Catalytic Asymmetric Total Syntheses of Naturally Occurring

Jul 20, 2018 - Using this strategy, collective total syntheses of Amaryllidaceae alkaloids such as (−)-epi-elwesine (1b), (−)-crinine (1c), (−)-...
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Catalytic Asymmetric Total Syntheses of Naturally Occurring Amarylidaceae Alkaloids, (−)-Crinine, (−)-epi-Crinine, (−)-Oxocrinine, (+)-epi-Elwesine, (+)-Vittatine, and (+)-epi-Vittatine* Mrinal K. Das, Nivesh Kumar, and Alakesh Bisai* Department of Chemistry, IISER Bhopal, Bhopal Bypass Road, Bhauri, Bhopal - 462 066, Madhya Pradesh, India

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ABSTRACT: An expeditious approach to catalytic enantioselective total syntheses of crinine-type Amaryllidaceae alkaloids has been accomplished via a Pd-catalyzed enantioselective decarboxylative allylation of allylenol carbonates as a key step (up to 96% ee). Using this strategy, collective total syntheses of Amaryllidaceae alkaloids such as (−)-epi-elwesine (1b), (−)-crinine (1c), (−)-epi-crinine (1e), (−)-oxocrinine (1f), and (−)-buphanisine (1d) have been accomplished. Gratifyingly, naturally occurring Amaryllidaceae alkaloids such as (+)-vittatine (1g), (+)-epi-vittatine (1h), and (+)-epi-elwesine (1i) [enantiomers of (−)-1c, (−)-1e, and (−)-1b, respectively] have also been achieved by switching the antipode of ligand used in the catalytic enantioselective step.

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center as present in crinine (1c) and related alkaloids.6 However, most of the literature reported strategies involve racemic products6 except few asymmetric variants.7−9 In this regard, the most fascinating way to devise concise strategies for the total syntheses of either enantiomer of these polycyclic natural products would be via catalytic enantioselective processes. Among them, the known catalytic method for the enantioselective construction of a polycyclic framework possessing all-carbon quaternary centers involves a key Pd(0)catalyzed decarboxylative allylation reaction to install such structures.10−12 Toward this end, Trost et al. (2002)13a have reported an elegant Pd(0)-catalyzed asymmetric decarboxylative allylic alkylation of allyl enol carbonates (3a in 90.5% ee using L8; Scheme 1) and, subsequently, allylation of 2-phenylcyclohexanone 4 (3a in 88% ee using L6, 2009). However, when it comes to the utilization of electron-rich aromatics, Kim et al.13c have reported that only 66% ee was obtained for 3b sharing 3,4-diOMePh as an aryl group using 5.5 mol % of L8 (Scheme 1), clearly indicating that utilization of such processes with a substrate sharing electron-donating aromatic rings is indeed a considerable challenge that is worth testing. Herein, based on Trost’s elegant report,13a,b we envisioned an enantioselective strategy, which takes advantage of an efficient Pd(0)-catalyzed decarboxylative allylation reaction via a DYKAT to set an allcarbon quaternary stereogenic center14,15 required for the Amaryllidaceae alkaloids.

wing to their significant bioactivities such as antitumor, antiviral, and antiacetylcholinesterase activities and fascinating structural diversity, Amaryllidaceae alkaloids (1a− j, Figure 1) have been long-standing synthetic targets.1,2

Figure 1. Selected Amaryllidaceae alkaloids 1a−i.

(−)-Crinine (1c) is a representative alkaloid of the Amaryllidaceae family, which was isolated from the bulbs of Crinum species from South Africa in 1995 (Figure 1), and displays significant biological activity.1,3 Interestingly, another alkaloid of this family, (+)-vittatine (1g), bearing opposite configuration to that of (−)-crinine (1c) also has been isolated.4 Structurally, they share a 5,10b-ethanophenathridine skeleton with vicinal quaternary and tertiary carbon stereocenters and a fused pyrrolidine ring, which poses a considerable synthetic challenge (Figure 1).5 This came as a driving force for the development of many elegant synthetic approaches for the construction of the 5,10bethanophenathridine skeleton bearing an all-carbon quaternary © 2018 American Chemical Society

Received: May 30, 2018 Published: July 20, 2018 4421

DOI: 10.1021/acs.orglett.8b01703 Org. Lett. 2018, 20, 4421−4424

Letter

Organic Letters

Table 1. Optimization of Enantioselective DcA Reactiona,b

Scheme 1. Literature Reports on Catalytic Enantioselective Allylation

Our retrosynthetic strategy to synthesize the core structure of 1b−f is shown in Scheme 2. We envisioned that cis-3aScheme 2. Retrosynthetic Analysis of 1 and Our Hypothesis

aryloctahydroindole scaffold 5 of Amaryllidaceae alkaloids 1b−f could be obtained from cyclohexanone 8 via the intermediate enone 7, which in turn could be accessed from an efficient Pd(0)-catalyzed decarboxylative allylation reaction of enolcarbonates 9 via enolate 1014 (Scheme 2). At the outset, we selected allylenolcarbonate 9a (1 equiv) as the substrate for initial studies (Table 1). We have utilized a number of enantioenriched phosphine-oxazoline ligands L1− L416 and C2-symmetric phosphine-carboxamide Trost ligands L5−L817 (Table 1). Initially, we found that 2.5 mol % Pd2(dba)3 and 7.5 mol % PHOX-ligands such as i-PrPHOX (L1), i-BuPHOX (L2), s-BuPHOX (L3), and t-BuPHOX (L4) afforded product 5a in the range 24−30% ee at room temperature under additive-free conditions (entries 1−5). The use of 5.5 mol % ligands L5−L8 afforded 8a with 66% ee, 74% ee, 52% ee, and −82% ee, respectively, at room temperature (entries 6−9). With L8 as the ligand of choice, we further carried out optimization with different solvents and temperatures. It was found that 7.5 mol % L8 provided 85% ee of 8a (entry 11). Among various solvents screened, it was found that toluene is superior over other solvents (entries 12−21). Following exhaustive optimization (entries 11−21), it was found that 2.5 mol % Pd2(dba)3 in combination with 7.5 mol % of L8 in toluene at −10 °C afforded 8a in 97% yield with 92% enantioselectivity (entry 14, standard conditions). Therefore, based on our optimization, we selected 2.5 mol % Pd2(dba)3 in combination with 7.5 mol % of L8 in toluene at −10 °C for

s. no.

ligand (mol %)

solvent

temp (°C)

time (h)

yield (%)

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

5.5 (L1) 5.5 (L2) 5.5 (L3) 5.5 (L4) 5.5 (L4) 5.5 (L5) 5.5 (L6) 5.5 (L7) 5.5 (L8) 5.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8) 7.5 (L8)

Et2O Et2O Et2O Et2O PhMe Et2O Et2O Et2O Et2O PhMe PhMe Et2O PhMe PhMe PhMe MTBE C6H6 xylene THF DCE DME CHCl3

25 25 25 25 25 25 25 25 25 25 25 0 0 −10 −20 −10 −10 −10 −10 −10 −10 −10

20 22 22 19 17 30 28 28 25 24 24 28 29 32 35 30 33 40 24 40 30 28

64 55 69 75 78 90 89 81 84 93 93 85 95 97 79 91 81 61 66 50 22 40

28 (S) 29 (S) 24 (S) 30 (S) 27 (S) 66 (S) 74 (S) 52 (S) 82 (R) 82 (R) 85 (R) 86 (R) 90 (R) 92 (R) 90 (R) 90 (R) 85 (R) 79 (R) 73 (R) 53 (R) 20 (R) 49 (R)

a

Reactions were carried out with 0.20 mmol of 9a in the presence of 2.5 mol % Pd2(dba)3 in combination with L1−L8 in 3 mL of solvents in a screw capped vial. bIsolated yields. cEnantioselectivities were determined by using chiral HPLC columns.

further substrate scope study. As shown in Scheme 3, our optimized conditions could be extended to a variety of enolcarbonates of type 9 with functionalization on the aromatic scaffolds. As a result, a wide range of cyclohexanones bearing all-carbon-quaternary centers at the C2-position are obtained in good to excellent enantioselectivities with high yields (8a−l; Scheme 3). We then proceeded to apply the new method for the asymmetric total synthesis of (−)-epi-elwesine (1b) (Scheme 4). Toward this end, (−)-8a was converted to enone (−)-7a in 92% yield over 2 steps viz. α-bromination using PTAB (phenyl trimethylammonium tribromide) followed by elimination using DBU. Enone (−)-7a upon oxidation with H2O2 in the presence of NaOH afforded (−)-13 as the sole diastereomer,18 which was reduced regioselectively to afford (−)-6a in 85.6% 4422

DOI: 10.1021/acs.orglett.8b01703 Org. Lett. 2018, 20, 4421−4424

Letter

Organic Letters Scheme 3. Substrate Scope of DcA of Enolcarbonates 9

Scheme 5. Total Synthesis of Naturally Occurring (−)-Crinine (1c), (−)-epi-Crinine (1e), (−)-Oxocrinine (1f), and (−)-Buphanisine (1d)

Scheme 4. Total Synthesis of (−)-epi-Elwesine (1b)

synthesis of (−)-oxocrinine (1f). Since, the total synthesis of 1d is known from (−)-crinine (1c) in one step, our effort culminated in the formal total synthesis of (−)-buphanisine (1d). Furthermore, in our search for total syntheses of naturally occurring (+)-vittatine (1g) and (+)-epi-vittatine (1h), we carried out a Pd-catalyzed enantioselective decarboxylative allylation of 9a in the presence of (R,R)-L8 to afford (+)-8a in 94% yield with 93% ee (Scheme 6). Utilizing the reaction sequence shown in Schemes 4 and 5, we have completed the total syntheses of naturally occurring (+)-vittatine (1g) and (+)-epi-vittatine (1h).

yield over 2 steps. TBS-protection of (−)-6a afforded (−)-14, followed by oxidative cleavage of the olefin functionality affording γ-keto-aldehyde (−)-15 in 85% yield over 3 steps. A reductive amination of (−)-15 with ammonium acetate in the presence of NaBH3CN afforded cis-3a-aryloctahydroindole (−)-16, which was subsequently reacted with Eschenmoser’s salt to afford (−)-17 in 76% yield over 2 steps. Next, the total synthesis of (−)-epi-elwesine (1b) was achieved by TBS-group removal (Scheme 4). Later, we moved ahead for the collective total synthesis of Amaryllidaceae alkaloids 1a−j shown in Figure 1. Toward this end, cis-3a-aryloctahydroindole (−)-16 was converted to ketone (−)-20 in 72% yield over 3 steps viz. N-Boc-protection, TBS-romoval, and DMP oxidation (Scheme 5). The latter was transformed to enone (−)-21 in 80% yield via Sagusa−Itoh oxidation [TMS enol ether was reacted with 10 mol % Pd(OAc)2 under an O2-atmosphere].19 Enone (−)-21 was reduced under Luche conditions to afford cis-3a-arylhexahydroindoles (−)-22 and (−)-23 in 95% yield with 3:1 dr in favor of (−)-22. Gratifyingly, both these diastereomers were separable via column chromatography. The only thing left at this stage was to craft the tetracyclic skeleton of Amaryllidaceae alkaloids following a Pictet−Spenglar cyclization.20 This was achieved by Boc-removal of allylalcohols (−)-22 and (−)-23 followed by reaction with formalin in the presence of HCl to complete the total synthesis of (−)-crinine (1c) (79% over 2 steps) and (−)-epi-crinine (1e) (81% over 2 steps). Oxidation of (−)-crinine (1c) via MnO2-oxidation ensures the total

Scheme 6. Total Synthesis of Naturally Occurring (+)-Vittatine (1g), (+)-epi-Vittatine (1h), and (+)-epiElwesine (1i)

In summary, a concise strategy for catalytic enantioselective total syntheses of Amaryllidaceae alkaloids, (−)-elwesine (1b), (−)-crinine (1c), (−)-vittatine (1e), (−)-oxocrinine (1f), and (−)-buphanisine (1d), has been accomplished. The key strategy in this report is a Pd(0)-catalyzed asymmetric decarboxylative allylation reaction of an allylenolcarbonate to obtain enantioenriched 2-aryl 2′-allycyclohexanone bearing an all-carbon quaternary center at the C2-position. Importantly, both enantiomers of naturally occurring Amaryllidaceae alkaloids have been achieved by switching the antipode of the ligand used in the catalytic enantioselective step (93% ee). 4423

DOI: 10.1021/acs.orglett.8b01703 Org. Lett. 2018, 20, 4421−4424

Letter

Organic Letters

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Shubhashish; Bisai, A. Synthesis 2016, 48, 2093. (j) Raghavan, S.; Ravi, A. Org. Biomol. Chem. 2016, 14, 10222. (k) Gao, N.; Banwell, M.; Willis, A. C. Org. Lett. 2017, 19, 162 and references cited therein. (7) For representative asymmetric syntheses, see: (a) Nishimata, T.; Sato, Y.; Mori, M. J. Org. Chem. 2004, 69, 1837. (b) Zuo, X.-D.; Guo, S.-M.; Yang, R.; Xie, J.-H.; Zhou, Q.-L. Chem. Sci. 2017, 8, 6202. (c) Du, K.; Yang, H.; Guo, P.; Feng, L.; Xu, G.; Zhou, Q.; Chung, L. W.; Tang, W. Chem. Sci. 2017, 8, 6247. (d) Gao, Y. R.; Wang, D.-Y.; Wang, Y.-Q. Org. Lett. 2017, 19, 3516 and references cited therein. (8) For a chiral-pool strategy from carbohydrates, see: (a) Baldwin, S. W.; Debenham, J. S. Org. Lett. 2000, 2, 99. (b) Bohno, M.; Imase, H.; Chida, N. Chem. Commun. 2004, 1086. (c) Findlay, A. D.; Banwell, M. G. Org. Lett. 2009, 11, 3160 (chemoenzymatic resolution). (9) (a) Lyle, R. E.; Kielar, E. A.; Crowder, J. R.; Wildman, W. C. J. Am. Chem. Soc. 1960, 82, 2620. (b) Viladomat, F.; Bastida, J.; Codina, C.; Campbell, W. E.; Mathee, S. Phytochemistry 1995, 40, 307. (10) For a general method for the construction of quaternary carbon stereocenters, see the following reviews: (a) Hong, A. Y.; Stoltz, B. M. Eur. J. Org. Chem. 2013, 2013, 2745. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5363. (c) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (d) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (11) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. (b) Reeves, C. M.; Behenna, D. C.; Stoltz, B. M. Org. Lett. 2014, 16, 2314. (c) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740. (d) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A., Jr; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. - Eur. J. 2011, 17, 14199. (12) For Pd(0)-catalyzed sequential allylations, see: (a) Enquist, J. A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228. (b) Trost, B. M.; Osipov, M. Angew. Chem., Int. Ed. 2013, 52, 9176. (c) Ghosh, S.; Bhunia, S.; Kakde, B. N.; De, S.; Bisai, A. Chem. Commun. 2014, 50, 2434. (13) (a) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem., Int. Ed. 2002, 41, 3492. (b) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343. (c) Park, J.; Kim, Y. K.; Kim, G. Bull. Korean Chem. Soc. 2011, 32, 3141. (14) For reviews, see: (a) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59. (b) Steinreiber, J.; Faber, K.; Griengl, H. Chem. Eur. J. 2008, 14, 8060 and references cited therein. (15) (a) Ghosh, S.; Chaudhuri, S.; Bisai, A. Chem. - Eur. J. 2015, 21, 17479. (b) Roy, A.; Das, M. K.; Chaudhuri, S.; Bisai, A. J. Org. Chem. 2018, 83, 403. (16) PHOX ligands: (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336. (b) Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth. 2009, 86, 181. (17) Trost ligands L5−L7: (a) Trost, B. M.; Van Vranken, D. L. Angew. Chem., Int. Ed. Engl. 1992, 31, 228. (b) Trost, B. M.; Thaisrivongs, D. A.; Hartwig, J. J. Am. Chem. Soc. 2011, 133, 12439. (18) The relative stereochemistry of epoxide (−)-13 was proven unambiguously by X-ray analysis (CCDC No. 1853119) of (±)-13 (synthesized from (±)-7a in 92% yield using a similar procedure as shown in Scheme 4). (19) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011. (b) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130, 7222. (20) For asymmetric synthesis of unnatural crinane 1a via Pictet− Spengler cyclization, see: (a) Kano, T.; Hayashi, Y.; Maruoka, K. J. Am. Chem. Soc. 2013, 135, 7134. (b) Pupo, G.; Properzi, R.; List, B. Angew. Chem., Int. Ed. 2016, 55, 6099. (c) Bao, X.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2018, 57, 1995.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01703. Experimental procedures, additional reaction optimization, details of stoichiometric reactions, spectroscopic data for all new compounds (PDF) Accession Codes

CCDC 1853119 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alakesh Bisai: 0000-0001-5295-9756 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the SERB, DST [EMR/2016/000214], MoES [09-DS/11/2018-PC-IV], and CSIR [02(0295)/17/ EMR-II], Govt. of India, is gratefully acknowledged. M.K.D. and N.K. thank the CSIR for senior research fellowships (SRFs). We sincerely thank Prof. Vinod K. Singh, Director, IISER Bhopal for excellent research facilities.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01703 Org. Lett. 2018, 20, 4421−4424