DOI:10.1002/open.201500187 Synthetic Studies on Tricyclic Diterpenoids:Direct Allylic Amination Reaction of Isopimaric Acid Derivatives** MariyaA.Timoshenko,[a, b] Yurii V. Kharitonov,[a, b] Makhmut M. Shakirov,[a] Irina Yu.Bagryanskaya,[a, b] andElviraE.Shults*[a, b] Aselective synthesis of 7- or 14-nitrogen containing tricyclic di- cohol with 3-nitroaniline, 3-(trifluoromethyl)aniline,and 4-(tri- terpenoids was completedaccordingtoastrategy in which fluoromethyl)anilineyield the subsequent7a-, 7b-and 14a- the key step was the catalyzed direct allylic amination of nitrogen-containing diterpenoids.The reactionwith 2-nitroani- methyl 14a-hydroxy-15,16-dihydroisopimarate with awide va- line, 4-nitro-2-chloroaniline, 4-methoxy-2-nitroaniline, phenyl- riety of nitrogenated nucleophiles. It was revealed that the se- sulfamide, or tert-butyl carbamate proceeds with the formation lectivity of the reaction dependsonthe nature of nucleophile. of 7a-nitrogen-substituted diterpenoids as the main products. The catalyzed reaction of the mentioned diterpenoid allylic al- Introduction Isopimaric acid (1)(Figure1)isawidely available tricyclic diter- emerged as potentially useful agents in the therapy of various penoid well represented in the resin of conifersofthe genera diseases associated with both the central nervous systemand Pinus, Larix,and Picea.[1] It exhibitsinteresting biological and smoothmuscle system,such as acute stroke, epilepsy,psycho- pharmaceutical properties such as antimicrobial,[2] antiviral,[3] ses, erectile dysfunction, arterial hypertension, asthma, and antiallergenic,[4] and anti-inflammatory[5] activities. Renewed in- bladder hyperactivity. As primary regulators of neuronal excita- terest in this natural compound started with the discovery of bility,potassium (K+)channels have been amajor research pimaranes belonging to aclass of potent potassium-channel focus in drugdiscovery and development.[7] Thus, there is now (BK channel)openers.[6] Openers of thesechannels have significant interestinthe preparationofisopimaric acid deriva- tives to possibly enhanceoralter its biological activity.Oxida- tive[8,9] and isomeric[10] transformationsof1 in addition to sev- eral modifications of the carboxyl group[11,12] have already been described. Accordingly,inlight of new isopimaranes con- taining anitrogen substituent in the diterpenoid core, we becameinterested in the targetedpreparation of isopimaric acid derivatives through allylic amination reaction of its acces- sible derivatives. Figure 1. Substrate scope. The substitution reaction of allylic alcohols with diverse nu- cleophiles has become an extremelyuseful tool for the con- struction of carbon heteroatom bonds. The direct use of allylic À [a] M. A. Timoshenko, Y. V. Kharitonov, M. M. Shakirov,I.Y.Bagryanskaya, alcohols as substrates, with the hydroxy group as the leaving E. E. Shults group and water as the only side product, allows this to be LaboratoryofMedicinal Chemistry,Novosibirsk Institute of Organic Chemis- [13] try,Siberian Branch,Russian Academy of Sciences, Lavrentyev Avenue, 9 agreen reactionwith good atom economy. In order to acti- 630090 Novosibirsk (Russia) vate the hydroxy functionality as aleaving group, Brønsted E-mail:[email protected] acids such as phosphotungstic acid,[14] calix[4]resorcinarene sul- [b] M. A. Timoshenko, Y. V. Kharitonov, I. Y. Bagryanskaya, E. E. Shults fonic acid,[15] or triflic acid[16] and Lewis acids such as transition Chemical and Physical Departments,Novosibirsk State University metal complexes or salts from FeIII,[16] BiIII,[17] MoVI,[18] AgI,[19] PirogovaSt. 2, 630090 Novosibirsk (Russia) AuIII,[20] and AuI[19,21] have been used as catalysts. Gold catalysts [**] This article is part of the Virtual Issue “Nature-Inspired Organic Chemistry” have recently gained much attention in organictransforma- Supporting informationfor this article is available on the WWW under http://dx.doi.org/10.1002/open.201500187. Included: 13CNMR data of tions. Reactions catalyzed by gold generally proceed under the synthesized compounds (TablesS1–S4), X-ray crystal data (Tables S5, mild conditions withoutexclusion of water and oxygen.Both S6), and copies of 1HNMR and 13CNMR spectra. AuIII and AuI salts have already been shown to activate allylic 2015 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA. alcohols under mild conditions. This is an openaccessarticleunder the termsofthe Creative Commons In this paper we presentacomparative study about the al- Attribution-NonCommercial License,which permits use, distribution and reproduction in any medium,provided the original work is properly lylic amination reaction of methyl 14a-hydroxy-15,16-dihydro- cited and is not used for commercial purposes. isopimarate (2)[9] with different nitrogenated compounds (sub- ChemistryOpen 2016, 5,65–70 65 2016 The Authors. PublishedbyWiley-VCH Verlag GmbH &Co. KGaA, Weinheim stitutedanilines, benzenesulfonamide, tert-butyl carbamate) sults are summarized in Table2.The completion of the reac- using gold catalysts. tion was increased to 92%, and the aminationproducts 12, 13, and 15 compose an over yield of 85%with 6mol%catalyst loading (Table 2, Entries1and 2). The yield of compound 15— Results and Discussion the product of allylic amination of allylic alcohol 14—was also The reactionbetween methyl 14a-hydroxy-15,16-dihydroisopi- increased. Exactly the same %conversion was obtained when the reaction was conducted with the catalytic system com- marate (2) and 2-nitroaniline(3)was studied using AuCl3, . TsOH, or BF Et Oatroom temperature in acetonitrile posed of 2% AuCl3 6% AgOTf (Table 2, Entry 3). However, the 3 2 À (Scheme 1, Table 1). The first experiment was carried out with reactionwas more selective for the formation of 7a-(3-nitroani- 2mol%ofAuCl3 as catalyst giving the expected product 4 in lino)-substituted diterpenoid (the ratio of 12:13 was changed from 4.7:1 to 6.4:1). In the case of employing the mentioned catalystinnitromethane, abetter %conversion and higherisolated yield of the ami- nation product (overall yield of 91%) than in acetonitrile was obtained (Table 2, Entry 4). We were pleased to find that the 7- hydroxydihydrosandaracopimaric Scheme1.Amination of methyl 14a-hydroxy-15,16-dihydroisopimarate (2)with 2-nitroaniline (3). Reagents and acid derivative 14 in this case conditions:a)catalyst, CH3CN, rt, 24 h. Catalysts and yields are giveninTable 1 was not formed. AgOTf-catalyzed direct amina- tion of primary alcohols was previously described by Shree- Table 1. Direct amination of dihydroisopimarate 2 with 2-nitroaniline (3). dar et al.[22] In the presence of Yield [%] this active catalyst, compound 2 Entry Catalyst Compound 4 Compound 5 Compound 6 Compound 7 reactedwith aniline 9 with the 1AuCl3 90 2––formation of the amination 2TsOH 24 24 28products with an overall yield of 3BF .OEt –28 623 3 2 68%. The amination reaction of alcohol 2 was considerably pro- 90%yield (Table 1, entry 1). When TsOH was used as catalyst, even with 10 mol%loading, only 24 %ofthe compound 4 was obtained. Additionally,diterpenoid dienes 5, 6,and methyl 7- (4-amino-3-nitrophenyl)-15,16-dihydrosandaracopimarate(7) . were isolated.Inthe case of employing of BF3 Et2Oascatalyst (10 mol %), the aminationproduct formation was not ob- served;only dienes 5 and 6 and the product of electrophilic substitution reaction, 7,wereobtained. We furtherexplored the reactivity of 2 with 4- and 3-nitro- Scheme2.AuCl3-catalyzed amination of compound 2 with 4-nitroaniline (8). Reagentsand conditions:a)AuCl3 (2 mol %), CH3CN, rt, 24 h, 10:74%, 11: substituted anilines 8 and 9 under the conditions mentioned 19%. above (Table 1, Entry 1). We found that the interaction of allylic alcohol 2 with anilines 8 and 9 under the AuCl3 catalystwas not so effective compared with 3.Inthe reaction of 2 with 4- motedalso by the addition of AgBF4 (Table 2, Entry 6), while nitroaniline (8), amination products at the C(7) (compound 10, using AgBF4 only resulted in lower reactivity;moreover,adiffer- 74%yield) and C(14) position (compound 11,19% yield) were ent selectivity of the formation of 7a-and 7b-compounds 12 isolated(Scheme 2). and 13 (ratio 6.4:1 and 8.5:1) wasobserved as afunction of Amination of alcohol 2 with 3-nitroaniline (9)inthe pres- the used Ag-salt catalyst(Table 2, Entries 5and 6). Severalex- ence of 2mol %ofcatalyst proceeds smoothly to give the de- amplesofstereoselective direct amination reaction of alcohols sired product 12 only in 24 %yield. The7b-(3-nitroanilino)- were described by using AuI-salt catalysts.[19] We found that in 15,16-dihydrosandaracopimarate(13), the allylic alcohol 14, the considered reaction with PPh3AuCl, the catalystwas inac- and 14a-(3-nitroanilino)-15,16-dihydroisopimarate (15)were tive, but by employing PPh3AuCl/AgBF4 or PPh3AuCl/AgOTf also isolated.The over-allconversion of this reaction was only catalysts, the amination reaction proceeded with moderate at 76%(Scheme 3, Table 2, Entry 1). Afurthersearch for more yield and conversion of allylic alcohol 2 (Table2,Entry 7,8). In- effective catalysts of this reaction was conducted, and some re- creasingofthe AgOTf content in the catalytic system provided ChemistryOpen 2016, 5,65–70 www.chemistryopen.org 66 2016 The Authors. PublishedbyWiley-VCH Verlag GmbH &Co. KGaA, Weinheim the conversionofcompound 2. Table 2. Catalyzed amination of isopimarate 2 with 3-nitroaniline (9). Ph3PAuOTf, generated in situ [a] Entry Catalyst (concentration) Yield[%] Conversion from Ph3PAuCland AgOTf, was [mol%] 12 13 14 15 [%] found to be the best catalyst for 1AuCl3 (2) 24 614 13 76 the direct amination reaction of 2AuCl3 (6) 52 11 522 92 methyl 14-hydroxy-15,16-dihy- 3AuCl (2) AgOTf (6) 51 8918 92 3 À droisopimarate (2). The best 4[b] AuCl (2) AgOTf (6) 63 9019 100 3 À 5AgOTf(6) 45 713 16 87 condition involved the use of I 6AgBF4 (4) 34 4812 62 a1:3 mixture of Au complex 7[PPh AuCl] (2) AgBF (4) 38 814 15 77 3 À 4 and AgOTf (Table 2, Entry 9), but 8[PPh AuCl] (2) AgOTf(2) 32 515 12 80 3 À the stereoselectivity of forma- 9[PPh AuCl] (2) AgOTf(6) 41 9616 96 3 À tion of 7a-(3-nitroanilino)-substi- [a] Isolated yields.[b] Reactionwas performedinCH3NO2.