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An intramolecular Tsuji-Trost reaction based approach to the synthesis of 6-methylene indolizidines
Tetrahedron Letters 52 (2011) 4878–4881
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
An intramolecular Tsuji-Trost reaction based approach to the synthesis of 6-methylene indolizidines Romy E. Martin, Marta E. Polomska, Lindsay T. Byrne, Scott G. Stewart ⇑ School of Biomedical, Biomolecular and Chemical Science, University of Western Australia, 35 Stirling Hwy, Crawley, 6009 WA, Australia
a r t i c l e
i n f o
Article history: Received 17 May 2011 Revised 23 June 2011 Accepted 11 July 2011 Available online 21 July 2011
a b s t r a c t Herein we describe the efficient stereoselective preparation of C8 substituted indolizidines bearing a 6methylene group, from the chiral pool starting material L-proline. This synthesis, employing a Tsuji-Trost reaction as the key step, represents a potentially, efficient route to pumiliotoxin natural product epimers. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Keywords: Indolizidines Intramolecular Tsuji-Trost reaction Allylation Pumiliotoxins
A wide range of biologically active alkaloids have been isolated from skin excretions of amphibians.1,2 The pumiliotoxins are one class of these alkaloids, comprising of approximately 24 members.3,4 Alkaloids which are designated as pumiliotoxins are characterised structurally by a (Z)-6-alkylidene-8-hydroxy-8-methylindolizidine ring system, with the general structure 1 (Fig. 1) and differ only in their alkylidene side chain. The pumiliotoxins were first isolated from the Panamanian poison frog Dendrobates pumilio in 1963.5 Since this time the physiological effects of the pumiliotoxins, mainly cardiotonic effects have been widely studied.6–8 It is the potential of pumiliotoxins as cardiotonic agents coupled with a limited availability of natural sources that drives efforts to obtain larger amounts of these compounds. Synthetic chemistry, through the efficient construction of indolizidines, will play a major role in the pharmaceutical development of these compounds. The preparation of pumiliotoxins has attracted many synthetic groups,9 with much of the pioneering work being carried out by Overman.1 Approaches to the indolizidine core within this group have focused on an intramolecular ene cyclisation,10 an iminium ion-vinylsilane cyclisation,11–13 as well as an iminium ion-alkyne variation to generate the N-heterocycle bearing an exocyclic double bond.13 Later studies by the group of Gallagher led to the preparation of 5-indolizidinone 2 which was used as an intermediate in the synthesis of pumiliotoxin 215D (3).14 As a result of the preparation of this indolizidinone 2, a number of procedures have emerged for the syntheses of several related pumiliotoxin alkaloids.15–20 More recently the group of Kibayashi prepared a common precursor to a pumiliotoxin bearing an alkyl halide side chain in ⇑ Corresponding author. E-mail address: [email protected] (S.G. Stewart).
HO H
H3C OH H
N 1
N
N R
2
O
H3C
RO CH3 H HO CH3 H OH H3C pumiliotoxin B (4)
pumiliotoxin215D (3)
N 5
N
HO CH3 H
CH3 CH3 OH
RO CH3 H N 6
Figure 1. Indolizidine alkaloids and some synthetic precursors.
order to access a range of these alkaloids.21 In this process, the key ring formation step was an intramolecular cyclodehydration from a diol precursor. Conveniently, this common halogenated intermediate was applied in the further synthesis of pumiliotoxins A and B (4) through a Negishi type cross-coupling reaction. In this study we describe the preparation of a protected 6-methylene indolizidine 5 as a potentially common intermediate for the synthesis of epimeric natural indolizidines. This synthetic pathway also offers an approach to the natural pumiliotoxins through similar transformations and preparation of indolizidine 6. The overall synthetic plan centres around the intramolecular Tsuji-Trost allylation reaction22–24 as the key ring-forming step, a reaction
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.07.047
R. E. Martin et al. / Tetrahedron Letters 52 (2011) 4878–4881
frequently utilised in the preparation of natural products25 and new heterocyclic systems.26,27 This approach using a secondary amine is unique in the synthesis of indolizidine systems and generally quite rare in the literature. The commercially available chiral pool material L-proline (7), containing one of the stereocentres required for the target indolizidines 5 or 6, was chosen as the starting material. Protection of the amine moiety afforded the Boc-L-proline 8 (82%) (Scheme 1).28 Additionally, it should be noted at this stage that compound 8 is also available commercially. Boc-L-proline 8 was converted into its corresponding Weinreb amide 9 upon treatment with N-methoxy-N-methylamine, DCC and triethylamine in excellent yield (82%),29 where more elaborate procedures resulted in only small amounts of the desired product being isolated. Treatment of this aforementioned compound with methyllithium at 78 °C generated the methyl ketone 10 in good yield (80%).30,31 The methyl ketone 10 was subsequently subjected to reaction with allylmagnesium bromide to deliver a mixture of the epimeric tertiary alcohols 11 and 12 (46:54 dr) which could be separated via standard chromatography. The new stereogenic centre formed at C2 within each of the epimers was initially investigated and later assigned by NOESY spectroscopy of both epimers 11 and 12. However, it was not until the rigid indolizidine core from one of these epimers was prepared that the configuration of this new stereogenic centre was confirmed. Following this initial trial, attempts to improve the diastereoselectivity and generate reasonable synthetically viable quantities of either diastereoisomer were sought (Table 1). The conditions developed by the Ley group32 (entry 2) were applied to this system, but unfortunately failed to improve the diastereoselectivity. Likewise, increasing the reaction temperature to access a potentially more thermodynamically favoured product failed to influence the diastereoselectivity. Reaction conditions based around the reagents BINOL and tetraallylstannane were then trialed, as devised by Walsh for asymmetric allylations.33 In this enantioselective reaction, R-BINOL was reported to generate the allyl addition product bearing an S-stereogenic centre in high ee. Even though we required a diastereoselective allylation, we were confident that this was a good foundation for producing the stereoselectivity of this reaction. Initially, we observed a dramatic improvement of diastereoselectivity [12:88 in favour of epimer 12 (entry 4, Table 1)] at ambient temperature using 20 mol % of the in situ [(BINOLate)Ti(OiPr)2]3 complex.34,35 Increasing the amount of catalyst in this system led to a decrease in the yield and diastereoselectivity for compound 12 (entry 5). Increasing the time failed to have any significant effect on the reaction, however, as expected, lowering the temperature increased the diastereoselectivity for epimer 12 (entry 6). In order to attempt to reverse the diastereoselectivity,
O
H
H OH
O H
a
OH
b
N OMe N CH3 Boc
N
N
Boc
H 7
O
8
9 c
H3 C OH H 2'
N Boc dr 46: 12
HO CH3 H +
2'
H
O
d
CH3
N Boc
N Boc
54: 11
10
Scheme 1. Reagents and conditions: (a) (Boc)2O, Et3N, CH2Cl2, reflux, 24 h, 82%; (b) MeONHMeHCl, DCC, Et3N, CH2Cl2, reflux, 16 h, 82%; (c) MeLi, THF, 78 °C ? rt, 2 h, 80%; (d) allylmagnesium bromide, THF, 0 °C, 3 h, 75%, dr = 46:54 (11:12).
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similar conditions using S-BINOL were investigated (entries 8–10, Table 1). The yield of the allylated products for these transformations was excellent, however the diastereoselectivity was not reversed and full conversion into both compounds 11 and 12 was sluggish. Interestingly, when the amount of S-BINOL and Ti(OiPr)4 was increased dramatically, the conversion was improved, but without a drastic effect on the diastereoselectivity. Since the diastereoisomer 12 was more accessible via the allylation method, with R-BINOL (entries 6 and 7, Table 1), the rest of the synthesis of the indolizidine core was carried out with this stereoisomer. In order to prevent any unwanted retro-aldol type processes later in the synthesis, the tertiary alcohol within compou nd 12 was protected (TBDMSOTf, 2,6-lutidine) to generate the corresponding TBDMS ether 13 (83%) (Scheme 2). The dihydroxylation of the olefin moiety within compound 13 was completed through treatment with AD-mix-a avoiding the use of hazardous OsO4 (Scheme 2).36 In this process, large quantities of the diol 14 as a diastereomeric mixture about C40 , could be obtained in excellent yields. Interestingly, this method required long reaction times. Reactions carried out at room temperature overnight (AD-mix-a 1.4 g/mmol) resulted in only 36% yield in comparison to 55% yield following stirring for 48 h. The optimum yield of 82% was achieved using a higher loading, AD-mix-a 1.8 g/mmol. This phenomenon is possibly due to the steric effects of the TBDMS protecting group within 13 and approach of the phthalazine-dihydroquinine osmium complex. Treatment of the diol 14 with acetic anhydride in the presence of triethylamine furnished the acetate 15 in excellent yield (86%), whereas other reactions incorporating DMAP in the reaction system only increased the likelihood of the corresponding diacetylated product forming. Treatment of 15 with Dess-Martin periodinane afforded the ketone 16 in 72% yield, while the precusor 2-iodoxybenzoic acid (IBX) gave an improved 96% yield. Subsequent treatment of this ketone with methyltriphenylphosphine ylide, gave alkene 17 in 64% yield, however upon scale-up, this yield was slightly lower. Under standard deprotection conditions, removal of the Boc moiety within compound 17 was achieved with TFA (added dropwise at 0 °C) to afford a mixture of the Tsuji-Trost precursor amine 18 and the related amine alcohol 19 (see Supplementary data). In the key ring-forming process the secondary amine 18 was treated with Pd(PPh3)4 (10 mol %) in the presence of triethylamine, to afford the desired indolizidine-based product 20 in a good yield (66%). An immediate reaction of the amine precursor was observed suggesting formation of the palladium p-allyl system is rapid. This clean transformation suggests that the pyrrolidine is an appropriate nucleophile for the intramolecular Tsuji-Trost reaction as observed for other N-heterocycles.23 The use of a secondary amine in an intermolecular Tsuji-Trost reaction has been reported in the literature, but has been more common in the synthesis of azaspirocyclic ring systems.27,37,38 To our knowledge, this is the first report of a secondary amine being used in this manner. Formation of the desired product was confirmed by the presence of two signals at 4.84 and 4.70 ppm in the 1H NMR spectrum assigned to the olefinic methylene protons, as well as the molecular ion of m/z 282 in the FAB high-resolution mass spectrum.39 The stereochemistry at C8 of the indolizidine 20 was confirmed with the aid of a series of 1D-NOESY experiments. The key NOE interactions are displayed in Figure 2. There was no interaction between the C8 methyl group and the proton at C8a which would be expected for the alternative stereochemistry at C8. Secondly, positive correlations between several other key protons on the indolizidine N-heterocyclic core were also observed. It should be noted here that the Overman group has produced a related free alcohol variant of compounds 20 and 6 previously, however in slightly lower yields.10 In order to carry this compound further to
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R. E. Martin et al. / Tetrahedron Letters 52 (2011) 4878–4881
Table 1 Diastereoselective allylation of ketone 10 Entry
Conditionsa
Yieldb (%)
drc S,S 11:S,R 12
1 2 3 4 5 6 7 8 9 10
Allylmagnesium bromide, THF, 3 h, 0 °C Allylmagnesium bromide, Ti(OiPr)4d THF, 0.5 h, 78 °C Allylmagnesium bromide, THF, 0.5 h, 35 °C Tetraallyltin, Ti(OiPr)4, R-BINOL (20 mol %), 2-propanol, CH2Cl2, 24 h, rt Tetraallyltin, Ti(OiPr)4, R-BINOL (30 mol %), 2-propanol, CH2Cl2, 12 h, rt Tetraallyltin, Ti(OiPr)4, R-BINOL (20 mol %), 2-propanol, CH2Cl2, 68 h, rt Tetraallyltin, Ti(OiPr)4, R-BINOL (30 mol %), 2-propanol, CH2Cl2, 12 h, 0 °C Tetraallyltin, Ti(OiPr)4, S-BINOL (30 mol %), 2-propanol, CH2Cl2, 12 h, rt Tetraallyltin, Ti(OiPr)4, S-BINOL (30 mol %), 2-propanol, CH2Cl2, 60 h, rt Tetraallyltin, Ti(OiPr)4, S-BINOL (60 mol %), 2-propanol, CH2Cl2, 60 h, rt
75 82 80 81 77 83 78 81e 80e 92
46:54 46:54 46:54 12:88 21:79 14:86 12:88 36:64 34:66 31:69
a Reactions were carried out on 150 mg of ketone 10 and each reaction was repeated twice where the yield and diastereomeric ratio (dr) are averaged over two experiments. b Isolated yields are reported, the two diastereoisomers were separated using standard column chromatography. c The configuration of the new stereogenic centre at C20 was determined later by NOESY spectroscopy for each indolizidine epimer. d 2 equiv. e The yield indicated was based on recovery of starting material 10.
H3C OH H
TBSO CH3 OH H
TBOS CH3 H a
b
N Boc
N Boc
12
13
4'
N Boc 14
OH
c TBSO CH3 H
TBSO CH3 O H
N Boc
Acknowledgements
TBSO CH3 OH H
e
d N Boc
OAc
OAc
N Boc
16
17
were the allylation which may be used to also generate a diastereomerically pure indolizidine, and a pyrrolidine-tethered intramolecular Tsuji-Trost reaction. Work is in progress in order to expand this synthetic protocol to the total synthesis of the pumiliotoxin alkaloids and derivatives.
OAc
15
The authors would like to thank Dr. Tony Reeder for mass spectra acquisition. Romy Martin is the recipient of an Australian Postgraduate Award (APA). Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2011.07.047.
f TBSO CH3 H g NH
CH3
H3C OTBS H
TBSO
8
a
N
OAc
Scheme 2. Reagents and conditions: (a) TBS-triflate, 2,6-lutidine, CH2Cl2, 0 °C, 2 h, 83%; (b) AD-mix-a, t-BuOH, H2O, Na2SO3, 0 °C ? rt, 48 h, 82%; (c) Ac2O, Et3N, CH2Cl2, rt, 24 h, 86%; (d) Dess-Martin periodinane, CH2Cl2, rt, 2 h, 72%; (e) BrCH3PPh3, NaHMDS, THF, rt, 2 h, 64%; (f) TFA, CH2Cl2, rt, 2 h; (g) Pd(PPh3)4 (10 mol %), Et3N, THF, 60 °C, 2 h, 66%.
CH3 X TBSO H
H
N H
H H
CH3 TBSO H H
H H H
N
References and notes
N
H 20
20
18
8
H H
Figure 2. Key NOE interactions for (8S,8aR)-methyleneindolizidine 20.
a series of pumiliotoxins, or their 8aR epimers, a Grubbs olefin metathesis will be considered. Another option for further synthetic studies towards these natural product alkaloids would be through the 6-indolizidinone available through oxidative cleavage of compound 20. In conclusion, we have demonstrated a new and concise synthesis of a compound bearing the indolizidine core with an exocyclic methylene and two stereogenic centres at C8 and C8a. The key transformations in the synthesis of this indolizidine derivative
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Franklin, A. S.; Overman, L. E. Chem. Rev. 1996, 96, 505. Daly, J. W. J. Med. Chem. 2003, 46, 445. Daly, J.; Spande, T.; Garraffo, H. J. Nat. Prod. 2005, 68, 1556. Daly, J. W.; Tokuyama, T.; Fujiwara, T.; Highet, R. J.; Karle, I. L. J. Am. Chem. Soc. 1980, 102, 830. Daly, J. W. J. Nat. Prod. 1998, 61, 162. Endoh, M. Br. J. Pharmacol. 2004, 143, 663. Albuquerque, E. X.; Warnick, J. E.; Maleque, M. A.; Kauffman, F. C.; Tamburini, R.; Nimit, Y.; Daly, J. W. Mol. Pharmacol. 1981, 19, 411. Gusovsky, F.; Padgett, W. L.; Creveling, C. R.; Daly, J. W. Mol. Pharmacol. 1992, 42, 1104. Michael, J. P. Nat. Prod. Rep. 2007, 24, 191. Overman, L. E.; Lesuisse, D. Tetrahedron Lett. 1985, 26, 4167. Overman, L. E.; Bell, K. L.; Ito, F. J. Am. Chem. Soc. 1984, 106, 4192. Koenig, K. E.; Weber, W. P. J. Am. Chem. Soc. 1973, 95, 3416. Lin, N. H.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9062. Fox, D.; Lathbury, D.; Mahon, M.; Molloy, K.; Gallagher, T. J. Am. Chem. Soc. 1991, 113, 2652. Martin, S. F.; Bur, S. K. Tetrahedron 1999, 55, 8905. Barrett, A. G. M.; Damiani, F. J. Org. Chem. 1999, 64, 1410. Wang, B.; Fang, K.; Lin, G.-Q. Tetrahedron Lett. 2003, 44, 7981. Sudau, A.; Münch, W.; Bats, J.; Nubbemeyer, U. Eur. J.Org. Chem. 2002, 3304. O’Mahony, G.; Nieuwenhuyzen, M.; Armstrong, P.; Stevenson, P. J. J.Org. Chem. 2004, 69, 3968. Ni, Y.; Zhao, G.; Ding, Y. J. Chem. Soc., Perkin Trans. 1 2000, 3264. Aoyagi, S.; Hirashima, S.; Saito, K.; Kibayashi, C. J. Org. Chem. 2002, 67, 5517. Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387. (a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921; (b) Trost, B. M.; Cossy, J. J. Am. Chem. Soc. 1982, 104, 6881–6882. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. Nicolaou, K. C.; Bulger, P.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442. Trost, B. M. J. Org. Chem. 2004, 69, 5813. Tietze, L. F.; Schirok, H. Angew. Chem., Int. Ed. 1997, 36, 1124. Wagger, J.; Groselj, U.; Meden, A.; Svete, J.; Stanovnik, B. Tetrahedron 2008, 64, 2801.
R. E. Martin et al. / Tetrahedron Letters 52 (2011) 4878–4881 29. Zhou, Z. H.; Tang, Y. L.; Li, K. Y.; Liu, B.; Tang, C. C. Heteroat. Chem. 2003, 14, 603. 30. Ferraris, D.; Ko, Y.-S.; Calvin, D.; Chiou, T.; Lautar, S.; Thomas, B.; Wozniak, K.; Rojas, C.; Kalish, V.; Belyakov, S. Bioorg. Med. Chem. Lett. 2004, 14, 5579. 31. Regis, V.; Laurent, T.; Michel, M.; Nicole, B.; Michele, R.; Catherine, C. J. Pept. Sci. 2003, 9, 282. 32. Andrews, S. P.; Ball, M.; Wierschem, F.; Cleator, E.; Oliver, S.; Högenauer, K.; Simic, O.; Antonello, A.; Hünger, U.; Smith, M. D.; Ley, S. V. Chem. Eur. J. 2007, 13, 5688. 33. Kim, J. G.; Waltz, K. M.; Garcia, I. F.; Kwiatkowski, D.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 12580. 34. Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001. 35. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc 1993, 115, 8467. 36. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M. J. Org. Chem. 1992, 57, 2768. 37. Godleski, S. A.; Meinhart, J. D.; Miller, D. J.; Van Wallendael, S. Tetrahedron Lett. 1981, 22, 2247. 38. Godleski, S. A.; Heacock, D. J.; Meinhart, J. D.; Van Wallendael, S. J. Org. Chem. 1983, 48, 2101. 39. Preparation of (8S,8aR)-8-[(tert-butyldimethylsilyl)oxy]-8-methyl-6-methyleneo ctahydroindolizine (20): Pd(PPh3)4 (24 mg, 0.02 mmol) and Et3N (0.03 mL,
4881
0.21 mmol) were added to a solution of secondary amine 18 (71 mg, 0.21 mmol) in THF. The reaction mixture was degassed using three freeze– pump–thaw cycles and then warmed to 60 °C and stirred for 2 h. THF was removed under reduced pressure and the resulting orange solid dissolved in EtOAc (20 mL) and washed with H2O (2 mL). The aqueous layer was then back extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give a pale-orange oil. Flash column chromatography (5:95 MeOH:EtOAc) afforded the indolizidine 20 (39 mg, 66%) as a pale-orange oil. 1H NMR (400 MHz, CDCl3): d 4.84 (s, 1H, C@CH2), 4.70 (s, 1H, C@CH2), 3.48 (dd, J = 11.6 and 1.2 Hz, 1H, H-5), 3.03–3.09 (m, 1H, H-4), 2.60 (d, J = 11.6 Hz, 1H, H-5), 2.36 (dd, 1H, J = 14.0 and 1.2 Hz, H-7), 2.01–2.11 (m, 2H, H-7 and H-4), 1.83–1.88 (m, 1H, H-1), 1.59–1.81 (m, 4H, H-2 and H-3), 1.18 (s, 3H, CH3), 0.86 (s, 9H, Si(CH3)2C(CH3)3), 0.09 (s, 3H, Si(CH3)2C(CH3)3), 0.08 (s, 3H, Si(CH3)2C(CH3)3) ppm; 13C NMR (400 MHz, CDCl3): d 142.8 (C@CH2), 110.8 (C@CH2), 72.9 (C-6), 72.2 (C-1), 58.7 (C-5), 54.5 (C-4), 46.9 (C-7), 28.2 (CH3), 26.2 (Si(CH3)2C(CH3)3), 23.6 (C-2), 21.4 (C-3), 18.7 (Si(CH3)2C(CH3)3), 1.6 (Si(CH3)2C(CH3)3) ppm; IR (neat): 3399 (N–H), 2957 (C–H), 2930 (C–H), 2856 (C–H), 1659, 1651 (C@C) cm1; MS (FAB) (m/z) = 282.3 [M+H]+ (92), 267.1 [MCH3]+ (27), 251.1 (26), 207.1 (46), 193.1 (75), 191.1 (80.01), 133.1 (100); HRMS (FAB) calculated for C16H32NOSi [M+H]: 282.2253, found: 282.2238.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
An intramolecular Tsuji-Trost reaction based approach to the synthesis of 6-methylene indolizidines Romy E. Martin, Marta E. Polomska, Lindsay T. Byrne, Scott G. Stewart ⇑ School of Biomedical, Biomolecular and Chemical Science, University of Western Australia, 35 Stirling Hwy, Crawley, 6009 WA, Australia
a r t i c l e
i n f o
Article history: Received 17 May 2011 Revised 23 June 2011 Accepted 11 July 2011 Available online 21 July 2011
a b s t r a c t Herein we describe the efficient stereoselective preparation of C8 substituted indolizidines bearing a 6methylene group, from the chiral pool starting material L-proline. This synthesis, employing a Tsuji-Trost reaction as the key step, represents a potentially, efficient route to pumiliotoxin natural product epimers. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Keywords: Indolizidines Intramolecular Tsuji-Trost reaction Allylation Pumiliotoxins
A wide range of biologically active alkaloids have been isolated from skin excretions of amphibians.1,2 The pumiliotoxins are one class of these alkaloids, comprising of approximately 24 members.3,4 Alkaloids which are designated as pumiliotoxins are characterised structurally by a (Z)-6-alkylidene-8-hydroxy-8-methylindolizidine ring system, with the general structure 1 (Fig. 1) and differ only in their alkylidene side chain. The pumiliotoxins were first isolated from the Panamanian poison frog Dendrobates pumilio in 1963.5 Since this time the physiological effects of the pumiliotoxins, mainly cardiotonic effects have been widely studied.6–8 It is the potential of pumiliotoxins as cardiotonic agents coupled with a limited availability of natural sources that drives efforts to obtain larger amounts of these compounds. Synthetic chemistry, through the efficient construction of indolizidines, will play a major role in the pharmaceutical development of these compounds. The preparation of pumiliotoxins has attracted many synthetic groups,9 with much of the pioneering work being carried out by Overman.1 Approaches to the indolizidine core within this group have focused on an intramolecular ene cyclisation,10 an iminium ion-vinylsilane cyclisation,11–13 as well as an iminium ion-alkyne variation to generate the N-heterocycle bearing an exocyclic double bond.13 Later studies by the group of Gallagher led to the preparation of 5-indolizidinone 2 which was used as an intermediate in the synthesis of pumiliotoxin 215D (3).14 As a result of the preparation of this indolizidinone 2, a number of procedures have emerged for the syntheses of several related pumiliotoxin alkaloids.15–20 More recently the group of Kibayashi prepared a common precursor to a pumiliotoxin bearing an alkyl halide side chain in ⇑ Corresponding author. E-mail address: [email protected] (S.G. Stewart).
HO H
H3C OH H
N 1
N
N R
2
O
H3C
RO CH3 H HO CH3 H OH H3C pumiliotoxin B (4)
pumiliotoxin215D (3)
N 5
N
HO CH3 H
CH3 CH3 OH
RO CH3 H N 6
Figure 1. Indolizidine alkaloids and some synthetic precursors.
order to access a range of these alkaloids.21 In this process, the key ring formation step was an intramolecular cyclodehydration from a diol precursor. Conveniently, this common halogenated intermediate was applied in the further synthesis of pumiliotoxins A and B (4) through a Negishi type cross-coupling reaction. In this study we describe the preparation of a protected 6-methylene indolizidine 5 as a potentially common intermediate for the synthesis of epimeric natural indolizidines. This synthetic pathway also offers an approach to the natural pumiliotoxins through similar transformations and preparation of indolizidine 6. The overall synthetic plan centres around the intramolecular Tsuji-Trost allylation reaction22–24 as the key ring-forming step, a reaction
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.07.047
R. E. Martin et al. / Tetrahedron Letters 52 (2011) 4878–4881
frequently utilised in the preparation of natural products25 and new heterocyclic systems.26,27 This approach using a secondary amine is unique in the synthesis of indolizidine systems and generally quite rare in the literature. The commercially available chiral pool material L-proline (7), containing one of the stereocentres required for the target indolizidines 5 or 6, was chosen as the starting material. Protection of the amine moiety afforded the Boc-L-proline 8 (82%) (Scheme 1).28 Additionally, it should be noted at this stage that compound 8 is also available commercially. Boc-L-proline 8 was converted into its corresponding Weinreb amide 9 upon treatment with N-methoxy-N-methylamine, DCC and triethylamine in excellent yield (82%),29 where more elaborate procedures resulted in only small amounts of the desired product being isolated. Treatment of this aforementioned compound with methyllithium at 78 °C generated the methyl ketone 10 in good yield (80%).30,31 The methyl ketone 10 was subsequently subjected to reaction with allylmagnesium bromide to deliver a mixture of the epimeric tertiary alcohols 11 and 12 (46:54 dr) which could be separated via standard chromatography. The new stereogenic centre formed at C2 within each of the epimers was initially investigated and later assigned by NOESY spectroscopy of both epimers 11 and 12. However, it was not until the rigid indolizidine core from one of these epimers was prepared that the configuration of this new stereogenic centre was confirmed. Following this initial trial, attempts to improve the diastereoselectivity and generate reasonable synthetically viable quantities of either diastereoisomer were sought (Table 1). The conditions developed by the Ley group32 (entry 2) were applied to this system, but unfortunately failed to improve the diastereoselectivity. Likewise, increasing the reaction temperature to access a potentially more thermodynamically favoured product failed to influence the diastereoselectivity. Reaction conditions based around the reagents BINOL and tetraallylstannane were then trialed, as devised by Walsh for asymmetric allylations.33 In this enantioselective reaction, R-BINOL was reported to generate the allyl addition product bearing an S-stereogenic centre in high ee. Even though we required a diastereoselective allylation, we were confident that this was a good foundation for producing the stereoselectivity of this reaction. Initially, we observed a dramatic improvement of diastereoselectivity [12:88 in favour of epimer 12 (entry 4, Table 1)] at ambient temperature using 20 mol % of the in situ [(BINOLate)Ti(OiPr)2]3 complex.34,35 Increasing the amount of catalyst in this system led to a decrease in the yield and diastereoselectivity for compound 12 (entry 5). Increasing the time failed to have any significant effect on the reaction, however, as expected, lowering the temperature increased the diastereoselectivity for epimer 12 (entry 6). In order to attempt to reverse the diastereoselectivity,
O
H
H OH
O H
a
OH
b
N OMe N CH3 Boc
N
N
Boc
H 7
O
8
9 c
H3 C OH H 2'
N Boc dr 46: 12
HO CH3 H +
2'
H
O
d
CH3
N Boc
N Boc
54: 11
10
Scheme 1. Reagents and conditions: (a) (Boc)2O, Et3N, CH2Cl2, reflux, 24 h, 82%; (b) MeONHMeHCl, DCC, Et3N, CH2Cl2, reflux, 16 h, 82%; (c) MeLi, THF, 78 °C ? rt, 2 h, 80%; (d) allylmagnesium bromide, THF, 0 °C, 3 h, 75%, dr = 46:54 (11:12).
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similar conditions using S-BINOL were investigated (entries 8–10, Table 1). The yield of the allylated products for these transformations was excellent, however the diastereoselectivity was not reversed and full conversion into both compounds 11 and 12 was sluggish. Interestingly, when the amount of S-BINOL and Ti(OiPr)4 was increased dramatically, the conversion was improved, but without a drastic effect on the diastereoselectivity. Since the diastereoisomer 12 was more accessible via the allylation method, with R-BINOL (entries 6 and 7, Table 1), the rest of the synthesis of the indolizidine core was carried out with this stereoisomer. In order to prevent any unwanted retro-aldol type processes later in the synthesis, the tertiary alcohol within compou nd 12 was protected (TBDMSOTf, 2,6-lutidine) to generate the corresponding TBDMS ether 13 (83%) (Scheme 2). The dihydroxylation of the olefin moiety within compound 13 was completed through treatment with AD-mix-a avoiding the use of hazardous OsO4 (Scheme 2).36 In this process, large quantities of the diol 14 as a diastereomeric mixture about C40 , could be obtained in excellent yields. Interestingly, this method required long reaction times. Reactions carried out at room temperature overnight (AD-mix-a 1.4 g/mmol) resulted in only 36% yield in comparison to 55% yield following stirring for 48 h. The optimum yield of 82% was achieved using a higher loading, AD-mix-a 1.8 g/mmol. This phenomenon is possibly due to the steric effects of the TBDMS protecting group within 13 and approach of the phthalazine-dihydroquinine osmium complex. Treatment of the diol 14 with acetic anhydride in the presence of triethylamine furnished the acetate 15 in excellent yield (86%), whereas other reactions incorporating DMAP in the reaction system only increased the likelihood of the corresponding diacetylated product forming. Treatment of 15 with Dess-Martin periodinane afforded the ketone 16 in 72% yield, while the precusor 2-iodoxybenzoic acid (IBX) gave an improved 96% yield. Subsequent treatment of this ketone with methyltriphenylphosphine ylide, gave alkene 17 in 64% yield, however upon scale-up, this yield was slightly lower. Under standard deprotection conditions, removal of the Boc moiety within compound 17 was achieved with TFA (added dropwise at 0 °C) to afford a mixture of the Tsuji-Trost precursor amine 18 and the related amine alcohol 19 (see Supplementary data). In the key ring-forming process the secondary amine 18 was treated with Pd(PPh3)4 (10 mol %) in the presence of triethylamine, to afford the desired indolizidine-based product 20 in a good yield (66%). An immediate reaction of the amine precursor was observed suggesting formation of the palladium p-allyl system is rapid. This clean transformation suggests that the pyrrolidine is an appropriate nucleophile for the intramolecular Tsuji-Trost reaction as observed for other N-heterocycles.23 The use of a secondary amine in an intermolecular Tsuji-Trost reaction has been reported in the literature, but has been more common in the synthesis of azaspirocyclic ring systems.27,37,38 To our knowledge, this is the first report of a secondary amine being used in this manner. Formation of the desired product was confirmed by the presence of two signals at 4.84 and 4.70 ppm in the 1H NMR spectrum assigned to the olefinic methylene protons, as well as the molecular ion of m/z 282 in the FAB high-resolution mass spectrum.39 The stereochemistry at C8 of the indolizidine 20 was confirmed with the aid of a series of 1D-NOESY experiments. The key NOE interactions are displayed in Figure 2. There was no interaction between the C8 methyl group and the proton at C8a which would be expected for the alternative stereochemistry at C8. Secondly, positive correlations between several other key protons on the indolizidine N-heterocyclic core were also observed. It should be noted here that the Overman group has produced a related free alcohol variant of compounds 20 and 6 previously, however in slightly lower yields.10 In order to carry this compound further to
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R. E. Martin et al. / Tetrahedron Letters 52 (2011) 4878–4881
Table 1 Diastereoselective allylation of ketone 10 Entry
Conditionsa
Yieldb (%)
drc S,S 11:S,R 12
1 2 3 4 5 6 7 8 9 10
Allylmagnesium bromide, THF, 3 h, 0 °C Allylmagnesium bromide, Ti(OiPr)4d THF, 0.5 h, 78 °C Allylmagnesium bromide, THF, 0.5 h, 35 °C Tetraallyltin, Ti(OiPr)4, R-BINOL (20 mol %), 2-propanol, CH2Cl2, 24 h, rt Tetraallyltin, Ti(OiPr)4, R-BINOL (30 mol %), 2-propanol, CH2Cl2, 12 h, rt Tetraallyltin, Ti(OiPr)4, R-BINOL (20 mol %), 2-propanol, CH2Cl2, 68 h, rt Tetraallyltin, Ti(OiPr)4, R-BINOL (30 mol %), 2-propanol, CH2Cl2, 12 h, 0 °C Tetraallyltin, Ti(OiPr)4, S-BINOL (30 mol %), 2-propanol, CH2Cl2, 12 h, rt Tetraallyltin, Ti(OiPr)4, S-BINOL (30 mol %), 2-propanol, CH2Cl2, 60 h, rt Tetraallyltin, Ti(OiPr)4, S-BINOL (60 mol %), 2-propanol, CH2Cl2, 60 h, rt
75 82 80 81 77 83 78 81e 80e 92
46:54 46:54 46:54 12:88 21:79 14:86 12:88 36:64 34:66 31:69
a Reactions were carried out on 150 mg of ketone 10 and each reaction was repeated twice where the yield and diastereomeric ratio (dr) are averaged over two experiments. b Isolated yields are reported, the two diastereoisomers were separated using standard column chromatography. c The configuration of the new stereogenic centre at C20 was determined later by NOESY spectroscopy for each indolizidine epimer. d 2 equiv. e The yield indicated was based on recovery of starting material 10.
H3C OH H
TBSO CH3 OH H
TBOS CH3 H a
b
N Boc
N Boc
12
13
4'
N Boc 14
OH
c TBSO CH3 H
TBSO CH3 O H
N Boc
Acknowledgements
TBSO CH3 OH H
e
d N Boc
OAc
OAc
N Boc
16
17
were the allylation which may be used to also generate a diastereomerically pure indolizidine, and a pyrrolidine-tethered intramolecular Tsuji-Trost reaction. Work is in progress in order to expand this synthetic protocol to the total synthesis of the pumiliotoxin alkaloids and derivatives.
OAc
15
The authors would like to thank Dr. Tony Reeder for mass spectra acquisition. Romy Martin is the recipient of an Australian Postgraduate Award (APA). Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2011.07.047.
f TBSO CH3 H g NH
CH3
H3C OTBS H
TBSO
8
a
N
OAc
Scheme 2. Reagents and conditions: (a) TBS-triflate, 2,6-lutidine, CH2Cl2, 0 °C, 2 h, 83%; (b) AD-mix-a, t-BuOH, H2O, Na2SO3, 0 °C ? rt, 48 h, 82%; (c) Ac2O, Et3N, CH2Cl2, rt, 24 h, 86%; (d) Dess-Martin periodinane, CH2Cl2, rt, 2 h, 72%; (e) BrCH3PPh3, NaHMDS, THF, rt, 2 h, 64%; (f) TFA, CH2Cl2, rt, 2 h; (g) Pd(PPh3)4 (10 mol %), Et3N, THF, 60 °C, 2 h, 66%.
CH3 X TBSO H
H
N H
H H
CH3 TBSO H H
H H H
N
References and notes
N
H 20
20
18
8
H H
Figure 2. Key NOE interactions for (8S,8aR)-methyleneindolizidine 20.
a series of pumiliotoxins, or their 8aR epimers, a Grubbs olefin metathesis will be considered. Another option for further synthetic studies towards these natural product alkaloids would be through the 6-indolizidinone available through oxidative cleavage of compound 20. In conclusion, we have demonstrated a new and concise synthesis of a compound bearing the indolizidine core with an exocyclic methylene and two stereogenic centres at C8 and C8a. The key transformations in the synthesis of this indolizidine derivative
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Franklin, A. S.; Overman, L. E. Chem. Rev. 1996, 96, 505. Daly, J. W. J. Med. Chem. 2003, 46, 445. Daly, J.; Spande, T.; Garraffo, H. J. Nat. Prod. 2005, 68, 1556. Daly, J. W.; Tokuyama, T.; Fujiwara, T.; Highet, R. J.; Karle, I. L. J. Am. Chem. Soc. 1980, 102, 830. Daly, J. W. J. Nat. Prod. 1998, 61, 162. Endoh, M. Br. J. Pharmacol. 2004, 143, 663. Albuquerque, E. X.; Warnick, J. E.; Maleque, M. A.; Kauffman, F. C.; Tamburini, R.; Nimit, Y.; Daly, J. W. Mol. Pharmacol. 1981, 19, 411. Gusovsky, F.; Padgett, W. L.; Creveling, C. R.; Daly, J. W. Mol. Pharmacol. 1992, 42, 1104. Michael, J. P. Nat. Prod. Rep. 2007, 24, 191. Overman, L. E.; Lesuisse, D. Tetrahedron Lett. 1985, 26, 4167. Overman, L. E.; Bell, K. L.; Ito, F. J. Am. Chem. Soc. 1984, 106, 4192. Koenig, K. E.; Weber, W. P. J. Am. Chem. Soc. 1973, 95, 3416. Lin, N. H.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9062. Fox, D.; Lathbury, D.; Mahon, M.; Molloy, K.; Gallagher, T. J. Am. Chem. Soc. 1991, 113, 2652. Martin, S. F.; Bur, S. K. Tetrahedron 1999, 55, 8905. Barrett, A. G. M.; Damiani, F. J. Org. Chem. 1999, 64, 1410. Wang, B.; Fang, K.; Lin, G.-Q. Tetrahedron Lett. 2003, 44, 7981. Sudau, A.; Münch, W.; Bats, J.; Nubbemeyer, U. Eur. J.Org. Chem. 2002, 3304. O’Mahony, G.; Nieuwenhuyzen, M.; Armstrong, P.; Stevenson, P. J. J.Org. Chem. 2004, 69, 3968. Ni, Y.; Zhao, G.; Ding, Y. J. Chem. Soc., Perkin Trans. 1 2000, 3264. Aoyagi, S.; Hirashima, S.; Saito, K.; Kibayashi, C. J. Org. Chem. 2002, 67, 5517. Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387. (a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921; (b) Trost, B. M.; Cossy, J. J. Am. Chem. Soc. 1982, 104, 6881–6882. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. Nicolaou, K. C.; Bulger, P.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442. Trost, B. M. J. Org. Chem. 2004, 69, 5813. Tietze, L. F.; Schirok, H. Angew. Chem., Int. Ed. 1997, 36, 1124. Wagger, J.; Groselj, U.; Meden, A.; Svete, J.; Stanovnik, B. Tetrahedron 2008, 64, 2801.
R. E. Martin et al. / Tetrahedron Letters 52 (2011) 4878–4881 29. Zhou, Z. H.; Tang, Y. L.; Li, K. Y.; Liu, B.; Tang, C. C. Heteroat. Chem. 2003, 14, 603. 30. Ferraris, D.; Ko, Y.-S.; Calvin, D.; Chiou, T.; Lautar, S.; Thomas, B.; Wozniak, K.; Rojas, C.; Kalish, V.; Belyakov, S. Bioorg. Med. Chem. Lett. 2004, 14, 5579. 31. Regis, V.; Laurent, T.; Michel, M.; Nicole, B.; Michele, R.; Catherine, C. J. Pept. Sci. 2003, 9, 282. 32. Andrews, S. P.; Ball, M.; Wierschem, F.; Cleator, E.; Oliver, S.; Högenauer, K.; Simic, O.; Antonello, A.; Hünger, U.; Smith, M. D.; Ley, S. V. Chem. Eur. J. 2007, 13, 5688. 33. Kim, J. G.; Waltz, K. M.; Garcia, I. F.; Kwiatkowski, D.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 12580. 34. Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001. 35. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc 1993, 115, 8467. 36. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M. J. Org. Chem. 1992, 57, 2768. 37. Godleski, S. A.; Meinhart, J. D.; Miller, D. J.; Van Wallendael, S. Tetrahedron Lett. 1981, 22, 2247. 38. Godleski, S. A.; Heacock, D. J.; Meinhart, J. D.; Van Wallendael, S. J. Org. Chem. 1983, 48, 2101. 39. Preparation of (8S,8aR)-8-[(tert-butyldimethylsilyl)oxy]-8-methyl-6-methyleneo ctahydroindolizine (20): Pd(PPh3)4 (24 mg, 0.02 mmol) and Et3N (0.03 mL,
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0.21 mmol) were added to a solution of secondary amine 18 (71 mg, 0.21 mmol) in THF. The reaction mixture was degassed using three freeze– pump–thaw cycles and then warmed to 60 °C and stirred for 2 h. THF was removed under reduced pressure and the resulting orange solid dissolved in EtOAc (20 mL) and washed with H2O (2 mL). The aqueous layer was then back extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give a pale-orange oil. Flash column chromatography (5:95 MeOH:EtOAc) afforded the indolizidine 20 (39 mg, 66%) as a pale-orange oil. 1H NMR (400 MHz, CDCl3): d 4.84 (s, 1H, C@CH2), 4.70 (s, 1H, C@CH2), 3.48 (dd, J = 11.6 and 1.2 Hz, 1H, H-5), 3.03–3.09 (m, 1H, H-4), 2.60 (d, J = 11.6 Hz, 1H, H-5), 2.36 (dd, 1H, J = 14.0 and 1.2 Hz, H-7), 2.01–2.11 (m, 2H, H-7 and H-4), 1.83–1.88 (m, 1H, H-1), 1.59–1.81 (m, 4H, H-2 and H-3), 1.18 (s, 3H, CH3), 0.86 (s, 9H, Si(CH3)2C(CH3)3), 0.09 (s, 3H, Si(CH3)2C(CH3)3), 0.08 (s, 3H, Si(CH3)2C(CH3)3) ppm; 13C NMR (400 MHz, CDCl3): d 142.8 (C@CH2), 110.8 (C@CH2), 72.9 (C-6), 72.2 (C-1), 58.7 (C-5), 54.5 (C-4), 46.9 (C-7), 28.2 (CH3), 26.2 (Si(CH3)2C(CH3)3), 23.6 (C-2), 21.4 (C-3), 18.7 (Si(CH3)2C(CH3)3), 1.6 (Si(CH3)2C(CH3)3) ppm; IR (neat): 3399 (N–H), 2957 (C–H), 2930 (C–H), 2856 (C–H), 1659, 1651 (C@C) cm1; MS (FAB) (m/z) = 282.3 [M+H]+ (92), 267.1 [MCH3]+ (27), 251.1 (26), 207.1 (46), 193.1 (75), 191.1 (80.01), 133.1 (100); HRMS (FAB) calculated for C16H32NOSi [M+H]: 282.2253, found: 282.2238.