Conjugate Addition of 2-Acetylindole Enolates to Unsaturated Oxazolopiperidone Lactams: Enantioselective Access to the Tetracyclic Ring System of Ervitsine

Dedicated to Prof. Carmen Najera on the occasion of her 60th birthday The stereochemical outcomes of the conjugate addition reac- tions of 2-acetylindole enolates to the unsaturated phenylgly- cinol-derived oxazolopiperidone lactams 1a-f have been studied. After reduction of the 2-acylindole carbonyl group,


Introduction
Phenylglycinol-derived oxazolopiperidone lactams have proven to be versatile scaffolds that allow the regio-and stereocontrolled introduction of substituents at the different positions of the piperidine ring, thus providing access to enantiopure piperidines bearing virtually any type of substitution pattern and also to more complex piperidine-containing alkaloids, including indole alkaloids. [1] In particular, the stereoselective introduction of carbon appendages at the piperidine 4-position by conjugate addition reactions requires the activation of this position, which can be accomplished by generation of a conjugated carbon-carbon double bond taking advantage of the lactam carbonyl group.

Results and Discussion
We report herein the conjugate addition of 2-acetylindole enolates to unsaturated phenylglycinol-derived oxazolopiperidone lactams and the subsequent construction of the tetracyclic framework of the indole alkaloid ervitsine by closure of the sevenmembered ring by intramolecular α-amidoalkylation on the indole 3-position (Scheme 1). As the starting unsaturated lactams we selected lactams 1a-f ( Figure 1 and Scheme 2), all of them bearing an ethyl substitutent at the 8-position of the oxazolopiperidone system. The preparation of 3,8a-cis lactams 1a-d [3,6,8] has previously been reported. The new 3,8a-trans lactams 1e and 1f were prepared from the known lactams 2a [11] and 2b [11] , via the respective seleno derivatives 3a and 3b, as outlined in Scheme 2.  [a] For the relative configuration of the epimerizable C-6 stereocenter, see the Experimental Section Scheme 2. Preparation of unsaturated lactams 1e and 1f. Table 1 summarizes the results obtained in the conjugate addition reactions of 2-acetylindole enolates 4a and 4b to unsaturated lactams 1a-d. The initial experiments were carried out using the enolate of 2-acetyl-1-methylindole (4a). Starting from unsaturated lactam 1a, which lacks the activating electronwithdrawing benzyloxycarbonyl group, the use of a slight excess (1.2 equiv.) of the nucleophile (entry 1) led to the expected adducts 5 in low yield (24%) as a 1:2 epimeric mixture of C-7/C-8 cis/trans isomers. A similar result was observed using the enolate of 2acetylindole (4b): compound 6 was obtained in 30% yield as a C-7/C-8 cis/trans epimeric mixture in a 1:3 ratio (entry 2). The yield grew progressively higher as the excess of the nucleophile was increased (entries 3 and 4), reaching 68% when using 5 equiv. of enolate.
The relative configuration of the cis and trans isomers was evident from the shielding of the oxazolopiperidone 6-carbon in the 13 C NMR spectrum of cis-6 (δ 37.9 ppm; compare with δ 42.0 ppm in trans-6) exerted by the axial ethyl substituent at C-8.
The facial selectivity of the conjugate addition reactions to lactam 1a (R 1 = H) can be accounted for by considering that the addition of stabilized anions to α,β-unsaturated carbonyl compounds is a reversible process that in the case of 5-substituted 5,6-dihydro-2-pyridones leads to the thermodynamically more stable trans-4,5-disubstituted derivative. [12] Accordingly, in the reaction of lactam 1a with acetylindole 4b an increase of the ratio of the isomer cis-6 was observed when the reaction was quenched after a short reaction time (Table 1, entry 5).
In clear contrast from the stereochemical standpoint, similar conjugate addition reactions from the activated lactams 1b-d, which bear an additional activating alcoxycarbonyl substituent, led to the respective adducts 7-10 as diastereoisomeric mixtures in which the C-7/C-8 cis isomers predominated (entries 6-10). [13] As in the above lactam 1a, the use of a 5 equiv. excess of nucleophile in these reactions resulted in higher yields, lactams 9 and 10 being formed in 90% (compare entries 8 and 9) and 87% yield (entry 10), respectively, even after shorter reaction times.
The C-7/C-8 cis relative configuration in the major isomer cis-9 was confirmed by its conversion [H2, Pd(OH)2; then toluene at reflux] to cis-6, the minor isomer obtained from lactam 1a (Scheme 3). On the other hand, the predominance of the cis isomer in the conjugate addition to lactams 1b-d (R 1 = CO2R) can be rationalized by considering that in these cases the equilibration takes place to a lesser extent as a consequence of the higher stability of the initially formed adduct (a 1,3-dicarbonyl enolate). The process would then occur mainly under stereoelectronic control, [14] which involves an axial approach of the nucleophile to the electrophilic carbon of the conjugate double bond from the exo face of the bicyclic system as depicted in Figure 2. In fact, irreversible conjugate additions (for instance, of organocuprates) to unsaturated oxazolopiperidone lactams (1a-f or related lactams) have been reported to occur under stereoelectronic control with complete exo facial selectivity. [15]  A similar stereoelectronically controlled facial stereoselectivity was observed in the conjugate addition of the enolate of 4b to the C-8 epimeric 3,8a-trans lactams 1e and 1f (Figure 2), the respective exo adducts cis-11 and trans-12 being formed as the major isomers (Scheme 4). To study the closure of the seven-membered ring characteristic of ervitsine, we initially selected lactam trans-6. However, all attempts to promote the cyclization under a variety of acidic conditions (TiCl4, CH2Cl2, reflux; BF3 . Et2O, CH2Cl2, reflux; HCl, MeOH or C6H6) resulted in failure. Enamide 13 [16] and the 8aepimer (14) and the 8,8a-diastereoisomer (15) of trans-6 were the only isolable products (Scheme 5). [17] The stereochemistry of 14 and 15 was confirmed when these compounds were unambiguously prepared from trans-12 and cis-11, respectively, by debenzylation [H2, Pd(OH)2] followed by decarboxylation. Scheme 5. Taking into account that the isolation of compounds 13-15 clearly indicated that the N-acyl iminium cation [18] had been formed, the failure of the cyclization was attributed to the deactivating effect of the carbonyl group conjugated with the indole ring. For this reason, acylindole trans-6 was converted to alcohol 16 and then to the indolylethyl derivative 18 by hydrogenolysis of the corresponding acetate 17.
The desired cyclization upon the indole 3-position did not occur from 16 or 18 either, under a variety of acidic conditions, only extensive decomposition being observed.
Bearing in mind that the closure of the seven-membered ring of ervitsine and analogs has been successfully achieved by a related intramolecular iminium ion cyclization, [19] at this point we reasoned that conformational factors could be responsible for the reluctance of the above C-7/C-8 trans derivatives to undergo intramolecular α-amidoalkylation: cyclization would involve an encumbered conformation in which both C-7 and C-8 substituents should be axial. To confirm this hypothesis, we decided to study related α-amidoalylation reactions from C-7/C-8 cis lactams.
However, no cyclized products were detected upon treatment of cis-6 with TiCl4, the 8a-epimer of cis-6 being the only isolable product. [20] As in the above C-7/C-8 trans series, 2-acylindole cis-6 was reduced to alcohol 19, and then converted to indolylethyl derivative 21 via the corresponding acetate 20 (Scheme 6). Scheme 6. Access to the tetracyclic ring system of ervitsine.
Although alcohol 19 underwent extensive decomposition upon acidic treatment, to our delight, when the reduced derivative 21 was treated with TiCl4 in refluxing CH2Cl2, tetracycle 22 was isolated in 58% yield.

Conclusions
In conclusion, conjugate addition reactions of 2-acetylindole enolates to phenylglycinol-derived unsaturated δ-lactams allow the stereocontrolled formation of C-C bonds at the piperidine 4position. Depending on the absence or presence of an additional electron-withdrawing substituent conjugated with the C-C double bond, the reaction predominantly leads to either transor cis-4,5disubtituted enantiopure 2-piperidone derivatives, respectively.
The synthetic potential of the resulting Michael adducts has been demonstrated with the enantioselective construction of the tetracyclic ring system of ervitsine, a minor indole alkaloid isolated from Pandaca boiteaui [21] that lacks the characteristic tryptamine moiety present in most monoterpenoid indole alkaloids. Starting from an appropriate lactam bearing a C-8 substituent precursor of the exocyclic methylene group, the strategy developed here, involving a stereoselective conjugate addition and an intramolecular α-amidoalkylation as the key steps (see Scheme 1), may be applied to the enantioselective synthesis of ervitsine. [22] Experimental Section  [11] (1.08 g, 4.24 mmol) in anhydrous THF (50 mL), and the resulting mixture was stirred for 90 min. Then, benzyl chloroformate (710 µL, 4.24 mmol) and, after 2 h of continuous stirring at −78 ºC, a solution of C6H5SeCl (1.14 g, 5.09 mmol) in anhydrous THF (5 mL) were added. The mixture was stirred for 2 h and poured into saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried and concentrated. Flash chromatography (hexane to 4:1 hexane-EtOAc) of the resulting oil afforded the corresponding selenides 3a as a mixture of C-6 epimers (1.40 g, 62%). Data for 3a: Orange oil. 1  until it turned pale blue (5 min). Then, the solution was purged with O2, and the temperature was slowly raised to 25 ºC. After 30 min of stirring, the mixture was poured intro brine, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried and concentrated to give unsaturated lactam 1e, which due to its instability was used in the next reaction without further purification. Data for 1e: Yellow oil. 1  General Procedure for the Conjugate Addition Reactions: LDA was added to a cooled (-78 ºC) solution of 2-acetylindole (4a or 4b) in THF, and the mixture was stirred at this temperature for 1 h. Then, a solution of unsaturated lactam 1 in THF was added to the solution (-78 ºC). The resulting mixture was stirred at room temperature until the disappearance of the starting material was observed by TLC. The reaction was quenched by the addition of saturated aqueous NH4Cl, and the mixture was extracted with EtOAc. The combined extracts were dried and concentrated to give a residue, which was purified by chromatography.  3R,7R,8S,8aR)-8-Ethyl-7-[2-(2-indolyl)-2-oxoethyl]-5-oxo-3phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (trans-6) and its 7S epimer (cis-6): Table 1, entry 4: Operating as described in the general procedure, from unsaturated lactam 1a [3b,8] (400 mg, 1.64 mmol) in THF (30 mL), LDA (11 mL of a solution 1.5 M in cyclohexane, 16.5 mmol), a solution of 2-acetylindole 4b (1.3 g, 8.2 mmol) in 50 mL of THF for 24 h, compound 6 was obtained as a mixture of C-7 epimers. Flash chromatography (from 1:1 to 3:7 hexane-EtOAc) afforded trans-6 (316 mg, 48%) and cis-6 (132 mg, 20%). Table 1

Conversion of cis-9 to cis-6:
A solution of cis-9 (200 mg, 0.43 mmol) in EtOAc (10 mL) containing Pd(OH)2 (20 mg) was hydrogenated with vigorous stirring at room temperature and atmospheric pressure for 24 h. The catalyst was removed by filtration, and the solvent was evaporated to give an oil, which was dissolved in toluene (30 mL). The resulting solution was heated at reflux for 16 h and concentrated to dryness. The residue was chromatographed (4:1 hexane−EtOAc to EtOAc) to give cis-6 (97 mg, 65%).  (16): NaBH4 (117 mg, 3.11 mmol) was slowly added to a solution of trans-6 (128 mg, 0.31 mmol) in MeOH (11 mL) at 0 ºC. The mixture was stirred at 0 ºC for 1 h and the temperature was slowly raised to 25 ºC. The mixture was concentrated, water was added, and the aqueous layer was extracted with Et2O. The combined organic extracts were dried and concentrated to give a foam, which was chromatographed (1:1 hexane−EtOAc to EtOAc) to afford alcohol 16 as a mixture of epimers (115 mg, 90%). Data for 16 (higher Rf epimer): Yellow foam. 1 (22): TiCl4 (1 mL of a 1.0 M solution in CH2Cl2, 1.0 mmol) was added to a solution of 21 (38 mg, 0.10 mmol) in CH2Cl2 (2 mL) at rt, and the resulting mixture was heated at reflux for 24 h. TiCl4 (1 mL of a 1.0 M solution in CH2Cl2, 1.0 mmol) was then added and once again after a further 24 h, and the mixture was maintained at reflux for an additional 48 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic extracts were dried and concentrated, and the resulting residue was chromatographed using a cartridge containing amine functionalized silica (1:1 hexane-EtOAc to 1:1 EtOAc-MeOH) to give 22 (