Intermolecular Conjugate Addition of Pyrroloindoline and Furoindoline Radicals to α,β-Unsaturated Enones via Photoredox Catalysis

DOI: 10.1002/adsc.201400702

Intermolecular Conjugate Addition of Pyrroloindoline andFuroindoline Radicals to a,b-Unsaturated Enones viaPhotoredox Catalysis

Shupeng Zhou,+a Deliang Zhang,+a Yu Sun,a Ruofan Li,a Wenhao Zhang,a

and Ang Lia,*a State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese

Academy of Sciences, 345 Lingling Road, Shanghai 200032, People�s Republic of ChinaFax: (+86)-21-5492-5125; e-mail: [email protected]

+ S.Z. and D.Z. contributed equally to this work.

Received: July 18, 2014; Revised: August 14, 2014; Published online: && &&, 0000

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400702.

Abstract: We have developed an intermolecularconjugate addition of 3a-pyrroloindoline/furoindo-line radicals to a,b-unsaturated enones, throughvisible-light photoredox catalysis. Ir ACHTUNGTRENNUNG(ppy)2ACHTUNGTRENNUNG(dtbbpy)PF6 was found to be an effective promoter to ini-tiate this reaction from readily available 3a-bromo-pyrroloindolines/furoindolines. This method was ex-ploited to prepare a series of indole terpenoid-likecompounds of potential biological interest.

Keywords: alkaloid-terpenoid hybrids; conjugateaddition; furoindolines; photoredox catalysis; pyr-roloindolines

The conjugate addition is a powerful C�C bond form-ing reaction.[1] From the stereochemical perspective,this reaction may provide the opportunity of generat-ing up to three stereogenic centers (two from the ac-ceptor and one from the donor). Carbanions, elec-tron-rich p systems, organometallic species, and freeradicals have been widely explored as the donors forconjugate addition reactions, which have found re-markable applications in the synthesis of naturalproducts and pharmaceutically interesting com-pounds. Notably, the addition of a tertiary carbon toan electron-deficient unsaturated system is rather lim-ited because of the steric and reactivity problems. Inprinciple, a free radical approach is a suitable meansto overcome both problems; however, the intermolec-ular radical 1,4-addition sometimes suffers fromsevere side reactions, such as the reductive quench,due to the high reactivity of the radical species.[2]

Recently, photoredox catalysis has emerged asa useful tool for controllable radical chemistry.[3] Asdemonstrated in some cases, the manner of the radicalinitiation and termination in a photoredox catalyticcycle overcomes some disadvantaged of conventionalradical chemistry; therefore, visible-light photoredoxcatalysis represents not only a “green” alternative totraditional radical protocols, but also a new avenuefor the discovery of synthetically useful reactions.[4] Inthe total synthesis of drimentine A (1, Figure 1), wetook advantage of photoredox catalysis to effect a rad-ical 1,4-addition as the key C�C bond (highlighted inbold in Figure 1) forming reaction.[5] Herein, wereport the photocatalyzed intermolecular conjugateaddition of 3a-pyrroloindoline/furoindoline radicals toa,b-unsaturated enones,[6,7] as a general and facileaccess to a series of indole terpenoid-like structures.

We first investigated the conditions for the conju-gate addition using enone 2 and racemic 3a-bromopyrroloindoline 3 as the substrates (Table 1). Conven-tional radical conditions (AlBN or Et3B/O2) afforded

Figure 1. The structure of pyrroloindoline natural productdrimentine A.

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trace amounts of the desired product 4 (entries 1 and2).[7] The reductive debromination of 3 was very rapidunder these conditions. Slow addition of a highly di-luted solution of Bu3SnH in benzene via a syringepump, which gave a reasonable yield of the conjugateadduct in the synthesis of drimentine A, proved to befruitless with this pair of substrates (entry 3). It maybe attributable to the lability of 2 under thermal con-ditions. Photoredox catalyst Ru ACHTUNGTRENNUNG(bpy)3Cl2 has beenemployed by Stephenson and co-workers for initiatingradicals from structurally similar 3a-bromopyrroloin-dolines.[4c,e] However, in our case, it only provided11% of 4 when Et3N was used as a reductant(entry 4). In this case, both 2 and 3 were partially re-covered. To our delight, [Ir ACHTUNGTRENNUNG(bpy)2ACHTUNGTRENNUNG(dtbbpy)]PF6 wasfound to be an effective catalyst and led to a satisfac-tory yield of 4 (90%) under the irradiation of blueLEDs (lmax = 454 nm). It should be noted that 4 wasobtained as a 1.4:1 diastereomeric mixture at C-2,and the stereochemistry of the pyrroloindoline motifwas retained through the radical process because ofits structurally rigidity.

We explored the scope of the conjugate additionwith a variety of electron-deficient olefins (2a–m) andtwo synthetically important pyrroloindoline/furoindo-line bromides. Conjugate adducts 4a–m were obtainedin good to excellent yields (Table 2). Arene-fusedcyclic enones 2a–c proved to be suitable substrates forthis reaction (entries 1–3). A series of a,b-unsaturatedenones 2d–j arising from naturally occurring ketoneswere then tested. As shown in entry 4, a (+)-cam-

phor-derived enone 2d served as a good acceptor forthe radical addition, and the product 4d was obtainedin 94% yield as a mixture of C-3 diastereomers (1.8:1dr). Enones 2e–j, derived from (+)-dehydroandroster-one, (+)-epiandrosterone, (+)-estrone, (+)-sclareo-lide, and (�)-carvone, respectively, also smoothly re-acted with the optically active 3a-bromopyrroloindo-line (entries 5–10). For entries 5, 6, 8, and 9, the ad-ducts 4e, f, h, i were isolated as single diastereomers,respectively. The structures of 4h and 4i were assignedaccording to the X-ray crystallographic analysis of ananalogue reported in the drimentine synthesis,[5] andthe relative configuration of 4f was verified by NOEstudies (see the Supporting Information). In someother cases, the low diastereoselectivity at the carbon-yl a position could be attributable to the weak stericbias of the particular ketone moieties, which may notdiminish the general advantage of this C�C bondforming process. Interestingly, for entry 7, a 1.6:1 drat C-16 of 4g was observed, despite the remarkablestructural similarity between 4g and 4e. This ratio canbe enhanced to 5:1 by treatment of the isolated prod-uct with DBU at 80 8C. The C-16 configuration of 4eand the major epimer of 4g was elucidated based onthe comparison with that of the thermodynamicallyfavorable C-16 substituted estrone derivative.[8] En-tries 9 and 10 show the selectivity of the 1,1- over 1,2-disubstituted enone in the conjugate addition. Itshould be noted that endocyclic and linear enoneswith the 1,2-disubstitution pattern do not participatein this reaction. The a,b-unsaturated aldehyde, ester,and lactone with exocyclic C=C bonds (e.g., 2k–m)are good acceptors for the conjugate addition (en-tries 11–13).

With the above results, we have demonstrated thepower of the intermolecular conjugate addition forforging together two biologically privileged motifs,the pyrroloindoline and steroid. This strategy was fur-ther applied to the synthesis of a pyrroloindoline-ole-anolic acid hybrid,[9] as shown in Scheme 1. Oleanolicacid methyl ester (5) was subjected to a two-step se-quence (DMP oxidation followed by exposure toEt3N and Eschenmoser�s salt), to give enone 6 in 78%overall yield. The conjugate addition proceeded wellwith the substrates 5 and 7, to deliver a complex alka-loid-terpenoid hybrid 8 (1.5:1 dr at C-18) in 87%yield. This compound may serve as a versatile inter-mediate to derive the corresponding diketopipera-zines for biological studies.

In Scheme 2 is depicted a postulated mechanismfor the photocatalyzed conjugate addition. The aro-matic moiety of 3 is reduced by an Ir(II) species, andthe mesolysis of the benzylic C�Br bond proceeds togenerate a pyrroloindoline radical 9, which then at-tacks enone 2, the resultant a-carbonyl radical 10 isfurther reduced by a reactive species (e.g., Et3N radi-cal cation).[10] The reductant is generated and then

Table 1. Conditions for the intermolecular conjugate addi-tion.

Entry Conditions[a] Yield

1 AIBN, Bu3SnH, toluene, 80 8C 8%2 Et3B, O2, Bu3SnH, THF, 22 8C 13%3 Bu3SnH (syringe pump), toluene, 80 8C[b] <2%4 [Ru ACHTUNGTRENNUNG(bpy)3]Cl2·6 H2O (2.5 mol%), blue LED,

Et3N, DMF, 22 8C[c]11%

5 [Ir ACHTUNGTRENNUNG(bpy)2ACHTUNGTRENNUNG(dtbbpy)]PF6 (2.5 mol%), blue LED,Et3N, DMF, 22 8C[c]

90%

[a] 2.0 equiv. of 2.[b] 10.0 equiv. of 2.[c] 2.0 equiv. of Et3N.

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Table 2. Intermolecular conjugate addition of 3a-pyrroloindoline/furoindoline radicals to a,b-unsaturated enones.[a]

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UPDATES Intermolecular Conjugate Addition of Pyrroloindoline and Furoindoline






consumed in the catalytic cycle, and thus maintainsa very low concentration, which suppresses the severedebrominative side-reaction of 3 that is often ob-served under conventional radical conditions. In thisparticular case, the stereochemistry at the carbonyla position of the product 4 cannot be well controlleddue to the weak stereochemical effect from the pyrro-loindoline motif. As for 4e, f, h, and i, the hydrogensource may prefer to approach the enol radical fromthe axial or pseudo-axial direction to develop lesssteric congestion, and therefore results in a high levelof diastereoselectivity.

In summary, we have developed an intermolecularradical conjugate addition via visible-light photoredoxcatalysis. 3a-Bromopyrroloindolines/-furoindolinesand a,b-unsaturated enones were employed as thesubstrates for this reaction. This method provides

a facile and efficient access to a collection of structur-ally complex alkaloid-terpenoid hybrids of potentialbiological interest.

Experimental Section

General Procedure for the Intermolecular ConjugateAddition

To a stirred solution of 3a-bromopyrroloindoline or -furoin-doline (0.500 mmol) and a,b-unsaturated enone (1.00 mmol)in DMF (2.0 mL) were sequentially added [IrACHTUNGTRENNUNG(ppy)2ACHTUNGTRENNUNG(dtbbpy)]PF6 (11.4 mg, 0.0125 mmol) and Et3N (102 mg,140 mL, 1.00 mmol) at 22 8C. The resulting mixture wasstirred at that temperature for 16 h upon the irradiation ofa blue LED (lmax =454 nm, 20 W). After removal of the sol-vent under vacuum, the residue was purified by flash

Scheme 1. Synthesis of a pyrroloindoline-oleanolic acidhybrid.

Scheme 2. A postulated mechanism of the photocatalyzedradical conjugate addition.

[a] [Ir ACHTUNGTRENNUNG(bpy)2ACHTUNGTRENNUNG(dtbbpy)]PF6 (2.5 mol%), enone (2.0 equiv.), Et3N (2.0 equiv.), blue LEDs (lmax = 454 nm), DMF, 22 8C, 16 h.



UPDATES Intermolecular Conjugate Addition of Pyrroloindoline and Furoindoline


column chromatography with EtOAc/petroleum ether togive the conjugate adduct.

Acknowledgements

We thank Prof. Wen-Jing Xiao and Dr. David Edmonds forhelpful discussions and Wenmin Wu for mass spectrometricassistance. Financial support was provided by Ministry ofScience & Technology (2013CB836900), National NaturalScience Foundation of China (21290180, 21172235, and21222202), Pujiang program (12PJ1410800), and ChineseAcademy of Sciences.

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7Intermolecular Conjugate Addition of Pyrroloindoline andFuroindoline Radicals to a,b-Unsaturated Enones viaPhotoredox Catalysis

Adv. Synth. Catal. 2014, 356, 1 – 7

Shupeng Zhou, Deliang Zhang, Yu Sun, Ruofan Li,Wenhao Zhang, Ang Li*




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Intermolecular Conjugate Addition of Pyrroloindoline and Furoindoline Radicals to α,β-Unsaturated Enones via Photoredox Catalysis