Double Cycloisomerization as a Novel and Expeditious Route to Tricyclic Heteroaromatic Compounds: Short and Highly Diastereoselective Synthesis of (±)-Tetraponerine T6

Abstract

Cu-Assisted double cycloisomerization of bis-alkynylpyrimidines afforded the 5–6–5 tricyclic heteroaromatic skeleton. This transformation was used as a key step in the highly diastereoselective total synthesis of (±)-tetraponerine T6.

We have recently reported a novel, general, and efficient method for the construction of 2-monosubstituted and 2,5- disubstituted pyrroles, as well as fused aromatic heterocycles containing a pyrrole ring, via the Cu-assisted cycloisomerization of alkynyl imines. The generality and synthetic usefulness of this novel methodology was demonstrated by achieving the shortest synthesis of (±)-monomorine in three steps and 47% overall yield¹ (Scheme 1). This successful result encouraged us to investigate a possible multiple pyrrolization protocol. If this unprecedented cascade transformation proves to be successful, combined with a further functionalization sequence, it can provide us with a conceptually novel and expeditious route to various polycyclic alkaloid skeletons.

Scheme 1.

Short Synthesis of (±)-Monomorine

Herein, we report the first example of double pyrrolization of pyrimidine derivatives into the bis-pyrrolopyrimidines and employment of this transformation in the short and highly diastereoselective synthesis of (±)-tetraponerine T6.

To examine the possibility of assembling a 5–6–5 tricyclic heteroaromatic skeleton, we synthesized bis-pro-pynylpyrimidine derivatives 1a-c and tested them under pyrrolization conditions. A sequential double pyrrolization of 1 posed a certain challenge. Indeed, as shown in Scheme 2, the first pyrrolization of 1 can proceed in three possible ways (paths A-C). Among them, paths A and B, after the first cycloisomerization, will produce pyrrolopyrimidines 3 and 4, which after the second pyrrolization will be converted into the desired product 2. In contrast to the above cases, path C leads to dead-end intermediate 5. Experiments have shown that in the presence of 1 equiv of CuBr in dilute Et₃N–DMA at 150 °C, bis-propynylpyrimidines 1a–c were smoothly converted into the tricyclic bis-pyrrolopyrimidines 2a–c in 48–51% yield.² Under these reaction conditions, no other low-molecular weight compounds, besides 2, 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 reduced copper loading (50 mol %), early stage GC-MS analyses revealed the presence of two isomeric compounds in about a 5:1 ratio, along with starting material 1 and product 2. As the reaction progressed, the amount of tricyclic product 2 increased and the amounts of the starting material and its two unidentified isomers decreased. At this stage, it is unclear which of these three structures (3–5) corresponded to the two fleeting isomers observed by GC-MS.³ Taking into account that the yield per each pyrrolization in the transformation 1 → 2 is about 70% and that the cycloisomerization yields for propyne derivatives are normally 10–20% lower than that of their higher homologues,⁵ we considered 48–51% yield for the double pyrrolization to be a rather satisfactory result.

Scheme 2.

Sequential Double Pyrrolizationa

^a Reagents and conditions: (a) CuBr, Et₃N-DMA, 150 °C, 10 h.

Encouraged by successful synthesis of 5–6–5 tricyclic bis-pyrrolopyrimidine core 2, we attempted a total synthesis of (±)-tetraponerine T6,⁶ which can be considered to be a reduced derivative of 2. Indeed, T6 could be made by complete reduction of heteroaromatic compound 7, a higher homologue of 2b, which, in turn, is the double-pyrrolization product of bis-propynylpyrimidine 8. The latter could be easily prepared from the known pyrimidine dione 9 (Scheme 3).

Scheme 3.

Retrosynthetic Analysis for 6

The synthesis began with pyrimidine dione 9,⁷ which was routinely prepared from ethyl acetoacetate. Treatment of 9 with phosphorus oxybromide in benzene followed by Sonogashira coupling⁸ with propyne proceeded uneventfully to give bis-propynylpyrimidine 8 in excellent overall yield. The next step, a sequential double pyrrolization of 8, gave 5–6–5 tricyclic bis-pyrrolopyrimidine 7 in 52% yield (Scheme 4).

Scheme 4.

Synthesis of Bis-pyrrolopyrimidine 7a

^a Reagents and conditions: (a) C₆H₅N(CH₃)₂, POBr₃, benzene, reflux, 2h, 81%; (b) CuI, Pd(PPh₃)₂Cl₂, propyne, Et₃N, 50 °C, 3 h, 100%; (c) CuBr, Et₃N-DMA, 150 °C, 10 h, 52%.

Direct complete hydrogenation of heteroaromatic compound 7 to 6 proved not to be simp catalytic hydrogenation of pyrimidine derivatives in acidic media is cis diastereoselective and stops at the stage of formation of stable amidinium derivatives.⁹ Accordingly, as expected, catalytic hydrogenation of 7 over PtO₂ under acidic conditions gave amidinium salt 11 as a single cis isomer.¹⁰ The total synthesis of (±)-tetraponerine T6 was completed by highly diastereoselective reduction of crude 11 with LiAlH₄ to give 6 as the sole stereoisomer in 64% yield for two steps (Scheme 5).

Scheme 5.

Reductive Transformations of 7a

^a Reagents and conditions: (a) H₂ (50 psi), PtO₂, HBr, MeOH, rt, 40 h; (b) LiAlH₄, THF, 4 Å MS, from 0 °C to rt, 2 h, 64% yield for two steps.

The highly stereoselective reduction of 9, which we believe is stereoelectronically controlled, deserves a special note.¹¹ Two possible transition states can account for the delivery of hydride to the newly formed stereogenic center at the C-4 position. Obviously, the nucleophilic attack of a hydride proceeds from the β-face to give (±)-T6 through the most favorable “chairlike” transition state i instead of an α-face delivery of a hydride through the disfavored “boatlike” transition state ii to form an epi (±)-T6 (Figure 1). The relative configuration of (±)-tetraponerine T6 was confirmed by NOESY and ¹H NOE experiments.¹²

Figure 1.

Transition states for the nucleophilic attack of hydride at the amidinium ion 11.

In conclusion, the first Cu-assisted double pyrrolization of bis-alkynylpyrimidine to the 5–6–5 heteroaromatic core was demonstrated. Highly selective hydrogenation/reduction of the resulting bis-pyrrolopyrimidine allowed for the short, efficient, and highly diastereoselective total synthesis of (±)- tetraponerine T6 in five steps and 27% overall yield. The multiple pyrrolization–reductive functionalization protocol can serve as a new, short, and efficient approach toward various polycyclic alkaloid structures.