Enantioselective Synthesis of Natural Epoxyquinoids

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2 Current Organic Synthesis, 2013, 10, 2-42 Enantioselective Synthesis of Natural Epoxyquinoids

Enrique Pandolfi,* Valeria Schapiro,* Viviana Heguaburu and Maitia Labora

Departamento de Química Orgánica, Facultad de Química, Universidad de la República, General Flores 2124, C. P. 11800, Monte- video, Uruguay

Abstract: Natural products play an important role as a source not only of potential therapeutic drugs but also of starting materials for semisynthetic new medicines. The epoxyquinoid family, composed by cyclohexane epoxides and related structures, exhibit these charac- teristics without doubt.

Since 2004, significant efforts have been devoted to the stereocontrolled synthesis of these molecules with different and interesting strategies. More than 50 works on this field have been published during this period of time. In addition, many of these polyoxygenated cyclohexenoids exhibit diverse and impressive bioactive shapes. This review aims to analyze the recent advances in the enantioselective processes that have been performed for the total syntheses of these target molecules. It includes a wide range of methodologies for the introduction of chirality either enzymatic or chemical ones. This summarizes microbial preparation of starting materials, lipase kinetic resolutions, use of compounds from the chiral pool, use of chiral auxiliaries and asymmetric catalysis. In a special section, syntheses of scyphostatin are also included.

Keywords: Chemocatalyst, enantioselective, enzymatic methods, epoxyquinoids, scyphostatin, synthesis.

INTRODUCTION lium claviforme [7] and exhibited antibiotic and cytotoxic activity. Epoxycyclohexenones are widely distributed in nature. Biolo- (+)-Epiepoformin (2) inhibited the germination of lettuce seeds [8]. gists and pharmacologists are very interested in them due to their This phytotoxin was separated from the culture of an unidentified many and varied biological properties. Also the highly functional- fungus on diseased crepe myrtle (Lagerstroemia indica) leaves. ized and challenging structures prompted the synthetic chemistry From the culture filtrate of Phyllosticta sp. S1019 [9] and Phorma community to redouble efforts in their total synthesis. After emerg- sp. [10] a secondary metabolite called (+)-epoxydon (3) was iso- ing reviews in the 80s [1] and 90s [2] dedicated to cyclohexene lated, which was described as phyto and cytotoxic agent. A quan- epoxides and related compounds, Marco-Contelles and co-workers tum-mechanical calculation of the optical rotatory power of 1, 2 and wrote an extensive and comprehensive apropos review [3]. They 3 was recently reported [11]. (+)-Epiepoxydon (4) was isolated covered a wide range of naturally occurring cyclohexane epoxides, from the same source as epiepoformin (2) [8]. (+)-Bromoxone (5) including sources, biological activities and syntheses. Since that together with its acetate (6) were isolated from marine acorn worms review was published, significant efforts have been devoted to the (Phyllum hemichordata) [12]. The haloepoxycyclohexenone acetate stereocontrolled synthesis of these types of molecules with different 6 possess antitumor activity in P388 cells (IC50 10mg/ml). Recently and interesting strategies. This review aims to describe the ad- Gong and co-workers [13] identified natural bromoxone as a potent vances in the enantioselective processes that have been performed caspase-1-pathway inhibitor among other properties and described a since 2004 for the total syntheses of epoxycyclohexene derivatives. possible mechanism of action. In 1986 Jarvis and Yatawara [14] We have classified the target molecules into: 1) epoxycyclohex- reported a new antibiotic (+)-isoepiepoformin (7) from cultures of enones (Fig. 1); 2) epoxycyclohexene-diols and diones (Fig. 2) and the fungus Myrothecium roridum CL-514 (ATCC20605). (+)-ECH 3) related dimeric epoxyquinoid structures (Fig. 3). We briefly de- (8) was first isolated from the culture broth of an unidentified fun- scribe natural sources and biological activities of these compounds. gus strain [15]. This epoxycyclohexenone inhibited Fas-mediated We have organized the advances in the field of synthesis in two apoptosis by blocking activation of pro-caspase-8 in the death in- broad sections according to the methodologies for the introduction ducing signaling complex [16]. Few months later synthetic (+)- of chirality in the strategy: 1) enzymatic mediated desymmetriza- RKTS-33 (9) and (+)-RKTS-34 (10) were reported as novel non- tions and 2) chemically stereocontrolled methodologies. Efficient peptide inhibitors towards death receptor-mediated apoptosis by syntheses starting with enantiomerically pure available synthons are Kakeya and co-workers [17]. Structure-activity relationships of also reviewed. Finally, scyphostatin chiral preparations will be several semisynthetic C-6 side chain derivatives were also de- separately presented. Epoxycyclohexenes derived from naphthole- scribed by the authors. In 2004, they described that ECH (8) and noid precursors are not included in this review. This topic was re- RKTS-33 (9) were specific inhibitors of the FasL-dependent killing viewed extensively by Krohn [4], Miyashita [5] and Cai [6]. pathway in CTL-mediated cytotoxicity [18,19]. (-)-Harveynone (11), a secondary metabolite with phytotoxic activity was isolated from the tea gray blight fungus Pestalotiopsis theae [20]. (-)- SOURCES AND BIOLOGICAL ACTIVITIES Tricholomenyn A (12) showed antimitotic activitiy and was iso- Concerning epoxycyclohexenones described in Figure 1: (+)- lated from the fruiting bodies of the mushroom Tricholoma acer- epoformin (1) was first isolated from the culture broth of Penicil- bum [21], together with a number of analogs called tricholomenyns B to E. It has been suggested that the biosynthesis of tricholomenyns C-E and maybe also B proceeds via a not yet isolated intermediate. Recently, the synthesis of a putative biogenetic *Address correspondence to these authors at the Departamento de Química Orgánica, precursor (13) was achieved by Banwell´s group [22]. An epoxycy- Facultad de Química, Universidad de la República, General Flores 2124, C. P. 11800, Montevideo, Uruguay; Tel: ++5982-9247881; Fax: ++5982-9241906; clohexenone that contains a fatty acid side chain was isolated from E-mail: [email protected]; [email protected] the related endophytic fungal species [23, 24] Pestalotiopsis and

O O OH O OH O O O O Br R O O O O O O O

OH OH OH OH OR OH OH OH

(+)-epoformin (1) (+)-epiepoformin (2) (+)-epoxydon (3) (+)-epiepoxydon (4) (+)-bromoxone R=H (5) (+)-isoepiepoformin (7) (+)-ECH R= CH3CH=HC- (E) (8) (+)-4-acetylbromoxone (+)-RKTS-33 R=H (9) R R=Ac (6) (+)-RKTS-34 R= -C(CH3)=CH-CH3 (E/Z) = 1:1 (10)

O COOH O O O O C H 5 11 O O O O O O

OH OH OH OAc OH OH OH

(-)-harveynone (11) (-)-tricholomenyn A R= CH3 (12) (+)-ambuic acid (14) central core of ambuic acid (15) (-)-cycloepoxydon (16) a putative biogenetic precursor of tricholomenyns B-E R=COOH (13)

O O O OH O OH OH O O O O O O HN N H O OH O 3 OH OH O OH

(-)-EI-1941-1 (17) (-)-EI-1941-2 (18) (+)-scyphostatin (19) (-)-DHMEQ (20) Fig. (1). Epoxycyclohexenones containing halogen, C-C and C-N side chains.

OH OH OH OH

HO HO O O O O C5H11 C3H7 OH OH OH OH (-)-theobroxide (21) (-)-asperpentyn (22) (-)-3´,4´-dihydrophomoxide (23) (-)-phomoxide (24) (revised 2004) O OH O OH

HO O O O O

C5H11 OH O OH C5H11 OH (+)-eupenoxide (25) (+)-integrasone (26) (-)-phyllostine (27) (revised 2008) Fig. (2). Natural epoxycyclohexene-diols and diones.

Monochaetia [25] living in the thalli of lichens. It was called am- immune and inflammation responses and apoptosis. In 2003, Koi- buic acid (14) and displayed antifungal activity against human zumi and co-wokers [31] reported the isolation of (-)-EI-1941-I (17) pathogenic fungi. Recently, ambuic acid derivatives were described and (-)-EI-1941-II (18) from the fermentation broth of Farrowia sp. in the same fungus (Pestalotiopsis sp.) by Ding et al. [26]. Ambuic According to these authors [32], 17 and 18 inhibited selectively acid and one of its metabolites displayed anti-microbial activity human recombinant interleukin-1 (1L-1) converting enzyme against the gram-positive bacterium Staphylococcus aureus accord- (ICE) activity with IC50 values of 0.086 and 0.006 μM, respec- ing to these authors. Nakayama´s group demonstrated that ambuic tively. ICE inhibitors have been suggested as potencial anti- acid inhibits the biosynthesis of cyclic peptide quormones of inflammatory drug candidates [33]. Staphylococcus aureus and Listenia innocua. This mode of action (+)-Scyphostatin (19) was first isolated from a mycelia extract suggests the potencial application of ambuic acid as a lead com- of Dasyscyphus mollissimus Sank 13892 [34]. Up to date, 19 exhib- pound targeting the quorum-sensing system of gram positive bacte- its the most potent (IC50 1.0 μM) inhibitory activity against the ria [27]. A model structure of ambuic acid having an epoxyquinoid neutral enzyme sphingomyelinase (N-SMase) [35-38]. Syntheti- structure (15) was published by our group in 2008 [28]. cally produced (-)-DHMEQ (20) was found as a potent and specific (-)-Cycloepoxydon (16) was isolated from the deuteromycete inhibitor of NF-B [39] and it showed potent anti-inflammatory and strain 45-93 [29] and exhibited activation of NF-B [30]. This natu- anticancer activities in animals [40-44]. ral product also showed an inducible ubiquitous transcription factor Epoxycyclohexene-diols and diones (Fig. 2) have also been that regulates the expression of various cellular genes involved in found in nature: (-)-theobroxide (21) was first isolated from the

4 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

O O O HO HO HO OH OH OH OH OH O O O O O O O O O O O O O O O O H H H CH3 O CH3 O CH3 O O O

(+)-epoxyquinol A (28) (+)-epoxyquinol B (29) (+)-epoxyquinol C (30) (+)-epoxytwinol A (31) R O HO Br COOH O O O O O O O O O O O H O N N NH N H O O O O H O 4 O O H H H C OH H C 11 5 O O OH O 11 5 COOH OH O Br O (+)-hexacyclinol (32) R= OH, (+)-panepophenanthrin (33) (+)-calafianin (37) (+)-torreyanic acid (38) R= CH3, (+)-RKTS-80 (34) R= C4H9, (+)-RKTS-81 (35) R= C8H17,(+)-RKTS-82 (36) Fig. (3). Dimeric epoxyquinoids. culture filtrate of the fungus Lasiodiplodia theobromae and showed fungus, with even more potent angiogenesis inhibition properties exceptional activity as a potato microtuber inducing in vitro [45- than epoxyquinol A. They also reported that 29 inhibits NF-B 50]. It also inhibits stem elongation in spinach and morning glory signaling by crosslinking TAK1[63]. Pentaketides epoxyquinols A, [51]. B and C (30) are postulated to be biosynthetically generated from Natural (-)-asperpentyn (22) was reported by Achenbach [52] in epoxyquinol monomer 8 by a cascade reaction sequence of oxida- 1988 from the antimicrobial extracts of Aspergillus duricaulis. Ac- tion, 6-electrocyclization and Diels-Alder dimerization [64]. Later cording to this author, asperpentyn showed no activity against in 2005, epoxytwinol A (31) was isolated from the same fungus [65]. This complex dimeric structure having a 17,19- Botrytis cinepea and Bacillus subtillis. To our knowledge, biologi- 2,9 3,8 11,16 cal activities of asperpentyn and its synthetic enantiomer have not dioxapentacyclo [8.6.2.2 .0 .0 ]icosa-3(8),11(16)-diene, inhib- yet been described. In 2003, Liu et al. [53] reported the isolation of ited endothelial cell migration stimulated by vascular endothelial a natural product miss-assigned as “eupenoxide” from the fermenta- growth factor (ED100 = 2.6 μM). tion of a marine-derived fungus of the genus Phoma sp.. Mehta The culture of the fungal strain of Panus rudis was the source reassigned this structure as 3´, 4´-dihydrophomoxide (23) based on of bioactive metabolite called (+)-hexacyclinol (32) [66]. Antipro- identical spectroscopic data compared with its enantiomer, previ- liferative effect of hexacyclinol on L-929 cells and its cytotoxic ously synthesized [54, 55]. (-)-Phomoxide, which also had to be effect on HeLa cells were demonstrated. Hexacyclinol also dis- revised, was originally isolated from the same natural source [53]. played moderate inhibitory activity against Plasmodium falciparum In 2004, Mehta [54] proposed the revised structure 24 by compari- (IC50 2.49 μg/ml). It can be suggested that hexacyclinol may serve son of the spectroscopic data reported for the natural sample with as a lead for the development of new antimalary agents. However, the ones of the synthetically prepared stereostructure. An endo- its complex chemical structure has been under controversy for phytic fungus of the genus Eupenicillium is the source of an anti- years. In 2006, Rychnovsky proposed a revised structure of hexacy- fungal agent called (+)-eupenoxide (25) [56]. The chemical struc- clinol based on prediction of NMR chemical shifts by modern com- ture of eupenoxide has been under revision for several years and putational methods [67]. Porco and co-workers confirmed in 2006 was finally clarified by Mehta and co-workers [55]. This compound the hexacyclinol structure [68] and they brought light to the “hexa- was also found in the endophytic fungi Phoma sp.[57] and Asper- cyclinol dispute” [69]. gillus japonicus [58]. (+)-Integrasone (26) was first isolated from (+)-Panepophenanthrin (33) was first isolated from the mush- an unidentified sterile mycellium (MF63896) [59]. Natural integra- room strain Panus rudis IFO 8994 [70]. This is the first natural sone inhibited HIV-1 integrase which is one of the critical enzymes product discovered that inhibits ubiquitin activating enzyme (E1). involved in viral replication. (-)-Phyllostine (27) was found in Phyl- This inhibition affects the ubiquitin-proteasome pathway (PPP) and losticta sp. [9]. It exhibited antibiotic and phytotoxic activity [60]. ubiquitin functions that are involved in serious diseases [71]. Con- Finally, amazingly complex structures have been reported for sidering this unique biological activity and the complex structure of dimeric epoxyquinoids of natural origin, as shown in figure 3. (+)- such dimeric epoxyquinoids, Shoji´s group reported three syntheti- Epoxyquinol A (28) was isolated from an uncharacterized fungus cally panepophenanthrin derivatives RKTS 80-82 (34-36) and in- from a soil sample, exhibiting potent angiogenesis inhibition prop- vestigated their structure-activity relationships [72]. In 2000, Chris- erties [15]. Cancer, reumatoid arthritis and other chronic inflamma- tophersen and co-workers [73] isolated from the methylene chloride tory diseases are characterized by extensive angiogenesis [61]. extract of the marine sponge Aplysina gerardogreeni a dimeric Osada´s group isolated (+)-epoxyquinol B (29) [62] from the same compound named calafianin [74]. Five years later Ogamino and

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 5

Nishiyama proposed a revised structure of (+)-calafianin (37) which bulky silylating agent and thus conversion of the other secondary spectroscopic data concur with the reported data of the natural sam- alcohol into a good leaving group, permitted us to obtain 41 that in ple. Surprisingly, spiroisoxazoline moiety that is usually involved basic medium led to epoxyenone 42. Mitsunobu inversion afforded in antimicrobial, cytotoxic and anti-inflammatory activities showed 15 that constitutes a model molecule for the central core of ambuic no significant biological activity. A secondary metabolite from acid. Pestalotiopsis microspora with selective cytotoxicity against hu- In 2009, Banwell and co-workers started to use these metabo- man cancer cell lines was isolated by Lee and co-workers in 1996 lites for the synthesis of natural epoxyquinols. In an extensive work [75]. The structural determination of torreyanic acid was estab- [83], they reported the chemoenzymatic preparation of ent- lished as the dimeric quinone 38 that could be biogenerated from bromoxone (ent-5), ent-epiepoformin (ent-2), (-)-harveynone (11), ambuic acid (14) as the monomer unit. Torreyanic acid demon- (+)-panepophenanthrin (33) and (+)-hexacyclinol (32). The key strated to be five to ten times more potent in cell lines that are sen- sitive to the protein kinase C (PKC) agonists and it was found to intermediates in this case were compounds 48a-c that can be easily cause programmed cell death (apoptosis). obtained from chiral halo-cis-cyclohexadiendiols 44a-c, as it is shown in scheme 2. Any of the three halo-diols, when treated with NBS yielded the corresponding bromohydrins 45a-c. These prod- ENANTIOSELECTIVE SYNTHESIS OF EPOXYQUINOIDS ucts, under basic conditions underwent epoxide ring closing by Enzymatic Methods nucleophilic attack of the C3-hydroxyl group (46a-c). Mitsunobu Enzymes have been used for the introduction of chirality of ep- inversion proceeded regioselectively on carbon 4 yielding 47a-c. oxyquinoids and related molecules, in two different ways: the use Further oxidation led to key intermediates 48a-c. ent-Bromoxone of chiral building blocks of microbial origin and the use of lipases (ent-5) and ent-epiepoformin (ent-2) were obtained efficiently from for kinetic resolution of enantiomeric mixtures. these epoxyenones. In the case of ent-bromoxone just deprotection of 48b afforded the desired product. In the case of ent- Use of Microbial Chiral Building Blocks epiepoformin, after switching protective groups on the iodo compound 48c to afford 49c, Stille cross-coupling reaction permitted to The first starting materials of this type we are going to consider introduce the methyl group. After silyl ether removal, ent- are the enantiomerically pure diols that exhibit the structure shown epiepoformin was obtained. In the case of (-)-harveynone (11), no in figure 4. These valuable synthons are available by means of change of protective group was necessary. Compound 48c reacted whole cell oxidation of the corresponding monosubstituted benzene under Stille conditions, and after removal of chloroacetate, the natu- [76,77]. They have been widely used for the synthesis of a great ral product was prepared. Taking advantage of this protocol, the variety of natural polyoxygenated products [78-81]. Concerning the dimeric compound (+)-panepophenanthrin (33) was also synthe- synthesis of natural epoxyquinoids, Banwell´s and our own group sized (scheme 3). In this case, Stille coupling was performed on have taken advantage of this chemoenzymatic methodology. iodoalcohol 47c, with 51a as the cross-coupling partner, and then it was oxidized to 52a. Deprotection yielded compound 53a. This X compound has been proposed to be a biosynthetic precursor of the OH dimer. In fact, it was spontaneously transformed into panepophenanthrin (33) just standing neat at room temperature. Appling exactly the same sequence, but using the methoxylated OH tin compound 51b, pre-hexacyclinol (54) was obtained. Under acid- X = CH , Cl, Br, I catalyzed conditions it was converted into (+)-hexacyclinol (32). 3 In an extension of this work, Banwell’s group published a very Fig. (4). Diols of microbial origin. concise synthesis of ent-bromoxone acetate (ent-6) and (-)- In 2008, we have reported the synthesis of a model compound tricholomenyn A (12) (scheme 4) [84]. In this case, Mitsunobu of the central core of ambuic acid [28], starting from toluene as the inversion was performed over compounds 46b and 46c with acetic aromatic substrate to be biotransformed into the corresponding cis- acid instead of chloroacetic acid. Acetates 55a-b were obtained. So, diol by Pseudomonas putida F39/D [76]. This constituted the first the enantiomer of bromoxone acetate (ent-6) was directly prepared, application of this methodology to the synthesis of a chiral ep- using the same strategy of the previous work. When the same pro- oxyenone (scheme 1). tocol was applied to the iodocompound 46c, having the appropriate tin compound in hands, they prepared (-)-tricholomenyn A (12) Enone 40 has been previously prepared from toluene-derived through a Stille cross coupling reaction performed on epoxyenone chiral diol 39 [82]. Protection of the less hindered alcohol with a 56.

CH 3 CH3 HO CH3 Pseudomonas O OH OH 1) THSCl, imidazole putida F39/D DMF, 98% OH OH 2) MsCl, Et3N 39 40 CH2Cl2, 45%

1) PPh3, benzene, then HO CH H3C 3 O p-nitrobenzoic acid, then O OMs 1) K2CO3, 18-crown-6 O DEAD. THF, 76% 15 OTHS 2) Py-HF, THF, 64% 2) K2CO3, MeOH, 22% 41 OH 42 Scheme 1.

6 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

X X X Pseudomonas OH OH putida F39/D NBS, H2O, THF NaOMe, THF

OH HO OH 44a: X = Cl, 43a: X = Cl, Br 43b:X=Br 44b: X = Br 44c: X = I 45a: 64% (X = Cl) 43c: X = I 45b: 89% (X = Br) 45c: 66% (X = I) X X X PDC, AcOH, OH (t-BuOCON)2, PPh3 OH CH Cl O ClCH2CO2H 2 2 O O HO O O O 46a:52%(X=Cl) O 47a: 72% (X = Cl) O 46b: 56% (X = Br) Cl 47b: 59% (X = Br) Cl 46c: 79% (X = I) 47c: 77% (X = I) 48a: 65% (X = Cl) Zn(OAc)2 MeOH 48b: 77% (X = Br) O ent-5 48c: 75% (X = I) 88% (X=Br) X O O O 1) Zn(OAc)2, MeOH X 87% (X=I) Me4Sn, Pd(0), Ph3As, O O O O 2) TES-Cl, 2,6-lutidine CuI, THF, 37% 55% Cl OTES OTES 49b (X=Br) 50 48a:65%(X=Cl) 49c (X=I) 48b: 77% (X = Br) HF.Py 48c: 75% (X = I) MeCN, 78%

1) Bu Sn 3 , Pd(0), Ph3As, CuI ent-2

THF, 61% (X=I) 11 2) Zn(OAc)2, MeOH, 76% Scheme 2.

I OR OH SnBu3 1) Pd(0), Ph3As, CuI, acetone, microwave Zn(OAc)2 O O + 2) PDC, AcOH, CH Cl , O 2 2 MeOH, 82% 32% over 2 steps O O OR O Cl O 51a: R=H 47c Cl 51b: R=OCH3 52a: R=H 52b: R=OCH3 OR HO O OH H H + + H / D , CDCl3 neat, quant. O 32 O O 99% R = OCH3

HO O O 53a: R=H OCH3 53b: R=OCH3 OCH3 neat, quant. (+)-pre-hexacyclinol (54) R=H 33 Scheme 3.

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 7

X X OH OH (t-BuOCON)2, PPh3,

HO O AcOH, THF AcO O

46b: X=Br 55a: 88% (X = Br) 46c: X=I 55b: 56% (X = I)

SnBu3

PDC, AcOH, O 12 CH Cl 2 2 AcO Pd(0), Ph As, CuI, Et O, O 3 2 72% (X=I) ent-6: 51% (X = Br) 56: 76% (X = I)

Scheme 4.

Br Br 1) AcOH 50%, OH 1) dimethoxypropane, O acetone, p-TsOH, 88% reflux, 94%

2) AcOH, AcOAg, I , 2) Bu4NHSO4, OH 2 AcO O 87% NaOH, CH2Cl2, 79% I 44b 57 Br Br OH K2CO3, MeOH formal synthesis OH ent-5 94% HO O AcO 58 O 46b 1) THSCl, OH Imidazole, OTHS HSnBu , ABCC 3 DMF, 100% 1) IBX, DMF, 85% AcO THF, reflux 2) MeOH, HO 2) HF, CH3CN, 71% 100% O O 59 K2CO3, 79% 60

OH OPNB PPh3, DIAD, PNBA, 1) Br2, CCl4, 43% 5 O benzene, 63% O 2) K2CO3, MeOH, 50% O O 61 62 Scheme 5.

While Banwell and co-workers were performing the syntheses ent-bromoxone (ent-5) (see scheme 2), thus constituting a formal shown above, our group was also using a closely related strategy. synthesis of this non-natural epoxyenone. The outcome of this work was the total enantiodivergent synthesis For the synthesis of the natural product, we needed to debromi- of (+) and (-)-bromoxone [85]. Our chiral starting material was the nate intermediate 58. Manipulation of protective groups on 59 led same as Banwell´s: the diol derived from bromobenzene (44b). In to 60, and oxidation with IBX provided epoxyenone 61 in very this case, we build a key intermediate from which both bromoxone good yield. Although it was not easy to achieve -bromination, it enantiomers could be obtained. The strategy is shown in scheme 5. was possible when it was assayed over the p-nitrobenzoate derived Bromodiol 44b was protected as acetonide and subsequently from the Mitsunobu inversion (62). Methanolysis of the benzoate iodohydroxylated to give iodo acetate 57. Removal of the acetonide yielded (+)-bromoxone (5). protective group and treatment with base permitted the cyclization Going on working on this methodology, Banwell and co- of the oxirane ring present in the key intermediate 58. Methanolysis workers accomplished the preparation of (+)-isoepiepoformin (7) of the acetate yielded epoxydiol 46b, from which Banwell obtained starting from the iodobenzene derived diol 44c [86]. This time, the

8 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

I I I 1) p-MBDMA, OH OPMB OH p-TsOH.H2O, + NBS, H2O, THF, 97% OH OH OPMB THF, 37% 2) DIBAL-H, 2.5 : 1 44c TBME 63 64 I I I OH OPMB 1) NaOMe, THF, 99% OPMB +

HO OPMB HO OH 2) DMP, CH2Cl2, 92% O Br Br O 65 66 67

CH3 1) (t-BuOCON)2, 1) Me4Sn, Pd2(dba)3, OH ClCH2CO2H, Ph3, 73% Ph3As, NMP, 63% 7 2) DDQ, H O, CH Cl , O 2) Zn(OAc)2.2H2O, 2 2 2 O 48% MeOH, 66% 68 Scheme 6.

I I OH 1) NBS, H2O, THF, 68% OH 2) NaOMe, THF, 85% + AcO 3) (iPrOCON)2, PPh3, AcOH, 64% OTBS OH O 44c 69 70 CHO

1) NaClO2, t-BuOH 1) PdCl2(Ph3P)2, CuI, Et2NH, 85% H2O, NaH2PO4, 89% 13 Putative biogenetic precursor 2) DDQ, CH2Cl2, 72% OH 2) DMP, CH2Cl2, 55% of tricholomenyns B, C, D and E

AcO O 71 Scheme 7. authors protected the diol 44c as a p-methoxybenzyl acetal that was Once the side chain was inserted, the aldehyde 71 was obtained reduced with DIBAL-H, to produce a mixture of the corresponding by treatment with DDQ. Further oxidative steps (Pinnick and Dess- monoprotected diols 63 and 64. As it is shown in scheme 6, the Martin oxidation) yielded 13, the putative precursor of mixture when treated with NBS yielded a mixture of bromohydrins tricholomenyns B, C, D and E. Nevertheless, the attempts to con- (65 and 66), but only regioisomer 66 could be isolated and purified. vert 13 into any of the corresponding tricholomenyns failed, show- Epoxide 67 was efficiently prepared, and then, Stille reaction fol- ing that maybe this is not a precursor or perhaps the conversion into lowed by deprotection of the hydroxyl group to form 68 permitted the natural products is an enzymatic process not easy to mimic the preparation of the epimer of the natural product. Mitsunobu chemically. protocol for inversion of configuration led to (+)-isoepiepoformin Besides of the use of the chiral diols derived from aromatics, (7). Tachihara and Kitahara reported the preparation of (+)-bromoxone The last work of Banwell´s group concerning these kind of (5), (+)-epiepoformin (2) and (+)-epiepoxydon (4) [88], from a molecules was the preparation of a putative biogenetic precursor of chiral building block enzymatically obtained. The starting material tricholomenyns B, C, D and E [87], once again starting from chiral was obtained by an enantioselective reduction with baker´s yeast of iododiol 44c (scheme 7). This diol was subsequently treated with the corresponding -ketoester 72, as shown in scheme 8, where the NBS, then with base for epoxide formation, and finally under Mit- preparation of the key intermediate 79, an organoselenium com- sunobu conditions to yield acetate 69. After a significant synthetic pound, is illustrated. Chiral 73 was subjected to hydrolysis and effort to construct the appropriate side chain (70), it was coupled further acetylation yielding 74. Iodine substitution generated 75, with compound 69 by means of a Sonogashira reaction. which upon elimination conditions yielded 76. Silyl ether formation

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 9

O OH OAc CO Et 2 CO2Et CO H 2 PIDA, I , CCl , 1) LiOH, MeOH, H O 2 4 dry baker´s yeast 2 h, 91%

OO 74%, 98.4% ee 2) Ac2O, Py, 87% (2 steps) OO OO

72 73 74 OAc OH OTBS I 1) DBU, PhMe 1) TBSCl, imidazole, 2) K CO , MeOH H O , Triton B, THF, 80% 2 3 DMF, 98% 2 2 78% (2 steps) OO OO2) PPTS, aq.Me2CO, 90% O 75 76 77 OTBS OTBS

1) LiHMDS, THF, then TMSCl O O 2) PhSeCl, CH2Cl2 PhSe O O 78 79 Scheme 8. OTBS

1) NaH, MeI, THF 1) DBU, HCHO aq., THF O 4 2 PhSe 2) H2O2, NaHCO3, THF 2) H2O2, NaHCO3, THF 50% (45% from 78) O 3) HF, MeCN, 62% 3) HF, MeCN, 53% 79

1) DBU, Br2, THF 2) H2O2, NaHCO3, THF, 68% 3) HF, MeCN, 59% 5 Scheme 9. Me Me Me Br urea-hydrogen Br Py-HBr3, peroxide 1) t-BuOK, THF O TFAA, Na CO , 2) O , rose bengal, CH2Cl2, Br 2 3 Br 2 o CH Cl , 96% THF, h ; then thiourea, 80 -78 C, 81% 81 2 2 82 46% (2 steps) OH OH OAc 1) TBAF, AcOH, TBSCl, Lipase TL, THF, 99% O O O ent-21 imidazole, vinyl acetate 2) aq.NH3, MeOH, DMF, 51% 32% >99% ee 93% OH OTBS OTBS (±)-21 83 84 Scheme 10. followed by ketal deprotection gave 77, which upon epoxidation 21), a reduced epoxyquinoid molecule, was reported making use of yielded 78. an acetylation with lipase to obtain the enantiomer of the natural product [89]. It consisted in a very concise synthesis starting from -Selenylation afforded key selenide 79 that was easily converted into the three target natural products, as shown in scheme 9. dihydrotoluene (80), as shown in scheme 10. (+)-Epiepoxydon (4) was prepared by -selenylcarbanion formation After trans-bromination of 80 to form 81, the epoxide 82 was and reaction with formaldehyde, followed by elimination of phenyl- obtained as a 1.2:1 mixture of diastereomers. Double elimination of selenide and deprotection. (+)-Bromoxone (5) was prepared by a bromide, followed by photosensitized oxidation and reduction of similar protocol involving an -bromination, and the strategy to the non-isolated endoperoxide yielded the racemic 21. It was selec- form (+)-epiepoformin (2) was achieved through an -methylation. tively silylated on the less hindered alcohol to give 83 and then the Use of Lipase-Mediated Kinetic Resolutions racemic mixture was resolved by means of a lipase, thus obtaining chiral acetate 84. Removal of the protective groups permitted to Lipases have been widely used in this synthetic field to resolve achieve the total synthesis of (+)-theobroxide (ent-21). racemic mixtures. In 2005, the preparation of (+)-theobroxide (ent-

10 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

O OO OO OO PhS PhS PhS PhS vinyl acetate NaH, MeI, + Novozym 435 THF, 93%

OH OAc OH OTBS (±)-85 86 (+)-87 (4R)-88 ee> 99% O O O PhS PhS PhS H2O2, 1) m-CPBA O + O Triton B 2) CHCl3, heat THF, 80% 72 % (2 steps) OTBS OTBS OTBS 89 90 91 O O

Et3N.3HF THF, 87% 1 O + O

OTBS OTBS 92 93 O O OO PhS PhS PhS NaH, MeI, 1) MeONa, MeOH t-BuOOH, 86 THF, 93% 2) Cryst. from CH2Cl2, Triton B, 75% (2 steps) THF, 96% OH OTBS OTBS (-)-87 (4S)-94 95 ee> 95% O O O O PhS PhS 1) m-CPBA O + O Et3N.3HF O + O 2 2) CHCl3, heat THF, 86% 87 % (2 steps) OTBS OTBS OTBS OTBS 98 99 96 97 Scheme 11. MeO OMe MeO OMe N(Boc)2 MeO OMe N(Boc)2 N-benzylcinchonidinium NH2 O TFAA, anisole, CH Cl , chloride, TBHP, NaOH, 2 2 O

76%, 79.8% ee. O 15-crown-5, toluene, O MS 4A, 57% O 100 101 102 HO HO 1) acetylsalicyloyl MeO OMe OH chloride, NH 1) BF3:Et2O, t-BuOLi, THF NH CH2Cl2, 42% O O 2) K CO , aq.MeOH, O O 2 3 2) NaBH(OAc)3, 67% (2 steps) MeOH O O 103 104 79.8% ee HO OR 1) (C5H11CO)2, DMAP, NH THF, 90% DHMEQ (20) O + 99.9% ee 2) B.cepacia lipase O (Amano PS-IM) acetone, H2O, 69% O 105 R=COC5H11 Scheme 12.

(+)-Epiepoformin (2) and (+)-epoformin (1) have been synthe- 4R (88) and 4S (94) silylated compounds became the starting mate- sized [90] using chiral hydroxyenones obtained by lipase resolution rials for (+)-epoformin and (+)-epiepoformin, respectively. in a previous work of the authors [91]. As it is shown in scheme 11, -Methylation of 88 rendered a mixture of diastereomers (89), racemic sulfur-functionalized hydroxycyclohexenone 85, protected which subjected to epoxidation conditions yielded the correspond- as a dioxolane, was resolved with Novozym 435 to yield (+)-87 ing diastereomeric oxiranes 90 and 91. The oxidation/pyrolysis with an ee higher than 99%. After protection-deprotection steps, the process of 91 gave a mixture of endo-and exocyclic olefins (92 and

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 11

OAc OH OAc Br Pig pancreas lipase Br Br pH 7.0 phosphate buffer LiOH, Et2O, MeOH, 85% + Br Br Br OAc OH OAc (+)-107 (±)-106 (+)-106 39%, ee>99% 36%, ee>99% OH OH Br Br m-CPBA, CH2Cl2, 55% 1) DMP, CH2Cl2 O ent-5 2) NaHCO3, Na2S2O3, O O 55% (2 steps) 108 109 OH O O Br Br TES-Cl, 2,6-lutidine, Bu3Sn O CH2Cl2, 90% O

10 mol % Pd2dba3, 30 % mol AsPh3, OH OTES toluene, 92% ent-5 49b OH OH O

+ O NH4F, MeOH, 89% O OH 33

H O OTES O 110 H OTES O OTES 111

neat, rt, overnight, >99% Scheme 13.

93) that when treated for removal of the silyl group, were trans- took advantage of the enzymatic resolution by PPL used in 2000 for formed into the corresponding natural product 1. In a parallel route, the synthesis of (+)-bromoxone [96] by Altenbach´s group. In this compound 86 was deacetylated and crystallized to give (-)-87. This case, they chose the other enantiomer of 106 (scheme 13) for pre- product was subjected to a similar protocol, obtaining subsequently paring (-)-bromoxone as the precursor for panepophenanthrin. ketone 94, methylated 95, a mixture of epoxides 96 and 97 and olefins 98 and 99, to afford 2. Enzymatic resolution of racemic 106 generated compounds (+)- 106 and (+)-107 in optically pure form. Methanolysis of (+)-106 Lipases have also been used in the synthesis of (-)-DHMEQ produced 108 which upon epoxidation yielded 109. Oxidation fol- (20) reported by Hamada et al. [92] In this case, the enzymatic lowed by epoxide opening and elimination generated ent-5. resolution was used to improve the ee obtained when preparing the starting material (102) by an asymmetric epoxidation of an amino- Having prepared (-)-bromoxone, the remaining alcohol was quinine monoketal (100) already described [93] (scheme 12). In the protected to produce 49b and Stille C-C coupling was performed, to hands of the authors, the methodology was not reproducible, and obtain the enantiomerically pure monomer 110. A biomimetic di- the best ee obtained was 79.8%. merization proceeded smoothly in an spontaneous way to yield 111. Deprotection of hydroxyl groups led to the natural dimer 33. Compound 100 was transformed into epoxide 101 and deprotected to furnish 102. Amide formation led to 103. Deprotection Mehta and co-workers synthesized a large number of natural and reduction generated 104. This compound was treated with hex- products of the epoxyenone family taking advantage of lipase reso- anoic anhydride to give a dihexanoate, which upon enzymatic resolutions. Their synthetic strategy starts from the readily available lution with Amano lipase generated DHMEQ (20) and hexanoate Diels–Alder adduct 112 [97] (scheme 14) and the key step is the 105. The lipase completely hydrolyzed the enantiomer (2S, 3S, 4S), lipase mediated enzymatic desymmetrization of 112 derivatives. bearing the absolute configuration of the synthetic target, thus con- O stituting a straightforward route to DHMEQ. H O During the revision process of this review, Niitsu et al. pub- + H lished a very similar synthetic sequence for DHMEQ [94]. In this case, the authors prepared epoxide 103 in a racemic way, and con- O verted it into a dihexanoate. This diester was resolved again with B. O 112 cepacia lipase (Amano PS-IM). Further oxidation, deprotection and reduction steps provided (-)-20 in an enantiomerically pure state. Scheme 14. In 2006, Comméiras et al. reported the total synthesis of the In 2004, Mehta and co-workers reported the enantioselective to- dimeric epoxyquinol (+)-panepophenanthrin (33) [95]. The authors tal synthesis of (-)-cycloepoxydon (16) [98]. As shown in scheme

12 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

OH O O H H O H2O2, Na2CO3, DBU, formalin, H H Ph2O acetone, 0˚C, 0˚C, quant. 240˚C, 97% O 95% HO O O O O 112 113 114

OH O OAc O OAc O

Lipase PS 30 (Amano), DIBAL-H, THF, O O vinyl acetate,TBME, O - 78˚C, 74% 0˚C, 82%, 99% ee.

OH O OH O OH OH 115 116 117

OAc O OAc O

1) TEMPO, O2, CuCl, DMF, 77% n-C4H9PPh3Br, t-BuOK, h, 450 W O O (Hanovia) 2) Ac O, pyridine, H THF, 0˚C, 54% 2 C3H7 I2, CDCl3, quant. DMAP, CH2Cl2, 0˚C, 71% O OAc OAc 119a : cis isomer 118 119b : trans isomer

OAc O OTBS O

1) LiOH, MeOH, 0˚C, 66% 1) m-CPBA, O O CH2Cl2, 86% 2) TBSCl, imidazole, 16 C3H7 C3H7 DMAP, CH2Cl2, 0˚C, 92% 2) HF, CH3CN, OAc OH 0˚C, 69% 119b 120 Scheme 15. OAc O O 1) C H PPh Br, t-BuOK, 6 13 3 AcO THF, 0˚C, 51% LiOH, MeOH O O C5H11 0˚C, 63% 2) h, 450W, I2, CDCl3, 98% OAc O OAc 122 118 O OH

HO HO O DIBAL-H, THF, 25 + O -78˚C, 81% C5H11 C5H11 OH OH (1 : 2) 124 123 Scheme 16.

15, they synthesized optically active epoxyketone 116 employing occurred stereoselectively. Removal of the protective group fur- lipase-mediated desymmetrization of meso-diol 115 which was nished (-)-cycloepoxydon (16). easily obtained from 112 [99]. Dione 112 was epoxidized to 113, In a previous work, [100] Metha had already prepared chiral followed by diformylation to give 114. Classical retro Diels-Alder epoxide 116 in the same way as shown in scheme 15. In that case, reaction of 114 afforded 115 in excellent yield. Both regio- and 116 was used as a key intermediate for the synthesis of (-)- stereoselective DIBAL-H reduction of 116 furnished 117. TEMPO- epoxyquinols A and B. This publication was discussed by Shoji in mediated oxidation of the allylic primary hydroxyl and protection 2007 [64]. of the secondary hydroxyl gave diacetate 118. The four-carbon side For the enantioselective synthesis of (+)-eupenoxide (25) and chain was constructed through a Wittig olefination while both iso- putative “(+)-phomoxide” (121), the enantiomerically pure diace- mers, 119a and 119b were obtained. Photochemical cis-trans iso- tate 118 was chosen as starting material (scheme 16) [54]. The side merization of the disubstituted double bond afforded 119b quantita- chain was linked through a Wittig olefination and then a photoiso- tively. Acetate hydrolysis and selective protection of the primary merization furnished the desired E-isomer 122. Protective group hydroxyl group rendered TBS derivative 120. Epoxidation of the removal gave 123 and further DIBAL-H reduction of the carbonyl double bond located at the side chain with m-chloroperbenzoic acid group led to a mixture of epimeric alcohols 25 and 124.

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 13

OAc O O 1) C H PPh Br, t-BuOK, 6 11 3 AcO LiOH, MeOH, THF, 0˚C, 25% O O 2) h, 450W, I , CDCl , 0˚C, 74% 2 3 C H 98% 3 7 O OAc OAc

118 125 O OH

HO HO DIBAL-H, THF, O ent-24 + O -78˚C, 78% C3H7 C3H7 OH OH 126 (1 : 1.6) 121

Scheme 17.

OAc O OAc OH OAc OAc

1) TESCl, Py, -15˚C, 70% 1) Ac2O, Py, DMAP, 97% O O O 2) NaBH , MeOH, -55˚C, H 4 2) PCC-SiO2, 80% 85% OH OH OTES OH O OAc 117 127 128

OAc OAc OAc OAc

C6H13MgBr, AcO AcO O + O + O THF, -10˚C AcO HO AcO

C6H13 OH C6H13 OAc OH

129 (10:1) 130 131

O OH

HO 1) K2CO3, MeOH, 0˚C, 85% O 26 HO 2) TEMPO, NaOCl, NaClO2, NaH2PO4, 50% C6H13 OH

132 Scheme 18.

On the other hand, to prepare a structure named as “(+)- The enantioselective synthesis of the natural product (+)- phomoxide” (121), an analogous strategy using (E)-2- integrasone (26) was accomplished by Mehta in 2005 [102]. As hexenyltriphenylphosphonium bromide in the Wittig reaction was shown in scheme 18, they used intermediate 117 as starting mate- employed in order to link the corresponding diene side chain rial, protecting selectively the primary hydroxyl group. Further (scheme 17). Deprotection of diacetate 125 to 126 and DIBAL-H stereoselective sodium borohydride reduction took place from the reduction led to a mixture of triols ent-24 and 121 where the major opposite face of the epoxide ring furnishing diol 127. Convenient epimer corresponds to the assigned structure for “(+)-phomoxide” manipulation led to aldehyde 128 through TES deprotection and (121). oxidation of the primary hydroxyl group. Treatment of aldehyde In this paper, the authors suggested the revision of the 128 with hexylmagnesium bromide afforded stereoselectively 129 stereostructures assigned previously by Duke and Rickards [101] in and 130 (10:1). The triacetate 131 was also obtained through the 1984, based on the mismatch of spectral data with the synthesized reduction of aldehyde 128 involving acetate migration. Careful base molecules. A few years later, they published a paper establishing hydrolysis over the major isomer 129 and selective oxidation of the the structure of the natural products eupenoxide and phomoxide primary hydroxyl functionality with sodium chlorite catalyzed by [55]. They concluded that (+)-eupenoxide, originally reported by TEMPO and bleach was accomplished. This reaction directly fur- Rickards, has stereostructure 25 while (-)-phomoxide must be re- nished integrasone 26 through the concomitant cyclization of the vised to 24 (Fig. 2). proposed carboxylic acid intermediate 132.

14 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

O OH OAc O OH O 1) TBSOTf, 2,6-lutidine 1) DIBAL-H, THF, C4H9PPh3Br, CH2Cl2, 0˚C, 98% -78˚C, 82% H t-BuOK, THF, O O O 2) LiOH, MeOH, 0˚C, 2) MnO , CH Cl , 79% 0˚C, 65% 85% 2 2 2 OTBS OH OH OTBS OTBS OTBS 117 133 134

OH OAc OAc

C3H7 1) Ac2O, Py, DMAP C3H7 CH2Cl2, 0˚C, 98% O O + O TBSO HO C3H7 2) HF, CH3CN, 0˚C, 80% OTBS OH OTBS OTBS (E:Z; 1:1) 135 136 137

C3H7 1) TEMPO, NaOCl, NaClO2, 1) 10% Pd-C, H2, EtOAc, 94% NaHPO4, cyclopentene, 35% O 137 O 18 2) LiOH, DME, 0˚C, 70% 2) MnO2, CH2Cl2,, 93% 3) TBAF, AcOH (1:1), THF, 90% O OTBS

138 Scheme 19. OH

O 1) H O , Na CO , 1) TBSCl, imidazole, 2 2 2 3 O acetone, 0˚C, 96% DMAP, DMF, 92%

2) DBU, formalin, O 2) NaBH4, MeOH, -15˚C, THF, 0˚C, 95% O O 81%

112 139

OTBS OTBS O OTBS Lipase PD-D O OAc (Amano), +

HO O vinyl acetate O HO O O (±)-140 (-)-140 (+)-141 Scheme 20.

Mehta also described the asymmetric synthesis of the natural face. Oxidation and silyl ether cleavage delivered (-)-EI-1941-2 product (-)-EI-1941-2 (18) starting from intermediate 117 [103]. (18) in good yield. Protection as di-TBS derivative and acetate hydrolysis led to hy- Epoxydon (3), epiepoxydon (4), and phyllostine (27) were syn- droxyenone 133 which was further reduced and oxidized in the thesized by Mehta and co-workers in 2004 [104]. The key reaction primary hydroxyl group to deliver the -hydroxyaldehyde 134 was the desymmetrization of 140 through enzymatic resolution (scheme 19). using lipase PD-D (Amano) (scheme 20). Precursor 139 was ob- Wittig olefination over 134 with the ylide derived from n- tained by epoxidation and hydroxymethylation of 112 in excellent butyltriphenylphosphonium bromide led to a 1:1 mixture of E:Z yield. Further protection of the primary hydroxyl group and stereoisomers not amenable to chromatographic separation. Acetylation selective reduction of the carbonyl moiety furnished 140 as a race- of 135 and chemoselective deprotection of the primary hydroxyl mic mixture. Enantiomerically pure (-)-140 and (+)-141 served as group afforded the readily separable olefines (Z)-136 and (E)-137. starting materials for the enantioselective preparation of the desired The primary hydroxyl group in E-isomer was subjected to oxi- compounds. dation with sodium chlorite in the presence of TEMPO and sodium As depicted in scheme 21, retro Diels-Alder reaction and re- hypochlorite to deliver lactone 138 after acetate hydrolysis. Al- moval of the acetate over (+)-141 furnished epoxyenone (+)-142 though the mecanism of formation of the lactone is not clear, the which after complete deprotection rendered (+)-epiepoxydon (4). authors suggested an oxidative 6-electrocyclization. Partial cata- Inversion of the configuration at C4 on (+)-142 using Mitsunobu´s lytic hydrogenation over 138 proceeded stereoselectively from the protocol and posterior removal of the silyl group furnished (+)-

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 15

1) PPh3, DIAD, PNBA, THF, -50˚C to rt 3 2) LiOH, MeOH, 0˚C, 65% 3) HF-Py, THF, 0˚C, 76% OTBS OH OAc 1) Ph2O, 240˚C, 93% HF-Py, THF O 4 2) LiOH, MeOH, 0˚C, 75% 0˚C, 80% O O OTBS O (+)-141 (+)-142

1) PDC, CH2Cl2, 0˚C, 89% 2) HF-Py, THF, 0˚C, 72% 27 Scheme 21. OAc

OTBS TBSOTf, OAc 1) Ph O, 230˚C, 93% 2 O 2,6-lutidine

2) NaBH4, MeOH, CH2Cl2, -10˚C, -50˚C, 87% 83% O O OTBS OH (+)-141 143 : = 1: 2 OAc O 1) LiOH, MeOH, 0˚C, 68% 2) MnO2, CH2Cl2, 86% O O , 3) HF, CH3CN, 0˚C, 80% OTBS OTBS OH OH 144 putative "parasitenone" + (2 : 1) 146 OAc 1) LiOH, MeOH, 0˚C, 70% 2) MnO , CH Cl , 83% O 2 2 2 ent-9

3) 40% HF, CH3CN, 0˚C, 80% OTBS OTBS 145 Scheme 22. epoxydon (3). Oxidation of the hydroxyl functionality in (+)-142 on a previously reported protocol [108]. Compound 147 was further and removal of the protective group led to (-)-phyllostine (27). converted to epoxide 148 and epoxyenone 149 following reported In 2005 Mehta reported the preparation of ent-RKTS-33 (ent-9) procedures, which involved epoxidation, hydroxymethylation and retro Diels-Alder reaction [109]. Stereoselective DIBAL-H reduc- and a putative structure of natural product “parasitenone” [105]. In tion and further oxidation of the primary hydroxyl group furnished this letter they used enantiomerically pure (+)-141 as starting mate- epoxyaldehyde 150. Wittig olefination rendered (E)-,- rial. Retro Diels-Alder reaction and further reduction, led to a epi- unsaturated ester 151 in high yield. Addition of methyl lithium meric mixture 143. Protection of the secondary hydroxyl group afforded tertiary alcohol and they obtained dienone 152 after oxida- afforded a separable mixture of 144 and 145. As shown in scheme tion of allylic sec-hydroxyl group. Exposure of 152 to Dowex-1 22, convenient manipulation of 145 furnished enantiomerically pure resin in methanol led to 53b through a concomitant methylation and ent-RKTS-33 (ent-9). In a similar strategy, manipulation of 144 desilylation reaction. Through a stereospecific intermolecular Diels- gave enone-diol 146 corresponding to the structure previously as- Alder reaction 53b was converted into the dimer 54. signed to the natural product “parasitenone”. However, the spectral data of this compound and those reported by Son et al. [106] were A second exposure to Dowex-1 resin triggered the SN2´ dis- different. Through a critical examination of the spectral data re- placement/cyclization in 54 to furnish exclusively the natural product (+)-hexacyclinol 32. ported for “parasitenone” the authors determined that the natural product isolated from Aspergillus parasiticus was already known epoxydon (3) instead of a new one called “parasitenone”. Non-enzymatic Methods In 2008 Mehta accomplished the enantioselective synthesis of Maycock´s synthesis of (+)-bromoxone natural (+)-hexacyclinol (32) (scheme 23) [107]. Using adduct 112 Maycock´s group prepared (+)-bromoxone (5) in a short and ef- as starting material, they obtained enantiomerically pure 147 based ficient synthesis, using a natural compound of the chiral pool as the

16 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

HO 1) NaBH4, CeCl3, 0˚C, 92% O H O O H 2) LipasePS (amano), 1) H2O2, Na2CO3, vinyl acetate, THF, 89% acetone, 67% H 3) TBSCl, imidazole, DMAP, H H 2) DBU, THF, 0˚C, CH2Cl2, 85% then formalin, 85% O 4) K2CO3, MeOH O TBSO 5) PDC, CH2Cl2, 87% TBSO 112 147 148 OH O O OH 1) DIBAL-H, THF, Ph O, 240˚C, 2 -78˚C, 88% H Ph3P=CHCOOMe, O 85% O 2) TEMPO, CuCl, C6H6, 92% O2, DMF, 95% OTBS OTBS 149 150 OH OH O MeOOC 1) MeLi, THF, -78˚C to -10˚C, 95% Dowex-1x8 O O 2) MnO2, CH2Cl2, 72% MeOH, 55%

OTBS OTBS 151 OMe 152

OMe O MeO O neat, 99% Dowex-1 x 8, O 32 H O EtOAc, 99% O OH H 53b OH OH O 54 Scheme 23. O O HO COOH

1) acetone, dry HCl, 89% Ac2O, DIPEA, DMAP 2) Ac2O, Py, 92% CH Cl , 0oC, 99% OH 2 2 HO OH 3) LiAlH4, Et2O O O 4) NaIO4, H2O, 91% O OH O (-)-quinic acid 153 154 155 O O O I I2, DMAP H2N-PMB, Cs2CO3, N-PMB 1,10-phenantroline, + N-PMB Py, 80% xylene, 95% O O O O O O

156 O 157 4:1 158 O

NaOH, THF, N-PMB TBSCl, DMAP, H O , Triton B, 157 N-PMB 2 2 0˚C, 88% DIPEA, CH2Cl2, THF, 0˚C, 90% 80% OH OTBS 159 160 O O Br HBr, MeOH, HF aq., CH3CN, O N-PMB O 5 80% 89%

OTBS OTBS 161 162 Scheme 24. source of chirality [110]. The methodology involved the use of an eutypoxide by the same authors [111]. -Iodination of this com- aziridine as protective and directing group in the cyclohexenone pound delivered 156, which was subjected to an aziridination with core (scheme 24). (-)-Quinic acid (153) was transformed to 155 4-methoxybenzylamine through a Michael addition cyclization. The through alcohol 154 as already reported for the synthesis of (+)- presence of an adjacent asymmetric center induced the stereoselec-

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 17

MeO OMe O p-Tol pro-S S 1) AlMe , CH Cl , -78˚C, 65% 1) (R) , LDA, THF, -78˚C 3 2 2 HO 2) oxalic acid, THF, H2O, 78% 2) NBS, THF, -78˚C, 53% S O O p-Tol 163 (R) 164 O O O Br

Li2CO3 , LiBr, m-CPBA, CH2Cl2, TBHP, Triton B, Me DMF, 100˚C, 86% Me 0˚C, 99% Me THF, 0˚C, 72% HO HO HO SOp-Tol SOp-Tol SO p-Tol (R) (R) 2 165 166 167 O OH

O DIBAL-H, THF, Cs2CO3 , CH3CN CeCl3 , NaBH4 O 2 21 Me -78˚C, 67% Me 54% 99% HO (77:23 dr) HO

SO2p-Tol SO p-Tol 168 2 169 Scheme 25. tivity in the formation of 157 in favor to 158 (anti:syn, 4:1). Elimi- thus allowing the epoxidation through the opposite side. In this nation of 157 afforded 159, which was protected to yield compound synthesis, asymmetric epoxidation afforded 172 in high yield with a 160. The aziridine group showed a directing ability for the epoxida- 93:7 enantiomeric ratio. Stereoselective reduction with DIBAL-H, tion of the double bond, delivering 161 exclusively. Hydrobromic followed by montmorillonite K10 deprotection afforded 173 in an acid treatment to eliminate the aziridine moiety afforded 162, which 85:15 anti:syn ratio. Finally, Stille cross-coupling reaction with the was deprotected to give (+)-bromoxone (5). appropriate alkynylstannane delivered (-)-harveynone (11) in a short and efficient route. Carreño’s Methodology MeO OMe MeO OMe In Carreño’s synthesis of (+)-epiepoformin (2) and (-)- I I I theobroxide (21) [112,113] the key step involved a stereocontrolled PIDA TrOOH, NaHMDS O conjugated addition of trimethylaluminium to a chiral sulfoxide-p- MeOH, 56% L-DIPT, toluene, 84% quinol [114] in order to introduce the required asymmetry (scheme OH 25). p-Benzoquinone dimethylmonoacetal (163) reacted with the O O lithium anion of (R)-methyl-p-tolylsulfoxide, and then was sub- 170 171 172 O jected to hydrolysis of the acetal to afford sulfoxide 164. Diastereo- and regioselective addition of AlMe occurred at the pro-S conju- I SnBu3 3 1) DIBAL-H, THF gated position, on the same face of the hydroxyl group. Trapping O 11 the enolate intermediate with NBS furnished -bromoketone 165. 2) montmorillonite K10, Pd(PhCN)2Cl2, HBr elimination with lithium salts afforded 166, which was oxi- 93%, (anti:syn = 85:15) AsPh3, THF, 83% OH dized to sulfone 167 with m-CPBA. Epoxidation with TBHP led to 173 168 as a unique diastereomer. Reduction of the carbonyl group with Scheme 26. DIBAL-H furnished a 77:23 mixture of diastereomers which were isolated after flash chromatography to afford 169 as the major com- Porco’s Methodology pound. Elimination of methyl p-tolylsulfone allowed the prepara- Porco’s synthesis of (-)-EI-1941-2 (18) [117] employed qui- tion of natural product (+)-epiepoformin (2) with 96% ee. Luche´s none 178 prepared from aromatic compound 174 as previously reduction of this natural compound afforded (-)-theobroxide (21) reported [116,118]. Aromatic compound 174 was (scheme 27) almost quantitatively. An advanced precursor of (+)-harveynone brominated and selectively protected to yield 175. Reduction of the (11) was also synthesized through this methodology [112], but the aldehyde and protection of the formed alcohol afforded 176. De- isolation of the natural product was not possible due to enone insta- silylation and oxidation gave 177 that when transacetalized, permit- bility under the basic conditions required to eliminate the - ted to obtain quinone 178. In this strategy, a tartrate-mediated nu- hydroxysulfone. This constitutes a limitation of the use of the - cleophilic epoxidation is used again for the asymmetric construc- hydroxysulfoxide group. tion of the natural product. Compound 178 reacted with tritylhy- droperoxide in the presence of NaHDMS and D-DIPT to furnish Taylor’s Synthesis of (-)-harveynone (11) 179 in a 99% ee. Stille cross-coupling for the insertion of the Taylor’s synthesis of (-)-harveynone (11) [115] (scheme 26) alkenyl side chain afforded 180, which upon hydrolysis delivered started with a double oxidation of 3-iodophenol (170) with an hy- epoxyquinone 181. Stereoselective reduction furnished 182 pervalent iodine reagent (PIDA) to afford ketal 171. Epoxide 172 (anti:syn, 9:1). Oxidation with CuCl/TEMPO/O2 followed by reac- was obtained through a tartrate-mediated asymmetric epoxidation tion with Bobbit’s reagent allowed the preparation of 183. Protec- methodology developed by Porco et al. [116], which was exten- tion of this compound as silyl ether afforded 184, which was previ- sively used by the authors. Porco postulated that NaHMDS and L- ously reported by Shoji and Mehta[103,119], thus consisting in a DIPT build a cavity that blocks one face of the quinone monoketal, formal synthesis of (-)-EI-1941-2 (18).

18 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

OH OMe BPSO OMe 1) TBAF, THF, OHC o 1) Br2, CHCl3, 94% OHC 1) NaBH4, EtOH, 0 C, 93% 0oC, 100% 2) TBSCl, imidazole, 2) PIDA, MeOH, 2) BPSCl, imidazole, CH Cl , 94% 84% 2 2 Br DMF, 93% Br 3) MeI, NaH, THF, OH OTBS 65oC, 72% OTBS 176 174 175 Et Et Et Et MeO OMe HO Et BPSO BPSO O O BPSO , PPTS, O O HO Et TrOOH, NaHDMS,

Br D-DIPT, toluene, O benzene, 70oC, 89% O Br 70%, 99% ee Br 177 O O 178 179 Et Et

n-Pr HO O HO OH SnBu BPSO HF aq., 3 O O DIBAL-H, THF, o Pd2dba3, AsPh3, CH3CN O -78 C, 77% O O toluene, 110oC, 89% 80% (anti:syn, 9:1) n-Pr n-Pr n-Pr O O O 180 181 182 O OH O OTBS formal 1) CuCl, TEMPO, O2, O TBSOTf, DBMP O O synthesis 2) Bobbit´s reagent, o 18 CH2Cl2, 0 C, 80% O SiO2, CH2Cl2, 56% n-Pr n-Pr O 183 O 184 Scheme 27. O OTBS O Br Br Br 1) i. neat, 180oC 1) TBAF, THF, 0oC, 100% BPSO ii. PIDA, MeOH, 70% 2) allyl bromide, K2CO3, O O DMF, 97% BPSO 2) HO(CH2)3OH, PPTS, BPSO OMe OMe benzene, 80oC, 90% 176 185 OH OH 186 O O Br Br 1) i.DMP, CH2Cl2, 1) NaIO4, OsO4, THF, TrOOH, NaHDMS, O H2O, 62% BPSO BPSO ii. o PPh3 O O L-DIPT, toluene, -40 C, O O 2) BH3, t-BuNH2, MeOH, 91%, 91% ee. COOt-Bu o H2O, THF, 0 C, 76% CH Cl , -5oC, 94% 187 188 2 2

COOt-Bu O COOt-Bu O C H Br 1) 5 11 C5H11 Bu3Sn MeOBEt3, O O Pd(PPh ) , toluene, 110oC, 94% o BPSO 3 4 NaBH4, -78 C 2) TBAF, AcOH, THF, 76% O O 3) HF aq. CH3CN, 93% OH O 190 189 COOt-Bu O COOt-Bu O

C5H11 C5H11 HF, CH CN, 70% O 3 O + 14

OH OH OH OH 191 192 39% 48% Scheme 28.

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 19

Porco’s group also completed the first enantioselective synthe- MeO O sis of (+)-ambuic acid (14) and its related dimer (+)-torreyanic acid O OMe (38), confirming their absolute stereochemistry [120]. By using a O similar strategy as shown above, ambuic acid synthesis (scheme 28) O O started with a selective deprotection and allylation of compound O O 176 to afford 185. OH H OH Upon Claisen rearrangement at high temperatures compound O 185 was transformed to an ortho-allylphenol, which was oxidized O O to quinone and then protected to afford 186. Oxidative cleavage and Grafe's former Rychynovsky's confirmed structure of hexacyclinol structure of (+)-hexacyclinol (32) further reduction allowed the formation of 187, which upon nucleophilic epoxidation afforded 188 with excellent yield and 91% ee. Fig. (5). Former and confirmed structure of (+)-hexacyclinol. Evidence showed that homoallylic alcohol directed the stereochem- endoperoxide moiety [66]. La Clair’s synthesis of this proposed istry of the epoxidation. Oxidation of this alcohol followed by Wit- structure [125] gave rise to an academic debate known as the “hex- tig reaction allowed the side chain insertion leading to 189. Stille acyclinol dispute’’ [69]. Therefore, Rychnovsky proposed an alter- cross-coupling permitted the insertion of the remaining side chain native structure [67] (Fig. 5) based on 13C-NMR chemical shifts and further deprotection steps led to key compound 190. By reduc- calculations. Porco and co-workers reported the first total synthesis tion, a diastereomeric mixture of 191 and 192 was formed (syn: of the revised structure of (+)-hexacyclinol along with the unambi- anti, 1.2: 1). After separation, the major compound 192 was depro- guous confirmation of the proposed reassignment for this com- tected furnishing (+)-ambuic acid (14). pound (Scheme 31) [124]. (+)-Torreyanic acid (38) was prepared from compound 190 Porco’s synthesis of compound 197 has been previously de- (scheme 29) by oxidation with Dess-Martin periodinane followed scribed by this group for the synthesis of panepophenanthrin (33) [126]. It involved an asymmetric epoxidation of 194 that yielded by deprotection, through an oxidative dimerization cascade. 195 in 95% ee., which by reduction afforded 196. Mitsunobu inversion produced compound 197, which was deprotected with mont- O COOt-Bu morillonite to deliver natural product (+)-bromoxone (5). Then it

C5H11 was protected as silyl ether 198 followed by Stille reaction to insert 1) DMP, CH2Cl2, 80% the alkenylic side chain to afford 199. Deprotection and further O 38 standing at room temperature allowed the preparation of “pre- o 2) TFA, CH2Cl2, 0 C, 100% hexacyclinol’’ (54) by a highly diastereoselective Diels-Alder di- OH O merization of the epoxyquinol monomer. SN2’ substitution- 190 cyclization was performed with montmorillonite affording (+)- Scheme 29. hexacyclinol (32). Porco and co-workers also prepared by the same strategy ECH Porco’s group also completed the synthesis of the spiroisoxa- (8), epoxyquinols A (28) and B (29), and epoxytwinol A (31). zoline natural product (+)-calafianin (37) by using an asymmetric [121,122] As shown in scheme 30, compound 178 was subjected to nucleophilic epoxidation and a zirconium-mediated nitrile oxide a tartrate-mediated asymmetric epoxidation to yield epoxide ent- cycloaddition as the key steps (scheme 32) [127]. Compound 194 179 with 96% ee. Stille reaction allowed the alkenyl side chain was prepared according to their previously described protocols insertion affording 193. Deprotection followed by stereoselective [126] which upon epoxidation led to ent-195. Methylenation of reduction delivered the monomeric precursor ECH in a high di- epoxyketone afforded 200. 1,3-Dipolar cycloaddition of vinyl epox- astereomeric ratio (18:1). Oxidation of hydroxymethyl alcohol al- ide with Zr(IV) alkoxide allowed spiroisoxazolidine 201 construc- lowed the dimerization cascade to afford epoxyquinol A, B and tion in a 1.8:1 dr, favoring the anti compound. Diamide 202 was epoxytwinol A, with a solvent dependent ratio. constructed by reaction of 201 and 1,4-diaminobutane with 2- hydroxypyridine as an activator along with Zr(O-t-Bu) and These authors also reported the synthesis of epoxytwinol A 4 Zn(OTf)2. Acetal deprotection in aqueous HF completed the syn- (31), from monomeric ECH (8), conducted through the formation of thesis of (+)-calafianin (37). Porco and co-workers completed the an alkoxysilanol to promote a formal [4+4] dimerization [123]. synthesis of all four stereoisomers of this compound, therefore con- (+)-Hexacyclinol (32) was prepared by Porco’s group [124], firming the stereochemical assignment for the natural product. bringing light to the debate of the previous mis-assigned structure Shoji’s Methodology of this natural product. Gräfe and co-workers isolated (+)- hexacyclinol from a siberian fungus and proposed the structure Shoji’s first generation syntheses of ECH (8) and epoxyquinols shown in figure 5, containing an epoxyketone and a highly strained A (28) and B (29), employed a hafnium-mediated diastereoselective

Et Et Et Et Et Et

BPSO BPSO BPSO O O TrOOH, NaHDMS O O O O SnBu3

L-DIPT, toluene, 50oC, O O Pd dba , AsPh , 97% , 96%ee 2 3 3 Br Br toluene, 110oC, 98% O O O 178 ent-179 193

1) HF aq., CH3CN, 84% 1) O , TEMPO, CuCl, DMF 8 2 28 ++29 31 o (36%) (30%) 2) DIBAL-H, THF, -78 C, 72% 2) MeOH, H2O (3%) Scheme 30.

20 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

O O O O O O Br Br Br TrOOH, NaHMDS LiEt3BH 1) PPh3, DIAD, THF O O L-DIPT, toluene, THF, 98% 4-nitrobenzoic acid 84%, 99% ee. 2) NaOMe, MeOH, 80% O O OH 194 195 196

O MeO O O Br Br SnBu3 montmorillonite K10 TESCl, 2,6-lutidine, O O 5 CH Cl , 98% DMAP, CH Cl , 83% Pd2dba3, AsPh3, 2 2 2 2 toluene, 96% OTES OH OMe 198 197

OMe MeO O O

1) Et3N.3HF, montmorillonite K10 H O 32 O O CH3CN EtOAc, 99% 2) neat, 87% H OH OTES OH 199 O "pre-hexacyclinol" (54) Scheme 31.

O N OH O O O O O O Br TrOOH, NaHMDS, Br Br CH3PPh3Br, EtO Cl D-DIPT, toluene, O O t-BuOK, THF, 95% 82%, 99% ee Zr(O-t-Bu)4, toluene, 93% (dr = 1.8: 1) O O 194 ent-195 200

O O Br H N NH HF aq., CH3CN, O O 2 2 O 37 Br CH Cl , 90% Zr(O-t-Bu) , Zn(OTf) , 2 2 O 4 2 O O 2-HYP, toluene, 78% H N N O N N H N O O

CO2Et 201 202 O Br O O

Scheme 32.

Diels-Alder reaction in the presence of a chiral auxiliary to generate tion with oxirane opening to construct the enone moiety. Deprotec- the required asymmetry (scheme 33) [128-130]. Diels-Alder reaction of 210 allowed the synthesis of the ECH analog, RKTS-33 (9). tion between furan and chiral acrylate 203, derived from Corey’s Protection followed by -iodination afforded 211. Suzuki cross- chiral auxiliary, in the presence of HfCl4 at low temperature, prefer- coupling with 1-propenylborate followed by deprotection gave the entially yielded the endo adduct 204 with high diastereoselectivity. monomeric ECH (8), which upon oxidation of the hydroxymethyl Iodolactonization of this compound allowed the recovery of the chain triggered the biomimetic cascade involving a 6- chiral auxiliary and recrystalization afforded 205 with 99% ee. electrocyclization and Diels-Alder dimerization [130] to form ep- Lactone hydrolysis permitted epoxide formation by nucleophillic oxyquinols A (28) and B (29). The authors also described the displacement and further esterification gave epoxymethylester 206. preparation of several ECH analogues with different side chain -Elimination rendered 207, and then Sharpless epoxidation pro- motifs, by variation of the cross-coupling partners at the Suzuki duced 208 as a single isomer. Reduction and protection delivered reaction step [17]. Evaluation of biological properties and structure- 209, which upon oxidation and SiO2 treatment, underwent elimina- activity relationship of these ECH-related molecules, defined as

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 21

O O SO2Np O 1) KOH, I , H O, furan, HfCl4, 2 2 I DMF, 60˚C * CH CN O toluene OR 3 2) MeI, 94% COOMe 81% O -45˚C, 83% O O O O (endo:exo, 68:32) 204 205 206 203 OH OH 1) NaBH4, MeOH VO(acac)2, TBHP LDA, THF, O O 2) TBSCl, NEt3, DMAP CH2Cl2, reflux, 96% CH Cl , 81% -90˚C, 92% COOMe COOMe 2 2 O 207 208 O OH 1) TEMPO, NaOCl, NaHCO3, 1) (MeO)2CMe2, PPTS, KBr, CH2Cl2, H2O, -10˚C Amberlyst 15 O CH2Cl2, 40˚C, 64% O 9 2) SiO2, toluene, 60˚C, 89% i-PrOH, 71% 2) I2, PhI(OCOCF3)2, Py, BHT, CH Cl , 86% O OTBS OH OTBS 2 2 209 210 O I O 1) (HO)2B , AsPh3,

Pd(PhCN) Cl ,THF, H O, 77% 1)MnO2, CH2Cl2, 0˚C 2 2 2 8 O O 28 (40%) + 29 (25%) 2) Amberlyst 15, MeOH, 84% 2) toluene

211 Scheme 33. O O O 1) NaOH aq. I 1) KOH, DMF, 60˚C furan Cl 2) I2, CH2Cl2, 0˚C O 2) MeI, 94% COCl 3) Na S O , 42% O 212 2 2 3 205 3) LDA, THF, -90˚C, 92% 213 OAc OH OH 28 (24%) Pseudomonas stutzersi O + O (Scheme 33) 29 (33%) O lipase (Meito TL) vinyl acetate COOMe COOMe 30 (1%) COOMe 214 (+)-207 31 (8%) (±)-207 48%, (96% ee) 49%, (99% ee) Scheme 34.

RKTS, showed that RKTS-33 (9) and RKTS-34 (10) proved to be scheme 33. This second generation synthesis, suitable for large- more effective than ECH towards Fas-mediated apoptosis. scale preparations, allowed in this case the formation of the minor In Shoji’s second generation synthesis of these compounds, the products epoxyquinol C (30) and epoxytwinol A (31) along with authors included a chromatography-free preparation of iodolactone the previously synthesized natural products. 205 and the introduction of chirality was achieved by a lipase- Shoji´s group also completed the first asymmetric synthesis of mediated kinetic resolution of cyclohexenol 207 (scheme 34) EI-1941-1 (17) and EI-1941-2 (18), featuring an intramolecular [65,129,131,132]. Diels-Alder reaction between furan and acryloyl carboxypalladation via a 6 -endo cyclization mode followed by - chloride (212) furnished 213, which upon hydrolysis and iodolac- hydride elimination (scheme 35) [119]. Compound ent-211 was tonization afforded compound 205, pure enough to be used in the readily synthesized from 205 (see scheme 33) [132]. Cleavage of next reaction. Lactone hydrolysis with epoxidation, followed by the acetonide afforded 215, which upon selective oxidation of the esterification and -elimination were performed with high yields. primary alcohol gave 216. Protection of the secondary alcohol gen- Racemic 207 was subjected to kinetic resolution with Meito TL erated 217 and oxidation under Kraus´s conditions yielded 218, lipase, which proceeded with high efficiency affording (+)-207 in which was protected as it p-methoxybenzyl ester 219. Introduction 99% ee, and its corresponding acetate antipode 214. Enantiomeri- of a side chain by Suzuki coupling produced 220. Acid treatment cally pure (+)-207 was then transformed into ECH (8) and epoxy- afforded 221, which was subjected to intramolecular cyclization quinols following their previous synthetic sequences shown in through carboxypalladation and -hydride elimination to afford

22 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

O O O O I I I I TFA, CH2Cl2, MnO , CH CN, TBSOTf, 2,6-lutidine O O 2 3 O O O O 0˚C, 96% 0˚C CH2Cl2,, 0˚C, 72% O O OH OH HO H TBSO H

ent-211 215 216 217 O O O I n-Pr I (HO)2B PMBOC(=NH)CCl3, n-Pr NaClO2, NaH2PO4, O O O t-BuOH, O O O CH2Cl2, 0˚C, 85% Pd(PhCN)2Cl2, AsPh3, 2-methyl-2-butene, Ag2O, THF, H2O, 97% H2O, 0˚C, 97% TBSO OH TBSO OPMB TBSO OPMB

218 219 220 O O OH OH n-Pr n-Pr n-Pr n-Pr TFA, O Pd(PhCN)2Cl2, O O O NaBH4, + O O O O CH2Cl2, 98% p-benzoquinone, MeOH, TBSO OH THF, 70% TBSO O 0˚C, 98% TBSO O TBSO O 221 222 223 1:1 224 OH OH O n-Pr n-Pr n-Pr O Pd/C/H2, O MnO , CH Cl , O O 2 2 2 HF.Py, CH3CN, O O 18 AcOEt 0˚C, 92% 0˚C, quant. TBSO O 95% TBSO O TBSO O 225 226 223 (95:5, dr) (95:5, dr)

OH O DIBAL-H, CH2Cl2 -90˚C, 76% n-Pr n-Pr O O MnO2, HF.Py, CH CN, O O 3 17 0˚C, quant. CH2Cl2, TBSO OH 0˚C, 95% TBSO OH 227 228 (95:5, dr)

Scheme 35.

222. Reduction of the carbonyl generated 223 and 224 which were Iodination led to 235 and further Stille side chain insertion and separated by column chromatography. Hydrogenation of 223 pro- deprotection afforded monomer 53a. Diels-Alder dimerization in ceeded stereoselectively, affording 225 with high diastereoselectiv- deuterium oxide produced (+)-panepophenanthrin (33). ity. Oxidation and deprotection of this compound allowed the The authors also reported the Suzuki reaction of 235 with dif- preparation of EI-1942-2 (18). Reduction of compound 225, fol- ferent cross-coupling partner followed by deprotection and dimeri- lowed by oxidation and deprotection completed the synthesis of EI- zation allowing the preparation of panepophenanthrin analogues 1941-1 (17). The authors also completed the synthesis of EI-1941-2 non-natural stereoisomers through similar strategies [133]. RKTS-80 (35), -81 (36) and -82 (37), along with the study of their biological properties. This group also completed the synthesis of (+)-panepophenanthrin (33) and analogues, through a catalytic asymmetric - Kuwahara’s Synthesis of Epoxyquinols A and B aminoxylation followed by several diastereoselective Diels-Alder reactions, including a biomimetic Diels-Alder reaction in water Kuwahara et al. prepared epoxyquinols A (28) and B (29) (scheme 36) [134]. -Aminoxylation of 1,4-cyclohexanedione through an Evans asymmetric aldol reaction as the key step monoethylene ketal 229 with nitrosobenzene and D-proline af- (scheme 37) [134]. Reaction between oxazolidinone 236 and alde- forded 230 with excellent ee. Regioselective reduction followed by hyde 237 afforded stereoselectively syn-aldol 238. Removal of reductive cleavage produced 231. Removal of acetal and dehydra- chiral auxiliary under reductive conditions, followed by protection tion afforded 232. Formation of silyl ether and epoxidation yielded of the hydroxyl groups, allowed a Wacker oxidation at the terminal 233. Double bond formation generated epoxyenone 234. - olefin to obtain 239 in high yields. Aldehyde 240 was obtained by

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 23

O O O O O O nitrosobenzene 1) K-selectride, THF, -78˚C D-proline, DMF, 0˚C 2) Pd/C, H2, MeOH, 72% 93%, (99% ee) PhNHO HO O O OH 229 230 231 O O

Amberlyst 15, THF 1) TBSCl, imidazole, DMF 1) LiHMDS, TMSCl, O THF, -25˚C acetone, H2O, reflux, 2) H2O2, Triton B, THF, 85% 0˚C, 92% 2) diallylcarbonate, [Pd2(dba)3].CHCl3, OTBS OH CH3CN, 78% 232 233 O O OH O OH I I2, Py, 1) Bu Sn O O 3 O D2O Et2O, 80% 33 [Pd2(dba)3].CHCl3, AsPh3, toluene, 110˚C, 77% OTBS OTBS 2) NH4F, MeOH, 75% OH 234 235 53a

1) (HO)2B R , Pd(PhCN)2Cl2, 34 (R = Me) AsPh3, THF, H2O (67-92%)

35 (R = n-C4H9) 2) NH4F, MeOH 3) neat (80-84%, 2 steps) 36 (R = n-C8H17) Scheme 36. O O O O O O O N H N OH Bu BOTf, 1) LiBH4, THF-MeOH + 2 237 (i-Pr)2NEt, 2) TBSCl, imidazole, DMF Bn CH Cl , 87% Bn 2 2 3) O2, PdCl2, Cu(OAc)2 236 93% 238 TBSO OTBS TBSO OTBS TBSO OTBS O 1) NaOH, Et2O, 70% O3, MeOH-CH2Cl2, 2) MsCl, NEt3, CH2Cl2, Me2S, 86% 93% O O O 239 240 241 TBSO OTBS TBSO OTBS

1) LDA, PhSeCl, THF TBHP, DBU O O Br2, NEt3,

toluene, quant. CH2Cl2, 93% 2) H2O2, CH2Cl2, 63% O O 243 242

TBSO OTBS SnBu 1) 3

Pd (dba) , 1) TEMPO, O2, CuCl, DMF 2 3 28 + 29 O 8 2) neat, rt Br Ph3As, toluene, 96% (46%) (20%) O 2) HF.Py, THF, 88% 244 Scheme 37.

24 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

OH OTBS 1)TBSCl, Et N, CH Cl , 3 2 2 1) PCC, 4A MS, CH2Cl2, O 2) (+)-DET, Ti(O-iPr)4, 2) BuLi, THF, 90% TBHP, 4A MS, CH2Cl2, -20˚C OH OH

245 246 O

OTBS OTBS

O O O O + OH (1 : 2) OH

247 248

1) H2, Lindlar , 83% 1 ) DMP, 83% 2) Ac2O/Py, 99% 249 2) (R)-Me-CBS, BH3.SMe2, 80% 3) H2, Lindlar, 81% 4) DIAD, PPh3, AcOH, 90%

O OTBS 1) HF, Py (89%) H O 2) DMP (88%) O O O OAc OAc 249 OTES 250

Et3Si Grubbs II, 62% 250 O

5 mol% Ph3SiF2.NBu4 O THF, CH2Cl2, rt, 73% OAc 251

OTES OTES

O + O

OAc OAc

252 253 Scheme 38. ozonolysis, and was then subjected to an intramolecular aldol con- product at room temperature to trigger the electrocyclization/Diels- densation and elimination to deliver enone 241. Stereoselective Alder dimerization cascade. epoxidation with t-butylhydroperoxide gave 242 quantitatively as a single stereoisomer. Completion of the epoxycyclohexenone core Lee´s Methodology was achieved through an -selenylation followed by oxidative Lee developed a strategy based on the sequence enyne ring- elimination. -Bromination of 243 permitted Stille cross-coupling closing metathesis (RCM) followed by metallotropic [1,3]-shift, to over 244 for the insertion of alkenyl side chain. Deprotection of the install the 1,5-dien-3-yne moiety of (+)-asperpentyn (ent-22), (-)- hydroxyl groups afforded the monomeric ECH (8). Finally epoxy- harveynone (11) and (-)-tricholomenyn A (12) [135]. The common quinols A (28) and B (29) were prepared by chemoselective oxida- intermediate to obtain these three natural products was aldehyde tion of the primary hydroxyl group and then by leaving the neat 250. It was prepared from commercially available diol 245, em-

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 25

OTES

KCN, EtOH, 87% O ent- 22

OAc 252

OTES OTES

1) KCN, EtOH, 88% 1) HF.Py, 78% O O

2) TIPSOTf, Et3N, 95% 2) MnO2, CHCl3, 93% OAc OTIPS

253 254 O

HF.Py, CH3CN, 98% O 11

OTIPS 255

O Et3Si 12 H + O O OAc 250 256

Scheme 39. ploying in the first step a Sharpless asymmetric epoxidation to af- One year later Lee and co-workers [136] reported details of the ford epoxide 246 (scheme 38). Separable diastereomeric alcohols synthesis of natural (+)-panepophenanthrin (33) based on tandem 247 and 248 were obtained in a 1:2 ratio when aldehyde derived metathesis strategy. With the common intermediate 250 in their from 246 was subjected to acetylide addition in basic media. Lind- hands a silyl ether was installed together with an acetylene group to lar hydrogenation of the correct epimer 247, followed by acetyla- obtain 257 according to scheme 40. Cross-metathesis between 257 tion gave 249 with high yield. and 3-buten-2-ol afforded 258. The authors also suggested a Lee also reported an efficiently method to obtain 249 from the mechanism for this transformation. Considering the previous C4- epimers mixture (247 + 248). This strategy included Dess-Martin deacetylation difficulties, they decided to transform 259 into silyl oxidation of the mixture, followed by an asymmetric reduction ether 260. Selective deprotection, followed by manganese oxide using (R)-Me-CBS as a chiral auxiliary. The authors clarified that oxidation and secondary alcohol deprotection yielded monomer 261 the use of this auxiliary provided the non-desirable epimer but in- as a precursor of (+)-panepophenanthrin. Cleavage of the silyl ether creased the stereoselectivity for the major product in a ratio of 10:1. and a highly stereoselective intramolecular Diels-Alder reaction on They obtained 249 after Lindlar hydrogenation and inversion at C4 neat 53a yielded (+)-panepophenanthrin (33). according to Mitsunobu`s protocol with acetic acid. Desilylation followed by oxidation of the primary alcohol afforded 250. Ryu’s Methodology The key step in this strategy was the RCM of enyne 251 fol- A catalytic enantioselective Diels-Alder strategy was achieved lowed by a metallotropic [1,3]-shift, as shown in scheme 38. A by Ryu’s group towards the synthesis of several natural epoxycy- second-generation Grubbs catalyst was added to 251 as a diluted clohexenones. In 2010 they reported the first chemocatalytic enantioselective process for the synthesis of natural bromoxone (5), solution in CH2Cl2 to obtain a mixture of epimers (252 and 253). Complete deprotection of 252 afforded (+)-asperpentyn (ent-22) epiepoxydon (4) and epiepoformin (2) [137]. The authors have (scheme 39). After selective deprotection of TES group, followed previously developed an oxazaborolidium chiral catalyst, which was used for the preparation of the antitumor agent (+)-ottelione A by oxidation with MnO2, the authors reported that C4-acetate could not be removed. To address this problematic protective group ma- [138]. Cyclopentadiene and 2-iodo-1,4-quinone monoketal (262) in nipulation, the researchers converted 253 into 254. Selective depro- the presence of catalytic amounts of oxazaborolidium chiral catalyst tection of 254 followed by oxidation gave 255, which was depro- at -78ºC afforded only the endo-cycloadduct 263 with 98% ee. tected to afford (-)-harveynone (11). Natural tricholomenyn A (12) Transition state shown in scheme 41 explained the high sterecontrol was also synthesized according to a similar procedure using com- of the reaction. Halogen was removed from 263 by treatment with mon intermediate 250 and the appropriated endiyne 256. tributyltin hydride, and then reduction yielded the correct epimer

26 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

O OTES

H Et3Si O O O 5 mol% Ph3SiF2.NBu4, O rt, 62% OAc OAc 250 257

OTES HO HO OH OTES

O O 1) MnO2 1) KCN/MeOH Grubbs II, CH Cl , 2 2 2) MeMgBr, 70% , 51% OAc OAc 2) TBSCl, Et3N, 51% 258 259

OTES HO O HO O HO

O 1) HF.Py NH F, 77% O 4 O neat, 30˚C 33

2) MnO2, CHCl3, OTBS 71% OTBS OH 260 53a 261 Scheme 40. Ph Ph

O N B O O O H N B I H3C H CF3SO3H I H O CF3SO3

H O , CH Cl , -78˚C, 97% O O I O O 2 2 O

262 263 (98% ee) pre-transtion-state Scheme 41. O OH OTBS H H 1) 1N H SO , H I 1) n-Bu3SnH, 2 4 acetone-THF 80oC, 88% 92%

2) CeCl3.7.H2O, 2) TBSCl, H o O O NaBH4, - 78 C, 92% H O O imidazole, DMF H 0oC, 90% O 263 264 265 OTBS OTBS H Ph O 1) Br2, NaHCO3, 30 wt% H2O2, 2 0˚C, 95% O O 5 DBU, 86% 240˚C, 97% 2) 50% HF, o H CH3CN, 0 C, 93% O O 266 267 Scheme 42.

264 as shown in scheme 42. It was first deprotected in acidic condi- dition-elimination reaction of bromine, followed by deprotection tions to give the corresponding ketone and the secondary hydroxyl led to natural bromoxone (5). group was protected as TBS silyl ether to give 265. The bulky Using Ogasawara’s previously reported protocol, the authors group induced the correct stereochemistry at the next epoxidation also obtained (+)-epiepoxydon and (+)-epiepoformin from 266 reaction to generate 266. A retro Diels-Alder reaction took place [139,140]. when 266 was heated at 240ºC in diphenylether affording 267. Ad-

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 27

O HO O H 1) 30wt % H2O2, DBU, 1) 1N H2SO4, CH3CN, 0˚C, 92% acetone-THF (1:1), 90% O ent-27 2) 37wt % formaldehyde, 2) Ph O, 230˚C, 98% DBU, THF, 0-25˚C, 98% 2 O H O O H O Ph 268 Ph 269

O N O B O H I I 5 steps CF3SO3H 27 6 steps, 72% overall yield O O O , CH2Cl2 , -78˚C H O

262 ent-263 Scheme 43.

iBu iBu Al O OH O O H iBu HO DiBAL-H HO Al O O iBu THF, -78˚C, 70% O

O O ent- 27 O 270 9

O O O O 1) (MeO) CMe , PPTS, 2 2 (E)-tributyl-1-propenyl-stannane, CH Cl , 25˚C, 87% 1N H2SO4, 2 2 O 8 O Pd2dba3, PhCH3, 110˚C acetone-THF (1:1) 2) I2 /PhI (OCOCF3)2, Py 25˚C, 78% I 76% ( two steps) O O 271 211 Scheme 44.

ent-Phyllostine (ent-27) was obtained starting from the endo McIntosh’s Method (the Noyori Desymmetrization) Diels-Alder adduct 268 that was obtained by deiodinating 263 Enantioselective reduction of epoxydiketone 113 based on [141]. Hydrogen peroxide epoxidation of enantiomerically pure Noyori desymmetrization was reported by McIntosh in 2011[142]. intermediate 268 gave the desirable exo-epoxide and a subsequent This article included studies in different solvents, scale-up condi- stereoselective hydroxymethylation afforded 269. Deprotection tions, and ratio formic acid/trialkyl amine as stoichometric reduc- under acidic conditions and typical retro Diels-Alder reaction gave tant. Optimization of Ru(p-cymene)[(S,S)-TsDPEN] percentage was ent-27 (scheme 43). also described. Typical retro Diels-Alder conditions (heating at Using an ent-oxazaborolidium catalyst, Ryu obtained ent-263, 170ºC) of 272 completed the preparation of epoxyquinol 273 which was used in a similar route to prepare natural phyllostine (27) (scheme 45). ECH (8) was also synthesized by Ryu and co-workers in the cited article [141]. Using ent-phyllostine (scheme 44) as a precur- Syntheses of Scyphostatin sor, under regioselective and stereoselective reduction conditions Finally, it’s scyphostatin’s turn. Scyphostatin (19) deserves its (Kiyooka’s protocol), the authors obtained alcohol RKTS-33 (9). own “chapter” in this review. Due to its complex structure and in The total stereocontrol of this reduction could be explained through concordance with the subject of this revision, we are going to focus the intermediacy of the aluminium complex 270. According to on the introduction of chirality and preparation of the epoxyenone Shoji´s methodology (see scheme 33), protection of 9 as acetonide central core, without going into details concerning the construction followed by -iodination, afforded the halogenated partner 211 of the chiral fatty acid side chain. Scyphostatin has been isolated in necessary for the Stille cross-coupling reaction. 211 was coupled 1997 [34], but no chiral preparation (either total or partial) was with (E)-1-tributyl-propenyl stannane to afford 271 and its depro- reported until 2004, when Katoh and co-workers published the first tection under acidic conditions gave ECH (8). synthesis [143].

28 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

O O O H H RuLn* (0.67%) Ph2O, 170˚C O O O HCO2H, Et3N (1:1) 60% -10 to 23˚C, 16h H O H OH OH 113 272 273 RuLn* = Ru(p-cymene)[(S,S)-TsDPEN]

Scheme 45.

OH BnO O 1) PMBCl, NaH, DMSO, 70% CO2Me 1) DMSO, (COCl)2, CH2Cl2, 2) H2, Raney Ni, EtOH, 86% -78 oC, DIPEA, -78-0oC PMBO PMBO O HO O + - O 3) Ph3P CH3Br , t-BuOK, 2) NaClO2, NaH2PO4, DMSO/H2O O O benzene, 86% O 3) CH2N2, Et2O, MeOH, 78% (2 steps)

274 275 276

OHC OH MeO2C MeO2C NO 1) NaHMDS, THF, CS2, then MeI Boc PMBO O O 2) n-Bu3SnH, AIBN, toluene, O PMBO O 53% (2 steps) O N (Garner´s aldehyde) O N Boc Boc NaHMDS, THF, 69% 278 277

OH 1) DIBAL-H, CH2Cl2, OTBS -100oC, 88% 1) (Cy3P)2RuCl2(=CHPh), CH2Cl2, 96% O 2) TBSOTf, 2,6-lutidine, CH Cl , 93% PMBO O 2 2 PPTS, EtOH, 57% OH 2) O N PMBO O MgBr NH Boc O THF, 93% Boc 279 280 Scheme 46.

The chiral starting material for the cyclohexenone moiety was Katoh and his group continued working on this molecule. In D-arabinose. When this sugar is O-benzylglycosydated and the 2006 they published an extensive work concerning an enantiocon- acetonide is formed, compound 274 is obtained. This was the start- trolled synthesis of the epoxycyclohexenone moiety [146]. This ing material in this case (scheme 46). Protection-deprotection steps, time, the starting material was (-)-quinic acid (scheme 48). followed by Wittig olefination yielded alcohol 275 that when oxi- The conversion of (-)-quinic acid (153) into ketone 154 has dized and esterified, was converted into 276. At this point, the cru- been reported previously [146]. Protection of free hydroxyl group cial aldol addition with Garner aldehyde could be performed with and reduction of the carbonyl provided the mixture of epimers 284 good results. Alcohol 277 was obtained as a single diastereomer. and 285. As elimination of hydroxyl group was not possible with Further deoxygenation provided compound 278 and reduction- 284, it was converted into 285 and then the olefin 286 could be Grignard sequence over the ester group yielded diene 279. Ring obtained. Diastereoselective epoxidation, followed by Sharpless closing methatesis proceeded successfully in the presence of protocol (ring opening and elimination of phenylselenoxide) and Grubbs catalyst. Final manipulation of the protective groups led to oxidation of the allylic alcohol yielded the key intermediate 287. As 280 that represents the cyclohexene segment to be coupled with the aldol addition of benzaldehyde failed, the double bond was masked corresponding fatty acid chloride segment 281 (scheme 47). This as the Diels-Alder bromo adduct 288 that was obtained through a one was efficiently prepared from a chiral well known aldehyde sequence Diels-Alder-desilylation-bromoetherification from 287. [144]. The aldol addition yielded the rearranged compound 289 success- The fatty acid chloride 281 was efficiently bonded to 280 and fully. Deoxygenation followed by cleavage of the cyclopropane the amide 282 was obtained. Acetylation of primary hydroxyl ring gave the iodoketone 290. Deiodination, retro Diels-Alder reac- group, mesylation of the secondary one and desilylation-oxidation tion, mesylation, acetonide removal and epoxide formation permit- of the protected one gave compound 283. Acetonide cleavage per- ted to obtain epoxycyclohexenone moiety 291. Once the methodol- mitted oxirane ring closure. Finally, lipase hydrolysis of the acetate ogy was proven, the authors decided to synthesize a fully function- led to (+)-scyphostatin after 24 reaction steps. This first total enan- alized epoxycyclohexenone moiety. This time, 288 was coupled tioselective synthesis was also discussed in 2007 [145]. with aldehyde 292 as shown in scheme 49.

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 29

OTBS 1) Ac2O, Py, DMAP, CH2Cl2, 72% 1) TMSOTf, 2,6-lutidine, CH2Cl2, MeOH OH 2) MsCl, Et N, CH Cl , 93% 280 HO O 3 2 2 2) NH O 3) TBAF, THF Cl 4) DMP, CH2Cl2, 98% (2 steps)

O O 281 282

Et3N, CH2Cl2, AcOH, 73% (2 steps)

OAc MsO O NH O 1) CCl3CO2H, CH2Cl2/H2O, NaOH, 45% 19 O 2) lipase PS, pH=7, phosphate buffer, acetone, 60% 283 Scheme 47. OH OH O HO2C OH 1) TBSCl, imidazole, DMF, 98% + 2) NaBH , THF-H O, 4 2 TBSO O TBSO O HO OH O HO O O OH O 284 53% 285 44% 153 154 (-)-quinic acid

1) DEAD, PPh3, benzoic acid, 98% 2) KOH, MeOH, quant. 1) m-CPBA, NaHCO , 3 O CH Cl , 92% , Et AlCl, CH Cl , DEAD, PPh3, 2 2 1) 2 2 2 97% THF, 67% 2) Se Ph , NaBH , EtOH; TBSO O 2 2 4 TBSO O H O , THF, 78% O 2 2 O 2) TBAF, THF, 75% 3) DMP, CH2Cl2,, 95% 3) NBS, CH2Cl2, 86% 286 287

Br O 1) phenylchlorothionoformate, LiHMDS, THF; O OH benzaldehyde, DMAP, MeCN, 92% O O 2) n-Bu3SnH, AIBN, toluene, 79% THF, 98% O O O 3) TMSI, CCl4, 89% 288 O 289

I O O 1) Zn, AcOH, MeOH, 91% o OH 2) Ph2O, 230 C, 81%

O O O 3) MsCl, Et3N, DMAP, CH2Cl2, 85% O 4) TFAA, H2O, 85% 5) NaOH, Et2O, 90% 290 291

Scheme 48.

30 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

Br O OH O O 1) NaN(SiMe3)2, OHC THF, CS , MeI, LiHDMS, O 2 O + 88% O O O O O O O N N N Ts THF, 98% 2) n-Bu SnH, O 3 O O Ts Et3B, toluene, Ts 95% 288 292 293 294

O I OH Ts O O N 1) 2,2-dimethoxypropane, TMSI, O p-TsOH, benzene, 83% Ph O, O O O O 2 CCl4, 91% NHTs N HO O HO 230oC, 25% O 2) Zn, AcOH, MeOH, 98% O O Ts 295 297 296 Scheme 49.

I O O O O O 1) HCl, THF O TMSI, O O CCl , 74% O O N O O N 4 O N 2) phosgen dimer, O Py, THF, O Ts O O Ts Ts 67% (2 steps) 294 298 299

O O 1) MsCl, Et N, DMAP, 83% 1) Zn, AcOH, MeOH, 95% O 3 O o 2) TFAA, H2O, quant. 2) Ph2O, 230 C, 59% HO O OH N O N O O 3) NaOH, Et2O, 75% O Ts Ts 300 301 Scheme 50.

Compound 293 was obtained with an excellent yield as an in- cellent yields. The primary hydroxyl group was then acetylated to separable mixture of epimers. Deoxygenation yielded 294 and afford 305a-f and subsequently the secondary alcohol was mesy- treatment with TMSI gave the iodo compound 295. Reaction with lated to give 306a-f. Silyl ether removal followed by oxidative con- 2,2-dimethoxypropane furnished an acetonide that when treated ditions permitted to obtain the cyclohexenones 307a-f. Cyclohex- with zinc powder was transformed into 296. Retro Diels-Alder enones 307a-f yielded epoxycyclohexenones 308a-f when treated reaction to obtain 297 proceeded with very poor yield. Therefore, under acidic conditions to remove acetonide and then treated with the N,O-isopropylidene group had to be replaced via a carbamate, base. Enzymatic hydrolysis of the acetate group afforded the six as shown in scheme 50. targeted scyphostatin analogs 309a-f. With 294 in their hands, the authors exchanged the N,O- A very interesting alternative to the use of quinic acid as the isopropyplidene moiety with the corresponding cyclic carbamate, source of chirality in Katho´s strategy was proposed by the same obtaining 298. Treatment with TMSI gave 299 that was subse- group in 2009 [148]. This work is about a new methology for de- quently converted, with a 59% yield for the retro Diels-Alder reac- symmetrization of meso-diols, based on the use of a chiral iridium tion, into 300. Mesylation of the free alcohol, followed by removal catalyst, that was applied to the preparation of a common interme- of acetonide and oxirane ring closure furnished 301, a fully func- diate of ottelione and scyphostatin. The synthetic route is shown in tionalized epoxyenone moiety of scyphostatin. scheme 52. After this fruitful work, Katoh and his group published a study p-Benzoquinone (310) was easily transformed into 311. Dihy- concerning the preparation of scyphostatin analogs with different droxylation and protection of the diol functionality rendered 312, saturated fatty acid chains [147], aiming to improve the stability of that was debrominated to yield 313. This diol was desymmetrized scyphostatin. Intermediate 280 was the cyclohexene moiety used to with the aid of the iridium catalyst (R,R)-314. Hydroxyketone 315 couple with the fatty acids, and has been previously prepared by the was obtained in an enantiomerically pure form, and constitutes a authors (see scheme 46). Six analogs of scyphostatin were obtained, value intermediate for the synthesis of scyphostatin as well as otte- as it is shown in scheme 51. lione. Protective groups Boc and PMB were simultaneously removed In 2005, the enantioselective synthesis of a scyphostatin ana- to give 302. The free amino group was then coupled with fatty acid logue was reported [149]. As shown in scheme 53, cyclohexanone chlorides 303a-f to give the corresponding amides 304a-f with ex- (316) was coupled with Garner´s aldehyde and then the aldol ob-

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 31

OTBS OTBS OH OH OTBS OH Cl TMSOTf, n Et3N, CH2Cl2 PMBO 2,6-lutidine, HO + O CH Cl O O HO O NHBoc 2 2 NH O O 2 303a: n=9 O HN b: n=11 n 280 c: n=12 O 302 d: n=13 304a-f: n = 9, 11-13, 15-16 e: n=15 (74-78%, 2 steps) f: n=16 OTBS OTBS O Ac2O, Py, 1) TBAF, THF DMAP MsCl, Et3N, 2) DMP, CH Cl CH2Cl2 OAc CH2Cl2 2 2 OAc HO O OAc MsO MsO O O O HN HN O HN O n n O n O O 305a-f: n = 9, 11-13, 15-16 306a-f: n = 9, 11-13, 15-16 307a-f: n = 9, 11-13, 15-16 (84-92%, 2 steps) (91-93%, 2 steps) (89-94%, 2 steps) O O TFAA, CH2Cl2, then NaOH aq. lipase PS, pH7 phosphate buffer, acetone OAc OH O OH HN O OH HN n n O O 308a-f: n = 9, 11-13, 15-16 309a-f: n = 9, 11-13, 15-16 (89-94%, 2 steps) (57-61%, 2 steps) Scheme 51. O 1) cyclopentadiene Br Br 1) OsO , NMO, OH 2) NaBH , CeCl OH 4 4 3 THF, 73%

3) NBS 2) Me C(OMe) , p-TsOH, 72% (3 steps) 2 2 O O O DMF, 85% O 311 312 O 310

OH O H (R,R)-314 (10 mol%), H Zn, AcOH, CH3OH, O t-BuOK (8 mol%), O reflux, 89%

O cyclohexanone, 60oC, O H 60%, > 99% ee H OH OH 313 315

(R,R)-314: Ir HN NTs

Ph Ph Scheme 52. tained was mesylated to give 317. After elimination/hydrogenation material was a natural chiral product. In this work, L-tyrosine was steps, deoxygenated compound 318 was obtained. Silyl enol ethers used to prepare chiral spirolactone 323, according to a procedure 319 and 320 were obtained in a 85:15 ratio. Silyl enol ether 319 previously reported [151]. The spirolactone reacted with cyclopen- reacted under asymmetric Sharpless hydroxylation conditions to tadiene with high -facial selectivity to give a 1:1 mixture of the yield 321 with 86% of diastereomeric excess. Fully deprotected 321 endo aducts 324 and 325. The first part of the synthesis is shown in reacted with palmitoyl chloride to give 322, a simplified scy- scheme 54. phostatin analogue. The mixture of Diels-Alder products gave a mixture of epox- In 2007, Takagi and co-workers reported the second total syn- ides (326 and 327), easy to separate. Epoxide 326 was opened in thesis of (+)-scyphostatin [150]. As in Katoh’s case, the starting the presence of SmI2 and after protection of the hydroxyl group,

32 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

O O O OMs 1) Garner´s aldehyde, 1) DBU, CH Cl ,, 73% LDA, THF, 84% 2 2 O HMDS, TMSI, O N 2) H (1atm), Pd/C 2) MsCl, Et N, N 2 THF, 89% 3 EtOH, 90% Boc CH2Cl2, 98% Boc 316 317 318

OSiMe OSiMe3 3

O + O N N Boc Boc 320 319 85:15 O O OH OH 1) ADmix , NaHCO3, OsO , t-BuOH/H O, 58% 1) TFAA, CH2Cl2, H2O, 89% 4 2 O OH NH N 2) CH3(CH2)14COCl, Et3N, 2) LDA, Br , THF, 98% 2 Boc THF, 91% O 3) DBU, 115oC, 62% (CH2)14CH3 322 321 Scheme 53. O O O O O

1) H2O2, LiOH, O + O + H2O, THF CH2Cl2, 98% 2) EDCI, CH Cl , 2 2 O O O O O 48% (2 steps)

CbzHN O CbzHN O CbzHN O CbzHN O CbzHN O O 326 327 323 324 325

O O o OH 1) , Ph2O, 230 C. 100% 1) SmI2, MeOH, THF O 326 2) TESCl, imidazole, OTES OTES O 2) NaBH4, CeCl3.7H2O, CH2Cl2, 83% (2 steps) THF, i-PrOH, 95% O

CbzHN O CbzHN O 328 329 Scheme 54. compound 328 was obtained. Retro Diels-Alder reaction followed which the same group prepared the polar core of scyphostatin in a by ketone reduction provided 329. As epoxidation of 329 gave the racemic way [156]. Once again, L-tyrosine was the source of chiral- incorrect stereochemistry, it was kept for later steps. The highlights ity. This time it was used to prepare the starting material 334 as it of the synthesis are illustrated in scheme 55. was previously reported [157]. The synthetic sequence is shown in Alcohol 329 was acetylated and then lactone ring was reduc- scheme 56. tively opened. After desilylation triol 330 was obtained. The pri- Enantiopure 334 was easily transformed into oxazolidinone mary alcohol was protected and then the epoxidation underwent 335. Oxidation and acetylation yielded the p-quinol 336. A rear- with the correct orientation to give epoxide 331. Nitrogen was de- ranged aromatic compound 337 was obtained by means of a treat- protected and the amide 333 was formed straightforward with fatty ment with sulphuric acid and acetic anhydride. Protection- acid 332 [152]. Oxidation of the secondary alcohol followed by deprotection steps afforded 338 which under basic conditions was deprotection of the primary one, permitted to accomplish the total transformed into the target compound 339, a chiral benzopyran en synthesis of (+)-scyphostatin. A similar strategy, but racemic, was route to (+)-scyphostatin. In 2010, this compound was successfully previously applied by Ohkata´s group for the preparation of scy- used by the same group as starting material for the total synthesis of phostatin analogs [153,154]. scyphostatin [158] that is shown in scheme 57. Pitsinos and co-workers published in 2007 the chiral synthesis The Boc group was replaced by trichloroacetate, and then the of an advanced intermediate towards the total synthesis of scy- aromatic ring was oxidized. The product was quinol 340 that was phostatin [155]. The strategy was based in a previous work in subsequently hydrolyzed and reduced to give 341. After reduction,

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 33

OAc OAc 1) Ac2O, Py, CH2Cl2, 99% 1) TBDPSOTf, 2) NaBH4, EtOH, 94% 2,6-lutidine, CH2Cl2, 83% O 329 2) m-CPBA, CH2Cl2, 84% OH 3) TBAF, THF, 98% OH OH OH

CbzHN OTBDPS CbzHN OH OAc 331 330

O 1) Pd(OH)2/C, H2 (1 atm), AcOH, MeOH OH OH 2) EDCI, DIPEA, DMF, 65% (2 steps) NH OTBDPS OH O O 1) (COCl)2, DMSO, 332 333 Et3N, CH2Cl2, 49% 19 2) TBAF, AcOH, THF, 61%

Scheme 55. O OBn OH 1) NaH, THF; then Ac2O, 95% 1) PIFA, CH3CN/H2O, 83% Ac2O, H2SO4, 82% 2) H2, Pd/C, 100% 2) Ac2O, Py, 95% AcO

O OH O AcN AcN BocHN O 334 335 O 336

OAc OAc OAc 1) NaOMe, MeOH 2) Ac O, Py 2 NaOMe, THF, 96%

OAc 3) Boc2O, DMAP, THF OAc O 79% (3 steps)

O O AcN BocN NHBoc O O 339 337 338 Scheme 56. treatment with p-MeOC6H4OH, in the presence of CSA proceeded tion with NBS gave bromide 347, which was debrominated, oxi- with allylic rearrangement. Epoxidation of the double bond yielded dized and hydrolyzed to yield 348. The chiral auxiliary was re- compound 342 and further oxidation with DDQ yielded 343. Re- moved, the alcohols were protected and the aldehyde was depro- moval of trichloroacetate permitted the assembly with fatty acid tected to obtain 349. The alcohol produced by addition of 4- 332 to yield 344. This time, an interesting carboalumination Zr- methoxyphenylmethyloxymethyl lithium to the aldehyde was con- catalized was used during the synthesis of the chiral fatty acid moi- verted into azide 350 under Mitsunobu conditions. The azide was ety [159]. When 344 was hydrolyzed in the presence of montmoril- reduced to the amine that was coupled with 332 (prepared as de- lonite K10, the total synthesis of scyphostatin was achieved. scribed by Hoye and Tennakoon [161]) and desilylated to give 351. The next total synthesis we are going to analyze was published To obtain (+)-scyphostatin epoxidation, oxidation, double bond by Kita in 2007 [160]. The “first generation” synthetic strategy is formation and deprotection were successfully performed. After shown in scheme 58. several studies for improvement of yields and optimization of various synthetic steps, a second generation total asymmetric synthesis 1,4-Cyclohexadiene (345) was coupled with bromoacetalde- of 19 could be accomplished. This second generation strategy is hyde diethyl acetal, and then the chiral auxiliary (R,R)- shown in scheme 59. hydrobenzoin was introduced to give acetal 346. Bromoetherifica-

34 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

OH O

1) TFAA, CH2Cl2, 1) 1N HCl, THF, 62% 2) (Cl3C)2CO, Et3N, CHCl3, 2) NaBH , CeCl H O, K CO , MeOH, 95% (2 steps) 4 3.7 2 O 2 3 MeOH HO 339 O 3) PIFA, K2CO3, CF3CH2OH, 65% O NHCOCCl Cl C N 341 3 3 340 Ar 1) PMBOH, CSA, 4A MS, THF O OCH Ar 2) m-CPBA, Na2HPO4, CH2Cl2, 2 45% (3 steps) O O O O DDQ, CH2Cl2, 65% HO O

NHCOCCl 342 3 343 NHCOCCl3 Ar = p-MeOC6H4 Ar

1) DIBAL-H, toluene, -92oC O O O 2) 332, DIPEA, PyBop, O CH2Cl2, DMF, 65% (2 steps) montmorillonite K 10, 64% 19

O 344

Scheme 57. Br 1) Bu3SnH, AIBN, benzene, 89% 1) sec-BuLi, TMEDA, THF, 2) SeO2, Py, then BrCH2CH(OEt)2, 75% NBS, O dioxane, 42% MeOH, 64% Ph 2) (R,R)-hydrobenzoin, p-TsOH, O 3) PPTS, MeOH, 91% 345 toluene, quant. Ph O O Ph MeO 346 Ph 347

HO OH 1) Ca, EtOH, NH3(l), 91% 1) Bu3SnCH2OMPM, 2) TBSCl, imidazole, DMF, 98% n-BuLi, THF, 81% O OH OTBS 3) TESOTf, 2,4,6-collidine, CH Cl , 2) DPPA, PPh3, DEAD, HO 2 2 TESO then H O, 93% CH2Cl2, 69% OMe 2 CHO

OMe 349 348

1) LiAlH4, THF OH 2) 332, DCC, DMAP, CH2Cl2 HO OTBS OMPM 3) TBAF, THF, 47% (3 steps) TESO NH OMPM O N3 350 351

1) TBHP, VO(acac2) , toluene, 69% 2) TPAP, NMO, CH2Cl2, 49% 19 3) LDA, 15-crown-5, Ph(Cl)S=NtBu, THF, 32% + - 4) PPh3C BF4 , CH2Cl2, 37% Scheme 58.

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 35

2,4 1) DMPMOCH2SnBu3, 1) LiAlH4, THF OTBS n-BuLi, THF, 56% 2) 332, DCC, DMAP, CH Cl OTBS 2 2 TESO TESO 3) TBAF, THF, 59% (3 steps) CHO 2) DPPA, PPh3, DEAD, O2,4DMPM 349 CH2Cl2, 75% 352 N3

OH HO O2,4DMPM NH 1) TBHP, VO(acac2) , toluene, 73% 2) DMP, CH2Cl2, 69% O 19 3) LDA, 15-crown-5, Ph(Cl)S=NtBu, THF, 35% 4) PPh3CBF4, CH2Cl2, 66% 353

Scheme 59. OH

O O NH NH H O, AcOH, 1) PIDA, acetone/H2O, 52% 2 2. 2 MeOH, 30-40% (2 steps) 2) H2O2, NaOH, MeOH HO

O TrocN O TrocN 355 354

O O O Amano PS, vinyl acetate, HO OH 4A MS, hexanes, rt, 46% OAc + HO HO HO O O O TrocN TrocN TrocN

357 358 356 Scheme 60.

Starting from aldehyde 349, the nucleophile was changed into racemic synthesis of scyphostatin analogs that includes an enanti- 2,4-dimethoxyphenylmethylmethyloxymethyl lithium. After Mit- oselective access, which is described in scheme 61. sunobu inversion azide 352 was obtained. The following steps are Hydrogenation of the double bond present in the starting mate- equivalent to the ones of the first generation synthesis, obtaining rial 359 was run in the presence of Burk´s Et-DuPHOS ligand to 353 and (+)-scyphostatin in 17 steps with an improved yield. yield enantiopure 360. Boc groups were then removed and an ana- In 2010, Hoye´s group published another approach to the polar logue of the side chain of scyphostatin was introduced. Ester hy- core of scyphostatin [162]. Again, the source of chirality was a drolysis and oxidative dearomatization yielded a 1:1.3 mixture of phenol derived from L-tyrosine (354). As it is illustrated in scheme 361 (desired S, S) and 362, with some loss of enantioselectivity. 60, the phenol was oxidized and the quinol formed was bis- Treatment with DBN of 362 permitted epimerization to give the (R, epoxidated to give 355. Wharton rearrengement of 355 produced a R) diastereomer with >97% ee. Further treatment with pyrrolidine, 1:1 mixture of alcohols 356 and 357. HPLC separation of these t-butylhydroperoxide and acetic acid yielded 363, thus demonstrat- diastereomers resulted in a return to the mixture, thus suggesting a ing that the enantiodivergent strategy for the synthesis of scy- vinilogous Payne rearrangement as the cause of the equilibration. phostatin analogs, including enantiomeric molecules, was success- ful. When the mixture was treated with vinyl acetate in the presence of a lipase, dynamic kinetic resolution worked, and a single acetate PERSPECTIVES 358 was produced, consisting in an advanced intermediate towards the synthesis of the central core of (+)-scyphostatin. In this section we describe reported epoxyquinoids that have not yet been enantioselectively synthesized. Some of them were The last and more recent article concerning scyphostatin was prepared in racemic form and due to their biological properties are published this year [163]. It consists in an extensive work for the expected to be synthesized in optically pure form in the near future.

36 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

1) TFAA; then EDCI, OBoc OBoc O (S,S)-Et-DuPHOS-RhOTf, , 77% R OH H2 (60 psi), CH2Cl2, MeOH, 98%

OMe OMe 2) LiOH.H2O 3) PhI(OAc)2, TFAA BocHN MeO2C 51% (2 steps)

CO2Me NHBoc R = TMS 359 360 (>98% ee)

O O O 1) DBN 2) Pyrrolidine + O 3) TBHP OMe OMe OMe 4) AcOH, 22% (4 steps) O O O

O O RHN RHN RHN O 363 361 (76% ee) 362 Scheme 61.

Isariotin E (364) is a spiro-epoxyenone (Fig. 6) isolated from A group of molecules that resemble the structure of harveynone entomophatic fungi-afflicting insects [164]. It has been proposed have been recently prepared by Taylor and co-workers through that isariotin E could be the biosynthetic progenitor of isariotin F racemic synthesis [166]. Speciosins A-F (365-370, Fig. 7) were and TK-57-164A, another isolated metabolites. Pettus and co- isolated by Jiang et al. from the chinese fungus Hexagonia speciosa workers recently reported the first total synthesis of these com- [167]. Ghisalberti described the isolation of the plant growth pro- pounds in a racemic fashion [165]. moting, anti-fungal metabolite from an ectotrophic australian fun- OH gus, SDEF 678 (371) [168]. O In 2000, Ireland and co-workers [169] reported the isolation and O structure elucidation of eight bioactive farnesylated epoxycyclo- NH hexenoids (Fig. 8) from an Aspergillus niger isolate, obtained from tissue homogenates of an orange Aplidium sp. ascidian. These com- O pounds were denominated yanuthones A-D (372-376), 1- O C9H19 hydroxyyanuthone A and C (377-378), and 22-deacetylyanuthone A (379), and they exhibited weak antimicrobial activity against isariotin E (364) methicillin resistant Staphilococcus aureus and vancomycin resistant Enterococcus. Also, deacetoxyyanuthone A (380), was isolated Fig. (6). Structure of isariotin E.

O O

O O OH OH

O O O O

OH OH OH OH

(+)-speciosin A (365) (+)-speciosin B (366) (+)-speciosin C (367) (+)-speciosin D (368)

OH OMe

OH OH O O O O O O OH OH OH (+)-speciosin E (369) (+)-speciosin F (370) SDEF 678 (371) Fig. (7). Structures of speciosins A-F and SDEF 678.

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 37

O O

O O R1

OR OR 3 2 OR3 O

yanuthone B(375): R3= Ac yanuthone A (372): R1= H, R2= H, R3= Ac O HO O

yanuthone C (373): R1= H, R2= Ac, R3= H yanuthone D (376) R3= OH O HO O yanuthone E (374): R1= H, R2= H, R3= OH

1-hydroxyyanuthone A(377): R1= OH, R2= H, R3= Ac OH OH

1-hydroxyyanuthone C (378): R1= OH, R2= Ac, R3= H O 22-deacetylyanuthone A (379): R1= H, R2= H, R3= H

OAc O oligosporon (381)

O OH OH O O OH

deacetoxyyanuthone A (380) OAc OH

oligosporol B (382) Fig. (8). Farnesyl epoxycyclohexenoids. HO HO O O OH OH OH O O O O O O O HO O O O O O O O H C H H 11 5 H11C5 H11C5 H11C5 O H11C5 O OH

cytosporin D (385) pestaloquinol A (383) pestaloquinol B (384) Fig. (9). Epoxyquinoids derived from Pestalotiopsis sp.. from a marine isolate of genus Penicillium sp., which displayed CONCLUSION mild antimicrobial activity against methicillin resistant and Almost 50 papers have been published since 2004 concerning multidrug resistant S. aureus [170]. Furthermore, oligosporon (381) chiral synthesis of epoxyquinoids. The volume of published work and oligosporol B (382), structurally related farnesyl epoxycyclo- shows that this is a field of great interest for the synthetic commu- hexenoids, were isolated from Arthrobotrys oligospora [171]. Me- nity, that needed to be reviewed. Enzymatic and chemical methods hta et al. reported in 2005 the total synthesis of yanuthones A, B, C for introduction of chirality have been developed and improved and 22-deacetylyanuthone A in racemic form [172]. during this period of time. Enzymatic methods have been used for In 2011, Cha and co-workers reported the isolation of pestalo- the preparation of enantiopure starting materials as well as for the quinols A and B (383-384), along with cytosporin D (385), their resolution of racemic mixtures. In particular, lipase mediated ki- putative biosynthetic precursor, from the plant endophytic fungus netic resolutions has been widely used by several authors, specially Pestalotiopsis sp. (Fig. 9) [173]. Resemblance of these structures by Mehta. Concerning microbially prepared chiral compounds, with antiangiogenic epoxyquinol A and related dimers, added to cyclohexadiene-cis-diols obtained from monosustituted benzenes their reported cytotoxicity against HeLa cells, surely will turn these have been used by Banwell´s and our own group for the preparation compounds attractive for synthetic chemistry. of 10 molecules of this family.

38 Current Organic Synthesis, 2013, Vol. 10, No. 1 Pandolfi et al.

With reference to chemical methods, the use of natural com- dr = diastereomeric ratio pounds from the chiral pool has been extensively applied. Many EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodi- synthesis of natural epoxyquinoids started form L-tyrosine, D- imide arabinose and (-)-quinic acid, among others. Nevertheless, the use of chiral auxiliaries and asymmetric catalysis have also found a ee = enantiomeric excess place in the desymmetrization processes discussed. HMDS = bis(trimethylsilyl)amide Almost all the molecules included are interesting not only from 2-HYP = 2-hydroxypyridine a synthetic point of view, but also regarding the biological activities they display, as antibiotic, antiangiogenic and enzyme inhibitors, IBX = o-iodoxybenzoic acid among others. K-10 = a type of montmorillonite clay We expect that the analysis of the synthetic challenges pre- LDA = lithium diisopropylamine sented, will be helpful to encourage synthetic organic chemists to m-CPBA = m-chloroperbenzoic acid go on deepening the knowledge on this attractive and interesting area. Me-CBS = methyl oxazaborolilidine MPM = p-methoxyphenylmethyl CONFLICT OF INTEREST Ms = methansulphonyl The author(s) confirm that this article content has no conflicts MS = molecular sieves of interest. NBS = N-bromosuccinimide ACKNOWLEDGEMENTS NMO = N-methylmorpholine-N-oxide The authors thank ANII (Agencia Nacional de Investigación e NMP = N-methyl-2-pyrrolidinone Innovación), PEDECIBA (PNUD/URU/06/004) and CSIC-UdelaR NMR = nuclear magnetic resonance for financial support. Np = naphthalene LIST OF ABBREVIATIONS PCC = pyridinium chlorochromate Ac = acetyl PDC = pyridinium dichromate acac = acetylacetonyl PIDA = phenyliodonium diacetate AIBN = azobisisobutyronitrile PIFA = phenyl iodonium bis(trifluoroacetate) aq. = aqueous PMB = p-methoxybenzyl BHT = 2,6-di-t-butyl-p-cresol p-MBDA = p-methoxybenzaldehyde dimethyl acetal Boc = t-butoxy carbonyl PNBA = p-nitrobenzoic acid BPS = t-butyldimethylsiliyl PPL = porcine pancreas lipase cryst. = crystallization PPTS = pyridinium p-toluenesulfonate CSA = camphorsulphonic acid p-TsOH = p-toluenesulphonic acid Cy = cyclohexyl Py = pyridine dba = dibenzylideneacetone PyBop = (benzotriazol-1-yloxy)tripyrrolidinopho- DBMP = 2,6-di-t–butyl-4-methylpyridine sphoniumhexafluorophosphate DBN = 1,5-diazabicyclo(4.3.0)non-5-ene quant. = quantitative DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene rt = room temperature DCC = dicyclohexylcarbodiimide TBAF = tetra-n-butylammonium fluoride DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone TBHP = t-butyl hydroperoxide DEAD = diethyl azodicarboxylate TBME = t-butylmethylether DET = diethyl tartrate TBS = t-butyldimethylsilyl DHMEQ = dehydromethylepoxyquinomicin TEMPO = 2,2,6,6-tetramethyl-1-piperidyloxy free radical DIAD = diisopropyl azodicarboxylate TES = triethylsilyl DIBAL-H = diisobutylaluminium hydride Tf = trifluoromethanesulfonyl DIPEA = diisopropylethylamine TFAA = trifluoroacetic acid DIPT = diisopropyl tartrate THF = tetrahydrofuran DMAP = N,N-4-dimethylaminopyridine THS = thexyltrimethylsilyl DME = 1,2-dimethoxyethane TIPS = triisopropylsilyl DMF = N,N-dimethylformamide TMEDA = tetramethylethylenediamine DMP = Dess-Martin periodinane TMS = trimethylsilyl 2,4 DMPM = 2,4-dimethoxyphenylmethyl TPAP = tetrapropylammonium perruthenate DPPA = diphenylphosphoryl azide Tr = triphenylmethyl

Enantioselective Synthesis of Natural Epoxyquinoids Current Organic Synthesis, 2013, Vol. 10, No. 1 39

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Received: August 12, 2011 Revised: September 19, 2011 Accepted: October 24, 2011