOF mass spectra were recorded on a JEOL JMS-S3000 mass spectrometer with a high-resolution mode. The sample was dispersed in the matrix of α-cyano-4-hydroxycinnamic acid or 2,5-dihydroxybenzoic acid with potassium iodide or sliver nitrate as a cationization agent and polyethylene glycol as an internal standard. All reactions for the synthesis were monitored by thin-layer chromatography, which was performed on precoated sheets of silica gel 60 purchased from Merck Millipore. Gel permeation chromatography (GPC) was performed with a JAI LC-918 high-performance liquid chromatograph (HPLC) system using CHCl₃ as an eluent. Racemic trans-3,4-dihydroxytetrahydroselenophene (or trans-3,4-dihydroxyselenolane, DHS, 5) was synthesized according to the literature procedure.⁵¹ All other chemicals were used as purchased without further purification.

Protection of DHS (5)

(3R,4R/3S,4S)-Tetrahydroselenophene-3,4-diyl Diacetate (6a)

To the solution of 5 (500 mg, 3.0 mmol) in tetrahydrofuran (THF, 7.5 mL) were added triethylamine (2.1 mL, 15 mmol) and acetic anhydride (1.1 mL, 12 mmol). The mixture was stirred at 35 °C overnight. After removal of the solvent by evaporation, the residual material was dissolved in diethyl ether. The organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, and then brine and was dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (hexane–diethyl ether 1:1) to afford 6a as a colorless solid. Yield 627 mg, 84%. mp 44–45 °C. ¹H NMR (CDCl₃): δ 5.36 (m, 2H), 3.23 (m, 2H), 2.96 (m, 2H), 2.07 (s, 6H). ¹³C NMR (CDCl₃): δ 169.8, 78.2, 24.4, 21.0. Anal. Calcd for C₈H₁₂O₄Se: C, 38.26; H, 4.82. Found: C, 38.50; H, 5.01.

(3R,4R/3S,4S)-Tetrahydroselenophene-3,4-diyl Dibenzoate (6b)

To the solution of 5 (100 mg, 0.6 mmol) in dichloromethane (DCM, 3 mL) were added triethylamine (0.17 mL, 1.2 mmol) and benzoyl chloride (0.14 mL, 1.2 mmol). The mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was added with water and extracted with DCM (×2). The combined organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, and then brine and was dried over magnesium sulfate. The crude product obtained was purified by silica gel column chromatography (hexane–diethyl ether 5:1) to afford 6b as colorless crystals. Yield 221 mg, 98%. mp 121–126 °C. ¹H NMR (CDCl₃): δ 8.03 (m, 4H), 7.58 (m, 2H), 7.45 (m, 4H), 5.79 (m, 2H), 3.45 (m, 2H), 3.18 (m, 2H). ¹³C NMR (CDCl₃): δ 171.7, 165.4, 133.8, 133.5, 130.2, 129.8, 129.5, 129.2, 128.5, 78.6, 24.4. ⁷⁷Se NMR (CDCl₃): δ 118.9. HRMS (APCI-TOF) m/z: calcd for C₁₈H₁₆NaO₄Se⁺ [M + Na]⁺, 399.0106; found, 399.0040. The molecular structure of 6b was determined by X-ray analysis.

(3R,4R/3S,4S)-3,4-Bis(benzyloxy)tetrahydroselenophene (6c)

To the solution of 5 (300 mg, 1.8 mmol) in DMF (4 mL) cooled on an ice bath were added sodium hydride (132 mg, 5.5 mmol) and benzyl bromide (0.42 mL, 3.0 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was further added with sodium hydride (60 mg, 2.5 mmol) and stirred. After completion of the reaction, the mixture was added with brine and extracted with ethyl acetate (×3). The combined organic layer was washed with water and then brine and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (hexane–ethyl acetate 17:1) to afford 6c as a colorless oil. Yield 503 mg, 82%. ¹H NMR (CDCl₃): δ 7.36–7.26 (m, 10H), 4.63 (d, J = 12.0 Hz, 2H), 4.56 (d, J = 12.0 Hz, 2H), 4.19 (m, 2H), 3.08 (dd, J = 4.0 and 10.0 Hz, 2H), 2.98 (dd, J = 3.0 and 10.0 Hz, 2H). ¹³C NMR (CDCl₃): δ 138.4, 128.6, 127.9, 127.8, 84.5, 71.4, 24.8. ⁷⁷Se NMR (CDCl₃): δ 98.3. Anal. Calcd for C₁₈H₂₀O₂Se: C, 62.25; H, 5.80. Found: C, 62.47; H, 5.79.

(3R,4R/3S,4S)-3,4-Bis((4-methoxybenzyl)oxy)tetrahydroselenophene (6d)

To the solution of 5 (32 mg, 0.19 mmol) in DMF (1.5 mL) were added sodium hydride (35 mg, 1.5 mmol) and p-methoxybenzyl chloride (0.090 mL, 0.66 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was added with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water and then brine and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (hexane–ethyl acetate 3:1) to afford 6d as a colorless oil. Yield 36 mg, 47%. ¹H NMR (CDCl₃): δ 7.23 (d, J = 9.0 Hz, 4H), 6.87 (d, J = 9.0 Hz, 4H), 4.53 (d, J = 12.0 Hz, 2H), 4.47 (d, J = 12.0 Hz, 2H), 4.13 (m, 2H), 3.81 (s, 6H), 3.04 (dd, J = 4.0 and 10.5 Hz, 2H), 2.93 (m, 2H). ¹³C NMR (CDCl₃): δ 159.3, 130.2, 129.3, 113.8, 83.9, 71.0, 55.3, 24.6. HRMS (MALDI-TOF-MS) m/z: calcd for C₂₀H₂₄AgO₄Se⁺ [M + Ag]⁺, 514.9885; found, 514.9996.

(3R,4R/3S,4S)-3,4-Bis((tert-butyldimethylsilyl))oxy)tetrahydroselenophene (6e)

To the solution of 5 (50 mg, 0.3 mmol) in DCM (3 mL) were added imidazole (16 mg, 0.24 mmol) and tert-butyldimethylsilyl chloride (47 mg, 0.3 mmol). The mixture was stirred at room temperature for 5 h. The reaction mixture was further added with imidazole (18 mg, 0.27 mmol) and tert-butyldimethylsilyl chloride (49 mg, 0.3 mmol) several times. After completion of the reaction, the mixture was added with water and extracted with DCM (×3). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (hexane–diethyl ether 3:1) to afford 6e as colorless crystals. Yield 105 mg, 88%. mp 38–39 °C. ¹H NMR (CDCl₃): δ 4.15 (m, 2H), 3.07 (dd, J = 3.5 and 10.0 Hz, 2H), 2.72 (dd, J = 2.5 and 9.0 Hz, 2H), 0.88 (s, 18H), 0.08 (s, 6H), 0.07 (s, 6H). ¹³C NMR (CDCl₃): δ 78.6, 24.4, 16.8, 0.0, −0.1,-4.3, −4.3. Anal. Calcd for C₁₆H₃₆O₂SeSi₂: C, 48.58; H, 9.17. Found: C, 48.86; H, 9.50.

(5aR,8aR/5aS,8aS)-2,2,4,4-Tetraisopropyltetrahydroselenopheno[3,4-f][1,3,5,2,4]trioxadisilepine (6f)

Under the nitrogen atmosphere, 5 (113 mg, 0.68 mmol) and imidazole (148 mg, 2.0 mmol) were dissolved in pyridine (5 mL) on an ice bath. To the solution was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (0.34 mL, 1.0 mmol). The mixture was stirred at room temperature overnight. The mixture was then added with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (hexane–diethyl ether 20:1) to afford 6f as a colorless oil. Yield 256 mg, 93%. ¹H NMR (CDCl₃): δ 4.17 (m, 2H), 2.85 (m, 2H), 2.74 (m, 2H), 1.06–0.87 (m, 28H). ¹³C NMR (CDCl₃): δ 81.1, 21.1, 17.5, 17.5, 17.3, 17.2, 13.0, 12.4. ⁷⁷Se NMR (CDCl₃): δ 39.4. HRMS (MALDI-TOF-MS) m/z: calcd for C₁₆H₃₄AgO₃SeSi₂⁺ [M + Ag]⁺, 517.0257; found, 517.0283.

General Procedure of Seleno-Pummerer Rearrangement

To the solution of 6 (0.40 mmol) in THF (3 mL) was added aqueous H₂O₂ (30%, 1–3 eq). The mixture was stirred at room temperature for 1–5 h. After the removal of the solvent by evaporation, the resulting selenoxide 7 was dissolved in Ac₂O (1.6 mL) or toluene (3 mL) containing excess Ac₂O. The mixture was stirred at 90–100 °C for 1–2 h. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (AcOEt) (×3). The combined organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then brine and dried over magnesium sulfate. The crude product obtained was purified by silica gel column chromatography (hexane–ethyl acetate) and/or GPC to yield 8 as a mixture of α and β anomers.

(3R,4R/3S,4S)-Tetrahydroselenophene-2,3,4-triyl Triacetate (8a)

Colorless oil. Yield 79% (α/β = 56:44). ¹H NMR (CDCl₃): δ 6.22 (d, J = 4.5 Hz, 1H, β), 6.03 (d, J = 3.5 Hz, 1H, α), 5.61 (dd, J = 3.5 and 5.5 Hz, 1H, α), 5.50 (m, 1H, β), 5.37 (q, J = 5.5 Hz, 1H, α), 5.24 (dd, J = 4.5 and 10.0 Hz, 1H, β), 3.31 (dd, J = 7.5 and 10.0 Hz, 1H, β), 3.25 (dd, J = 5.0 and 5.5 Hz, 1H, α), 3.14 (dd, J = 5.0 and 5.5 Hz, 1H, α), 2.68 (dd, J = 9.0 and 9.5 Hz, 1H, β), 2.09–2.08 (s, 9H, α and β). ¹³C NMR (CDCl₃): δ 170.3, 170.1, 170.0, 169.9, 169.9, 169.3, 80.1, 77.0, 76.6, 74.8, 74.7, 67.1, 24.7, 21.1, 20.9, 20.8, 20.7, 18.6. ⁷⁷Se NMR (CDCl₃): δ 311.5 (α), 289.6 (β). Anal. Calcd for C₁₀H₁₄O₆Se: C, 38.85; H, 4.56. Found: C, 38.77; H, 4.65.

(3R,4R/3S,4S)-2-Acetoxytetrahydroselenophene-3,4-diyl Dibenzoate (8b)

Colorless solid. Yield 83% (α/β = 45:55). mp 80–108 °C. ¹H NMR (CDCl₃): δ 8.07–7.99 (m, 4H, α and β), 7.60–7.54 (m, 2H, α and β), 7.47–7.40 (m, 4H, α and β), 6.41 (d, J = 4.5 Hz, 1H, β), 6.28 (d, J = 2.5 Hz, 1H, α), 6.04 (dd, J = 2.5 and 5.0 Hz, 1H, α), 5.94 (m, 1H, β), 5.80 (q, J = 5.0 Hz, 1H, α), 5.68 (dd, J = 5.0 and 10.0 Hz, 1H, β), 3.52–3.48 (m, 1H, α and β), 3.37 (dd, J = 4.5 and 11.0 Hz, 1H, α), 2.91 (dd, J = 9.0 and 9.5 Hz, 1H, β), 2.082 (s, 3H, β), 2.079 (s, 3H, α). ¹³C NMR (CDCl₃): δ 170.0, 169.9, 165.9, 165.5, 165.4, 164.8, 133.7, 133.5, 133.5, 133.5, 129.9, 129.9, 129.8, 129.8, 129.4, 129.3, 129.1, 128.9, 128.6, 128.5, 128.4, 80.6, 77.7, 77.2, 75.7, 75.4, 67.2, 25.8, 21.1, 21.0, 18.8. ⁷⁷Se NMR (CDCl₃): δ 322.2 (α), 294.8 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₂₀H₁₈NaO₆Se⁺ [M + Na]⁺, 457.0161; found, 457.0140.

(3R,4R/3S,4S)-3,4-Bis(benzyloxy)tetrahydroselenophen-2-yl Acetate (8c)

Colorless oil. Yield 94% (α/β = 68:32). ¹H NMR (CDCl₃): δ 7.36–7.30 (m, 10H, α and β), 6.17 (d, J = 4.0 Hz, 1H, β), 6.05 (d, J = 4.5 Hz, 1H, α), 4.82–4.65 (m, 4H, α and β), 4.33 (m, 1H, β), 4.22 (dd, J = 4.0 and 6.5 Hz, 1H, α), 4.15 (m, 1H, α), 3.97 (dd, J = 4.5 and 9.0 Hz, 1H, β), 3.09–3.01 (m, 2H, α, 1H, β), 2.70 (t, J = 9.0 Hz, 1H, β), 2.11 (s, 3H, β), 2.06 (s, 3H, α). ¹³C NMR (CDCl₃): δ 170.5, 170.4, 138.3, 138.0, 137.8, 137.7, 128.5, 128.5, 128.4, 127.9, 127.9, 127.9, 127.8, 127.8, 127.7, 87.6, 85.3, 83.3, 82.1, 74.7, 72.9, 72.8, 72.8, 72.0, 67.9, 24.1, 21.3, 21.1, 20.0. ⁷⁷Se NMR (CDCl₃): δ 272.9 (α), 261.5 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₂₀H₂₂NaO₄Se⁺ [M + Na]⁺, 429.0576; found, 429.0530.

(3R,4R/3S,4S)-3,4-Bis((4-methoxybenzyl)oxy)tetrahydroselenophen-2-yl Acetate (8d)

Colorless oil. Yield 87% (α/β = 69:31). ¹H NMR (CDCl₃): δ 7.26–7.21 (m, 4H, α and β), 6.86–6.82 (m, 4H, α and β), 6.10 (d, J = 4.5 Hz, 1H, β), 5.99 (d, J = 4.5 Hz, 1H, α), 4.70–4.53 (m, 4H, α and β), 4.23 (m, 1H, β), 4.14 (dd, J = 4.5 and 6.5 Hz, 1H, α), 4.06 (m, 1H, α), 3.97 (dd, J = 4.5 and 9.5 Hz, 1H, β), 3.77 (m, 6H, α and β), 3.01–2.93 (m, 2H, α, 1H, β), 2.62 (t, J = 4.5 Hz, 1H, β), 2.07 (s, 3H, β), 2.03 (s, 3H, α). ¹³C NMR (CDCl₃): δ 170.5, 170.4, 159.4, 159.4, 159.3, 159.3, 130.4, 130.1, 129.9, 129.8, 129.5, 129.5, 129.3, 113.9, 113.8, 113.8, 87.2, 85.0, 83.1, 81.8, 74.9, 72.6, 72.5, 71.6, 68.0, 55.3, 24.3, 21.4, 21.1, 20.1. ⁷⁷Se NMR (CDCl₃): δ 272.6 (α), 260.5 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₂₂H₂₆AgO₆Se⁺ [M + Ag]⁺, 572.9940; found, 572.9966.

(3R,4R/3S,4S)-3,4-Bis((tert-butyldimethylsilyl))oxy)tetrahydroselenophen-2-yl Acetate (8e)

Colorless oil. Yield 88% (α/β = 70:30). ¹H NMR (CDCl₃): δ 6.01 (d, J = 4.5 Hz, 1H, β), 5.81 (m, 1H, α), 4.23 (m, 1H, β), 4.16–4.13 (m, 2H, α), 3.93 (dd, J = 4.5 and 7.5 Hz, 1H, β), 3.05–2.99 (m, 1H, α and β), 2.90 (m, 1H, α), 2.61 (dd, J = 8.0 and 9.5 Hz, 1H, β), 2.07 (s, 3H, β), 2.03 (s, 3H, α), 0.88–0.86 (m, 18H, α and β), 0.08 (m, 12H, α and β). ¹³C NMR (CDCl₃): δ 170.5, 83.0, 79.5, 78.4, 78.1, 76.5, 71.0, 28.1, 25.9, 25.8, 25.8, 25.7, 23.9, 21.2, 21.0, 18.0, 17.9, −4.4, −4.4, −4.5, −4.6, −4.6, −4.7, −4.8. ⁷⁷Se NMR (CDCl₃): δ 268.1 (α), 242.2 (β). Anal. Calcd for C₁₈H₃₈O₄SeSi₂: C, 47.66; H, 8.44. Found: C, 47.92; H, 8.73.

(5aR,8aR/5aS,8aS)-2,2,4,4-Tetraisopropyltetrahydroselenopheno[3,4-f][1,3,5,2,4]trioxadisilepin-6-yl Acetate (8f)

Colorless solid. Yield 98% (α/β = 81:19). m.p. 50–80 °C. ¹H NMR (CDCl₃): δ 6.12 (d, J = 4.5 Hz, 1H, β), 5.74 (m, 1H, α), 4.52 (m, 1H, β), 4.26–4.21 (m, 2H, α), 4.17 (dd, J = 4.5 and 9.5 Hz, 1H, β), 3.02–2.98 (m, 1H, α and β), 2.80 (m, 1H, α), 2.71 (t, J = 9.5 Hz, 1H, β), 2.05 (s, 3H, β), 2.05 (s, 3H, α), 1.08–0.91 (m, 28H, α and β). ¹³C NMR (CDCl₃): δ 170.7, 170.2, 84.2, 81.7, 78.1, 77.9, 73.0, 69.3 23.5, 21.5, 21.2, 20.8, 17.6, 17.5, 17.4, 17.3, 17.2, 17.2, 17.2, 17.1, 17.1, 17.0, 13.0, 13.0, 12.9, 12.8, 12.3, 12.2, 12.2, 12.1. ⁷⁷Se NMR (CDCl₃): δ 246.3 (β), 232.0 (α). HRMS (MALDI-TOF-MS) m/z: calcd for C₁₈H₃₆NaO₅SeSi₂⁺ [M + Na]⁺, 491.1159; found, 491.1163.

(3R,4R/3S,4S)-Tetrahydroselenophene-2,3,4-triyl Tribenzoate (8b′)

Colorless solid. Yield 77% (α/β = 50:50). m.p. 100–150 °C. ¹H NMR (CDCl₃): δ 8.05–7.92 (m, 6H, α and β), 7.58–7.29 (m, 9H, α and β), 6.62 (d, J = 5.0 Hz, 1H, β), 6.51 (dd, J = 0.5 and 2.5 Hz, 1H, α), 6.20 (dd, J = 2.5 and 4.5 Hz, 1H, α), 6.04 (m, 1H, β), 5.88 (q, J = 4.5 Hz, 1H, α), 5.80 (dd, J = 4.5 and 9.5 Hz, 1H, β), 3.56–3.51 (m, 1H, α and β), 3.40 (dd, J = 4.0 and 11.0 Hz, 1H, α), 2.96 (dd, J = 9.0 and 9.5 Hz, 1H, β). ¹³C NMR (CDCl₃): δ 166.0, 165.7, 165.5, 164.8, 133.8, 133.6, 133.5, 133.5, 130.0, 130.0, 129.9, 129.8, 129.8, 129.8, 129.4, 129.3, 129.1, 129.0, 128.9, 128.6, 128.6, 128.5, 128.5, 128.5, 128.4, 80.9, 77.9, 77.4, 76.9, 75.7, 68.0, 26.4, 19.1. ⁷⁷Se NMR (CDCl₃): δ 327.0 (α), 295.1 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₂₅H₂₀AgO₆Se⁺ [M + Ag]⁺, 602.9471; found, 602.9373.

The α anomer of 8b′ was isolated as single crystals by recrystallization from ethanol–DCM. The molecular structure was determined by X-ray analysis. m.p. 160–162 °C. ¹H NMR (CDCl₃): δ 8.05–7.92 (m, 6H), 7.59–7.29 (m, 9H), 6.51 (dd, J = 0.5 and 2.5 Hz, 1H), 6.20 (dd, J = 2.5 and 4.5 Hz, 1H), 5.88 (q, J = 4.5 Hz, 1H), 3.55 (dd, J = 5.0 and 11.0 Hz, 1H), 3.40 (dd, J = 4.0 and 11.0 Hz, 1H). ¹³C NMR (CDCl₃): δ 165.7, 165.5, 164.8, 133.8, 133.5, 133.5, 130.0, 130.0, 129.9, 129.3, 129.0, 128.9, 128.6, 128.5, 128.4, 80.9, 77.9, 76.9, 26.3.

(3R,4R/3S,4S)-3,4-Bis(benzyloxy)tetrahydroselenophen-2-yl Benzoate (8c′)

Colorless oil. Yield 99% (α/β = 75:25). ¹H NMR (CDCl₃): δ 8.18–7.27 (m, 15H, α and β), 6.42 (d, J = 4.5 Hz, 1H, β), 6.37 (d, J = 4.0 Hz, 1H, α), 4.85–4.71 (m, 4H, α and β), 4.45–4.43 (m, 1H, α and β), 4.27 (m, 1H, α), 4.10 (m, 1H, β), 3.16–3.11 (m, 2H, α, 1H, β), 2.77 (t, J = 9.5 Hz, 1H, β). ¹³C NMR (CDCl₃): δ 171.5, 166.1, 138.3, 138.0, 137.8, 137.7, 133.8, 133.4, 133.4, 130.2, 129.9, 129.9, 129.8, 129.4, 129.3, 128.5, 128.5, 128.5, 128.4, 128.4, 127.9, 127.8, 127.8, 127.8, 127.7, 87.5, 85.5, 83.7, 82.1, 75.6, 72.8, 72.8, 72.6, 72.0, 68.5, 24.5, 20.1. ⁷⁷Se NMR (CDCl₃): δ 278.7 (α), 263.4 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₂₅H₂₄AgO₄Se⁺ [M + Ag]⁺, 574.9885; found, 574.9842.

Methanolysis and Glycosylation of 8

(3R,4R/3S,4S)-3,4-Bis(benzyloxy)tetrahydroselenophen-2-ol (9c)

To the solution of 8c (115 mg, 0.28 mmol) in methanol (5 mL) cooled on an ice bath was added BF₃·OEt₂ (0.21 mL, 1.6 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was added with a saturated aqueous solution of sodium bicarbonate and extracted with AcOEt (×3). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (hexane–ethyl acetate 4:1) to yield 9c (90 mg, 88% yield) as a mixture of α and β anomers (66:34). Colorless oil. ¹H NMR (CDCl₃): δ 7.36–7.29 (m, 10H, α and β), 5.86 (s, 1H, α), 5.81 (d, J = 4.0 Hz, 1H, β), 4.69–4.51 (m, 4H, α and β), 4.33 (m, 1H, α), 4.24 (m, 1H, α), 4.21 (q, J = 5.5 Hz, 1H, β), 3.92 (dd, J = 4.0 and 6.0 Hz, 1H, β), 3.41 (d, J = 10.5 Hz, 1H, α), 3.27 (dd, J = 5.0 and 10.0 Hz, 1H, β), 3.18 (dd, J = 3.5 and 11.0 Hz, 1H, α), 2.85 (dd, J = 5.5 and 10.0 Hz, 1H, β). ¹³C NMR (CDCl₃): δ 138.0, 137.5, 137.4, 137.0, 128.7, 128.6, 128.5, 128.5, 128.2, 128.0, 127.9, 127.7, 88.5, 85.6, 84.7, 82.2, 81.8, 73.3, 72.9, 72.0, 71.9, 71.5, 27.7, 23.7. ⁷⁷Se NMR (CDCl₃): δ 319.5 (α), 255.0 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₁₈H₂₀AgO₃Se⁺ [M + Ag]⁺, 470.9623; found, 470.9634.

(3R,4R/3S,4S)-3,4-Bis(benzyloxy)-2-methoxytetrahydroselenophene (10c)

To the solution of 8c (108 mg, 0.27 mmol) in methanol (5 mL) was added BF₃·OEt₂ (52 μL, 0.40 mmol). The mixture was refluxed overnight. The reaction mixture was added with an aqueous solution of sodium carbonate (10%) and extracted with AcOEt (×3). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (hexane–ethyl acetate 7:1) to yield 10c (97 mg, 95% yield) as a mixture of α and β anomers (72:28). The anomers could be separated by silica gel column chromatography.

α Anomer (α-10c)

Colorless oil. ¹H NMR (CDCl₃): δ 7.35–7.29 (m, 10H), 5.31 (d, J = 4.5 Hz, 1H), 4.74–4.66 (m, 4H), 4.13 (dd, J = 4.5 and 9.0 Hz, 2H), 4.07 (m, 1H), 3.30 (s, 3H), 3.04 (m, 2H). ¹³C NMR (CDCl₃): δ 138.2, 138.2, 128.4, 128.4, 127.8, 127.7, 127.7, 89.8, 86.5, 83.3, 72.9, 72.0, 58.3, 22.7. ⁷⁷Se NMR (CDCl₃): δ 215.5. HRMS (MALDI-TOF-MS) m/z: calcd for C₁₉H₂₂AgO₃Se⁺ [M + Ag]⁺, 484.9780; found, 484.9737.

β Anomer (β-10c)

Colorless oil. ¹H NMR (CDCl₃): δ 7.38–7.29 (m, 10H), 5.01 (d, J = 4.0 Hz, 1H), 4.82–4.67 (m, 4H), 4.37 (m, 1H), 3.94 (dd, J = 4.5 and 9.5 Hz, 1H), 3.31 (s, 3H), 3.01 (dd, J = 7.5 and 9.5 Hz, 1H), 2.70 (t, J = 9.5 Hz, 1H). ¹³C NMR (CDCl₃): δ 138.5, 138.2, 128.4, 128.0, 127.8, 127.7, 127.7, 86.7, 82.5, 80.9, 72.9, 72.6, 57.4, 19.1. ⁷⁷Se NMR (CDCl₃): δ 213.2. HRMS (MALDI-TOF-MS) m/z: calcd for C₁₉H₂₂AgO₃Se⁺ [M + Ag]⁺, 484.9780; found, 484.9793.

(2R,3R,4R/2R,3S,4S)-3,4-Bis(benzyloxy)-2-ethoxytetrahydroselenophene (11c)

Similarly, 11c was obtained from 8c in refluxing ethanol. The α and β anomers could be separated by silica gel column chromatography (hexane–ethyl acetate 10:1). Colorless oil. Yield 84% (α/β = 53:47).

α Anomer (α-11c)

Colorless oil. ¹H NMR (CDCl₃): δ 7.36–7.28 (m, 10H), 5.39 (d, J = 5.0 Hz, 1H), 4.80–4.65 (m, 4H), 4.13 (dd, J = 5.0 and 8.0 Hz, 1H), 4.05 (m, 1H), 3.55 (m, 1H), 3.34 (m, 1H), 3.09–2.99 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H). ¹³C NMR (CDCl₃): δ 138.3, 138.3, 128.4, 128.4, 127.8, 127.7, 127.7, 89.7, 83.7, 82.9, 73.0, 72.0, 66.7, 22.3, 14.9. ⁷⁷Se NMR (CDCl₃): δ 215.2. HRMS (MALDI-TOF-MS) m/z: calcd for C₂₀H₂₄AgO₃Se⁺ [M + Ag]⁺, 498.9936; found, 498.9881.

β Anomer (β-11c)

Colorless oil. ¹H NMR (CDCl₃): δ 7.36–7.29 (m, 10H), 5.17 (d, J = 4.0 Hz, 1H), 4.83–4.66 (m, 4H), 4.39 (m, 1H), 3.94 (dd, J = 4.5 and 9.0 Hz, 1H), 3.69 (m, 1H), 3.27 (m, 1H), 3.06 (dd, J = 7.5 and 9.5 Hz, 1H), 2.71 (dd, J = 8.5 and 9.9 Hz, 1H), 1.26 (t, J = 7.0 Hz, 3H). ¹³C NMR (CDCl₃): δ 138.6, 138.3, 128.4, 128.4, 127.9, 127.8, 127.7, 127.6, 86.7, 82.7, 78.9, 72.9, 72.5, 65.7, 19.4, 14.6. ⁷⁷Se NMR (CDCl₃): δ 222.2. HRMS (MALDI-TOF-MS) m/z: calcd for C₂₀H₂₄NaO₃Se⁺ [M + Na]⁺, 415.0783; found, 415.0775.

(3R,4R/3S,4S)-2-Allyl-3,4-bis(benzyloxy)tetrahydroselenophene (12c)

To the solution of 8c (96 mg, 0.24 mmol) in toluene (3 mL) were added allylTMS (75 μL, 0.47 mmol) and BF₃·OEt₂ (0.13 mL, 1.0 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was added with a saturated aqueous solution of sodium bicarbonate and extracted with AcOEt (×3). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by GPC. 8c was obtained as a colorless oil. Yield 48 mg, 52% (α/β = 70:30). ¹H NMR (CDCl₃): δ 7.35–7.30 (m, 10H, α and β), 5.76 (m, 1H, α and β), 5.09–5.00 (m, 2H, α and β), 4.83–4.50 (m, 4H, α and β), 4.22 (m, 1H, β), 4.15 (m, 1H, α), 3.95 (t, J = 5.0 Hz, 1H, β), 3.82 (m, 1H, β), 3.78 (t, J = 5.0 Hz, 1H, α), 3.48 (m, 1H, α), 3.16 (dd, J = 5.0 and 5.0 Hz, 1H, β), 3.05 (dd, J = 5.0 and 5.0 Hz, 1H, α), 2.95 (dd, J = 2.5 and 10.5 Hz, 1H, β), 2.86 (dd, J = 5.0 and 5.0 Hz, 1H, α), 2.78 (m, 1H, α), 2.68 (m, 1H, β), 2.49 (m, 1H, β), 2.32 (m, 1H, α). ¹³C NMR (CDCl₃): δ 137.8, 134.1, 132.3, 129.4, 128.5, 127.8, 127.7, 127.2, 126.9, 124.6, 85.5, 82.4, 71.2, 67.5, 40.6, 29.8. ⁷⁷Se NMR (CDCl₃): δ 316.9 (β), 279.7 (α). HRMS (MALDI-TOF-MS): m/z calcd for C₂₁H₂₄AgO₂Se⁺ [M + Ag]⁺, 494.9987; found, 495.0134.

(((3R,4R/3S,4S)-2-Allyltetrahydroselenophene-3,4-diyl)bis(oxy))bis(tert-butyldimethylsilane) (12e)

To the solution of 8e (132 mg, 0.29 mmol) in toluene (4 mL) were added allylTMS (97 μL, 0.58 mmol) and BF₃·OEt₂ (160 μL, 1.2 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was added with a saturated aqueous solution of sodium bicarbonate and extracted with AcOEt (×3). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by GPC. 8e was obtained as a mixture with a small amount of an unknown compound (<10%), which could not be separated by chromatography. Colorless oil. Yield 19 mg, 15% (α/β = 59:41). ¹H NMR (CDCl₃): δ 5.82–5.68 (m, 1H, α and β), 5.10–4.96 (m, 2H, α and β), 4.23–4.19 (m, 1H, α and β), 3.93–3.89 (m, 1H, α and β), 3.76 (m, 1H, β), 3.33 (m, 1H, α), 3.19–3.14 (m, 1H, α and β), 2.83–2.65 (m, 2H, α and β), 2.55 (m, 1H, β), 2.44–2.37 (m, 1H, α and β), 0.88–0.85 (s, 18H, α and β), 0.07–0.04 (s, 12H, α and β). ¹³C NMR (CDCl₃): δ 137.8, 137.4, 116.2, 115.7, 83.7, 81.3, 81.0, 79.8, 48.7, 45.9, 40.3, 35.3, 29.3, 28.9, 25.9, 25.8, 25.8, 18.1, 18.0, 18.0, 17.9, −4.2, −4.5, −4.6, −4.6, −4.7, −4.7. ⁷⁷Se NMR (CDCl₃): δ 196.0 (β), 179.5 (α). HRMS (MALDI-TOF-MS) m/z: calcd for C₁₉H₄₀AgO₂SeSi₂⁺ [M + Ag]⁺, 543.0777; found, 543.0836.

(3R,4R/3S,4S)-3,4-Bis(benzyloxy)-2-(4-methoxyphenyl)tetrahydroselenophene (13c)

To the solution of 8c (64 mg, 0.16 mmol) in toluene (4 mL) were added anisole (51 μL, 0.47 mmol) and BF₃·OEt₂ (89 μL, 0.68 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was added with an aqueous solution of sodium carbonate (10%) and extracted with AcOEt (×3). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by GPC. Colorless oil. Yield 24 mg, 34% (α/β = 58:42). ¹H NMR (CDCl₃): δ 7.54–6.85 (m, 14H, α and β), 5.10–4.49 (m, 4H, α and β), 4.41–3.97 (m, 3H, α and β), 3.85 (s, 3H, α and β), 3.50 (dd, J = 4.5 and 11.0 Hz, 1H, β), 3.16–3.10 (m, 2H, α and β). ¹³C NMR (CDCl₃): δ 158.9, 158.8, 138.3, 138.1, 138.1, 138.0, 132.7, 131.4, 129.6, 129.5, 128.5, 128.5, 128.3, 128.2, 128.0, 127.8, 127.8, 127.7, 127.7, 127.7, 127.6, 127.6, 114.0, 113.4, 90.8, 87.0, 84.6, 84.6, 73.5, 72.4, 72.3, 71.3, 55.3, 55.3, 47.5, 41.9, 27.4, 20.9. ⁷⁷Se NMR (CDCl₃): δ 224.5 (α), 212.3 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₂₅H₂₆AgO₃Se⁺ [M + Ag]⁺, 561.0093; found, 561.0027.

(3R,4R/3S,4S)-2-Acetamidotetrahydroselenophene-3,4-diyl Diacetate (14a)

To the solution of 8a (15 mg, 0.05 mmol) in acetonitrile (1 mL) cooled on an ice bath was added BF₃·OEt₂ (27 μL, 0.21 mmol). The mixture was stirred at 0 °C for 1.5 h. The reaction mixture was added with a saturated aqueous solution of sodium bicarbonate and extracted with AcOEt (×3). The combined organic layer was washed with water and then brine and dried over magnesium sulfate. The crude product was purified by GPC to yield 14a as colorless crystals. Yield 9.2 mg, 63% (α/β = 57:43). mp 96–139 °C. ¹H NMR (CDCl₃): δ 6.30 (d, J = 8.5 Hz, 1H, β), 5.98 (dd, J = 5.0 and 9.0 Hz, 1H, α), 5.92 (d, J = 9.0 Hz, 1H, α), 5.61 (dd, J = 5.5 and 8.5 Hz, 1H, β), 5.39–5.23 (m, 2H, α and β), 3.38 (dd, J = 5.5 and 11.0 Hz, 1H, α), 3.24 (dd, J = 5.5 and 10.5 Hz, 1H, β), 3.12 (dd, J = 6.0 and 10.5 Hz, 1H, β), 2.89 (dd, J = 5.0 and 11.0 Hz, 1H, α), 2.14–1.98 (s, 9H, α and β). ¹³C NMR (CDCl₃): δ 170.5, 170.0, 169.6, 169.6, 169.4, 169.4, 80.3, 77.1, 76.2, 75.7, 49.5, 47.2, 23.5, 23.4, 23.3, 23.1, 21.0, 20.9, 20.9. ⁷⁷Se NMR (CDCl₃): δ 286.3 (α), 267.6 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₁₀H₁₅NNaO₅Se⁺ [M + Na]⁺, 332.0008; found, 332.0027. The molecular structure of the anomeric mixture was determined by X-ray analysis.

(3R,4R/3S,4S)-2-Acetamidotetrahydroselenophene-3,4-diyl Dibenzoate (14b)

To the solution of 8b (63 mg, 0.15 mmol) in acetonitrile (4 mL) cooled on an ice bath was added BF₃·OEt₂ (47 μL, 0.36 mmol). After stirring at 0 °C for 1.5 h, the mixture was further added with BF₃·OEt₂ (24 μL, 0.18 mmol) and stirred at 0 °C for 1 h. The reaction mixture was added with a saturated aqueous solution of sodium bicarbonate and extracted with AcOEt (×3). The combined organic layer was washed with water and then brine and dried over magnesium sulfate. The crude product was purified by GPC to yield 14b as a white solid. Yield 59 mg, 94% yield as a mixture of α and β anomers (58:42). mp 180–185 °C. ¹H NMR (CDCl₃): δ 8.01 (m, 4H, α and β), 7.60–7.40 (m, 6H, α and β), 6.63 (d, J = 8.0 Hz, 1H, β), 6.30 (d, J = 9.0 Hz, 1H, α), 6.23 (dd, J = 5.5 and 9.5 Hz, 1H, α), 5.81–5.68 (m, 2H, α and β), 3.60 (dd, J = 5.5 and 11.0 Hz, 1H, α), 3.42 (dd, J = 5.5 and 10.5 Hz, 1H, β), 3.32 (dd, J = 6.5 and 10.5 Hz, 1H, β), 3.10 (dd, J = 5.0 and 11.0 Hz, 1H, α), 1.96 (s, 3H, α and β). ¹³C NMR (CDCl₃): δ 169.8, 166.1, 165.5, 165.2, 165.0, 133.9, 133.8, 133.7, 130.0, 129.9, 129.9, 129.6, 129.2, 129.1, 128.9, 128.7, 128.7, 128.7, 128.6, 128.6, 80.6, 77.6, 76.5, 49.1, 47.8, 23.9, 23.3, 23.2, 22.6. ⁷⁷Se NMR (CDCl₃): δ 288.0 (α), 272.9 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₂₀H₁₉NaO₅Se⁺ [M + Na]⁺, 456.0321; found, 456.0317.

9-((3R,4R/3S,4S)-3,4-Bis(benzyloxy)tetrahydroselenophen-2-yl)-6-chloro-9H-purine (15c) and 7-((3R,4R/3S,4S)-3,4-Bis(benzyloxy)tetrahydroselenophen-2-yl)-6-chloro-7H-purine (16c)

In a 50 mL two-neck round-bottom flask, 6-chloropurine (326 mg, 2.0 mmol) and BSA (80%, 1.08 mL, 3.4 mmol) were dissolved in toluene (14 mL) under a nitrogen atmosphere. The mixture was stirred at 90 °C for 1 h. To the resulting yellow solution was added a solution of 8c (418 mg, 1.0 mmol) and TMSOTf (190 μL, 1.0 mmol) in toluene (4.5 mL). The mixture was stirred at 90 °C overnight to afford an orange solution with a brown oily material. The reaction mixture was added with a saturated aqueous sodium bicarbonate solution and extracted with AcOEt (×3). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude products were purified by silica gel column chromatography (hexane–ethyl acetate 1:2 to 1:1).

Spectral Data for 15c

Yellow viscous oil. Yield 139 mg, 27% (α/β = 66:34). ¹H NMR (CDCl₃): δ 8.70 (s, 1H, α), 8.61 (s, 2H, β), 8.52 (s, 1H, α), 7.36–6.83 (m, 10H, α and β), 6.64 (d, J = 4.6 Hz, 1H, β), 6.35 (d, J = 2.8 Hz, 1H, α), 4.79–4.07 (m, 6H, α and β), 3.60 (dd, J = 4.1 and 10.7 Hz, 1H, β), 3.47 (dd, J = 3.5 and 10.5 Hz, 1H, α), 3.39 (dd, J = 4.3 and 10.5 Hz, 1H, α), 3.17 (dd, J = 2.8 and 10.5 Hz, 1H, β). ¹³C NMR (CDCl₃): δ 151.7, 151.6, 151.5, 150.7, 150.7, 147.6, 147.0, 137.3, 137.0, 136.8, 136.0, 132.2, 131.7, 128.7, 128.6, 128.4, 128.3, 128.2, 128.2, 128.1, 128.0, 127.9, 127.8, 87.9, 84.7, 83.0, 82.6, 73.0, 72.4, 71.9, 71.8, 55.4, 52.7, 29.2, 28.2. ⁷⁷Se NMR (CDCl₃): δ 267.1 (α), 248.2 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C₂₃H₂₁AgClN₄O₂Se⁺ [M + Ag]⁺, 606.9564; found, 606.9551.

Spectral Data for 16c

Yellow viscous oil. Yield 186 mg, 36% (α/β = 65:35). ¹H NMR (CDCl₃): δ 8.93 (s, 1H, β), 8.91 (br s, 1H, α), 8.82 (s, 1H, α), 8.77 (s, 1H, β), 7.39–6.94 (m, 10H, α and β), 6.69 (m, 1H, α and β), 4.70–4.01 (m, 6H, α and β), 3.67 (dd, J = 3.8 and 10.7 Hz, 1H, β), 3.45 (dd, J = 3.2 and 10.4 Hz, 1H, α), 3.38 (dd, J = 4.2 and 10.4 Hz, 1H, α), 3.20 (dd, J = 1.9 and 10.6 Hz, 1H, β). ¹³C NMR (CDCl₃): δ 162.5, 162.2, 152.2, 152.0, 151.7, 151.2, 142.4, 142.1, 137.3, 136.7, 136.6, 135.6, 128.7, 128.6, 128.5, 128.3, 128.2, 128.2, 128.0, 127.9, 127.7, 122.3, 122.3, 89.7, 83.9, 82.8, 82.3, 73.2, 72.8, 72.2, 71.8, 59.1, 56.5, 29.8, 29.3. ⁷⁷Se NMR (CDCl₃): δ 290.4 (β), 249.2 (α). HRMS (MALDI-TOF-MS) m/z: calcd for C₂₃H₂₁AgClN₄O₂Se⁺ [M + Ag]⁺, 606.9564; found, 606.9534.

6-Chloro-9-((5aR,8aR/5aS,8aS)-2,2,4,4-tetraisopropyltetrahydroselenopheno[3,4-f][1,3,5,2,4]trioxadisilepin-6-yl)-9H-purine (15f) and 6-Chloro-7-((5aR,8aR/5aS,8aS)-2,2,4,4-tetraisopropyltetrahydroselenopheno[3,4-f][1,3,5,2,4]trioxadisilepin-6-yl)-7H-purine (16f)

In a 50 mL two-neck round-bottom flask, 6-chloropurine (194 mg, 1.2 mmol) and BSA (80%, 0.62 mL, 2.0 mmol) were dissolved in toluene (13 mL) under a nitrogen atmosphere. The mixture was stirred at 90 °C for 1 h. To the resulting yellow solution was added a solution of 8f (472 mg, 1.0 mmol) and TMSOTf (190 μL, 1.0 mmol) dissolved in toluene (4 mL). The mixture was stirred at 90 °C overnight to afford an orange solution with a brown oily material. The reaction mixture was added with a saturated aqueous sodium bicarbonate solution and extracted with AcOEt (×3). The combined organic layer was washed with brine and dried over magnesium sulfate. The crude products were purified by silica gel column chromatography (hexane–ethyl acetate 3:1 to 2:1).

Spectral Data for α-15f

Pale yellow crystals. Yield 64.5 mg, 11%. mp 123–127 °C. R_f 0.37 (hexane–ethyl acetate 3:1). ¹H NMR (CDCl₃): δ 8.74 (s, 1H), 8.41 (s, 1H), 6.08 (d, J = 8.5 Hz, 1H), 4.59 (t, J = 8.5, 1H), 4.40 (m, 1H), 3.38 (t, J = 10.0, 1H), 3.10 (dd, J = 6.5 and 9.5 Hz, 1H), 1.08–0.74 (m, 25H), 0.37–0.35 (m, 3H). ¹³C NMR (CDCl₃): δ 152.0, 151.9, 151.3, 144.5, 132.1, 85.2, 78.0, 50.1, 24.2, 17.5, 17.2, 17.2, 17.1, 17.0, 17.0, 16.8, 16.6, 13.0, 12.5, 12.2, 12.2. ⁷⁷Se NMR (CDCl₃): δ 213.8. HRMS (MALDI-TOF-MS) m/z: calcd for C₂₁H₃₅AgClN₄O₃SeSi₂⁺ [M + Ag]⁺, 669.0147; found, 669.0076. The molecular structure was determined by X-ray analysis.

Spectral Data for β-15f

Pale yellow crystals. Yield 60.6 mg, 11%. mp 124–145 °C. R_f 0.31 (hexane–ethyl acetate 3:1). ¹H NMR (CDCl₃): δ 8.68 (s, 1H), 8.46 (s, 1H), 6.27 (d, J = 7.0 Hz, 1H), 4.59 (m, 1H), 4.39 (dd, J = 7.0 and 9.0 Hz, 1H), 3.27 (dd, J = 7.0 and 10.0 Hz, 1H), 2.95 (t, J = 10.0 Hz, 1H), 1.00–0.96 (m, 22H), 0.42 (m, 3H), 0.27 (m, 3H). ¹³C NMR (CDCl₃): δ 152.9, 151.8, 151.0, 145.9, 131.8, 81.5, 79.1, 47.7, 22.6, 17.5, 17.3, 17.1, 17.1, 17.1, 17.0, 16.4, 16.1, 12.9, 12.7, 12.1, 11.6. ⁷⁷Se NMR (CDCl₃): δ 221.7. HRMS (MALDI-TOF-MS) m/z: calcd for C₂₁H₃₅AgClN₄O₃SeSi₂⁺ [M + Ag]⁺, 669.0147; found, 669.0021. The molecular structure was determined by X-ray analysis.

Spectral Data for α-16f

Pale yellow crystals. Yield 53.7 mg, 9%. mp 209–212 °C. R_f 0.15 (hexane–ethyl acetate 3:1). ¹H NMR (CDCl₃): δ 8.90 (br s, 1H), 8.85 (s, 1H), 6.60 (br d, J = 5.5 Hz, 1H), 4.41 (m, 1H), 4.24 (br t, J = 7.5, 1H), 3.33 (t, J = 10.0, 1H), 3.13 (dd, J = 6.5 and 10.0 Hz, 1H), 1.08–0.72 (m, 25H), 0.32 (d, J = 7.0, 3H). ¹³C NMR (CDCl₃): δ 161.9, 152.5, 148.3, 143.1, 123.0, 88.1, 77.5, 51.3, 24.1, 17.5, 17.1, 17.1, 16.8, 16.8, 16.7, 16.5, 12.9, 12.4, 12.1, 11.9. ⁷⁷Se NMR (CDCl₃): δ 222.4. HRMS (MALDI-TOF-MS) m/z: calcd for C₂₁H₃₅AgClN₄O₃SeSi₂⁺ [M + Ag]⁺, 669.0147; found, 669.0090. The molecular structure was determined by X-ray analysis.

Spectral Data for β-16f

Pale yellow crystals. 89.7 mg, Yield 16%. m.p. 195–199 °C. R_f 0.09 (hexane–ethyl acetate 3:1). ¹H NMR (CDCl₃): δ 8.86 (s, 1H), 8.80 (s, 1H), 6.64 (d, J = 6.0 Hz, 1H), 4.44–4.34 (m, 2H), 3.27 (dd, J = 7.0 and 10.0 Hz, 1H), 2.93 (t, J = 10.0 Hz, 1H), 1.02–0.81 (m, 21H), 0.43 (m, 4H), 0.15–0.14 (m, 3H). ¹³C NMR (CDCl₃): δ 162.1, 152.1, 149.6, 143.3, 124.4, 82.0, 77.7, 50.6, 22.2, 17.5, 17.4, 17.3, 17.2, 17.0, 16.3, 15.9, 13.0, 12.6, 12.2, 11.5. ⁷⁷Se NMR (CDCl₃): δ 220.3. HRMS (MALDI-TOF-MS) m/z: calcd for C₂₁H₃₅AgClN₄O₃SeSi₂⁺ [M + Ag]⁺, 669.0147; found, 669.0100. The molecular structure was determined by X-ray analysis.

X-ray Analysis

Single-crystal X-ray diffraction measurements were performed on a Rigaku XtaLAB P200 diffractometer using graphite monochromated Mo Kα radiation (λ = 0.71075 Å) or Cu Kα radiation (λ = 1.54187 Å). Diffraction data were collected and processed with CrysAlisPro version 1.171.39.46 (Rigaku Corporation) for 6b, 14a, α-15f, β-15f, α-16f, and β-16f and with CrystalClear (Rigaku Corporation) for 8b′. The structures were solved by the dual-space algorithm using SHELXT (Version 2014/5)⁵² and refined by the full-matrix least-squares method on F² using SHELXL (Version 2018/3).⁵³ All calculations were performed using the CrystalStructure software package (Rigaku Corporation). The CIF files for these compounds were deposited on CCDC (CCDC 2046025–2046027, 2061703–2061704, and 2064007–2064008).

Theoretical Calculation

Quantum chemical calculation was performed using a Gaussian09 rev.B.01 program⁵⁴ at the B3LYP/6-31+G(d,p) level in vacuo. The geometries of cations 18′, 18″A, 18″B, 19′, 19″A, and 19″B were fully optimized. The resulting structure was characterized as a stationary point with no imaginary vibrational frequency. The atomic charges were obtained by NPA.⁵⁵

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c02160.

• Comparison of the ¹H NMR chemical shifts and coupling constant, summary of X-ray analysis for 6b, 8b′, 14a, α-15f, β-15f, α-16f, and β-16f, atomic coordinates calculated for 18′, 18″AB, 19′, and 19″AB, and NMR and MS spectra for 6 and 8–16 (PDF)

• Crystallographic data of compounds deposited on ccdc (ZIP)

Author Contributions

M.I. organized the project, carried out the calculation, and prepared the manuscript. Y.H. and S.A. performed the experiments. T.I. carried out X-ray analysis. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.