Amino Acid Derivatives - MDPI

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Nov 27, 2015 - Loránd Kiss 1, Enik˝o Forró 1, György Orsy 1, Renáta Ábrahámi 1 and Ferenc Fülöp 1,2,*. Received: 15 October 2015 ; Accepted: 19 November ...
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Stereo- and Regiocontrolled Syntheses of Exomethylenic Cyclohexane β-Amino Acid Derivatives Loránd Kiss 1 , Eniko˝ Forró 1 , György Orsy 1 , Renáta Ábrahámi 1 and Ferenc Fülöp 1,2, * Received: 15 October 2015 ; Accepted: 19 November 2015 ; Published: 27 November 2015 Academic Editor: Derek J. McPhee 1

2

*

Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary; [email protected] (L.K.); [email protected] (E.F.); [email protected] (G.O.); [email protected] (R.Á.) Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös 6, Hungary Correspondence: [email protected]; Tel.: +36-62-545-564

Abstract: Cyclohexane analogues of the antifungal icofungipen [(1R,2S)-2-amino-4-methylenecy clopentanecarboxylic acid] were selectively synthesized from unsaturated bicyclic β-lactams by transformation of the ring olefinic bond through three different regio- and stereocontrolled hydroxylation techniques, followed by hydroxy group oxidation and oxo-methylene interconversion with a phosphorane. Starting from an enantiomerically pure bicyclic β-lactam obtained by enzymatic resolution of the racemic compound, an enantiodivergent procedure led to the preparation of both dextro- and levorotatory cyclohexane analogues of icofungipen. Keywords: amino acids; selectivity; hydroxylation; Wittig reaction; icofungipen

1. Introduction As a consequence of their high biological potential, cyclic β-amino acids are of importance in medicinal chemistry. These compounds are both elements of bioactive products and building blocks in peptide research. Several small molecular entities, such as the cyclopentane derivative cispentacin (1) and oxetane derivative oxetin (2), possess strong antifungal and antibacterial activities [1–13]. An exomethylene function plays an essential role in the structures of some cyclic β-amino acids. The β-amino acid (1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid (icofungipen, PLD-118, 3) and several analogues (4–6) exhibit strong antifungal properties (Figure 1). The (´)-(1R,2S)-2-Amino-4-methylenecyclopentane carboxylic acid was analyzed by Bayer. This compound, previously known as BAY 10-8888, was licensed to Glaxo-SmithKline Research Centre Zagreb Ltd. (formerly PLIVA) and renamed PLD-118; its generic name is icofungipen. Icofungipen is a cyclic β-amino acid, which differs in chemistry, biology, and mechanism of action from other antifungal compound classes. Its mechanism of action is based on the inhibition of isoleucyl-tRNA synthetase, intracellular inhibitory concentrations at the target site being achieved by active accumulation in susceptible fungi [14–18]. The most efficient multigram-scale asymmetric synthetic route to icofungipen involves the asymmetric desymmetrization of the meso-anhydride of a cyclopentane exo-methylenedicarboxylic acid. In the key step, highly enantioselective, quinine-mediated alcoholysis of the meso-anhydride, followed by Curtius rearrangement and Pd-catalyzed removal of the protecting groups affords icofungipen (absolute configurations 1R,2S) with ee = 99.5% [14–18].

Molecules 2015, 20, 21094–21102; doi:10.3390/molecules201219749

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Molecules 2015, 20, 21094–21102 Molecules 2015, 20, page–page Molecules 2015, 20, page–page

CO2H CO2H NH2 NH2 cispentacin (1) cispentacin (1) Molecules 2015, 20, page–page

NH2 NH2 oxetin (2) oxetin (2)

CO2H

NH2 NH2 icofungipen (3) icofungipen (3)

CO2H CO2H

CO2H CO2H

NH2 4 NH2 4 NH2

CO2H CO2H

CO2H CO2H

O O

O

CO2H

NH2 5 NH2 5

CO2H CO2H CO2H

6

NH2 NH2

NH2 NH2 6 cispentacin (1) icofungipen (3) Figure 1. 1. Some Some biologically biologically interesting cyclic β-amino acids. acids. oxetin (2) Figure interesting cyclic β-amino Figure 1. Some biologically interesting cyclic β-amino acids. CO2H CO2H CO2H 2. Results and Discussion

2. Results Resultsand andDiscussion Discussion 2. A convenient and simple novel regio- and stereocontrolled synthetic procedure for the access to NH2 NHregioNH2 procedure A convenient convenient and and simplenovel novel andstereocontrolled stereocontrolled synthetic procedure access 2regio-and A synthetic forfor thethe access to 5with an exomethylene 4 cyclohexane analogues simple of icofungipen is described, group in different positions. 6 to cyclohexane analogues of icofungipen is described, with an exomethylene group in different cyclohexane of icofungipen is described, exomethylenehydroxylation, group in different positions. Cyclohexeneanalogues β-amino acids were subjected to regio-with andan stereoselective oxidation and Figuresubjected 1. Some biologically interesting cyclic β-amino acids. positions. Cyclohexene β-amino acids were subjected to regioand stereoselective hydroxylation, Cyclohexene β-amino acids were to regioand stereoselective hydroxylation, oxidation and oxo-methylene interconversion as illustrated in the retrosynthetic scheme (Scheme 1). oxidation and oxo-methylene interconversion illustrated in the retrosynthetic scheme oxo-methylene interconversion as illustrated inasthe retrosynthetic scheme (Scheme 1). (Scheme 1). 2. Results and Discussion

CO2Et CO2Et stereo- and CO2A Etconvenient and simple novel regioand stereocontrolled synthetic forand the access to CO2Et oxidation regioselective CO2procedure Et stereoCO2Et Wittig reaction O HO cyclohexane analogues with an exomethylene groupregioselective in different positions. Wittig reactionof icofungipen is described, oxidation O HO NHBoc NHBoc Cyclohexene β-amino acids were subjected to regio- and stereoselectiveNHBoc hydroxylation, oxidation and hydroxylation NHBoc NHBoc NHBoc hydroxylation oxo-methylene interconversion as illustrated in the retrosynthetic scheme (Scheme 1). Scheme 1. Retrosynthetic route to exomethylene cyclohexane β-amino esters. and Scheme Retrosynthetic route β-amino esters. COto CO2Et stereoCO2Et 1. 2Etexomethylene cyclohexane Scheme 1. Retrosynthetic route to exomethylene cyclohexane β-amino esters.CO2H Wittig reaction oxidation regioselective O

CO2H CO2H NH2 NH2

HO

The first synthetic approach was based on selective hydroxylation via iodolactonization. NHBoc NHBoc hydroxylation NHBoc NH2 The cyclohexene first synthetic approach was based on selective hydroxylation via iodolactonization. Racemic cis-β-amino acid (±)-7 underwent regioand stereoselective iodolactonization and The first synthetic approach was based on selective hydroxylation via iodolactonization. Scheme 1. Retrosynthetic route to exomethylene cyclohexane β-amino esters. iodolactonization and Racemic cyclohexene cis-β-amino acid (±)-7 underwent regioand stereoselective deiodination by elimination to afford lactone (±)-8. Subsequent lactone opening in iodolactonization (±)-8 with NaOEt Racemic cyclohexene cis-β-amino acidlactone (˘)-7 underwent regio- and stereoselective deiodination byfollowed elimination to afford (±)-8. Subsequent lactone opening in (±)-8 with NaOEt at 0 °C for 1 h, by C-C double bond saturation, yielded 5-hydroxylated β-amino ester (±)-9. The first synthetic approach was based on selective hydroxylation via iodolactonization. and deiodination by elimination to afford lactone (˘)-8.yielded Subsequent lactone opening in (˘)-8 with at 0 °C for 1 h, followed by C-C double bond saturation, 5-hydroxylated β-amino ester (±)-9. Racemic cyclohexene cis-β-amino acid (±)-7 underwent regioand stereoselective iodolactonization and When the lactone opening with NaOEt was performed at 20 °C for 12 h, isomerization occurred with ˝ C for 1 h, followed by C-C double bond saturation, yielded 5-hydroxylated β-amino NaOEt at 0 When the lactone opening with NaOEt performed at 20 °C for 12 h, isomerization occurred with deiodination by elimination to affordwas lactone (±)-8. Subsequent lactone opening in (±)-8 with NaOEt the participation of the the lactone active hydrogen at C-1,NaOEt leading, after C=C reduction, to the thermodynamically ester (˘)-9. with was performed at 20 ˝β-amino C the for thermodynamically 12 h, (±)-9. isomerization at 0When °C for 1the h, followed byopening C-C double bond leading, saturation, yielded 5-hydroxylated ester the participation ofdiastereoisomer active hydrogen at C-1, after C=C reduction, to more stable trans (±)-10 (Scheme 2) [19]. When the the lactone opening with NaOEt was performed at 20 °C for 12 h, isomerization occurred with occurred with participation of the active hydrogen at C-1, leading, after C=C reduction, to the more stable trans diastereoisomer (±)-10 (Scheme 2) [19]. the participation of the active hydrogen at C-1, leading, after C=C reduction, to the thermodynamically thermodynamically more stable trans diastereoisomer (˘)-10 (Scheme 2) [19]. more stable trans diastereoisomer (±)-10 (Scheme 2) [19].

Scheme 2. Synthesis of 5-hydroxylated β-amino ester diastereoisomers (±)-9 and (±)-10 [19].

Scheme 2. Synthesis of 5-hydroxylated β-amino ester diastereoisomers (˘)-9 and (˘)-10 [19]. By a2.modification earlier-describedβ-amino method, [3] oxidation of (±)-9 and (±)-10 Scheme Synthesis of of an 5-hydroxylated ester diastereoisomers (±)-9with andpyridinium (±)-10 [19].

2. Synthesis β-amino ester and (±)-10 [19]. afforded the diastereoisomers corresponding oxo(±)-9 ester stereoisomers chlorochromate (PCC) in5-hydroxylated CH2Cl2 at 20 °C By aScheme modification of of an earlier-described method, [3] oxidation of (˘)-9 and (˘)-10 with (±)-11 and (±)-12 [19]. Icofungipen analogues (±)-13 and (±)-14 were next synthesized from (±)-11 and ˝ By a modification of an earlier-described method, [3] oxidation of (±)-9 and (±)-10 with pyridinium at 20 C afforded the corresponding oxo ester pyridinium chlorochromate (PCC) in CH2 Cl2 exchange (±)-12 via Wittig reactions by oxo-methylene with the phosphorane generated from By a modification of an earlier-described method, [3] oxidation of (±)-9 and (±)-10 with pyridinium 2Cl 2 atIcofungipen 20 °C afforded the corresponding oxo ester stereoisomers chlorochromate (PCC) in CH stereoisomers (˘)-11 and (˘)-12 [19]. analogues (˘)-13 and (˘)-14 were next synthesized methyltriphenylphosponium bromide/t-BuOK at 0 °C (Scheme 3). at 20 °C (±)-13 afforded corresponding oxo esterfrom stereoisomers chlorochromate (PCC)Icofungipen in CH2Cl2 analogues (±)-11 (˘)-11 and (±)-12 and the (±)-14 wereexchange next synthesized (±)-11 and from and[19]. (˘)-12 via Wittig reactions by oxo-methylene with the phosphorane (±)-11 and (±)-12 [19]. Icofungipen analogues (±)-13 and (±)-14 were next synthesized from (±)-11from and ˝ (±)-12 via Wittig reactions by oxo-methylene exchange with the phosphorane generated generated from methyltriphenylphosponium bromide/t-BuOK at 0 C (Scheme 3). (±)-12 via Wittig reactions by oxo-methyleneatexchange with3).the phosphorane generated from methyltriphenylphosponium bromide/t-BuOK 0 °C (Scheme methyltriphenylphosponium bromide/t-BuOK at 02 °C (Scheme 3).

21095 2 2

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Molecules 2015, 20, page–page Molecules HO2015, 20, page–page CO2Et

HO HO

PCC, CH2Cl2

CO2Et

O

CO2Et O PCC, CH2Cl73% 2 °C, 14 CO O 2Et 20 PCC, CHh, NHBoc 2Cl2 (±)-9 20 °C, 14 h, 73% NHBoc 20 °C, 14 h, 73% NHBoc (±)-9 (±)-9 O CO2Et PCC, CH2Cl2

CO2Et

Ph3P-Me Br

CO2Et THF, t-BuOK CO2Et Ph P-Me Br CO CO 2Et 2Et NHBoc NHBoc Ph33P-Me Br 0 °C, t-BuOK 7 h, 66% (±)-13 THF, (±)-11 NHBoc THF, t-BuOK NHBoc NHBoc 0 °C, 7 h, 66% (±)-13 NHBoc (±)-11 0 °C, 7 h, 66% (±)-13 (±)-11 CO Et HO CO2Et 2 Ph3P-Me Br O CO2Et THF, t-BuOK HO CO2Et CO2Et PCC, CH2Cl77% 2 Ph P-Me Br 20 °C, 14 O CO HO CO CO PCC, CHh, 2Et 2Et 2Et NHBoc NHBoc 2Cl2 NHBoc Ph33P-Me Br 0 °C, 7 h, 70% (±)-12 (±)-10 THF, t-BuOK (±)-14 NHBoc THF, t-BuOK NHBoc 20 °C, 14 h, 77% NHBoc NHBoc 0 °C, 7 h, 70% NHBoc 20 °C, 14 h, 77% NHBoc (±)-12 (±)-10 3. Synthesis of racemic exomethylene (±)-14 0 °C, 7 h, 70% Scheme cyclohexane β-amino esters (±)-13 and (±)-14. (±)-12 Scheme cyclohexane β-amino esters (˘)-13 (±)-14 and (˘)-14. (±)-103. Synthesis of racemic exomethylene Scheme 3. Synthesis of racemic exomethylene cyclohexane β-amino esters (±)-13 and (±)-14.

3. Synthesisapproach of racemic exomethylene cyclohexane icofungipen β-amino esters analogues (±)-13 and (±)-14. The Scheme next synthetic to novel cyclohexane consisted in The next synthetic approach to novel cyclohexane icofungipen analogues consisted hydroxylation of the olefinic bond of the cyclohexene cis-β-amino ester (±)-15 via cis-diastereoselective The next synthetic approach to novel cyclohexane icofungipen analogues consisted in in hydroxylation of theapproach olefinic to bond of cyclohexane the cyclohexene cis-β-amino ester consisted (˘)-15 via The next synthetic novel icofungipen analogues in epoxidation with MCPBA and regioselective reductive oxirane opening with NaBH 4, [20–21] with the hydroxylation of the olefinic bond of the cyclohexene cis-β-amino ester (±)-15 via cis-diastereoselective cis-diastereoselective epoxidation with MCPBA andcis-β-amino regioselective reductive opening with hydroxylation ofatthe olefinic bondinof the4-hydroxylated cyclohexene ester (±)-15 viaoxirane cis-diastereoselective hydride attack C-5, resulting the β-aminoopening ester diastereoisomers (±)-17with and,the at epoxidation with MCPBA and regioselective reductive oxirane with NaBH 4 , [20–21] NaBH4 , [20,21] with the and hydride attack atreductive C-5, resulting in the 4-hydroxylated β-amino ester epoxidation with MCPBA regioselective oxirane opening with NaBH 4, [20–21] with the higher temperature, isomerization at the active methyne (±)-18 (Scheme 4) [22]. It may hydride attack at (˘)-17 C-5,through resulting inhigher the 4-hydroxylated β-amino ester diastereoisomers (±)-17 and, be at diastereoisomers and, atin temperature, through isomerization at the active hydride attack atwas C-5,synthesized resulting the 4-hydroxylated β-amino ester(±)-15 diastereoisomers (±)-17methyne and, at noted that (±)-18 earlier in an alternative way from [22]. higher temperature, through isomerization at the was active methyne earlier (±)-18 (Scheme 4) [22]. It may be (˘)-18 (Scheme 4) [22]. It may be noted that (˘)-18 synthesized in an alternative way from higher temperature, through isomerization at the active methyne (±)-18 (Scheme 4) [22]. It may be noted that (±)-18 was synthesized earlier in an alternative way from (±)-15 [22]. (˘)-15that [22].(±)-18 noted was synthesized earlier in an alternative way from (±)-15 [22]. CO2Et NaBH , EtOH 4

CO2Et MCPBA, CH Cl 2 2 CO2Et MCPBA, Cl 0 °C, 5 h,CH 63% CO 2Et MCPBA, CH22Cl22 NHBoc (±)-15 0 °C, 5 h, 63% NHBoc 0 °C, 5 h, 63% NHBoc (±)-15 (±)-15

CO2Et O O O

CO2Et CO 2Et NHBoc (±)-16

NHBoc NHBoc

20 °C, 3 h, 62% NaBH , EtOH NaBH44, EtOH HO 20 °C, 3 h, 62% 20 °C, 3 h, 62% HO HO NaBH4, EtOH

CO2Et CO 2Et NHBoc (±)-17 (±)-17 (±)-17

NHBoc NHBoc CO2Et

CO2Et 70 °C, 3, h, 53% NaBH EtOH CO 2Et NHBoc NaBH44, EtOH HO (±)-18 70 °C, 3 h, 53% NHBoc 70 °C, 3 h, 53% HO HO NHBoc (±)-18 Scheme 4. Synthesis of 4-hydroxylated β-amino ester diastereoisomers (±)-17 and (±)-18 (±)-18 [22]. (±)-16 (±)-16

Scheme4.4.Synthesis Synthesisof of4-hydroxylated 4-hydroxylatedβ-amino β-aminoester esterdiastereoisomers diastereoisomers(˘)-17 (±)-17 and (±)-18 [22]. Scheme and (˘)-18 [22].

Scheme 4. Synthesis of 4-hydroxylated β-amino ester oxidized diastereoisomers (±)-17toand [22]. Hydroxylated esters (±)-17 and (±)-18 were readily with PCC oxo(±)-18 esters (±)-19 and (±)-20Hydroxylated [22]. Compounds (±)-21 and (±)-22, with the methylene function at position 4, isomers of (±)-13 esters (±)-17 and (±)-18 were readily oxidized with PCC to oxo esters (±)-19 and Hydroxylated esters esters (±)-17 (˘)-17and and(±)-18 (˘)-18 were readily oxidized with PCC to oxo esters (˘)-19 were readily oxidized with PCC to oxo esters (±)-19 and and (±)-14, were readily prepared from (±)-19 and (±)-20 in Wittig reactions with the phosphorane (±)-20 [22]. Compounds (±)-21 and (±)-22, with the methylene function at position 4, isomers of (±)-13 and (˘)-20 [22]. Compounds and with (˘)-22, the methylene at position 4, of isomers (±)-20 [22]. in Compounds (±)-21 (˘)-21 and (±)-22, thewith methylene functionfunction at position isomers (±)-13 generated situ from methyltriphenylphosponium bromide/t-BuOK (Scheme 5).4, the and (±)-14, were readily prepared from (±)-19 and (±)-20 in Wittig reactions with phosphorane of (˘)-13 (˘)-14, were readilyfrom prepared (˘)-19inand (˘)-20 in Wittig with the and (±)-14,and were readily prepared (±)-19 from and (±)-20 Wittig reactions withreactions the phosphorane generated in situ from methyltriphenylphosponium bromide/t-BuOK (Scheme 5). (Scheme 5). phosphorane generated in situ from methyltriphenylphosponium bromide/t-BuOK generated in situ from methyltriphenylphosponium bromide/t-BuOK (Scheme 5). CO Et

CO2Et

CO2Et

PCC, CH2Cl2

Ph3P-Me Br

2

CO2Et CO2Et Ph THF, t-BuOK Br P-Me CO CO 2Et 2Et Ph 3P-Me Br NHBoc NHBoc 3 0 °C, 7 h, 63% THF, t-BuOK (±)-19 (±)-21 NHBoc t-BuOK HO O NHBoc THF, °C, 7 h, 63% NHBoc HO O NHBoc 00 °C, 7 h, 63% (±)-19 (±)-21 (±)-19 (±)-21 CO2Et CO2Et Ph3P-Me Br CO2Et CO2Et CO2Et PCC, CH2Cl79% 2 THF, t-BuOK 20 °C, 14 CO Br CO 2Et Ph CO PCC, CHh, 2Et 3P-Me Br O NHBoc HO NHBoc 2Et 2Cl2 NHBoc Ph 3P-Me 0 °C, 7 h, 66% (±)-18 (±)-20 t-BuOK (±)-22 NHBoc THF, t-BuOK HO NHBoc 20 °C, 14 h, 79% O NHBoc NHBoc 0THF, HO (±)-18 NHBoc 20 °C, 14 h, 79% O °C, 7 h, 66% NHBoc (±)-20 0 °C, 7 h, 66% (±)-22 Scheme cyclohexane β-amino esters (±)-21 and (±)-22. (±)-185. Synthesis of racemic exomethylene (±)-20 (±)-22 Scheme 5. Synthesis of racemic exomethylene cyclohexane β-amino esters (±)-21 and (±)-22. Scheme Synthesis of racemic exomethylene cyclohexane β-amino esters (±)-21 and (±)-22. Other regio-5.5.and stereoisomers synthesized by regioand stereoselective iodolactonization Scheme Synthesis of racemicwere exomethylene cyclohexane β-amino esters (˘)-21 and (˘)-22. HO

CO2Et PCC, CH2Cl82% 2 °C, 14 CO PCC, CHh, 2Et 20 NHBoc 2Cl2 (±)-17 NHBoc 20 °C, 14 h, 82% NHBoc 20 °C, 14 h, 82% (±)-17 (±)-17 CO2Et PCC, CH2Cl2

O

and deiodination β-aminocyclohex-3-enecarboxylic (±)-23,and followed by selective lactone opening Other regio- of and stereoisomers were synthesizedacid by regiostereoselective iodolactonization Other regioand stereoisomers were synthesized by regioand stereoselective iodolactonization withdeiodination NaOEtregioand of hydrogenation of the amino lactone intermediate (±)-24bytoselective furnish analogously to Other and stereoisomers were synthesized by regiostereoselective iodolactonization and β-aminocyclohex-3-enecarboxylic acid (±)-23,and followed lactone opening and deiodination of β-aminocyclohex-3-enecarboxylic acid (±)-23, followed by (±)-26 selective lactone6)opening (±)-8 (Scheme 2) the 3-hydroxylated β-amino ester stereoisomers (±)-25 and (Scheme [23]. and deiodination of β-aminocyclohex-3-enecarboxylic acid (˘)-23,(±)-24 followed by selective lactone with NaOEt and hydrogenation of the amino lactone intermediate to furnish analogously to with NaOEt and hydrogenation of the amino lactone intermediate (±)-24 to furnish analogously to (±)-8 (Scheme 2) the 3-hydroxylated β-amino ester stereoisomers (±)-25 and (±)-26 (Scheme 6) [23]. (±)-8 (Scheme 2) the 3-hydroxylated β-amino ester stereoisomers (±)-25 and (±)-26 (Scheme 6) [23]. 21096 3 3 3

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opening with NaOEt and hydrogenation of the amino lactone intermediate (˘)-24 to furnish Molecules 2015, 20, page–page analogously to (˘)-8 (Scheme 2) the 3-hydroxylated β-amino ester stereoisomers (˘)-25 and (˘)-26 Molecules 2015, 20, page–page (Scheme 6)Molecules [23]. 2015, 20, page–page

Scheme 6. Synthesis of 3-hydroxylated β-amino ester stereoisomers (±)-25 and (±)-26 [6].

Scheme [6]. Scheme6.6.Synthesis Synthesisof of3-hydroxylated 3-hydroxylatedβ-amino β-aminoester esterstereoisomers stereoisomers(˘)-25 (±)-25 and and (˘)-26 (±)-26 [6]. A modification of an earlier-described method [23] was next used: oxidation of hydroxylated Scheme 6. Synthesis of 3-hydroxylated β-amino ester stereoisomers (±)-25 and (±)-26 [6]. amino esters (±)-25 (±)-26 with PCC in method CH 2Cl2 at room temperature led to the corresponding cis A modification of earlier-described [23] of an anand earlier-described method [23] was was next next used: used: oxidation of hydroxylated and trans keto esters (±)-27 and (±)-28 [23]. Although cis-keto aminocarboxylate (±)-27 afforded the amino esters (±)-25 (˘)-25and and(±)-26 (˘)-26with withPCC PCCininCH CH Cl at room temperature to the corresponding 2Cl 2 at room temperature ledinled to the corresponding cis 2 2 Wittig productofonan treatment with methyltriphenylphosphonium tetrahydrofurane A modification earlier-described method [23] wasbromide/t-BuOK next used: oxidation of hydroxylated cis keto esters (˘)-27 and (˘)-28 [23]. cis-keto Although (˘)-27 andand transtrans ketoto esters (±)-27of and (±)-28 [23]. Although afforded the due the presence thewith active hydrogen isomerization occurredaminocarboxylate atcis-keto C-2 under aminocarboxylate alkaline (±)-27 conditions amino esters (±)-25 and (±)-26 PCC in CH 2Cl2 at room temperature led to the corresponding cis afforded the Wittig productwith on methyltriphenylphosphonium treatment with bromide/t-BuOK and gave thermodynamically more stable (±)-29methyltriphenylphosphonium (only the relative stereochemistry isin shown), in Wittig product on the treatment bromide/t-BuOK tetrahydrofurane and trans which keto esters (±)-27 and (±)-28 [23]. Although cis-keto aminocarboxylate (±)-27 afforded the the amino andto carboxylate functionsof arethe in a trans relationship; trans amino ester (±)-28 reactedconditions in the hydrogen presence active hydrogen occurred at C-2 duetetrahydrofurane to the presence ofdue the active isomerization occurred atisomerization C-2 under alkaline Wittig product onphosphonium treatment with in ester tetrahydrofurane with the salt inmethyltriphenylphosphonium the presence of t-BuOK to yield (±)-29bromide/t-BuOK stereoisomer with the and under alkaline conditions and gave thestable thermodynamically stable (˘)-29 (onlyisthe relative and gave the thermodynamically more (±)-29 (only the more relative stereochemistry shown), in thethe transactive arrangement (Scheme 7). due to thecarbamate presenceinof hydrogen isomerization occurred at C-2 under alkaline conditions

stereochemistry shown), in which the amino and carboxylate functions in aester trans(±)-28 relationship; which the aminoisand carboxylate functions are in a trans relationship; transare amino reacted and gave the thermodynamically more stable (±)-29 (only the relative stereochemistry is shown), in CO2Et CO Et 2 trans amino ester (˘)-28 reacted with the phosphonium salt in the presence of t-BuOK to yield (˘)-29 with the phosphonium salt in the presence of t-BuOK to yield (±)-29 stereoisomer with the ester and which the amino and carboxylate functions are in a trans relationship; trans amino ester (±)-28 reacted stereoisomer the ester and carbamate in the trans arrangement (Scheme 7). carbamate in with the trans arrangement (Scheme 7). NHBoc with the phosphonium saltNHBoc in the presence of t-BuOK to yield (±)-29 stereoisomer with the ester and OH OH carbamate in the trans arrangement (Scheme 7). CO Et CO Et (±)-26 (±)-25 2

2

PCC, CH2Cl2 CO220 Et °C, 14 h, 72%

PCC, CH2Cl2 20 °C, 14 h, 72%

NHBoc

CO2Et NHBoc

CO2Et CO2Et OH CO2Et OH Ph3P-Me Br Ph3P-Me Br NHBoc NHBoc (±)-26 (±)-25 THF, t-BuOK THF, t-BuOK NHBoc NHBoc OH OH NHBoc 0 °C,PCC, 7 h, 61% PCC, CH2Cl2 0 °C, 7 h, 63% CH2Cl 2 (±)-26 O (±)-25 O (±)-27 20 °C, 14 h, 72% (±)-29 20 °C, 14 h,(±)-28 72% PCC, CH2Cl2 PCC, CH2Cl2 Scheme 7. Synthesis of racemic (±)-29. CO2Et 20 °C, 14 h, 72% 20CO °C,2Et 14 h,Ph 72% CO2Et Ph3P-Me Br 3P-Me Br The isomerization of cis-(±)-27 at C-2 during theCO Wittig reaction with methyltriphenylphosponium CO2Et THF, CO2Et 2Et t-BuOK THF, t-BuOK Br through trans Phto3P-Me Ph3(±)-28 P-Me NHBoc NHBoc NHBoc bromide/t-BuOK in THF give (±)-29 amino ester isBr depicted in Scheme 8. 0 °C, 7 h, 63% 0 °C, 7 h, 61% O O THF, t-BuOK NHBoc NHBoc THF, t-BuOK NHBoc (±)-27 (±)-29 0 °C, 7 h, 63% 0 °C, 7 h, 61% (±)-28 O O (±)-27 Scheme7.7. Synthesis Synthesis of racemic racemic(˘)-29. (±)-29. (±)-29 of (±)-28 Scheme

Scheme 7. Synthesis of racemic (±)-29.

The isomerization of cis-(±)-27 at C-2 during the Wittig reaction with methyltriphenylphosponium The isomerization of cis-(˘)-27 at C-2 during the Wittig reaction with bromide/t-BuOK in THF to give (±)-29 of through trans ester (±)-28 is(±)-28. depicted in Scheme 8. Scheme 8. Formation (±)-29 from (±)-27amino through trans-amino ester The isomerization of cis-(±)-27 at C-2 during the Wittig with methyltriphenylphosponium methyltriphenylphosponium bromide/t-BuOK in THF toreaction give (˘)-29 through trans amino ester bromide/t-BuOK to give through trans amino ester (±)-28 is to depicted 8. (˘)-28 is depicted inTHF Scheme 8. (±)-29 The in above experiments (27→29 and 28→29) with the racemates led us suppose in thatScheme both enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam. For this purpose, therefore, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by CAL-B-catalyzed ring-opening of racemic lactam (±)-30 (Scheme 9) [24]. 4

Scheme 8. Formation of (±)-29 from (±)-27 through trans-amino ester (±)-28. Scheme 8. Formation of (±)-29 from (±)-27 through trans-amino ester (±)-28.

8. Formation of (˘)-29 from (˘)-27 through trans-amino ester The aboveScheme experiments (27→29 and 28→29) with the racemates led us (˘)-28. to suppose that both enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam. The above experiments (27→29 and 28→29) with the racemates led us to suppose that both For this purpose, therefore, enantiomerically21097 pure β-lactam (+)-30 (ee = 99%) was prepared by enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam. CAL-B-catalyzed ring-opening of racemic lactam (±)-30 (Scheme 9) [24]. For this purpose, therefore, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by CAL-B-catalyzed ring-opening of racemic lactam (±)-30 (Scheme 9) [24]. 4

Molecules 2015, 20, 21094–21102

The above experiments (27Ñ29 and 28Ñ29) with the racemates led us to suppose that both enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam. For this purpose, therefore, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by CAL-B-catalyzed ring-opening of racemic lactam (˘)-30 (Scheme 9) [24]. Molecules 2015, 20, page–page

Molecules 2015, 20, page–page

Molecules 2015, 20, page–page

Scheme 9. Synthesis Synthesis of of enantiomerically enantiomerically pure lactam lactam (+)-30. Scheme Scheme 9. 9. Synthesis of enantiomerically pure pure lactam (+)-30. (+)-30.

Enantiomerically pure β-lactam (+)-30 was next transformed by an earlier-published procedure [23] Enantiomerically β-lactam (+)-30(+)-30 was next transformed by an earlier-published procedure [23] Enantiomericallypure pure β-lactam was next transformed by an earlier-published to the corresponding N-Boc amino acid, which was then converted to enantiopure bicyclic lactone to the corresponding amino acid, which was then converted to enantiopure bicyclic lactone procedure [23] to the N-Boc corresponding N-Boc amino acid, which was then converted to enantiopure Scheme 9. Synthesis of enantiomerically pure lactam (+)-30. (−)-24 (Scheme 10). (−)-24 (Scheme 10). bicyclic lactone (´)-24 (Scheme 10). Enantiomerically pure β-lactam (+)-30 was next transformed by an earlier-published procedure [23] Boc2O, NaOH 1S CO H 1S was 1S O CO then H converted 2 to the corresponding N-Boc amino acid, which to enantiopure Boc O, NaOH 1S bicyclic CO2H lactone 1S CO22H 1S O 18% HCl, 0 °C H22O/THF (−)-24 (Scheme 10). 18% HCl, 0 °C H2O/THF

NH

6R NH 6R 1S

(+)-30 (+)-30

6R

O

0 °C to RT

1 h, 76% 1 h, 76%

18% HCl, 0 °C

NH

1 h, 76%

(+)-30

0 °C to RT 2R NH2HCl 14 h,NaOH 88% 2HCl Boc14 2O,h, 2R NH 1S 88% (-)-32CO2H H2O/THF

(-)-32

2R NH2HCl

0 °C to RT 14 h, 88%

(-)-32 1S 1S O 8S O 8S NHBoc

1S 5R O NHBoc O 5R O 8S

(-)-24 (-)-24

DBU, THF DBU, THF 65 °C, 5 h, 69% 65 °C, 5 h, 69% DBU, THF

4S 4S I

I

4S

1S 1S

2R NHBoc

NHBoc 1S 2R CO2H

(-)-23 (-)-23 KI, NHBoc I2, NaHCO3 2R KI, 2, NaHCO H2IO, CH2Cl23 (-)-23 H O, CH 2 2Cl2 20 °C, 18 h, 74% 20KI, °C, 18 h, 74% I , NaHCO 2

3

O H2O, CH2Cl2 8S O 8S 20 °C, NHBoc 18 h, 74% 5S 1S O NHBoc 5S O O 8S (-)-33

(-)-33NHBoc NHBoc 65 °C, 5 h, 69% I 5S O 5R O Scheme 10. Synthesis of enantiomer lactone (−)-24. (-)-24 Scheme 10. Synthesis of enantiomer lactone (−)-24. Scheme 10. Synthesis of enantiomer(-)-33 lactone (´)-24.

On treatment with NaOEt at 0 °C, optically pure lactone (−)-24 gave the all-cis 3-hydroxylated Scheme 10. Synthesis of enantiomer lactone (−)-24. On treatment with NaOEt at 0 °C, optically pure lactone (−)-24 gave the all-cis 3-hydroxylated ˝ β-amino ester (−)-34, [23] whereas at room temperature for 14 h isomerization atall-cis C-1 led to (−)-35 [23]. On treatment with NaOEt at at 0 room C, optically pure lactone (´)-24 gave theat 3-hydroxylated β-amino ester (−)-34, [23] whereas temperature for 14 h(−)-24 isomerization C-1 led to (−)-35 [23]. On treatment with NaOEt at 0 °C, optically pure lactone gave the all-cis 3-hydroxylated On catalytic hydrogenation, these compounds afforded hydroxylated cyclohexane β-amino esterhydrogenation, (´)-34, [23] whereas room temperature for14 14hhisomerization isomerization at C-1 ledβ-amino to (´)-35esters [23]. On catalytic theseatcompounds afforded cyclohexane β-amino ester (−)-34, [23] whereas at room temperature for hydroxylated at C-1 led toβ-amino (−)-35 [23].esters (+)-25 and (−)-26, [6] respectively, in enantiomerically pure form (Scheme 11) [23]. On catalytic hydrogenation, these hydroxylated cyclohexane β-amino On catalytic hydrogenation, these compounds afforded afforded hydroxylated cyclohexane estersesters (+)-25 and (−)-26, [6] respectively, incompounds enantiomerically pure form (Scheme 11) [23]. β-amino (+)-25(+)-25 and and (´)-26, [6] respectively, in enantiomerically pure form (Scheme 11) [23]. (−)-26, [6] respectively, in enantiomerically pure form (Scheme 11) [23].

Scheme 11.11. Synthesis stereoisomers (+)-25 and (−)-26. Scheme Synthesisofofamino amino ester ester stereoisomers (+)-25 and (−)-26. Scheme Scheme 11. 11. Synthesis Synthesis of of amino amino ester ester stereoisomers stereoisomers (+)-25 (+)-25 and and (´)-26. (−)-26.

Analogously to the racemates,(+)-25 (+)-25and and (−)-26 (−)-26 [23] oxidation to the corresponding Analogously to the racemates, [23]underwent underwent oxidation to the corresponding Analogously (+)-25 (−)-26 [23] underwent oxidation to the corresponding to the racemates, (+)-25 and (´)-26 [23] underwent oxidation enantiopure cis and trans (+)-27 and (−)-28 (ee = 99%). enantiopure cis and trans (+)-27 and (−)-28 (ee = 99%). enantiopure and trans (+)-27 and (−)-28 (ee On cis reaction with phosphorane generated in situ bromide/ (´)-28 (ee==99%). 99%). On reaction with phosphorane generated in situ from frommethyltriphenyphosphonium methyltriphenyphosphonium bromide/ t-BuOK, (+)-27with participated in isomerization at C-2 to give themethyltriphenyphosphonium thermodynamically more stable (+)-29 On reaction phosphorane generated in situ from bromide/ t-BuOK, (+)-27 participated in isomerization at C-2 to give the thermodynamically more stable (+)-29 (ee =(+)-27 90.6%),participated while under in similar conditions (−)-28 yielded opposite enantiomer (−)-29 (ee =stable 86.6%).(+)-29 t-BuOK, isomerization at C-2 to giveitsthe thermodynamically more 21098 (ee = 90.6%), while under similar conditions (−)-28 yielded its opposite enantiomer (−)-29 (ee = 86.6%). The chiral centers at C-1 or C-2 in (+)-27 may theoretically both be affected (both active hydrogens) (ee = 90.6%), while under similar conditions (−)-28 yielded its opposite enantiomer (−)-29 (ee = 86.6%). The chiral centers at C-1 or C-2 in (+)-27 may theoretically both be affected (both active hydrogens) but this was not C-2 underwent isomerization, to the(both thermodynamically The chiral centers at observed. C-1 or C-2Only in (+)-27 may theoretically bothleading be affected active hydrogens) but this was not observed. Only C-2 underwent isomerization, leading to the thermodynamically more stable derivative (+)-29 with the carbamate and ester groups in a trans relative relationship. but this was not observed. Only C-2 underwent isomerization, leading to the thermodynamically more stable derivative (+)-29 with the carbamate and ester groups in a trans relative relationship.

Molecules 2015, 20, 21094–21102

On reaction with phosphorane generated in situ from methyltriphenyphosphonium bromide/t-BuOK, (+)-27 participated in isomerization at C-2 to give the thermodynamically more stable (+)-29 (ee = 90.6%), while under similar conditions (´)-28 yielded its opposite enantiomer (´)-29 (ee = 86.6%). The chiral centers at C-1 or C-2 in (+)-27 may theoretically both be affected (both active hydrogens) but this was not observed. Only C-2 underwent isomerization, leading to the thermodynamically more stable derivative (+)-29 with the carbamate and ester groups in a trans relative relationship. (Scheme 12). Molecules 2015, 20, page–page 1S CO2Et 2S 3R

NHBoc

20 °C, 14 h, 70%

OH (+)-25

1S CO2Et 2S

NHBoc O (+)-27

1R CO2Et 2S 3R

PCC, CH2Cl2

PCC, CH2Cl2

NHBoc 20 °C, 14 h, 76%

OH (-)-26

1R CO2Et 2S

NHBoc O (-)-28

Ph3P-Me Br

1S CO2Et 2R

t-BuOK, THF 0 °C, 7 h, 39%

NHBoc (+)-29

Ph3P-Me Br

1R CO2Et 2S

t-BuOK, THF 0 °C, 7 h, 42%

NHBoc (-)-29

Scheme 12. Synthesis of amino ester enantiomers (+)-29 and (−)-29.

Scheme 12. Synthesis of amino ester enantiomers (+)-29 and (´)-29.

3. Experimental Section

3. Experimental Section

3.1. General Procedure for the Methylenation of Oxo Esters

3.1. General Procedure for the Methylenation of Oxo Esters

To a solution of methyltriphenylphosphonium bromide (2 mmol) in THF (15 mL), t-BuOK

To a solution of methyltriphenylphosphonium in THF (15 mL), t-BuOK (1 equiv.) was added and the solution was stirred for bromide 15 min at (2 20 mmol) °C. The β-aminooxocarboxylate (1 equiv.) thenand added the mixture was further After 6 h, water (1 equiv.) was was added theand solution was stirred for 15stirred min at this 20 ˝temperature. C. The β-aminooxocarboxylate (15 mL) was added, and the mixture was extracted with CH 2 Cl 2 (2 × 15 mL). The organic layer6 was (1 equiv.) was then added and the mixture was further stirred at this temperature. After h, water dried (Na 2SO4) and concentrated, and the crude product was purified by column chromatography on (15 mL) was added, and the mixture was extracted with CH2 Cl2 (2 ˆ 15 mL). The organic layer was 9:1). driedsilica (Na2gel SO(n-hexane/EtOAc 4 ) and concentrated, and the crude product was purified by column chromatography on silica gel (n-hexane/EtOAc 9:1). Ethyl (1R*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate [(±)-13]. A colorless oil, yield: 66%. Rf = 0.65 (n-hexane/EtOAc 4:1); 1H-NMR (CDCl3, 400 MHz): δ = 1.22 (t, 3H, CH3, J = 7.00 Hz),

Ethyl1.41 (1R*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate [(˘)-13]. A colorless (s, 9H, t-Bu), 1.71–1.80 (m, 1H, CH2), 1.83–1.90 (m, 1H, CH2), 2.09–21 (m, 1H, CH2), 2.23–2.30 (m, oil, 1 yield:1H, 66%. (n-hexane/EtOAc (CDCl(m, MHz): δ = 1.22 (t, 3H, 3 , 400 f = 0.65(m, CH2),R2.32–2.38 1H, CH2), 2.57–2.634:1); (m, 1H,H-NMR CH2), 2.82–2.88 1H, H-1), 3.96–4.02 (m, 1H, H-2),CH3 , 13C-NMR J = 7.00 Hz), 1.41 (s, OCH 9H, t-Bu), 1.71–1.80 (m, CH(brs, 1H, CH (m, 1H, 4.07–4.20 (m, 2H, 2), 4.63–4.70 (m, 2H, CH1H, 2), 5.38 1H, N-H). (m, (DMSO, 100 MHz): 2 ), 1.83–1.90 2 ), 2.09–21 14.9, 29.1,(m, 30.1,1H, 32.3,CH 32.8, 46.8, 47.9, 60.6, 78.6, 109.4, 147.1, 158.0, 173.0. Anal. Calcd for C 15 H 25 NO 4: 1H, CH2 ),δ =2.23–2.30 ), 2.32–2.38 (m, 1H, CH ), 2.57–2.63 (m, 1H, CH ), 2.82–2.88 (m, 2 2 2 C 63.58, H 8.89, N 4.94; found: C 63.20, H 8.61, N 4.68. H-1), 3.96–4.02 (m, 1H, H-2), 4.07–4.20 (m, 2H, OCH2 ), 4.63–4.70 (m, 2H, CH2 ), 5.38 (brs, 1H, N-H). 13 C-NMR (DMSO, 100 MHz): δ = 14.9, 29.1, 30.1, 32.3, 32.8, 46.8, 47.9, 60.6, 78.6, 109.4, 147.1, 158.0, Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate [(±)-14]. A white solid, 173.0. Anal. Calcd for C15 H25 NO4 : C 63.58, H 8.89, N 4.94; found: C 63.20, H 8.61, N 4.68. 1

mp 102–103 °C; yield: 70%. Rf = 0.6 (n-hexane/EtOAc 4:1); H-NMR (CDCl3, 400 MHz): δ = 1.21 (t, 3H, CH3, J = 7.00 Hz), 1.41 (s, 9H, t-Bu), 2.06–2.19 (m, 1H, CH2), 2.24–2.43 (m, 5H, CH2, H-1), 3.79–3.86 Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate [(˘)-14]. A white solid, (m, 1H, H-2), 4.11–4.20 (m, 2H, OCH2), 4.42 (brs, 1H, N-H), 4.70–4.73 (m, 2H, CH2). 13C-NMR (DMSO, ˝ C; yield: 70%. R = 0.6 (n-hexane/EtOAc 4:1); 1 H-NMR (CDCl , 400 MHz): δ = 1.21 mp 102–103 3 Anal. Calcd for 100 MHz): δ = 14.9, 29.1, 33.3,f33.6, 36.7, 50.3, 50.9, 60.7, 78.3, 110.2, 146.0, 156.0, 173.7. (t, 3H, , J 4:=C7.00 Hz), 1.41N(s, 9H, t-Bu), 2.06–2.19 (m, C15CH H253NO 63.58, H 8.89, 4.94; found: C 63.22, H 9.11, N 1H, 4.69. CH2 ), 2.24–2.43 (m, 5H, CH2 , H-1),

3.79–3.86 (m, 1H, H-2), 4.11–4.20 (m, 2H, OCH2 ), 4.42 (brs, 1H, N-H), 4.70–4.73 (m, 2H, CH2 ). 13 C-NMR Ethyl (1R*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate [(±)-21]. A white solid,156.0, (DMSO, 100 MHz): δ = 14.9, 29.1, 33.3, 33.6, 36.7, 50.3, 50.9, 60.7, 78.3, 110.2, 146.0, mp 56–58 °C; yield: 63%. R f = 0.6 (n-hexane/EtOAc 4:1); 1H-NMR (CDCl3, 400 MHz): δ = 1.16 (t, 3H, 173.7. Anal. Calcd for C15 H25 NO4 : C 63.58, H 8.89, N 4.94; found: C 63.22, H 9.11, N 4.69.

CH3, J = 7.10 Hz), 1.43 (s, 9H, t-Bu), 1.79–1.86 (m, 1H, CH2), 1.88–2.03 (m, 1H, CH2), 2.11–2.19 (m, 1H, CH 2), 1.23–1.33 (m, 1H, CH2), 2.38–2.45 (m, 2H, CH2), 2.77–2.82 (m, 1H, H-1), 4.09–4.23 (m, 3H, OCH2, Ethyl (1R*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate [(˘)-21]. A white solid, H-2), 4.78–4.80 (m, 1H, =CH), 4. 83–4.86 (m, 1H, =CH), 5.06 1(brs, 1H, N-H). 13C-NMR (CDCl3, 100 MHz): ˝ mp 56–58 C; yield: 63%. Rf = 0.6 (n-hexane/EtOAc 4:1); H-NMR (CDCl3 , 400 MHz): δ = 1.16 (t, 3H, δ = 14.6, 26.4, 28.8, 32.5, 39.8, 45.4, 49.7, 60.9, 79.6, 111.4, 144.5, 155.4, 173.7. Anal. Calcd for C15H25NO4: CH3 , J = 7.10 Hz), 1.43 (s, 9H, t-Bu), 1.79–1.86 (m, 1H, CH2 ), 1.88–2.03 (m, 1H, CH2 ), 2.11–2.19 (m, 1H, C 63.58, H 8.89, N 4.94; found: C 63.23, H 8.60, N 4.68.

CH2 ), 1.23–1.33 (m, 1H, CH2 ), 2.38–2.45 (m, 2H, CH2 ), 2.77–2.82 (m, 1H, H-1), 4.09–4.23 (m, 3H, Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate [(±)-22]. A white solid, mp 99–101 °C; yield: 66%. Rf = 0.55 (n-hexane/EtOAc 4:1); 1H-NMR (CDCl3, 400 MHz): δ = 1.21 (t, 3H, CH3, J = 7.10 Hz), 1.41 (s, 9H, t-Bu), 1.78–1.88 (m, 1H, CH2), 1.89–1.98 (m, 1H, CH2), 2.00–2.10 (m, 2H, 21099 CH2), 2.29–2.38 (m, 1H, CH2), 2.56–2.61 (m, 1H, CH2), 2.62–2.69 (m, 1H, H-1), 3.83–3.96 (m, 1H, H-2), 4.17–4.24 (m, 2H, OCH2), 4.60 (brs, 1H, N-H), 5.79–5.82 (m, 2H, =CH), 13C-NMR (DMSO, 100 MHz):

Molecules 2015, 20, 21094–21102

OCH2 , H-2), 4.78–4.80 (m, 1H, =CH), 4. 83–4.86 (m, 1H, =CH), 5.06 (brs, 1H, N-H). 13 C-NMR (CDCl3 , 100 MHz): δ = 14.6, 26.4, 28.8, 32.5, 39.8, 45.4, 49.7, 60.9, 79.6, 111.4, 144.5, 155.4, 173.7. Anal. Calcd for C15 H25 NO4 : C 63.58, H 8.89, N 4.94; found: C 63.23, H 8.60, N 4.68. Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate [(˘)-22]. A white solid, mp 99–101 ˝ C; yield: 66%. Rf = 0.55 (n-hexane/EtOAc 4:1); 1 H-NMR (CDCl3 , 400 MHz): δ = 1.21 (t, 3H, CH3 , J = 7.10 Hz), 1.41 (s, 9H, t-Bu), 1.78–1.88 (m, 1H, CH2 ), 1.89–1.98 (m, 1H, CH2 ), 2.00–2.10 (m, 2H, CH2 ), 2.29–2.38 (m, 1H, CH2 ), 2.56–2.61 (m, 1H, CH2 ), 2.62–2.69 (m, 1H, H-1), 3.83–3.96 (m, 1H, H-2), 4.17–4.24 (m, 2H, OCH2 ), 4.60 (brs, 1H, N-H), 5.79–5.82 (m, 2H, =CH), 13 C-NMR (DMSO, 100 MHz): δ = 14.6, 27.8, 28.8, 32.8, 40.5, 48.2, 61.0, 78.0, 110.9, 144.9, 152.0, 173.8. Anal. Calcd for C15 H25 NO4 : C 63.58, H 8.89, N 4.94; found: C 63.78, H 8.66, N 5.23. Ethyl (1S*,2R*)-2-(tert-butoxycarbonylamino)-3-methylenecyclohexanecarboxylate [(˘)-29]. A white solid, mp 75–77 ˝ C; yield: 63%. Rf = 0.65 (n-hexane/EtOAc 4:1); 1 H-NMR (CDCl3 , 400 MHz): δ = 1.22 (t, 3H, CH3 , J = 7.10 Hz), 1.22–1.30 (m, 1H, CH2 ) 1.40 (s, 9H, t-Bu), 1.75–1.84 (m, 2H, CH2 ), 1.95–2.02 (m, 1H, CH2 ), 2.07–2.19 (m, 1H, CH2 ), 2.21–2.28 (m, 1H, CH2 ), 2.39–2.43 (m, 1H, H-1), 4.11–4.20 (m, 2H, OCH2 ), 4.24–4.35 (m, 1H, H-2), 4.39 (brs, 1H, N-H), 4.79–4.83 (m, 2H, CH2 ). 13 C-NMR (DMSO, 100 MHz): δ = 14.9, 26.6, 29.1, 29.7, 34.8, 50.7, 55.0, 60.6, 78.3, 107.7, 147.9, 155.7, 173.9. Anal. Calcd for C15 H25 NO4 : C 63.58, H 8.89, N 4.94; found: C 63.80, H 8.60, N 5.22. 3.2. Characterization of the Enantiomerically Pure Substances The ee values for (+)-27 and (´)-28 were determined on a HPLC (ChiralPak IA, Chiral Technologies Europe, Illkirch-Graffenstaden, France) 5 µ column (0.4 cm ˆ 1 cm): for (+)-27 (ee 99%), mobile phase: n-hexane/2-propanol (80/20); flow rate 0.5 mL/min; detection at 205 nm; retention time (min): 11.14 (for antipode: 10.68); for (´)-28 (ee 99%), mobile phase: n-hexane/2-propanol (70/30); flow rate 0.5 mL/min; detection at 205 nm; retention time (min): 11.8 (for antipode: 25.1). The ee values for (´)-29 and (+)-29 were determined on a HPLC (ChiralPak IA) 5 µ column (0.4 cm ˆ 1 cm), for (´)-29 (ee 90%): mobile phase: n-hexane/2-propanol (70/30); flow rate 0.5 mL/min; detection at 205 nm; retention time (min): 9.25; for (+)-29 (ee 86%): mobile phase: n-hexane/2-propanol (70/30); flow rate 0.5 mL/min; detection at 205 nm; retention time (min): 10.36. All 1 H-NMR spectra recorded for the enantiomeric substances were the same as for the corresponding racemic counterparts. (1S,2R)-2-Aminocyclohex-3-enecarboxylic acid hydrochloride mp 203–206 ˝ C; yield: 76%. rαs25 D = ´89.5 (c 0.335, EtOH).

[(´)-32]

[20,21].

A

white

solid;

(1S,2R)-2-(tert-Butoxycarbonyl)cyclohex-3-enecarboxylic acid [(´)-23]. A white solid; mp 115–118 ˝ C; yield: 88%. rαs25 D = ´26.6 (c 0.315, EtOH), (for the opposite enantiomer see reference [23]). tert-Butyl (1S,4S,5S,8S)-4-iodo-7-oxo-6-oxabicyclo[3.2.1]octan-8-ylcarbamate [(´)-33]. A white solid; mp 50–53 ˝ C; yield: 74%. rαs25 D = ´54.4 (c 1.9, EtOH) (for the opposite enantiomer, see reference [23]). tert-Butyl (1S,5R,8S)-7-oxo-6-oxabicyclo[3.2.1]oct-3-en-8-ylcarbamate [(´)-24]. A white solid; mp 157–159 ˝ C; yield: 69%. rαs25 D = ´107.6 (c 0.35, EtOH) (for the opposite enantiomer, see reference [23]). Ethyl (1S,5R,6S)-6-(tert-butoxycarbonyl)-5-hydroxycyclohex-3-enecarboxylate [(´)-34]. A colorless oil; yield: 92%. rαs25 D = ´21.6 (c 0.375, EtOH) (for the opposite enantiomer, see reference [23]). Ethyl (1R,5R,6S)-6-(tert-butoxycarbonyl)-5-hydroxycyclohex-3-enecarboxylate [(´)-35]. A colorless oil; yield: 56%. rαs25 D = ´79.6 (c 0.48, EtOH) (for the opposite enantiomer, see reference [23]). 21100

Molecules 2015, 20, 21094–21102

Ethyl (1S,2S,3R)-2-(tert-butoxycarbonyl)-3-hydroxycyclohexanecarboxylate [(+)-25]. A white solid; mp 76–79 ˝ C; yield: 87%. rαs25 D = +24.6 (c 0.62, EtOH). Ethyl (1R,2S,3R)-2-(tert-butoxycarbonyl)-3-hydroxycyclohexanecarboxylate [(´)-26]. A white solid; mp 92–94 ˝ C; Yield: 47%. rαs25 D = ´38.4 (c 0.61, EtOH), (for the opposite enantiomer see reference [23]). Ethyl (1S,2S)-2-(tert-butoxycarbonyl)-3-oxocyclohexanecarboxylate [(+)-27]. A colorless oil; yield: 70%. rαs25 D = +54.3 (c 0.415, EtOH), (for the racemic compound, see reference [23]). Ethyl (1R,2S)-2-(tert-butoxycarbonyl)-3-oxocyclohexanecarboxylate [(´)-28]. A white solid; mp 85–88 ˝ C; yield: 76%. rαs25 D = ´12.7 (c 0.53, EtOH) (for the racemic compound see reference [23]). Ethyl (1S,2R)-2-(tert-butoxycarbonyl)-3-methylenecyclohexanecarboxylate [(+)-29]. A colorless oil; yield: 39%. rαs25 D = +25.8 (c 0.38, EtOH); ee = 90.6%. Ethyl (1R,2S)-2-(tert-butoxycarbonyl)-3-methylenecyclohexanecarboxylate [(´)-29]. A colorless oil; yield: 42%. rαs25 D = ´14.1 (c 0.33, EtOH); ee = 86.7%. 4. Conclusions Cyclohexane β-amino esters with an extracyclic methylene at position 3, 4 or 5 have been regio- and stereoselectively synthetized from 2-aminocyclohexenecarboxylic acid regioisomers by transformation of the ring olefinic bond via three different regio- and stereocontrolled hydroxylation procedures, followed by deoxygenation through oxo-methylene interconversion via Wittig reactions. An enantiodivergent route starting from a bicyclic β-lactam enantiomer permitted the synthesis of both enantiomers of a cyclohexane icofungipen analogue. Acknowledgments: We are grateful to the Hungarian Research Foundation (OTKA No K100530 and K115731) for financial support. This paper was supported by the János Bolyai Research Scholarship (L.K.) of the Hungarian Academy of Sciences. Author Contributions: L.K. and F.F. designed, planed research and interpreted the results. E.F., G.O. and R.A. carried out of the synthetic work. All authors discussed the results, prepared and commented on the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors in mg quantities. © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).

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