Novel stereocontrolled syntheses of tashiromine and epitashiromine

Abstract

A novel stereocontrolled approach has been developed for the syntheses of tashiromine and epitashiromine alkaloids from cyclooctene β-amino acids. The synthetic concept is based on the azetidinone opening of a bicyclic β-lactam, followed by oxidative ring opening through ring C–C double bond and reductive ring-closure reactions of the cis- or trans-cyclooctene β-amino acids.

Introduction

Indolizidine alkaloids are an important class of naturally occurring compounds which have received considerable attention as a result of their valuable physiological properties. A number of representatives of this class exhibit glycosidase inhibitory activity or antimetastatic, anticancer, antitumour or anti-HIV properties [1–3]. A large number of natural products contain an indolizidine framework, among them (−)-δ-coniceine, (−)-swainsonine, indolizidine 167B [4–10], (+)-lentiginosine [11–15], (+)-slaframine [16], (−)-elaeokanine C [17], (+)-cyclizidine [18], lepadiformine [19], the highly oxygenated (+)-castanospermine [20–21], or pumiliotoxin [22]. Figure 1 illustrates the structures of several such compounds.

Figure 1.

Some indolizidine alkaloids.

Tashiromine is a natural indolizidine alkaloid isolated from Maackia tashiroi (1990). Strategies for the synthesis of indolizidine derivatives have received considerable interest from synthetic and medicinal chemists (Figure 2). A number of synthetic approaches have been described earlier for construction of the indolizidine framework; access to tashiromine in racemic form can be achieved through the alkylation of succinimide, followed by ring closure via acyliminium intermediates [23–24], the reduction of cyclized pyridinium salts [25], iminium cascade cyclization [26], alkyne-mediated hydroformylation–cyclization [27], or electrophilic pyrolidinone alkylation followed by ring closure [28–29]. Pyrrolidine alkylation and nucleophilic ring closure followed by C–C double bond hydroboration [30] leads to racemic epitashiromine, as does the N-alkylated succinimide transformation through the corresponding indolizidinone [31].

Figure 2.

Approaches to racemic tashiromine and epitashiromine.

Several synthetic procedures have also been developed for the preparation of tashiromine or epitashiromine enantiomers.

(+)-Tashiromine has been synthetized from a pyrrolidinone derivative through chiral Lewis acid-catalysed cyclization to substituted pyrrolidinones [17], by the intramolecular cyclization of a chiral alkenylated pyrrolidinone, followed by hydroxylation [32], or by the intramolecular ring closure of chiral pyrrolidine diesters followed by ester and oxo group reduction [33], while the syntheses of (+)-epitashiromine starts from a chiral morpholine derivative, with nitrone 1,3-dipolar cycloaddition and reduction [34] (Figure 3).

Figure 3.

Synthetic routes to (+)-tashiromine and (+)-epitashiromine.

(−)-Tashiromine has been accessed through the ring closure of difunctionalized acyclic chiral sulfonamide-based β-amino acids [35], the cyclization of pyrrole derivatives with a chiral side-chain [36], or the enantioselective arylation of pyrrole, followed by saturation [37]. The transformation of chiral functionalized pyrrole or pyrrolidine derivatives has served as the basis of the construction of (−)-epitashiromine [38–39] (Figure 4).

Figure 4.

Synthetic routes to (−)-tashiromine and (−)-epitashiromine.

The oxidative functionalization of cyclic β-amino acid derivatives has been reported to be a convenient route for the preparation of N-heterocyclic β-amino acid derivatives [40–41] or for the stereocontrolled synthesis of functionalized cispentacins [42] and their acyclic counterparts [43–44] (Figure 5). The oxidative ring cleavage of various vicinal diols and the transformation of the resulting dialdehyde intermediates has been efficiently applied in recent years for the synthesis of a series of valuable organic molecules [45–52]. In particular, Davies and co-workers have utilized the oxidative ring opening of cyclic vicinal diols followed by ring closure for access to pyrrolizidine alkaloids [45].

Figure 5.

Oxidative functionalizations of cyclic β-amino acids.

Results and Discussion

We describe here a novel access route for the synthesis of tashiromine and epitashiromine by starting from an unsaturated bicyclic β-lactam. The retrosynthetic concept of the synthesis is represented on Scheme 1 and was based on the lactam ring opening, in continuation followed by oxidative ring opening of the formed β-amino esters and by reductive ring closure as key steps.

Scheme 1.

Retrosynthesis of tashiromine and epitashiromine.

Bicyclic β-lactam (±)-1 [53–54] was first transformed by azetidinone opening to the corresponding amino ester hydrochloride (±)-2 [53–54], N-protection of which with benzyl chloroformate (Z-Cl) afforded protected amino ester (±)-3 in 78% yield. In agreement with our earlier observations [40–42] C–C double bond functionalization of the cyclooctene β-amino ester via dihydroxylation with N-methyl morpholine N-oxide (NMO) in the presence of OsO₄ afforded the corresponding all-cis dihydroxylated ethyl β-aminocyclooctanecarboxylate (±)-4 in 90% yield (for dihydroxylation, see also reference [54]) (Scheme 2). Amino ester (±)-4 was next subjected through its vicinal diol moiety to oxidative ring opening with NaIO₄ in MeOH at 20 °C, which resulted (monitored by TLC) in the corresponding ring-opened unstable diformyl intermediate (I1), which after work-up was immediately used without further purification (for several similar types of acyclic diformyl intermediates, see references [40–41,43–44]). Thus, the crude material was submitted to catalytic hydrogenolysis and after N-deprotection underwent double cyclization–reduction to furnish indolizidine ester (±)-5 in 41% yield after purification by chromatography.

Scheme 2.

Synthesis of (±)-tashiromine ((±)-6).

Reduction of the ester group of (±)-5 with an excess of LiAlH₄ in THF at 20 °C gave the corresponding tashiromine (±)-6 [35–37], which was isolated in 48% yield after purification by column chromatography (Scheme 2). The stereochemistry of (±)-6 was unequivocally assigned by NMR data, which were consistent with those reported [35–37].

A similar strategy was applied for the synthesis of epitashiromine. On reaction with NaOEt in EtOH at 20 °C, ethyl cis-β-aminocyclooctenecarboxylate (±)-3 underwent epimerization at C-1, leading after 18 h to an equilibrium mixture of cis and trans amino esters (1:1 ratio determined by ¹H NMR on the crude mixture), the required trans isomer (±)-7 being separated from the cis counterpart and isolated in a yield of 48% by means of column chromatography. Dihydroxylation of (±)-7 with NMO/OsO₄ next afforded an oily mixture of cis and trans dihydroxylated cyclooctane β-amino esters (diastereomeric mixture of (±)-8) in 77% overall yield after column chromatography. Our attempts to separate this nearly 1:1 mixture of the two dihydroxylated stereoisomers (determined on the basis of ¹H NMR data) failed, but the mixture could be applied in the next ring-opening oxidation step, since it gave only one open-chain diformyl intermediate I2.

Similarly to the cis isomer, this unstable dialdehyde intermediate was subjected without isolation to catalytic hydrogenolysis, followed by reductive cyclization, to give the corresponding indolizidine ester (±)-9 in 40% yield. Finally, ester reduction with LiAlH₄ in THF resulted in epitashiromine (±)-10 [32,34,39] in 53% yield after isolation by chromatography (Scheme 3). The stereochemistry of (±)-epitashiromine was assigned by NMR data, which were in agreement with those reported [32,34,39].

Scheme 3.

Synthesis of (±)-epitashiromine ((±)-10).

Conclusion

In summary, a novel stereocontrolled efficient method has been presented for the synthesis of tashiromine and epitashiromine alkaloids in six or seven steps, based on the preparation of cis or trans cyclooctene β-amino esters, followed by their oxidative ring cleavage and double reductive ring-closure reactions.

Experimental

General procedure for the Z-protection of amino esters

To a solution of amino ester hydrochloride ((±)-2 or (−)-2) [29] (17.8 mmol) in THF (40 mL), Et₃N (9 mL) was added at 0 °C, followed by 7.8 mL (1 equivalent) of Z-Cl (a 50% solution in toluene). The mixture was stirred for 14 h at 20 °C, and then was diluted with EtOAc (120 mL). The organic layer was washed with H₂O (3 × 60 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (n-hexane/EtOAc 4:1), affording the amino ester.

General procedure for the dihydroxylation of amino esters

To a solution of cis or trans Z-protected amino ester ((±)-3, (−)-3 or (±)-7) (2.9 mmol) in acetone (30 mL) and H₂O (1 mL), NMO (1.5 equivalents) and 2% OsO₄ in t-BuOH (0.7 mL) were added and the mixture was stirred at 20 °C for 4 h. A saturated aqueous solution of Na₂SO₃ (40 mL) was then added, the mixture was extracted with CH₂Cl₂ (3 × 30 mL), and the organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (n-hexane/EtOAc 1:4) to give the dihydroxylated amino ester.

General procedure for epimerization of the cis-amino ester

To a solution of cis N-protected amino ester ((±)-3 or (−)-3) (3.3 mmol) in EtOH (30 mL), EtONa (1.5 equivalents) was added at 0 °C and the mixture was stirred at 20 °C for 18 h. H₂O (70 mL) was then added, the mixture was extracted with CH₂Cl₂ (3 × 30 mL), and the organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (n-hexane/EtOAc 9:1) to give the trans isomer as a colourless oil.

General procedure for the oxidative ring opening/reductive ring closure of dihydroxylated amino esters

To a solution of dihydroxylated amino ester ((±)-4, (±)-8 or (−)-8) (2.46 mmol) in MeOH (25 mL), NaIO₄ (2 equivalents) was added and the mixture was stirred at 20 °C for 45 min. It was then diluted with H₂O (50 mL) and extracted with CH₂Cl₂ (3 × 20 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The crude mixture was dissolved in EtOAc (30 mL), Pd/C (150 mg) was added and the mixture was stirred at 20 °C for 16 h. The catalyst was next filtered off through Celite. The crude mixture was then purified by column chromatography on silica gel (CH₂Cl₂/MeOH 95:5 or CH₂Cl₂/MeOH 9:1) to give the indolizidine derivative.

General procedure for reduction of the ester

To a solution of indolizidine carboxylate ((±)-5, (±)-9 or (−)-9) (1 mmol) in dry THF (15 mL), LiAlH₄ (5 equivalents) was added at 0 °C and the mixture was stirred at 20 °C for 4 h. It was then cooled to 0 °C, H₂O (2 mL) was added dropwise and the solid formed was filtered off through Celite. The filtrate was extracted with CH₂Cl₂ (3 × 15 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH 90:8:2 or CH₂Cl₂/MeOH/NH₄OH 90:5:5) to give the alkaloid.

Ethyl (1R*,2S*)-2-(benzyloxycarbonylamino)cyclooct-5-enecarboxylate ((±)-3)

A colourless oil (R_f 0.6, n-hexane/EtOAc 4:1); yield: 78%; ¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J = 7.1 Hz, 3H, CH₃), 1.76–1.87 (m, 2H, CH₂), 1.88–1.97 (m, 1H, CH₂), 1.98–2.07 (m, 1H, CH₂), 2.09–2.18 (m, 2H, CH₂), 2.22–2.31 (m, 1H, CH₂), 2.43–2.52 (m, 1H, CH₂), 2.82–2.89 (m, 1H, H-1), 4.12–4.21 (m, 2H, OCH₂), 4.22–4.30 (m, 1H, H-2), 5.08 (s, 2H, OCH₂), 5.30 (brs, 1H, N-H), 5.60–5.74 (m, 2H, H-5 and H-6), 7.33–7.48 (m, 5H, Ar-H); ¹³C NMR (100 MHz, DMSO) δ 14.9, 24.4, 25.1, 26.6, 32.3, 46.4, 52.1, 60.6, 66.1, 128.5, 128.6, 129.2, 129.5, 130.7, 138.0, 156.3, 174.5; anal. calcd for C₁₉H₂₅NO₄: C, 68.86; H, 7.60; N, 4.23; found: C, 68.59; H, 7.31; N, 3.93.

Ethyl (1R*,2S*,5R*,6S*)-2-(benzyloxycarbonylamino)-5,6-dihydroxycyclooctanecarboxylate ((±)-4)

A colourless oil (R_f 0.4, n-hexane/EtOAc 1:4); yield: 90%; ¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, J = 7.15 Hz, 3H, CH₃), 1.62–1.94 (m, 4H, CH₂), 1.97–2.28 (m, 4H, CH₂), 2.77–2.82 (m, 1H, H-1), 3.83–3.89 (m, 2H, H-5 and H-6), 4.02–4.10 (m, 1H, H-2), 4.11–4.19 (m, 2H, OCH₂), 5.09 (m, 2H, OCH₂), 5.49 (brs, 1H, N-H), 7.36–7.48 (m, 5H, Ar-H); ¹³C NMR (100 MHz, DMSO) δ 14.8, 21.2, 26.9, 28.5, 29.0, 45.4, 51.6, 60.7, 65.9, 72.3, 72.4, 128.4, 128.5, 129.1, 138.1, 156.3, 174.6; anal. calcd for C₁₉H₂₇NO₆: C, 62.45; H, 7.45; N, 3.83; found: C, 62.19; H, 7.10; N, 4.13.

Ethyl (8R*,8aS*)-octahydroindolizine-8-carboxylate ((±)-5)

A yellow oil (R_f 0.55, CH₂Cl₂/MeOH 95:5); yield: 41%; ¹H NMR (400 MHz, CDCl₃) δ 1.27 (t, J = 7.15 Hz, 3H, CH₃), 1.46–1.53 (m, 2H, CH₂), 1.57–1.92 (m, 5H, CH₂), 1.99–2.10 (m, 3H, CH₂), 2.13–2.20 (m, 1H, CH₂), 2.25–2.31 (m, 1H, H-8), 3.03–3.10 (m, 2H, CH₂ and H-8a); ¹³C NMR (100 MHz, CDCl₃) δ 14.6, 20.9, 25.1, 29.5, 30.1, 48.4, 52.6, 54.4, 60.6, 65.6, 174.6; MS (ESI) m/z: 198.5 [M + 1]; anal. calcd for C₁₁H₁₉NO₂: C, 66.97; H, 9.71; N, 7.10; found: C, 66.60; H, 10.02; N, 7.39.

((8R*,8aS*)-Octahydroindolizin-8-yl)methanol; ((±)-tashiromine (±)-6) [35–37]

A yellow oil (R_f 0.45, CH₂Cl₂/MeOH/NH₄OH 90:8:2); yield: 48%; ¹H NMR (400 MHz, CDCl₃) δ 1.00–1.11 (m, 1H, CH₂), 1.42–1.53 (m, 2H, CH₂), 1.58–1.83 (m, 5H, CH₂), 1.84–1.99 (m, 3H, CH₂), 2.04–2.11 (m, 1H, CH₂), 3.03–3.10 (m, 2H, N-CH), 3.41–3.46 (m, 1H, OCH₂), 3.59–3.64 (m, 1H, OCH₂); ¹³C NMR (100 MHz, CDCl₃) δ 21.1, 25.5, 28.0, 29.4, 44.9, 53.1, 54.5, 66.0, 66.9; MS (ESI) m/z: 156.6 [M + 1]; anal. calcd for C₉H₁₇NO: C, 69.63; H, 11.04; N, 9.02; found: C, 69.28; H, 10.70; N, 8.76.

Ethyl (1S*,2S*)-2-(benzyloxycarbonylamino)cyclooct-5-enecarboxylate ((±)-7)

A colourless oil (R_f 0.55, n-hexane/EtOAc 4:1); yield: 48%; ¹H NMR (400 MHz, DMSO) δ 1.18 (t, J = 7.10 Hz, 3H, CH₃), 1.55–1.64 (m, 2H, CH₂), 1.73–1.97 (m, 2H, CH₂), 2.04–2.19 (m, 2H, CH₂), 2.33–2.47 (m, 2H, CH₂), 2.68–2.75 (m, 1H, H-1), 3.88–4.02 (m, 3H, OCH₂ and H-2), 4.96–5.02 (m, 2H, OCH₂), 5.53–5.60 (m, 2H, H-5 and H-6), 7.30–7.44 (m, 5H, Ar-H); ¹³C NMR (100 MHz, DMSO) δ 14.8, 24.5, 25.1, 29.2, 33.8, 49.2, 52.1, 60.4, 65.9, 128.0, 128.4, 129.0, 129.1, 130.7, 138.2, 156.9, 174.5; anal. calcd for C₁₉H₂₅NO4: C, 68.86; H, 7.60; N, 4.23; found: C, 68.57; H, 7.28; N, 3.97.

Ethyl (8S*,8aS*)-octahydroindolizine-8-carboxylate ((±)-9)

A yellow oil (R_f 0.45, CH₂Cl₂/MeOH 4:1); yield: 40%; ¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J = 7.15 Hz, 3H, CH₃), 1.28–1.33 (m, 1H, CH₂), 1.42–1.55 (m, 2H, CH₂), 1.58–1.64 (m, 1H, CH₂), 1.68–1.86 (m, 3H, CH₂), 2.02–2.18 (m, 3H, CH₂), 2.23–2.27 (m, 1H, CH₂), 2.78–2.81 (m, 1H, H-8), 3.04–3.10 (m, 2H, CH₂ and H-8a), 4.09–4.17 (m, 2H, OCH₂); ¹³C NMR (100 MHz, DMSO) δ 15.1, 21.2, 22.6, 26.8, 27.3, 42.0, 53.4, 55.0, 60.5, 64.9, 170.4; MS (ESI) m/z: 198.7 [M + 1]; anal. calcd for C₁₁H₁₉NO₂: C, 66.97; H, 9.71; N, 7.10; found: C, 67.28; H, 9.40; N, 6.78.

((8S*,8aS*)-Octahydroindolizin-8-yl)methanol; ((±)-epitashiromine, (±)-10) [32,34,39]

A yellow oil (R_f 0.45, CH₂Cl₂/MeOH/NH₄OH 88:8:4); yield: 53%; ¹H NMR (400 MHz, CDCl₃) δ 1.56–1.62 (m, 2H, CH₂), 1.65–1.74 (m, 4H, CH₂), 1.97–2.12 (m, 5H, CH₂), 2.20–2.28 (m, 1H, H-8), 2.94–3.00 (m, 1H, CH₂), 3.08–3.14 (m, 1H, N-CH), 3.70–3.75 (m, 1H, OCH₂), 4.13–4.19 (m, 1H, OCH₂); ¹³C NMR (100 MHz, CDCl₃) δ 21.2, 23.7, 26.3, 30.1, 35.7, 54.0, 54.9, 66.0, 66.8; MS (ESI) m/z: 156.4 [M + 1]; anal. calcd for C₉H₁₇NO: C, 69.63; H, 11.04; N 9.02; found: C, 69.30; H, 10.71; N, 8.79.