Synthesis of an aspidosperma alkaloid precursor: synthesis of (+)-aspidospermidine

The aspidosperma alkaloid precursor (-)-(4a R ,8a S ,8 R )-4a-ethyl-decahydroquinolin-7-one 7 (hydrolilolidone) was prepared from (+)-(1' S ,4a R ,8a S )-4a-ethyl-1-(1'-phenylethyl)- octahydroquinolin-7-one 3 . In addition, a synthesis of (+)-aspidospermidine 9 using compound 7 as starting material is described.


Introduction
The Aspidosperma family represents one of the largest groups of indole alkaloids with more than 250 compounds isolated from various biological sources and among these is naturally occurring aspidospermidine.The basic skeletal features of these compounds, particularly the complex pentacyclic ABCDE framework, can be seen in the namesake of the family aspidospermidine.The pioneering work of Stork in 1963, who succeeded in achieving the first total synthesis of racemic aspidospermine, was focused upon the use of the racemic 4a-ethyl-octahydroquinolin-7one, precursor of the pivotal CDE-type tricyclic keto-amine intermediate (hydrolilolidone), which was converted into aspidospermine through a Fischer indole synthesis 1,2,3 (Scheme 1).

Scheme 2
Compound (+)-(1'S,4aR,8aS)-3 is stereochemically interesting and synthetically important after removal the 2-phenylethyl auxiliary.In this context, we investigated the catalytic hydrogenation conditions to remove this auxiliary.When the catalytic hydrogenation is carried out at pH ca.1-4, compound 4 is obtained in 15% yield.However, if this process is carried out at pH ca.5-6, this compound is obtained in 90% yield.(Scheme 3).In order to determine the absolute configuration of the stereogenic centers C(4a) and C(8a) and the CD ring junction stereochemistry of 4, this compound was converted into the corresponding hydrobromide 4HBr, crystallized and analyzed by X-ray diffraction.The absolute configuration of the stereogenic centers C(4a) and C(8a) were unambiguously determined as (R) and (S) respectively.The X-ray absolute configurations are thus in agreement with that observed in 3 and support the fact that the cis CD ring junction was controlled after hydrogenolisis of 3. (Figure 1).

Figure 1
Considering the adequate stereochemistry of 4 (4aR,8aS), this compound was used to prepare 6.For this purpose, compound 4 was treated with chloroacetyl chloride in presence of triethylamine giving the chloroacetamide 5. Further, treatment of 5 with potassium tert-butoxide at room temperature afforded the enantiopure tricyclic keto-lactam 6 in quantitative yield.The cis alignment CH 3 -CH 2 /C-H8 and C-H8/C-H8a of 6 was established by 1

Scheme 4
The diastereospecific cyclization observed in this process can be explained by the presence of a rigid transition state (Enol-5), where the chloro-acetyl group is located exclusively over the favorable diastereotopic face and the anion at C-8 generated in equilibrium with the Enol-5, can displace the chlorine atom through an S N 2 mechanism to give the enantiopure compound 6. (Figure 2).Furthermore, ketalization of 6 with ethylenglycol in presence of p-toluensulfonic acid, reduction with lithium aluminium hydride, and regeneration of the ketonic function, afforded 7. Assignments in 1 H NMR for 7 were confirmed by 1 H and 13 C NMR correlation techniques.(Scheme 5).Synthesis of (+)-Aspidospermidine 9. Having established the stereochemistry 2 and the CDE ring junction of 7 2 , this compound was treated with phenyhydrazine 1 to produce the 1,2dehydroaspidospermidine 8. Later, reduction of 8 with sodium borohydride in methanol gave the aspidospermidine 9.All data of compound 9, were found to be comparable to those reported. 6,7,8Scheme 6).We have described a simple and clean procedure in four steps to prepare the enantiopure alkaloid precursor 7 (hydrolilolidone) in 63.3 % overall yield using chiral, nonracemic bicyclic lactam 3 as starting material.Finally, the synthesis of (+)-aspidospermidine 9 was completed using 3 as starting material in six steps with 37.0 % overall yield.

Experimental Section
General Procedures. 1 H NMR spectra of CDCl 3 solutions were recorded with a Varian Unity instrument at 400 MHz (internal tetramethylsilane as reference).IR spectra were obtained with a Nicolet FT-IR Magna 750 spectrometer.Chromatography was carried out using Al 2 O 3 .Optical rotations were determined at room temperature with a Perkin-Elmer 341 polarimeter, using a 1dm cell with a total volume of 1 mL and are referenced to the D-line of sodium.Mass spectra were recorded with a JEOL JEM-AX505HA instrument at a voltage of 70 eV.Melting points were determined using a Fisher-Johns apparatus and are uncorrected.