Short Enantioselective Total Synthesis of (−)-Rhazinilam Using a Gold

Letter pubs.acs.org/OrgLett

Short Enantioselective Total Synthesis of (−)-Rhazinilam Using a Gold(I)-Catalyzed Cyclization Valentin Magné, Charlotte Lorton, Angela Marinetti, Xavier Guinchard, and Arnaud Voituriez* Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1 av. de la Terrasse, 91198 Gif-sur-Yvette, France S Supporting Information *

ABSTRACT: (R)-(−)-Rhazinilam has been synthesized in nine steps and 20% overall yield. The key steps involve two metal-catalyzed processes: the enantioselective gold(I)-catalyzed cycloisomerization of an allene-functionalized pyrrole and the palladium-catalyzed hydrocarboxylation of a vinyl moiety with formate as a CO surrogate. This novel strategy represents the shortest and highest yielding enantioselective total synthesis of (−)-rhazinilam.

enantioselective total synthesis of (R)-(−)-rhazinilam 1 (12 steps, 16.4% overall yield, 86% ee). With the aim of accessing (R)-(−)-rhazinilam via a robust and efficient procedure involving a smaller number of synthetic steps, we have envisioned the retrosynthetic approach depicted in Figure 2.

(R)-(−)-Rhazinilam 1 has been isolated initially through extraction procedures from Melodinus australis,1a Rhazya stricta,1b and from Malaysian Apocynaceae.1c It was demonstrated later that its isolation is an artifact of the extraction procedure by which the natural precursor, dihydropyrrole 2, was oxidized into pyrrole 1 (Figure 1).1c,d (R)-(−)-Rhazinilam

Figure 1. Structure of (−)-rhazinilam 1 and its precursor 2.

has attracted significant attention due to its strong biological activity, acting as an inhibitor of the tubulin−microtubule equilibrium.2 Moreover, its complex structure represents a highly challenging synthetic target for organic chemists.3,4 The tetracyclic structure of 1 features indeed an all-carbon quaternary stereogenic center, an axially chiral arylpyrrole group, and a 9-membered lactam ring. Due to this synthetic interest, seven asymmetric total syntheses have been reported, giving 1 in 1.6−19.8% overall yields, over 12−18 chemical steps.5 Among others, Zhu recently reported an elegant strategy involving a tandem Staudinger reduction/aza-Wittig reaction and the heteroannulation of a tetrahydropyridine with bromoacetaldehyde as the key steps.5g The enantioselective step is a palladium-(S)tBuPHOX catalyzed decarboxylative allylation reaction on a cyclopentanone derivative, which generates the stereogenic quaternary carbon center of 1. To date, this is the shortest © 2017 American Chemical Society

Figure 2. Retrosynthetic approach to (R)-(−)-rhazinilam 1.

Overall, according to our strategy in Figure 2, rhazinilam 1 would be obtained by a final macrolactamization step from amino acid i. The carboxylic acid function will be installed by means of a palladium-catalyzed hydrocarboxylation of olefin ii. The aniline moiety of ii will be installed by a Suzuki crosscoupling after iodination of the tetrahydroindolizine iii, this bicyclic derivative being obtained via an enantioselective gold(I)-catalyzed cycloisomerization (hydroarylation) of the Received: July 19, 2017 Published: September 6, 2017 4794

DOI: 10.1021/acs.orglett.7b02210 Org. Lett. 2017, 19, 4794−4797

Letter

Organic Letters

catalysis and offers interesting possibilities to our strategy. The cycloisomerization of 3 into 4 has been investigated at first by using 5 mol % of the achiral [Ph3PAuCl/AgOTf] catalytic system in toluene at room temperature (entry 1 in Table 1). The desired tetrahydroindolizine 4 could be obtained in 97% isolated yield through 6-exo-trig hydroarylation of the allene. We next turned our attention to the development of an enantioselective variant of this reaction. A systematic screening of chiral gold(I) precatalysts revealed that complexes of either the chiral phosphoramidite I or BINAP ligands II and III, combined with AgSbF6 as the silver salt, gave low ee’s (Table 1, entries 2−4). Other digold(I) complexes of atropochiral SEGPHOS-diphosphines, such as IV or V, triggered low to moderate enantioselectivities (entries 5 and 6). The use of the (i-Pr-MeO-BIPHEP)(AuCl)2 precatalyst VI led to a moderate 11% ee (entry 7). The first promising results were obtained with the ((R)-DTBM-MeO-BIPHEP)(AuCl)2 precatalyst VII (entry 8, 53% yield, 73% ee), showing the huge impact of the phosphorus substituents of the diphosphine on the reaction outcome. Encouraged by this result, we retained precatalyst VII and screened different silver salts under the same reaction conditions (toluene as the solvent, room temperature) (entries 8−12). The reaction reached 72% yield and 78% ee using silver triflate (entry 12). Finally, a solvent screening (entries 12−16) revealed that mesitylene is the best solvent for this reaction, giving the chiral tetrahydroindolizine derivative 4 in 81% isolated yield and 84% ee (entry 16). Neither decrease of the reaction temperature to 10 °C (entry 17) nor variation of the reaction concentration improved this result. After optimization of the enantioselective Au(I)-catalyzed cyclization reaction, the first steps of the total synthesis of (R)(−)-rhazinilam have been performed, as shown in Scheme 1.

allene-functionalized pyrrole iv. This transformation will establish the absolute configuration of the stereogenic quaternary carbon center of iii. This step has been inspired by the diastereoselective gold-catalyzed 6-exo-trig hydroarylation reaction developed by Nelson for the synthesis of (−)-rhazinilam,5b which involved, however, an enantioenriched allene as the starting material. The method led to (R)(−)-rhazinilam in 11 steps, 19.8% overall yield, and 94% de. With our retrosynthetic analysis in mind, we have investigated the cycloisomerization of pyrrole 3 under gold(I) catalysis (Table 1). Gold catalysis is known to be a highly Table 1. Optimization of the Enantioselective Gold(I)Catalyzed Cycloisomerization of 3

entry c

1 2c 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17e

[LAuCl] Ph3PAuCl I II III IV V VI VII VII VII VII VII VII VII VII VII VII

X OTf SbF6 SbF6 SbF6 SbF6 SbF6 SbF6 SbF6 PF6 BF4 NTf2 OTf OTf OTf OTf OTf OTf

solvent toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene CH2Cl2 PhCF3 xylene mesitylene mesitylene

yielda (%) 97 39 83 68 61 64 44 53 66 62 84 72 64 97 73 81d 63

eeb (%)

d

5 2 11 2 41 11 73 76 78 62 78 36 65 81 84 80

Scheme 1. Synthesis of the 5,6,7,8-Tetrahydroindolizine 5

a

Yields were determined by 1H NMR using trimethoxybenzene as internal standard. bDetermined by HPLC on a chiral stationary phase, on compound 5 (see Scheme 1 for synthetic details). c5 mol % of silver salt. dIsolated yield at a 0.05 mmol scale. eAt 10 °C.

Starting from the commercially available or readily prepared 1-(3-bromopropyl)-1H-pyrrole, addition of the corresponding Grignard reagent to pent-2-yn-1-yl methanesulfonate, in the presence of 8 mol % of CuCN and 16 mol % of LiBr, the conjugate nucleophilic substitution furnished the desired pyrrole−allene substrate 3 in quantitative yield on a multigram scale. Next, the reaction conditions described in Table 1, entry 16, being satisfactory in terms of both yield and enantioselectivity, a key point in the context of this total synthesis was the larger scale applicability of the method. Consequently, the enantioselective gold-promoted cycloisomerization of 3 was performed on a 1 mmol scale with the [(R)-DTBM-MeOBIPHEP-(AuCl)2/AgOTf] catalytic system under the opti-

powerful tool for the synthesis of polycyclic molecules via cycloisomerization of unsaturated substrates.6 Several applications to the synthesis of complex natural products demonstrate the maturity attained nowadays by these methods.7 Furthermore, the recent development of efficient chiral gold catalysts8 has increased significantly the synthetic potential of gold 4795

DOI: 10.1021/acs.orglett.7b02210 Org. Lett. 2017, 19, 4794−4797

Letter

Organic Letters

knowledge, this example represents the first application of this hydrocarboxylation method in total synthesis. The end-game procedure (Scheme 3) starts with a carefully optimized procedure, enabling the saponification, the HCl-

mized conditions. The 6-exo-trig cyclization reaction afforded the desired chiral 5,6,7,8-tetrahydroindolizine 4 in 89% yield (156 mg) and 83% ee. Thus, the isolated yield and enantioselectivity are approximately the same after a 20-fold scale-up of the reaction. After the efficient formation of this key intermediate displaying the required all-carbon quaternary stereogenic center, the pyrrole ring was stabilized by introduction of a methyl carboxylate function, according to the literature strategy.5a,b The tetrahydroindolizine ester 5 was obtained in 94% yield via the two-step, one-pot procedure in Scheme 1. It proved to be easier to handle and more stable toward oxidation than its unsubstituted precursor 4. Consequently, the enantioselectivities were measured at this stage using HPLC with a chiral stationary phase. The following three steps of the total synthesis of (R)(−)-razinilam are displayed in Scheme 2. To install the aniline

Scheme 3. Total Synthesis of (−)-Rhazinilam 1

Scheme 2. Synthesis of Intermediate 8

catalyzed decarboxylation of the pyrrole−methyl ester protecting group and the removal of the formamide moiety of compound 8 to recover the amino acid 9 in a simple operation. Toward this goal, the ester 8 was reacted in methanol in the presence of sodium hydroxide and then the mixture was acidified to promote decarboxylation. Under these reaction conditions, esterification of the propanoic side chain also occurred. Additional exposure to a potassium hydroxide solution finally furnished the desired carboxylic acid 9. The final lactamization step was then accomplished using classical conditions (EDC, HOBt, TEA), which led to (−)-rhazinilam 1 in 45% yield over the last two steps.14 Thus, the strategy developed in this study (Schemes 1−3) proceeds in nine chemical steps and affords (−)-rhazinilam in 20% overall yield. The key gold(I)-catalyzed enantioselective 6exo-trig cyclization of substrate 3 yields the tetrahydroindolizine 4 in 89% yield and 83% enantiomeric excess. (−)-Rhazinilam is obtained then, with the same enantiomeric excess, through the seven-step sequence described. This novel synthetic pathway is to date the shortest enantioselective total synthesis of (−)-rhazinilam.

moiety, a regioselective electrophilic iodination of 5 was first carried out, leading to 6 in 75% yield. A Suzuki−Miyaura coupling between 6 and the N-unprotected 2-aminophenylpinacol boronate was next performed. The reaction was carried out with [Pd(OAc)2/SPhos] (SPhos = 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) as the catalyst, K3PO4 as the base, in DMSO at 120 °C for 4 h. It delivered the known5a coupling product 7 in 75% yield. Changing either the palladium precursor or the phosphine ligand [PdCl2SPhos2, Pd(PPh3)4] or the base (NaHCO3, Na2CO3, Cs2CO3) did not improve the isolated yield.9 The next step, namely the palladium-catalyzed hydrocarboxylation of the vinyl moiety of 7 to create the propanoic acid unit, was undertaken under Pd catalysis using the very efficient and robust reaction conditions developed by Shi.10 Our attention was attracted by Shi’s method since it uses a formate as a user-friendly CO surrogate instead of the toxic and difficult to handle CO gas, as in the Sames approach.5a Furthermore, if a number of methods have been developed for the carbonylation of aryl and alkene groups on simple substrates,11 applications of this key reaction to the synthesis of complex natural products remain rare.12 Accordingly, the reaction of 7 with stoichiometric amounts of formic acid and phenyl formate, in the presence of a catalytic amount of [Pd(OAc)2/dppf] (dppf = 1,1′-ferrocenediyl-bis(diphenylphosphine) in toluene, afforded the desired propanoic acid 8 in 95% yield as its formamide adduct.13 To the best of our

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02210. Experimental procedures and full spectroscopic data for all new compounds (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Arnaud Voituriez: 0000-0002-7330-0819 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We acknowledge the support of the Institut de Chimie des Substances Naturelles (ICSN) and the Centre National de la Recherche Scientifique (CNRS). 4796

DOI: 10.1021/acs.orglett.7b02210 Org. Lett. 2017, 19, 4794−4797

Letter

Organic Letters

■

1, 28. (g) Grigg, R.; Mutton, S. P. Tetrahedron 2010, 66, 5515. (h) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1. (12) For reviews on the application of carbonylation reactions in total synthesis, see: (a) Bai, Y.; Davis, D. C.; Dai, M. J. J. Org. Chem. 2017, 82, 2319. (b) Gehrtz, P. H.; Hirschbeck, V.; Ciszek, B.; Fleischer, I. Synthesis 2016, 48, 1573. (13) For representative examples of N-formylation of amines with aromatic formates, see: (a) Yale, H. J. Org. Chem. 1971, 36, 3238. (b) Batuta, S.; Begum, N. A. Synth. Commun. 2017, 47, 137. (c) Shen, G.; Wang, M.; Welch, T. R.; Blagg, B. S. J. J. Org. Chem. 2006, 71, 7618. (14) The spectral data and the negative value for the optical rotation of the product 1 were consistent with previously reported data of (R)(−)-rhazinilam (ref 5). The enantiomeric excess of compound 1 was measured by HPLC on a chiral stationary phase (see the Supporting Information).

REFERENCES

(1) (a) Linde, H. H. A. Helv. Chim. Acta 1965, 48, 1822. (b) Banerji, A.; Majumder, P. L.; Chatterjee, A. Phytochemistry 1970, 9, 1491. (c) Thoison, O.; Guénard, D.; Sévenet, T.; Kan-Fan, C.; Quirion, J. C.; Husson, H. P.; Deverre, J. R.; Chan, K. C.; Potier, P. C. R. Acad. Sci. Paris II 1987, 304, 157. (d) De Silva, K. T.; Ratcliffe, A. H.; Smith, G. F.; Smith, G. N. Tetrahedron Lett. 1972, 13, 913. (2) (a) David, B.; Sévenet, T.; Morgat, M.; Guénard, D.; Moisand, A.; Tollon, Y.; Thoison, O.; Wright, M. Cell Motil. Cytoskeleton 1994, 28, 317. (b) David, B.; Sévenet, T.; Thoison, O.; Awang, K.; Pais, M.; Wright, M.; Guénard, D. Bioorg. Med. Chem. Lett. 1997, 7, 2155. (c) Dupont, C.; Guénard, D.; Tchertanov, L.; Thoret, S.; Guéritte, F. Bioorg. Med. Chem. 1999, 7, 2961. (d) Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.; Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2007, 70, 1783. (−)-Rhazinilam 1 showed in vitro cytotoxicity against various cancer cells but no in vivo activity, probably because of the formation of less active metabolites after oxidation of 1 by human liver microsomes; see: (e) Baudoin, O.; Guénard, D.; Guéritte, F. Mini-Rev. Org. Chem. 2004, 1, 333. (f) Décor, A.; Bellocq, D.; Thoison, O.; Lekieffre, N.; Chiaroni, A.; Ouazzani, J.; Cresteil, T.; Guéritte, F.; Baudoin, O. Bioorg. Med. Chem. 2006, 14, 1558. (3) Reviews: (a) Neier, R.; Kholod, I.; Vallat, O.; Buciumas, A. M. Heterocycles 2011, 82, 917. (b) Crossley, S. W. M.; Shenvi, R. A. Chem. Rev. 2015, 115, 9465. (4) Racemic syntheses: (a) Ratcliffe, A. H.; Smith, G. F.; Smith, G. N. Tetrahedron Lett. 1973, 14, 5179. (b) Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2000, 122, 6321. (c) Magnus, P.; Rainey, T. Tetrahedron 2001, 57, 8647. (d) Bowie, A. L.; Hughes, C. C.; Trauner, D. Org. Lett. 2005, 7, 5207. (e) Gu, Z. H.; Zakarian, A. Org. Lett. 2010, 12, 4224. (f) McMurray, L.; Beck, E. M.; Gaunt, M. J. Angew. Chem., Int. Ed. 2012, 51, 9288. (g) Yang, Y.; Bai, Y.; Sun, S. Y.; Dai, M. J. Org. Lett. 2014, 16, 6216. (h) Su, Y.; Zhou, H.; Chen, J.; Xu, J.; Wu, X.; Lin, A.; Yao, H. Org. Lett. 2014, 16, 4884. (5) Asymmetric syntheses: (a) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900. (b) Liu, Z.; Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 10352. (c) Banwell, M. G.; Beck, D. A. S.; Willis, A. C. ARKIVOC 2006, 163. (d) Sugimoto, K.; Toyoshima, K.; Nonaka, S.; Kotaki, K.; Ueda, H.; Tokuyama, H. Angew. Chem., Int. Ed. 2013, 52, 7168. (e) Gualtierotti, J. B.; Pasche, D.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2014, 53, 9926. (f) Sugimoto, K.; Miyakawa, Y.; Tokuyama, H. Tetrahedron 2015, 71, 3619. (g) Dagoneau, D.; Xu, Z.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 760. (6) (a) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896. (b) Arcadi, A. Chem. Rev. 2008, 108, 3266. (c) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (d) Chiarucci, M.; Bandini, M. Beilstein J. Org. Chem. 2013, 9, 2586. (e) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028. (7) (a) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41, 2448. (b) Fürstner, A. Acc. Chem. Res. 2014, 47, 925. (c) Zhang, Y.; Luo, T.; Yang, Z. Nat. Prod. Rep. 2014, 31, 489. (d) Pflasterer, D.; Hashmi, A. S. K. Chem. Soc. Rev. 2016, 45, 1331. (8) (a) Pradal, A.; Toullec, P. Y.; Michelet, V. Synthesis 2011, 2011, 1501. (b) Marinetti, A.; Jullien, H.; Voituriez, A. Chem. Soc. Rev. 2012, 41, 4884. (c) López, F.; Mascareñas, J. L. Beilstein J. Org. Chem. 2013, 9, 2250. (d) Wang, Y.-M.; Lackner, A. D.; Toste, F. D. Acc. Chem. Res. 2014, 47, 889. (e) Zi, W. W.; Toste, F. D. Chem. Soc. Rev. 2016, 45, 4567. (9) For other examples of iodation/Suzuki−Miyaura coupling reactions in the synthesis of 1, see ref 5a,c. (10) Wang, Y.; Ren, W.; Li, J.; Wang, H.; Shi, Y. Org. Lett. 2014, 16, 5960. (11) For reviews on carbonylations with CO surrogates, see: (a) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5580. (b) Wu, L.; Liu, Q.; Jackstell, R.; Beller, M. Angew. Chem., Int. Ed. 2014, 53, 6310. (c) Friis, S. D.; Lindhardt, A. T.; Skrydstrup, T. Acc. Chem. Res. 2016, 49, 594. (d) Cao, J.; Zheng, Z. J.; Xu, Z.; Xu, L. W. Coord. Chem. Rev. 2017, 336, 43. For reviews on carbonylation with CO gas, see: (e) Kiss, G. Chem. Rev. 2001, 101, 3435. (f) Brennfuhrer, A.; Neumann, H.; Beller, M. ChemCatChem 2009, 4797

DOI: 10.1021/acs.orglett.7b02210 Org. Lett. 2017, 19, 4794−4797