DOI: 10.1002/chem.201405246

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A Stereoselective Switch: Enantiodivergent Approach to the Synthesis of Isoflavanones Robert Doran,[a] Michael P. Carroll,[a] Ramulu Akula,[a] Bryan F. Hogan,[a] Marta Martins,[b] Samus Fanning,[b] and Patrick J. Guiry*[a] reported the enantioselective Cu-catalyzed a-arylation of silylN-acyloxazolidinones with diaryliodonium salts using bisoxazoline ligands.[7] Zhou reported the Pd-catalyzed a-arylation of silyl ketene acetals to form tertiary a-aryl esters[8] and, more recently, the arylation of Sn-enolates or Li-enolates to produce aaryl ketones[9] or lactones.[10] All of these approaches introduce the aryl group during the enantiodetermining step. Isoflavanones are a member of the flavonoid class of secondary plant metabolites whose natural occurrence is limited chiefly to the Leguminosae family of flowering plants.[11] Isoflavanones display a range of biological activity and have been shown to act as immunosuppressive agents,[12] possess antibacterial[13] and anti-cancer[14] activity and act as a-glucosidase inhibitors.[15] To the best of our knowledge, the synthesis of any naturally occurring isoflavanones in high enantioselectivity has yet to be reported. A common feature of many isoflavanones isolated from nature is the presence of an oxygen-containing group in the 7 position with additional oxygen-containing groups often found on the 2’ and 4’ positions (Figure 1).

Abstract: A modular six-step asymmetric synthesis of two naturally occurring and three non-natural isoflavanones containing tertiary a-aryl carbonyls is reported. This synthetic route, utilising a Pd-catalyzed decarboxylative asymmetric protonation, produces isoflavanones in excellent enantioselectivities from 76–97 %. A switch in the sense of stereoinduction was observed when different H + sources were employed, showing the first example of dual stereocontrol in an asymmetric protonation reaction. The first enantioselective synthesis of the naturally occurring isoflavanones sativanone and 3-o-methylviolanone has been accomplished.

The asymmetric synthesis of a-aryl carbonyl-containing compounds has been a key area of research over the last decade, due to the prevalence of this structural motif in biologically active natural products, such as isoflavanones and active pharmaceutical ingredients.[1] A number of a-arylation strategies have been developed to generate quaternary stereocenters with high enantiomeric excesses.[2] Unfortunately, due to the requirement of basic conditions, most of these examples are unsuitable for the synthesis of enantioenriched tertiary a-aryl carbonyls that contain an acidic a-proton.[3] To date, there are a limited number of reports on the use of asymmetric a-arylation to generate tertiary stereocenters. Jørgensen developed an organocatalytic enantioselective a-arylation of aldehydes with quinones.[4] Fu reported Ni-catalyzed Kumada and Negishi coupling reactions using bisoxazoline ligands to generate aaryl ketones.[5] MacMillan described enantioselective a-arylations of aldehydes with diaryliodonium salts in the presence of an organocatalyst.[6] Also, MacMillan and Gaunt independently

Figure 1. Common substitution patterns in naturally occurring isoflavanones.

Two examples of these types of isoflavanones are the naturally occurring sativanone (1 a) and 3-O-methylviolanone (1 b). Sativanone (1 a) was first isolated in 1973 by Donnelly from the heart wood of Dalbergia stevensonii[16] and has been shown to display activity against human cancer cell lines as well as antibacterial activity.[17] There has been one reported racemic synthesis of sativanone (1 a) by a four-step synthesis involving intramolecular cyclisation to form the B ring of the isoflavanone.[18] 3-O-Methylviolanone, first isolated in 1975 from Dalbergia cearensis,[19] has displayed anti-inflammatory activity and anti-cancer activity.[17b, 20] To date, a synthesis of 3-O-methylviolanone has yet to be reported. Unsurprisingly, due to their potential as medicinal agents, there have been many reported synthetic routes to isoflavanones, including the reduction of corresponding isoflavones,[21] benzylic oxidation of isoflavans,[22] gold-catalyzed annula-

[a] Dr. R. Doran, Dr. M. P. Carroll, Dr. R. Akula, B. F. Hogan, Prof. P. J. Guiry Centre for Synthesis and Chemical Biology School of Chemistry and Chemical Biology University College Dublin Belfield, Dublin 4 (Ireland) E-mail: [email protected] [b] Dr. M. Martins, Prof. S. Fanning UCD Centre for Food Safety School of Public Health Physiotherapy and Population Science University College Dublin Belfield, Dublin 4 (Ireland) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405246. Chem. Eur. J. 2014, 20, 1 – 7

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Communication tions,[23] addition of CO bonds to arynes[24] and palladium-catalyzed a-arylation.[25] Despite the multitude of syntheses reported over the past 70 years, few routes have been shown to be truly modular with respect to substituents on the isoflavanone skeleton and only one route was asymmetric, relying on the use of chiral auxiliaries.[26] Recently we reported the first general catalytic asymmetric synthesis of isoflavanones, which featured a lead-mediated arylation to generate 2, followed by an asymmetric palladium-catalyzed decarboxylative asymmetric protonation to generate the chiral center in 3 (Scheme 1).[27] Having applied this meth-

Scheme 2. Synthesis of isoflavanone precursors 8 a–e. a) i) AlCl3, 3-chloropropionyl chloride, nitrobenzene 0!80 8C; ii) 5 % w/v NaOH, 55 %; b) 1-(bromomethyl)-naphthalene, TBAI, K2CO3, 2-Butanone, D, 94 %; c) allyl cyanoformate, LiHMDS, THF, 78 8C to RT, 62 %.; d) ArPb(OAc)3, pyridine, CHCl3, 40 8C. Scheme 1. Catalytic asymmetric synthesis of isoflavanones. Pd2dba3 = tris(dibenzylideneacetone)dipalladium.

ic groups in the synthesis of natural products and natural product analogues has been well-documented[29] and, using the standard conditions for arylation,[30] common intermediate 7 was arylated with five different aryllead triacetates to provide the isoflavanone precursors 8 a–e in very good yields of 72– 83 %. The isoflavanone precursors 8 a–e were then used in the decarboxylative asymmetric protonation reaction. Recently, palladium-catalyzed decarboxylative reactions have emerged as a powerful tool in organic synthesis.[31] Because of the often mild reaction conditions employed, coupled with the high yields and enantioselectivities attainable, this methodology has been applied in several syntheses[32] and continues to be an area of rapid growth in asymmetric catalysis. Our previously optimized conditions for the decarboxylative asymmetric protonation of isoflavanones substrates were applied to these substrates.[27] Beginning with the 2’,4’,6’(MeO)3C6H2-substituted b-ketoester (8 c), the aryl group that gave the highest levels of enantioselectivity in our previous study, we carried out the reaction to yield the R-enantiomer in 67 % ee (Scheme 3). We then observed a sharp drop in enantio-

odology to the construction of several non-natural isoflavanones, we now wished to expand its scope to include the asymmetric synthesis of naturally occurring isoflavanones that featured oxygenation at the 7 position. We aimed to carry out the first asymmetric synthesis of sativanone (1 a) and the first synthesis of 3-O-methylviolanone (1 b). In addition to the two naturally occurring isoflavanones, we sought to synthesise a number of novel isoflavanones containing a 7-hydroxy substituent and different a-aryl groups: 2’,4’,6’-trimethoxyphenyl (1 c), 2’,6’-dimethoxyphenyl (1 d) and 2’-methoxynaphthyl (1 e), which we felt would be good candidates for biological studies due to their similarities to both 1 a and 1 b (Figure 2).

Figure 2. Naturally occurring isoflavanones sativanone (1 a), 3-O-methylviolanone (1 b) and non-natural isoflavanone targets.

Our synthesis of the 7-hydroxy-substituted isoflavanones 1 a–e had to take into account protection of the hydroxy group due to the likely interference with the synthetic route and, in particular, the key decarboxylative asymmetric-protonation step. The synthesis of 1 a–e could be accomplished by a series of lead-mediated arylations of allyl-b-keto ester 7. This was carried out by Friedel–Crafts acylation, cyclization, NAPprotection (NAP = 2-naphthylmethyl) and subsequent acylation with allyl cyanoformate (Scheme 2).[28] We were able to generate isoflavanone precursors 8 a–e from the allyl-b-keto ester (7) by introducing various aryl groups through the use of aryllead triacetates. The use of aryllead triacetates to introduce aromat&

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Scheme 3. Catalytic asymmetric synthesis of isoflavanones.

selectivity to 25 % for the 2’,3’,4’-(MeO)3C6H2 aryl group (8 b), which was further lowered to effectively racemic using the 2’,4’-(MeO)2C6H3 aryl group (8 a) present in sativanone. At this point, disappointed with the levels of enantioselectivity, we decided to explore different catalytic conditions. Given that the 2

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Communication conversion after 36 h, albeit with a slightly lower ee of 92 %, which suggests that the complex will not turn over sufficiently at room temperature (entry 7 in Table 1). Attempting the reaction at 40 8C led to full conversion in 10 h, with an ee of 84 % (entry 8 in Table 1). Although pleased with this improvement, we thought we could improve the enantioselectivity further using the (S)(CF3)3–tBu–PHOX ligand. Gratifyingly, this increased the ee to 97 % S with an isolated yield of 87 % (entry 9 in Table 1). We then applied the optimized conditions to the other four substrates to obtain ee values ranging from 76 to 97 % and these results are summarized in Scheme 4.

Table 1. Optimization of decarboxylative asymmetric protonation of isoflavanone b-ketoester (8 a).

Entry[a]

Ligand

H + Source

T [8C]

Time

ee [%]

1 2 3 4 5 6 7 8 9

L1 L1 L1 L1 L2 L2 L2 L2 L1

Meldrum’s acid Meldrum’s acid Meldrum’s acid Meldrum’s acid Meldrum’s acid formic acid formic acid formic acid formic acid

7 RT 40 0 RT RT RT 40 40

12 h 12 h 12 h 12 h 12 h 5d 36 h 10 h 10 h

2 (R) 12 (R) 20 (R) 30 14 96[b] 92[c] 84 97

[a] Entries 1–5: Pd2dba3·CHCl3 (5 mol % of Pd), THF; entries 6–9: Pd(OAc)2, 1,4-dioxane, reaction carried out in the presence of 4  powdered molecular sieves. [b] 1H NMR, 60 % conversion. [c] Pd(OAc)2 (1.0 equiv), (S)-tBuPHOX L2 (1.25 equiv).

2’,4’-(MeO)2C6H3 aryl group gave the poorest results, and that we wished to develop an asymmetric synthesis of sativanone, we chose this as our model substrate in an attempt to improve the enantioselectivity (Table 1). We attempted to carry out the reaction using the same reaction conditions at room temperature. Sampling the reaction after 30 min showed complete conversion of starting material with an ee of 21 % of the S-enantiomer. However, when the reaction was sampled again after 12 h, the ee had changed to 12 % of the R-enantiomer and this remained unchanged after further reaction time (entry 2 in Table 1). Following this surprising result, we increased the reaction temperature to 40 8C. This time, after 30 min an ee of 4 % S was observed. Again, after 12 h, this had switched to 20 % R (entry 3 in Table 1). Lowering the reaction temperature to 0 8C led to an increase in ee to 30 % S, which remained unchanged after warming to room temperature (entry 4 in Table 1). We then changed the ligand to (S)-tBu–PHOX L2 (PHOX = diphenylphosphinooxazoline), which gave an ee of 26 % S after 30 min at room temperature, which switched to 14 % S after 12 h (entry 5 in Table 1). At this point, given the difficulty in controlling the enantioselectivity under these conditions, we were eager to test these substrates using the heterogeneous decarboxylative protonation conditions of Pd(OAc)2, (S)-tBu–PHOX L2 with formic acid as the proton source in the presence of molecular sieves.[33] We initially carried out the reaction at room temperature and we observed a significant increase in ee to 96 % S, however, with a low conversion of 50 % after over 5 days (entry 6 in Table 1). Using a stoichiometric quantity of Pd(OAc)2 led to full Chem. Eur. J. 2014, 20, 1 – 7

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Scheme 4. Decarboxylative asymmetric protonation in the synthesis of 7substituted isoflavanones.

The final step of our synthesis was the removal of the NAP group to yield the free hydroxy group of the isoflavanones. Several conditions were screened in order to find a mild method of deprotection that would leave the stereocenter intact.[34] Ultimately, stirring the protected isoflavanones 9 a– e overnight with Pd/C (10 %) in ethyl acetate under 1 atmosphere of hydrogen, resulted in full deprotection of the isoflavanones without erosion of the enantiomeric excess (Scheme 5).

Scheme 5. Deprotection of the NAP-protected isoflavanones.

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Communication The [a]20 D for sativanone 1 a was measured to be + 31.2 (c = 0.50, acetone), the positive rotation indicating that it was the S-enantiomer. This was confirmed by obtaining an X-ray crystal structure of NAP-protected sativanone 9 a.[35] Interestingly, the sense of stereoinduction (S) observed following decarboxylative protonation is opposite to that observed in our previous report, using Meldrum’s acid as the H + source, with isoflavanone substrates without oxygenation at the 7 position of type 3 (Scheme 1). Intrigued by this finding, we reinvestigated the reaction of substrate 2 c using formic acid as the H + source (Scheme 6). This confirmed that the

source in which initial coordination of the Pd0–complex to the allyl group is followed by oxidative insertion and decarboxylation to generate a Pd–enolate. This Pd–enolate is then protonated by Meldrum’s acid.[37] In the case where formic acid is used as a proton source, we carried out some deuterium-labelling studies to determine whether the source of the proton was the OH or the formyl–H (see Scheme 7). The use of HCOOD resulted in 38 % D-incorpo-

Scheme 7. Deuterium-labelling studies.

ration, whereas DCOOH led to no incorporation of deuterium, in line with the previous report by Stoltz.[33] These results suggest that the formyl–H is not the proton source; however, the low level of incorporation using HCOOD is puzzling. To determine if the proton source was expeditious H2O, the catalysis was carried out using DCOOD in the presence of D2O (0.5 equiv). This resulted in the same level of deuterium incorporation as observed using DCOOD alone. The use of acetic acid instead of formic acid led to no reaction. Preliminary 1H NMR spectroscopic studies have been carried out to ascertain whether a Pd–hydride was formed in the presence of formic acid, as has been previously shown,[39] however, this was not observed for the Pd–ligand complex in the presence of formic acid or during the course of the reaction Interestingly, the rates of the reactions are significantly different, such that the Meldrum’s acid reaction is complete in 30 min, whereas the formic acid reaction takes up to 10 h. This may suggest the necessity for a carbopalladation to occur, which is subsequently quenched by formic acid. Alternatively, some pre-coordination of formic acid to the chiral Pd–enolate complex may result in an inner-sphere-type protonation to a different face of the enolate than with Meldrum’s acid. The five isoflavanones synthesised in this report were assayed to determine the antibacterial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA).[40] Unfortunately, none of the compounds showed any significant antibacterial activity. In conclusion, we have reported a modular six-step synthetic sequence to construct isoflavanones with a range of substitutions on the C ring and a free hydroxy group on the 7 position. Key features of this synthesis are the Pb-mediated arylation to allow a variety of aryl groups to be introduced from a common intermediate and the palladium-catalyzed decarboxylative asymmetric protonation to generate a tertiary a-aryl carbonyl. Initial enantioselectivities obtained were poor to moderate. Optimization of the conditions led to an increase in

Scheme 6. Enantiodivergence observed with different H + sources. A: Pd2dba3·CHCl3 , L1, Meldrum’s acid, THF, 7 8C, 0.5 h. B: Pd(OAc)2, L1, formic acid, 4  molecular sieves, dioxane, 40 8C, 10 h.

enantiodivergence of this process was retained as we observed the formation of (R)–3 c in 91 % ee and 91 % yield.[36] This finding shows a remarkable switch in enantioselectivity from 92 % R to 91 % S as a result of changing the H + source. In the previous reports by Stoltz and co-workers, the sense of stereoinduction observed was different for monocyclic substrates versus fused aromatic systems; for example, cyclohexanone versus tetralone. This was consistent with both the formic acid and Meldrum’s acid methods.[33, 37] However, we have observed the opposite sense of stereoinduction on the same substrate. The ability to obtain both enantiomers of a particular chiral molecule using the same chiral ligand is a valuable methodology in organic synthesis and represents a significant challenge. Previously, dual stereocontrol has been achieved by variation of catalyst substituents, changing of the metal center or precursor and changing the reaction solvent or temperature. In this instance we have shown that these factors are not the cause of our observed switch in enantioselectivity. We are unaware of any other reports of dual stereocontrol in an asymmetric protonation reaction in which the same chiral ligand is used with a different achiral proton donor to impart dual stereocontrol.[38] The key to the switch is most likely a result of the significantly different proton sources used, an oxo-acid (formic acid) and an organic acid (Meldrum’s acid). A catalytic cycle has previously been proposed using Meldrum’s acid as the proton &

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Communication enantioselectivity up to 97 % ee. The first asymmetric isoflavanone synthesis containing oxygenation in the 7 position, a substitution commonly seen in many bioactive isoflavanones isolated from nature, has been achieved, resulting in the first asymmetric synthesis of sativanone (1 a). We have also accomplished the first synthesis of 3-O-methylviolanone (1 b). A switch in enantiomer was observed for the decarboxylative protonation of substrate 8 c using different H + sources. This was subsequently confirmed with substrate 2 c. We are currently investigating methods to understand this unusual selectivity and we hope to expand the substrate scope of tertiary a-aryl ketone formation.[41]

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Acknowledgements R.D. is grateful for the award of an Irish Research Council (IRC) EMBARK Initiative PhD Scholarship. M.P.C. acknowledges financial support from the Higher Education Authority’s Programme for Research in Third-level institutions (PRTLI), Cycle 4. R.A. acknowledges post-doctoral funding from the Synthesis and Solid State Pharmaceutical Centre (SSPC) under grant no, 12\RC\2275. M.M. was funded through the Newman Fellowship Programme for Post-Doctoral Scientists. We acknowledge facilities provided by the Centre for Synthesis and Chemical Biology (CSCB), funded by the Higher Education Authority’s PRTLI. We would like to thank Dr. Helge Mller-Bunz for X-ray crystal structure analysis. We would also like to thank Dr Yannick Ortin for help with the NMR spectroscopic studies. Keywords: asymmetric catalysis · dual isoflavanones · natural products · palladium

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Communication [33] J. T. Mohr, T. Nishimata, D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2006, 128, 11348 – 11349. [34] Reagents screened included: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), cerium (IV) ammonium nitrate (CAN), aectic acid, trfluoroacetic acid, and iodine/methanol mixtures. All of these reagents either gave unsatisfactory yields of no reaction at all. [35] CCDC-998836 (9 a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [36] Using Pd(OAc)2 in place of Pd2dba3 with Meldrum’s acid as the H + source in THF formed the R-enantiomer albeit in a lower ee of 14 %. Using Pd2dba3 in place of Pd(OAc)2 with formic acid as the H + source formed the S-enantiomer albeit in a lower ee of 44 %. Using Pd(OAc)2

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[37] [38] [39]

[40] [41]

with formic acid in THF instead of 1,4-dioxane also formed the S-enantiomer in 85 % ee. S. C. Marinescu, T. Nishimata, J. T. Mohr, B. M. Stoltz, Org. Lett. 2008, 10, 1039 – 1042. J. Escorihuela, M. I. Burguete, S. V. Luis, Chem. Soc. Rev. 2013, 42, 5595 – 5617. a) C. Amatore, A. Jutand, G. Meyer, I. Carelli, I. Chiarotto, Eur. J. Inorg. Chem. 2000, 1855 – 1859; b) M. Oshima, I. Shimizu, A. Yamamoto, F. Ozawa, Organometallics 1991, 10, 1221 – 1223. For details of the assay see the Supporting Information. R. Doran, P. J. Guiry, J. Org. Chem. 2014, 79, 9112 – 9119.

Received: September 12, 2014 Published online on && &&, 0000

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Communication

COMMUNICATION & Asymmetric Catalysis R. Doran, M. P. Carroll, R. Akula, B. F. Hogan, M. Martins, S. Fanning, P. J. Guiry* Proton Haze—Don’t know if I’m comin’ up or down: The first asymmetric synthesis of the naturally occurring isoflavanones, sativanone and 3-Omethylviolanone, containing tertiary aaryl carbonyls, has been accomplished.

Chem. Eur. J. 2014, 20, 1 – 7

This was achieved through a Pd-catalyzed decarboxylative asymmetric protonation in excellent enantioselectivities from 76–97 %. A switch in the sense of stereoinduction was observed when different H + sources were employed.

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&& – && A Stereoselective Switch: Enantiodivergent Approach to the Synthesis of Isoflavanones

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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A stereoselective switch: enantiodivergent approach to the synthesis of isoflavanones.

A modular six-step asymmetric synthesis of two naturally occurring and three non-natural isoflavanones containing tertiary α-aryl carbonyls is reporte...
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