Novel stereocontrolled syntheses of tashiromine and epitashiromine

Summary 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.

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]. Several synthetic procedures have also been developed for the preparation of tashiromine or epitashiromine enantiomers.
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][46][47][48][49][50][51][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].

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.
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.
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 1 H 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/OsO 4 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 1 H NMR data) failed, but the mixture could be applied in the next ring-opening oxidation step, since it gave only one openchain diformyl intermediate I2.

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.
trated 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 H 2 O (1 mL), NMO (1.5 equivalents) and 2% OsO 4 in t-BuOH (0.7 mL) were added and the mixture was stirred at 20 °C for 4 h. A saturated aqueous solution of Na 2 SO 3 (40 mL) was then added, the mixture was extracted with CH 2 Cl 2 (3 × 30 mL), and the organic layer was dried (Na 2 SO 4 ) 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. H 2 O (70 mL) was then added, the mixture was extracted with CH 2 Cl 2 (3 × 30 mL), and the organic layer was dried over Na 2 SO 4 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), NaIO 4 (2 equivalents) was added and the mixture was stirred at 20 °C for 45 min. It was then diluted with H 2 O (50 mL) and extracted with CH 2 Cl 2 (3 × 20 mL). The organic layer was dried (Na 2 SO 4 ) 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 (CH 2 Cl 2 /MeOH 95:5 or CH 2 Cl 2 /MeOH 9:1) to give the indolizidine derivative.