A synthetic approach to ervatamine-silicine alkaloids. Enantioselective total synthesis of (-)-16-episilicine.

Starting from an appropriate unsaturated phenylglycinol-derived oxazolopiperidone lactam, the synthesis of (-)-16-episilicine is reported, the key steps being a stereoselective conjugate addition, a stereoselective alkylation, and a ring-closing metathesis reaction. This represents the first enantioselective total synthesis of an alkaloid of the silicine group.


Introduction
The ervatamine-silicine alkaloids 1 constitute a relatively numerous group of Corynanthean-type 2 2acylindole alkaloids with a rearranged skeleton that lacks the characteristic tryptamine moiety (Ind−C 6 −C 5 −N) 3 present in most indole alkaloids, having an unusual Ind-C 6 −C 16 −C 5 −N connectivity instead ( Figure 1).
Biogenetically, these alkaloids derive from secologanin via a vobasine N-oxide equivalent, 2 which undergoes a fragmentation reaction and then a cyclization to form the central carbocyclic sevenmembered ring characteristic of these natural products (Scheme 1). As a consequence of their biogenetic origin, the configuration of the C-15 stereocenter in these alkaloids is usually S (H-15β), 4 the same configuration as in C-15 in secologanin. However, they differ in the relative stereochemistry of C-16 (cis or trans C/D ring fusion) and C-20 (there are also C-20 E-ethylidene derivatives), the oxidation level at C-6 (some are 6-oxo derivatives), and the presence or not of a C-16 methoxycarbonyl group. SCHEME 1. Biosynthetic Pathway to Ervatamine-Silicine Alkaloids. The Absolute Configuration of C-15 3 The alkaloids of the ervatamine-silicine group have received scarce attention from the synthetic standpoint 5 and, with the exception of our preliminary report 6 on the synthesis of (−)- 16-episilicine, no enantioselective total syntheses for these alkaloids have been reported so far.
Ervatamines and silicines can be envisaged as enantiopure 3,4,5-trisubstituted piperidines (the former with an additional methoxycarbonyl substituent) that embody an ethyl substituent and a sevenmembered carbocyclic ring fused on the c side of the heterocycle.
Bearing in mind the versatility of aminoalcohol-derived oxazolopiperidone lactams as chiral building blocks for the enantioselective construction of complex piperidine-containing derivatives, 7 the above structural features prompted us to explore the utility of these lactams as starting scaffolds for the synthesis of ervatamine-silicine alkaloids. Scheme 2 outlines our synthetic strategy, whose key steps would be i) the stereoselective conjugate addition of a vinyl residue to an unsaturated lactam already incorporating the ethyl substituent present in the natural targets; ii) a stereoselective alkylation to introduce a 2-vinyl-3-indolylmethyl fragment; and iii) a ring-closing olefin metathesis (RCM) reaction 8 to construct the carbocyclic seven-membered C ring. Subsequent oxidation-reduction and protectingdeprotecting steps would complete the synthesis of ervatamines. The alcoxycarbonyl substituent in the starting lactam would not only facilitate the subsequent conjugate addition 9 and alkylation steps but could also be removed in advanced stages of the synthesis to provide access to the silicine series.

Results and discussion
The known 10 lactam 1 was selected to carry out our initial studies. The conjugate addition of the vinyl group was accomplished in excellent chemical yield and complete exo-facial selectivity, cis with respect to the ethyl substituent. The subsequent alkylation of the resulting mixture of C-6 epimeric lactams 2 11 with 3-(bromomethyl)indole 3 12 took place stereoselectively on the most accessible face of the piperidine ring providing derivative 4 in excellent yield (84%) as a single stereoisomer (Scheme 3).
Surprisingly, treatment of 4 with the second−generation Grubbs catalyst in refluxing toluene led to hexacycle 5 (33% yield), resulting from an intramolecular Diels−Alder process, 13 instead of the expected ring-closing metathesis product. A similar result was obtained using the Hoveyda−Grubbs catalyst. As might be expected, hexacycle 5 was also obtained (60% yield) when a solution of 4 in toluene was heated at reflux in the absence of a RCM catalyst.

SCHEME 3. First Synthetic
Approach. An Unexpected Diels-Alder Reaction 7 in 86% yield. The absolute configuration of 16a was unambiguously established by X-ray crystallographic analysis (Figure 2), thus confirming both the stereochemical outcome of the conjugate addition reaction, which leads to the unnatural configuration at C-15 (H-15α), and the trans-C/D ring fusion. 16b 16a FIGURE 2. X-ray crystal structure of pentacycles 16a and 16b.
In fact, the conjugate addition of organocuprates to unsaturated oxazolopiperidone lactams is highly stereoselective 15 as a consequence of the conformational rigidity of the bicyclic system, occurring under stereoelectronic control, 16 axial to the electrophilic carbon of the conjugate double bond and, consequently, cis with respect to the adjacent pseudoequatorial ethyl substituent (see 11a in Scheme 6).
To obtain the natural (H-15β) absolute configuration at C-15, an obvious solution was to start from the enantiomeric lactam ent-11a, which would be accessible from the S-phenylglycinol-derived lactam ent-10a. However, taking into account the availability of lactam 10b, 17 to access the natural C-15 absolute configuration we decided to use the unsaturated lactam 11b, which presumably would also undergo a stereoselective conjugate addition ultimately leading to H-15β isomers. This lactam incorporates a C-8 8 ethyl substituent with the absolute configuration required for the synthesis of 16-episilicine, an alkaloid isolated in 1975 from Pandaca caducifolia. 18

SCHEME 6. Control of the C-15 Configuration
The synthetic sequence for the preparation of the key intermediate 16b starting from lactam 10b is outlined in Scheme 7 and parallels that previously developed starting from the diastereoisomeric lactam 10a. As expected, the conjugate addition of the vinyl group to the unsaturated lactam 11b took place stereoselectively leading to the exo isomer 12b (mixture of C-6 epimers). A subsequent alkylation with the N-protected indole derivative 6 afforded 13b in 75% yield as a single stereoisomer, thus confirming the facial stereoselectivity of the conjugate addition reaction. Witttig methylenation of 13b followed by removal of the tert-butoxycarbonyl group gave diene 15b in 58% overall yield. Minor amounts (10%) of the C-6 epimer (6-epi-15b) were also isolated. The crucial ring−closing metathesis of 15b was efficiently performed using the second−generation Grubbs catalyst under refluxing toluene to give the trans-fused pentacycle 16b in 87% yield. Quite unexpectedly, a similar treatment from 6-epi-15b led to the anticipated cis-fused pentacycle 16-epi-16b in only 24% yield, the main product (50%) being the Diels−Alder adduct 21 (Scheme 8). As in the failure of the RCM reactions from dienes 4 and 8, the different behavior of 15b and 6-epi-15b under RCM reaction conditions can most probably be explained on conformational grounds. The absolute configuration of 16b (Figure 2), coinciding at C−15 with the natural configuration (15β-H), and 21 were unambiguously established by X-ray crystallographic analysis.

SCHEME 8. RCM Reaction from Diene 6-epi-15b
Once the tetracyclic ring system of the target alkaloid, with the required trans-C 15 −C 16 and cis-C 15 −C 20 configuration, was assembled, to complete the synthesis from 16b we only needed to remove the chiral auxiliary and the indole protecting group, and to adjust the oxidation level. Catalytic hydrogenation of the carbon-carbon double bond of 16b followed by treatment with LiAlH 4 -AlCl 3 , which brought about both the reduction of the lactam carbonyl group and the reductive opening of the oxazolidine ring, gave tetracycle 17 in 64% overall yield. Deprotection of the indole nitrogen under smooth conditions, followed by a catalytic debenzylation in the presence of (Boc) 2

Conclusion
In summary, we have accomplished for the first time the enantioselective total synthesis of an alkaloid of the silicine group, thus further illustrating the potential and versatility of phenylglycinol-derived oxazolopiperidone lactams in the synthesis of enantiopure piperidine-containing complex natural      Then, the solution was purged with O 2 , 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 CH 2 Cl 2 . The combined organic extracts were dried and concentrated to give unsaturated lactam 11a (2.5 g) as an oil, which due to its unstability was used in the next reaction without further purification: 1