Author Topic: Hydroamination Enantioselective Syn. Benzomorphans  (Read 2079 times)

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Hydroamination Enantioselective Syn. Benzomorphans
« on: June 16, 2004, 05:45:00 PM »
If someone can post this with the pictures, then please switch it out.  I don't think I can put up the images at the moment.  I could have sworn that this paper was brought to the Hive a while back, possibly by me, but I couldn't find it anywhere.  I think phenazocine is more fun than this paper wants to admit and it should be easily attained by a similar route to below.  Metazocine is definitely fun but much less potent.  Pentazocine sux.

Side question: O-acetyl-phenazocine, better or the same activity as phenazocine?

Here's the important experimental:

J. Am. Chem. Soc., 125 (29), 8744 -8745, 2003. 10.1021/ja0360539 S0002-7863(03)06053-0
Web Release Date: June 28, 2003

Copyright © 2003 American Chemical Society
Migratory Hydroamination: A Facile Enantioselective Synthesis of Benzomorphans

Barry M. Trost* and Weiping Tang

Department of Chemistry, Stanford University, Stanford, California 94305-5080
Received May 9, 2003


We describe a highly efficient, general strategy for the enantioselective synthesis of benzomorphans (45-46% overall yield from commercially available material). The new synthesis demonstrates the effectiveness of an unprecedented diastereoselective cycloisomerization via migratory hydroamination and the power of palladium-catalyzed asymmetric allylic alkylation (AAA) of simple ketone enolates in the context of complex synthesis. The strategy outlined here for the enantioselective synthesis of three contiguous stereogenic centers and the novel cycloisomerization should have many applications in alkaloid synthesis.

Naturally occurring (-)-morphine is extremely important as an analgesic but suffers from side effects such as addiction.1 Much effort has been devoted to overcoming this problem by structural modification.2 As a result, certain nonnatural benzomorphans and morphinans have succeeded in reducing the addicting effect to a considerable extent, such as the clinically used pentazocine 4 and phenazocine 5.3 In addition to their use as analgesics, benzomorphans are also useful in the treatment of cocaine addiction (e.g., 6).4 Not surprisingly, pharmacological activity in these series is dramatically dependent on absolute configuration. For example, (-)-pentazocine is 20 times more potent than its enantiomer.5 Despite the importance of benzomorphans, previous enantioselective syntheses of benzomorphans (3-6, Figure 1) utilized either resolution6 or chiral auxiliaries7-9 all through Grewe-type cyclizations2,10 with one exception.11

 Figure 1 Opium alkaloids and benzomorphans. 

We12 recently described a new asymmetric synthesis of opium alkaloids (1 and 2) involving a novel base-promoted intramolecular hydroamination13 which requires tungsten light irradiation. This reaction forges the key piperidine ring of this family of alkaloids, which previously were cyclized using stoichiometric mercury salts14 or via the chromium tricarbonyl complex15 from free amine. The benzomorphans served as an ideal target to gain better understanding of the key cyclization reaction and assess the possibility of establishing the rather challenging benzylic quaternary carbon center16 through palladium-catalyzed asymmetric allylic alkylation (AAA) of a prochiral ketone.17 In formulating a route (Scheme 1), we envisioned two olefinic intermediates 9 and 8, the former to set the stereochemistry of the methyl group and the latter to effect cyclization. Typically, the conversion of 9 to 8 involves multiple steps requiring stoichiometric reduction and oxidation. Inspired by a recent report of intermolecular hydroamination of allyl- and homoallylbenzene,18 the fact that benzomorphan 7 itself is an isomer of olefin 9 emboldened us to ask a conceptually intriguing question. Is it possible to cycloisomerize 9 to 7 diastereoselectively in one catalytic step by a migratory hydroamination? In this communication we explore the cycloisomerization via a catalytic migratory hydroamination and the power of palladium-catalyzed AAA of a prochiral ketone for simplifying problems in alkaloid synthesis.

 Scheme 1. Retrosynthetic Analysis 

Discrimination of enantiotopic faces of the nucleophile in the palladium-catalyzed AAA is very challenging as the nucleophile attacks on the face of the -allyl system opposite to that of the chirality inducing metal-ligand complex.19 Gratifyingly, performing the allylic alkylation of tetralone 1020 and allyl acetate with a catalyst derived from -allylpalladium chloride dimer (0.5%) and (R,R)-ligand 12 (1.0%) in the presence of cesium carbonate21 in DME gave 11 in good yield and ee as shown in eq 1.

Wittig olefination gave almost quantitative yield of exocyclic olefin 13 (Scheme 2). Although one-pot cleavage (OsO4, NaIO4) of 13 was not successful, stepwise operations selectively cleaved the less hindered terminal olefin in the presence of the 1,1-disubstituted olefin. Reductive amination provided amine 15 in good yield.

 Scheme 2. Synthesis of (-)-Metazocinea a Reaction conditions: a) CH2=PPh3, THF; b) 2% OsO4, NMO; c) NaIO4; d) MeNH2, MgSO4, NaBH4; e) 1.5 equiv TsOH, toluene, reflux; f) 20 mol % BuLi, 20 mol % iPr2NH, THF, rt, 30 min; g) 20 mol % BuLi, 20 mol % iPr2NH, 40 mol % TMEDA, THF, rt, 8 h; h) BBr3, CH2Cl2. 

The stage was set for the key speculative step, the migratory hydroamination. Treatment of amine 15 with a catalytic amount or even a full equivalent of LDA gave only recovered starting material, presumably due to the difficulty of the initial isomerization. Thus, we examined the isomerization under acidic conditions and found the exocyclic olefin was isomerized to the internal olefin 16 (not all the way to conjugation!). Despite the need to isomerize 16 to 8 (R = CH3) first and the difficulty of subsequent addition of a lithium amide to an electron-rich styrene,12,22 subjecting amine 16 to 20 mol % LDA in THF led to cycloisomerization to form 17 as a single diastereomer23 in less than 30 min at room temperature. This result suggests that the failure of cyclization using base alone in the case of morphine might be due to the more electronically rich aromatic ring compared to benzomorphans. Increasing the basicity of the medium by addition of 40 mol % TMEDA18 allowed reaction of 15 and provided 17 more slowly (8 h) but still nearly quantitatively. We hypothesized that the high diastereoselective control of C-11 came from intramolecular protonation of the allylic anion 18 from the alpha face (i.e., cis to the aminoethyl substituent as depicted in 18') of an almost flat six-membered ring. This is in contrast to previous approaches employing Grewe cyclizations which often gave both epimers.7,24 Finally, demethylation gave (-)-metazocine (3), whose spectral data is identical to that previously reported.7,9

To test the scope and selectivity of the migratory hydroamination, amine 19 was prepared from 14 in a similar way (85% yield) and treated with the catalyst system as for 15 (eq 2). Amine 20 was obtained in quantitative yield as a single diastereomer. It is noteworthy that the olefin of the prenyl substituent was unchanged. Demethylation with NaSEt provided (-)-pentazocine (4)25 cleanly. Thus, simply changing the amine in the reductive amination allows easy variation of the N substituent.

In conclusion, we have developed a highly efficient general strategy for the enantioselective synthesis of benzomorphans (46% and 45% overall yield from commercially available material for (-)-metazocine and (-)-pentazocine, respectively). It demonstrates for the first time the efficacy of palladium-catalyzed AAA of simple ketones in the context of complex synthesis. The unprecedented diastereoselective migratory hydroamination addresses the control of C-11 stereogenic center, and should have many applications in alkaloid synthesis. The strategy outlined here opens the way to access either enantiomer26 of a variety of C-6, C-11, and N-3 substituted benzomorphan analogues.

* In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

1. Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, 343; [ChemPort] Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum, A. G.; Stabile, M. R. Stud. Nat. Prod. Chem. 1996, 18, 43; [ChemPort] Blakemore, P. R.; White, J. D. Chem. Commun. 2002, 1159. [ChemPort] [CrossRef]

2. Palmer, D. C.; Strauss, M. J. Chem. Rev. 1977, 77, 1. [ChemPort]

3. Kametani, T.; Kigasawa, K.; Hiiragi, M.; Wagatsuma, N. Heterocycles 1974, 2, 79; [ChemPort] Clarke, E. G. C. Nature 1959, 184, 451.

4. Neumeyer, J. L.; Bidlack, J. M.; Zong, R.; Bakthavachalam, V.; Gao, P.; Cohen, D. J.; Negus, S. S.; Mello, N. K. J. Med. Chem. 2000, 43, 114;[Full text - ACS] [ChemPort] [Medline] Glick, S. D.; Visker, K. E.; Maisonneuve, I. M. Eur. J. Pharm. 1998, 357, 9. [CrossRef]

5. Tullar, B. F.; Harris, L. S.; Perry, R. L.; Pierson, A. K.; Soria, A. E.; Wetterau, W. F.; Albertson, N. F. J. Med. Chem. 1967, 10, 383. [ChemPort] It has been reported that the inactive enantiomer has side effects: Berkowitz, B. A. Eur. J. Pharm. 1974, 26, 359. [CrossRef]

6. Boulanger, W. A. Synth. Commun. 1999, 29, 2201; [ChemPort] Brine, G. A.; Berrang, B.; Hayes, J. P.; Carroll, F. I. J. Heterocycl. Chem. 1990, 27, 2139; [ChemPort] Rice, K. C.; Jacobson, A. E. J. Med. Chem. 1976, 19, 430. [ChemPort] [Medline]

7. Comins, D. L.; Zhang, Y.-m.; Joseph, S. P. Org. Lett. 1999, 1, 657.[Full text - ACS] [ChemPort] [Medline]

8. Genisson, Y.; Marazano, C.; Das, B. C. J. Org. Chem. 1993, 58, 2052. [ChemPort]

9. Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J. Am. Chem. Soc. 1985, 107, 7974. [ChemPort]

10. Grewe, R.; Mondon, A. Chem. Ber. 1948, 81, 279. [ChemPort]

11. A key intermediate for Grewe cyclization was prepared using catalytic asymmetric hydrogenation of an enamide. Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117; Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya, H.; Noyori, R. J. Org. Chem. 1994, 59, 297. [ChemPort]

12. Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2002, 124, 14542.[Full text - ACS] [ChemPort] [Medline]

13. Molander, G. A.; Romero, J. A. C. Chem. Rev. 2002, 102, 2161;[Full text - ACS] [ChemPort] [Medline] Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795. [ChemPort] [CrossRef]

14. Carroll, F. I.; Bai, X.; Dehghani, A.; Mascarella, S. W.; Williams, W.; Bowen, W. D. J. Med. Chem. 1999, 42, 4621.[Full text - ACS] [ChemPort] [Medline]

15. Sainsbury, M.; Williams, C. S.; Naylor, A.; Scopes, D. I. C. Tetrahedron Lett. 1990, 31, 2763. [ChemPort] [CrossRef]

16. For reviews see: Corey, E. J. Angew. Chem., Int. Ed. 1998, 388; Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994; The benzylic quaternary carbon center has been prepared by catalytic asymmetric Heck reaction for the synthesis of a similar compound. Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 8477.

17. Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem., Int. Ed. 2002, 41, 3492; [ChemPort] [CrossRef] Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759.[Full text - ACS] [ChemPort]

18. Hartung, C. G.; Breindl, C.; Tillack, A.; Beller, M. Tetrahedron 2000, 56, 5157. [ChemPort] [CrossRef]

19. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.[Full text - ACS] [ChemPort] [Medline]

20. Prepared in one step (83% yield) from commercially available 7-methoxy-2-tetralone. Kuehne, M. E. J. Am. Chem. Soc. 1961, 83, 1492.

21. Sodium carbonate or potassium carbonate gave lower yield and ee.

22. Tokuda, M.; Fujita, H.; Miyamoto, T.; Suginome, H. Tetrahedron 1993, 49, 2413. [ChemPort] [CrossRef]

23. The relative stereochemistry was determined by NOE (see Supporting Information).

24. May, E. L.; Ager, J. H. J. Org. Chem. 1959, 24, 1432. [ChemPort]

25. Kametani, T.; Kigasawa, K.; Hiiragi, M.; Hayasaka, T.; Wagatsuma, N.; Wakisaka, K. J. Heterocycl. Chem. 1969, 6, 43. [ChemPort]

26. Ligand ent-12 is also readily available. Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327. [ChemPort]