A New Acyl Radical-based Route to the 1,5-Methanoazocino[4,3-b]indole Framework of Uleine and Strychnos Alkaloids M.-Lluı¨sa Bennasar,* Toma`s Roca, and Davinia Garcı´a-Dı´az Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institut de Biomedicina (IBUB), UniVersity of Barcelona, Barcelona 08028, Spain
[email protected] ReceiVed September 10, 2008
C-4 or C-12 ethyl substituted 1,5-methanoazocino[4,3-b]indoles, which constitute the tetracyclic framework of uleine alkaloids as well as the ABDE substructure of the Strychnos alkaloid family, have been synthesized by novel 6-exo and 6-endo cyclizations of selenoester-derived 2-indolylacyl radicals upon 5-ethyl-1,2,3,6- and 3-ethyl-1,2,5,6-tetrahydropyridines, respectively.
Introduction In the last years we have been involved in the development of a novel general synthetic entry to indole compounds taking advantage of the reactions of phenyl selenoester derived 2-indolylacyl radicals.1,2 In particular, we have shown that several alkaloid structures embodying the 2-acylindole moiety can be efficiently assembled by intramolecular reactions of these radical intermediates with a variety of indole-tethered carboncarbon double bond acceptors.2b,3 On the basis of our earlier work, we considered extending this methodology for the construction of the 1,5-methanoazocino[4,3-b]indole system, which constitutes the bridged arrangement of the indole alkaloids of the uleine group4 (uleine, dasycarpidone and their C-20 epimers, Figure 1) as well as the ABDE substructure of the * Tel: 34 934 024 540. Fax: 34 934 024 539. (1) For a review on the chemistry of acyl radicals, see: (a) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991–2069. (2) (a) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. Org. Lett. 2001, 3, 1697–1700. (b) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2004, 6, 759– 762. (3) (a) Bennasar, M.-L.; Roca, T.; Ferrando, F. J. Org. Chem. 2005, 70, 9077– 9080. (b) Bennasar, M.-L.; Roca, T.; Ferrando, F. J. Org. Chem. 2006, 71, 1746– 1749. (c) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2006, 8, 561–564. (d) Bennasar, M.-L.; Roca, T.; Garcı´a-Dı´az, D. J. Org. Chem. 2007, 72, 4562– 4565. (4) For reviews, see: (a) Joule, J. A. In Indoles. The Monoterpenoid Indole Alkaloids, Saxton, J. E., Ed.; The Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, 1983; Vol. 25, Part 4, Ch 6. (b) Alvarez, M.; Joule, J. A. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; The Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.;Wiley: Chichester, 1994; Supplement to Vol. 25, Part 4, Ch 6. (c) Alvarez, M.; Joule, J. A. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 2001; Vol. 57, Ch 4.
10.1021/jo801998h CCC: $40.75 2008 American Chemical Society Published on Web 10/17/2008
FIGURE 1. Uleine and Strychnos Alkaloids.
Strychnos alkaloid family,5 exemplified by the pentacyclic components tubifolidine or strychnopivotine (strychnan biogenetic type) and tubotaiwine (aspidospermatan biogenetic type). Although these natural products have long attracted the attention of the synthetic community and, consequently, a great variety of synthetic approaches have been reported,4,5 radical methodologies have been little explored in this field.6 (5) For reviews, see: (a) Bosch, J.; Bonjoch, J. In Studies in Natural Products Chemistry; Atta-ur-Rahman, , Ed.; Elsevier: Amsterdam, 1988; pp 31-88. (b) Sapi, J.; Massiot, G. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; The Chemistry of Heterocylic Compounds; Taylor, E. C., Ed.; Wiley: Chichester, 1994; Supplement to Vol. 25, Part 4, Ch 7. (c) Bosch, J.; Bonjoch, J.; Amat, M. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1996; Vol. 48, pp 75-189.
J. Org. Chem. 2008, 73, 9033–9039 9033
Bennasar et al. SCHEME 1.
Synthetic Strategy
As depicted in Scheme 1, our strategy for the assembly of this bridged tetracyclic framework relies on the closure of the carbocyclic 6-membered ring by cyclization of 3-(tetrahydro2-pyridyl)-2-indolylacyl radicals.7,8 We anticipated that placing both the double bond acceptor and the required two-carbon appendage at different positions of the pyridine ring (as depicted in A and B) would enable two radical cyclization pathways to generate complementary substituted tetracycles. Thus, either strychnan (C-4 ethyl) or aspidospermatan (C-12 ethyl) substructures would be produced by regioselective 6-exo or 6-endo cyclizations upon 1,2,3,6- or 1,2,5,6-tetrahydropyridines, respectively. Critical to the success of our synthetic plan was the efficient construction of the cyclization substrates. To this end, we devised two closely related flexible routes starting from the N-protected indole-3-carbaldehyde 1, which involve an amina(6) (a) Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996, 61, 7873– 7881. (b) Kuehne, M. E.; Bandarage, U. K.; Hammach, A.; Li, Y.-L.; Wang, T. J. Org. Chem. 1998, 63, 2172–2173. (c) Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt, M.; Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324–9337. (7) For a leading review on the synthesis of nitrogen heterocycles by radical cyclization, see: Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem. Soc., Perkin Trans. 1 2002, 2747–2762. (8) For relevant radical cyclizations leading to bridged nitrogen heterocycles, see: (a) Della, E. W.; Knill, A. M. J. Org. Chem. 1996, 61, 7529–7533. (b) Quirante, J.; Escolano, C.; Massot, M.; Bonjoch, J. Tetrahedron 1997, 53, 1391– 1402. (c) Quirante, J.; Escolano, C.; Merino, A.; Bonjoch, J. J. Org. Chem. 1998, 63, 968–976. (d) Della, E. W.; Smith, P. A. J. Org. Chem. 2000, 65, 6627– 6633. (e) Hoepping, A.; George, C.; Flippen-Anderson, J.; Kozikowski, A. P. Tetrahedron Lett. 2000, 41, 7427–7432. (f) Tamura, O.; Yanagimachi, T.; Kobayashi, T.; Ishibashi, H. Org. Lett. 2001, 3, 2427–2429. (g) Quirante, J.; Vila, X.; Escolano, C.; Bonjoch, J. J. Org. Chem. 2002, 67, 2323–2328. (h) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565–7581. (i) Bower, J. F.; Szeto, P.; Gallagher, T. Chem. Commun. 2005, 5793–5795. (j) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 143–150. (k) Grainger, R. S.; Welsh, E. J. Angew. Chem., Int. Ed. 2007, 46, 5377–5380. (l) Dandapani, S.; Duduta, M.; Panek, J. S.; Porco, Jr., J. A. Org. Lett. 2007, 9, 3849–3852. (m) Yoshimitsu, T.; Atsumi, C.; Iimori, E.; Nagaoka, H.; Tanaka, T. Tetrahedron Lett. 2008, 49, 4473–4475. (n) See also ref 6.
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SCHEME 2.
Model 6-Exo Cyclization
tion (bond a)-imine allylation or alkenylation (bond b)-ring closing metathesis (RCM, bond c) sequence. In addition, carboxylation of a 2-lithioindole derivative (bond d) at some stage would install the carboxylic acid function from which the acyl radical precursor selenoester would be prepared. Results and Discussion We set out to study the construction of the 6-oxo-1,5methanoazocino[4,3-b]indole system by 6-exo cyclization of 2-indolylacyl radicals upon 1,2,3,6-tetrahydropyridines (6heptenoyl radicals A). To test the feasibility of the proposal we first targeted the model selenoester 5, which incorporated an unsubstituted tetrahydropyridine moiety at the indole 3-position.9 As anticipated, this compound was available from the N-Bocprotected indole 1, following the synthetic sequence depicted in Scheme 2. Thus, reaction of 1 with allylamine and alkylation of the resulting imine with allylmagnesium bromide led to an unstable secondary amine, which was not isolated10 but was subsequently acylated with methyl chloroformate to give carbamate 2 in 68% overall yield. At this point, the carboxy group could be introduced with high efficiency by treatment with LDA and reaction of the intermediate 2-lithioindole derivative with carbon dioxide. The next closure of the tetrahydropyridine ring of the resulting sensitive carboxylic acid by RCM was accomplished uneventfully by reaction with the second generation Grubbs catalyst (Im)(PCy3)2(Cl)2RudCHPh (9) For a preliminary report of this part of the work, see: Bennasar, M.-L.; Roca, T.; Garcı´a-Dı´az, D. Synlett 2008, 1487–1490. (10) All attempts to carry out the amination-imine allylation sequence from an indole-3-carbaldehyde already incorporating a carboxylic ester at the 2-position resulted in lactamization.
1,5-Methanoazocino[4,3-b]indoles by Acyl Radical Cyclization
at room temperature in CH2Cl2 to give tetrahydropyridine 3 in 85% overall yield from 2. Selective removal of the indole protecting group under the usual acid (TFA) conditions resulted in intensive decomposition, but it was also achieved in high yield (92%) using a basic protocol (MeONa, reflux). Finally, the resulting tetrahydropyridine carboxylic acid 4 was converted into selenoester 5 by phenylselenation under Batty and Crich conditions11 (60%). With a reliable route to the radical precursor in hand, attention was focused on the key cyclization step. Satisfactorily, treatment of selenoester 5 with 2 equiv of n-Bu3SnH in the presence of Et3B as the initiator at room temperature in benzene (concentration 0.07 M) led to azocinoindole 6 as the major product in 60% yield. The formation of 6 was consistent with the predicted 6-exo cyclization of the initially formed 2-indolylacyl radical to give a bridged azabicyclo[3.3.1]nonane ring system after reduction of the cyclized secondary radical C. Minor amounts of tetracycle 7, containing the regioisomeric bicyclo[3.2.2]nonane system derived from the radical attack at the C-5 tetrahydropyridine position instead of C-4, were also obtained (10% yield). No evidence of acyl radical reduction (i.e., formation of an aldehyde), either from direct hydrogen abstraction from the hydride or an eventual [1,5]-hydrogen transfer, was observed. We experimented with different hydride concentrations to ascertain if the regiochemical outcome was a reflection of the kinetic composition of the initially formed cyclized radicals C and D or the result of a partial equilibration between these intermediates through one-carbon ring expansion.12 As compounds 6 and 7 were invariably obtained in the same 6:1 ratio (combined yields 30-40%) working at a higher (0.14 M) or lower (0.005 M) hydride concentration, we assumed that the aforementioned equilibration was not included in the reaction pathway. Following the success in the model deethyl series, we endeavored to complete the strychnan core structure (C-4 ethyl) by extending the chemistry outlined above to a more elaborated radical precursor (e.g., selenoester 10, Scheme 3). We expected that the presence of an ethyl substituent at the site of attack on the tetrahydropyridine double bond would preclude the undesired cyclization pathway, thus favoring the exclusive formation of the 6-membered ring. Our synthetic route to 10 began with the sequential reaction of aldehyde 1 with 2-ethylallylamine,13 allylmagnesium bromide, and methyl chloroformate to give carbamate 8 in 65% yield. Introduction of the R-carboxy group was less efficient than in the above series as it suffered from competitive interaction of the intermediate 2-lithioindole with the N-(methoxycarbonyl) group, resulting in partial lactamization.14 Indeed, after RCM of the rather unstable carboxylic acid, performed in the presence of benzoquinone to prevent the unwanted isomerization of the terminal double bond,15 the N-Boc tetrahydropyridine 9 was obtained in a modest 45% yield from 8. Changing the order of the synthetic steps, that is, first performing the RCM of 8 and then the carboxylation at the tetrahydropyridine stage, resulted in an even higher undesired (11) Batty, D.; Crich, D. Synthesis 1990, 273–275. (12) For discussions, see: (a) Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1987, 110, 2565–2575. (b) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429–1443. (c) Dowd, P.; Zhang, W. Chem. ReV. 1993, 93, 2091–2115. (d) Chatgilialoglu, C.; Ferreri, C.; Lucarini, M.; Venturini, A.; Zavitsas, A. A. Chem.sEur. J. 1997, 3, 376–387. (13) Prepared from 2-ethylallyl methanesulfonate: (a) Plamondon, L.; Wuest, J. D. J. Org. Chem. 1991, 56, 2066–75, See Supporting Information. (14) See Supporting Information for details. (15) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160–17161.
SCHEME 3.
Cyclization of Selenoester 10
lactamization and, consequently, a lower yield of 9 (
