Highly Diastereoselective Approach toward (±)-Tetraponerine T6 and Analogues via the Double Cycloisomerization–Reduction of Bis-alkynylpyrimidines

Abstract

A new, short, and efficient approach toward tricyclic alkaloids, involving the double cycloisomerization-reduction of bisalkynylpyrimidines 3a–m, has been developed. The requisite bis-alkynylpyrimidines 3a–m were readily prepared via regioselective sequential Sonogashira coupling reactions of dibromopyrimidines 1. Bis-alkynylpyrimidines 3a–m were converted into the 5-6-5 tricyclic heteroaromatic cores 4a–m via the Cu(I)-assisted double cycloisomerization reaction. The reaction proceeded stepwise, which was confirmed by the isolation of the mono-pyrrolization intermediate 5. The structure of 5 was assigned by 2D NMR and by independent synthesis. Cycloisomerization of 5 under standard conditions afforded tricyclic 4g in 89% yield. The PtO₂-catalyzed hydrogenation of bis-pyrrolopyrimidines 4d, 4g, and 4i in acidic media afforded stable amidinium derivatives, 11a, 11b, and 11c. Further reduction of the latter with LiAlH₄ allowed for the highly diastereoselective total synthesis of (±)-tetraponerine T6 and its analogues.

Introduction

The tetraponerines are a group of eight toxic alkaloids that are found in the venom of the New Guinean pseudomyrmecine ant Tetraonera sp.¹ and are composed of 1,3-diaza tricyclic systems (5–6–5 and 6–5–6), highly unusual cores for alkaloids isolated from animals. Moreover, these alkaloids represent the major constituents of the contact poison, showing profound insecticidal activities (LD₅₀ of 5 × 10⁻⁹ mol/ant mg). The unprecedented tricyclic skeleton, along with the interesting insecticidal activities of the tetraponerines, has made them attractive targets for total synthesis. Tetraponerine T6 is made of a 5–6–5 skeleton and is one of the major venom alkaloids. Prior to our studies, four diastereo- and enantioselective syntheses of tetraponerine T6 had been reported.² These syntheses, representing two synthetic approaches toward assembling a tricyclic core of tetraponerine T6, are summarized in Scheme 1. Blechert assembled the tricyclic 5–6–5 core via a cascade Pd-catalyzed cyclization.^2a Another approach, utilized by Plehiers,^2b Royer,^2c and Devijver,^2d employed different modes of double condensation of proline homologues with cyclic imines. We have recently communicated a short and highly diastereoselective synthesis of (±)-tetraponerine T6, employing a totally different approach³ involving exhaustive hydrogenation/reduction of the bispyrrolopyrimidine skeleton obtained via the double cycloisomerization of bisalkynylpyrimidine (Scheme 1). This strategy represents a conceptually novel and highly expeditious route toward certain polycyclic alkaloid skeletons. Herein, we provide a full account of this work as well as additional mechanistic studies and syntheses of tetraponerine analogues.

Scheme 1. Approaches toward Tetraponerine T6.

Results and Discussion

Recently, we developed a novel, general, and efficient method for the construction of pyrrole rings and fused aromatic pyrroloheterocycles via the Cu-assisted cycloisomerization of alkynyl imines.⁴ The synthetic usefulness of this novel methodology was further demonstrated by achieving the shortest synthesis of (±)-monomorine in three steps and 47% overall yield (Scheme 2). This successful result encouraged us to investigate the prospect of multiple pyrrolization protocols en route to tricyclic alkaloid structures. To test this idea, we investigated the possibility of constructing a 5–6–5 tricyclic heteroaromatic skeleton via the double Cu(I)-assisted cycloisomerization of bis-alkynylpyrimidines.

Scheme 2. Short Synthesis of (±)-Monomorine.

To this end, we synthesized various bis-alkynylpyrimidine derivatives 3a∓m employing Sonogashira coupling reactions⁵ of 1,3-dibromopyrimidines 1 (Table 1). Double-fold Sonogashira coupling of dibromopyrimidines⁶ with propyne proceeded smoothly to give bispropynylpyrimide derivatives in quantitative yields (Table 1, entries 1–5). Analogously, employment of higher alkyne analogues, such as pentyne and hexyne, allowed for the efficient syntheses of symmetric bis-alkynylpyrimidines 3f∓i (Table 1, entries 6–9). Next, we synthesized bisalkynylpyrimidines 3j–m, possessing different alkynyl substituents (Table 1, entries 10-13). Here, we took advantage of the known, different reactivity of bromides in dibromopyrimidines 1.⁷ First, we accessed bisalkynylpyrimidines 3j–l in stepwise fashion. Accordingly, employment of 1 equiv of alkyne allowed for selective coupling at the C-4 position to give the corresponding bromopyrimidine 2 in reasonable to good yields. Subsequent coupling of the C-2 bromide with another alkyne provided the unsymmetrical bisalkynylpyrimidines in excellent overall yield (Table 1, entries 10–12). It was also found that the cross-coupling of 1 with two different alkynes can efficiently be performed under a one-pot procedure condition without isolation of monobromopyrimidine intermediate 2 (Table 1, entry 13).

Table 1. Synthesis of Bis-alkynylpyrimidines.

					yielda (%)
entry	R1	R2	R3	R4	2	3
1	H	H	H	H		100 (a)
2	H	CH3	H	H		100 (b)
3	CH3	H	H	H		100 (c)
4	H	C5H11	H	H		100 (d)
5	CH3	CH3	H	H		100 (e)
6	H	H	C2H5	C2H5		77 (f)
7	H	C5H11	C3H7	C3H7		79 (g)
8	CH3	H	C2H5	C2H5		100 (h)
9	CH3	CH3	C2H5	C2H5		100 (i)
10	CH3	CH3	(CH2)2Ph	OCH3	80	82 (j)
11	CH3	CH3	OCH3	(CH2)2Ph	46b	100 (k)
12	CH3	CH3	(CH2)2Ph	C3H7	c	100 (l)
13	CH3	CH3	C3H7	(CH2)2Ph		75 (m)d

^aIsolated yields. All reactions were performed with 0.4 mol % of CuI and 0.2 mol % of Pd(PPh₃)₂Cl₂ in Et₃N. See the Experimental Section for details.

^b18% of the starting material was recovered.

^cMonoalkynyl pyrimidine 2j, which was obtained in 80% yield (entry 10), was subjected to the reaction with 1-pentyne in stepwise fashion.

^dThe reaction was performed under one-pot procedure conditions.

Next, bis-alkynylpyrimidine 3d, a potential precursor of tetraponerine T6, was chosen for optimization of the double cycloisomerization process (Table 2). The attempts at double cycloisomerization of 3d in the presence of 2 equiv of CuI at various temperatures were unsuccessful; at higher temperatures (Table 2, entries 1, 2), the substrate polymerized, whereas at lower temperatures (Table 2, entry 3), no reaction occurred. Reduction of the CuI amount had a somewhat positive effect on the reaction course (Table 2, entries 4–6). Further improvement was achieved by switching to CuBr (Table 2, entry 9). Dilution of the reaction mixture allowed for additional improvement of the reaction yields (Table 2, entries 10, 11). Taking into account that the yield for each pyrrolization in the transformation of 3d to 4d is about 70% and that the cycloisomerization yields for propyne derivatives are normally 10–20% lower than that of their higher homologues,⁸ we considered 50–52% yield for the double pyrrolization to be a rather satisfactory result.

Table 2. Optimization of the Cu(I)-Assisted Double Cycloisomerization of 3d.

entry	Cu(I) (equiv)	concn (M)	temp (°C)	time (h)	yielda (%)
1	CuI (2)	0.5	130	12	<5
2	CuI (2)	0.1	110	9	<5
3	CuI (2)	0.1	80	2	NR
4	CuI (1)	0.1	150	6	27
5	CuI (0.5)	0.1	150	6	30
6	CuI (0.3)	0.1	150	12	24
7	CuI (0.3)	0.1	110	5	<5
8	CuCl (1)	0.1	150	6	28
9	CuBr (1)	0.1	150	6	34
10	CuBr (1)	0.02	150	6	50
11	CuBr (1)	0.02b	150	10	52
12c	CuBr (1)	0.02d	150	22	34
13	CuBr (1)	0.02e	150	12	47

^aIsolated yields.

^bSlow addition of 3d via syringe pump over 5 h at 150 °C.

^cBu₃N was used instead of Et₃N.

^dSlow addition of 3d via syringe pump over 20 h at 150 °C.

^eSlow addition of 3d via syringe pump over 12 h at 150 °C.

The optimized conditions were applied to the double cycloisomerization of the differently substituted bisalkynylpyrimidines (Table 3). It was found that the double cycloisomerization of bisalkynylpyrimidines generally allowed for the assembly of tricyclic aromatic compounds in moderate to good yields. Double cycloisomerization of 3a provided low yield of nonsubstituted bis-pyrrolopyrimidine 4a (Table 3, entry 1). Notably, introduction of additional alkyl substituents into bis-alkynylpyrimidines had a positive effect on the yields of the resulting bis-pyrrolopyrimidines, ranging from moderate yields for mono-, di-, and trisubstituted heterocycles (Table 3, entries 2–8) to good yields for tetra-alkyl-substituted heterocycles (Table 3, entries 9, 12, 13). For reasons which are not completely understood, the introduction of a methoxy substituent (R³ or R⁴) led to substantial decrease in the reaction yields (Table 3, entries 10, 11).

Table 3. Cycloisomerization of Differently Substituted Bis-alkynylpyrimidines.

entry	R1	R2	R3	R4	yielda (%)
1	H	H	H	H (a)	37
2	H	CH3	H	H (b)	51
3	CH3	H	H	H (c)	48
4	H	C5H11	H	H (d)	52
5	CH3	CH3	H	H (e)	51
6	H	H	C2H5	C2H5 (f)	41
7	H	C5H11	C3H7	C3H7 (g)	68
8	CH3	H	C2H5	C2H5 (h)	40
9	CH3	CH3	C2H5	C2H5 (i)	70
10	CH3	CH3	(CH2)2Ph	OCH3 (j)	40
11	CH3	CH3	OCH3	(CH2)2Ph (k)	43
12	CH3	CH3	(CH2)2Ph	C3H7 (l)	75
13	CH3	CH3	C3H7	(CH2)2Ph (m)	64

^aIsolated yields.

Apparently, the double cycloisomerization of bis-alkynylpyrimidines proceeds via an alternative sequence of single cycloisomerization steps. As depicted in Scheme 3, the first pyrrolization of bis-alkynylpyrimidine 3g can proceed in three possible ways (Scheme 3, paths A–C). Among them, paths A and B, after the first cycloisomerization, will produce pyrrolopyrimidines 5 and 6, which, after the second pyrrolization, will give rise to the desired product 4g. In contrast to these cases, path C leads to the dead-end intermediate 7. Under standard reaction conditions (1 equiv of CuBr in dilute Et₃N–DMA at 150°C), no other low-molecular-weight compounds, besides 4g, were detected by GC–MS analyses of the crude reaction mixture. In contrast, when the reaction was performed at both reduced temperature (130 °C) and copper loading (30 mol %), GC–MS analysis revealed the presence of one isomeric compound along with starting material 3g and product 4g. This intermediate had quite a different R_f value from those of starting material 3g or product 4g, and thus it was easily separated by column chromatography and its structure assigned as 5 on the basis of extensive 2D NMR studies, including COSY, heteronuclear multiple-quantum coherence (HMQC), and heteronuclear multiple-bond correlation (HMBC). The structure of intermediate 5 was additionally proven by an independent synthesis, depicted in Scheme 4. Thus, known dichloropyrimidine 8 (Scheme 4) was first coupled with 1 equiv of hexyne under mild Sonogashira reaction conditions to give mono-alkynylated pyrimidine 9, which was cycloisomerized into mono-pyrrolopyrimidine 10. The subsequent high-temperature Sonogashira coupling of 10 with another molecule of hexyne produced 5, which was identical to the isolated intermediate in all respects. When 5 was subjected to the cycloisomerization conditions, it was smoothly converted into 4g in 89% yield (Scheme 4).

Scheme 3. Possible Pathways toward Bis-pyrrolopyrimidine 4g.

Scheme 4. Synthesis of Mono-pyrrolopyrimidine Intermediate 5.

Next, we drew our attention to the exhaustive reduction of bispyrrolopyrimidines (Table 4). Direct, complete hydrogenation of heteroaromatic compound 4d to 12a proved not to be straightforward. It is well-known that catalytic hydrogenation of pyrimidine derivatives in acidic media is cis-diastereoselective and stops at the stage of formation of stable amidinium derivatives.⁹ Accordingly, catalytic hydrogenation of 4d over PtO₂ under acidic conditions gave stable amidinium salt 11a as a single cis-isomer.¹⁰ The total synthesis of (±)- tetraponerine T6 was completed by a highly diastereo-selective reduction of crude 11a with LiAlH₄ to give 12a (T6) as the sole stereoisomer in 64% yield over two steps.

Table 4. Exhaustive Reduction of Bis-pyrrolopyrimidines.

entry	R1	R2	R3	R4	yield of 12a (%)	drb (%)
1	H	C5H11	H	H (4d)	64 (a)	100:0
2	H	C5H11	C3H7	C3H7(4g)	87 (b)c	88:12
3	CH3	CH3	C2H5	C2H5(4i)	41 (c)	88:12

^aIsolated yield over two steps.

^bDiastereomeric ratios were determined by ¹H NMR and GC–MS analyses of the crude reaction mixture.

^cNMR yield using CH₂Br₂ as an internal standard.

Exhaustive hydrogenation/reduction of trisubstituted bis-pyrrolopyrimidine 4g and the tetrasubstituted analogue 4i proceeded with high diastereoselectivity, producing all-cis-multisubstituted tetraponerine analogues 12b–c in 88:12 diastereomeric ratios with a minor unidentified diastereomer. Notably, tetraponerine 12a and its tetra-substituted analogue 12c are very stable compounds. In contrast, 12b, possessing slightly longer side chains, appeared to be extremely unstable and was characterized as crude. Diastereomeric purity of each compound was determined by ¹H NMR and GC–MS analyses of the crude reaction mixtures.

The highly diastereoselective installation of the last stereogenic center at C-2 via the reduction of 11a, which we believe is both sterically and stereoelectronically controlled, deserves a special note.¹¹ Our molecular mechanics force field (MMFF) calculations predicted that delivery of the hydride can be sterically controlled, favoring β-face attack at the most stable amidinium ion conformer with alkyl substituents occupying the equatorial position (11a-eq), as well as at another conformer 11a-ax (Figure 1). Stereoelectronic reasons can also account for the delivery of hydride to the C-2 of the amidinium ion. The nucleophilic attack by the hydride proceeds from the β-face to give (±)-T6 through the most favorable chairlike transition state i, instead of an a-face delivery of a hydride through the disfavored boatlike transition state ii to form an epi-(±)-T6 (Figure 2). The relative configurations of (±)-tetraponerine T6 and its analogues were confirmed by NOESY and ¹H NOE experiments.

Figure 1.

Two major conformations of amidinium ion 11a.

Figure 2.

Proposed transition states for the nucleophilic attack of hydride at amidinium ion 11a.

Conclusions

In summary, the Cu(I)-assisted double pyrrolization of bis-alkynylpyrimidine to the 5–6–5 heteroaromatic core was demonstrated. A highly selective hydrogenation/reduction of the resulting bis-pyrrolopyrimidine allowed for the short, efficient, and highly diastereoselective total synthesis of (±)-tetraponerine T6 and its analogues. Considering that the assembly of a 5–6–5 tricyclic skeleton by this double pyrrolization-reduction functionalization protocol allows for the quick installation of up to 6 stereo centers in a highly diastereoselective manner, this method can serve as a new, short, and efficient approach toward selected polycylic alkaloid structures.

Experimental Section

All manipulations were conducted under argon atmosphere using a combination of glovebox and standard Schlenk techniques. Anhydrous Et₃N and DMA were purchased from Aldrich and stored over calcium hydride. Anhydrous THF and benzene were distilled over sodium/benzophenone. 6-Pentyl-1H-pyrimidine-2,4-dione was prepared according to the known procedures.¹²

Representative Procedure for Syntheses of Dibromopyrimidines (1, R₁ = CH₃, R₂ = CH₃)

5,6-Dimethyl-2,4-(1H,3H)-pyrimidinedione (2.08 g, 14.84 mmol), potassium carbonate (6.15 g, 44.50 mmol), and phosphorus oxybromide (12.76 g, 44.50 mmol) were heated to reflux in dry acetonitrile (100 mL) for 72 h. The mixture was cooled to room temperature, poured into ice, and neutralized (solid potassium carbonate). The aqueous phase was thoroughly extracted with CH₂Cl₂. The combined organic extracts were washed (brine), dried (anhydrous Na₂SO₄), and concentrated under reduced pressure. The residue was purified by silica gel chromatography with 10% EtOAc/hexanes to give 2,4-dibromo-5,6-dimethyl-pyrimidine as a solid with mp 125 °C (3.28 g, 83%).

Representative Procedure for Mono-Sonogashira Reaction 2j

The mixture of 2,4-dibromo-5,6-dimethylpyrimidine (580 mg, 2.18 mmol), CuI (17 mg, 0.09 mmol), and Pd(PPh₃)₂-Cl₂ (31 mg, 0.04 mmol) was stirred at room temperature, and then pent-4-ynyl-bezene (280 μL, 2.43 mmol) was added to the mixture and stirred for 12 h. The mixture was quenched (aqueous NH₄Cl). The phases were separated, and the aqueous phase was thoroughly extracted with hexanes. The combined organic extracts were washed (brine), dried (anhydrous Na₂-SO₄), and concentrated under reduced pressure. The residue was purified by silica gel chromatography with 5-10% EtOAc/hexanes to give 2j as an oil (574 mg, 80%).

2j. ¹H NMR (500 MHz, CDCl₃, δ): 7.30–7.18 (5H, m), 2.77 (2H, t, J = 7.6 Hz), 2.50 (2H, t, J = 7.1 Hz), 2.48 (3H, s), 2.32 (3H, s), 1.97 (2H, quint, J = 7.5 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 168.9, 152.0, 148.9, 141.0, 129.4, 128.5 (×4), 126.1, 100.7, 77.7, 34.9, 29.6, 22.5, 19.0, 15.0. MS m/z (relative intensity): 329 (M⁺, 14), 300 (27), 224 (100), 91 (89).

2k. ¹H NMR (500 MHz, CDCl₃, δ): 4.32 (2H, s), 3.39 (3H, s), 2.44 (3H, s), 2.29 (3H, s). ¹³C NMR (125 MHz, CDCl₃, δ): 169.4, 150.8, 148.9, 129.7, 94.5, 82.0, 60.1, 58.1, 22.5, 14.9. MS m/z (relative intensity): 255 (M⁺, 1), 224 (100), 143 (48), 77 (62).

Representative Procedure for Syntheses of Di-prop-1-ynyl-pyrimidine (3c)

Using a high-pressure tube, propyne (10 mL) was condensed in a mixture of 2,4-dibromo-5-methylpyrimidine (2.50 g, 9.92 mmol), CuI (76 mg, 0.4 mmol), Pd-(PPh₃)₂Cl₂ (140 mg, 0.2 mmol), and Et₃N (50 mL) at −78 °C. The mixture was slowly warmed and stirred at 50 °C for 3 h. Then, the mixture was cooled to room temperature and quenched (aqueous NH₄Cl). The phases were separated, and the aqueous phase was thoroughly extracted with hexanes. The combined organic extracts were washed (brine), dried (anhydrous Na₂SO₄), and concentrated under reduced pressure. The residue was purified by silica gel chromatography with 20% EtOAc/hexanes to give 3c as a solid (1.69 g, >99%).

Representative Procedure for Sequential Sonogashira Reaction (3m)

The mixture of 2,4-dibromo-5,6-dimethyl-pyrimidine (380 mg, 1.43 mmol), CuI (11 mg, 0.06 mmol), and Pd(PPh₃)₂Cl₂ (20 mg, 0.03 mmol) was stirred at room temperature, and then n-hexyne (173 μL, 1.5 mmol) was added to the mixture and stirred for 12 h. The reaction progress was monitored by TLC and GC–MS analyses. Pent-4-ynyl-benzene (430 μL, 2.83 mmol) was added to the mixture and stirred for 12 h at 45 °C. The mixture was cooled to room temperature and quenched (aqueous NH₄Cl). The phases were separated, and the aqueous phase was thoroughly extracted with hexanes. The combined organic extracts were washed (brine), dried (anhydrous Na₂SO₄), and concentrated under reduced pressure. The residue was purified by silica gel chromatography with 2–10% EtOAc/hexanes to give 3m as an oil (355 mg, 75%).

3a. Mp 58 °C. ¹H NMR (500 MHz, CDCl₃, δ): 8.49 (1H, d, J = 5.1 Hz), 7.08 (1H, d, J = 5.1 Hz), 2.00 (3H, s), 1.99 (3H, s). ¹³C NMR (125 MHz, CDCl₃, δ): 157.5, 153.5, 151.8, 121.6, 93.2, 86.9, 79.4, 78.2, 4.8, 4.6. MS m/z (relative intensity): 156 (M⁺, 100), 128 (5), 91 (14), 64 (52).

3b. Mp 68 °C. ¹H NMR (500 MHz, CDCl₃, δ): 6.88 (1H, s), 2.29 (3H, s), 1.90 (3H, s), 1.89 (3H, s). ¹³C NMR (125 MHz, CDCl₃, δ): 167.8, 152.9, 151.3, 121.1, 92.2, 86.3, 79.3, 78.2, 24.2, 4.7, 4.5. MS m/z (relative intensity): 170 (M⁺, 100), 78 (14), 64 (38).

3c. Mp 143 °C. ¹H NMR (500 MHz, CDCl₃, δ): 8.44 (1H, s), 2.31 (3H, s), 2.12 (3H, s), 2.04 (3H, s). ¹³C NMR (125 MHz, CDCl₃, δ): 157.8, 151.4, 151.1, 130.8, 96.6, 85.9, 79.3, 77.0, 16.6, 5.0, 4.7. MS m/z (relative intensity): 170 (M⁺, 100), 78 (33), 66 (33).

3d. ¹H NMR (500 MHz, CDCl₃, δ): 6.99 (1H, s), 2.63 (2H, t, J = 7.8 Hz), 2.03 (3H, s), 2.02 (3H, s), 1.64 (2H, quint, J = 7.7 Hz), 1.28–1.25 (4H, m), 0.83 (3H, t, 3.2 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 171.8, 153.1, 151.4, 120.5, 92.0, 86.1, 79.5, 78.3, 38.0, 31.7, 28.9, 22.7, 14.2, 4.7, 4.6. MS m/z (relative intensity): 226 (M⁺, 2), 197 (8), 183 (17), 170 (100). Anal. Calcd for C₁₅H₁₈N₂: C, 79.61; H, 8.02; N, 12.38. Found: C, 79.57; H, 7.98; N, 12.29.

3e. Mp 122 °C. ¹H NMR (500 MHz, CDCl₃, δ): 2.36 (3H, s), 2.23 (3H, s), 2.02 (3H, s), 1.95 (3H, s). ¹³C NMR (125 MHz, CDCl₃, δ): 166.1, 151.2, 150.6, 129.0, 93.8, 83.8, 81.0, 78.2, 22.5, 15.1, 4.1, 3.8. MS m/z (relative intensity): 184 (M⁺, 100), 142 (14), 78 (52).

3f. ¹H NMR (500 MHz, CDCl₃, δ): 8.15 (1H, d, J = 5.1 Hz), 7.11 (1H, d, J = 5.1 Hz), 2.37–2.33 (4H, m), 1.61–1.55 (4H, m), 0.99–0.94 (6H, m). ¹³C NMR (125 MHz, CDCl₃, δ): 157.0, 153.2, 151.5, 121.3, 97.0, 90.6, 79.9, 78.7, 21.4 (×2), 21.3, 21.2, 13.6, 13.5. MS m/z (relative intensity): 212 (M⁺, 5), 184 (100), 164 (11).

3g. ¹H NMR (500 MHz, CDCl₃, δ): 7.01 (1H, s), 2.65 (2H, t, J = 7.8 Hz), 2.40 (4H, t, J = 7.3 Hz), 1.66–1.64 (2H, m), 1.60– 1.55 (4H, m), 1.42 (4H, sext, J = 7.5 Hz), 1.30–1.27 (4H, m), 0.90 (3H, t, J = 7.4 Hz), 0.88 (3H, t, J = 7.1 Hz), 0.85 (3H, t, J = 7.1 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 171.8, 153.2, 151.6, 120.7, 96.5, 90.5, 80.4, 79.2, 38.1, 31.9, 30.4 (×2), 29.0, 22.8, 22.5, 22.4, 19.5, 19.4, 14.3, 14.0, 13.9. MS m/z (relative intensity): 310 (M⁺, 2), 281 (10), 267 (16), 254 (100).

3h. ¹H NMR (500 MHz, CDCl₃, δ): 8.44 (1H, s), 2.45 (2H, t, J = 7.0 Hz), 2.38 (2H, t, J = 7.0 Hz), 2.31 (3H, s), 1.66–1.61 (4H, m), 1.03 (3H, t, J = 7.3 Hz), 1.01 (3H, t, J = 7.3 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 157.7, 151.6, 151.2, 130.8, 101.1, 90.0, 80.2, 77.9, 44.3, 22.0, 21.9, 21.6, 16.7, 14.1, 14.0. MS m/z (relative intensity): 226 (M⁺, 8), 198 (100), 181 (9), 169 (9).

3i. ¹H NMR (500 MHz, CDCl₃, δ): 2.41 (3H, s), 2.40 (2H, t, J = 7.1 Hz), 2.34 (2H, t, J = 7.1 Hz), 2.29 (3H, s), 1.62–1.57 (4H, m), 0.99 (3H, t, J = 7.4 Hz), 0.97 (3H, t, J = 7.4 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 166.4, 150.7, 150.4, 129.1, 99.6, 89.3, 80.3, 78.3, 22.9, 22.0, 21.9 (×2), 21.6, 15.6, 14.1, 14.0. MS m/z (relative intensity): 240 (M⁺, 8), 225 (9), 212 (100), 195 (8).

3j. ¹H NMR (500 MHz, CDCl₃, δ): 7.29–7.17 (5H, m), 4.31 (2H, s), 3.43 (3H, s), 2.77 (2H, t, J = 7.5 Hz), 2.48 (2H, t, J = 7.1 Hz), 2.47 (3H, s), 2.37 (3H, s), 1.95 (2H, quint, J = 7.5 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 166.3, 150.3, 149.2, 141.1, 129.6, 128.5 (×4), 126.1, 99.2, 84.9, 82.9, 78.1, 60.0, 57.9, 34.9, 29.7, 22.6, 19.0, 15.4. MS m/z (relative intensity): 318 (M⁺, 23), 290 (14), 214 (100), 91 (93).

3k. ¹H NMR (500 MHz, CDCl₃, δ): 7.21–7.08 (5H, m), 4.30 (2H, s), 3.38 (3H, s), 2.70 (2H, t, J = 7.5 Hz), 2.41 (3H, s), 2.38 (2H, t, J = 7.1 Hz), 2.30 (3H, s), 1.89 (2H, quint, J = 7.6 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 166.6, 150.0, 149.1, 141.2, 129.2, 128.4 (×2), 128.3 (×2), 125.9, 92.7, 88.9, 82.7, 80.0, 60.1, 58.0, 34.8, 29.5, 22.6, 18.7, 15.3. MS m/z (relative intensity): 318 (M⁺ − 1, 19), 214 (100), 91 (73).

3l. ¹H NMR (500 MHz, CDCl₃, δ): 7.24–7.12 (5H, m), 2.72 (2H, t, J = 7.5 Hz), 2.44 (2H, t, J = 7.1 Hz), 2.42 (3H, s), 2.37 (2H, t, J = 7.2 Hz), 2.30 (3H, s), 1.90 (2H, quint, J = 7.6 Hz), 1.55 (2H, quint, J = 7.3 Hz), 1.40 (2H, sext, J = 7.3 Hz), 0.86 (3H, t, J = 7.3 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 166.1, 150.1, 149.9, 141.1, 128.8, 128.4 (×4), 126.0, 98.8, 89.4, 79.7, 78.2, 34.8, 30.0, 29.7, 22.5, 22.1, 18.9 (×2), 15.3, 13.6. MS m/z (relative intensity): 330 (M⁺, 35), 301 (29), 226 (90), 91 (100).

3m. ¹H NMR (500 MHz, CDCl₃, δ): 7.26–7.11 (5H, m), 2.72 (2H, t, J = 7.6 Hz), 2.44 (2H, t, J = 7.1 Hz), 2.42 (3H, s), 2.40 (2H, t, J = 7.1 Hz), 2.29 (3H, s), 1.91 (2H, quint, J = 7.5 Hz), 1.57 (2H, quint, J = 7.5 Hz), 1.44 (2H, sext, J = 7.6 Hz), 0.88 (3H, t, J = 7.3 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 166.0, 150.3, 149.9, 141.3, 128.6, 128.4 (×4), 125.9, 99.4, 88.5, 80.2, 77.7, 34.9, 30.1, 29.7, 29.5, 22.6, 19.2, 18.7, 15.2, 13.5. MS m/z (relative intensity): 229 (M⁺ − 1, 19), 239 (11), 226 (100), 91 (49).

Representative Procedure for Double Cycloisomerization Reaction (4l)

Using a high-pressure tube, the mixture of compound 3l (370 mg, 1.12 mmol) and CuBr (161 mg, 1.12 mmol) in Et₃N (6 mL) and DMA (40 mL) was stirred at 150 °C for 18 h. The reaction was protected from the light by covering the flask with aluminum foil. Then, the mixture was cooled to room temperature and quenched (aqueous NH₄-Cl). The phases were separated, and the aqueous phase was thoroughly extracted with hexanes. The combined organic extracts were washed (brine), dried (anhydrous Na₂SO₄), and concentrated under reduced pressure. The residue was purified by silica gel chromatography with 5% EtOAc/hexanes (1% Et₃N was used for deactivation of the silica gel) to give 4l as a solid (278 mg, 75%).

4a. Mp 145 °C. ¹H NMR (500 MHz, CDCl₃, δ): 7.34–7.33 (1H, m), 7.23 (1H, d, J = 7.6 Hz), 6.86 (1H, dd, J = 3.1, 1.7 Hz), 2.42 (3H, s), 6.64 (1H, dd, J = 3.7, 2.8 Hz), 6.58 (1H, d, J = 7.6 Hz), 6.48 (1H, t, J = 3.3 Hz), 6.40 (1H, dd, J = 3.7, 1.3 Hz), 6.17–6.16 (1H, m). ¹³C NMR (125 MHz, CDCl₃, δ): 129.0, 126.1, 118.9, 113.2, 112.4, 112.1, 110.1, 103.6, 103.3, 88.1. MS m/z (relative intensity): 156 (M⁺, 100), 129 (14), 102 (10). Anal. Calcd for C₁₀H₈N₂: C, 76.90; H, 5.16; N, 17.94. Found: C, 76.94; H, 5.21; N, 17.91.

4b. Mp 45 °C. ¹H NMR (500 MHz, CDCl₃, δ): 7.34 (1H, d, J = 1.0 Hz), 6.91 (1H, dd, J = 3.1, 1.6 Hz), 6.65 (1H, dd, J = 3.5, 2.8 Hz), 6.55 (1H, t, J = 3.4 Hz), 6.43 (1H, s), 6.32 (1H, dd, J = 3.6, 1.1 Hz), 6.25 (1H, dd, J = 3.8, 1.6 Hz), 2.47 (3H, s). ¹³C NMR (125 MHz, CDCl₃, δ): 129.4, 126.9, 126.8, 112.3, 112.2, 110.0, 109.4, 101.9, 101.5, 88.5, 18.3. MS m/z (relative intensity): 170 (M⁺, 100), 155 (24), 142 (10), 115 (7), 85 (10). Anal. Calcd for C₁₁H₁₀N₂: C, 77.62; H, 5.92; N, 16.46. Found: C, 77.69; H, 5.95; N, 16.45.

4c. Mp 68 °C. ¹H NMR (500 MHz, CDCl₃, δ): 7.37 (1H, dd, J = 2.7, 1.4 Hz), 7.07 (1H, d, J = 1.2 Hz), 6.83 (1H, d, J = 1.4 Hz), 6.67 (1H, dd, J = 3.7, 2.8 Hz), 6.47 (1H, t, J = 3.1 Hz), 6.41 (1H, dd, J = 3.7, 1.4 Hz), 6.16 (1H, d, J = 3.6 Hz), 2.28 (3H. s). ¹³C NMR (125 MHz, CDCl₃, δ): 128.5, 128.4, 116.6, 113.5, 112.2, 111.9, 111.5, 109.6, 102.2, 87.5, 15.4. MS m/z (relative intensity): 170 (M⁺, 100), 155 (43), 142 (14), 115 (10), 85 (11). Anal. Calcd for C₁₁H₁₀N₂: C, 77.62; H, 5.92; N, 16.46. Found: C, 77.38; H, 5.92; N, 16.46.

4d. Mp 53 °C. ¹H NMR (500 MHz, CDCl₃, δ): 7.29 (1H, dd, J = 2.4, 1.2 Hz), 6.93 (1H, dd, J = 3.1, 1.6 Hz), 6.59 (1H, dd, J = 3.6, 2.9 Hz), 6.50 (1H, t, J = 3.5 Hz), 6.41 (1H, s), 6.28 (1H, dd, J = 3.6, 1.3 Hz), 6.19 (1H, dd, J = 3.8, 1.6 Hz), 2.75 (2H, t, J = 7.6 Hz), 1.77 (2H, quint, J = 7.6 Hz), 1.47–1.38 (4H, m), 0.94 (3H, t, J = 7.1 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 131.0, 129.4, 126.8, 112.2 (×2), 109.9, 109.3, 101.6, 100.7, 88.2, 32.0, 31.6, 26.9, 22.9, 14.4. MS m/z (relative intensity): 226 (M⁺, 50), 197 (7), 183 (14), 170 (100). Anal. Calcd for C₁₅H₁₈N₂: C, 79.61; H, 8.02; N, 12.38. Found: C, 79.67; H, 8.03; N, 12.40.

4e. Mp 116 °C. ¹H NMR (500 MHz, CDCl₃, δ): 7.34 (1H, dd, J = 2.7, 1.4 Hz), 6.90 (1H, dd, J = 2.8, 1.5 Hz), 6.64 (1H, dd, J = 3.6, 3.0 Hz), 6.50 (1H, t, J = 3.4 Hz), 6.33 (1H, dd, J = 3.7, 1.3 Hz), 6.20 (1H, dd, J = 3.7, 1.2 Hz), 2.44 (3H, s), 2.30 (3H, s). ¹³C NMR (125 MHz, CDCl₃, δ): 129.0, 128.9, 123.0, 112.6, 112.0, 109.4, 109.3, 107.9, 100.9, 87.8, 14.1, 13.6. MS m/z (relative intensity): 184 (M⁺, 100), 142 (14), 115 (7), 104 (10), 78 (52). Anal. Calcd for C₁₂H₁₂N₂: C, 78.23; H, 6.57; N, 15.21. Found: C, 78.41; H, 6.57; N, 15.20.

4f. ¹H NMR (500 MHz, C₆D₆, δ): 6.58 (1H, d, J = 7.6 Hz), 6.46 (1H, d, J = 3.7 Hz), 6.44 (1H, d, J = 3.7 Hz), 6.27 (1H, d, J = 5.0 Hz), 6.26 (1H, s), 6.23 (1H, d, J = 3.7 Hz), 3.00 (2H, q, J = 7.4 Hz), 2.37 (2H, q, J = 7.4 Hz), 1.29 (3H, t, J = 7.4 Hz), 1.18 (3H, t, J = 7.4 Hz). ¹³C NMR (125 MHz, C₆D₆, δ): 131.2, 128.5, 125.9, 124.6, 114.6, 109.1, 105.8, 102.9, 102.5, 89.7, 22.0, 19.2, 13.3, 12.5. MS m/z (relative intensity): 212 (M⁺, 43), 197 (100), 181 (16), 91 (21), 78 (52). HRMS (EI) calcd for C₁₄H₁₆N₂ (M⁺) 212.1314, found 212.1314.

4g. Mp 60 °C. ¹H NMR (500 MHz, CDCl₃, δ): 6.28 (1H, d, J = 3.9 Hz), 6.25 (1H, s), 6.24 (1H, d, J = 3.7 Hz), 6.21 (1H, d, J = 3.9 Hz), 6.12 (1H, d, J = 3.7 Hz), 3.30 (2H, t, J = 7.5 Hz), 2.90 (2H, t, J = 7.4 Hz), 2.87 (2H, t, J = 7.7 Hz), 1.80 (2H, sext, J = 7.5 Hz), 1.72–1.63 (4H, m), 1.44–1.35 (4H, m), 1.08 (3H, t, J = 7.3 Hz), 1.03 (3H, t, J = 7.3 Hz), 0.93 (3H, t, J = 7.1 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 131.5, 130.3, 128.8, 126.1, 125.6, 109.7, 109.1, 102.7, 99.6, 89.4, 32.8, 32.0, 31.3, 30.9, 28.8, 23.5, 22.5, 22.2, 14.0 (×2). MS m/z (relative intensity): 310 (M⁺, 33), 281 (100), 209 (26), 195 (23). HRMS (EI) calcd for C₂₁H₃₀N₂ (M⁺) 310.2409, found 310.2398.

4h. Mp 55 °C. ¹H NMR (500 MHz, CDCl₃, δ): 6.95 (1H, s), 6.35 (1H, d, J = 3.6 Hz), 6.32 (1H, d, J = 3.6 Hz), 6.25 (1H, d, J = 2.3 Hz), 6.18 (1H, s), 3.19 (2H, q, J = 3.4 Hz), 2.77 (2H, q, J = 7.4 Hz), 2.27 (3H, s), 1.44 (3H, t, J = 7.4 Hz), 1.38 (3H, t, J = 7.4 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 131.5, 127.8, 127.7, 124.2, 112.4, 111.1, 108.1, 104.7, 100.2, 86.3, 21.7, 19.1, 15.1, 13.1, 12.3. MS m/z (relative intensity): 226 (M⁺, 45), 211 (100), 195 (19), 98 (17). HRMS (EI) calcd for C₁₅H₁₈N₂ (M⁺) 226.1470, found 226.1484.

4i. Mp 123 °C. ¹H NMR (500 MHz, CDCl₃, δ): 6.31 (1H, m), 6.24 (1H, s), 6.20 (1H, d, J = 3.5 Hz), 3.16–3.10 (4H, m), 2.61 (3H, s), 1.44 (3H, t, J) 7.3 Hz), 1.36 (3H, t, J) 7.3 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 130.9, 129.8, 128.3, 127.3, 123.7, 108.4, 108.9, 107.7, 99.2, 88.7, 23.8, 22.1, 16.0, 14.2, 13.6, 13.1. MS m/z (relative intensity): 240 (M⁺, 54), 225 (100), 210 (21), 105 (24). HRMS (EI) calcd for C₁₆H₂₀N₂ (M⁺) 240.1627, found 240.1614.

4j. ¹H NMR (500 MHz, CDCl₃, δ): 7.38–7.26 (5H, m), 6.28 (1H, d, J) 3.3 Hz), 6.16 (1H, d, J) 3.6 Hz), 6.10 (1H, s), 5.56 (1H, s), 3.86 (3H, s), 3.37 (2H, t, J) 7.9 Hz), 3.11 (2H, t, J) 7.9 Hz), 2.60 (3H, s), 2.19 (3H, s). ¹³C NMR (125 MHz, CDCl₃, δ): 142.7, 141.6, 128.5, 128.4 (×4), 126.0, 123.1, 122.7, 109.0, 107.5, 99.5, 85.6, 85.1, 58.6, 35.1, 30.6, 14.8, 13.1. MS m/z (relative intensity): 318 (M⁺, 26), 227 (100), 212 (74), 183 (64), 91 (40). HRMS (EI) calcd for C₂₁H₂₂N₂O (M⁺) 318.1732, found 318.1738.

4k. Mp 122 °C. ¹H NMR (500 MHz, CDCl₃, δ): 7.36–7.25 (5H, m), 6.48 (1H, s), 6.24 (1H, s), 6.06 (1H, d, J) 2.4 Hz), 5.73 (1H, s), 3.98 (3H, s), 3.35 (2H, t, J = 8.1 Hz), 3.03 (2H, t, J = 8.1 Hz), 2.59 (3H, s), 2.17 (3H, s). ¹³C NMR (125 MHz, CDCl₃, δ): 144.2, 141.6, 128.3 (×4), 127.4, 126.0, 125.0, 122.7, 120.7, 108.6, 108.2, 97.0, 89.2, 87.4, 58.4, 36.5, 32.6, 16.0, 13.1. MS m/z (relative intensity): 318 (M⁺, 23), 227 (90), 212 (100), 183 (96), 91 (40). HRMS (EI) calcd for C₂₁H₂₂N₂O (M⁺) 318.1732, found 318.1729.

4l. Mp 79 °C. ¹H NMR (500 MHz, CDCl₃, δ): 7.46–7.34 (5H, m), 6.42 (1H, d, J = 3.0 Hz), 6.41 (1H, s), 6.31 (1H, s), 6.29 (1H, d, J = 3.5 Hz), 3.50 (2H, d, J = 7.9 Hz), 3.21 (2H, d, J = 7.9 Hz), 3.10 (2H, d, J = 7.7 Hz), 2.67 (3H, s), 2.30 (3H, s), 1.82 (2H, sext, J = 7.6 Hz), 1.14 (3H, t, J= 7.3 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 141.5 (×2), 129.5, 128.4 (×4), 125.9, 125.7, 123.7 (×2), 109.5, 108.8, 108.4, 99.3, 88.6, 35.1, 32.7, 30.7, 23.4, 15.8, 14.0, 13.6. MS m/z (relative intensity): 330 (M⁺, 30), 239 (100), 209 (19), 91 (9). HRMS (EI) calcd for C₂₃H₂₆N₂ (M⁺) 330.2096, found 330.2092.

4m. Mp 76 °C. ¹H NMR (500 MHz, CDCl₃, δ): 7.41–7.30 (5H, m), 6.37 (1H, d, J = 3.5 Hz), 6.33 (2H, s), 6.25 (1H, d, J = 3.4 Hz), 3.41 (2H, d, J = 7.8 Hz), 3.12–3.06 (4H, m), 2.65 (3H, s), 2.26 (3H, s), 1.89 (2H, sext, J = 7.5 Hz), 1.17 (3H, t, J = 7.3 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 141.5 (×2), 129.3 (×2), 128.4 (×4), 126.0, 124.9, 123.4, 109.6, 108.9, 108.7, 99.4, 88.7, 36.5, 32.8, 31.0, 22.1, 16.1, 14.0, 13.7. MS m/z (relative intensity): 330 (M⁺, 23), 239 (100), 209 (21), 91 (11). HRMS (EI) calcd for C₂₃H₂₆N₂ (M⁺) 330.2096, found 330.2080.

Representative Procedure for Exhaustive Reduction of Bis-pyrrolopyrimidines (12a, T6)

PtO₂ (23 mg) and HBr (235 μL, 2.1 mmol, 48% in H₂O) were added to the solution of 4d (230 mg, 1.02 mmol) in MeOH (10 mL). The mixture was stirred under hydrogen pressure (50 psi) for 40 h. After this period, the mixture was filtered through Celite and concentrated under reduced pressure to give the amidinium salt 11a.

Without further purification, crude 11a was dissolved in anhydrous THF (10 mL). Molecular sieves (4Å)(300 mg) were added to the mixture, stirred for 30 min and cooled to 0 °C. LiAlH₄ (5.0 mL, 1.0 M in THF) was added to the mixture dropwise at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. After this period, saturated aqueous Na₂SO₄ was added to the mixture dropwise, and the white precipitate was filtered off through Celite. The filtrate was concentrated under reduce pressure and purified by silica gel chromatography with 5% EtOH/CH₂Cl₂ to give (±)-tetraponerine T6 (12a) as an oil (154 mg, 64%).

12a (T6). ¹H NMR (500 MHz, C₆D₆, δ): 3.14 (1H, m), 3.02 (1H, dt, J = 8.6, 2.4 Hz), 2.98 (1H, t, J = 5.2 Hz), 2.52 (1H, m), 2.44 (1H, m), 2.05–1.98 (2H, m), 1.90–1.34 (18H, m), 0.99 (3H, t, J = 7.2 Hz). ¹³C NMR (125 MHz, C₆D₆, δ): 83.3, 64.1, 59.6, 49.1, 45.7, 34.7, 33.3, 32.6, 30.6, 29.2, 25.9, 23.1, 21.3, 21.0, 14.4. MS m/z (relative intensity): 235 (M⁺ − 1, 100), 179 (87), 138 (81), 96 (81), 70 (52). HRMS (EI) calcd for C₁₅H₂₇N₂ (M⁺ − 1) 235.2174, found 235.2163.

12b (Crude). ¹H NMR (500 MHz, C₆D₆, δ): 2.71 (2H, m), 2.44 (1H, m), 2.36–2.32 (1H, m), 2.0 (1H, m), 1.90–1.65 (9H, m), 1.54–1.25 (17H, m), 1.03–0.89 (9H, m). ¹³C NMR (125 MHz, C₆D₆, δ): 87.7, 66.7, 62.5, 61.2, 58.6, 42.2, 39.3, 36.7, 35.5, 32.5, 30.3, 30.2, 29.8, 29.5, 28.7, 25.7, 22.9, 19.6, 14.5, 14.4, 14.1. MS m/z (relative intensity): 319 (M⁺ − 1, 11), 263 (16), 152 (100), 82 (32). HRMS (EI) calcd for C₂₁H₃₉N₂ (M⁺ − 1) 319.3113, found 319.3089.

12c. ¹H NMR (500 MHz, C₆D₆, δ): 2.63 (1H, dd, J = 10.0, 3.9 Hz), 2.58–2.54 (1H, m), 2.51 (1H, dq, J = 6.8, 2.6 Hz), 2.40–2.34 (1H, m), 2.21 (1H, ddd, J = 11.3, 5.0, 2.8 Hz), 1.83– 1.45 (13H, m), 1.19 (3H, d, J = 4.2 Hz), 1.17 (3H, d, J = 4.3), 0.98 (3H, t, J = 7.5 Hz), 0.96 (3H, t, J = 7.5 Hz). ¹³C NMR (125 MHz, C₆D₆, δ): 89.0, 71.3, 62.6, 62.0, 59.9, 38.1, 32.1, 30.6, 29.8, 29.1, 28.1, 26.3, 19.8, 10.2, 10.0, 8.0. MS m/z (relative intensity): 249 (M⁺ − 1, 36), 125 (20), 96 (100), 82 (24). HRMS (EI) calcd for C₁₆H₂₉N₂ (M⁺ − 1) 249.2331, found 249.2327.

5. ¹H NMR (500 MHz, CDCl₃, δ): 6.93 (1H, s), 6.56 (1H, d, J = 3.8 Hz), 6.27 (1H, d, J = 3.8 Hz), 3.31 (2H, t, J = 7.6 Hz), 2.58 (2H, t, J = 7.6 Hz), 2.52 (2H, t, J = 7.3 Hz), 1.76 (2H, sext, J = 7.6 Hz), 1.68–1.66 (4H, m), 1.49 (2H, sext, J = 7.6 Hz), 1.34–1.32 (4H, m), 1.00 (3H, t, J = 7.3 Hz), 0.95 (3H, t, J = 7.4 Hz), 0.88 (3H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 142.9, 134.0, 131.1, 126.3, 115.5, 110.1, 97.7, 95.3, 76.6, 36.5, 31.5, 30.5, 29.7, 28.9, 23.4, 22.6, 22.3, 19.6, 13.9, 13.6. MS m/z (relative intensity): 310 (M⁺, 33), 281 (100), 254 (10), 182 (19).

9. ¹H NMR (400 MHz, CDCl₃, δ): 7.06 (1H, s), 2.67 (2H, t, J = 9.6 Hz), 2.43 (2H, t, J = 8.8 Hz), 1.68 (2H, quint, J = 9.4 Hz), 2.59 (2H, quint, J = 9.0 Hz), 1.43 (2H, sext, J = 9.6 Hz), 1.33–1.28 (4H, m), 0.90 (3H, t, J = 9.2 Hz), 0.86 (3H, t, J = 8.5 Hz). ¹³C NMR (100 MHz, CDCl₃, δ): 174.5, 160.9, 153.2, 120.5, 98.1, 78.2, 37.5, 31.4, 29.9, 28.4, 22.4, 22.0, 19.1, 13.9, 13.5. MS m/z (relative intensity): 263 (M⁺ − 1, 1), 235 (11), 221 (23), 208 (100).

10. ¹H NMR (500 MHz, CDCl₃, δ): 6.90 (1H, s), 6.58 (1H, d, J = 3.8 Hz), 6.31 (1H, d, J = 3.8 Hz), 3.22 (2H, t, J = 7.6 Hz), 2.56 (2H, t, J = 7.5 Hz), 1.76 (2H, sext, J = 7.5 Hz), 1.70– 1.64 (2H, m), 1.37–1.30 (4H, m), 1.01 (3H, t, J = 7.3 Hz), 0.90 (3H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃, δ): 143.3, 136.4, 135.8, 127.4, 117.1, 109.7, 99.5, 36.4, 32.1, 31.8, 29.0, 24.4, 23.0, 14.5, 14.2. MS m/z (relative intensity): 264 (M⁺, 14), 235 (100), 178 (14).