Studies on the Regioselectivity of the Cyclization of Tryptophanol-Derived Oxazolopiperidone Lactams

Tryptophanol-derived oxazolopiperidone lactams have proven to be versatile chiral building blocks for the enantioselective synthesis of indole alkaloids.[1] These lactams are easily accessible in enantiopure form in a single synthetic step by a stereoselective cyclocondensation reaction between (S)-tryptophanol and an appropriate δ-oxo acid derivative.[2] Tryptophanol not only constitutes the source of chirality but can also be used in subsequent steps to assemble complex polycyclic targets by regioand stereocontrolled cyclization reactions on the indole ring. Taking advantage of the functionalization present in the oxazolopiperidone lactam, an electrophilic cyclization on the indole 2-position can involve either the hemiaminal ether carbon via an N-acyliminium cation (Scheme 1, via a) [1a–1d,2] or the lactam carbonyl through a Bischler–Napieralski type reaction (Scheme 1, via b),[1e,3] leading to regioisomeric indolo[2,3-a]quinolizidines (when R1 H). Additionally, by choosing the appropriate reaction conditions, intramolecular α-amidoalkylation allows the stereocontrolled generation of C-12b epimeric derivatives. On the other hand, a Lewis acid/Et3SiH-promoted cyclization on the indole 3-position from Na-tosyl derivatives provides straightforward access to the spiro[indole-3,1 -indolizidine] framework,[4] which is present in a large number of alkaloids (via c). These complementary types of cyclization are shown in Scheme 1.


Introduction
Tryptophanol-derived oxazolopiperidone lactams have proven to be versatile chiral building blocks for the enantioselective synthesis of indole alkaloids. [1] These lactams are easily accessible in enantiopure form in a single synthetic step by a stereoselective cyclocondensation reaction between (S)-tryptophanol and an appropriate δ-oxo acid derivative. [2] Tryptophanol not only constitutes the source of chirality but can also be used in subsequent steps to assemble complex polycyclic targets by regioand stereocontrolled cyclization reactions on the indole ring.
Taking advantage of the functionalization present in the oxazolopiperidone lactam, an electrophilic cyclization on the indole 2-position can involve either the hemiaminal ether carbon via an N-acyliminium cation (via a) [1a-d,2] or the lactam carbonyl via a Bischler−Napieralski-type reaction (via b), [1e,3] leading to regioisomeric indolo[2,3-a]quinolizidines (when R 1 ≠ H). Additionally, by choosing the appropriate reaction conditions, the intramolecular α-amidoalkylation allows the stereocontrolled generation of C-12b epimeric derivatives. On the other hand, a Lewis acid/Et 3 SiH-promoted cyclization on the indole 3-position from N a -tosyl derivatives provides straightforward access to the spiro[indole-3,1'-indolizidine] framework [4] present in a large number of alkaloids (via c). These  Although there are many examples of acid-promoted intramolecular α-amidoalkylation reactions from (S)-tryptophanolderived oxazolopiperidone lactams, cyclizations involving the lactam carbonyl have been little explored. In fact, our initial attempts to perform a Bischler−Napieralski cyclization under the classical conditions (POCl 3 , then NaBH 4 ) were unsuccessful [1e,5] due to the tendency of these lactams to undergo acid-promoted intramolecular α-amidoalkylation reactions. However, the desired cyclization on the lactam carbonyl can be satisfactorily performed under non-acidic conditions by a modified Bischler−Napieralski procedure via a (benzylthio)iminium intermediate. [1e] In the only example reported to date of a successful POCl 3 -promoted Bischler−Napieralski cyclization from a tryptophanol-derived oxazolopiperidone lactam, [3] the hemiaminal ether carbon incorporates an additional substituent, which, for steric reasons, seems to hamper the intramolecular α-amidoalkylation reaction. Scheme 2. Studies on the synthesis of normalindine. Cyclization under Bischler−Napieralski conditions.

Results and Discussion
With these precedents in mind, we decided to explore if the methodology could be applied to the synthesis of malindine alkaloids, for instance normalindine, [6] which are characterized by the presence of a partially reduced 1-methyl-2,7-naphthyridine moiety (Scheme 2). The synthesis would involve as the key steps a cyclocondensation reaction between (S)-tryptophanol and pyridine δ-keto ester 1, a Bischler−Napieralski cyclization from the resulting tricyclic lactam, and finally, the reductive opening of the oxazolidine ring with subsequent removal of the hydroxymethyl appendage. [7] The quaternary carbon 10b on the oxazolidine ring would hamper the α-amidoalkylation process in favor of the Bischler−Napieralski cyclization.
The formation of 3 can be rationalized by considering a rapid generation of an N-acyliminium cation [9] and its cyclization on the indole ring, a subsequent interaction of the hydroxymethyl substituent with the chloroiminium intermediate generated from the lactam carbonyl, and a final reduction by NaBH 4 of the resulting oxazolinium salt. [10] A further reduction, with opening of the oxazolidine ring, would lead to 4.
The cis 1-Me/3-H relative stereochemistry for the tetrahydro−βcarboline moiety, established by NOE experiments, probably results from an acid-promoted epimerization [11] of the quaternary stereocenter initially formed in the cyclization, [12] driven by the generation of a cis oxazolinium intermediate, A. A final stereoelectronically controlled [13] axial attack of the hydride installs the all-cis relative configuration of 3.
To avoid the undesirable acid-promoted α-amidoalkylation reaction, we decided to perform a Bischler−Napieralski-type cyclization under neutral conditions [1e] from the thiolactam derived from 2. Surprisingly, treatment of lactam 2 with Lawesson's reagent led in excellent yield (81%) to the hexacyclic thioderivative 5 instead of the expected thiolactam (Scheme 3). The formation of 5 can be accounted for by considering that, once the thiolactam was formed, the generation of the N-thioacyl iminium ion B was facilitated by the lower electronegativity of the sulfur atom. Cyclization on the indole ring would afford pentacyclic intermediate C. A subsequent cyclization via the Oalkyl phenylphosphonodithioic acid intermediate D [14] would lead to 5.
The above results indicate that an acidic environment is not the only factor to favor the competitive α-amidoalkylation reaction. Most probably, due to the presence of the fused π-deficient pyridine, the benzylic character of the N-acyl (or thioacyl) iminium species generated by the opening of the oxazolidine ring also plays an important role. To gain further insight into the factors governing the regioselectivity of the cyclization on the carbonyl group of tryptophanol-derived oxazolopiperidone lactams, we decided to study the Bischler−Napieralski cyclization from a model lactam 6, which lacks the pyridine ring present in 2. This lactam was prepared by cyclocondensation between (S)-tryptophanol and 5oxohexanoic acid. Under the usual reaction conditions (toluene, reflux), a mixture of 6 and its 8a-epimer (80% yield, 87:13 ratio) was obtained [15] (Scheme 4). A more convenient experimental procedure involved the use of microwaves: [16] irradiation of an equimolecular mixture of the starting materials for 10 min at 110 ºC provided a 92:8 diastereoisomeric mixture of 6 and its 8aepimer in 77% yield, with only traces of the cyclized product 9 (Scheme 5) being detected. As expected, cyclization on the lactam carbonyl took place satisfactorily from lactams 6, not only under neutral conditions via a thiolactam but also under the classical POCl 3 -promoted Bischler−Napieralski conditions. Thus, the epimeric mixture of 6 was converted to the corresponding thiolactams (54%), which were treated with benzyl bromide and then NaBH 4 , to regio-and stereoselectively give (51%) a single pentacyclic indoloquinolizidine derivative 7. Similarly, treatment of the epimeric mixture of 6 with POCl 3 and then NaBH 4 stereoselectively led to a 3:2 mixture of pentacycle 7 and indoloquinolizidine 8 in 52% overall yield. [17] The former was quantitatively converted to 8 by additional treatment with NaBH 4 . [18] The all-cis stereochemistry of 7, established by NOE experiments (4-Me/6-H, 4-Me/12b-H, and 6-H/12b-H), deserves some comment as the sterocenters bearing the methyl substituent in the major starting lactam 6 and in the cyclized product 7 have the opposite relative configuration. This indicates that during the above cyclization an equilibration has occurred via an open oxazolidine intermediate, ultimately leading to the less strained cis 4-Me/6-H iminium salt E (Figure 1), which undergoes a final stereoelectronically controlled [13] axial attack of the hydride. Finally, also worthy of comment is the inversion of the configuration during the reductive opening of the oxazolidine ring to give 8, once again involving a stereoelectronically controlled attack of the hydride on the less hindered face of the intermediate iminium species F. The above successful Bischler−Napieralski-type cyclizations make evident that the intramolecular α-amidoalkylation process is slowed down by the presence of the additional substituent at the 2position of the oxazolidine ring. In fact, lactams 6 were recovered unchanged (only trace amounts of the cyclized product 9 were detected) after treatment with HCl (0.6 M in EtOH, rt, 24 h), whereas these reaction conditions promote a clean and highly stereoselective α-amidoalkylation (95% yield) when applied to the corresponding lactams lacking the angular methyl substituent. [5] Under more drastic conditions (1.25 M HCl in EtOH, 70 ºC, 72 h), cyclization of 6 took place in good yield (70%) but with a low stereoselectivity to give a nearly 1:1 mixture of trans and cis indoloquinolizidines 10 and 12b-epi-9, probably because the strong acidity causes the epimerization at C-12b of the indolo[2,3a]quinolizidine system [12] (Scheme 5). From the synthetic standpoint, the best results were obtained using a 0.9 M solution of TFA in CH 2 Cl 2 (rt, 20 h), since a 4:1 stereoisomeric mixture of indoloquinolizidines 9 and 12b-epi-9 was obtained in 86% yield. The absolute configuration of the cyclized products 9 and 12b-epi-9 was unambiguously determined by X-ray crystallographic analysis. [19] Scheme 5. α-Amidoalkylation reaction from lactams 6.
The stereoselective formation of 9 leading to a trans 6-H/12b-Me stereochemistry can be rationalized by analyzing the two possible reactive chair-like conformations (X and Y; R= Me) of the intermediate N-acyliminium cation. [9] Cyclization takes place faster from conformation X, which avoids the severe A (1,3) strain between the hydroxymethyl substituent and the lactam carbonyl group in the transition state. [20] The lower stereoselectivity in the cyclization of 6 compared with that of the corresponding demethyl lactam [2a,5] can be explained by the stronger A (1,3) CH 2 OH/R strain present in the conformation X when R= Me than when R= H.

Conclusions
Although under the classical POCl 3 -promoted Bischler−Napieralski reaction conditions tryptophanol-derived oxazolopiperidone lactams unsubstituted at the hemiaminal ether carbon (i.e. generated from aldehyde-esters) undergo an intramolecular α-amidoalkylation reaction instead of the expected cyclization on the lactam carbonyl, lactams substituted at this position (e.g. 6, derived from a ketone-ester) successfully undergo a regioselective Bischler−Napieralski cyclization on the lactam carbonyl, avoiding the competitive α-amidoalkylation process.
The unexpected behavior of tricyclic lactam 2, which exclusively leads to products coming from an α-amidoalkylation process, is a consequence of the presence of the fused π-deficient pyridine ring that originates a reactive benzylic-type N-acyl (or thioacyl) iminium ion.

Supporting Information
Crystal data and structure refinement for compound 9