An Update on the Stereoselective Synthesis of Î³-Amino Acids

Home , Arbaclofen placarbil, Diphenylphosphoryl azide, GABA analogue

Tetrahedron: Asymmetry 27 (2016) 999–1055

Contents lists available at ScienceDirect

Tetrahedron: Asymmetry

journal homepage: www.elsevier.com/locate/tetasy

Tetrahedron: Asymmetry report number 163 An update on the stereoselective synthesis of c-amino acids ⇑ ⇑ Mario Ordóñez a, , Carlos Cativiela b, , Iván Romero-Estudillo c a Centro de Investigaciones Químicas–IICBA, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, Mexico b Departamento de Química Orgánica, Universidad de Zaragoza–CSIC, ISQCH, 50009 Zaragoza, Spain c CONACyT Research Fellow–Centro de Investigaciones Químicas–IICBA, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, Mexico article info abstract

Article history: This review outlines the most recent papers describing the stereoselective synthesis of c-amino acids. In Received 29 July 2016 this update, the c-amino acids have been classified according to the type of compounds, position and Accepted 5 August 2016 number of substituents, and depending on the type of substrate, acyclic, carbocyclic or azacyclic deriva- Available online 22 September 2016 tives, following in the first case an order related to the strategy used, whereas in the second and third cases the classification is based on the ring size. Ó 2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction ...... 1000 2. Stereoselective synthesis of acyclic c-amino acids ...... 1000 2.1. a-Substituted and a,a-disubstituted c-amino acids ...... 1000

Abbreviations: ABO, 2,7,8-trioxabicyclo[3.2.1]octane; Ac, acetyl; ACPECA, 4-aminocyclopent-2-ene-1-carboxylic acid; AHPPA, 4-amino-3-hydroxy-5-phenylpentanoic acid; AMCP, 2-(aminomethyl)-cyclopentanecarboxylic acid; APCH, 2-(1-aminopropyl)cyclohexanecarboxylic acid; APTS, (3-aminopropyl)triethoxysilane; ATCAs, 4-amino (methyl)-1,3-thiazole-5-carboxylic acids; BBB, blood–brain-barrier; 9-BBN, 9-borabyciclo[3.3.1]nonane; BGT-1, mammalian betaine transporter; BINAP, 2,2-bis (diphenylphosphino)-1,1-binaphthyl; Bn, benzyl; Boc, tert-butoxycarbonyl; CACP, cis-3-aminocyclopentane-1-carboxylic acid; CAL, Candida antarctica; CAMP, cis-2- aminomethylcyclopropane-1-carboxylic acid; CAN, cerium ammonium nitrate; Cbz, carbobenzyloxy; CDI, N,N-carbonyldiimidazole; Cinn, cinnamyl; CPME, cyclopentyl methyl ether; CPP, 3-amino-4-difluoromethylenecyclo-pentanercarboxylic acid; DABCO, 1,4-diazabicyclo[2.2.2]octano; Dap, dolaproine; DBAD, di-tert-butyl azodicarboxylate; DBF, dibromoformaldoxime; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC, dicyclohexylcarbodiimide; DCE, 1,2-dichloroethane; DCR, diaza-cope rearrangement; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; d.e., diastereoisomeric excess; DEAD, diethyl azodicarboxylate; DIAD, diisopropyl azodicarboxylate; DIB, (diacetoxyiodo) benzene (also BAIB); DIBAL-H, diisobutylaluminum hydride; DIEA, diisopropyl ethylamine; Dil, dolaisoleucine; DIPEA, diisopropylethylamine; DMAP, 4-(dimethylamino) pyridine; DME, dimethyl ether; DME, dimethoxyethane; DMF, N,N-dimethylformamide; DMP, 2,2-dimethoxypropane; DMP, Dess-Martin-Periodinane; DMSO, dimethyl sulfoxide; DPPA, diphenylphosphoryl azide; d.r., diastereoisomeric ratio; E, entgegen (opposite, trans); e.e., enantiomeric excess; Fmoc, 9-fluorenylmethoxycarbonyl; GABA, c-aminobutyric acid; GABA-AT, c-aminobutyric acid aminotransferase; GABA-T, c-aminobutyric acid transaminase; GABOB, c-amino-b-hydroxybutyric acid; HBTU, N,N,N0, N0-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexafluorophosphate; HMPA, hexamethylphosphoramide; HOBt, 1-hydroxybenzotriazole; HWE, Horner-Wadsworth-Emmons; hpen,(R,R)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane; HPLC, high performance liquid chromatography; HLAP, horse liver acetone powder; IBX, 2-iodoxybenzoic acid; IPA, isopropyl alcohol; Ipc2BAll, allyldiiso-2-caranylborane; LDA, lithium diisopropylamide; LiHMDS, lithium bis(trimethylsilyl)amide; LiTMP, lithium 2,2,6,6-tetramethylpiperidide; MAHT, malonic acid half thioester; MBA, methylbenzylamine; m-CBPA, m- chloroperoxybenzoic acid; MMMAH, 3-methoxy-5-methyl-4-(methylamino) hexanoic acid; MMPP, magnesium monoperoxyphtalate; MNBA, 2-methyl-6-nitrobenzoic anhydride; MSA, methanesulfonic acid; MsCl, methanesulfonyl chloride; MTBE, tert-butyl ether; MW, microwave; NaHDMS, sodium bis(trimethylsilyl)amide; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphonate; NBS, N-bromosuccinimide; NFI, N-fluorobenzenesulfonimide; NMM, N- methylmorpholine; NMO, 4-methylmorpholine N-oxide; Ns, p-nitrobenzenesulfonyl; OYE, Old Yellow Enzyme; PDC, pyridinium dichromate; PhMe, toluene; PhthN, phthalimido; PMHS, polymethyldrosiloxane; PIFA, [bis(trifluoroacetoxy)iodo]benzene; PLAP, Porcine Liver Acetone Powder; PLP, pyridoxal phosphate; PMB, p-methoxybenzyl; PMP, p-methoxyphenyl; PPTS, pyridinium p-toluenesulfonic acid; PTC, phase transfer catalyst; Py, pyridine; rt, room temperature; SAAs, sugar amino acids; x-TABG, x-transaminase from Burkholderia graminis; TAc, trichloroacetamide; TACP, trans-3-aminocyclopentane-1-carboxylic acid; TAMP, trans-2-aminomethylcyclopropane-1- carboxylic acid; x-TAPO, x-transaminase from Polaromonas sp.; TBAB, tetra-n-butylammonium bromide; TBAF, tetra-n-butylammonium fluoride; TBAI, tetra-n- butylammonium iodide; TBD, 1,5,7-triazabicyclo[4.4.0]dec-5-ene; TBDPS, tert-butyldiphenylsilyl; TBME, tert-butyl methyl ether; TBS, tert-butyldimethylsilyl (also TBDMS); TBSOTf, tert-butyldimethylsilyl trifluoromethanesulfonate; t-Bu, tert-butyl; TCCA, trichloroisocyanuric acid; TEMPO, 2,2,6,6-tetramethyl-1-piperidinyloxy; Tf, trifluoromethanesulfonyl; TFA, trifluoroacetic acid; TFAA, trifluoroacetic anhydride; THF, tetrahydrofuran; TMS, trimethylsilylchloride; TMSBr, trimethylsilylbromide; TMSCl, trimethylsilylchloride; TMSCN, trimethylsilylcyanide; TMSOTf, trimethylsilyl trifluoromethanesulfonate; TBSOTf, tert-butyldimethylsilyl trifluoromethanesulfonate; Ts, p- toluenesulfonyl; TBTA, tert-butyl 2,2,2-trichloroacetimidate; TIPS, triisopropylsilyl (alcohol protection); TMDS, 1,1,3,3-tetramethyldisiloxane; Tris, 2-amino-2-(hydroxymethyl)-1,3-propanediol. ⇑ Corresponding authors. http://dx.doi.org/10.1016/j.tetasy.2016.08.011 0957-4166/Ó 2016 Elsevier Ltd. All rights reserved. 1000 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

2.2. b-Substituted and b,b-disubstituted c-amino acids ...... 1002 2.3. b-Hydroxysubstituted c-amino acids...... 1019 2.4. c-Substituted c-amino acids...... 1021 2.5. Polysubstituted c-amino acids ...... 1028 2.5.1. a,b-Disubstituted c-amino acids ...... 1028 2.5.2. a,c-Disubstituted c-amino acids ...... 1029 2.5.3. b,c-Disubstituted c-amino acids ...... 1031 2.5.4. a,b,c-Trisubstituted c-amino acids ...... 1033 3. Stereoselective synthesis of cyclic c-amino acids ...... 1034 3 3.1. Synthesis of Ca;b derivatives ...... 1034 3 3.2. Synthesis of Cb;c derivatives ...... 1039 4 3.3. Synthesis of Ca;b derivatives ...... 1040 4 3.4. Synthesis of Cb;c derivatives ...... 1040 4 3.5. Synthesis of Ca;c derivatives ...... 1041 5 3.6. Synthesis of Ca;b derivatives ...... 1041 5 3.7. Synthesis of Ca;c derivatives ...... 1042 6 3.8. Synthesis of Ca;b derivatives ...... 1045 6 3.9. Synthesis of Cb;c derivatives ...... 1046 6 3.10. Synthesis of Ca;c derivatives ...... 1047 4. Stereoselective synthesis of azacyclic c-amino acids...... 1048 5 4.1. Synthesis of N; Cc derivatives ...... 1048 5 4.2. Synthesis of N; Cb derivatives ...... 1048 6 4.3. Synthesis of N; Cc derivatives ...... 1050 5. Conclusions...... 1051 Acknowledgements ...... 1051 References ...... 1052

1. Introduction procedures for their stereoselective synthesis, and the purpose of this review is to describe a summary of the most relevant proce- c-Aminobutyric acid 1 (GABA), is the major inhibitory neuro- dures reported during the last few years. It is important to take into transmitter in the mammalian central nervous system modulated account that a summary of procedures was already reported us in 1 24 by three types of receptors: GABAA, GABAB and GABAC, and plays early 2007, and hence this report specially covers the new strate- a significant role in several brain disorders including epilepsy,2 gies or methodologies trying to focus the subject in an advanta- neuropathic pain,3 depression and anxiety,4 migraine,5 Parkinson’s geous classification that can be useful to specialized readers on disease,6 Alzheimer’s disease7 and Huntington’s chorea.8 However, this area, covering only the years from 2007 until early 2016. In the administration of GABA orally or intravenously is not an effi- this update the c-amino acids have been classified according on cient therapy due to its low lipophilicity, and its very poor ability the type of compounds, position and number of substituents, and to cross the blood–brain barrier (BBB).9 Consequently, the synthe- depending on the type of substrate, acyclic, carbocyclic or azacyclic sis of more lipophilic GABA derivatives capable of crossing the derivatives, following in the first case an order related to the strat- blood–brain barrier, which would inhibit the GABA transaminase egy used, whereas in the second and third cases the classification (GABA-T), the enzyme that degrades GABA,10 has been the target will be based on the ring size. of a great number of studies. For example, the first major agonist Ò of the GABAB receptor is the Baclofen 2 (Lioresal ), which was orig- 2. Stereoselective synthesis of acyclic c-amino acids inally designed as a lipophilic analogue of GABA that would display 11 enhanced permeability through the blood–brain barrier. It has 2.1. a-Substituted and a,a-disubstituted c-amino acids been found that the (R)-enantiomer is substantially more active than the (S)-enantiomer and is used as a muscle relaxant and The approach reported for the diastereoselective and enantios- 12 antispastic agent, whereas Arbaclofen placarbil 3 serves as a pro- elective synthesis of a-substituted and a,a-disubstituted c-amino drug of (R)-Baclofen, which was developed to enhance oral absorp- acids is the reaction between appropriate enolates as nucleophiles 13,14 tion compared to the parent compound. (R)-Phenibut 4,is with bromoacetonitrile or the corresponding nitroethylene and N- 15 another agonist at the GABAB receptor, and has been used as psy- chotropic, anticonvulsant, antidepressant and antineuropathic 16,17 Ò Cl drug. (S)-Pregabalin 5 (Lyrika ) is used for the treatment of Cl epilepsy, neuropathic pain, antihyperalgesic and generalized anxi- 18 Ò ety disorders. (S)-Vigabatrin 6 (Sabril ), is another potent irre- H O O O versible inhibitor of GABA-T and is used in cases where classic O O N H2N H2N 19 OH OH OH antiepileptics are ineffective, and has been shown to be effective O 20 Ò in the treatment of addiction. Gabapentin 7 (Neurontin ), an GABA, 1 Baclofen, 2 Arbaclofen placarbil, 3 achiral b,b-disubstituted GABA analogue, is commercialized for (Lioresal®) the treatment of several cerebral disorders diseases, principally O 21 for the treatment of peripheral neuropathic pain (Fig. 1). Addi- H N O O 2 O H N OH tionally, the c-amino acids represent great potential as building H N 2 H2N 2 OH OH blocks for the synthesis of c-peptides22 and heterogeneous back- OH 23 Phenibut, 4 Pregabalin, 5 Vigabatrin, 6 Gabapentin, 7 bone foldamers. (Lyrica®) (Sabril) (Neurotin®) The therapeutic potential of GABA derivatives in enantiomerically pure form has prompted organic chemists to report numerous Figure 1. Structure of GABA and pharmaceutical analogues. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1001

O O CN CN R R OR'' OR'' H2, [Rh(COD)]2 O CO2Me CO2Me R' R' (S,S)-17,CH2Cl2 H2N + OH + R R 97% e.e. N SO2Ar (Z)-16a;R=H R R' BrCH2CN (R)-18a;R=H,98% (Z)-16b;R=OMe (R)-18b;R=OMe,96% . NaBH4, NiCl2 6H2O O (Boc)2O/MeOH R O N 2 + OR'' P NHBoc R' Fe P CO2Me Scheme 1. Retrosynthetic analysis of a-substituted and a,a-disubstituted c-amino acids. R (S,S)-f-spiroPhos, 17 97% e.e. (R)-19a;R=H,83% (R)-19b;R=OMe,79% sulfonyl aziridines derivatives as electrophiles under diastereoselective or enantioselective process (Scheme 1). Scheme 4. For example, the reaction of phenylacetic acid dianions generated using (+)-ephedrine 8 or ()-1-(benzylamino)propan-2-ol 9 as chiral bases, with bromoacetonitrile, produced the b-cyano acid O O a Baker's yeast derivative 10, which by hydrogenation was transformed into - NC OMe NC OMe c 72% substituted -amino acid (S)- and (R)-11 in good yield, although Et Et 25 with very poor enantiomeric excesses (Scheme 2). (E)-20 (S)-21; 99% e.e.

On the other hand, the enantioselective organocatalytic Michael . NaBH4, NiCl2 6H2O addition of aldehydes to nitroethylene derivatives constitutes a 70% (Boc)2O, MeOH method for the formal aminoethylation of aldehydes, and it is a powerful tool to obtain a-alkyl c-amino acids. Thus, the Michael O BocHN addition of n-butanaldehyde to nitroethylene in the presence of a OMe catalytic amount of enantiomerically pure (S)-diphenylprolinol Et silyl ether 1226 and 3-nitrobenzoic acid (MNBA) as a co-catalyst (S)-22; 99% e.e. followed by the NaBH4 reduction, provided the b-substituted d- nitrobutanol derivative (R)-13 in 96% yield and 98% enantiomeric Scheme 5.

excess (e.e.). Jones oxidation of hydroxyl group in (R)-13, gave O O the a-ethyl c-nitrobutyric acid (R)-14 in 92% yield and >95% enan- Ph 1. (+)-8 or (-)-9 OH NC OH tiomeric excess, which by reduction of nitro group followed by the 2. BrCH2CN + Ph treatment with di-tert-butyl dicarbonate (Boc) O, afforded the N- 3. H3O 2 10 Boc a-ethyl c-amino acid (R)-15 in 71% and >95% enantiomeric OH 27 NHMe H2,Pd/C excess (Scheme 3). Ph Rh-catalyzed asymmetric hydrogenation provides a highly efﬁ- Me O cient and enantioselective method for the synthesis of a-substi- (+)-8 H2N tuted c-amino acids. In this context, the asymmetric Me OH BnHN Ph hydrogenation of (Z)-methyl 3-cyano-2-phenyl acrylates 16a,b OH (S)-11;85%,10%e.e.,using(+)-8 using the complex of Rh-(S,S)-f-spiroPhos 17 as the catalyst, gave (-)-9 (R)-11; 84%, 8% e.e., using (-)-9 the a-substituted b-cyano esters (R)-18a and (R)-18b in 98% and 96% yield, respectively, and 97% enantiomeric excess. Reduction Scheme 2. of the cyano group in (R)-18a and (R)-18b with NaBH4/NiCl26H2O in the presence of (Boc)2O, afforded the N-Boc a-substituted c- amino esters (R)-19a and (R)-19b in good yield and 97% enan- 28 O tiomeric excess (Scheme 4). 1. (S)-12 (2 mol%) Et H MNBA (20 mol%) O2N + OH 2. NaBH4/MeOH O N NO O 2 96% Et O 2 CO2t-Bu (R)-13; 98% e.e. CO2t-Bu AcOEt/PhMe Jones (R)-24-Ni 92% 2 reagent (2.5 mol%) NO2 MeO MeO O 90% O 23 1. H , Pd/C (S)-25; 98% e.e. BocHN 2 O2N OH OH H , Ra-Ni 2. (Boc)2O 72% 2 (Boc) O Et 71% Et 2 (R)-15; >95% e.e. (R)-14; >95% e.e. O O N O Ni Ni CO2t-Bu Ph N O N O Ph NHBoc H OTMS MeO (S)-12 (R)-24-Ni2 (S)-26

Scheme 3. Scheme 6. 1002 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

O O R' O O O R R' O 29 (10 mol%) Ot-Bu R R'' Ot-Bu + N SO2Ar K HPO H2N 2 4 * OH + Ar = 2-CF3C6H4 NHSO2Ar - - 27 :CH2NO2 or :CN 28 (S)-30a-e

O O O O O O Scheme 9. Retrosynthetic analysis of b-substituted and b,b-disubstituted c-amino acids. Ot-Bu Ot-Bu Ot-Bu

NHSO2Ar NHSO Ar NHSO Ar 2 Cl 2 a a c (S)-30a ; 78%, 82% (S)-30b; 80%, 97% e.e. (S)-30c; 85%, 97% e.e. (PTC), produced the diprotected , -disubstituted -amino acid e.e. derivatives (S)-30a–e in good yields and with good enantiomeric O O O O - OR Cl excess for (S)-30a–d and good diastereoisomeric excess for (R,R)- + 31 MeO Ot-Bu Ot-Bu N 30e (Scheme 7). The organocatalytic asymmetric ring-opening of N-tosyl pro- NHSO2Ar NHSO2Ar N An Ph tected aziridine 32 by the enolates derived from b-ketoesters 31 (S)-30d; 85%, 95% e.e. (R R)-30e; 75%, 29; An = anthracenyl 92% e.e., >95% d.e. R = adamantoyl under PTC-conditions using N-9-anthracenylmethyl O-adamantyl derivatized cinchonine 33, afforded the optically active diprotected Scheme 7. a,a-disubstituted c-amino acids (S)-34a–f with good yields and enantiomeric excess (Scheme 8).32

Bioreduction of methyl (E)-2-(cyanomethylene)butanoate 20 2.2. b-Substituted and b,b-disubstituted c-amino acids with either fermenting cells of Baker’s yeast (BY) or isolated OYE1-3 (with in situ regeneration of the NAD(P)H cofactor with a Probably the stereoselective syntheses of b-substituted c- glucose dehydrogenase and glucose as a sacriﬁcial cosubstrate), amino acids are the most studied and several research groups have gave the methyl 2-(cyanomethyl)butanoate (S)-21 in 72% yield focused their interest in the development of new methods for the and 99% enantiomeric excess, which by reduction of the cyano preparation of these compounds. In this context, the direct Michael group with NaBH4/NiCl26H2O in the presence of (Boc)2O, afforded a c addition of the carbanion derived from nitromethane or cyanide the N-Boc -substituted -amino ester (S)-22 in 70% yield and 99% ion to a,b-unsaturated carbonyl compounds is probably the most 29 enantiomeric excess (Scheme 5). studied methodology for the synthesis of b-substituted and b,b- b Catalytic asymmetric 1,4-addition of -ketoester 23 to disubstituted c-amino acids. The Michael addition can be per- nitroethylene catalyzed by a homodinuclear Schiff base (R)-24- formed incorporating a chiral auxiliary in the unsaturated carbonyl Ni2, gave the nitro derivative (S)-25 in 90% yield and 98% enan- compounds (diastereoselective reaction) or in the presence of a tiomeric excess. Reduction of nitro group in (S)-25 over Ra-Ni in a a c chiral catalyst (enantioselective reaction), in particular in the pres- the presence of (Boc)2O, provided the N-Boc , -disubstituted - ence of an organocatalysts (Scheme 9). 30 amino ester (S)-26 in 72% yield (Scheme 6). For example, the hydrogenation of enantiopure bicyclo[3.2.0] Enantio- and diastereoselective catalytic alkylation reactions of hept-2-en-6-one (1S,5R)-35 followed by a Horner-Wadsworth- the appropriate enolates with aziridines have been considered as a a a c Emmons (HWE) reaction with triethyl phosphonoacetate, gave valuable tool to obtain , -disubstituted -amino acid derivatives. the a,b-unsaturated ester (1R,5R)-36 in 72% yield, which by a con- In this context, the ring opening of the N-sulfonyl aziridine 28 by jugate addition of nitromethane under PTC-conditions using n- b the nucleophilic addition of enolates derived from -ketoesters tetrabutylammonium ﬂuoride (TBAF), afforded the nitroester 27 and cinchona alkaloid derived 29 as phase transfer catalyst (1R,5R,6S)-37 in 87% yield as a single diastereoisomer derived by

O O 33 (6 mol%) O O K2CO3 or K2HPO4 OR +NSO2p-T ol OR o-xylene/CHCl3

31 32 NHSO2p-Tol (S)-34a-f O O O O O O

Ot-Bu Ot-Bu Ot-Bu MeO

NHSO p-Tol NHSO p-Tol NHSO2 p-Tol MeO 2 MeO 2 Cl (S)-34a; 87%, 97% e.e. (S)-34b;86%,90%e.e. (S)-34c; 83%, 93% e.e.

O O O O O O

Ot-Bu OMe Ot-Bu

NHSO p-Tol NHSO2p-Tol NHSO2p-Tol 2 (S)-34d; 87%, 87% e.e. (S)-34e;89%,70%e.e. (S)-34f;53%,77%e.e.

Et - OR Cl + N

N An 33; An = anthracenyl R = adamantoyl

Scheme 8. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1003

O Me Me Me Me 1. H2,Pd/C,EtOAc CO Et O O H 2 CO2Me MeNO2 CO2Me O O O TBAF O NO 2. (EtO) P Me 95% Me H 2 (1S,5R)-35 2 OEt (1R,5R)-36;72% (R,R)-45 NaH, THF (R,R,S)-46 MeNO /THF HCO2NH4 87% 2 84% TBAF Pd/C H N Me Me Me NO Me O O 2 O H O H 3' O (Boc) O H2,MeOH 2 CO2Et Ni sponge O DMAP, Et3N O N Me H N Me H 54% Boc 98% H (1R,3'S,5R)-38 (1R,5R,6S)-37 (R,R,S)-48 (R,R,S)-47

72% 6NHCl 1. 1 M LiOH 100% 2. CH2N2

NH2.HCl Me Me Me Me CO H H 2 O CO2Me O H CO2Me

(1R,5R,6S)-39; 98% e.e. O Me H NHBoc HO H NHBoc (R,R,S)-49 (R,R,S)-50 Scheme 10.

Me Me Me Me H CO2Me CO2H the exclusive attack from the less hindered exo face. Catalytic hydrogenation of the nitro group in (1R,5R,6S)-37 in the presence BnO BnO H NH2 of a Ni sponge and subsequent cyclization of the intermediate (R,R)-51 (R,R,S)-52 amino ester, produced the c-lactam (1R,30S,5R)-38 in 54% yield, Scheme 12. which by hydrolysis with 6 N HCl, led to the b-substituted c-amino acid (1R,5R,6S)-39 as the hydrochloride in 72% yield and 98% enantiomeric excess (Scheme 10).33 On the other hand, Ortuño et al.34 reported the synthesis of the In a similar way, the reaction of a,b-unsaturated ester (R,R)-45 b-cyclobutyl-c-amino acid (R,R,S)-44 using as key intermediate the with nitromethane in the presence of TBAF, afforded the nitro a,b-unsaturated ester (R,R)-40 as a homochiral starting material derivative (R,R,S)-46 in 95% yield as a single diastereoisomer, obtained from ()-verbenone, which was transformed into (R,R)- which by reduction of the nitro group with ammonium formate 40 as a mixture of (Z/E)-isomers.35 Michael addition of nitro- in the presence of Pd/C, furnished the c-lactam (R,R,S)-47 in 84% 37 c methane to a,b-unsaturated ester (R,R)-40 in the presence of TBAF, yield. Reaction of the -lactam (R,R,S)-47 with (Boc)2O and 4- gave the c-nitro derivative (R,R,S)-41 in 85% yield as a single (dimethylamino)pyridine (DMAP) and Et3N, provided the N-Boc diastereoisomer. Reduction of the nitro group in (R,R,S)-41 with c-lactam (R,R,S)-48 in 98% yield. Hydrolysis of the c-lactam (R,R, ammonium formate in the presence of Pd(OH)2/C, provided the S)-48 with LiOH followed by the esteriﬁcation with diazomethane, c-amino ester (R,R,S)-42 in 96% yield, which was treated with ben- gave the diprotected b-cyclobutyl-c-amino acid (R,R,S)-49, which zyl chloroformate (CbzCl) to obtain the diprotected c-amino acid under identical conditions described above was transformed into (R,R,S)-43 in 70% yield. Hydrolysis of the acetonide in (R,R,S)-43 with pyridinium p-toluenesulfonate (PPTS) in acetone, followed O O O by Lieben degradation using sodium hypobromite, produced the CO Et O (EtO)2P O 2 diprotected c-amino acid (R,R,S)-44 in excellent yield H OEt (Scheme 11).36 O t-BuOK, CH2Cl2 O (R)-5380% 54; E:Z = 9:1 MeNO /THF 75% 2 TBAF

Me O CO Et Me Me 2 O CO t-Bu 2 N H HCO2NH4 O NO2 O Me O Pd(OH)2/C O Me O Me O 85% (-)-verbenone (R,R)-40 (S,S)-56 (S,S)-55

MeNO2/THF 85% 1. (Boc) O, DMAP/Et N TBAF 2 3 100% 2. AcOH 3. NaIO , MeOH/H O Me Me Me Me 4 2 O H CO t-Bu O H CO t-Bu 2 HCO2NH4 2 O O

O Pd(OH)2/C O H NH2 H NO2 Ph3P=CMe2 Me 96% Me O N Boc N Boc THF (R,R,S)-42 (R,R,S)-41 60% CbzCl H (S)-58 70% (S)-57 3MNaOH 1. 1 M LiOH/THF 100% 2. H2, Pd(OH)2/C Me Me Me Me O H CO t-Bu O H 2 1. PPTS CO2t-Bu CO2H O 2. NaOBr H NHCbz HO H NHCbz NH2 Me 97% (R,R,S)-43 (R,R,S)-44 (S)-Pregabalin, 5

Scheme 11. Scheme 13. 1004 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 diprotected c-amino acid (R,R,S)-50. Similarly, the a,b-unsaturated reaction of poorly electrophilic D-gulo derivative (E)-59 with nitroester (R,R)-51 was converted into b-cyclobutyl-c-amino acid (R,R, methane as reagent and solvent in the presence of TBAF, afforded S)-52 (Scheme 12).34 the corresponding c-nitro esters in 75% yield as a mixture of insep- A synthesis of enantiomerically pure (S)-Pregabalin 5 using arable anomeric isomers 60a and 60b (1:9 ratio), which by saponi- enantiopure (R)-glyceraldehyde acetonide 53 easily obtained from fication with LiOH in THF/H2O, produced, after chromatographic D-mannitol as a source of chirality has been reported by Ortuño separation, the c-nitro carboxylic acid 61 in 70% yield. Catalytic et al.38 Thus, the HWE reaction of (R)-glyceraldehyde acetonide hydrogenation of the nitro group in 61 using Pd/C, furnished the 53 with triethyl phosphonoacetate, produced the a,b-unsaturated amine that without additional purification was treated with CbzCl, ester 54 as a mixture of (E/Z) 9:1 diastereoisomers in 80% yield, chlorotrimethylsilane (TMSCl) and N,N-diisopropylethylamine which by a conjugate addition of nitromethane in the presence of (DIPEA), to afford the N-Cbz protected c-amino acid 62 in 45% TBAF, gave the b-substituted c-nitroester (S,S)-55 in 75% yield as yield. Under identical conditions, the activated exo-glycal (E)-63 single diastereoisomer after purification, derived of an excellent was transformed into N-Cbz protected c-amino acid 64 p-facial diastereoselectivity. Reduction of the nitro group in (S,S)- (Scheme 14).41 The same authors reported the synthesis of others

55 with ammonium formate catalyzed with Pd(OH)2/C, afforded N-Cbz protected c-amino acids using furano-exo-glycals (erythro, the c-lactam (S,S)-56 in 85% yield.39 Protection of amino group in mano and ribo) derivatives as starting materials. the c-lactam (S,S)-56 with (Boc)2O, followed by the hydrolysis of Cyanation of a,b-unsaturated carbonyl compound derivatives is the acetonide with AcOH and subsequent oxidation with NaIO4, also of synthetic importance, and this process could be used for the furnished the b-formyl c-lactam (S)-57 in quantitative yield, which synthesis of various enantiomerically enriched b-substituted c- through a Wittig reaction with isopropylidenetriphenyl phospho- aminobutyric acids. For example, the Michael addition of diethyl rane, provided the b-isobutenyl c-lactam (S)-58 in 60% yield. aluminum cyanide to a,b-unsaturated N-enoyl derivative (R)-65 Hydrolysis of the c-lactam (S)-58 with LiOH followed by the cat- bearing the (R)-4-phenyl-2-oxazolidinone as a chiral auxiliary, pro- alytic hydrogenation of double bond using Pd(OH)2/C, gave the vided a mixture of the 1,4-adducts (S,R)-66 and (R,R)-67 in 66% enantiomerically pure (S)-Pregabalin 5 in quantitative yield yield and 87:13 diastereoisomeric ratio, which was easily sepa- (Scheme 13). rated by column chromatography, to give the enantiomerically Recently, Pellegrini-Moïse et al.40 reported the synthesis of pure (S,R)-66 and (R,R)-67. Cleavage of chiral auxiliary fragment N-Cbz protected c-amino acids incorporating sugars. Thus, the in (S,R)-66 by treatment with lithium peroxide in aqueous THF, followed by the reduction of the cyano group over Ra-Ni, afforded the (S)-Pregabalin 5 in 95% yield (Scheme 15).42

H H NO2 O MeNO2 O O Me O CO2Me (excess) Me CO2Me Ar Me TBAF Me O OO O OO 75% O Ar2CuMgBr O O O Me Me Me Me N O 68% N O O O (E)-59 60α + 60β (1:9) Boc Me Boc Me (S)-68 (2S,3R)-69 70% LiOH THF/H2O 75% HCl, MeOH H NHCbz H NO O O 2 Ar Ar Me O Me O CO2H 1. H2,Pd/C CO2H Me Me O OO 2. TMSCl, CbzCl O OO OMe NaH, THF OMe O N O N DIPEA, CH2Cl2 BnBr O O Me Me 45% Me Me Bn 55% H 62 61 (2S,3R)-71 (2S,3R)-70

O 98% 1 M LiOH/THF Me Me O 3 steps Me O O CO2H Ar O Me O ref. 44 O Ar CO2Me H H NHCbz 1. Barton decarbox. . NH2 HCl OH 2. H , Pd(OH) HO OO OO 2 2 O N 3. 6 N HCl Ar = 4-ClC6H4 O Me Me Me Me Bn (R)-Baclofen, 2 (E)-63 64 (2S,3R)-72

Scheme 14. Scheme 16.

O O CN O O CN O O

Et2AlCN N O N O +ON PhMe, 0 oC

Ph 66% Ph Ph (R)-65 (S,R)-66 87 : 13 (R,R)-67

1. H2O2,LiOH 95% 2. H2, Ra-Ni

NH2

CO2H

(S)-Pregabalin, 5

Scheme 15. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1005

NO2 NO2 CHO (S)-12 (10 mol%) CHO CHO (2S,4R)-78 (10 mol%) CHO CH3NO2 Cl MeNO2,MeOH,r.t. 83% Cl (E)-73a 99% (S)-74a; 94% e.e. (E)-73c (S)-74c; 94% e.e.

NaClO2/NaH2PO4 PDC, DMF 96% 74% 2-methyl-2-butene 25 oC t-BuOH/H2O NH2 NO2 NH2 NO2 CO H CO H 2 ref. 49 2 CO2H H2,Pd/C CO2H

Cl Cl (S)-Phenibut, 4 (S)-75c; 94% e.e. (S)-Baclofen, 2 (S)-75a; 94% e.e.

NH2 N + N O Ph CHO Me () 3 Ph CO2H PF6 O N OTMS (E)-73b (S)-Pregabalin, 5 H (2S,4R)-78 Scheme 17.

Scheme 19. Nishiyama et al.43 reported the stereoselective synthesis of (R)- Baclofen 2 via a Michael addition to 3,4-didehydropyroglutamate derivative (S)-68 in which the carboxyl function is protected as a On the other hand, the Michael addition of nitromethane to a,b- 2,7,8-trioxabicyclo[3.2.1]octane (ABO) ester. For this purpose, they unsaturated aldehyde (E)-73a catalyzed with (S)-diphenylprolinol carried out the Michael addition of Grignard-cuprate reagent to silyl ether 12 in MeOH at room temperature, followed by the 3,4-didehydropyroglutamate derivative (S)-68, obtaining the 1,4- oxidative esteriﬁcation using N-bromosuccinimide (NBS), pro- adduct (2S,3R)-69 in 68% yield, which by treatment with HCl/ duced the chiral b-substituted c-nitro methyl ester (S)-76a in MeOH, afforded the pyroglutamate methyl ester derivative 67% yield and 94% enantiomeric excess. Reduction of the nitro

(2S,3R)-70 in 75% yield. Reaction of (2S,3R)-70 with NaH and ben- group in (S)-76a using NaBH4/NiCl26H2O followed by the treat- zyl bromide, gave the N-benzyl derivative (2S,3R)-71 in 55% yield, ment with 6 M NaOH, furnished the b-substituted c-lactam (S)- which by saponiﬁcation of methyl ester with LiOH, produced the 77a in 88% yield,46 which by hydrolysis with 6 M HCl, afforded pyroglutamic acid derivative (2S,3R)-72 in 98% yield. The deriva- the (S)-Baclofen 2 as the hydrochloride in 94% yield (Scheme 18).47 tive (2S,3R)-72 can be converted into (R)-Baclofen 2 hydrochloride Zlotin et al.48 reported the Michael addition of nitromethane to 44 as has been described previously (Scheme 16). a,b-unsaturated aldehyde (E)-73c catalyzed by chiral ionic liquids Organocatalytic enantioselective conjugate addition of nitro- O-silylated a,a-diphenyl prolinol derivative (2S,4R)-78, obtaining methane to a,b-unsaturated carbonyl derivatives is another impor- the c-nitro aldehyde (S)-74c in quantitative yield and 94% enan- tant strategy for the synthesis of b-substituted c-amino acids. For tiomeric excess, which by oxidation with pyridinium dichromate example, the Michael addition of nitromethane to a,b-unsaturated (PDC) in N,N-dimethylformamide (DMF), gave the c-nitro acid aldehyde (E)-73a catalyzed with enantiomerically pure (S)- (S)-75c in 74% yield and 94% enantiomeric excess. The c-nitro acid diphenylprolinol silyl ether 12 at room temperature, afforded the (S)-75c was transformed into (R)-Phenibut 4 according to the prochiral b-substituted c-nitro aldehyde (S)-74a in 83% yield and cedures described in the literature49 (Scheme 19). 94% enantiomeric excess. Oxidation of b-substituted c-nitro alde- Michael addition of nitromethane to a,b-unsaturated aldehyde b hyde (S)-74a with NaClO2 and NaH2PO4, gave the -substituted (E)-73a catalyzed by the chiral squaramide (S)-79a, gave the c- c-nitro carboxylic acid (S)-75a in 96% yield, which through known procedures was transformed into (S)-Baclofen 2. In a similar way, the a,b-unsaturated aldehyde (E)-73b was transformed into (S)- NO2 MeNO Pregabalin 5 using the (R)-diphenylprolinol silyl ether 12 as cata- CHO 2 CHO (S)-79 (5 mol%) lyst in the ﬁrst step (Scheme 17).45 AcONa (30 mol%) Cl Cl CH2Cl2/MeOH, r.t. (E)-73a 64% (R)-74a; 92% e.e.

KH2PO4/MeCN 61% H2O2, NaClO2 NO2 1. (S)-12 (10 mol%) . CHO CO Me NH2 HCl NO PhCO2H (20 mol%) 2 2

1. H2, Ra-Ni MeNO2 CO2H CO2H o Cl 2. NBS, MeOH, 4 C Cl 2. HCl (E)-73a (S)-76a; 94% e.e. 67% Cl 64% Cl

1. NaBH4,EtOH (R)-Baclofen, 2 (R)-75a . 88% NiCl2 6H2O 2. 6 M NaOH O O

H NH .HCl 2 N N N 6MHCl O CO2H H H 94% F3C H N

Cl Cl CF 3 (S)-79a (S)-Baclofen, 2 (S)-77a

Scheme 18. Scheme 20. 1006 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 nitro aldehyde (S)-74a in 64% yield and 92% enantiomeric excess, Enantioselective Michael addition of nitromethane to a,b- which by oxidation with KH2PO4/H2O2/NaClO2, afforded the c- unsaturated ketones is another key step for the synthesis of b-sub- nitro acid (S)-75a in 61% yield. Catalytic hydrogenation of the nitro stituted c-amino acids. For example, the addition of nitromethane group in (S)-75a followed by the treatment with HCl, produced the (E)-1-(4-chlorophenyl)-4-methylpent-1-en-3-one 86a and (E)-4- (R)-Baclofen 2 as the hydrochloride in 64% yield (Scheme 20).50 methyl-1-phenylpent-1-en-3-one 86b in the presence of catalytic b,b-Disubstituted c-amino acids can be also obtained by conju- amounts of the amine-thiourea 87 based on dehydroabietic amine, gate addition of nitromethane to a,b-unsaturated aldehydes. For afforded the c-nitro ketones (R)-88a,b in good yield and 98% enan- example, the Michael addition of nitromethane to b,b-disubsti- tiomeric excess, which by a Baeyer-Villiger oxidation with meta- tuted a,b-unsaturated aldehydes (E)-80a,b catalyzed with the chloroperoxybenzoic acid (m-CPBA) and triﬂuoroacetic acid resin-supported peptide 81, furnished the b,b-disubstituted c-nitro (TFA), produced the c-nitro esters (R)-89a,b in 92% and 93% yield. aldehydes (R)-82a,b in good yield and with 98% and 95% enan- Reduction of the nitro group in (R)-89a,b with NaBH4/NiCl26H2O, tiomeric excess, respectively, which by oxidation with NaClO2 furnished the b-substituted c-amino esters (R)-90a,b in 90% and and NaH2PO4, afforded the b,b-disubstituted c-nitro acids (R)- 88% yield, respectively, which by hydrolysis with 6 M HCl, afforded 83a,b in 92% and 86% yield, respectively. Reduction of the nitro the enantiomerically pure (R)-Baclofen 2 and (R)-phenibut 4 in 93% group and phenyl group in (R)-83a with platinum(IV) oxide, pro- and 95% yield, respectively (Scheme 22).52 duced the b-methyl-b-cyclohexyl c-amino acid (R)-84 in 97% yield, A three-component reaction of 4-chlorobenzaldehyde or isobu- whereas the reduction of the nitro group in (R)-83b using Ra-Ni as tyraldehyde, nitromethane and dimethyl malonate in o-xylene at catalyst, produced the b-methyl-b-4-chlorophenyl c-amino acid 70 °C, catalyzed by the chiral multisite organic–inorganic hybrid (R)-85 in 91% yield (Scheme 21).51 catalyst 91 derived from quinidine, gave after recrystallization the nitro esters (S)-92a in 75% yield with 76% enantiomeric excess and (R)-92b in 45% yield with 52% enantiomeric excess. Catalytic MeNO Me O 2 Me R O 81 (20 mol%) hydrogenation of the nitro group in (S)-92a and (R)-92b using O2N Pd/C as catalyst in o-xylene at 130 °C, afforded the c-lactams (S)- R H MeOH/H2O H (R)-82a;R=CH ,82%,98%e.e. (E)-80a;R=C6H5 6 5 77a and (R)-77b in 58% and 85% yield, respectively, which by (R)-82b;R=4-ClCH , 70%, 95% e.e. (E)-80b;R=4-ClC6H4 6 4 hydrolysis with 6 N HCl, produced the (S)-Baclofen 2 as the NaClO2,NaH2PO4 hydrochloride in 95% yield with >98% enantiomeric excess and 2-methyl-2-butene (R)-Pregabalin 5 as the hydrochloride in 80% yield with 63% enan- t-BuOH/H2O tiomeric excess (Scheme 23).53 Me R O Me R O In the similar way, the three-component reaction of isobu- H2,PtO2 H2N O2N OH MeOH, r.t. OH tyraldehyde, nitromethane and dimethyl malonate in PhMe/MeOH (R)-84;R=CH 97% (R)-83a;R=CH ,92% at room temperature, in the presence of catalytic amounts of 6 11 6 5 0 (R)-83b; R=4-ClC6H4,86% microencapsulated Ni(II)-bis[(R,R)-N,N -dibenzylcyclohexane-1,2-

H2,Ra-Ni diamine]Br2 93, with 94 afforded the nitro ester (S)-92b in 94% 91% MeOH, r.t. yield and 72% enantiomeric excess, which by reduction of the nitro Pro-D-Pro-Aib-(Trp)2-(Leu)6- group with NaBH4/NiCl26H2O, furnished the chiral c-lactam (S)- Me R O 81 95a in 96% yield. Hydrolysis and decarboxylation of the methyl H2N OH ester in the c-lactam (S)-95a, produced (S)-Pregabalin 5 in 95% 54 (R)-85; R=4-ClC6H4 yield and 72% enantiomeric excess (Scheme 24). Of course, it is possible to change the strategy by changing the Scheme 21. starting material. For example, it is possible to use other active nitro derivatives or unsaturated nitro compounds. For example, the organocatalytic enantioselective Michael addition of nitro-

O O2N methane to 3-methyl-4-nitro-5-arylidenisoxazole (E)-96a in the O 87 (10 mol%) presence of catalytic amounts of cinchonidine 3,5-bis(triﬂuo- AcOH (10 mol%) romethyl)benzyl derivative 97, produced the c-nitro derivative MeNO2,PhMe,r.t. R R (S)-98a in 74% yield and 91% enantiomeric excess, which by treat- 99% (E)-86a;R=Cl (R)-88a;R=Cl,85%,98%e.e. ment with NaOH, provided the b-substituted c-nitro butyric acid (E)-86b;R=H (R)-88b;R=H,83%,98%e.e. (S)-75a in 54% yield and 97% enantiomeric excess.55 Reduction of m-CPBA, TFA the nitro group in (S)-75a over Ra-Ni followed by the treatment Δ CH2Cl2, with 2 M HCl, gave the (S)-Baclofen 2 as the hydrochloride in 56 c H2N O2N 91% yield. Under identical conditions, the -nitro derivative O O (R)-98a obtained using epi-97 as catalyst, was transformed into NaBH ,EtOH O 4 O (R)-Baclofen 2 as the hydrochloride (Scheme 25). . NiCl2 6H2O 57 R R Recently, Moccia et al. carried out the conjugate addition of (R)-90a;R=Cl,90% (R)-89a;R=Cl,92% nitromethane to a,b-unsaturated derivative (E)-96b incorporating (R)-90b;R=H,88% (R)-89b;R=H,93% the 3-methyl-4-nitro-5-arylidenisoxazole in the presence of cat- 6 M HCl alytic amounts of cinchona based ammonium salt 99, to obtain o 100 C the nitro derivative (S)-98b in 65% yield and 99.9% enantiomeric excess after crystallization. Basic hydrolysis of (S)-98b followed . HCl H2N O by the catalytic hydrogenation of the nitro group over Ra-Ni, S afforded the enantiomerically pure (S)-Pregabalin 5 in excellent OH N N yield (Scheme 26). R 58 H H NH2 Recently, Feng et al. reported that the enantioselective conju- R=Cl,(R)-Baclofen, 2 93% 87 a b R=H,(R)-Phenibut, 4 95% gate addition of nitromethane to , -unsaturated pyrazolamides (E)-100a,b catalyzed by chiral N,N0-dioxide/Gd(III) complex 101, Scheme 22. gave the c-nitropyrazolamides (S)-102a and (R)-102b in good yield M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1007

CO Me MeO2C CO2Me Hyb-Cat, 91 MeO2C 2 SiO H2N 2 o NO O o-xylene, 70 C 2 + R MeNO (S)-92a;R=4-ClC H ,75%,76%e.e. CF3 R H 2 6 4 (R)-92b;R=i-Bu, 45%, 52% e.e. HN H2,Pd/C o o-xylene, 130 C F3C NH O O O O NH CO2H . 6 N HCl N H N NH2 HCl o R 100 C R N (S)-2;R=4-ClC H ,95%,>98%e.e. (S)-77a;R=4-ClCH ,58% 6 4 6 4 Hyb-Cat, 91 (R)-5;R=i-Bu, 80%, 63% e.e. (R)-77b;R=i-Bu, 85%

Scheme 23.

MeO C CO Me MeNO2 O N 2 2 93 (7.4 mol %) O N 2 O N MeO C CO Me 94 (6.9 mol %) 2 2 Me 99,K2CO3 Me O + PhMe, 21 oC PhMe/MeOH, r.t. NO2 MeNO NO 65% NO H 2 94% 2 2 (S)-92b; 72% e.e. (E)-96b (S)-98b;99.9%e.e.

H2, Ra-Ni 96% 1. NaOH/H O EtOH, r.t. OMe 94% 2 2. H Ra-Ni OH Y- 2, O + CO2H MeO2C N H N 5 N HCl 2 O N H o N NH2 115 C 95% OH (S)-Pregabalin, 5 (S)-95a t-Bu t-Bu - 72% e.e. 99;Y = Polysulfonated (S)-Pregabalin, 5 Polystyrene beads >99.9% e.e. Bn Bn NH2 Br NH HN Scheme 26. Ni ( N )Y ( N )X NH Br HN H Bn Bn be transformed into (S)-Baclofen 2 as the hydrochloride,47 whereas 93 94 the reduction of the nitro group in (R)-76b with NaBH4/NiCl26H2O b Scheme 24. followed by the treatment with 6 M NaOH, furnished the -substituted c-lactam (R)-77b in 95% yield, which by hydrolysis with 6 M HCl, afforded the (R)-Pregabalin 5 as the hydrochloride67 (Scheme 27). N CH NO O2N N O 3 2 O 59 Me 97 (10 mol%) Me Fernández et al. also reported the enantioselective conjugate

K2CO3, PhMe addition of 1-methylene-aminopyrrolidine to hydroxy enone (E)- NO2 NO2 Cl 74% Cl 103 catalyzed by Zn(OTf)2/t-BuBOX 104 in toluene at room tem- (E)-96a (S)-98a; 91% e.e. perature, obtaining the adduct (S)-105 in 95% yield and 80% enan- 54% NaOH, THF tiomeric excess, which by oxidative cleavage of the hydrazone with magnesium monoperoxyphthalate (MMPP), produced the nitrile HCl.H N O N 2 O 2 O (S)-106 in 64% yield and 80% enantiomeric excess. Further oxida- 1. H2, Ra-Ni OH OH tion of the hydroxy ketone in (S)-106 with periodic acid, afforded 2. 2 M HCl the b-cyano acid (S)-107 in quantitative yield, which under known 91% Cl Cl 60 (S)-Baclofen, 2 (S)-75a; 97% e.e. conditions was transformed into (S)-Pregabalin 5 (Scheme 28). On the other hand, asymmetric catalytic cyanation of diethyl . O2N N HClH2N O epi-97 O benzylidenemalonate 108 with ethyl cyanoformate (NCCO2Et) as Me OH the cyanide source and 20 mol % of cinchonidine 109/Ti(O-i-Pr)4/ NO biphenol 110 (1:1:1) mixture as the catalyst, produced the com- Cl 2 Cl (R)-98a (R)-Baclofen, 2 pound (R)-111a in 92% yield and 93% enantiomeric excess, which by hydrogenation using Ra-Ni or Pd/C as catalyst, gave the ethyl 4-phenyl-2-oxopyrrolidine-3-carboxylate trans-112a in 76% yield OH - OH - + Br + Br and 93% enantiomeric excess. Saponiﬁcation of ester function in N N 112a with potassium hydroxide followed by decarboxylation, CF3 CF3 N N afforded the c-lactam (R)-77c in 80% yield and 93% enantiomeric excess, a key intermediate for the synthesis of (R)-Phenibut 4 61,62 CF3 CF3 (Scheme 29). The preparation of b-cyano derivatives as a key 97 epi-97 intermediates for the synthesis of (R)-Baclofen 2 and (S)-Pregabalin

Scheme 25. 5 are also described for the same authors. Catalytic asymmetric conjugate addition of trimethylsilyl cyanide (TMSCN) to a,c-unsaturated N-acylpyrroles (E)-113a,b in and 98% enantiomeric excess, which by treatment with MeOH and the presence of catalytic amounts of Gd(Oi-Pr)3 and the ligand 1,8-diazabicycloundec-7-ene (DBU), gave the c-nitroesters (S)-76a 114, produced the cyano derivatives (S)-115a in 89% yield and in 92% yield and (R)-76b in 95% yield. The nitro ester (S)-76a could (R)-115b in 90% yield with a good enantiomeric excess. Reaction 1008 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

O O N CN 2 O N CH3NO2 CO2Et CO2Et R N Me N NCCO2Et 101-Gd(OTf)3 R N Me 109/Ti(Oi-Pr) /110 CO Et CH Cl , 4 Å MS CO2Et 4 2 Me 2 2 iPrOH Me 108 100a,b 92% (R)-111a; 93% e.e. 98% e.e. 102a (S)- ; R = 4-ClC6H4, 99% 76% H2, Pd/C (R)-102b; R = i-Bu, 83% or Ra-Ni

DBU, MeOH H H

. O N N N HClH2N 2 O O O 1. KOH, MeOH O 2. m-xylene, Δ R OH R OMe 80% CO2Et (S)-76a ; R = 4-ClC H , 92% (S)-2; R = 4-ClC6H4 6 4 (R)-76b; R = i-Bu, 95% (R)-77c; 93% e.e. trans-112a; 93% e.e. . 1. NiCl2 6H2O 95% R NaBH4/MeOH 2. 6 M NaOH CO H 2 N OH H OH . NH2 HClH2N OH O N O N R R OH R (R)-Phenibut, 4 109 110; R = 9-phenantryl (R)-5; R = i-Bu (R)-77b; R = i-Bu, Scheme 29.

+ +N N O O H H 116a,b in the presence of catalytic amounts of enantiomerically O N N O pure (S)-diphenylprolinol silyl ether 12 at room temperature, R R obtaining the chiral b-substituted c-nitro aldehydes (R)-74a and R = 2,6-i-Pr C H , 101 2 6 3 (S)-74b in moderate yield and excellent enantiomeric excess, which under known procedures45 were transformed into (R)- Scheme 27. Baclofen 2 and (S)-Pregabalin 5, respectively (Scheme 31). Enantioselective Michael addition of dimethyl malonate to nitroalkene (E)-116a catalyzed by chiral squaramide (S)-79b, pro- N duced the c-nitro ester (R)-92a in 76% yield and 86% enantiomeric N N N excess, which by reduction of the nitro group with NaBH4/NiCl2- H H 6H O, furnished the methyl 4-(4-chlorophenyl)-2-oxopyrro- HO HO H 2 104,Zn(OTf)2 O O lidine-3-carboxylate (R)-95b in 90% yield. Hydrolysis and 95% (E)-103 decarboxylation of the methyl ester in the c-lactam (R)-95b, (S)-105; 80% e.e. afforded the c-lactam (R)-77a in 89% yield, which by treatment MMPP 64% with 6 M HCl gave the (R)-Baclofen 2 as the hydrochloride in 92% MeOH, 0oC yield (Scheme 32).50 On the other hand, the Michael addition of dimethyl malonate

HO CN H5IO6,Et2O CN to nitroalkene (E)-116b catalyzed with dihydroquinidine-based HO 100% squaramide HQD-SQA 117, afforded the c-nitro ester (S)-92b with O O 91% enantiomeric excess, which by catalytic hydrogenation of the

(S)-107 (S)-106; 80% e.e. nitro group over Ra-Ni, gave the methyl 4-isobutyl-2-oxopyrrolidine-3-carboxylate (3S,4S)-95a in 86% yield. Hydrolysis and H2,PtO2 decarboxylation of the methyl ester in the c-lactam 95a, produced HO O O the (S)-Pregabalin 5 in 95% yield and 91% enantiomeric excess NH 66 2 NN (Scheme 33). This procedure was applied for the scalable synthe- O t-Bu t-Bu sis of (S)-Pregabalin 5. 104 Alternatively, a highly enantioselective synthesis of (S)-Prega- (S)-Pregabalin,5 balin 5 has been described through a Michael addition of diethyl malonate to nitroalkenes under solvent-free conditions and cat- Scheme 28. alyzed by the chiral thiourea (R,R)-118. Thus, Michael addition of diethyl malonate to nitroalkene (E)-116b, easily obtained from of (S)-115a with 1 M NaOH, afforded the b-cyano acid (S)-107 in condensation of isobutyraldehyde with nitromethane in the pres- 94% yield, which by catalytic hydrogenation of the cyano group ence of catalytic amounts of (R,R)-118 under solvent-free condi- using PtO2, gave the (S)-Pregabalin 5. On the other hand, the cat- tions, produced the nitro ester (S)-119 in 73% yield and 88% alytic hydrogenation of (R)-115b followed by the treatment with enantiomeric excess, which by hydrogenation over Ra-Ni, provided

Et3N, provided the c-lactam (R)-77c in 84% yield, which by hydrol- the ethyl (S)-4-isobutyl-2-oxopyrrolidine-3-carboxylate 112b in ysis with 6 M HCl, furnished the (R)-Phenibut 4 (Scheme 30).63 72% yield. Saponification of the ethyl ester in the c-lactam 112b Of course, the enantioselective organocatalytic Michael addition followed by decarboxylation, afforded the c-lactam (S)-77b in of acetaldehyde, malonate derivatives and ketone equivalents to 90% yield and 98% enantiomeric excess, which by hydrolysis with nitroolefins, is another good method for the synthesis of b-substi- 6 N HCl, gave the enantiomerically pure (S)-Pregabalin 5 as the tuted c-amino acids. For example, the Hayashi64 and List65 groups hydrochloride in 95% yield. Additionally, treatment of ethyl (S)-4- carried out the addition of acetaldehyde to the nitroolefins (E)- isobutyl-2-oxopyrrolidine-3-carboxylate 112b with 6 N HCl at M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1009

O Gd(Oi-Pr)3 CN O CN 114,TMSCN 1 M NaOH CO2H R N 2,6-dimethoxyphenol R N 94% EtCN, -20 oC (S)-107 (E)-113a; R = i-Bu (S)-115a; R = i-Pr; 89%, 97% e.e. PtO2,H2 (E)-113b; R = Ph (R)-115b; R=Ph; 90%, 91% e.e. HCl, H2O

1. H2, Pd/C, AcOH 84% 2. Et3N NH2

H CO2H N O (S)-Pregabalin, 5 Ph O P Ph O HO O F (R)-77c; 84%

6 M HCl HO F

114 NH2

CO2H

(R)-Phenibut, 4

Scheme 30.

CHO MeO2C CO2Me (S)-12 (20 mol%) CH (CO Me) NO2 + MeCHO NO 2 2 2 R 2 NO 1,4-dioxane, r.t. NO2 HQD-SQA, 117 2 R (5 mol%) (E)-116a; R = p-ClC6H4 (R)-74a; R = p-ClC6H4, 75%, 92% e.e. (E)-116b (S)-92b; 91% e.e. (E)-116b; R =i-Bu (S)-74b; R = i-Bu, 61%, >99% e.e. 86% H2, Ra-Ni

ref. 45 NH2 O O

CO2H CO2H CO2H 1. 6 N HCl, Δ MeO N H NH2 2. NaOH NH2 Cl 95% (S)-Pregabalin, 5 (R)-Baclofen, 2 (S)-Pregabalin, 5 91% e.e. (3S,4S)-95a

Scheme 31. OMe

N Et HN MeO2C CO2Me H NO2 F3C N CH2(CO2Me)2 NO N O (S)-79b (5 mol%) 2 Cl CH2Cl2 O (E)-116a Cl 76% F3C (R)-92a; 86% e.e. HQD-SQA, 117

90% NaBH4/MeOH . Scheme 33. NiCl2 6H2O

O O MeO2C N H 1. NaOH, EtOH N H EtO2C CO2Et CH (CO Et) 2. PhMe, Δ NO2 2 2 2 NO 89% 118 (10 mol%) 2 73% Cl Cl (E)-116b (S)-119, 88% e.e. (R)-77a (R)-95b 72% H2, Ra-Ni MeOH 92% 6 M HCl, Δ O O O O CO H EtO2C 2 N 1. NaOH, EtOH, r.t. N N H . N H NH2 HCl H H 2. PhMe, Δ F3C Me2N 90% (S)-77b, 98% e.e (S)-112b Cl Δ 95% 6 N HCl l, (R)-Baclofen, 2 CF3 HC (S)-79b N % 6 92 CO2H Scheme 32. . NH2 HCl H H NMe2 N (S)-Pregabalin, 5 F3C N reﬂux, produced also the (S)-Pregabalin 5 as the hydrochloride in S 67 92% yield (Scheme 34). CF3 (R,R)-118 Koskinen et al.68 carried out the reaction of nitroalkene (E)- 116b with the Meldrum’s acid catalyzed by the quinidine derived Scheme 34. 1010 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 thiourea 120 in dichloromethane at room temperature, obtaining O O O O the nitro derivative (S)-122 in 84% yield and 74.6% enantiomeric NO PhO Ot-Bu PhO Ot-Bu 69 2 excess after puriﬁcation. On the other hand, Šebesta et al. (R,R)-93 (5 mol%) NO2 reported the same reaction but catalyzed by the chiral squaramide PhMe 92% (S)-121, obtaining the compound (S)-122 in similar yield and 94% (E)-116c (S)-124; 93% e.e., 1.8:1 d.r. enantiomeric excess. Catalytic hydrogenation of (S)-122 over Ra- NaBH /MeOH Ni in acetic acid at room temperature, afforded the c-amino diacid 85% 4 . (S)-123 in 75% yield, which by treatment with 6 M HCl, gave the NiCl2 6H2O

(S)-Pregabalin 5 as the hydrochloride in 94% yield and 80% enan- O O tiomeric excess (Scheme 35). CO2H 6NHCl,Δ t-BuO On the other hand, a highly enantioselective Michael addition of . N H NH2 HCl >99% tert-butyl phenyl malonate to the b-nitrostyrene (E)-116c catalyzed by the Ni(II)-bis[(R,R)-N,N0-dibenzylcyclohexane-1,2-dia- (S)-Phenibut, 4 (3R,4S)-125; 93% e.e. mine]Br2 93, gave the c-nitro derivative (S)-124 in 92% yield and 93% enantiomeric excess (1.8:1 diastereoisomeric ratio), which Scheme 36. by reduction of the nitro group with NaBH4/NiCl26H2O, afforded, the tert-butyl 4-isobutyl-2-oxopyrrolidine-3-carboxylate (3R,4S)- 125 in 85% yield and 93% enantiomeric excess. Finally, the hydrolysis and decarboxylation of the c-lactam (3R,4S)-125 with 6 N HCl, O produced the enantiomerically enriched (S)-Phenibut 4 as the O O 70 hydrochloride in quantitative yield (Scheme 36). SAr HO SAr NO2 Similarly, a highly enantioselective Michael addition reaction of MAHT NO2 malonic acid half thioester (MAHT) to the 4-chloro-b-nitrostyrene 126 (5 mol%) Cl MTBE, 45 oC Cl (E)-116a on a scale of 5 g and catalyzed by the cinchona-based (E)-116a c 82% Ar = 4-MeOC6H4 squaramide 126, furnished the -nitro derivative (S)-127 in 82% (S)-127;90% e.e. yield and 90% enantiomeric excess, which by hydrogenation over H2, Ra-Ni Ra-Ni, gave the c-lactam (S)-77a in 67% yield and >99% enan- 67% H3PO4, THF tiomeric excess after recrystallization. Finally, hydrolysis of the c O -lactam (S)-77a with 6 M HCl, afforded the enantiomerically pure CO H 71 2 (S)-Baclofen 2 as the hydrochloride in 76% yield (Scheme 37). HCl N H NH .HCl On the other hand, the enantioselective Michael addition of 2 76% b diphenyl dithiomalonate to -nitrostyrene (E)-116c in presence Cl Cl of catalytic amounts of (S,R)-128, afforded the nitro derivative (S)-Baclofen, 2; >99% e.e. (S)-77a; >99% e.e. (R)-129 in 94% yield and 98% enantiomeric excess. Reduction of the nitro group in (R)-129 using zinc powder in acetic acid fol- OMe lowed by the treatment with TiCl3, produced the c-lactam N (3S,4R)-130 in 90% yield, which by hydrolysis with 6 N HCl, furnished the (R)-Phenibut 4 as the hydrochloride in 85% yield NH H (Scheme 38).72 N O N

O CF3

O F3C 126 O

O O Scheme 37. O O NO2 120 (10 mol%) O2N O or O O O O O (E)-116b (S)-121 (5 mol%) (S)-122 CH Cl , r.t. PhS SPh 2 2 74.6% e.e., using 120 NO2 PhS SPh Ph 128 84% 94% e.e., using (S)-121 (S,R)- (5 mol%) NO o 2 (E)-116c PhMe, -40 C Ph H , Ra-Ni 75% 2 94% (R)-129; 98% e.e. AcOH, r.t. (after recrystallization)

O 1. Zn powder, AcOH O 90% OH OH 2. TiCl3 (10 mol%) 6 N HCl, 100 oC . 94% O O HCl H2N H2N OH O Ph (S)-Pregabalin,5 . 6N HCl PhS (S)-123 HClH2N CO2H NH 80% e.e. 85% (R)-Phenibut, 4 Ph S O O (3S,4R)-130 F3C TrHN NH Ph N N N N H H H N CF N Me HN 3 F3C N O OMe CF 120 (S)-121 (S,R)-128 3

Scheme 35. Scheme 38. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1011

X formed using a known procedure into the enantiomerically pure (S)-Baclofen 2 and (S)-Phenibut 4 as the hydrochlorides. In a simi- O lar way, the 4-chloro-b-nitrostyrene (E)-116a and b-nitrostyrene NO2 Ph O Me (E)-116c were transformed into (R)-Baclofen 2 and (R)-Phenibut 131; CHCl , r.t. NO 3 Ph 2 73 X 96-99% 4 using ent-131 as catalyst (Scheme 39). (E)-116a; X = Cl (S)-132a; X = Cl, >99% e.e. On the other hand, the reaction of 4-chloro-b-nitrostyrene (E)- (S)-132b; X = H, >98% e.e. (E)-116c; X = H 116a with commercially available 1,3-dithiane-2-ethylcarboxylate m-CBPA, TFA as a glyoxylate anion equivalent in the presence of catalytic CH Cl , 70 oC 2 2 amounts of cinchona-thiourea bifunctional derivative 134, X X afforded the c-nitro derivative (S)-135 in 81% yield and 86% enantiomeric excess, which by treatment with zinc powder and 6 M HCl, gave the enantiomerically enriched c-lactam (S)-77a in 69% O Ra-Ni O c NH .HCl yield. Finally, hydrolysis of the -lactam (S)-77a with HCl, afforded HO 2 NO 74 AcOH/HCl PhO 2 the (S)-Baclofen 2 as the hydrochloride in 73% yield (Scheme 40). (S)-2; X = Cl (S)-133a ; X = Cl, 80% Regiodivergent parallel kinetic resolution of aziridine (±)-136 (S)-4; X = H (S)-133b ; X = H, 73% i with dimethyl malonate under Y(OTf)3/La(O Pr)3/dinuclear Schiff X base 137 as catalyst, gave the malonate derivatives (R)-138 and (S)-138 in 49% yield and excellent enantiomeric excess. Decarboxy-

ent-131 lation of (R)-138 using (LiCl/H2O/DMSO), afforded the monoester NO2 O derivative (R)-139 in 81% yield, which by reaction with (Boc) O . 2 NH2 HCl X HO and Et3N/DMAP and subsequent treatment with NaOMe, gave the (E)-116a; X = Cl (R)-2; X = Cl N-Boc-protected c-amino ester (R)-140 in 87% yield (Scheme 41).75 (R)-4; X = H (E)-116c; X = H Other strategies for the synthesis of b-substituted c-amino b a b b t-BuO2C acids are the catalytic hydrogenation of -substituted , - and , S Ph c-unsaturated c-amino acid derivatives, or b-aryl-b-cyano-a,b- Ph t-BuO2C N N unsaturated carboxylates and the alkenylation of a,b-unsaturated

H H NH2 c-amino acids derivatives (Scheme 42). 131 Based in the retrosynthetic analysis shown in the Scheme 42, Barisova et al.76 reported the synthesis of (R)- and (S)-b-triﬂuo- Scheme 39. romethyl c-aminobutyric acid 145 by catalytic hydrogenation of chiral c-phthalimido a,b-unsaturated amides. In fact, the reaction of racemic c-phthalimido b-hydroxy substituted derivative 141

with SOCl2 in DMF followed by the addition of (S)-a-methylbenzy- S S a a b SCH2CF3 lamine [(S)- -MBA], furnished the , -unsaturated amide (S)-142 H S S NO SCH2CF3 as the main product of dehydration, which by catalytic hydrogena- 2 O O2N 134, PhMe, r.t. O tion in formic acid, produced the diastereoisomeric amides (R,S)- Cl 81% 143 and (S,S)-144 in 25% and 31% yield, respectively. Treatment (E)-116a of separated (R,S)-143 and (S,S)-144 with HCl/AcOH, produced Cl b c (S)-135; 86% e.e. the (R)- and (S)- -triﬂuoromethyl -aminobutyric acid 145 in 74% yield (Scheme 43). Zn powder, 6 M HCl 69% EtOH/AcOEt Asymmetric hydrogenation of c-phthalimido a,b-unsaturated carboxylic acid derivatives is another methodology to obtain enan- H tiomerically enriched precursors of b-substituted c-amino acids. . NH2 HCl N For example, the asymmetric hydrogenation of ethyl 3-(4-chloro- HCl O CO2H phenyl)-4-phthalimidobut-2-enoate (Z)-146, catalyzed by the [Rh 73% (COD)2]BF4-complex phosphineaminophosphine ligand (SC,RFc,RP)- Cl Cl 147, produced the ethyl 3-(4-chlorophenyl)-4-phthalimidobu- (S)-Baclofen, 2 (S)-77a tanoate (R)-148 in 95% yield and >99% enantiomeric excess after recrystallization, which by treatment with 6 N HCl, produced the OMe enantiomerically pure (R)-Baclofen 2 as the hydrochloride in quan- N titative yield (Scheme 44).77 CF3 H The enantioselective synthesis of b-aryl c-amino acid deriva- N N tives via Cu-catalyzed enantioselective conjugate reduction of b-

S N CF3 phthalimido a,b-unsaturated carboxylates has been also reported. 134 H Speciﬁcally, the enantioselective hydrogenation of ethyl 3-(4- chlorophenyl)-4-phthalimidobut-2-enoate (Z)-146, in the presence Scheme 40. of catalytic amounts of Cu(OAc)2/H2O, (R)-BINAP 149 and poly- methylhydrosiloxane (PMHS) as the hydride source and t-BuOH as an additive, afforded ethyl 3-(4-chlorophenyl)-4-phthalimi- Enantioselective organocatalytic Michael addition of acetophe- dobutanoate (R)-148 in 92% yield and 98% enantiomeric excess none to 4-chloro-b-nitrostyrene (E)-116a and b-nitrostyrene (E)- after recrystallization, which by treatment with 6 N HCl produced 116c in the presence of catalytic amounts of chiral thiourea 131, the enantiomerically pure (R)-Baclofen 2 as the hydrochloride in gave the nitro derivatives (S)-132a,b in quantitative yield and 90% yield (Scheme 45).78 excellent enantioselectivity, which by a Baeyer-Villiger oxidation On the other hand, the chemoenzymatic hydrogenation of with m-CPBA, afforded the c-nitro esters (S)-133a,b in 80% and potassium 3-(4-chlorophenyl)-3-cyano-a,b-unsaturated carboxy- 73% yield, respectively. The c-nitro esters (S)-133a,b were trans- late (Z)-150, using the anaerobic bacteria Clostridium sporogenes, 1012 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

CO2Me CO2Me CH2(CO2Me)2 O La(OiPr) /Y(OTf) 3 3 CO2Me + CO2Me N Schiff base 137 Ar DMPA NH NH (±)-136 Ar O Ar O [Ar = 3,5-(CF3)2C6H3] (R)-138;49%,99%e.e. (S)-138;49%,>99.5%e.e.

LiCl/H2O 81% DMSO

OMe 1. (Boc)2O, Et3N CO2Me N OH DMPA, THF CO2Me 2. NaOMe, MeOH NH N OH OMe NHBoc 87% Ar O (R)-140 (R)-139 137

Scheme 41.

NPhth NPhth R O [Rh(COD)2]BF4 CO2Et CO2Et H2N (SC,RFc,RP)-147 OR H2, CH2Cl2, r.t. Cl Cl 95% (Z)-146 (R)-148; >99% e.e.

F3C CF3 quant. 6 N HCl O R O R O H2N H N H2N * 2 P NH .HCl R OH OR 2 N Me Fe P CO2H Me Cl CN O (R)-Baclofen, 2; 98% e.e. (SC,RFc,RP)-147 R OR Scheme 44. Scheme 42. Retrosynthetic analysis of b-substituted c-amino acids.

NPhth (R)-BINAP 149 NPhth Cu(OAc)2,H2O H CO2Et CO2Et PMHS, t-BuOH N Me 1. SOCl2 PhMe NPhth CO2H NPhth α Cl Cl F C 2. (S)- -MBA O 92% 3 OH CF3 Ph (Z)-146 148 63% (R)- ; 98% e.e. 141 (S)-142 90% 6 N HCl H2, Pd/C HCO H 2 PPh2 NH2.HCl H PPh2 CO2H HCl N Me H2N CO2H NPhth AcOH (R)-BINAP,149 Cl CF CF O Ph 3 74% 3 (R)-Baclofen, 2;98%e.e. (R)-145 (R,S)-143; 25% : (S,S)-144; 31%

74% HCl/AcOH Scheme 45.

H2N CO2H CN CN CF3 CO K CO2Me (S)-145 2 1. Enzyme + 2. H3O Cl Cl Scheme 43. 3. Me3SiCH2N2 (Z)-150 (S)-151a, 83%, >99% e.e. Enzyme: C. sporogenes, R. productus, 70% NaBH4, NiCl2 A. woodii MeOH Acetobacterium woodii and Ruminococcus productus, followed by the H . NH2 HCl protonation and esteriﬁcation with Me3SiCH2N2, afforded methyl N 6 N HCl O ester (S)-151a in 83% yield and 99% enantiomeric excess. The CO2H 82% reduction of the cyano group in (S)-151a with NaBH4/NiCl2, provided the c-lactam (S)-77a in 70% yield and >99% enantiomeric Cl Cl (S)-77a; 70%, >99% e.e. excess, which by hydrolysis with 6 N HCl, gave the enantiomeri- (S)-Baclofen, 2 cally pure (S)-Baclofen 2 as the hydrochloride in 82% yield Scheme 46. (Scheme 46).79 Enantioselective bioreduction of ethyl (E)-b-isobutyl-b- cyanoacrylate 152 with an ene-reductase (OPR1 from Lycopersicon conversion and enantioselectivity. The cyanoester (S)-153 was esculentum), gave the cyanoester (S)-153 in 69% yield and >99% transformed into (S)-Pregabalin 5 following known procedures enantiomeric excess. Under these conditions, (Z)-152 gave lower (Scheme 47).80 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1013

CO2Et O ene-reductase CO2Et PhthN OEt + Cl B(OH)2 CN CN NAD(P)H NAD(P)+ O (S)-153; 69%, >99% e.e. (E)-155 or (E)-152 (R,R)-156-RhCl] (2.5 mol%) [PI/CB Rh/Ag] (0.5 mol%) NHt-Bu 1. KOH/H2O 2 CH2Cl2/H2O, KOH (50 mol%) 157 (0.1 mol %) 2. H2/Ra-Ni o o 3. AcOH 40 C PhMe/H2O, 100 C 157 85% 95%

CO2H Cl Cl

NH2 S (S)-Pregabalin, 5 O O 6 N HCl O O . Scheme 47. S PhthN HCl H2N OEt OH (S)-148; 99% e.e. (S)-Baclofen, 2

(R,R)-156 CN CN CO Me 2 OYE-W116L CO2Me Scheme 49. NADP+ X GDH, glucose X (Z)-154a; X = Cl (R)-151a; X = Cl, 92%, 88% e.e. Cl B(OH)2 O (Z)-154b; X = H (R)-151b; X = H, 100%, 94% e.e. O Boc [RhCl(C2H4)2]2 N Boc NaBH4 . N NiCl2 6H2O (S,S)-159, Et3N o PhMe/H2O, 60 C H 158 Cl Ph H NH .HCl 99% 2 N (R)-160; 97% e.e. O CO2H 6 N HCl 99% TFA H Ph X X O CO H (S,S)-159 X = Cl; (R)-Baclofen, 2 (R)-77a; X = Cl, 68% 2 X = H; (R)-Phenibut, 4 R 77c 6 N HCl N H ( )- ; X = H, 61% NH2.HCl 94% Scheme 48. Cl Cl (R)-Baclofen, 2 (R)-77a

Scheme 50. Bioreduction of (Z)-b-aryl-b-cyanoacrylates mediated by the tryptophan 116 mutants of Old Yellow Enzyme 1 (OYE1) is another strategy for the synthesis of key intermediates for the preparation A highly enantioselective alkenylation of cyclic a,b-unsaturated of b-substituted c-amino acids. For example, the bioreduction of c-lactams catalyzed by a rhodium–diene complex, gives also key (Z)-154a,b with OYE1-W116L, afforded the b-aryl b-cyanoesters intermediates for the synthesis of b-substituted c-amino acids. (R)-151a,b in excellent yield and with 88% and 94% enantiomeric For example, the Michael addition of potassium 1-triﬂuorobo- excess, respectively. Reduction of the cyano group in (R)-151a,b rate-2-methylprop-1-ene to a,b-unsaturated c-lactam 158 cat- c with NaBH4 and NiCl2 6H2O, produced the -lactams (R)-77a,c in alyzed with freshly prepared [{Rh(OH)((S,S)-159)2}] in toluene/ moderate yield, which by hydrolysis with 6 N HCl, gave the (R)- H2O/Et3N at room temperature, produced the c-lactam (S)-58 in Baclofen 2 and (R)-Phenibut 4 as the hydrochlorides (Scheme 48).81 97% yield and 99% enantiomeric excess, which by catalytic hydro- Asymmetric addition of arylboronic acids to a,b-unsaturated genation, furnished the c-lactam (S)-161 in quantitative yield. carbonyl compounds is another method for the preparation of Hydrolysis of (S)-161 with 6 M HCl, gave the (S)-Pregabalin 5 as key intermediates for the synthesis of b-aryl c-amino acids. For the hydrochloride in 96% yield (Scheme 51).85 example, the addition of 4-chlorophenylboronic acid to ethyl 4- Chiral pool processes are another important strategy for the phthalimidobutanoate (E)-155 Rh-catalyzed using the bis-sulfox- stereoselective synthesis of b-substituted c-amino acids. For exam- ide (R,R)-156 as ligand, gave the ethyl 3-(4-chlorophenyl)-4- ple, hydroboration of (R)-1-chloro-4-(1-nitrobut-3-en-2-yl)ben- phthalimidobutanoate (S)-148 in 85% yield and 99% enantiomeric excess after recrystallization.82 In the similar way, the compound (S)-148 was obtained in 95% yield and 99% enantiomeric excess O O BF3K Boc when nanoparticle catalysts in the presence of chiral diene 157 Boc [{Rh(OH)((S,S)-159)}2] N were used.83 Following known procedures (S)-148 was trans- N PhMe/H2O/Et3N formed into (S)-Baclofen 2 as the hydrochloride (Scheme 49). 158 97% a b A highly enantioselective alkenylation of cyclic , -unsaturated (S)-58; 99% e.e. c-lactams catalyzed by rhodium-diene complex, is also another H , Pd/C c 100% 2 methodology to obtain key intermediates for the synthesis of - MeOH amino acids. For example, Michael addition of arylboronic acid to O a,b-unsaturated c-lactam 158 catalyzed by [RhCl(C2H4)2]2 and CO2H Boc 6 M HCl N the chiral diene (S,S)-159 in toluene/H2Oat60°C, afforded the c- NH .HCl lactam (R)-160 in 99% yield and 97% enantiomeric excess, which 2 96% by treatment with TFA, produced the c-lactam (R)-77a in 99% (S)-Pregabalin, 5 (S)-161 yield. Hydrolysis of the c-lactam (R)-77a with 6 N HCl, gave the 84 (R)-Baclofen 2 as the hydrochloride in 94% yield (Scheme 50). Scheme 51. 1014 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 zene 162 (96% e.e.) obtained by Pd-catalyzed asymmetric allylic O 5 steps alkylation reaction of nitromethane with (E)-3-(4-chlorophenyl)al- Ph CO2H lyl methyl carbonate, with 9-borabicyclo(3.3.1)nonane (9-BBN) followed by treatment with H2O2/NaOH, furnished the nitro-alcohol Me Me derivative (R)-163 in 73% yield and 96% enantiomeric excess, (R)-169 (S,R)-170 which by a Dess-Martin-Periodinane (DMP) oxidation and subse- (CO) Cl , DMF c 100% TMSCHN2 88% 2 2 quent treatment with NaH2PO4/NaClO2, gave the -nitro carboxylic PhMe t-BuOH, DIPEA acid (R)-75a in 67% yield. Catalytic hydrogenation of the nitro group in (R)-75a using Ra-Ni followed by the hydrolysis with 2 M Ph CO2Me Ph CO2t-Bu HCl, afforded the (R)-Baclofen 2 as the hydrochloride in 69% yield 86 (Scheme 52). Me Me Ozonolysis of the double bond in the ethyl ester (R)-164 (93% e. (S,R)-171 (S,R)-175 e.) obtained from enzymatic kinetic resolution of 3-phenyl-4-pen- RuCl3,NaIO4 CCl , MeCN, H O tenoic acid, produced the aldehyde (S)-165 in 40% yield, which by 4 2 reduction with sodium cyanoborohydride in EtOAc/AcOH, gave the HO2C CO2Me HO2C CO2t-Bu ethyl b-phenyl-c-hydroxybutyrate (S)-166 in 76% yield. The reaction of alcohol (S)-166 with methanesulfonyl chloride (MsCl) and Me Me Et3N, afforded the mesylated derivative (S)-167 in 90% yield, which (S,R)-172; 82% (S,R)-176; 73% by treatment with sodium azide and 1,4-diazabicyclo[2.2.2]octane b c 47% DPPA, Et3N 92% TMSCHN2 (DABCO), provided the ethyl -phenyl- -azidobutyrate (S)-168 in PhMe, MeOH PHMe 66% yield. Finally, the catalytic hydrogenation of the azide group O CO t-Bu in (S)-168 using Pd/C followed by the hydrolysis with 6 M HCl, pro- MeO N CO2Me MeO2C 2 duced the (S)-Phenilbut 4 as the hydrochloride in 89% yield H 87 (Scheme 53). Me Me Reaction of carboxylic acid (S,R)-170 obtained from 3-methylcy- (R,R)-173 (S,R)-177 1. TFA, CH Cl clopentanone (R)-169, with trimethylsilyldiazomethane 6NHCl 2 2 85% 37% 2. DPPA, Et N 1,4-dioxane 3 (TMSCHN2) in toluene, gave the methyl ester (S,R)-171 in 100% 3. 6 N HCl, 1,4-dioxane yield, which by oxidation-cleavage of the phenyl ring with RuCl3/ H N 2 CO2H HO2C NH NaIO4, produced the carboxylic acid derivative (S,R)-172 in 82% 2 yield. Curtius rearrangement in (S,R)-172 using diphenylphospho- Me Me (R,R)-174; 98% e.e. (S,R)-178; 98% e.e.

Scheme 54. NO2 NO2 1. 9-BBN, THF

2. H2O2,NaOH OH 73% ryl azide (DPPA) followed by the addition of MeOH, provided the Cl Cl (R)-162;96%e.e. (R)-163; 96% e.e. methyl carbamate (R,R)-173 in 47% yield, which by hydrolysis with 6 M HCl, afforded the conformationally constrained c-amino acid 1. DMP, CH Cl 2 2 (R,R)-174 (a Gababutin derivative) in 85% yield and 98% enan- 67% 2. NaH2PO4 NaClO 2, t-BuOH tiomeric excess. On the other hand, reaction of carboxylic acid (S,

. R)-170 with oxalyl chloride and t-BuOH in dichloromethane, gave NH2 HCl NO2 the tert-butyl ester (S,R)-175 in 88% yield, which by oxidative CO2H 1. H2,Ra-Ni CO2H cleavage of the phenyl ring with RuCl3/NaIO4, afforded the car- 2. 2 M HCl boxylic acid (S,R)-176 in 73% yield. Reaction of (S,R)-176 with Cl 69 % Cl (R)-Baclofen, 2 (R)-75a TMSCHN2 in toluene, produced the diester (S,R)-177 in 92% yield, which by treatment with TFA followed by a Curtius rearrangement Scheme 52. and subsequent hydrolysis with 6 M HCl, afforded the c-amino acid (S,R)-178 in 37% yield and 98% enantiomeric excess (Scheme 54).88 CHO 1. O3,CH2Cl2 The chiral pool has been also employed in the synthesis of (S)- Ph Ph 2. Me S Pregabalin 5. For example, the regioselective ring opening of enan- CO2Et 2 CO Et 40% 2 tiomerically pure epoxide (S)-179 obtained from 3-buten-1-ol and (R)-164; 93% e.e. (S)-165 subsequent hydrolytic kinetic resolution,89 with isopropyl magne- 76% NaBH3CN sium chloride in the presence of CuI, afforded the secondary alco- AcOEt/AcOH hol (R)-180 in 90% yield. Reaction of alcohol (R)-180 with MsCl and OMs OH MsCl Et3N followed by the treatment with TMSCN and TBAF in MeCN, Ph Ph Et3N/CH2Cl2 produced the cyano derivative (S)-181 in 71% yield. Simultaneous CO2Et CO2Et 90% catalytic hydrogenation of the cyano group and hydrogenolysis of (S)-167 (S)-166 the O-Bn in (S)-181 using Ra-Ni in the presence of (Boc)2O, pro- 66% NaN3/CH2Cl2 vided the protected amino alcohol (S)-182 in 86% yield, which by DABCO oxidation with NaClO2/NaOCl in the presence of catalytic amounts . N3 NH2 HCl 1. H2,Pd/C of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), furnished the Ph Ph 2. 6 M HCl/AcOH N-Boc (S)-Pregabalin 183 in 85% yield. Finally, cleavage of Boc pro- CO2Et CO2H 89% tecting group in (S)-183 with HCl in acetone, gave the enantiomer- (S)-168 (S)-Phenibut, 4 ically pure (S)-Pregabalin 5 as the hydrochloride in 95% yield 90 Scheme 53. (Scheme 55). M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1015

OH Synthesis of enantiomerically pure (S)-Pregabalin 5 from b-sub- O i-PrMgCl stituted c-butyrolactones (1R,5S)-bicyclic c-lactone 191 easily pre- BnO BnO CuI, THF pared in one pot from homochiral epichlorohydrin by an (S)-179 90% intramolecular double displacement with alkyl malonate anion fol- (R)-180 lowed by lactonization.92 Thus, the nucleophilic cyclopropane ring 1. MsCl, Et N 71% 3 2. TMSCN, TBAF opening of the (1R,5S)-bicyclic c-lactone 191 with isopropyl cup- NHBoc rate followed by a decarboxylation using LiCl/DMSO, furnished CN H2, Ra-Ni the (S)-3-isobutyl-c-butyrolactone 192 in 75% yield, which by

HO (Boc)2O, MeOH BnO treatment with bromotrimethylsilane (TMSBr) in ethanol, gave 86% the ethyl c-bromo butyrate (S)-193 in 90% yield. Reaction of (S)- (S)-182 (S)-181 193 with NaN3 in DMF, afforded the azide derivative (S)-194 in NaClO ,NaOCl 93% yield and >99% enantiomeric excess, which by saponiﬁcation 85% 2 TEMPO, MeCN of the ethyl ester and subsequent catalytic hydrogenation of the

NHBoc NH2.HCl azide group, provided enantiomerically pure (S)-Pregabalin 5 in O O 93 HCl 91% yield (Scheme 57). HO acetone HO A highly enantioselective synthesis of (S)-Pregabalin 5 has also 95% been reported using the desymmetrization of cyclic anhydrides. (S)-183 (S)-Pregabalin, 5 For example, the reaction of 3-isobutylglutaric anhydride 195 with >99% e.e. quinine and cinnamyl alcohol (CinnOH) in toluene at 30 °C, fol- a Scheme 55. lowed by resolution with (S)- -MBA, afforded the monoester (R)- 196 in 72% yield and 97% enantiomeric excess. Curtius rearrange-

ment of (R)-196 using DPPA/Et3N followed by the reaction with Murtagh et al.91 reported the synthesis of kilograms of (3S,5R)- benzyl alcohol, produced the benzyl carbamate (S)-197, which c 3-(aminomethyl)-5-methyloctanoic acid 190, a lipophilic - without further puriﬁcation was treated with Pd(OAc)2/Ph3Pto aminobutyric acid (GABA) analogue from (S)-b-citronellol 184, give the N-Cbz protected Pregabalin (S)-198 in 88% yield. which initially was transformed in 3 steps into (R)-4-methylhep- Hydrogenolysis of N-Cbz bond in (S)-198 using Pd/C, furnished tanoic acid (R)-185. In the next step, acid (R)-185 was reacted with the enantiomerically pure (S)-Pregabalin 5 in 60% yield 94 pivaloyl chloride and Et3N followed by the treatment with the oxa- (Scheme 58). zolidinone (4R,5S)-186, to obtain the acyl oxazolidinone Curtius rearrangement of hemiester (R)-200 (90% e.e.) obtained (4R,40R,5S)-187 in 91% yield, which by reaction with lithium diiso- by enantioselective alcoholysis of 3-isobutylglutaric anhydride 195 propylamide (LDA) in THF at 50 °C followed by the addition of catalyzed by the chinchona-base sulfonamide 199, using DPPA/ tert-butyl bromoacetate and subsequent oxidative cleavage of the Et3N followed by the addition of benzyl alcohol, afforded the dipro- chiral auxiliary with LiOH/H2O2, produced the succinic acid deriva- tected (S)-Pregabalin 201 in 88% yield, which by hydrogenolysis tive (2S,4R)-188 in 62% yield. Reduction of the carboxylic acid in using Pd/C, produced the (S)-Pregabalin 5 in quantitative yield 95 (2S,4R)-188 with BH3SMe2 in methyl tert-butyl ether (MTBE) fol- and 90% enantiomeric excess (Scheme 59). lowed by mesylation and subsequent reaction with sodium azide, In the similar way, desymmetrization of 3-isobutylglutaric afforded the azido-ester derivative (3S,5R)-189 in excellent yield, anhydride 195 by enantioselective thiolysis catalyzed by the sul- which by cleavage of tert-butyl protecting group with H2SO4 and fonamide 202, afforded the hemiester (R)-203 in 89% yield and HCO2H followed by the reduction of the azide group, produced 94% enantiomeric excess, which by a Curtius rearrangement using b c the -substituted -amino acid (3S,5R)-190 in 73% yield DPPA/Et3N followed by addition of benzyl alcohol, afforded the (Scheme 56). diprotected (S)-Pregabalin 204 in 85% yield. Finally, hydrolysis of

the thioester in (S)-204 with LiOH/H2O2 followed by the hydrogenolysis using Pd/C, produced the (S)-Pregabalin 5 in 40% yield and 98% enantiomeric excess (Scheme 60).96 Catalyzed enantioselective alcoholysis of prochiral 3-(4-chloro- O OH 3 steps phenyl)glutaric acid anhydride 205 with (DHQD)2AQN 206 in HO

(S)-184 (R)-185 O O O O O 1. i-PrMgCl, CuI, THF t-BuCOCl O NH 2. LiCl, H2O, DMSO Et N/THF CO Et 3 2 75% Ph Me (1R,5S)-191 (S)-192 (4R,5S)-186 TMSBr, EtOH O 90% O O CH2Cl2 1. LDA, THF, -50 oC 4' HO O N N3 Br 2. BrCH2CO 2t-Bu NaN3,DMF t-BuO2C 3. LiOH/H2O2 CO2Et CO2Et Ph Me 93% (2S,4R)-188 62% (4R,4'R,5S)-187; 91% (S)-194;>99%e.e. (S)-193; 99% e.e. 1. BH .SMe ,MTBE 3 2 1. LiOH, H O 95% 2. MsCl, Et N, MTBE 2 3 91% THF/MeOH 3. NaN3, DMSO 2. H2,Pd/C,MeOH

1. H2SO4, HCO2H NH2 N3 H2N 2. H2,Pd(OH)2/C CO2H t-BuO2C 3. IPA, reslurry HO2C (3S,5R)-189 73% (3S,5R)-190 (S)-Pregabalin, 5

Scheme 56. Scheme 57. 1016 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

O O chemoenzymatic resolution of b-substituted c-amino acids, b-sub- 1. quinine, PhMe stituted c-nitro and b-cyano acids derivatives and b-substituted c- O CinnOH OCinn α CO2H amides (Scheme 62). O 2. (S)- -MBA 72% For example, CAL-B catalyzed desymmetrization of prochiral 195 (R)-196; 97% e.e. allyl 3-isobutylglutarate 211 in phosphate buffer solution at pH 1. DPPA/Et3N 2. BnOH 7, afforded the monoallyl ester of 3-isobutylglutaric acid (S)-212 in 93% enantiomeric excess, which by reaction with Mg3N2 in O O methanol at 80 °C, gave the amide (S)-213 in 93% yield and without OH Pd(OAc)2,PPh3 OCinn racemization. The amide (S)-213 was transformed into (S)-Prega- NHCbz morpholine, EtOH NHCbz balin 5 as the hydrochloride using known procedures 88% 100 (S)-198 (S)-197 (Scheme 63). On the other hand, the chemoenzymatic resolution of ethyl 2- 60% H2,Pd/C 101 MeOH carboxyethyl-3-cyano-5-methylhexanoate (±)-111b using a commercially available Lipolase in the presence of Ca(OAc)2/ O NaOH,102 afforded the sodium carboxylate (S)-214 in >98% enan- OH tiomeric excess, which without further purification was decar- NH2 boxylated to give the ethyl (S)-3-cyano-5-methylhexanoate (S)-Pregabalin, 5 153.103 Finally, the saponification of the ester group in (S)-153 fol- 99.7%e.e. lowed by the catalytic hydrogenation of the cyano group over sponge Ni, provided the enantiomerically pure (S)-Pregabalin 5 in Scheme 58. moderate yield (Scheme 64).104,105 Biocatalytic desymmetrization of 3-substituted glutaronitriles 0 O 215a,b by nitrilases in phosphate buffer solution, gave the 3-(4 - CO2Bn chlorophenyl)-4-cyanobutanoic acid (S)-216a in 80% yield and O 199 (3 mol%) CO2H 99% enantiomeric excess, and the 3-(cyanomethyl)-5-methylhex- O BnOH, MTBE OMe anoic acid (S)-216b in 93% yield and 90% enantiomeric excess, (R)-200; 90% e.e. 195 N which by Curtius rearrangement using DPPA/Et3N followed by 1. DPPA/Et N 88% 3 the addition of MeOH, produced the methyl carbamates (R)-217a 2. BnOH NHSO2Ar N and (S)-217b in 69% and 48% yield, respectively. Finally, hydrolysis CO2H CO2Bn of 217a,b with HCl, afforded the enantiomeric enriched (R)-Baclo- Ar = 3,5-(CF3)2C6H3 H2, Pd/C 106 NH2 NHCbz 199 fen 2 and (S)-Pregabalin 5 in 73% yield (Scheme 65). 100% It has been described that the 4-amino-3-(trimethylsilyl) (S)-Pregabalin, 5 (S)-201 90% e.e. methylbutanoic acids (R)- and (S)-220 ameliorate the neuropathic pain without central nervous system-related side effects. These c- Scheme 59. amino acids can be obtained involving the creation of C–C bond and an enzymatic resolution. In fact, enzymatic hydrolysis of cyanoester (±)-218 easily obtained from ethyl cyanomalonate, with O Novozym 435, produced the optically active carboxylic acid (R)- COSBn 219 and the recovered ester (S)-218. Catalytic hydrogenation of O 202 (20 mol%) CO2H the cyano group in the carboxylic acid (R)-219 using Pd(OH)2/C, O BnSH, MTBE NHSO2Ar produced the b-trimethylsilyl c-amino acid (R)-220 in 15–25% 195 89% (R)-203; 94% e.e. yield. On the other hand, the saponification of the ethyl ester in 1. DPPA/Et N OTr 85% 3 (S)-218 with LiOH followed by the catalytic hydrogenation of the 2. BnOH NMe2 O2N cyano group, gave the b-trimethylsilyl c-amino acid (S)-220 in CO2H COSBn Ar = 3,5-(CF3)2C6H3 107 1. LiOH/H2O2 15–25% yield (Scheme 66). THF 202 NH2 NHCbz Enzymatic separation of multikilograms of the diastereoiso- 2. H2,Pd/C meric mixture of methyl 3-cyano-5-methyloctanoate 222 obtained (S)-Pregabalin, 5 40% (S)-204 98% e.e. in 3 steps from (R)-2-methylpentanol 221, with Amano Lipase PS- SD in TBME, afforded methyl (3S,5R)-3-cyano-5-methyloctanoate Scheme 60. 222 in 46% yield. Saponification of the diastereoisomerically

enriched ester (3S,5R)-222 with NaOH in THF/H2O, followed by the catalytic hydrogenation of the cyano group over Ni sponge 97 methanol at 40 °C, or with chloramphenicol-base-derived and subsequent treatment with AcOH/EtOH/H2O, produced the b- thiourea 207,98 gave the hemiester (S)-208 in 77% yield and 95% substituted c-amino acid (3S,5R)-190 in 87% yield (Scheme 67).91 enantiomeric excess after recrystallization, which by a Curtius Enantioselective hydrolisis of ethyl c-nitrobutanoates 223a–d rearrangement using DPPA/Et3N followed by the addition of MeOH, with Novozym 435 (Candida Antarctica B), and 223e with a-Chy- produced the diprotected (S)-Baclofen 209 in 62% yield. Cleavage of motrypsin, afforded the c-nitro acids (S)-224a–e in 18–23% yield the protecting groups in (S)-209 with HCl/AcOH, afforded the (S)- with 65–94% enantiomeric excess, and the c-nitro esters (R)- Baclofen 2 as the hydrochloride in 86% yield. On the other hand, 223a–e in 21–60% yield and 42 to >99% enantiomeric excess. Cat- the ammonolysis of hemiester (S)-208 with NH4OH, produced alytic hydrogenation of the nitro group in the c-nitro acids (S)- the amide (S)-210 in 95% yield,99 which by reaction with [bis(tri- 224a–e in the presence of Ra-Ni followed by the treatment with ﬂuoroacetoxy)iodo]benzene (PIFA) at room temperature followed 6 M HCl, provided the (S)-Pregabalin 5 and the GABA analogues by the treatment with HCl, furnished the (R)-Baclofen 2 as the (S)-225a–d as the hydrochlorides in good enantiomeric excess. In hydrochloride in 60% yield (Scheme 61). a similar way, the catalytic hydrogenation of the nitro group in Another strategy used for the synthesis of enantiomerically the c-nitro esters (R)-223a–e, afforded the c-lactams (R)-77b and enriched b-substituted c-amino acids, is the chemical and (R)-226a–d in 69–81%, which by hydrolysis with 6 M HCl, provided M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1017

CO H O (DHQD)2AQN CO2H 2 206 (10 mol%) NH4OH O o CO Me C(O)NH2 MeOH, -40 C 2 95% O or 207 (10 mol%) Cl Cl (S)-210 Cl MeOH, MTBE (S)-208; 95% e.e. 205 1. PIFA, CH CN 77% 62% 1. DDPA/Et3N 60% 3 2. MeOH 2. conc. HCl

. CO H NH2 HCl NHCO2Me 2 HCl/AcOH NH .HCl CO2H CO2Me 2 86%

Cl Cl Cl (S)-Baclofen, 2 (S)-209 (R)-Baclofen, 2

Me Me Et Et N N N OTBS O O H MeO O O OMe N N CF3 O2N H N N S

207 CF (DHQ)2AQN, 206 3

Scheme 61.

R O CN Nitrilases CO2H R O Na3PO4 buffer CN CN H2N * X OR 100% OH R R X=COR, CN, conversion 2 (S)-216a; 80%, 99% e.e. CH2NO2,CH2NH2 215a; R = 4-ClC6H4 215b; R = i-Bu (S)-216b; 93%, 90% e.e.

DPPA/Et3N O PhMe, MeOH

N H NH2 NHCO2Me HCl, Δ R CO2H CN R 73% R b c Scheme 62. Retrosynthetic analysis of -substituted -amino acids by resolution. (R)-Baclofen, 2; 99% e.e. (R)-217a; 69% (S)-Pregabalin, 5; 89% e.e. (S)-217b; 48%.

Scheme 65. CO2Allyl CAL-B CO2Allyl Buffer pH 7 CO Allyl CO H 2 100% 2 conversion 211 (S)-212;93%e.e. CN

TMS CO2Et 93% Mg3N2 MeOH, 80 oC (±)-218

. NH2 HCl C(O)NH2 Novozym 435

1. Br2,NaOH CO2H CO2H 2. HCl (S)-Pregabalin, 5 75% (S)-213 CN CN TMS CO2H TMS CO2Et Scheme 63. (R)-219 (S)-218

H2 1. LiOH/MeOH 15-25% DME/H O Pd(OH)2/C 15-25% 2 2. H2,Pd(OH)2/C CO2Et CO2Et NH Lipolase 2 NH - + 2 CO2Et CO2 Na Ca(OAc)2/NaOH TMS CO2H TMS CO2H CN 40-45% conv. CN (±)-111b (S)-214; >98% e.e. (R)-220 (S)-220

80-85 oC Scheme 66.

1. KOH CO2H CO2Et 2. H2, sponge Ni CN Hydrolytic resolution of racemic b,b-disubstituted c-nitroesters NH2 40-45% (S)-Preagabalin, 5 (S)-153; >99% e.e. 227a–c with commercially available Horse Liver Acetone Powder 99.75% e.e. (HLAP) or Porcine Liver Acetone Powder (PLAP), afforded the b,b- disubstituted c-nitrobutyric acids (R)-228a,b and (S)-228c in 15– Scheme 64. 18% with 71–75% enantiomeric excess, and the unreacted c-nitroesters (S)-227a,b and (R)-227c in 12–40% yield with 39–88% enan- the (R)-Pregabalin 5 and the c-amino acids (R)-225a–d as the tiomeric excess. Catalytic hydrogenation of the nitro group in the hydrochlorides in good enantiomeric excess (Scheme 68).108 chiral c-nitroesters 227a,c over Ra-Ni, afforded the c-lactams (S)- 229a,b and (R)-229c in 74–90%, which by hydrolysis with 6 M 1018 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

3steps NC Me CO2Et HO R NO Me MeO2C 2 (±)-227a-c (R)-221 222 Lipasa PS SD HLAP 46% TBME, NaCl

NC Me CO2Et H2N 1. NaOH, THF/H2O R CO2H 2. H2, Ni sponge Me R NO HO2C MeO2C NO2 2 3. AcOH/EtOH/H2O (3S,5R)-190 (3S,5R)-222 87% (R)-228a;R=n-Bu, 15%, 74% e.e. (S)-227a;R=n-Bu, 12%, 62% e.e. (R)-228b;R=i-Bu, 18%, 75% e.e. (S)-227b;R=i-Bu, 22%, 88% e.e. 227c Scheme 67. (S)-228c; R = Bn, 18%, 75% e.e. (R)- ;R=Bn,40%,63%e.e.

H2,Ra-Ni

HCl, provided the b,b-disubstituted c-amino acids (S)-230a,b and O Me CO2H Me (R)-230c as the hydrochlorides in 63–91% enantiomeric excess 6MHCl 109 R NH2.HCl R N (Scheme 69). H Under identical conditions, the same authors reported the syn- (S)-230a;R=n-Bu, 63% e.e. (S)-229a;R=n-Bu, 74%, 63% e.e. thesis of cyclic Gabapentin-related analogues (1S,5S,6R)-39 and (S)-230b;R=i-Bu, 88% e.e. (S)-229b;R=i-Bu, 90%, 88% e.e. (R)-230c;R=Bn,91%e.e. (R)-229c;R=Bn,82%,91%e.e. (1S,3R)-232 from the cyclic nitro esters derivatives 37 and 231, 109 respectively (Scheme 70). Scheme 69. On the other hand, the resolution of (±)-Pregabalin 5 with (S)- mandelic acid in ethanol followed by the treatment of the diastereoisomeric salt with NH3/H2O, afforded the (S)-Pregabalin 1 110 NO . 5 in 33% yield (Scheme 71). 2 5 NH2 HCl 6 Diastereoisomeric separation of the mixture of 3-(amino- CO2Et CO2H 37 methyl)-5-methyloctanoic acid 190 obtained in 5 steps from (R)- (1S,5S,6R)-39;98%e.e. 2-methylpentan-1-ol 221, with (S)-mandelic acid in EtOH/H O, 2 Me Me gave the (3S,5R)-3-(aminomethyl)-5-methyloctanoic acid 190 in 91 24% yield and 99.4% enantiomeric excess (Scheme 72). CO2Et CO2H

Very recently, we carried out the synthesis of (±)-4-(4-chloro- NO . 2 NH2 HCl phenyl)-pyrrolidin-2-one 77a in ﬁve steps from dimethyl malo- 231 (1S,3R)-232 nate, which by reaction with LDA in dry THF at 78 °C followed by the addition of (S)-naproxen acyl chloride 233, produced the Scheme 70. imides (R,S)-234 and (S,S)-235 in 49% and 51% yield, respectively, after separation. Treatment of the diastereoisomerically pure imides (R,S)-234 and (S,S)-235 with 1 N KOH in THF, followed by the Treatment of the bromo-amide (S)-236 easily obtained from (S)- a hydrolysis of the c-lactams with 6 N HCl, gave the (R)- and (S)- -MBA, under reductive radical reaction conditions with Bu3SnH/ . Baclofen 2 as the hydrochloride in 79% and 96% yield, respectively BEt3/O2/BF3OEt2 in THF, afforded the (S,S)- and (R,S)-pyrrolidin-4- (Scheme 73).111 ones 237 and 238 in 76% yield and 88:12 diastereoisomeric ratio, through the stereoselective 5-exo-trig radical cyclization. The

CO2Et

NO2 R 223a-e Novozym 435 or α-Chymotrypsin

CO2H CO2Et

NO2 NO2 R R (S)-224a; R = i-Bu, 21%, 92% e.e. (R)-223a; R = i-Bu, 30%, >99% e.e. (S)-224b; R = n-Bu, 18%, 87% e.e. (R)-223b; R = n-Bu, 21%, >99% e.e. (S)-224c; R = n-Pent, 23%, 94% e.e. (R)-223c; R = n-Pent, 32%, >99% e.e. (S)-224d; R = neo-Pent, 18%, 65% e.e. (R)-223d; R = neo-Pent, 22%, 95% e.e. (S)-224e; R = Bn, 18%, 94% e.e. (R)-223e; R = Bn, 60%, 42% e.e.

1. Ra-Ni, H2 Ra-Ni, H2 EtOH/AcOEt EtOH/AcOEt 2. 6 M HCl O CO2H CO2H . N H 6 M HCl . NH2 HCl NH2 HCl R R R (S)-5;R=i-Bu, 92% e.e. (R)-77b; R = i-Bu, 81% (R)-5; R = i-Bu, >99% e.e. (S)-225a; R = n-Bu, 87% e.e. (R)-226a; R = n-Bu, 70% (R)-225a; R = n-Bu, >99% e.e. (S)-225b; R = n-Pent, 94% e.e. (R)-226b; R = n-Pent, 72% (R)-225b; R = n-Pent, >99% e.e. (S)-225c; R = neo-Pent, 65.6% e.e. (R)-226c; R= neo-Pent, 76% (R)-225c; R = neo-Pent, 95% e.e. (S)-225d; R=Bn, 94% e.e. (R)-226d; R = Bn, 69% (R)-225d; R = Bn, 94% e.e.

Scheme 68. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1019

CO2H CO2H 2.3. b-Hydroxysubstituted c-amino acids 1. (S)-Mandelic acid NH2 NH2 2. NH3/H2O In this section we present separately the b-hydroxy-c-amino 5 (±)-Pregabalin, 33% (S)-Pregabalin, 5 acids. The b-hydroxy-c-amino acids have also attracted signiﬁcant attention as biologically active compounds. For example, the (R)- Scheme 71. and (S)-b-hydroxy-c-aminobutyric acid (GABOB) 239 considered as an unusual amino acids, act as an agonist of c-aminobutyric acid 113 5 steps (GABA) 3, and it have various biological activities and may,

HO H2N among other applications, be used in the treatment of personality 114 Me disorder conditions such as epilepsy and schizophrenia, and HO2C (R)-221 190 have also been identiﬁed as a key fragments of the microscleroder-

(S)-Mandelic acid mins, a family of marine cyclic peptides possessing antitumor and 24% 115 EtOH, H2O antifungal activity. However, (R)-GABOB 239 has been found to have a greater biological activity than the (S)-enantiomer.116 Addi- H2N tionally, the (R)- and (S)-b-hydroxy-c-aminobutyric acids have 117 HO2C been used as G- and T-speciﬁc recognition elements. (3S,5R)-190; 99.4% e.e.

OH OH Scheme 72. H N H2N CO2H 2 CO2H

(R)-GABOB, 239 (S)-GABOB, 239 O OMe O

N H + Cl 118 Ar Me For the synthesis of (S)-GABOB, Banerjee, et al. carried out (±)-77a (S)-233 the Zn-mediated allylation of (R)-glyceraldehyde acetonide 53,to Ar = 4-ClC6H4 LDA/THF, -78 oC obtain the hydroxyalkene (S,S)-240 in 84% yield and 95:5 diastereoisomeric ratio. Reaction of (S,S)-240 with NaH and benzyl bromide, gave the O-benzyl derivative (S,S)-241 in 85% yield, which OMe OMe O O O O by treatment with AcOH followed by oxidative cleavage of diol S S N N with NaIO4, produced the aldehyde (S)-242 in 74% yield. Reductive R S Me Me amination of the aldehyde (S)-242 with benzylamine and sodium Ar Ar triacetoxyborohydride followed by the N-Cbz protection, produced (R,S)-234;49% (S,S)-235;51% @ 1. KOH, THF, r.t. the benzyl carbamate (S)-243 in 72% yield. Dihydroxylation of C C Δ 2. 6 N HCl, bond using OsO4 and N-methylmorpholine-N-oxide (NMO) in (S)- 243 followed by oxidative cleavage with NaIO in MeOH-H O CO2H CO2H 4 2 and subsequent oxidation with NaClO2/NaH2PO4, furnished the NH .HCl NH .HCl 2 2 triprotected derivative (S)-244 in 77% yield. Finally, the full depro- Cl Cl tection in (S)-244 under hydrogenolysis conditions, gave the (S)- (R)-Baclofen, 2,79% (S)-Baclofen, 2,96% GABOB 239 in 87% yield (Scheme 75).

Scheme 73. O OH allyl bromide O H O O Me O Me Zn dust O O O Br 84% N S Ph N S Ph N Me Bu3SnH/BEt3/O2 (R)-53 (S,S)-240 95:5 d.r. + BF .OEt ,THF S R 3 2 85% NaH, BnBr Ph 76% (S)-236 (S,S)-237 88 : 12 (R,S)-238 OBn OBn 1. AcOH Li, NH3,THF H 2. NaIO4,H2O O O 74% O O

CO2H H (S)-242 (S,S)-241 KOH N 1. BnNH /NaBH(OAc) NH2 68% 72% 2 3 2. CbzCl (S)-Pragabalin, 5 (S)-77b 98% e.e. Bn OBn Bn OBn O 1. OsO 4,NMO N N Cbz 2. NaIO , MeOH/H O Cbz OH Scheme 74. 4 2 (S)-243 3. NaClO2,NaH2PO4 (S)-244 77% 87% H2,Pd/C removal of (S)-a-MBA fragment in the diastereoisomerically pure OH pyrrolidin-4-one (S,S)-237 under Birch conditions, afforded the c- H2N CO2H lactam (S)-77b in good yield, which by treatment with KOH, gave (S)-GABOB, 239 the (S)-Pregabalin 5 with >98% enantiomeric excess (Scheme 74).112 Scheme 75. 1020 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

OBn QT-S, 246 OBn CinnOH CO Cinn HO2C 2 MTBE O O O 84% (S)-247; 88% e.e. 245 1. DPPA/Et3N 76% 2. BnOH

Ph P OBn 3 OBn Pd(OAc) 2 CbzHN CO2Cinn CbzHN CO2H OMe morpholine (S)-249 85% (S)-248 N

H2,Pd/C H 80% N MeOH N O S OH O

H2N CO2H Me Q-TS, 246 (S)-239; 99% e.e.

Scheme 76.

OH O OH O OEt 1. TMSCN/Et N OEt NaN F3C 3 3 H2N Cl N3 2. LiAlH OEt DMF, 95 oC 4 OEt O 3. Tartaric acid F3C OH 80% (R)-250 (R)-251 253 (S)-255 phthalic H2,Pd/C 95% anhydride, Py EtOH/CHCl3

CrO OEt OH O OH O 3 PhthN CO2H PhthN 1. 6 M HCl H2SO4 H2N H2N F3C OH F3C OH OH 2. Amberlite OEt (S)-141 (S)-256 (R)-239 92% (R)-252 1. HCl, AcOH, Δ 2. Amberlite IRA-120 Scheme 77.

H2N CO2H F3C OH OEt F3C OEt TMSCN NC (S)-258 Et3N OTMS O F3C 80% Scheme 79. 253 254

1. LiAlH4/Et2O 88% 2. NaOH/H2O - Cl OH phthalic O OEt OEt anhydride Me N PhthN H N 3 2 NH2 Py, 110 oC F3C OH F3C OH (±)-259 71% 256 255 crystallization (R)-259, MeOH 78% 1. HCl, MeCN/H2O Me 2. CrO3/H2SO4 + Me H3N Ph Cl- Cl- H2N Ph - OH O OH O PhthN CO2H PhthN CO2 F C OH CH2Cl2/ether F C OH Me3N Me3N 3 3 NH2 NH2 (±)-141 31% (R,R)-257; >99% d.e. (R)-259; >98% e.e. (S)-259; 74.3% e.e.

Scheme 78. Scheme 80.

Amberlite, produced the (R)-GABOB 239 in 92% yield Desymmetrization of 3-OBn glutaric anhydride derivative 245 (Scheme 77).120 with (Q-TS, 246) and CinnOH in MTBE, gave the diprotected deriva- The synthesis of enantiopure b-hydroxy-b-ﬂuoromethyl-c- tive (S)-247 in 84% yield and 88% enantiomeric excess, which by a amino acid by resolution using (R)-a-MBA has also been reported.

Curtius rearrangement using DPPA/Et3N followed by the addition Thus, the addition of TMSCN to readily available b-ethoxyvinyl tri- of benzyl alcohol, afforded the benzyl carbamate (S)-248 in 76% ﬂuoromethyl ketone 253 in the presence of Et3N, produced regios- yield. The selective cleavage of cinnamyl ester in (S)-248 using electively the 1,2-adduct 254 in 80% yield, which by reduction of

Pd(OAc)2/Ph3P in morpholine, afforded the diprotected (S)-GABOB the cyano group and simultaneous removal of the protecting 249 in 85% yield, which by hydrogenolysis using Pd/C, produced TMS group with LiAlH4, gave the aminoalcohol derivative 255 in the enantiomerically pure (S)-GABOB 239 in 80% yield 88% yield. Reaction of 255 with phthalic anhydride in the presence (Scheme 76).119 of pyridine at 110 °C, afforded the compound 256 in 71% yield, On the other hand, reaction of commercially available ethyl 4- which by treatment with HCl and oxidation of the generated alde- chloro-3-hydroxybutanoate (R)-250 with NaN3 in DMF, afforded hyde with Jones reagent, produced the racemic carboxylic acid (±)- the azide derivative (R)-251 in 80% yield, which by catalytic hydro- 141 in 78% yield. Finally, the reaction of racemic carboxylic acid genation of the azide group using Pd/C, gave the ethyl (R)-hydroxy- (±)-141 with (R)-a-MBA followed by crystallization, gave the c-aminobutanoate (R)-252 in 95% yield. Finally, the hydrolysis of diastereoisomeric salt (R,R)-257 in 31% yield and >99% the ethyl ester in (R)-252 with 6 M HCI followed by treatment with diastereoisomeric excess (Scheme 78).121 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1021

Regioselective addition of TMSCN to b-ethoxyvinyl trifluo- 2.4. c-Substituted c-amino acids romethyl ketone 253 followed by reduction of the cyano group with LiAlH4 and subsequent resolution with tartaric acid, afforded The approaches reported for the diastereoselective and enan- the aminoalcohol derivative (S)-255, which by reaction with tioselective synthesis of c-substituted c-amino acids are: (a) phthalic anhydride in the presence of pyridine, gave the compound reduction or nucleophilic addition on imines and derivatives, (b) (S)-256. Jones oxidation of (S)-256, produced the carboxylic acid electrophilic amination of a,b-unsaturated aldehydes and esters, (S)-141, which by reaction with HCl in AcOH followed by treatment (c) nucleophilic addition of carbanions derived from N-ben- with Amberlite IRA-120, produced the b-hydroxy-b-trifluo- zyldiphenylphosphinamides to a,b-unsaturated esters, (d) from romethyl-c-aminobutyric acid (S)-258 (Scheme 79).76 1,5-diols, (e) from allyl amines, (f) homologation of a-amino alde- The ready available of (±)-carnitinamide hydrochloride 259 the hydes, and (g) from glutamic acid derivatives (Scheme 82). synthetic precursor of (R)-carnitine, can be efficiently resolved by Based in the retrosynthetic analysis shown in the Scheme 82, preferential crystallization with (R)-carnitinamide hydrochloride Friestad and Banerjee126 reported the synthesis of c-amino esters in methanol, affording the (R)- and (S)-carnitinamide hydrochlo- via Mn-mediated radical addition to chiral c-hydrazones. Thus, ride 259 in >98% and 74.3% enantiomeric excess, respectively the Mn-mediated coupling of isopropyl iodide with chiral N-acyl- (Scheme 80).122 hydrazone (S)-265 bearing an ester functionality, afforded the c- The synthesis of b-fluoro-c-aminobutyric acid (R)- and (S)-264 hydrazino ester (R,S)-266 in 99% yield and 94:6 diastereoisomeric analogue of neurotransmitter GABA has also been reported.123 ratio, which by microwave-assisted acylation with trifluoroacetic For this purpose, the reaction of N,N-dibenzyl (S)-phenylalaninol anhydride (TFAA) followed by the reductive N–N bond cleavage TM 260 with Deoxo-Fluor , afforded after separation the fluoro deriva- using SmI2, produced the c-substituted c-amino ester (R)-267 in tive (R)-261 in 75% yield. Cleavage of the benzyl groups in (R)-261 76% yield (Scheme 83). 127 under hydrogenolysis followed by the reaction with (Boc)2O, gave Reddy et al. reported an efficient synthesis of c-substituted the N-Boc derivative (R)-262 in 80% yield, which by oxidation of c-amino esters from N-tert-butanesulfinyl ketimines. In this con- the phenyl group with NaIO4/RuCl3, furnished the N-Boc b-flu- text, the reaction of readily available b,c-butenolides 268a,b with oro-c-aminobutyric acid (R)-263 in 76% yield. Finally, the cleavage (S)-N-tert-butanesulfinamide in the presence of Ti(OEt)4 and EtOH of the N-Boc bond in (R)-263 with HCl, afforded the (R)-b-fluoro-c- in THF, provided the (S)-N-tert-butanesulfinyl ketimine derivatives aminobutyric acid 264 in 80% yield.124,125 Under identical 269a,b, which by reduction with L-Selectride, produced the N-tert- conditions the N,N-dibenzyl (R)-phenylalaninol 260 was trans- butanesulfinyl c-amino esters (S,S)-270a and (R,S)-270b in 94% and formed into (S)-b-fluoro-c-aminobutyric acid 264 (Scheme 81). 89% yield, respectively, and with excellent diastereoselectivity.128 Finally, cleavage of the sulfinyl group in 270a,b with 1 N HCl, afforded the c-substituted c-amino esters (S)-271a and (R)-271b Deoxo-FluorTM Ph OH Ph NBn2 as the hydrochlorides in excellent yield (Scheme 84). 75% NBn2 F (S)-260 (R)-261 1. H ,Pd(OH) /C O 80% 2 2 O O 2. (Boc2)O, DMPA O H N N N NaIO4 N HO2C NBoc2 Ph NBoc2 i-PrI, hv Bn RuCl3 MeO Bn MeO F F H 76% Mn2(CO)10 263 (R)-262 O O (R)- CH2Cl2 (S)-265 (R,S)-266; 94:6 d.r. 80% HCl 99% 1. TFAA, DMAP

76% Et3N, mw HO2C NH .HCl 2 2. SmI2, MeOH F (R)-264 NHTFA MeO Ph OH HO2C NH2.HCl O NH 2 F (R)-267 (R)-260 (S)-264 Scheme 83. Scheme 81.

R O N O S OR S N t-Bu R R O O H2N t-Bu NH OEt 2 O Ti(OEt) ,EtOH R R 4 HO OH o (a) R THF, 40 C O (b) 268a; R = Me (g) O (S)-269a,b O O 268b; R = 4-MeOC6H4 R=H,OR L-Selectride NH 2 THF, -78 oC OH R (f) (c) O NHP O O R S H OR NH2.HCl HN t-Bu (e) Ph2P + R (d) N OEt 1 N HCl OEt O O R o R R MeOH, 0 C O O NH2 OH (S)-271a; R = Me, 92% 98:2 d.r. R (R)-271b; R = 4-MeOC6H4, 89% (S,S)-270a; 94% R OH (R,S)-270b; 89%

Scheme 82. Retrosynthetic analysis of c-substituted c-amino acids. Scheme 84. 1022 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

CbzHN Bn PMP CbzHN Bn PMP (R,S)-280 N HN (10 mol%) H 1. DIB, I2, hv H + Ot-Bu Ot-Bu N O O Ar Cl3SiH, DCE Ar * 2. TMSOTf N O O or 279a-k S 281a-k MeO2C CO2H . MeO2C ( )- BF3 OEt3 PMP = 4-MeOC H 6 4 281a; Ar = C6H5, 94%, 96% e.e. (S,S)-272 (S)-273 281b; Ar = 4-MeC6H4, 93%, 96% e.e. PivO OTMS 281c; Ar = 4-EtC6H4, 94%, 97% e.e. p-Tol 281d; Ar = 3,4-Me2C6H3, 96%, 95% e.e. R N p-Tol 281e; Ar = 4-MeOC6H4, 92%, 96% e.e. OH 281f; Ar = 3-MeOC6H4, 91%, 96% e.e. CbzHN Bn N O 281g; Ar = 4-FC6H4, 95%, 95% e.e. 281h; Ar = 3-FC6H4, 91%, 94% e.e. H N O (R,S)-280 281i; Ar = 4-ClC6H4, 96%, 95% e.e. 281j; Ar = 4-BrC6H4, 95%, 95% e.e. 281k; Ar = 2-thienyl, 95%, 95% e.e. MeO2C

O R Scheme 87. 274a;R=Ph,(S,S)49%,(S,R)26% 274b;R=t-Bu, (S,S)36%,(S,R)31% alyzed by the chiral Lewis base picolinamide (R,S)-280 in Scheme 85. dichloroethane (DCE), obtaining the enantiomerically enriched c- amino esters (S)-281a–k in excellent yield (Scheme 87). Cascade reactions catalyzed by secondary amines combining OH OH iminium- and/or dienamine has been introduced for the synthesis 132 NH2 N R of (S)-Vigabatrin 6. Thus, the one-pot cascade reaction of the a, 1. RCHO b-unsaturated aldehyde 282 with dibenzyl azodicarboxylate O OEt NH N 2 2. OEt (DBnAD) in the presence of catalytic amounts of 2-bis[3,5-bis(tri- H OH O O OH ﬂuoromethyl)phenyl][(trimethylsilyl)oxy]methylpyrrolidine (S)- a b c (R,R)-hpen, 275 (R,R)-276a-c 283 and PhCO2H, afforded the , -unsaturated -amino aldehyde (S)-284, which by reduction with NaBH4 in the presence of the [3,3] dihydropyridine derivative 285, produced the c-amino alcohol

OH (S)-286 in 37% yield and 72% enantiomeric excess. Protection of

. the alcohol function in (S)-286 with tert-butyldimethylsilyl trifluo- HCl H2N R N R HCl/THF romethanesulfonate (TBSOTf), produced the ether (S)-287 in 97% OEt OEt . yield, which by N–N bond cleavage over Ra-Ni followed by the HCl H2N N O O treatment with (Boc)2O, produced the triprotected compound (S)- OH (S,S)-278a; R = 2-furyl, 85% 288 in 72% yield. Hydrogenolysis of the benzyl ether in (S)-288, (S,S)-278b; R = isopropyl, 87% >99% e.e. gave the alcohol (S)-289 in excellent yield, which by oxidation with (S,S)-278c; R = cyclohexyl, 88% (S,S)-277a; R = 2-furyl, 79% (S,S)-277b; R =isopropyl, 62% DMP and subsequent Wittig olefination, afforded the allylamine (S,S)-277c; R = cyclohexyl, 53% derivative (S)-290 in 69% yield. Finally, the cleavage of O-TBS bond in (S)-290 with TBAF followed by the oxidation of the alcohol with Scheme 86. PDC and subsequent treatment with 5 N HCl,133 gave the (S)-Viga- batrin 6 in 95% yield and 72% enantiomeric excess (Scheme 88). An efficient method for the one-pot conversion of peptides con- Ye et al.134 has also reported a highly enantioselective c-amina- taining (S)-glutamic acid residues into a,c-peptides with unnatural tion of a,b-unsaturated acyl chlorides with azodicarboxylates. For c-amino acids has been reported by Boto et al.129 The transforma- example, the reaction of a,b-unsaturated acyl chlorides 291a,b tion is achieved using a sequential radical decarboxylation–oxida- with di-tert-butyl azodicarboxylate (DBAD) and Et3N in the pres- tion–alkylation process. Thus, the a-carboxyl group in the peptide ence of catalytic amounts of Cinchona alkaloid TMS-QD 292, CbzPhe-Glu(OMe)OH (S,S)-272 was transformed into N-acyl imi- afforded the cycloadducts (S)-293a,b in 82% and 90% yield, respec- nium ion (S)-273 by treatment with (diacetoxyiodo)benzene tively and with 97% enantiomeric excess, which by catalytic hydro- (DIB) followed by the addition of trimethylsilyl trifluoromethane- genation followed by the hydrolysis with NaOH, produced the sulfonate (TMSOTf) or BF3Et2O, which by reaction with the eno- carboxylic acid derivatives (S)-294a,b in 85% and 88% yield, respec- lates derived from acetophenone or pinacolone, gave the a,c- tively. Treatment of (S)-294a,b with TFA followed by the N–N bond peptides 274a,b in moderate diastereoselectivity (Scheme 85). cleavage over Ra-Ni, produced the c-substituted c-amino acids On the other hand, Chin et al.130 reported the synthesis of enan- (S)-295a,b in moderate yield and good enantiomeric excess tiomerically pure a,b-unsaturated-c,d-diamino esters. Thus, the (Scheme 89). reaction of (R,R)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane Ye et al.135 also reported the enantioselective synthesis of c- (hpen) 275 with the corresponding aldehydes at room temperature substituted c-amino esters through c-amination by N-heterocyclic followed by the addition of ethyl (E)-4-oxo-2-butenoate, gave the carbene catalyzed [4+2] annulation of oxidized enals and azodicar- diimines 276a–c, which by a diaza-Cope rearrangement in DMSO boxylates. Thus, the reaction of the a,b-unsaturated aldehydes or toluene, afforded the (S,S)-diimines 277a–c in 53% to 79% yield 296a,b with DBAD/K2CO3 catalyzed with chiral azolium 297, gave and >99% enantiomeric excess. Treatment of the (S,S)-diimines the cycloadducts (S)-298a,b in good yield and excellent enan- 277a–c with concentrated HCl, provided the a,b-unsaturated-c,d- tiomeric excess, which after several reactions were transformed diamino esters (S,S)-278a–c in good yield (Scheme 86). into enantiomerically enriched c-substituted c-amino esters (S)- Chiral Lewis base organocatalyzed enantioselective hydrosilyla- 299a,b in good yield (Scheme 90). tion of c-ketimino esters is also a method used for the synthesis of Enantioselective iridium-catalyzed aminations of allylic carbon- c-amino esters. For example, Zhang et al.131 reported the hydrosi- ates is another methodology for the synthesis of (S)-Vigabatrin 6. lylation of the c-ketimino esters 279a–k with trichlorosilane cat- For example, the amination of carbonate derivative 300 obtained M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1023

Ar EtO2C CO 2Et N Ar H OTMS Me N Me Ar = 3,5-(CF3)2C6H3 CbzHN Cbz H N CbzHN Cbz (S)-283 285 N BnO H CbzN NCbz BnO H OH NaBH4 BnO O PhCO2H O 37% 282 (S)-286;72%e.e. (S)-284

97% TBSOTf

CbzHN Cbz NHBoc NHBoc N H2,Pd/C 1. H2,Ra-Ni HO OTBS BnO OTBS BnO OTBS 97% 2. (Boc)2O (S)-289 (S)-288 72% (S)-287 1. DMP, CH Cl 69% 2 2 2. Ph3PCH3Br/KHMDS

NHBoc NH2 1. TBAF OTBS OH 2. PDC 3.5NHCl (S)-290 O 95% (S)-Vigabatrin, 6; 72% e.e.

Scheme 88.

O O 3 steps O OCO2Me O MeO Cl Boc Boc NNBoc N 300 TMS-QD, 292 N Boc (Boc)2NH, [Ir(cod)Cl]2 Et3N, PhMe 85% R (R,R)-301, TBD, THF R 291a;R=CH2CH3 (S)-293a; 82%, 97% ee TMSO O 291b;R=n-C H O 7 15 (S)-293b; 90%, 97% ee 1. AcOH, HCl N 1. H2,Pd/C HO 2. Dowex WX8 MeO 2. NaOH, THF N NH2 94% N(Boc)2 (S)-Vigabatrin, 6; 98% e.e. (S)-302; 98% e.e. CO2H CO2H OMe NH TMS-QD, 292 2 1. TFA, DCM NBoc Ar 2. H2,Ra-Ni NHBoc O Me R R P N (S)-294a; 85% (S)-295a; 69%, 98% ee O Me (S)-294b; 88% (S)-295b; 71%, 96% ee Ar

Scheme 89. Ar = 2-MeOC6H4 (R,R)-301

O Scheme 91. O Boc NNBoc Boc Ar 297 (20 mol%) N H K2CO3,PhMe N Boc OCO2Me in 85% yield and 98% enantiomeric excess, which by hydrolysis Ar with AcOH/HCl, afforded the enantiomerically pure (S)-Vigabatrin 296a;Ar=4-MeC6H4 136 296b;Ar=4-FC6H4 (S)-298a; 81%, 99% e.e. 6 in 94% yield (Scheme 91). (S)-298b; 80%, 98% e.e. Sharma and Hartwig137 reported the one-pot sequence com- 1. H2,Pd/C prising C–H bond oxidation and asymmetric allylic substitution. 2. NaOH, THF The two steps involve a palladium-catalyzed oxidation of the 3. TMSCHN2, PhMe/MeOH 4. TFA, CH2Cl2 methyl hex-5-enoate under neutral conditions and iridium-cat- 5. H2,Ra-Ni,EtOH alyzed allylic substitution with phthalimide in the presence of (R, O c BF4 CO2Me R,R)-303 as a chiral catalyst and the ligand 304, produced the - N N + amino ester (R)-305 in 55% yield and 90% enantiomeric excess. N NH2 Mes Removal of phthalimide protecting group by treatment with Ar 297 10 M NaOH and subsequent reaction with NaBH4, produced the (S)-299a; 77%, 97% e.e. optically enriched (S)-Vigabatrin 6 in 50% yield and 90% enan- (S)-299b; 78%, 97% e.e. tiomeric excess (Scheme 92). Scheme 90. The enantioselective allylic amination of unactivated terminal oleﬁns represents a direct and attractive strategy for the synthesis of enantioenriched amines. For example, Bao and Tambar138 in three steps from readily available vinyloxirane, with (Boc)2NH reported for the ﬁrst time the use of benzenesulfonyl sulfurdiimide catalyzed by [Ir(cod)Cl]2/(R,R)-301 in 1,5,7-triazabicyclo[4.4.0] reagent and a chiral palladium catalyst using (R,R)-307 to convert c dec-5-ene (TBD) and THF, gave the N(Boc)2 -amino ester (S)-302 the methyl hex-5-enoate into c-amino ester (R)-308 in 87% yield 1024 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

O Ar 313 (10 mol%) O (R,R,R)-303 (5 mol%) NBn2 CO2CH2t-Bu CO2CH2t-Bu Bn NH 304 (5 mol%), 2 MeO . MeO Ni(ClO4)2 6H2O Ar CO2CH2t-Bu Pd(OAc)2/K2CO 3 CO2CH2t-Bu NPhth DME, r.t. PhthNH 312 (S)-314; 94% e.e. 55% (R)-305; 90% e.e. 99% Ar = 4-MeOC6H4 77% HCl, MeOH 1. 10 M NaOH 50% O 2. NaBH4,H2O/EtOH O P Me NBn2 NBn CO Me Ir 2 2 N O O LiOH, H2O Ph Ar CO2Me DMSO, 140 oC Ar CO Me HO 2 O Ph 81% NH (S)-316 (S)-315 =(R)-BINOL N 2 O N 304 (S)-Vigabatrin, 6; 90% e.e. (R,R,R)-303 O

N Scheme 92. O O N N

O O BsN=S=NBs 313 o MeO Et2O, 4 C MeO + S Scheme 95. - N NHBs Bs O O 306 O O O NN (R,R)-307 (12 mol%) CO2Me Ph P Ph P 4 87% Pd(TFA) (10 mol%) 2 OMe 2 Ph Ph 2 N Ph N Ph t-BuLi, Et O (R,R)-307 NaOH, MeOH/THF 2 5 -90 oC Me Ph Me Ph O O 84% (S)-317 (4R,5S)-318 Na, naphthalene HO MeO DME, -78 to 0 oC 92% HCl/THF NH .HCl NHBs 2 aq. HCl (R)-308; 92% e.e. (S)-Vigabatrin, 6 79% CO2H

Scheme 93. . HClH2N Ph (R)-295c

O Scheme 96. O H F C N OEt 3 F3CNH2 R OEt (S)-310 (10 mol%) R c O HCl/MeOH, afforded the -amino dimethyl ester derivative (S)- o 309a-g TBME, 10 C O 315 in 77% yield. Decarboxylation of (S)-315 with LiOH/DMSO, pro- (R)-311a-g duced the diprotected c-substituted c-amino acid (S)-316 in 81% (R)-311a; R = Me, 89%, 86% e.e. yield (Scheme 95).140 (R)-311b;R=n-Pr, 90%, 87% e.e. (R)-311c;R=i-Pr, 92%, 88% e.e. Deprotonation at the N-Ca of (S)-a-methylbenzylphosphi- P Ph (R)-311d;R=(CH2)2Ph, 94%, 88% e.e. namide 317 with tert-BuLi in Et2Oat90 °C followed by the addi- 311e (R)- ;R=(CH2)4OBn, 87%, 89% e.e. tion of methyl acrylate, gave the N-phosphoryl c-amino methyl (R)-311f;R=(CH2)2CO2Me,68%,82%e.e. (S)-310 ester (4R,5S)-318 in 84% yield, which by treatment with concen- (R)-311g;R=(CH2)2 ,86%,89%e.e. trated HCl in THF at room temperature, gave the c-phenyl c-amino 141 Scheme 94. acid (R)-295c as the hydrochloride in 92% yield (Scheme 96). Possibly, the most general method for the synthesis of c-substituted c-amino acids is the homologation of a-amino aldehydes a and 92% enantiomeric excess via an ene reaction/[2,3]-rearrange- easily obtained from -amino acids. For example, the HWE reac- a ment of 306. Cleavage of the sulfonamide group in (R)-308 using tion of chiral -aminoaldehyde (S)-319 with triethyl phosphonoac- sodium in naphthalene followed by the hydrolysis with HCl, fur- etate and t-BuOK followed by the reduction of the double bond c nished the enantiomerically enriched (R)-Vigabatrin 6 in 79% yield with NaBH4/NiCl2, produced the N-protected -amino ethyl ester (Scheme 93). Enantioselective phosphine-catalyzed C–N bond formation via intramolecular c-addition of nitrogen nucleophiles to allenoates O O a b 1. (EtO) P is an important methodology for the synthesis of , -unsaturated O 2 OEt O 139 c-amino esters. For example, Fu et al. reported for the first time Bn t-BuOK, THF Bn H OEt the enantioselective intermolecular c-addition of 2,2,2-trifluoroac- 2. NaBH4,NiCl2 NPhth THF - 30 oC NPhth etamide to allenoates 309a–g catalyzed by the spirophosphine (S)- (S)-319 89% (S)-320 310, obtaining the a,b-unsaturated c-amino esters (R)-311a–g in 95% 6MHCl 68–94% yield and 82–89% enantiomeric excess (Scheme 94). dioxane Ni-catalyzed asymmetric ring-opening reaction of 2-(4- O methoxyphenyl)cyclopropane-1,1-dicarboxylate 312 with diben- Bn OH zylamine catalyzed by the chiral indane-trisoxazoline (In-TOX) NH ligand 313 and Ni(ClO ) 6H O in dimethoxyethane (DME), pro- 2 4 2 2 (S)-295d vided the chiral c-substituted c-amino diester (S)-314 in 99% yield and 94% enantiomeric excess, which by transesterification with Scheme 97. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1025

(S)-320 in 89% yield, which by hydrolysis with HCl in dioxane, NHBoc 5 steps NHBoc c c HO OH afforded the -benzyl -amino acid (S)-295d in 95% yield N H (Scheme 97).142 H O O On the other hand, Gopi et al.143 carried out the reaction of the O O (S)-327 N-Boc a-amino aldehydes (S)-321a–i with the phosphoryl-stabi- (S,S)-328 O lized carbanion derived from ethyl or benzyl 2-(diphenylphospho- 75% Ph3P ryl)acetate, to obtain the N-Boc a,b-unsaturated c-amino esters OEt (S)-322a–i in 70–95% yield. Catalytic hydrogenation of the double NHBoc bond followed by saponiﬁcation and subsequent cleavage of N- N OEt H 144 c c Boc bond in (S)-322a, produced the -isobutyl -amino acid O 145 O (S)-295e (Scheme 98). (S,S)-329 In a similar way, the reaction of the N-Fmoc a-amino aldehydes (S)-323a–f with the ylide obtained from benzyl 2-(diphenylphos- Scheme 101. phoryl)acetate, afforded the N-Fmoc a,b-unsaturated c-amino esters (S)-324a–f in 78–90% yield (Scheme 99).146 O Reaction of enantiomerically pure N-silylated a-amino aldehy- O O Ph3P des (S)-325a–g with phosphoryl-stabilized carbanion derived from R OBn R H OBn THF ethyl 2-(diphenylphosphoryl)acetate followed by the cleavage of NHBoc NHBoc N-TIPS bond with HCl and subsequent treatment with Na2CO3, (S)-330a-l (S)-331a-l afforded the enantiomerically pure a,b-unsaturated c-amino esters (S)-332a;R=CH ,82% H2,Pd/C (S)-326a–g in 67–80% yield (Scheme 100).147 3 (S)-332b;R=CH(CH3)2,76% O (R)-332c;R=CH(CH3)2,70% (S)-332d;R=CH CH(CH ) ,86% R 2 3 2 OH (S)-332e; R = CH(CH3)(CH2CH3), 65% NHBoc (S)-332f;R=CH2Ot-Bu, 75% (S)-332g;R=CH(OH)CH,80% (S)-332a-l O O O 3 Ph P (S)-332h;R=CH2CONH2,90% R 3 OEt R (S)-332i;R= CHCH CO t-Bu, 81% H OEt 2 2 2 THF, r.t. (S)-332j;R= Trp,80% NHBoc NHBoc 70-95% (S)-332k;R=Tyr,85% (S)-321a-l (S)-322a-i (S)-332l;R=Aib,60%

322a;R=i-Pr, 90% 322f;R=CH2Ot-Bu, 81% 322b;R=i-Bu, 95% 322g;R=CH2CO2t-Bu, 80% Scheme 102. 322c;R=Bn,84% 322h;R=Me,93% 322d; R = CH(Me)Et, 92% 322i;R=Proline,83%

322e;R=CH2NHBoc, 70%

O 1. H2,Pd/C O Me O 2. LiOH, THF OEt OH Ar H MeOH/H2O O NHBoc NH .HCl 3. 4 M HCl 2 Ph NHBoc (S)-322a (S)-295e Ar = 3,5-(CF3)2C6H3 (S,R)-333 Scheme 98. O O 92% (EtO)2P OMe NaH, THF 0 oC O O O Ph3P Me O R OBn R Me O H OBn H ,Pd/C THF Ar OEt 2 O Ar O OEt NHFmoc NHFmoc 91% Ph NHBoc (S)-323a-f (S)-324a-f Ph NHBoc 324 a; R = Me, 83% (S,R)-334 (S,R)-335 324 b; R = (CH2)4NHBoc, 78% 324 c; R = CH CONHTr, 90% 2 Scheme 103. 324 d; R = CH2STr, 80% 324 e; R = 4-t-BuOC6H4CH2, 90% 324 f; R = CH CO t-Bu, 80% 2 2 On the other hand, the reaction of enantiomerically pure a Scheme 99. -amino aldehyde (S,S)-328 obtained in ﬁve steps from N-Boc (S)-glutamic acid 327, with the ylide derived from ethyl 2-(diphenylphosphoryl)-acetate, produced the a,b-unsaturated c-amino ester (S,S)-329 in 75% yield (Scheme 101).148 O O O The reaction of the N-Cbz a-amino aldehydes (S)-330a–l with R 1. Ph3P R H OEt OEt the ylide obtained from benzyl 2-(diphenylphosphoryl)acetate, 2. HCl, Et2O NHTIPS NH2 afforded the N-Cbz a,b-unsaturated c-amino esters (S)-331a–l, 3. Na2CO3,CH2Cl2 (S)-325a-g (S)-326a-g; 98-99% e.e. which by catalytic hydrogenation of the double bond, produced 326a;R=Me,67% the c-substituted c-amino acids (S)-332a–l in 60–90% yield 326b;R=Pr,72% (Scheme 102).149 326c;R=(CH2)2SMe, 74% 326d;R=i-Bu, 73% The HWE reaction of N-Boc a-amino aldehyde (S,R)-333 with 326e; R = Bn, 77% methyl diethylphosphonoacetate and NaH, gave the N-Boc 326f ;R=CH2OBn, 75% a b c 326g;R=Ph,80% , -unsaturated -amino ester (S,R)-334 in 92% yield, which by catalytic hydrogenation of the double bond, afforded the N-Boc 150 Scheme 100. c-amino ester (S,R)-335 in 91% yield (Scheme 103). 1026 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

O O of ethyl ester in (R)-338 with KOH followed by the treatment with 3 steps Me Me c c H OEt (Boc)2O, afforded the N-Boc -substituted -amino acid (R)-339 in OTBS OH 83% yield. Under identical conditions, the (Z)-allyl alcohol 337 was (S)-336 (E)-337 transformed into N-Boc c-substituted c-amino acid (S)-339, useful 1. Cl CCN, DBU in the synthesis of other c-substituted c-amino acids 60% 3 2. xylene, Δ (Scheme 104). O O Regiospeciﬁc ring opening of epoxide (R)-340 obtained from Me 1. KOH Me hydrolytic kinetic resolution, with dimethylsulfonium methylide, OH OEt EtOH/H2O produced the allyl alcohol (R)-341 in 89% yield, which by reaction NHBoc NHTAc 2. (Boc)2O with NaN /Ph P in DMF, afforded the azide derivative (S)-342 in (R)-339 83% (R)-338 3 3 79% yield. Reduction of the azide function in (S)-342 with Ph3P fol- Me O O lowed by treatment with Ac2O, gave the N-Ac derivative (S)-343 in Me OH OH 86% yield. Cleavage of the 4-methoxybenzyl (PMB) group in (S)- OEt NHBoc 343 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) pro- (Z)-337 (S)-339 vided the alcohol (S)-344 in 93% yield, which by further oxidation with 2-iodoxybenzoic acid (IBX) followed by treatment with Scheme 104. NaClO2 and NaH2PO4, afforded the N-Ac (S)-Vigabatrin 345 in 77% yield. Finally, the hydrolysis of N-Ac bond in (S)-345 with

+ - hydrazine, produced the enantiomerically pure (S)-Vigabatrin 6 Me3S I 152 OPMB OPMB in 87% yield (Scheme 105). O n-BuLi, THF OH Tandem ring-opening decarboxylation of cyclopropane hemi- 89% (R)-340 (R)-341 malonate (S)-346 with NaN3/NH4Cl, produced the methyl c-phenyl c 79% NaN3/Ph3P -azidobutyrate (S)-347 in 78% yield and 90% enantiomeric excess DMF, CCl4 via a [3,3]-sigmatropic rearrangement, which by catalytic hydro- c c 1. Ph3P/THF/H2O genation, afforded the methyl -phenyl -aminobutyrate (S)- OPMB OPMB 153 2. Ac2O/Py 299c in 93% yield (Scheme 106). NHAc N 86% 3 Preparation of aldimine–borane adducts from nitriles followed (S)-343 (S)-342 by the allylboration is another method for the synthesis of chiral c c 93% DDQ, CH2Cl2 -substituted -amino acids. For example, the reduction of nitriles O 348a–d with Super-Hydride (LiBHEt3) at room temperature, 1. IBX, DMSO afforded the iminotriethylborates 349a–d, which by treatment OH OH 2. NaClO 2 with ()-B-allyldiisopinocampheylborane (Ipc2BAll) 350 followed NHAc NaH PO NHAc 2 4 by the oxidation with H O , gave the homoallylic amines (S)- (S)-344 77% (S)-345 2 2 351a–d in 79–90% yield and good enantiomeric excess. Hydrobora- N H .H O 87% 2 4 2 tion of (S)-351a–d using BH SMe and H O /NaOH, produced the THF/MeOH 3 2 2 2 d-amino alcohols (S)-352a–d in moderate yield, which by reaction O with (Boc)2O and subsequent oxidation with PDC, provided the N- OH Boc c-substituted c-amino acids (S)-353a–d in 70–72% yield and 154 NH2 84–99% enantiomeric excess (Scheme 107). (S)-Vigabatrin, 6 Silverman et al.155 reported the synthesis of new analogues of 98% e.e. 4-amino-5-ﬂuorohexanoic acids (4S,5S)-358 and (4S,5R)-361, which were tested as potential inactivators of c-aminobutyric acid Scheme 105. aminotransferase (GABA-AT). The synthesis starts with the ﬂuori- nation of hydroxyethyl c-lactone (R,R)-354 obtained from asym-

Ph N metric dihydroxylation/lactonization of ethyl hex-4-enoate, with 3 Ò CO2Me (diethylamino)difluorosulfonium tetrafluoroborate (XtalFluor-E ) NaN3,NH4Cl OMe Ph and DBU, to obtain the fluoroethyl c-lactone (R,S)-355 in 42% yield, CO H MeOCH2CH2OH 2 O 78% (S)-346 which by treatment with KOH and benzyl bromide, afforded the (S)-347; 90% e.e. H , 93% 2 Pd/C MeOH N H BEt3 N NH2 NH2 LiEt3BH 1. Ipc2BAll, 350 Et O OMe R 2 R 2. H2O2 R Ph H (S)-351a; 79%, 92% e.e. O 348a-d 349a;R=C6H5 (S)-351b; 86%, 94% e.e. (S)-299c 349b;R=4-MeC6H4 Me 349c;R=4-MeOC6H4 (S)-351c; 90%, 94% e.e. )2BAll 349d; R = 2-Thienyl (S)-351d; 82%, 99% e.e. Scheme 106. . 1. BH3 SMe2

2. NaOH, H2O2 lpc2BAll, 350 Talukdar et al.151 reported the synthesis of both enantiomers of c c NHBoc NH2 -unsaturated -amino acids (R)- and (S)-339 via the enantiodiver- 1. (Boc) O OH 2 OH gent [3,3]-sigmatropic rearrangement strategy. Thus, the reaction R 2. PDC R of (E)-allyl alcohol 337 obtained from aldehyde (S)-336, with O 70-72% (S)-352a; 75% (S)-352b; 66% trichloroacetonitrile (Cl3CCN) and DBU followed by the [3,3]-sig- (S)-353a-d c 84-99% e.e. (S)-352c; 71% matropic rearrangement, produced the N-TAc -amino ester (S)-352d; 55% (R)-338 in 60% yield and with excellent transfer of chirality of the parent hydroxyl group at the e-position. Finally, saponiﬁcation Scheme 107. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1027

O O CO Bn CO Et 2 2 O - O AD-Mix β [Et2N=SF2]BF4 1. KOH, MeOH HO HO F MsNH2 DBU, CH2Cl2 2. BnBr. DMF t-BuOH/H O H H 2 Me 42% Me 89% F Me Me 61% (R,R)-354 (R,S)-355 (4R,5S)-356

4-O NC H CO H DPPA, DIAD 94% 2 6 4 2 85% PPh ,THF DIAD, PPh3 3

O O CO2Bn O2N N O O 3 1. KOH, MeOH O HO 2. H SO ,THF 2 4 F Me H 72% H O Me Me (4S,5S)-357 (R,S)-360 (R,S)-359 H2,Pd/C 82% MeOH

CO2H

CO2H H2N

H2N F Me F Me (4S,5S)-358 (4S,5R)-361

Scheme 108.

O O O O hydroxyethyl c-lactone (R,S)-360 in 72% yield. Under identical con- SOCl2, BtH ditions, the c-lactone (R,S)-360 was transformed into 4-amino-5- MeO OH MeO Bt CH2Cl2 ﬂuorohexanoic acid (4S,5R)-361 (Scheme 108). The same authors NHTFA 93% NHTFA (S)-362 (S)-363 reported the synthesis of 4-amino-5-ﬂuorohexanoic acid (4R,5R)- 358. ArH TiCl4,CH2Cl2 Starting from (S)-glutamic acid and using the chiral pool methodology, of course doing stereocontrolled transformations it O O O is possible to obtain the desired enantiopure c-substituted c- Et3SiH/TFA MeO Ar MeO Ar amino acids. For example, reaction of N-TFA-aspartic monoester NHTFA NHTFA (S)-362 with SOCl2 and benzotriazole (BtH), afforded the N-TFA- (S)-365a,b (S)-364 Asp(OMe)-Bt (S)-363 in 93% yield, which by reaction with aromatic 365a;Ar=2,4-(MeO) C H ,84% 364a; Ar = 2,4-(MeO)2C6H3,46% 2 6 3 derivatives in the presence of TiCl4 at 20 °C, gave the d-keto-c- 365b; Ar = 2,4,6-(MeO)3C6H2,88% 364b; Ar = 2,4,6-(MeO)3C6H2,46% 364c; Ar = Indol-3-yl, 70% amino esters (S)-364a–d in 46–70% yield. The reduction of the 364d; Ar = 1-Me-indol-3-yl, 59% ketone function in (S)-364a,b with triethylsilane in the presence c c NaBH4 of TFA, provided the -substituted -amino esters (S)-365a,b in

DMF/H2O 84% and 88% yield, respectively. On the other hand, the reduction of the ketone function in (S)-364c,d with sodium borohydride, pro- O duced the c-substituted c-amino acids (S)-366c,d in 87% and 73% HO Ar yield, respectively (Scheme 109).156 NHTFA Recently, Bihel et al.157 reported the selective ruthenium cat- (S)-366c,d alyzed reduction of the tertiary amide on the (S)-glutamic deriva- 366c; Ar = Indol-3-yl, 87% 366d; Ar = 1-Me-indol-3-yl, 73% tive 367 with Ru3(CO)12 and 1,1,3,3-tetramethyldisiloxane

Scheme 109. O O 4 steps OMs acyclic fluorinated alcohol (4R,5S)-356 in 89% yield. Reaction of HO OH O N (4R,5S)-356 with DPPA and diisopropyl azodicarboxylate (DIAD), NH2 H (S)-Glutamic acid (S)-369 gave the azide derivative (4S,5S)-357 in 85% yield, which by catalytic hydrogenation, produced the 4-amino-5-fluorohexanoic acid Ar-X-X-Ar NaBH4 (4S,5S)-358 in 82% yield and 92% enantiomeric excess. On the other THF/EtOH hand, reaction of hydroxyethyl c-lactone (R,R)-354 with 4- O 1. (Boc)2O/DMAP c Ar nitrobenzoic acid and DIAD/Ph3P, gave the -lactone-ester deriva- Et3N, CH2Cl2 X HO X O N Ar tive (R,S)-359 in 94% yield, which by saponification afforded the 2. LiOH, THF NHBoc H (S)-371a-f (S)-370a-f 371a;Ar=CH ,X=Se,70% 370a;Ar=C H ,X=Se,80% O O O 6 5 6 5 1. Ru3(CO)12 371b; Ar = 4-ClC6H4,X=Se,75% 370b; Ar = 4-ClC6H4,X=Se,75% TMDS, THF N Ot-Bu N OH 371c; Ar = C6H5,X=Te,72% 370c;Ar=C6H5,X=Te,75% 2. TFA, CH2Cl2 371d;Ar=4-ClCH ,X=Se,80% 370d;Ar=4-ClC H ,X=Se,73% NHFmoc NH .HCl 6 4 6 4 3. HCl, Et O 2 2 371e;Ar=C6H5,X=S,60% 370e; Ar = C6H5,X=S,75% (S)-367 84% (S)-368 371f; Ar = 4-ClC6H4,X=S,84% 370f; Ar = 4-ClC6H4,X=S,69%

Scheme 110. Scheme 111. 1028 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

(TMDS) followed by the cleavage of the O-t-Bu and N-Fmoc bonds O ω-TAPO, Tris/HCl NH with TFA and HCl, obtaining the c-substituted c-amino acid (S)- OH (S)-MBA, PLP 2 R OH iso-octane, 37 oC 368 in 84% yield (Scheme 110). O R Braga et al.158 reported the synthesis of new chiral seleno-, tel- 376 67-100% conv. O luro- and thio-N-Boc c-amino acids from (S)-glutamic acid. Thus, (S)-295c and (S)-295e-i the reaction of mesylate derivative (S)-369 obtained in 4 steps >99% e.e (S)-295c; R = C H from (S)-glutamic acid, with the organoselenium anions generated 6 5 (S)-295e; R = 4-FC6H4 through the reaction of diphenyl diselenide and NaBH4, gave the (S)-295f; R = 4-MeC6H4 seleno-c-lactams (S)-370a,b in 80% and 75% yield, respectively. (S)-295g; R = 4-MeOC6H4 (S)-295h; R = 2,4-(Me) C H In the same way, the teluro- and thio-c-lactams (S)-370c,f were 2 6 3 (S)-295i; R = 2,5-(MeO)2 C6H3 obtained in good yields. The protection of the c-lactams (S)-

370a–f with (Boc)2O in the presence of Et3N/DMAP and subsequent Scheme 114. hydrolysis with LiOH, gave the N-Boc c-substituted c-amino acids (S)-371a–f in 60–84% yield (Scheme 111). c Reaction of the diprotected (S)-glutamic acid 372 with ethyl polysubstituted -amino acids with biological interest. In this context, the c-amino acids have been classified depending on the chloroformate followed by the reduction with NaBH4, gave the alcohol (S)-373 in 83% yield, which by reaction with thioacetic acid number and position of the substituents. and Ph3P/DIAD, afforded the thioacetate (S)-374 in 84% yield. a b c Finally, the cleavage of the protecting groups in (S)-374 with HCl, 2.5.1. , -Disubstituted -amino acids b c produced the (S)-4-Amino-5-mercaptopentanoic acid (S)-375 in Enantiomerically pure -hydroxy- -amino acids can be 98% yield (Scheme 112).159 obtained from aldol condensations. For example, the aldol reaction Yun et al.160 reported the enzymatic resolution of c-substituted of the chiral oxazolidinone (R)-377 with n-dibutylboron triflate (n- c-amino acids (±)-295c and (±)-295e-i using x-transaminase from Bu2BOTf) and Et3N followed by the addition of N(Me)Boc glycinal Polaromonas sp. (x-TAPO) and x-transaminase from Burkholderia and subsequent cleavage of the chiral auxiliary with LiOH/H2O2, a b c graminis (x-TABG) in 2-amino-2-(hydroxymethyl)-1,3-propane- afforded the N(Me)Boc -methyl- -hydroxy- -amino acid diol/HCl buffer, obtaining the c-substituted c-amino acids (R)- (2R,3R)-378 in 82% yield and 99:1 diastereoisomeric ratio. On the 295c and (R)-295e–i in excellent conversion and >99% enan- other hand, the reaction of the norephedrine propionate derivative tiomeric excess (Scheme 113). (1R,2S)-379 with dicyclohexylboron triflate (Cy2BOTf) and Et3N fol- On the other hand, bioreduction of c-keto acids using x-TAPO lowed by the addition of N(Me)Boc glycinal and subsequent in Tris/HCl buffer, pyridoxal phosphate (PDP) and (S)-a-MBA, pro- saponification of the chiral ester with NaOH/H2O2, gave the N a b c duced the enantiomerically pure (S)-c-amino acids 295c and (Me)Boc -methyl- -hydroxy- -amino acid (2R,3S)-380 in 99% 161 295e–i in excellent conversion (Scheme 114).160 yield and 90:10 diastereoisomeric ratio (Scheme 115). Very recently Yuan et al.162 reported the diastereoselective syn- a b c 2.5. Polysubstituted c-amino acids thesis of ethyl , -diphenyl -amino butyrate (2R,3S)-384. The Michael addition of phenylacetyl phosphonate 381 to nitrostyrene With the group of acyclic compounds and combining properly (E)-116c catalyzed by chiral bifunctional amine-thiourea 382 fol- c the different strategies described below it is possible to obtain lowed by treatment with DBU/EtOH, afforded the -nitro ester (2R,3S)-383 in 72% yield and 94% enantiomeric excess, which by

reduction of the nitro group with NaBH4/NiCl2, furnished the ethyl a,b-diphenyl c-amino butyrate (2R,3S)-384 in 92% enantiomeric HO CO2H excess (Scheme 116). OBn 1. ClCO2Et, Et3N OBn Hunter et al.163 described the stereoselective synthesis of a,b- BocHN BocHN 2. NaBH4,H2O/THF c O O difluoro -amino acids (2R,3R)-390 and (2R,3S)-394. For this pur- 83% (S)-372 (S)-373 pose, they initially carried out the Sharpless asymmetric dihydrox- AcSH ylation of cinnamyl bromide followed by the reaction with 84% Ph3P, DIAD potassium phthalimide, obtaining the diol (S,S)-385 in 56% yield and 98% enantiomeric excess. Reaction of diol (S,S)-385 with thio- HS AcS nyl chloride followed by the oxidation with NaIO4/RuCl3, gave the OH HCl OBn . cyclic sulfate (S,S)-386 in 92% yield, which by ring-opening with HCl H2N 98% BocHN O O TBAF and subsequent treatment with H2SO4, afforded the fluorohy- (S)-375 (S)-374 drin (R,S)-387 in 66% yield. Reaction of (R,S)-387 with the Deoxo- FluorTM reagent, produced the difluoro derivative (R,R)-388 in 21% Scheme 112.

O OH Me ω ω O O 1. n-Bu2BOTf, Et3N NH2 -TAPO or -TABG NH2 2. BocMeNCH CHO N OH Tris/HCl 2 Boc OH ON HO R DMSO, PLP R 3. LiOH/H2O2 Me Me O THF/H2O 46-50% conv. O Bn 82% (2R,3R)-378, 99:1 d.r. (±)-295c and (±)-295d-i (R)-295c and (R)-295d-i (R)-377 >99% e.e (R)-295c;R=CH Me 6 5 Ph O 1. Cy2BOTf, Et3N O OH (R)-295d;R=4-FC6H4 Me 2. BocMeNCH2CHO N (R)-295e;R=4-MeCH O HO Boc 6 4 3. NaOH/H O (R)-295f;R=4-MeOCH 2 2 6 4 N Me t-BuOH/MeOH Me Me Mes (R)-295h;R=2,4-(Me)2C6H3 99% (2R,3S)-380, 90:10 d.r. (R)-295i;R=2,5-(MeO)2C6H3 (1R,2S)-379

Scheme 113. Scheme 115. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1029

NO 2 Boc Boc O Ph Ph CO2Et N 1. LiHMDS (E)-116c Bn O o Bn N O (MeO)2P THF, -78 C Ph 1. 382 (20 mol%) NO2 2. MeI O Ph 2. DBU/EtOH (5R)-395 24% Me 381 72% (2R,3S)-383; 94% e.e. (3S,5R)-396; 12:1 d.r.

NaBH4,NiCl2 CF3 MeOH 75% LiOH S O O F C N Ph CO2Et 3 N BocHN H H N N NH OH H 2 Ph Bn MeO Me (2R,3S)-384; 92% e.e. (2S,4R)-397; 100 e.e. N

382 Scheme 118.

Scheme 116. ically pure N-Boc a,c-disubstituted c-amino acid (2S,4R)-397 in yield as a single diastereoisomer, which by oxidation of the phenyl 75% yield, an intermediate in the synthesis of Tubulysin analogues 164 group with NaIO /RuCl , furnished the N-protected a,b-difluoro c- (Scheme 118). 4 3 a c c amino acid (2R,3R)-389 in 72% yield. Cleavage of the phthalimide Diastereoisomerically enriched , -disubstituted -amino acids group in (2R,3R)-389 with hydrazine followed by treatment with have also been obtained by ring-opening of enantiopure chiral HCl, provided the a,b-difluoro c-amino acid (2R,3R)-390 as the aziridines with enolates. For example, the ring-opening of com- hydrochloride in 95% yield. On the other hand, the reaction of diol mercially available (S)-N-tosyl-2-benzylaziridine 399, with the (S,S)-385 with trifluoromethanesulfonic anhydride/DABCO, gave propanoyl anion derived from pseudoephedrine (1S,2S)-398, pro- c 0 0 the epoxide (S,R)-391 in 67% yield and with high enantiomeric pur- duced the -amino amide (2S,4R,1 S,2 S)-400 in 86% yield and ity, which by ring-opening with HF/Et N, afforded the fluorohydrin 81:19 diastereoisomeric ratio. Hydrolysis of diastereoisomeric 3 0 0 a c (R,R)-392 in 67% yield. Finally, the reaction of fluorohydrin (R,R)- pure (2S,4R,1 S,2 S)-400 with 4 M H2SO4, gave the N-tosyl , -dis- c 392 with Deoxo-FluorTM, afforded the difluoro derivative (R,S)-393 ubstituted -amino acid (2S,4R)-401 in 91% yield, which by ester- in 51% yield, which under identical conditions described for the ification with MeOH/HCl followed by N-protection with (Boc)2O, c synthesis of (2R,3R)-390, was transformed into a,b-difluoro c- afforded the -amino ester (2S,4R)-402 in 85% yield. Finally, the amino acid (2R,3S)-394 as the hydrochloride (Scheme 117). cleavage of the N-tosyl in (2S,4R)-402 with Mg in MeOH and the cleavage of the N-Boc with 4 M HCl, furnished the a,c-disubsti- c 2.5.2. a,c-Disubstituted c-amino acids tuted -amino ester (2S,4R)-403 as the hydrochloride in 70% yield, Reaction of the N-Boc 5-benzyl c-lactam (R)-395 with lithium which is an intermediate in the synthesis of the Tubulysin U 165 hexamethyldisilazide (LiHMDS) in THF at 78 °C followed by the (Scheme 119). addition of MeI, afforded the 3,5-dialkylated c-lactam (3S,5R)- In a similar way, the regioselective ring-opening of enantiopure 396 in 24% yield and 12:1 diastereoisomeric ratio, which by sepa- chiral N-nosyl and N-trifluoromethanesulfonyl aziridines (S)-404 ration and subsequent hydrolysis with LiOH, gave the enantiomer- with the enolates derived from cyclopentanone, indanone, tetra-

O O α OH 1. AD-mix , t-BuOH S MeSO NH 1. SOCl2,Py O O Ph Br 2 2 Ph NPhth o 2. PhthNK/DMF, 80 C 2. NaIO4,RuCl3 OH 56% 92% Ph NPhth (S,S)-385, 98% e.e. (S,S)-386 (CF3SO2)2O 67% 1. TBAF, THF/MeCN DABCO, CH2Cl2 66% 2. H2SO4,H2O/THF F O HF, Et3N F Ph NPhth 67% Ph NPhth OH Ph NPhth (R,R)-392 (S,R)-391 OH 51% Deoxo-Fluor TM (R,S)-387 21% Deoxo-FluorTM F

F Ph NPhth F HO NaIO4 F NPhth Ph NPhth (R,S)-393 RuCl3 O F F 72% (2R,3R)-389 (R,R)-388

1. H NNH ,H O 95% 2 2 2 F 2. HCl, H2O HO . NH2 HCl F O F HO . (2R,3S)-394 NH2 HCl O F (2R,3R)-390

Scheme 117. 1030 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

Me OH TsHN Me Me OH BnO BnO N 1. LDA, LiCl/THF 1 N 1' 1. TEMPO Ph S S Ph Me Bn Bn R S O Me O O Me OH OEt Me 2. Ph3P 2. N Ts BocHN OEt BocHN (1S,2S)-398 (2S,4R,1'S,2'S)-400 (S)-399 Me O 86%, 81:19 d.r. (S)-406 (S)-407, 44% /C 4MH2SO4 91% , Pd Δ 2 dioxane, H OH Me % Boc 7 Ts 7 N Me TsHN Me OMe 1. MeOH, HCl OH BnO BnO Bn 2. (Boc)2O, DMAP Bn O 85% O Me Me (2S,4R)-402 (2S,4R)-401 OEt + OEt BocHN BocHN 1. Mg, MeOH 70% O O 2. 4 N HCl, dioxane (2S,4R)-408 2.5 : 1.0 (2R,4R)-409

. HCl H2N Me 1. LiOH, THF/H2O OMe 2. HCl, AcOEt/H2O Bn O BnO BnO (2S,4R)-403 Me Me OH OH Scheme 119. . . HCl H2N HCl H2N O O lone, c-lactams and succinimides 27 in the presence of 29 as a PTC (2S,4R)-410 (2R,4R)-411 agent, afforded the diprotected a,a,c-trisubstituted c-amino esters Scheme 121. 405a–h in good yields and with moderate to good diastereoisomeric ratio, derived from matched stereocontrol (Scheme 120).31 produced the N-protected a,c-disubstituted c-amino esters Wessjohann et al.166 reported the diastereoselective synthesis 415a–g in 1.0:1.3 to 13:1.0 diastereoisomeric ratio of a,c-disubstituted c-amino acids (2S,4R)-410 and (2R,4R)-411 (Scheme 122).167 as key intermediates in the preparation of Tubulysin B. Thus, the The Ireland-Claisen rearrangement is another key step in the oxidation of the commercially available N,O-diprotected tyrosinol synthesis of a,c-disubstituted c-amino esters 421a–c, which are (S)-406 with TEMPO followed by the Wittig-Horner reaction, intermediates in the synthesis of the highly antitumor-active afforded the N-Boc a,b-unsaturated c-amino ester (S)-407 in 44% Tubulysins. For example, Becker and Kazmaier,168 carried out the yield, which by catalytic hydrogenation of the double bond, gave Ireland-Claisen rearrangement of allylic esters 417a–c obtained the N-Boc a,c-disubstituted c-amino esters (2S,4R)-408 and from resolution and esteriﬁcation of racemic allyl alcohols (±)- (2R,4R)-409 in 77% yield and 2.5:1.0 diastereoisomeric ratio. 416, using LDA/TMSCl, to obtain the a,b-disubstituted b-amino Saponiﬁcation of the ethyl ester and cleavage of N-Boc bond in acids 418a–c in excellent yield, which by decarboxylation using (2S,4R)-408 and (2R,4R)-409, furnished after separation the a,c- 2-mercaptopyridine N-oxide and dicyclohexyl carbodiimide c disubstituted -amino acids (2S,4R)-410 and (2R,4R)-411 as the (DCC) followed by the radical reaction using BEt3 and t-BuSH, gave hydrochlorides (Scheme 121). the amines (2R,4S)-419a–c in 78% to 93% yield. Diprotection of the

On the other hand, the reduction of the Weinreb amides (S)- amine in (2R,4S)-419a–c with (Boc)2O/n-BuLi, afforded the N(Boc)2 412a–g with diisobutylaluminium hydride (DIBAL-H) followed by amines (2R,4S)-420a–c in good yield, which by oxidative cleavage a b the Wittig-Horner oleﬁnation, produced the N-protected , - of the double bond by ozonolysis, furnished the N(Boc)2 a,c-disub- unsaturated c-amino esters (S)-413a–g, which by catalytic asym- stituted c-amino esters (2S,4R)-421a,b and (2R,4R)-421c in good metric hydrogenation of the double bond mediated by (S)-414, yield and excellent diastereoisomeric ratio (Scheme 123).

O O O O 29 (10 mol%) OR OR + N GP Cs2CO 3 R 0-25 ºC 27 R' NHP (S)-404 405a-h R= Me,i-Pr GP = protecting group

O O O O O O O O

Ot-Bu Ot-Bu Ot-Bu Ot-Bu

NHTf NHNs NHNs NHTf

405a; 91%, 24:1 d.r. 405b; 78%, 30:1 d.r. 405c; 87%, 30:1 d.r. 405d; 88%, 30:1 d.r.

O O O O O O O Ts Ph Bu OEt N Ot-Bu N Ot-Bu N Ot-Bu

O O NHTf NHTf NHTf NHTf

405e; 84%, 10:1 d.r. 405f; 95%, 9:1 d.r. 405g; 75%, 9:2 d.r. 405h; 72%, 9:2 d.r.

Scheme 120. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1031

R Me R Me 1. DIBAL, CH2Cl2 GP N GP OMe N OMe O N 2. Ph3P H O OEt H O (S)-412a-g Me (S)-413a-g H ,(S)-414 + 2 CH2Cl2 i-Pr i-Pr (COD) R Me N Ir GP OMe N N O N H O (S)-414 415a-g

R Me Bn Me Me Me 5 GP OMe GP OMe Me N N GP OMe H O H O N 4 O (2R,4R):(2S,4R) (2R,4R):(2S,4R) H (2R,4R,5S):(2S,4R,5S) 415a; GP = Boc, R = 4-t-BuOC6H4,4.7:1.0 415c; GP = Fmoc, 4.4:1.0 415f; GP = Ns, 13:1.0 415b;GP=Phth,R=4-HOC6H4,1.0:1.3 415d;GP=Boc,4.1:1.0 415e; GP = Phth, 1.0:1.4 415g; GP = Phth, 1.0:2.9

Scheme 122.

Bn O OH 1. Novozym 435 NHBoc NHBoc vinylacetate BF K BocHN O H 3 R Me 2. DCC/DMAP TBAI (±)-416a-c Et2O,0oCtor.t. R Me O CH2Cl2/H2O OH Bn O 417a-c (S)-321a 93% (3S,4R)-427;>98:2d.r. BocHN OH LDA, TMSCl Me2SO4 o 80% HS THF, -78 C NaH/H2O

Me Me Bn R O N Bn R Boc Boc N N DCC/DMAP BocHN Me BocHN Me OH RuO2/H2O t-BuSH, BEt3,THF CO2H AcCN/CCl4 (2R,4S)-419a;R=Me,85% OMe O OMe 83% (2R,4S)-419b;R=Et,93% 418a;R=Me,93% (3R,4S)-429 (3S,4R)-428 (2R,4S)-419c; R = TBSOCH2,78% 418b; R=Et,91% 418c; R=TBSOCH2,93% NHBoc Boc Me 1. n-BuLi, THF N 2. (Boc)2O H OH O Bn R Bn R OMe O (2S,3R)-321d O3, NaOH, MeOH OMe (3R,4S,5R)-430 (Boc)2N Me (Boc)2N CH Cl ,-78oC 2 2 O (2R,4S)-420a;R=Me,88% (2S,4R)-421a;R=Me,82%,>97:3d.r. Scheme 124. (2R,4S)-420b;R=Et,83% (2S,4R)-421b; R = Et, 79%, >99:1 d.r. (2R,4S)-420c; R = TBSOCH2, 86% (2R,4R)-421c; R = TBSOCH2,81%,>98:2d.r.

Scheme 123. (Dil) 425 and Dolaproine (Dap) 426 (Fig. 2) are essential compo- nents of several natural and synthetic compounds. These key struc- tural units are found in molecules showing several types of OH O OH O pharmacological activities including protease inhibitors, antibacte- OH OH rial and antineoplastic agents and as anticancer drugs, therefore NH2 NH2 several methods for their synthesis have been reported. Statine, 422 Norstatine, 423 In this context, Stefani et al.169 carried out the 1,2-addition reac- OH O OMe O tion of potassium allyltriﬂuoroborate salt to N-Boc (S)-valinal 321a in the presence of n-tetrabutylammonium iodide (TBAI) as a PTC OH OH NHMe agent, to obtain the aminoalcohol (3S,4R)-427 in 93% yield and NH2 Isostatine, 424 Dolaisoleucine (Dil), 425 >98:2 diastereoisomeric ratio, which by N,O-dimethylation using NaH/Me2SO4, afforded the dimethylated product (3S,4R)-428 in OH 80% yield. Finally, the oxidative cleavage of the double bond in N (3S,4R)-428 with RuO2, produced the N-Boc 3-methoxy-5- H OMe O methyl-4-(methylamino)hexanoic acid (3R,4S)-429 in 83% yield. Dolaproine (Dap), 426 In a similar way, the N-Boc L-allo-isoleucinal (2S,3R)-321d was Figure 2. Structure of some b-hydroxy-c-amino acids. transformed into N-Boc dolaisoleucine derivative (3R,4S,5R)-430 in 80% and (Scheme 124). On the other hand, reaction of the (S)-valinal derivative 431a 2.5.3. b,c-Disubstituted c-amino acids with the lithium enolate of t-BuOAc, produced the tert-butyl b- The b-hydroxy-c-alkyl-c-amino acids also called statines, such hydroxyhexanoates 432 in 5:4 diastereoisomeric ratio, which after as the Statine 422, Norstatine 423, Isostatine 424, Dolaisoleucine puriﬁcation, afforded the diastereoisomerically pure (3R,4S)-432 in 1032 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

Cbz Me Cbz Me Identically, the reaction of a-chloroacetyloxazolidinone (S)-438 N N 1. t-BuOAc/LDA with the aldehyde (R)-444 and SmI2, produced the b-hydroxy H Ot-Bu THF,-78 oC derivative (R,S,R)-445 in 95% yield and >99% diastereoisomeric 2. Separation O 47% OH O ratio, which by cleavage of the chiral auxiliary with H2O2/LiOH, fur- (S)-431a (3R,4S)-432 nished the N-Boc b-hydroxy-c-amino acid derivative (3S,4R)-446 in 96%, which was used in the synthesis of Prepiscibactin BF4OMe3 87% 175 1,2-DCE (Scheme 129). Ruthenium-catalyzed asymmetric hydrogenation of N-Boc (S)- Cbz Me N b-keto-c-amino esters is also a key step for the synthesis of enan- Ot-Bu tiomerically pure dolaisoleucine (Dil). Thus, the catalytic hydro- Malevamide D genation of N-Boc b-keto-c-amino ester (4S,5S)-447 using the OMe O in situ generated [RuBr2((S)-SYNPHOS 448)] as catalyst, afforded (3R,4S)-433 the N-Boc b-hydroxy-c-amino ester (3R,4S,5S)-449 in quantitative Scheme 125. yield and 92:8 diastereoisomeric ratio, which by N,O-dimethylation using LiHMDS and MeOTf at 20 °C, gave the dimethylated compound (3R,4S,5S)-450 in 74% yield. Finally, the saponification 47% yield, which by O-methylation with trimethyloxonium of methyl ester in (3R,4S,5S)-450 with NaOH, produced the N-Boc tetrafluoroborate (BF4OMe3) in DCE, gave the N-Cbz protected Dolaisoleucine (Dil) 443 in 81% yield (Scheme 130).176 MMMAH tert-butyl ester (3R,4S)-433 in 87% yield, an intermediate Kim et al.177 reported the stereodivergent synthesis of both 170 in the synthesis of Malevamide D (Scheme 125). diastereoisomers of b-hydroxy-c-amino acids (3R,4S)-AHPPA 455 a The reaction of N-Boc -amino aldehydes (S)-321a–c with ethyl and (3S,4S)-AHPPA 458 via an intramolecular conjugate addition diazoacetate catalyzed by anhydrous tin(II) chloride in CH2Cl2, pro- and an intramolecular epoxidation key steps. Thus, the acetylation b c 171 vided the N-Boc -keto- -amino esters (S)-434a–c in 80% yield, of N-hydroxymethyl a,b-unsaturated c-amino methyl ester (E)-(S)- which by reduction of the ketone function with NaBH in THF at 4 451 obtained from N-Boc L-phenylalanine in three steps, followed 78 °C, afforded the N-Boc b-hydroxy-c-amino esters 435a-c in by the oxidation with H2O2 in the presence of p-toluenesulfonic 92–95% yield and from 64:36 to 68:32 diastereoisomeric ratio. In acid (PTSA) and MgSO4, gave the N-hydroperoxymethyl derivative a similar way, the N-Boc L-isoleucinal (2S,3S)-436 was transformed 452 in 98% yield, which by treatment with K CO in MeOH, pro- b c 2 3 into N-Boc -hydroxy- -amino ester 437 in good yield and 68:32 duced the epoxide (2R,3S,4S)-453 in 77% yield and >20:1 172 diastereoisomeric ratio (Scheme 126). diastereoisomeric ratio, derived from an intramolecular reaction. 173 Metal-catalyzed Reformatsky reactions between aldehydes Cleavage of N-hydroxymethyl group in (2R,3S,4S)-453 by oxidation a and compounds containing -halo carbonyls is another strategy with PDC followed by the treatment with K CO and MeOH, b c 2 3 for the synthesis of -hydroxy- -amino acids. For example, the afforded the epoxide (2R,3S,4S)-454 in 86% yield and 20:1 a reaction of the -chloroacetyloxazolidinone (R)-438 with N-Boc- diastereoisomeric ratio.178 Catalytic hydrogenation of epoxide in D-allo-isoleucinal (2R,3S)-321d catalyzed by SmI2, produced the (2R,3S,4S)-454 followed by the saponification, furnished the N- b -hydroxy derivative 439 in 76% yield, which by treatment under Boc b-hydroxy-c-amino acid (3R,4S)-AHPPA 455 in 55% yield. oxidative conditions (LiOH/H2O2), afforded the N-Boc isostatine Additionally, the reaction of N-hydroxymethyl a,b-unsaturated c- 174 440 in 85% yield and 3:1 diastereoisomeric ratio (Scheme 127). amino methyl ester (E)-(S)-451 with K CO in MeOH, provided a 2 3 In a similar way, the reaction of -chloroacetyloxazolidinone the trans-oxazolidine (3S,4S)-456 in 92% yield and 91% (S)-438 with the N-Boc N-methylisoleucinal (2S,3S)-441 and diastereoisomeric ratio, which by Ru-catalyzed oxidation with t- SmI2, produced the b-hydroxy derivative 442 in 86% yield, which BuO2H, gave the derivative (3S,4S)-457 in 77% yield and 91% by O-methylation with BF4OMe3 in the presence of proton sponge, diastereoisomeric ratio. Finally, cleavage of O-CHO bond with followed by oxidative cleavage of the chiral auxiliary with LiOH/ PTSA/MeOH followed by the saponification of the methyl ester in H2O2, furnished the N-Boc Dolaisoleucine (Dil) 443 in 95% yield (3S,4S)-457, produced the b-hydroxy-c-amino acid (3S,4S)-HPPA 174 (Scheme 128). 458 in 55% yield (Scheme 131). Michael addition of nitromethane to the a,b-unsaturated c-

NHBoc NHBoc amino esters (S)-322a–i and (S)-322b,d,m in the presence of b c c H N2CHCO2Et OEt DBU, produced the -nitromethane -alkyl -amino ester deriva- R R SnCl2, CH2Cl2 tives (3R,4S)-459a–l and (3S,4S)-460a–l in 72–92% yield and with O O O 80% 61:39 to 100:00 diastereoisomeric ratio, which are used in the syn- (S)-321a-c (S)-434a-c thesis of c-peptides foldamers (Scheme 132).179

NaBH4, THF -78 oC

NHBoc NHBoc OEt H NHBoc R N O OH O O (3R,4S):(3S,4S)-435a-c (2R,3S)-321d N O OH O O 435a ; R = i-Pr, 93%, 68:32 d.r. Cl SmI 2 439 435b ; R = i-Bu, 92%, 64:36 d.r. O O 76% 435c ; R = Bn, 95%, 65:35 d.r. (R)-438 85% LiOH, H2O2

NHBoc NHBoc NHBoc H OEt OH

O OH O OH O (2S,3S)-436 (3S,4S,5S):(3R,4S,5S)-437 N-Boc Isostatine, 440 68:32 d.r. 3:1 d.r.

Scheme 126. Scheme 127. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1033

Boc Me NHBoc NHBoc N RuBr -(S)-448 OEt 2 OEt H H2, EtOH O O O Boc Me O 100% OH N (2S,3S)-441 (4S,5S)-447 (3R,4S,5S)-449; 92:8 d.r. O N O N O Cl SmI 1. LiHMDS, HMPA 2 O PPh 86% THF, -78 oC 2 O O OH O O 74% O PPh 2. MeOTf, -20 oC 2 (S)-438 442 O 1. BF4OMe3 Boc Me Boc Me 82% proton sponge N N (S)-SYNPHOS 2. LiOH/H O 2 2 OH NaOH OEt 448 H O/EtOH Boc Me 2 O OMe O N OMe 81% OH N-Boc Dil, 443 (3R,4S,5S)-450

OMe O Scheme 130. N-Boc Dil, 443

Scheme 128. Boc 1. Ac O, DMAP Boc NOH 2 NOOH Et3N, CH2Cl2

The ring-opening reaction of the tetrahydrofurans (2S,3R,5S)- Bn CO2Me 2. H2O2,DME Bn CO2Me 462a,b obtained from (S)-phenylbutyrolactone (S)-461 in four (4S)-451 APTS, MgSO4 452 98% steps, with catalytic amounts of Zn(OTf)2 and acetic anhydride in 92% K2CO 3,MeOH 77% K2CO 3,MeOH toluene at reﬂux, produced the b-acetoxy esters (3S,4R)-463a,b in 60% and 90% yield, respectively. Oxidative cleavage of the double Boc Boc N O N OH bond in (3S,4R)-463a,b with OsO4/oxone, afforded the carboxylic acids 464a,b, which by reaction with DPPA/Et N followed by the Bn CO2Me Bn CO2Me 3 O (3S,4S)-456; 91% d.r. addition of benzyl alcohol, provided the N-Cbz b-acetoxy-c-amino (2R,3S,4S)-453; >20:1 d.r. ethyl esters (3S,4S)-465a,b in 99% and 67% yield, respectively 77% RuCl , t-BuO H 3 2 1. PDC, CH Cl (Scheme 133).180 86% 2 2 2. K2CO 3,MeOH Reaction of N-tosyl 4-aminocrotonate 466 with (2-nitrovinyl)- NHBoc NHBoc cyclohexane (E)-116d in the presence of catalytic amounts of Bn CO2Me

467, afforded the trisubstituted pyrrolidines (3S,4R,5S)-468 and OCHO Bn CO2Me (3R,4R,5S)-469 in 96% yield and 68:32 diastereoisomeric ratio with (3S,4S)-457; 91% d.r. O (2R,3S,4S)-454; 20:1 d.r. 92% and 36% enantiomeric excess, respectively. Catalytic hydro- 1. APTS, MeOH 55% 2. NaOH, H O 1. H ,Pd/C genation of the nitro group in (3S,4R,5S)-468 using Pd/C and HCO2- 2 55% 2 2. NaOH;H O NH , gave the conformationally restricted b,c-disubstituted c- 2 4 NHBoc 181 amino ester (3S,4R,5S)-470 in 60% yield (Scheme 134). OH NHBoc Bn OH Bn 2.5.4. a,b,c-Trisubstituted c-amino acids OH O (3S,4S)-458 OH O Chandrasekhar et al.182 reported the synthesis of the unusual c- (3R,4S)-455 amino acid (2R,3S,4R,5S)-476, which is part of the cyclic peptide Solomonamide A, a very powerful anti-inflammatory agent. For Scheme 131. this purpose, they carried out the Sharpless asymmetric dihydroxylation of (E)-isomer (3R,4R,5R)-471 with AD-mix-b to obtain the tive cleavage of PMB group using DDQ, produced the primary alco- diol (1R,2R,3S,4R,5R)-472 in 74% yield, which by a selective oxida- hol (2R,3S,4R,5R)-475 in 85% yield. Finally, treatment of 475 with tion of the benzylic hydroxy group with DMP in CH Cl , afforded bis(acetoxy)iodobenzene (BAIB) and TEMPO in MeCN, furnished 2 2 c the a-hydroxy ketone (2R,3S,4R,5R)-473 in 83% yield. The protec- the polysubstituted -amino acid (2R,3S,4R,5S)-476 in 78% yield tion of a-hydroxy group in 473 with TBSOTf/DIPEA, provided the (Scheme 135). b b silylated derivative (2R,3S,4R,5R)-474 in 76% yield, which by oxida- Conjugate addition of 3-phenylpropionaldehyde to -methyl- - nitrostyrene 477 catalyzed with the tripeptide 478, gave the c- nitroaldehyde (2R,3S,4R)-479 in 65% yield and 87:8:4:1 O diastereoisomeric ratio and 99% enantiomeric excess, which by c H oxidation with CrO3 produced the -nitro acid (2R,3S,4R)-480 in S N c Boc 98% yield. In the next step, the -nitro acid 480 was reacted with OH O O isobutylene and H2SO4 to obtain the tert-butyl c-nitro ester (R)-444 N O S N O (2R,3S,4R)-481 in 67% yield, which by reduction of the nitro group Cl SmI2 NBoc with Zn/AcOH, provided the tert-butyl c-amino ester (2R,3S,4R)- O 95% O 482 in 99% yield. Finally, the reaction of (2R,3S,4R)-482 with 9-flu- (S)-438 (R,S,R)-445; >99% d.r. orenylmethyl chloroformate (FmocCl) followed by treatment with LiOH TFA, afforded the N-Fmoc trisubstituted c-amino acid (2R,3S,4R)- 96% 183 THF,H2O 483 in 87% yield (Scheme 136). Proline-catalyzed a-amination of 3-phenylpropionaldehyde OH O with dibenzyl azodicarboxylate (DBnAD), produced the a- Prepiscibactin S OH aminoaldehyde (R)-484, which by olefination with triethyl phos- NBoc phonoacetate and LiCl/DBU, afforded the a,b-unsaturated c-amino

(3S,4R)-446 ester (R)-485 in 88% yield and 99% enantiomeric excess. Dihydrox- ylation of the double bond in (R)-485 with OsO4/NMO, gave the Scheme 129. aminodiol (2R,3S,4R)-486 in 92% yield, which by catalytic 1034 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

R Recently, Maillard et al.185 reported the synthesis of (S)-4-ami- OR' nomethyl-1,3-thiazole-5-carboxylic acids (ATCAs) 490a–k, which BocHN c O are considered as restricted heterocyclic -amino acids built (S)-322a-i;R'=Et around a thiazole ring and are valuable as design mimics of the (S)-331b,d,m;R'=Bn secondary structures of proteins such as helices, b-sheets, turns, MeNO b a 72-92% 2 and -hairpins. Initially, the N-Fmoc -amino acids (S)-488 were DBU treated with N,N0-carbonyldiimidazole (CDI) and DMAP followed R R by the reaction with the enolate generated from 1,1-dimethylallyl OR' + OR' b c BocHN BocHN acetate and LiHMDS, obtaining the -keto- -amino esters (S)-489 O O in 34–80% yield, derived of the cross-Claisen condensation. Bromi- O N O N 2 2 nation of (S)-489 with NBS in the presence of catalytic amounts of (3R,4S)-459a-l (major) (3S,4S)-460a-l (minor) Mg(ClO4)2 at 45 °C followed by the Hantzsch heterocyclization a;R=i-Pr, R' = Et, 90%, 89:11 d.r. g;R=CH2CO2t-Bu, R' = Et, 82%, 81:19 d.r. b;R=i-Bu, R' = Et, 86%, 82:18 d.r. h;R=Me,R'=Et,92%,80:20d.r. using primary thioamides, thiourea and thiosemicarbazones, pro- c; R = Bn, R' = Et, 88%, 80:20 d.r. i; R = Proline, R' = Et, 91%, 61:39 d.r. duced the ATCAs (S)-490a–k in 51–90% yield (Scheme 138). d;R=CH(Me)Et,R'=Et,89%,83:17d.r. j;R=i-Pr, R' = Bn, 80%, 86:14 d.r. Hunter et al.186 recently reported the diastereoselective synthe- e;R=CH2NHBoc, R' = Et, 87%, 90:10 d.r. k;R=i-Bu, R' = Bn, 79%, 81:19 d.r. f;R=CH2Ot-Bu, R' = Et, 84%, 100:0 d.r. l;R=Bn,R'=Bn,72%,89:11d.r. sis of the fluorostatines (2R,3R,4S)-494 and (2S,3R,4S)-496 using the organocatalytic electrophilic fluorination as a key step. For this Scheme 132. purpose, the chiral aldehyde (3S,4S)-491 obtained from L- leucine,187 was treated with N-fluorobenzenesulfonimide (NFSI) in the presence of catalytic amounts of the (R)-pyrrolidine 283 fol- CO2Et 4 steps lowed by the reduction with NaBH4, obtaining the fluorohydrin Ph O O Ph O derivative (2S,3R,4S)-492 in 64% yield and with >20:1 diastereoiso-

meric ratio, which by oxidation with NaIO4/RuCl3, afforded the a- (S)-461 R (2S,3R,5S)-462a,b fluoro-c-amino acid (2R,3R,4S)-493 in 78% yield. Finally, the cleavage of the acetal and N-Boc in (2R,3R,4S)-493 with 4 M HCl, gave Zn(OTf)2/Ac2O PhMe, Δ the fluorostatine (2R,3R,4S)-494 in quantitative yield. In a similar way, the fluorination of aldehyde (3S,4S)-491 catalyzed with (S)- R CO Et R CO2Et 2 283, furnished the fluorohydrin derivative (2R,3R,4S)-495 in 62% HO OsO4, oxone Ph yield and with 7:1 diastereoisomeric ratio, which under identical DMF a c O OAc OAc conditions was transformed into -fluoro- -amino acid 464a,b (3S,4R)-463a,b (2S,3R,5S)-496 (Scheme 139).

(PhO)2P(O)N3 a;R=Et,60% b; R=4-O NC H CH ,90% Et3N, BnOH 2 6 4 2 3. Stereoselective synthesis of cyclic c-amino acids

R CO2Et Cycloalkanes are used to induce conformational restriction of CbzHN many compounds with pharmacological interest.188 For example, OAc the ()-trans-2-aminomethylcyclopropanecarboxylic acid (TAMP- (3S,4S)-465a,b 497)or()-cis-2-aminomethylcyclopropanecarboxylic acid a;R=Et,99% (CAMP) 498, which are cyclopropane analogues of GABA and have b;R=4-O2NC6H4CH2,67% 189 been tested on GABAA and GABAC receptors. Additionally, the c- Scheme 133. amino acids 499–507 have been used as a key intermediates in the synthesis of a/c-, b/c- and c/c-peptides190 (Fig. 3).

3 hydrogenation over Ra-Ni followed by the reaction with acetic 3.1. Synthesis of Ca;b derivatives anhydride /Et3N/DMAP, provided the triacetate derivative (2R,3S,4R)-487 in 77% yield. This compound is a building block in Oikawa et. al.191 reported the enantioselective synthesis of ()- the synthesis of sphingosines (Scheme 137).184 trans-2-aminomethylcyclopropane-carboxylic acid ()-TAMP 497,

Ts EtO2C NO2 EtO2C NO2 N CO2Et 467 (10 mol%) H 466 + PhH, r.t. N N + 96% NO2 Ts Ts (3S,4R,5S)-468 68:32 (3R,4R,5S)-469 92% e.e. 36% e.e. (E)-116d Pd/C, HCO NH 60% 2 4 Et THF/EtOH OMe N EtO2C NH2 H N N N H S N Ts (3S,4R,5S)-470

F C 3 CF3 467

Scheme 134. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1035

Cbz H Cbz H NO2 N Me AD-mix β NO2 OH N Me OPMB MeSO2NH2 OPMB t-BuOH OTBS OTBS MeO 74% MeO OH (3R,4R,5R)-471 (1R,2R,3S,4R,5R)-472

83% DMP, CH2Cl2

Cbz H Cbz H NO2 O N Me NO2 O N Me OPMB TBSOTf OPMB

DIPEA/CH2Cl2 OTBS OTBS MeO TBSO 76% MeO OH (2R,3S,4R,5R)-474 (2R,3S,4R,5R)-473

85% DDQ, CH2Cl2

Cbz H Cbz H NO2 O N Me NO2 O N Me OH BAIB, MeCN TEMPO/Buffer CO2H OTBS TBSO OTBS MeO TBSO 78% MeO (2R,3S,4R,5R)-475 (2R,3S,4R,5S)-476

Scheme 135.

O Ph O Bn CbzHN Cbz O2N H O2N N Ph H H L-Proline 478(5 mol%) Bn H Me Me Bn DBnAD, MeCN Bn CHCl3, i-PrOH O 477 65% (2R,3S,4R)-479 O 87:8:4:1 d.r.; 99% e.e. (R)-484 O CrO O 98% 3 acetone 88% (EtO)2P H O OEt N LiCl, DBU, MeCN Ph Ph N OH O CbzHN Cbz CbzHN Cbz O2N CO2t-Bu O2N CO2H O N OH N H SO 2 4 N O OH Me Bn Me Bn H OEt OsO4,NMO OEt 67% 478 Bn Bn (2R,3S,4R)-481 (2R,3S,4R)-480 THF, H2O OH O 92% O Zn 99% (2R,3S,4R)-486 (R)-485; 99% e.e. AcOH/EtOAc

H2,Ra-Ni Ph 1. FmocCl Ph 77% O Ac2O, Et3N, DMAP NaHCO3 H2N CO2t-Bu FmocHN OH 2. TFA/CH2Cl2 AcHN Me Bn 87% Me Bn OAc OEt (2R,3S,4R)-482 R S R 483 (2 ,3 ,4 )- Bn OAc O Scheme 136. (2R,3S,4R)-487

Scheme 137. a partial agonist for GABA receptor. For this purpose, they carried out the cleavage of tert-butyl ester in (1R,2R)-509 obtained from cyclopropanation of L-menthyl acrylate 508, with TFA in CH2Cl2 tected c-amino acid (1R,2S)-515 in 44% yield, which by N-protec- followed by the reduction of carboxylic acid intermediate with tion with (Boc)2O/Et3N, afforded the triprotected c-amino acid BH3THF at room temperature, to obtain the alcohol (1R,2R)-510 (1R,2S)-516 in 89% yield. Finally, the cleavage of N-OBn bond in in 55% yield, which by reaction with phthalimide, DEAD and (1R,2S)-516 with Ra-Ni followed by the full deprotection with

Ph3P, produced the diprotected c-amino acid (1R,2R)-511 in 26% 6 M HCl, furnished the enantiomerically pure ()-CAMP 498 in yield and >99.5% diastereoisomeric excess after recrystallization. 85% yield (Scheme 141). Reaction of (1R,2R)-511 with hydrazine followed by the N-protec- Reaction of the bicyclic c-lactone (1R,5S)-517 obtained from tion with (Boc)2O and subsequent full deprotection with 6 M HCl, (R)-epichlorohydrin, with N,O-dimethylhydroxylamine hydrochlo- produced the ()-TAMP 497 as the hydrochloride in 76% yield ride and AlCl3/Et3N followed by the addition of triphenylmethyl (Scheme 140). chloride (TrCl) and pyridine in CH2Cl2, produced the Weinreb The same authors192 reported also the enantioselective synthe- amide (1R,2S)-518 in 77% yield, which by reductive desulfonyla- sis of ()-cis-2-aminomethyl-cyclopropanecarboxylic acid ()- tion with Mg in MeOH, gave the amide (1R,2R)-519 in 54% yield CAMP 498 from bicyclic c-lactone 512 obtained in four steps from and (1S,2R)-520 in 36% yield. Reduction of the Weinreb amide moi-

2-furaldehyde. Thus, the reaction of the bicyclic c-lactone 512 with ety in (1R,2R)-519 with LiAlH4 and NaBH4 followed by treatment O-benzylhydroxylamine hydrochloride, gave the oxime (1R,2S)- with PPh3/CBr4 and subsequent addition of NaN3 in DMF, afforded 513 in 88% yield, which by esteriﬁcation with TMSCHN2, produced the azide (1R,2R)-521 in 70% yield, which by catalytic hydrogena- the methyl ester (1R,2S)-514 in 94% yield. Reduction of the oxime tion using Pd/C in the presence of (Boc)2O, furnished the N-Boc function in (1R,2S)-514 with NaBH3CN/AcOH, produced the dipro- derivative (1R,2R)-522 in 89% yield. Cleavage of O–Tr bond in 1036 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

Me Me O Me Me O O 1. CDI, THF 1. NBS, Mg(ClO4)2 S FmocHN O O R OH O Me Me FmocHN 2. thioamide FmocHN 2. O EtOH, Δ N R Me O R (S)-488 R LiHMDS, THF (S)-489;34-80% (S)-490a-k Me Me O Me Me O Me Me O S S Me O O O S Me Me FmocHN FmocHN FmocHN N N N Me H R NHPbf N O (S)-490a;R=Me,69% (S)-490b;R=i-Bu, 81% NH Ot-Bu (S)-490c;R=Bn,75% (S)-490e; 70% (S)-490f; 70% (S)-490d;R=CH2(CH2)3NHBoc, 81%

Me Me O Me Me O Me Me O S S NHCbz O O O S NH Me FmocHN 2 FmocHN N N FmocHN N Me R Me (S)-490g;R=i-Bu, 85% BocN BocN (S)-490h; R = Bn, 90% (S)-490i;R=CH2(CH2)3NHBoc, 82%

(S)-490j;72% (S,R)-490k; 51%

Scheme 138.

OO O O O BocN 1. (R)-283 (5 mol%) BocN NaIO 4 BocN

H NFSI, MTBE OH RuCl3 OH 2. NaBH4 F 78% F (3S,4S)-491 64% (2S,3R,4S)-492; >20:1 d.r. (2R,3R,4S)-493

1. (S)-283 (5 mol%) 100% 4MHCl 62% NFSI, MTBE 2. NaBH 4 OH O H N OH O 2 OH O H2N BocN OH F OH F F (2R,3R,4S)-494 (2R,3R,4S)-495; 7:1 d.r. (2S,3R,4S)-496

Scheme 139.

O O OH H N OH H N H2N 2 H2N 2 OH OH O O (−)-TAMP, 497 (−)-CAMP, 498 (1S,2S)-499 (1R,2S)-500

O O O O H2N OH H2N H2N H2N OH OH OH

(1R,4S)-ACPECA, 502 (1S,3R)-CACP, 503 (1S,3S)-TACP, 504 (1R,2R)-AMCP, 501

O NH2 O H2N OH OH H2N OH O

(1S,2R)-505 (1S,2S)-506 (1S,3R)-507

Figure 3. Structure of some cyclic c-amino acids.

(1R,2R)-522 with AcOH followed by the oxidation with DMP and The allyl alcohol (S,S,R)-524 bearing the oxazolidin-2-one

NaClO2/NaH2PO4, gave the N-Boc c-amino acid (1R,2R)-523 in obtained by aldol condensation, was reacted under Furukawa- 194 84% yield, which by treatment with HCl/AcOEt, produced the con- modiﬁed Simmons-Smith cyclopropanation (Et2Zn/CH2I2), to formationally restricted ()-TAMP 497 as the hydrochloride in 89% obtain the cyclopropane-aldol product 525 in 92% yield and >95% yield. Under identical conditions, (1S,2R)-520 was transformed into diastereoisomeric excess, which by treatment with LiHMDS in ()-CAMP 498 as the hydrochloride (Scheme 142).193 toluene at 0 °C, gave the aldehyde (2S,3S)-526 in 92% yield, M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1037

O 1. Me(MeO)NH.HCl PhO2S PhO S OTr BrCH CO t-Bu 2 AlCl , Et N O OR 2 2 t-BuO OR 3 3 quinidine, MeCN 2. TrCl/Py O O Cs CO O N 3 3 O Me 508 77% OMe (1R,2R)-509 (1R,5S)-517 (1R,2S)-518 R = (1S,2S,5R)-menthyl Mg/MeOH 1. TFA, CH2Cl2 55% . 2. BH3 THF 1. LiAlH4, THF O 2. NaBH4, MeOH MeO NPhth OR PhthNH/DEAD N3 OTr N OTr HO OR 3. PPh3/CBr4 Ph3P, PhMe 4. NaN3, DMF Me O O 26% (1R,2R)-521 70% (1R,2R)-519, 54% (1R,2R)-511; >99.5% e.e. (1R,2R)-510

. H2, Pd/C 1. NH2NH2 H2O 89% (Boc)2O 76% 2. (Boc)2O, Et3N 3. 6 M HCl 1. 80% AcOH aq.

2. DMP, CH2Cl2 BocHN OTr BocHN OH . 3. NaClO2/NaH2PO4 HClH2N OH 84% O O (1R,2R)-522 (1R,2R)-523 (−)-TAMP, 497 89% HCl, AcOEt Scheme 140. . OH HClH2N

O . (−)-TAMP, 497 BnONH2 HCl N OH BnO Me O NaOH, EtOH/H2O RO O O 88% N OTr HCl.H N OH 512 (1R,2S)-513 MeO 2 R = (1S,2S,5R)-menthyl O 94% TMSCHN2 O MeOH (1S,2R)-520 (−)-CAMP, 498

Scheme 142. BnOHN OMe NaBH3CN N OMe BnO AcOH O O 44% (1R,2S)-515 (1R,2S)-514 O O OH O O OH Et Zn, CH I 3 2 2 OBn 89% (Boc)2O/Et3N OBn O N CH Cl O N MeOH 2 2 Me 92% Me Bn Bn Boc 1. Ra-Ni OH (S,S,R)-524; >95% d.e. (S,S,R)-525; >95% d.e. BnON OMe H2N LiHMDS (W-7), EtOH 92% o O 2. 6 M HCl O PhMe, 0 C (1R,2S)-516 85% (−)-CAMP; 498 O OBn OBn Scheme 141. Bn2NH Bn2N H NaBH(OAc)2 (2S,3S)-527 62% (2S,3S)-526 obtained by a retro-aldol reaction. The reductive amination of 1. HCO2H, Pd/C (2S,3S)-526 with dibenzylamine in the presence of sodium triace- 2. (Boc)2O, NaOH toxyborohydride, afforded the compound (2S,3S)-527 in 62% yield, Boc OH Boc OH which by hydrogenolysis using HCO2H and Pd/C in methanol fol- N Jones reagent N acetone lowed by the N-Boc protection, produced the N-Boc protected H H O 63% cyclopropane (2S,3S)-528 in 50% yield and the N-benzyl-N-Boc (2S,3S)-528; 50% (2S,3S)-530 derivative (2S,3S)-529 in 50% yield. Finally, the oxidation of the + alcohol group in (2S,3S)-528, furnished the N-Boc 2-amino- Boc OH N methyl-cyclopropanecarboxylic acid (2S,3S)-530 in 63% yield (Scheme 143).195 Bn Sartillo-Piscil et al.196 reported the synthesis of ()-CAMP 498 (2S,3S)-529; 50% from chiral N-allyl-a-bromoacetamide (S)-531 via a tandem 5- Scheme 143. exo-trig radical cyclization-bromine atom-transfer reaction. Thus, the reaction of chiral allylic bromoamide (S)-531 with BEt3 and . 197 BF3OEt2 in dry toluene at 78 °C, afforded the b-bromoethyl c-lac- Hansen et al. reported the synthesis of enantiomerically pure 0 0 tams (1 S,4S)-532 and (1 S,4R)-533 in 88% yield and 90:10 Milnacipran analogues (1R,2S)-537a–j, which were tested as inhi- 0 diastereoisomeric ratio. Treatment of (1 S,4S)-532 with t-BuOK in bitors of dopamine, serotonin and norepinephrine transporters. 0 THF, gave the bicyclic c-lactam (1 S,3R,4S)-534 in quantitative For this purpose, the reaction of enantiomerically enriched bicyclic yield, which by cleavage of methylbenzyl fragment under Birch c-lactones (1R,2S)-535a–j obtained from (S)-epichlorohydrin, with conditions followed by the hydrolysis, produced the enantiomeri- AlCl3 and Et2NH followed by the transformation of the hydroxy cally pure ( )-CAMP 498 in 88% yield (Scheme 144). group into a bromide by treatment with CBr4 and PPh3 and subse- 1038 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

Me Me Ph Ph Me 1' 1' Et2NH Et2N OH o Br Br BEt3,MeOH,-78 C Ph N Ph N AlCl + O O 3 Ph N . BF3 OEt2,PhMe 90% O Br O O (1S,2R)-535a 538 O 88% (1S,2R)- (1'S,4S)-532 90 : 10 (1'S,4R)-533 (S)-531 84% 1. SOCl2 98% t-BuOK, THF 2. PhthN-K+

Me Ph Ph H NOH 1' 2 Et2N NPhth Et2N NH 1. Li/NH3 Ph N 2 . OH 89% HCl H2N + 2. H3O O O O 88% (1S,2R)-539 O (1S,2R)-Milnacipran, 537a (−)-CAMP, 498 (1'S,3R,4S)-534 88% e.e.

Scheme 144. Scheme 146.

Ar 1. AlCl ,EtNH Ar 3 2 Ar - Ar N3 NEt2 1. PhthN K+/DMF Cl NPhth 2. CBr4, PPh3 2. SOCl , Δ O 3. NaN 2 O 3 O O O O 47-97% (1R,2S)-535a-j (1R,2S)-536a-j (1S,2R)-535j-p (1S,2R)-540a-g 1. H2,Pd/C Y 1. Et2NH, CH2Cl2 537a; Ar = C6H5, 97% 2. HCl, Et2O 2. H2NNH2,EtOH 537b; Ar = 4-ClC6H4, 75% F 537c; Ar = 3,4-(Cl) C H , 78% 2 6 3 Ar 537k; Y = O Ar . 537j 537d; Ar = 4-FC H , 65% HClH N NEt2 6 4 2 Ar= 537l; Y = S Et2N NH2 537e; Ar = 4-MeOC H , 58% 6 4 Y 537f; Ar = 1-Naphthyl, 78% O O O ()n 537g; Ar = 2-Naphthyl, 81% (1R,2S)-537a-j O (1S,2R)-537j-p 537h; Ar = 2-Thienyl, 60% 537m; Y = O 537o; n = 1 537i; Ar = 3-Thienyl, 93% 537n; Y = CH2 537p; n = 2 537j; Ar = 3-ClC6H4,11% Scheme 147. Scheme 145.

nished the enantiomerically pure ()-Dysibetaine CPa 546 in 80% quent reaction with sodium azide, afforded the azides (1R,2S)- yield. In a similar way, the dicarboxylic acid (1R,2R)-541 was trans- 536a–j in 47–97% yield, which by catalytic hydrogenation and sub- formed into (+)-Dysibetaine CPa 546 with high enantiomeric purity sequent hydrolysis with HCl, produced the c-amino amides (Scheme 148). (1R,2S)-537a–j as the hydrochlorides in 11–97% yield On the other hand, reaction of bromide (1R,2R)-547201 with (Scheme 145). NaN /TBAI in DMF, afforded the azide derivative (1R,2R)-548 in Additionally, the reaction of enantiomerically enriched bicyclic 3 82% yield, which by catalytic hydrogenation in the presence of c-lactone (1S,2R)-535a with AlCl3 and Et2NH, produced the amide- alcohol derivative (1S,2R)-538 in 90% yield, which by reaction with CO H CO2t-Bu SOCl followed by the nucleophilic substitution with potassium 2 2 2S 1S (Boc) O, DMAP phthalimide, afforded the derivative (1S,2R)-539 in 84% yield. MeO OH 2 MeO Ot-Bu Cleavage of the phthalimide function in (1S,2R)-539 with ethanola- t-BuOH 93% mine, gave the milnacipran (1S,2R)-537a in 89% yield and 88% O O O O (1R,2R)-542 enantiomeric excess (Scheme 146).198 (1S,2S)-541 84% LiOH On the other hand, the reaction of enantiomerically enriched MeOH, H2O bicyclic c-lactones (1S,2R)-535j–p with potassium phthalimide fol- CO2t-Bu CO2t-Bu lowed by treatment with SOCl2, afforded the N-protected c- chloroacyl derivatives (1S,2R)-540a–g, which by reaction with Et - 1. BH3.THF 2 HO Ot-Bu HO Ot-Bu NH and cleavage of the phthalimide function with hydrazine, gave 2. Chiral HPLC the c-amino amides (1S,2R)-537j–p analogues of Milnacipran, O 81% O O (1R,2R)-544; 100% e.e. (2R,3R)-543 which were tested as monoamine transporter inhibitors 199 (Scheme 147). 1. CBr4,PPh3 Oikawa, et al.200 reported the ﬁrst total enantioselective synthe- 53% 2. Me2NH, PhMe 3. Me2SO4/PhMe ses of ()- and (+)-Dysibetaine CPa 546 from dicarboxylic acid (1S,2S)- and (1R,2R)-541, respectively. Thus, the dicarboxylic acid - CO2t-Bu CO2H MeSO4 (1S,2S)-541 obtained in 4 steps from diethyl fumarate, was treated + 1. 6 M HCl + - Me3N Ot-Bu Me3N O with (Boc)2O/DMAP and t-BuOH to obtain the triester (1R,2R)-542 2. Dowex 1-X8 in 93% yield, which by saponiﬁcation of the methyl ester, afforded O 80% O the monocarboxylic acid (2R,3R)-543 in 84% yield. Selective reduc- (1R,2R)-545; 100% e.e. (-)-Dysibetaine CPa, 546 tion of the carboxylic acid in (2R,3R)-543 with BH THF, gave the 3 CO2H CO2H enantiopure alcohol (1R,2R)-544 in 81% yield, which by reaction 2R + HO 1R - with CBr4/PPh3 followed by the addition of Me2NH, and subse- OMe O NMe3 quent treatment with dimethyl sulfate, afforded the enantiomeri- O O O cally pure trimethyl ammonium salt (1R,2R)-545 in 53% yield. (1R,2R)-541 (+)-Dysibetaine CPa, 546 Finally, cleavage of the tert-butyl esters in (1R,2R)-545 with 6 M HCl followed by ion-exchange chromatography (Dowex 1-X8), fur- Scheme 148. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1039

CO2t-Bu CO2t-Bu afforded the amino-alcohol derivative (1S,2R)-555 in 95% yield,

NaN3,TBAI which by hydrogenolysis of the N-Bn bond using HCO2H/Pd fol- Ot-Bu Br Ot-Bu DMF N3 lowed by N-Boc protection and subsequent hydrogenolysis of the 82% O O chiral auxiliary fragment with Pd(OH)2/Pd, produced the N-Boc (1R,2R)-547 (1R,2R)-548 amino-alcohol (1S,2R)-556 in 53% yield. Finally, oxidation of the

H ,Pd(OH)/C alcohol function in (1S,2R)-556 with KMnO4 in t-BuOH, provided 69% 2 2 c (Boc)2O the conformationally restricted N-Boc -amino acid (1S,2R)-557 in 52% yield as a single enantiomer. In a similar way, the cyclo- CO H 2 CO2t-Bu propylamine (1S,2R)-554 was transformed into N-Boc c-amino + acid (1R,2S)-557 (Scheme 150). - 6MHCl H3N O BocHN Ot-Bu 94% Wittig reaction of the aldehyde (1R,2R)-558 with the ylide O O + obtained from Ph3P CH2OMeCl and sodium hexamethyldisilazide (1R,2R)-550 (1R,2R)-549 (NaHMDS) followed by the hydrolysis and subsequent reduction of the aldehyde generated with NaBH in MeOH, afforded the alcohol Scheme 149. 4 (1S,2R)-559 in 66% yield, which by O-benzylation with NaH/BnBr/ TBAI followed by the cleavage of the O-TBDPS bond with TBAF, (Boc) O, gave the N-Boc derivative (1R,2R)-549 in 69% yield. Full 2 gave the hydroxy derivative (1R,2S)-560 in 84% yield. Full oxida- deprotection of (1R,2R)-549 with 6 M HCl, furnished the N-(des- tion of the alcohol in (1R,2S)-560, produced the carboxylic acid methyl)dysibetaine (1R,2R)-550 in 94% yield (Scheme 149).200 (1R,2S)-561 in 97% yield, which by reaction with DPPA/Et3N and 3 subsequent treatment with t-BuOH, provided the N-Boc protected 3.2. Synthesis of C derivatives b;c derivative (1R,2S)-562 in 75% yield. Hydrogenolysis of the O-Bn in (1R,2S)-562 followed by the oxidation, furnished the N-Boc c- For the synthesis of N-Boc c-amino acids (1R,2S)- and (1S,2R)- amino acid (1S,2R)-557 in 91% yield, which by deprotection of 557, Aitken et al.202 carried out the reaction of the chiral for- the N-Boc group with HCl, gave the conformationally restricted mamide (R)-552 obtained in 91% from (R)-N-benzyl-a-methylben- c-amino acid (1S,2R)-563 as the hydrochloride in 76% yield. Under zylamine 551, with 3-butenyl magnesium bromide in the presence identical conditions the aldehyde (1S,2R)-564 was transformed of methyltitanium triisopropoxide, to obtain the cyclopropylami- into restricted c-amino acid (1R,2R)-565 as the hydrochloride nes (1R,2S)-553 and (1S,2R)-554 as principal products in 81% yield. (Scheme 151).193 Hydroboration of enantiomerically pure (1R,2S)-553 with 9-BBN,

MgBr H CHO Bn N Ph HCO H, Ac O N Ph Ph 2 2 N (R) Ph Bn (R) + o Bn CH2Cl2, 20 C MeTi(Oi-Pr)3 N Me Me o 91% THF, 0 C Bn Me Me (R)-551 (R)-552 81% (1R,2S)-553 (1S,2R)-554 1. 9-BBN, THF 95% 2. H2O2, NaOH

1. HCO H, Pd/C 2 O HO HO HO NHBoc KMnO4 2. (Boc)2O, NaOH Ph (R) HO O NHBoc t-BuOH NHBoc 3. H2, Pd(OH)2/C N 52% (1R,2S)-557 (1S,2R)-557 (1S,2R)-556 53% Bn Me (1S,2R)-555

Scheme 150.

O + - 1. Ph3P CH2OMeCl 1. NaH, BnBr, TBAI NaHMDS, THF HO DMF/THF, -10 oC BnO H o 2. HCl/THF, 0 C 2. Bu4NF, THF OTBDPS 3. NaBH4, THF/MeOH OTBDPS 84% OH (1R,2R)-558 (1S,2R)-559, 66% (1R,2S)-560

1. DMP, CH2Cl2 97% 2. NaClO2,NaH2PO4

1. H ,Pd/C,MeOH 2 1. DPPA/Et N HO 3 2. DMP, CH2Cl2 BnO CH Cl BnO 2 2 O NHBoc 3. NaClO ,NaH PO 2. t-BuOH, Δ O 2 2 4 NHBoc 91% (1R,2S)-562 75% OH (1S,2R)-557 (1R,2S)-561 76% HCl aq.

O HO H OTBDPS HO NH .HCl NH .HCl 2 O 2 O (1R,2R)-565 (1S,2R)-563 (1S,2R)-564

Scheme 151. 1040 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

1. DMP, CH2Cl2 2. NaClO/NaH PO O CO2Bn 2 4 CO2Bn 1. O3,AcOH O O t-BuOH/H2O 2. Na Cr O HO N3 2 2 7 HO 3. DPPA, Et3N H2SO4 Me (1S,2S,5R)-572 (1S,2S,5R)-573 53% (1R,3S)-566 (+)-3-carene 1. PhMe, Δ HCl/MeOH 2. HCl aq.

CO H O O O HCl.H N 2 m-CBPA 2 OAc MeO MeO CH2Cl2 (1S,2S,5R)-574 (1R,3S)-568 84% 80% overall yield (1R,3S)-567 1. K2CO3/MeOH 2. Na Cr O /H SO 2 2 7 2 4 CO2Bn . CO2H HCl H2N HO O O DPPA, Et N (1S,2R,5R)-575 (1S,2R,5R)-576 OH 3 MeO BnOH, PhMe MeO NHCbz 60% overall yield O (1R,3S)-570 (1S,3R)-569 Scheme 153. 1. NaOH, EtOH/H O 88% 2 2. H ,Pd/C,MeOH 2 yield. Finally, cleavage of the N-Boc in (1R,2S)-579 with TFA fol- + O lowed by ion-exchange Dowex-H , produced the conformationally restricted c-amino acid (1R,2S)-580 in 95% yield. Under identical HO NH2 conditions, the bicyclic c-lactam (1S,5R)-577 was transformed into (1R,3S)-571 conformationally restricted c-amino acid (1S,2R)-580 Scheme 152. (Scheme 154). On the other hand, the reaction of the N-Boc bicyclic c-lactam

(1R,5S)-578 with AlMe3/NH3 in CH2Cl2, produced the N-Boc c- The conformationally restricted c-amino acid (1R,3S)-571 ana- amino amide (1R,2S)-581 in 70% yield, which by hydrolysis with logue of GABA 1 is expected to be of interest as potential inhibitor 6 M NaOH in MeOH at reflux, afforded the N-Boc c-amino acid of GABA receptors, has been obtained from monoterpene (+)-3-car- (1S,2S)-582 in 92% yield, derived from an epimerization/hydrolysis ene. In this context, the ozonolysis of (+)-3-carene in acetic acid process. Finally, cleavage of the N-Boc in (1S,2S)-582 with TFA fol- + followed by the oxidation with Na2Cr2O7/H2SO4, afforded the keto- lowed by ion-exchange Dowex-H , gave the conformationally carboxylic acid (1R,3S)-566 in 53% yield, which by esterification restricted c-amino acid (1S,2S)-583 in 65% yield. Under identical with HCl in MeOH, gave the methyl ester (1R,3S)-567. Oxidation conditions, the N-Boc bicyclic c-lactam (1S,5R)-578 was trans- of (1R,3S)-567 with m-CPBA in CH2Cl2, afforded the acetoxy ester formed into conformationally restricted c-amino acid (1R,2R)- (1R,3S)-568 in 84% yield, which by hydrolysis of the acetoxy ester 583 (Scheme 155).205 with K2CO3/MeOH followed by oxidation with Na2Cr2O7/H2SO4, 4 furnished the carboxylic acid-methyl ester derivative (1S,3R)-569. 3.4. Synthesis of Cb;c derivatives Reaction of (1S,3R)-569 with DPPA/Et3N/BnOH, produced the N- Cbz c-amino ester (1R,3S)-570, which by saponification followed Aitken et al.206 reported a practical synthesis of conformation- by the cleavage of the N-Cbz by hydrogenolysis, provided the con- ally restricted (1S,2S)- and (1R,2R)-cis-(2-aminocyclobutyl)acetic formationally restricted c-amino acid (1R,3S)-571 in 88% yield acid 499 analogues of GABA 1. Thus, the reaction of (±)-cis-2- (Scheme 152).203 aminocyclobutanecarboxylic acid 584 with the (4S,5R)-4-methyl- Shuto et al.204 reported the synthesis of conformationally 5-phenyl-oxazolidin-2-one 585, produced the diastereoisomeric restricted GABA derivatives 574 and 576 with bicyclo[3.1.0]hex- mixture (1S,2S,40S,50R)-586 and (1R,2R,40S,50R)-587 in 40% and anes backbone as the first highly selective BGT-1 inhibitor. For this 45% yield, respectively. Removal of chiral auxiliary in diastereoiso- purpose, the oxidation of (1S,2S,5R)-572 obtained from (R)- merically pure (1S,2S,40S,50R)-586 and (1R,2R,40S,50R)-587 with epichlorohydrin, and subsequent reaction with DPPA/Et3NinCH2- Cl2, provided the benzyl ester-azide derivative (1S,2S,5R)-573, H O H O which by heating in toluene followed by the hydrolysis of benzyl Me 1. Na, NH3, t-BuOH ester with aqueous HCl, afforded the conformationally restricted N N Boc c-amino acid (1S,2S,5R)-574 in 80% overall yield. In a similar Ph 2. (Boc)2O, DMAP H way, the compound (1S,2R,5R)-575 was transformed into the con- 65% H (1R,5S)-577 (1R,5S)-578 formationally restricted c-amino acid (1S,2R,5R)-576 in 60% overall 1. LiOH, H O/THF 86% 2 (Scheme 153). + 2. H3O

4 O O 3.3. Synthesis of Ca;b derivatives

OH 1. TFA, CH2Cl2 OH Aitken et al.205 reported the synthesis of 2-(aminomethyl)cy- NH2 2. Dowex-H+ NHBoc 95% clobutane-1-carboxylic acids (1R,2S)-and (1S,2R)-580 from c-lac- (1R,2S)-580 (1R,2S)-579 tams (1R,5S)- and (1S,5R)-577 obtained from 1-[(S)-1- H O O phenylethyl]-1H-pyrrolidin-2(5H)-one. For this purpose, the Me OH reductive cleavage of the methylbenzyl fragment in (1R,2S)-577 N NH with Na/NH followed by the reaction with (Boc) O/DMAP, gave Ph 2 3 2 H (1S,2R)-580 the N-Boc bicyclic c-lactam (1R,5S)-578 in 65% yield, which by (1S,5R)-577 hydrolysis, afforded the N-Boc c-amino acid (1R,2S)-579 in 86% Scheme 154. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1041

O H O O 1. MeI, Cs2CO 3 CO2H AcHN CO2Me AlMe3,NH3 NH2 N Boc 2. NaN3,MsOH CH2Cl2 NHBoc Me 64% (1S,3R)-589 H 70% (-)-cis-pinononic acid (1R,2S)-581 (1R,5S)-578 91% 0.25 M NaOH 6MNaOH 92% MeOH, Δ

O O AcHN CO2H OH 1. TFA/CH2Cl2 OH NH2 2. Dowex-H+ NHBoc (1S,3R)-590 65% (1S,2S)-583 (1S,2S)-582 Scheme 157.

H O O OH N Boc NH2 O O O O 1. ClCO2Et H (1R,2R)-583 2. NaN3 (1S,5R)-578 Me OH Me 90% N3 (-)-cis-pinononic acid (1S,3R)-591 Scheme 155. 92% BnOH, Δ

O O O O NaOBr O O NHCbz NHCbz 5' 5' dioxane/H O Ph HO 2 Ph N 4' Me O OH O N 4' O (1R,3S)-593 80% 1. PivCl/Et3N (1S,3R)-592 o Me THF, 0 C Me + 2. n-BuLi Scheme 158. O NHBoc O NHBoc NHBoc Ph (±)-584 N (1S,2S,4'S,5'R)-586 (1R,2R,4'S,5'R)-587 H Me restricted N-Cbz c-amino acid (1R,3S)-593 in 80% yield LiOH, H2O2 (4S,5R)-585 207 THF/H2O (Scheme 158). Alternatively, the same authors207 carried out the esteriﬁcation O OH O OH of ()-cis-pinononic acid with tert-butyl 2,2,2-trichloroacetimidate (TBTA) followed by degradation of the methyl ketone with NaOBr, obtaining the acid-ester derivative (1S,3R)-594 in 54% yield, which NHBoc NHBoc by reaction with ethyl chloroformate and sodium azide and subse- (1S,2S)-588; 96% (1R,2R)-588; 100% quent addition of benzyl alcohol, produced the N-Cbz c-amino

1. TFA/CH2Cl2 ester (1S,3R)-595 in 88% yield. Cleavage of the tert-butyl protecting 2. Dowex-H+ group in (1S,3R)-595 with Et3SiH and TFA, afforded the N-Cbz c- c O OH O OH amino acid (1S,3R)-593 in 94% yield (Scheme 159). The -amino acids (1R,3S)- and (1S,3R)-593 have been used in the synthesis of hybrid cyclobutane-proline peptides.208

NH NH2 2 5 (1S,2S)-499; 83% (1R,2R)-499; 96% 3.6. Synthesis of Ca;b derivatives

209 Scheme 156. Gellman et al. reported the stereoselective synthesis of the c- amino acid (1R,2R)-2-aminomethyl-1-cyclopentane carboxylic acid (AMCP) 501 in multigram quantities and its incorporation in

H2O2/LiOH, afforded the N-Boc c-amino acids (1S,2S)- and (1R,2R)- a/c-peptides. For this purpose, the stereoselective Michael addi- 588 in excellent yields, which by cleavage of the N-Boc bond with tion of nitromethane to cyclopentene-1-carboxaldehyde 596 in TFA, gave the conformationally restricted c-amino acids (1S,2S)- the presence of catalytic amounts of (S)-12 and benzoic acid, fol- and (1R,2R)-499 in good yield (Scheme 156). lowed by reduction with NaBH4, gave the d-nitro alcohol (1R,2R)- 597 in 95% yield and >99% enantiomeric excess, which by reduc- 4 3.5. Synthesis of Ca;c derivatives tion of the nitro group by catalytic hydrogenation over Ra-Ni fol-

lowed by the protection with (Boc)2O/DIPEA and subsequent Esteriﬁcation of ()-cis-pinononic acid obtained from ()-ver- oxidation of the alcohol with H2Cr2O7, produced the conformation- 35 benone, with MeI and Cs2CO3 followed by the reaction with ally restricted (1R,2R)-c-amino acid AMCP 501 in 25% yield sodium azide and methanesulfonic acid (MsOH), afforded the N- (Scheme 160). Ac c-amino esther (1S,3R)-589 in 64% yield, which by saponiﬁca- Cascade organocatalytic asymmetric Michael addition and tion of the methyl ester with 0.25 M NaOH, gave the N-Boc 3- intramolecular alkylation has been developed for the synthesis of amino-2,2-dimethyl-1-carboxylic acid (1S,3R)-590 in 91% yield conformationally restricted c-amino acid trans-601. Thus, the (Scheme 157).207 Michael addition of propionaldehyde to iodo-nitroalkene 598 in On the other hand, the reaction of ()-cis-pinononic acid with the presence of catalytic amounts of (S)-12 and benzoic acid, ethyl chloroformate followed by addition of sodium azide, gave afforded the conformationally restricted c-nitro aldehydes trans- the acyl-azide derivative (1S,3R)-591 in 90% yield, which by reac- and cis-599 in 62% yield and 66:34 diastereoisomeric ratio and tion with benzyl alcohol, produced the N-Cbz c-amino ketone high enantioselectivity (trans: 94% e.e. and cis: 96% e.e.). Oxidation (1S,3R)-592 in 92% yield. Finally, the degradation of the methyl of the aldehyde group in enantiomerically pure trans-599, gave the ketone in (1S,3R)-592 with NaOBr, gave the conformationally conformationally restricted c-nitro acid trans-600 in 88% yield, 1042 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

H O O O O O O 1. Cl3CC(=NH)Ot-Bu N SOCl2 . HCl H2N 2. NaOBr MeOH OMe Me HO OH 54% Ot-Bu 95% (-)-cis-pinononic acid (1S,3R)-594 (1S,4R)-602 (1R,4S)-603

1. ClCO2Et 88% 2. NaN3 Scheme 162. 3. BnOH, Δ

O O Et3SiH, TFA aminocyclopentane carboxylic acid (1R,3S)-604 in 97% enan- CbzHN CbzHN CH2Cl2 tiomeric excess. Additionally, hydrolysis of the bicyclic c-lactam OH 94% Ot-Bu (1S,3R)-593 (1S,3R)-595 (±)-602 with HCl, followed by N-Boc protection and subsequent resolution with (R)-a-MBA, gave the N-Boc 4-aminocyclopent-2- Scheme 159. ene carboxylic acid (1S,4R)-605 in 70% yield, which by catalytic hydrogenation of the double bond using Pd/C, produced the N- Boc c-amino acid (1R,3S)-604 in 98% yield and 97% enantiomeric

O 1. (S)-12 (20 mol%) OH excess, which is used in the synthesis of peptides and foldamers 213 PhCO2H, EtOH (Scheme 163). CH NO H 3 2 Resolution of bicyclic c-lactam (±)-602 with (+)-c-lactamase, 2,4,6-collidine O2N 596 2. NaBH4,MeOH produced the 4-aminocyclopent-2-ene carboxylic acid ACPECA 95% (1R,2R)-597; >99% e.e (1R,4S)-502 and the bicyclic c-lactam (1R,4S)-602, whereas the 1. H2,Ra-Ni,MeOH resolution of (±)-602 using ()-c-lactamase, gave the 4-aminocy- 25% 2. (Boc) O/DIPEA 2 clopent-2-ene carboxylic acid ACPECA (1S,4R)-502 and the bicyclic 3. H2Cr2O7, acetone c-lactam (1S,4R)-602 with >99% enantiomeric excess O (Scheme 164).214 215 HO On the other hand, Forró and Fülöp reported a very efﬁcient H2N enzymatic method for the preparation of enantiomerically pure (1R,2R)-501 bicyclic c-lactams and c-amino acids. For example, the resolution of the bicyclic c-lactam (±)-602 with CAL-B lipase B from Candida Scheme 160. antarctica in H2O, gave 4-aminocyclopent-2-ene carboxylic acid ACPECA (1S,4R)-502 in 48% yield and 98% enantiomeric excess, and the bicyclic c-lactam (1S,4R)-602 in 46% yield and >99% enan- O tiomeric excess; whereas resolution of the bicyclic c-lactam (±)- Me O H 606, afforded the 3-aminocyclopentane carboxylic acid CACP I (S)-12 (20 mo%) H (1R,3S)-503 in 42% yield and 98% enantiomeric excess, and the PhCO H, DMSO Me NO 2 bicyclic c-lactam (1R,3S)-606 in 47% yield and >99% enantiomeric 2 62% 598 NO2 excess (Scheme 165). trans:cis-599 (36:34) The biocatalytic hydrolysis of racemic amino nitrile cis-(±)-607 NaClO2,KH2PO4 88% 2-butyl-2-butene using nitrilase NIT-106, afforded the cis-3-(toluene-4-sulfony- H2O/acetone O O

H2,Pd/C OH OH H O O 85% Me Me N 1. H2,Pd/C BocHN OH 2. HCl (10%) NH2 NO2 3. (Boc)2O/DIPEA trans-601 trans-600 (±)-602 78% (±)-604 1. HCl (10%) Scheme 161. (R)-α-MBA 70% 2. (Boc)2O, DIPEA, 3. (R)-α-MBA

O O which by catalytic hydrogenation of the nitro group using Pd/C, BocHN H2,Pd/C BocHN c 210 OH OH produced the -amino acid trans-601 in 85% yield (Scheme 161). 98% (1S,4R)-605 (1R,3S)-604; 97% e.e. 5 3.7. Synthesis of Ca;c derivatives Scheme 163. A very interesting review on the use of the 2-azabicyclo[2.2.1] hept-5-en-3-one (1R,4S)- and (1S,4R)-602 have recently appeared. In fact, all information concerning to the synthesis and the chem- O H O ical proﬁle of this synthetic building block (Vince lactam) and its N (+)-γ-lactamase H2N impact on the development of therapeutics has been reviewed.211 OH + H O In this context, the ring opening of commercially available bicyclic (1R,4S)-ACPECA, 502 c N (1R,4S)-602 -lactam (1S,4R)-602 with SOCl2 in MeOH, produced the methyl 4- >99% e.e. aminocyclopent-2-ene carboxylate (1R,4S)-603 as the hydrochloride in 95% yield (Scheme 162).212 (±)-602 O H O N H2N + On the other hand, catalytic hydrogenation of commercially (-)-γ-lactamase OH available bicyclic c-lactam (±)-602 followed by hydrolysis with (1S,4R)-ACPECA, 502 (1S,4R)-602 HCl and subsequent reaction with (Boc)2O/DIPEA, gave the N-Boc >99% e.e. 3-aminocyclopentane carboxylic acid cis-(±)-604 in 78% yield, which by resolution with (R)-a-MBA, produced the N-Boc 3- Scheme 164. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1043

H O O H O O O N N MeI/K CO H N BocHN 2 3 BocHN CAL-B 2 + OMe OH OH DMF H O 2 99% (1R,4S)-611a (±)-602 (1S,4R)-ACPECA, 502 (1S,4R)-602 (1R,4S)-605 46%, >99% e.e. 1. LHMDS, THF 48%, 98% e.e. 78% 2. i-PrI H H O O O N N O O CAL-B H2N OH + BocHN LiOH, H2O BocHN H O OH OMe 2 i-Pr THF/MeOH i-Pr (±)-606 (1R,3S)-CACP, 503 (1R,3S)-606 crystallization 612; 80:20 d.r. 42%, 98% e.e. 47%, >99% e.e. (1S,4S)-613 56% H , Pd/C 96% 2 Scheme 165. EtOH

O BocHN TsHN CN TsHN CO H OH NIT-106 2 i-Pr 45% (1S,3R)-614 cis-(±)-607 (1R,3S)-608; 97% e.e. Scheme 167. TsHN CN NIT-106 TsHN CO2H 36% trans-(±)-609 (1R,3R)-610; 55% e.e. H O O N 1. H ,Pd/C H2N 2 OMe Scheme 166. 2. SOCl2/MeOH (1S,4R)-602 96% (1S,3R)-615 Ph C=NH 100% 2 lamino)cyclopentane carboxylic acid (1R,3S)-608 in 45% yield and CH2Cl2 97% enantiomeric excess, whereas the biocatalytic hydrolysis of O 1. LDA, THF Ph O racemic amino nitrile trans-(±)-609 using nitrilase NIT-106, pro- BocHN 2. i-PrI, -78 oC N OMe Ph OMe duced the trans-3-(toluene-4-sulfonylamino)cyclopentane car- i-Pr 3. 1 M HCl 4. (Boc) O/NaHCO boxylic acid (1R,3R)-610 in 36% yield and 55% enantiomeric (1S,3R)-617 2 3 (1S,3R)-616 excess (Scheme 166).216 30%

Esteriﬁcation of commercially available N-Boc 4-aminocy- Scheme 168. clopent-2-ene carboxylic acid (1R,4S)-605 with iodomethane and

K2CO3 in DMF, afforded the methyl ester (1R,4S)-611a in 99% yield, which by treatment with LHMDS followed by the addition of iso- O O propyl iodide, gave the alkylated product 612 in 78% yield as a mix- O MsCl, Et3N ture of cis and trans diastereoisomers in 80:20 ratio. The HO OH 86% O saponiﬁcation of the methyl ester in the enantiomerically pure O cis-diastereoisomer (1R,4S)-612 with LiOH, produced the enantiop- (1R,3S)-618 (1R,3S)-619 c ure N-Boc -amino acid (1S,4S)-613 in 56% yield, which by catalytic 1. BnOH hydrogenation of the double bond using Pd/C, provided the confor- 43% DMAP, Et3N mationally restricted N-Boc c-amino acid (1S,3R)-614 in 96% yield 2. DPPA 217 (Scheme 167). O O Catalytic hydrogenation of the double bond in the bicyclic c- H2N H2,Pd/C CbzHN OH OBn lactam (1S,4R)-602 followed the ring opening with SOCl in MeOH, AcOEt 2 72% produced the conformationally restricted c-amino esther (1S,3R)- (1S,3R)-621 (1S,3R)-620 615 in 96% yield, which by reaction with the benzophenone imine, gave the c-imine-ester derivative (1S,3R)-616 in quantitative yield. Scheme 169. Treatment of (1S,3R)-616 with LDA followed by the addition of isopropyl iodide and subsequent separation, hydrolysis of the imine 623 in 76% yield as single diastereoisomer. Reaction of the c-lac- function and N-Boc protection, afforded the conformationally tam (1S,4S,6R)-623 with HCl, gave the c-amino acid (1S,3S,4R)- restricted N-Boc c-amino ester (1S,3R)-617 in 30% 624 in 76% yield as the hydrochloride. Under similar conditions, (Scheme 168).218 the N-PMB bicyclic c-lactam (1R,4S)-625 was transformed into Synthesis of the c-amino acid (1R,3S)-621 from (1R,3S)-cam- the c-amino acid (1R,3R,4S)-626 as triﬂuoroacetate (Scheme 170). 221 phoric acid has been described by Eagles and Hitchcock.219 Thus, Fülöp et al. reported the synthesis of (1R,2S,3S,4S)-1,2,3-tria- the reaction of camphoric acid (1R,3S)-618 with methanesulfonyl zole-functionalized 630a–c conformationally restricted c-amino chloride (MsCl) and Et N, afforded the camphoric anhydride esters. The oxidation of the N-Boc c-amino ethyl ester (1R,4S)- 3 c (1R,3S)-619 in 86% yield, which by treatment with benzyl alcohol 611b with m-CPBA in CH2Cl2, produced the epoxy -amino ester and catalytic amounts of DMAP followed by the reaction with (1R,2R,4S,5S)-627 in 76% yield as only diastereoisomer, which by DPPA, gave the N-Cbz c-amino benzyl ester (1S,3R)-620 in 43% ring-opening with sodium azide in the presence of catalytic yield. Finally, the cleavage of the O-Bn and N-Cbz bonds in amounts of ammonium chloride, afforded the two regioisomers (1S,3R)-620 by hydrogenolysis, produced the conformationally (1R,2S,3S,4S)-628 in 52% yield and (1R,2R,3R,4S)-629 in 26% yield. restricted c-amino acid (1S,3R)-621 in 72% yield (Scheme 169). Finally, the reaction of azide function in (1R,2S,3S,4S)-628 with Kamlet et al.220 reported the regioselective Rh-catalyzed ethyl propiolate, phenylacetylene and 1-pentyne in the presence hydroarylation of bicyclic c-lactam (1S,4R)-602 with 4-methoxy- of CuI in MeCN, furnished the N-Boc c-amino esters derivatives carbonylphenylboronic acid in the presence of catalytic amounts (1R,2S,3S,4S)-630a–c in 67–70% yield. The azide (1R,2R,3R,4S)- of Josiphos ligand (R,SP)-622, obtaining the c-lactam (1S,4S,6R)- 629 was also transformed into triazole derivatives (Scheme 171). 1044 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

ArB(OH) H O H O 2 O [{Rh(cod)OH] ] N . N 2 1MHCl ClH H2N o OH (R,Sp)-622 (10%mol) 100 C, 1 h 99% THF/H2O Ar Ar (1S,4R)-602 89% (1S,4S,6R)-623 Ar = 4-MeO2CC6H4 (1S,3S,4R)-624 - CF3CO2 PMB O O + P(t-Bu) N 2 H2N Ph P OH 2 Fe Me Ph (1R,4S)-625 (R,Sp)-623 (1R,3R,4S)-626

Scheme 170.

O O BocHN m-CPBA BocHN 1 OEt o OEt CH2Cl2,20 C 2 (1R,4S)-611b 76% O (1R,2R,3S,4S)-627

NaN3,NH4Cl EtOH/H2O

O O O 1 1 BocHN R BocHN BocHN 1 OEt OEt OEt 2 2 + 2 CuI, MeCN

HO N N HO N3 N3 OH N (1R,2S,3S,4S)-628; 52% (1R,2R,3R,4S)-629; 26% R (1R,2S,3S,4S)-630a-c

630a;R=CO2Et, 70% 630b;R=Ph,70% 630c;R=n-Pr, 67%

Scheme 171.

Conti et al.222 carried out the synthesis of new bicyclic c-amino acids fused with 3-Br-isoxazoline ring as inhibitors of c-aminobu- H tyrate aminotransferase. For this purpose, they carried out the 1,3- N c dipolar cycloaddition of commercially available bicyclic -lactam O 223 (1S,4R)-602 with dibromoformaldoxime (DBF), to obtain the (1S,4R)-602 two regioisomeric cycloadducts (3aR,4S,7R,7aS)-631 and (3aS,4R,7- Br S,7aS)-632 in 84% yield, which were separated by preparative 84% N HPLC. Hydrolysis of the cycloadducts (3aR,4S,7R,7aS)-631 and Br OH (3aS,4R,7S,7aS)-632 with MsOH in H O/THF at reﬂux, produced 2 Br H the conformationally restricted c-amino acids derivatives H N O N N (3aR,4S,6R,6aS)-633 and (3aS,4R,6S,6aS)-634 in 90% and 95% yield, N + O O respectively. Under identical conditions, the bicyclic c-lactam O Br (1R,4S)-602 was transformed into conformationally restricted c- (3aR,4S,7R,7aS)-631 (3aS,4R,7S,7aS)-632 amino acids (3aS,4R,6S,6aR)-633 and (3aR,4S,6R,6aR)-634 MsOH (Scheme 172). H2O/THF The sugar amino acids (SAAs) are carbohydrate derivatives - - bearing both amino and carboxylic acid functionalities and are MeSO3 H3N Br H3N MeSO3 very versatile building blocks amenable to serve as glyco- or pep- O 224 tidomimetics. For example, the protection of the D-xylose 635 N N O with acetone catalyzed with sulfuric acid followed by the reaction Br HO2C HO2C with MsCl and subsequent treatment with TFA/MeOH and K2CO3, gave the epoxide (1R,2R,5R)-636 in 85%, which by the ring-opening (3aR,4S,6R,6aS)-633; 90% (3aS,4R,6S,6aS)-634; 95% with sodium azide followed by the protection of the alcohol with - MeSO - MeSO3 H3N Br H3N 3 NaH and benzyl bromide under PTC using TBAI, afforded the azide H N O derivative (2R,3R,4S)-637 in 72% yield. Hydrolysis of the dimethyl N N O acetal in (2R,3R,4S)-637 with TFA/H2O followed by oxidation of O (1R,4S)-602 HO C HO C Br the resulting aldehyde with NBS in the presence of K2CO3 and sub- 2 2 sequent saponiﬁcation, produced the carboxylic acid derivative (3aS,4R,6S,6aR)-633 (3aR,4S,6R,6aR)-634 (2R,3R,4S)-638 in 80% yield. Finally, the reduction of the azide Scheme 172. function in (2R,3R,4S)-638 with Ph3P followed by the protection M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1045

HO HO O 1. acetone/H SO O CH(OMe) O O 2 4 2 Me Me 2. MsCl, Et N DBU, TBAB 3 OMe Me OMe Me OH 3. TFA/MeOH MeNO2, MW O NO2 OH 4. K CO 73% 2 3 (1R,2R,5R)-636 635 85% (1R,5S)-648 (1S,2S,3S,5R)-649 1. NaN , MeOH/H O 3 2 LiOH 72% 2. NaH, BnBr 91% THF/H2O TBAI, THF O O 1. TFA/H2O Me Me O CO2H O CH(OMe)2 2. NBS, K2CO3 OH 1. H2, Ra-Ni OH Me . Me MeCN/MeOH NH2 HCl 2. HCl/EtOH NO2 N OBn 3. LiOH, H2O N OBn 63% 3 3 (1S,2S,3S,5R)-651 (1S,2S,3S,5R)-650 (2R,3R,4S)-638 80% (2R,3R,4S)-637 65% 1. Ph3P, THF Scheme 175. 2. (Boc)2O, DIPEA

O CO2H of n-tetrabutylammonium bromide (TBAB) and DBU, afforded the c-nitro ester (1S,2S,3S,5R)-649 in 73% yield, which by saponiﬁca- BocHN OBn tion of the methyl ester with LiOH, produced the c-nitro acid (2R,3R,4S)-639 (1S,2S,3S,5R)-650 in 91% yield. Finally, catalytic hydrogenation of

Scheme 173. the nitro group in (1S,2S,3S,5R)-650 over Ra-Ni followed by the addition of HCl, gave the conformationally restricted c-amino acid (1S,2S,3S,5R)-651 in 63% yield as the hydrochloride with (Boc) O/DIPEA, provided the [c-Ahf(Bn)-OH] (2R,3R,4S)-639 2 (Scheme 175).226 in 65% yield, which has been used in the synthesis of foldamers On the other hand, addition of nitromethane to cyclohexene-1- and peptide nanotubes (Scheme 173).213 carboxaldehyde 652 in the presence of catalytic amounts of (S)-12 Protection of commercially available (R)-cysteine methyl ester and benzoic acid, followed by the reduction of the aldehyde func- hydrochloride 640 with (Boc) O followed by the reaction with 2 tion with NaBH , produced the c-nitro alcohols (1R,2R)-653 and ethyl bromoacetate, produced the thioether (R)-641 in 74% yield, 4 (1S,2R)-654 in 90% yield and 4.5:1 diastereoisomeric ratio, which which by reaction of TMSOTf/Et N and subsequent treatment with 3 after puriﬁcation gave the stereoisomers with >95% enantiomeric lithium 2,2,6,6-tetramethylpiperidide (LiTMP)/THF, afforded the excesses. Oxidation of the alcohol group in enantiomerically compound (3R,4R)-642 in 36% yield. Cleavage of O-TMS bond in enriched (1R,2R)-653 and (1S,2R)-654 with H Cr O , provided the (3R,4R)-642 with HF/TBAF followed by reaction with MsCl/Et N, 2 2 7 3 c-nitro acids (1R,2R)-655 and (1S,2R)-656 in 80% yield, which by gave the dihydrothiophene (S)-643, which by hydrogenation of catalytic hydrogenation of the nitro group using Pd/C followed by the double bond with magnesium in methanol, furnished the thio- the treatment with TMSCl/DIPEA and (Boc) O, afforded the confor- phene derivatives (2S,4S)-644 and (2R,4S)-645 in 25% and 32% 2 mationally restricted N-Boc c-amino acids (1R,2R)-657 and yield, respectively. Finally, the deprotection of the amino group (1S,2R)-658 in 80% yield and >95% enantiomeric excess and hydrolysis of the ester group in (2S,4S)-644 and (2R,4S)-645 (Scheme 176).227 These compounds are used as foldamer building with 4 N HCl and AcOH, gave the 4-aminotetrahydrothiophene-2- blocks. carboxylic acids (2S,4S)-646 and (2R,4S)-647 good yield as the Michael addition of nitropropane to cyclohexene-1-carboxalde- hydrochlorides, in which were tested as aminotransferase inactiva- hyde 652 catalyzed by (S)-12 and benzoic acid in N-methylmor- tors (Scheme 174).225 pholine (NMM), produced the c-nitro aldehyde (1R,2R,3S)-659 in 6 92% yield and >97% enantiomeric excess, which by oxidation with 3.8. Synthesis of Ca;b derivatives oxone in DMF, afforded the c-nitro acid (1R,2R,3S)-660 in 95% yield. Finally, the reduction of the nitro group in (1R,2R,3S)-660 Microwave-assisted conjugate addition of nitromethane to with a large excess of zinc dust in HCl followed by treatment with (1R,5S)-methyl myrtenate 648 in the presence of catalytic amounts

SH CO Me S 2 S CO2Me 1. (Boc)2O, Et3N 1. TMSOTf, Et3N OH OH 2. BrCH CO Me 2. LiTMP, THF HCl.H2N 2 2 BocHN OMe 74% 36% BocHN O O OTMS (R)-640 (R)-641 (3R,4R)-642 1. HF, TBAF o 2. NaBH4, 0 C

3. MsCl, Et3N

CO Me S CO2Me S CO2Me S 2 Mg, NH4Cl + MeOH BocHN BocHN BocHN (2R,4S)-645; 32% (2S,4S)-644; 25% (S)-643; 64%

4 N HCl AcOH

S CO2H S CO2H +

HCl.H2N HCl.H2N (2R,4S)-647; 87% (2S,4S)-646; 89%

Scheme 174. 1046 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

O NHCOAr 1. (S)-12 (20 mol %) CH2(CO2Me)2 R S N COAr PhCO H/MeNO HO HO H 2 2 (R)-128 CO2Me R + R 2. NaBH4, MeOH O2N O2N La(Oi-Pr) /Yb(OTf) 662 3 3 90% CO2Me 652 (1R,2R)-653 4.5:1 (1S,2R)-654 99% Ar = 3,5-(O2N)C6H3 (1S,2R)-663; >99.5% e.e. >95% e.e. >95% e.e. LiCl 80% H2Cr2O7 85% H2O/DMSO O O O NHBoc NHCOAr 1. (Boc)2O, Et3N HO 1. H2, Pd/C HO HO DMAP, THF BocHN 2. TMSCl, DIPEA O2N O2N (Boc)2O 2. NaOMe/MeOH (1R,2R)-657; >95% e.e. (1R,2R)-655 (1S,2R)-656 80% 95% O OMe O OMe 1. H , Pd/C 80% 2 2. TMSCl, DIPEA (1S,2R)-665 (1S,2R)-664

(Boc)2O O Scheme 178.

HO BocHN O O (1S,2R)-658; >95% e.e. Boc Cl Boc NNBoc N TMS-QD, 277 N Scheme 176. Boc Et3N/PhMe 90% 666 (S)-667; 99% e.e. TMSCl/DIPEA and (Boc)2O, gave the N-Boc 2-((S)-1-aminopropyl)- 1. H , Pd/C 87% 2 cyclohexanecarboxylic acid APCH (1R,2R,3S)-661 in 30% yield 2. NaOH, THF (Scheme 177).228

CO2H CO2H 6 3.9. Synthesis of Cb;c derivatives NH2 1. TFA, CH2Cl2 NBoc

2. H2, Ra-Ni NHBoc Catalytic asymmetric ring-opening of meso-aziridines with mal- 80% onates is another efﬁcient method for the synthesis of conforma- (1S,2S)-506 (1S,2S)-668 98% e.e. tionally restricted c-amino acids. For example, the ring-opening reaction of meso-aziridine 662 with dimethyl malonate in the pres- Scheme 179. ence of catalytic amounts of the heterobimetallic Schiff base (R)- i 128/La(O- Pr)3/Yb(OTf)3, afforded the N-protected c-amino diester

(1S,2R)-663 in 99% yield and >99.5% enantiomeric excess, which by NO2 NO2 decarboxylation with LiCl/DMSO/H O, produced the c-amino ester OEt OEt 2 670 (10 mol%) (1S,2R)-664 in 85% yield. Finally, reaction of (1S,2R)-664 with O MeCN O (Boc)2O/DMAP followed by cleavage of the 3,5-dinitrobenzoyl 87% 669 (1R,2S)-671; 96% e.e. group with NaOMe, furnished the enantiomerically pure N-Boc c- 229 Et amino ester (1S,2R)-665 in 95% yield (Scheme 178). 54% H2, Ra-Ni a b On the other hand, the reaction of , -unsaturated acyl chloride N NH2 666 with DBAD and Et3N in the presence of catalytic amounts of NH OEt cinchona alkaloid TMS-QD 277, afforded the cycloadduct (S)-667 N in 90% yield and 99% enantiomeric excess, which by catalytic S NH O hydrogenation using Pd/C followed by the hydrolysis with NaOH, (1R,2S)-672 produced the carboxylic acid derivative (1S,2S)-668 in 87% yield. F3C CF3 Finally, treatment of (1S,2S)-668 with TFA followed by N–N bond 670 cleavage by catalytic hydrogenation using Ra-Ni, produced the enantiomerically enriched cyclic c-amino acid (1S,2S)-506 in 80% Scheme 180. yield (Scheme 179).134

Conformationally restricted cyclic c-amino acids can also be O O obtained by intramolecular cyclization of a nitronate onto conju- (S)-12 (20 mol %) 230 H gated esters. For example, Cobb et al. reported the stereoselec- H PhCO2H, n-PrNO2 c NMM, EtOH O2N tive synthesis of cyclic -nitro ester (1R,2S)-671 in 87% yield and 652 92% H 96% enantiomeric excess by intramolecular Michael addition of Et nitronate onto conjugated ester 669 in the presence of catalytic (1R,2R,3S)-659 97% e.e. amounts of the bifunctional cinchona (1R,2S)-670. Catalytic hydro-

95% oxone/DMF genation of the nitro group in (1R,2S)-671 over Ra-Ni, produced the cyclic c-amino ester (1R,2S)-672 in 54% yield (Scheme 180). O O Conjugate addition of butanaldehyde to 1-nitrocyclohexene 673 catalyzed by (R)-12 and MNBA followed by the reduction of alde- HO 1. Zn/HCl HO hyde with NaBH , gave the c-nitroalcohol (1S,2S,3S)-674 in 87% BocHN 2. TMSCl, DIPEA O2N 4 H (Boc)2O H yield and 99% enantiomeric excess, which by oxidation with Et Et 30% H2Cr2O7, afforded the c-nitro acid (1S,2S,3S)-675 in 80% yield and (1R,2R,3S)-661 (1R,2R,3S)-660 >95% enantiomeric excess. Finally, catalytic hydrogenation of the Scheme 177. nitro group in (1S,2S,3S)-675 over Ra-Ni and subsequent reaction M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1047

NO NHBoc with TMSCl/DIPEA and (Boc)2O, provided the conformationally 2 restricted N-Boc c-amino acid (1S,2S,3S)-676 in 80% yield and 1. H2, Ra-Ni 231 >95% enantiomeric excess (Scheme 181). 2. (Boc)2O, DIEA On the other hand, treatment of c-nitroalcohol (1S,2S,3S)-674 HO O 64% HO O γ with NaHCO3 in ethanol at reﬂux, induced epimerization at the Boc- -Ach-OH, (±)-679

c BA nitro-bearing carbon, to give the -nitroalcohol (1R,2S,3S)-677 in M α- (R)-α-MBA )- quantitative yield and >95% enantiomeric excess, which under (S identical conditions to those described above, was transformed NHBoc into conformationally restricted c-amino acid (1R,2S,3S)-678 with NHBoc >95% enantiomeric excess (Scheme 182).231

O 6 HO 3.10. Synthesis of Ca;c derivatives HO O Boc-γ-Ach, (1R,3S)-679 Boc-γ-Ach, (1S,3R)-679 >97% e.e. Cyclic c-amino acids are molecular building blocks of great >97% e.e. interest in peptide and foldamer chemistry. For example, Granja Scheme 183. et al.213 reported the synthesis of Boc-c-Ach-OH (1R,3S)- and (1S,3R)-679. For this purpose, they carried out the simultaneous hydrogenation of the nitro group and aromatic ring in the 3- nitrobenzoic acid with Ra-Ni under hydrogen pressure followed O O 1. H ,Ra-Ni c H2N 2 H2N by treatment with (Boc)2O/DIPEA, to obtain the racemic Boc- - OH RhAl2O3, i-PrOH Oi-Pr Ach-OH (±)-679 in 64% yield. Crystallization of (±)-679 in the pres- 2. AcOi-Pr 232 ence of (R)-a-MBA, afforded the Boc-c-Ach-OH (1R,3S)-679, 46% cis-680;>99%e.e. while the crystallization with (S)-a-MBA, gave the Boc-c-Ach-OH 1. Novozym 435 40% AcOi-Pr (1S,3R)-679, both with >97% enantiomeric excess (Scheme 183). 2. crystallization On the other hand, catalytic hydrogenation of the aromatic ring O O in the 3-aminobenzoic acid with Ra-Ni and RhAl O under hydro- 2 3 AcHN 1. NaOH AcHN gen pressure followed by the reaction with isopropyl acetate, gave OH Oi-Pr 2. HCl the racemic c-Ach-Oi-Pr (±)-680 in 46% yield, which by enzymatic 96% resolution using Novozym 435 and subsequent crystallization, (1S,3R)-682 (1S,3R)-681;>99%e.e. afforded the Ac-c-Ach-Oi-Pr (1S,3R)-681 in 40% yield and >99% Scheme 184. enantiomeric excess. Finally, saponification of the isopropyl ester in (1S,3R)-681 with NaOH followed by the treatment with HCl, gave the enantiomerically pure Ac-c-Ach-OH (1S,3R)-682 in 96% 233 TsHN CN TsHN CO2H yield (Scheme 184). NIT-106 48% cis-(±)-683 (1R,3S)-684;88%e.e. NO NO2 Et 2 O 1. (R)-12 (20mol%) Scheme 185. MNBA (20 mol%) 13 + H 2. NaBH ,MeOH Et 4 OH Biocatalytic hydrolysis of racemic amino nitrile cis-(±)-683 673 87% (1S,2S,3S)-674 using nitrilase NIT-106, afforded the cis-3-(toluene-4-sulfony- 99% e.e. lamino)cyclohexanecarboxylic acid (1R,3S)-684 in 48% yield and 80% H2Cr2O7 88% enantiomeric excess (Scheme 185).216 Reduction of the ketone group in (1S,2S,3R,4S)-685 obtained NO Et BocHN Et 2 from ()-quinic acid, with NaBH in MeOH followed by the treat- OH OH 4 1. H ,Ra-Ni 1 3 2 1 3 ment with TFA and subsequent saponification of the methyl ester 2. TMSCl/DIPEA O O with LiOH, produced the azido acid derivative (1S,2S,3R,4S,5S)- (Boc)2O (1S,2S,3S)-675 (1S,2S,3S)-676 80%, 686 in 88% yield, which by acetylation with Ac2O/Py followed by >95% e.e. >95% e.e. the catalytic hydrogenation of the azide function using PtO2 in the presence of (Boc)2O and subsequent saponification with LiOH, Scheme 181. afforded the cyclic c-amino acid (1S,2S,3R,4S,5S)-687 in 56% yield (Scheme 186).234 Lewis et al.235 described the synthesis of azacarbasugar derivatives 691 and 693. To achieve this, they carried out the oxidation of NO Et NO2 Et 2 the double bond in the chiral tricyclic derivative 688 obtained in NaHCO3 3 four steps from benzoic acid, with NMO/OsO to obtain the diol 13 EtOH, Δ 1 4 OH 100% OH 689 in 39% yield, which by catalytic hydrogenation using Pd/C, (1S,2S,3S)-674 (1R,2S,3S)-677; >95% e.e. gave the polyhydroxylated derivative (3aS,4R,5R,6R,7S,7aR)-690 in quantitative yield, which by treatment with HCl followed by reversed-phase chromatography, provided the inosaminoacid (1R,2R,3R,4R,5R,6R)-691 in 70% yield. On the other hand, the cat- BocHN Et alytic hydrogenation of the double bond in the chiral tricyclic OH 1 3 derivative 688 using Pd/C, gave the compound (3aS,4R,7R,7aR)- O 692 in 97% yield, which by cleavage of the acetonide group with (1R,2S,3S)-678 >95% e.e. HCl followed by reversed-phase chromatography, provided the inosaminoacid (1S,2R,3S,6R)-693 in 16% yield (Scheme 187). Scheme 182. 1048 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

HO CO2H TBSO CO2Me N3 OTBS O HO OBz Ph AcOH/H O O O 2 Δ HO HO OH O N 3 R 98% O OMe N OMe OH OH 3 (2S,3S,4R,5R,6S)-694 693; R = OBz (-)-Quinic acid (1S,2S,3R,4S)-685 77% TEMPO/TCCA 1. NaBH4,MeOH NaBr/NaHCO3 88% 2. TFA, H2O 3. LiOH, H2O N3 N3 HO OBz HO OBz TBSO CO2H TBSO CO2H TMSCHN2 1. Ac O, Py OTBS 2 OTBS MeO MeOH/MeCN HO 2. H2/PtO2,(Boc)2O O OMe O OMe 84% 3. LiOH, H2O O O HO NHBoc HO N3 56% (2S,3S,4R,5R,6S)-696 (2S,3S,4R,5R,6S)-695 OH OH (1S,2S,3R,4S,5S)-687 (1S,2S,3R,4S,5S)-686 100% H2, Pd/C, MeOH

Scheme 186. NH2 HO OBz O Cbz O Cbz N HO N MeO NMO, OsO4 HO O OMe acetone/H O O 2 O O O 39% O (2S,3S,4R,5R,6S)-697

688 689 Scheme 188. H ,Pd/C H ,Pd/C 97% 2 100% 2 MeOH MeOH Reaction of (S)-pyroglutamic acid (S)-700 with the Meldrum’s acid in presence of DCC/DMAP followed by the reduction with OH OH NaBH4 in AcOH, afforded the diester (S)-701 in 29% yield, which HO OH c H3N CO2 by decarboxylation with H2O/Py, produced the -amino acid O 237 O H3N CO2 derivative (S)-702 in 96% yield (Scheme 190). O O The reaction of N-Boc (S)-prolinal 703 with ethyl diazoacetate (3aS,4R,7S,7aR)-692 catalyzed by anhydrous tin(II) chloride in CH2Cl2 at room temper- b c (3aS,4R,5R,6R,7S,7aR)-690 ature, provided the N-Boc -keto- -amino ester (S)-704 in 91% yield, which by reduction of the ketone function with NaBH4 in 1. 1 M HCl THF at 78 °C, gave the N-Boc b-hydroxy-c-amino esters (3R,4S)- 2. C18 reversed- phase chromatography 705 and (3S,4S)-706 in 58% and 42% yield, respectively (Scheme 191).172 OH OH The reaction of N-Boc (S)-prolinal 703 with the a-chloroacety- HO OH loxazolidinone (S)-438 and SmI2, produced the b-hydroxy deriva- H3N CO2 OH tive (S,R,S)-707 in 74% yield, which by cleavage of the chiral HO H3N CO2 OH auxiliary under oxidative conditions (LiOH/H2O2), afforded the N- HO (1S,2R,3S,6R)-693; 16% Boc b-hydroxy-c-amino acid (3R,4S)-708 in 96% yield. In a similar (1R,2R,3S,4R,5R,6R)-691; 70% way, the N-Boc (S)-prolinal 703 was transformed into N-Boc b- Scheme 187. hydroxy-c-amino acid (3S,4S)-709 in good yield using the a- chloroacetyloxazolidinone (R)-438 (Scheme 192).174 Cabrera-Escribano et al.236 reported the synthesis of the confor- The 1,2-addition reaction of potassium allyltrifluoroborate salt mationally restricted sugar derivative c-amino acid 697. Initially, to N-Boc (S)-prolinal 703 under PTC using TBAI, produced the alco- they carried out the hydrolysis of methyl a-D-allopyranoside with hol (S,R,S)-710 in 89% yield and 94:6 diastereoisomeric ratio, which AcOH/H2O, to obtain the compound (2S,3S,4R,5R,6S)-694 in 98% by O-methylation using NaH/MeI in DMF, gave the dimethylated yield, which by selective oxidation of the primary alcohol with product (S,R,S)-711 in 76% yield. Finally, oxidative cleavage of the TEMPO/NaBr and trichloroisocyanuric acid (TCCA), afforded the double bond in (S,R,S)-711 with RuO , provided the N-Boc Dola- carboxylic acid (2S,3S,4R,5R,6S)-695 in 77% yield. Esterification of 2 proine (Dap) (2R,3R,4S)-712 in 75% yield (Scheme 193).169 (2S,3S,4R,5R,6S)-695 with TMSCHN2, provided the methyl ester Ruthenium-catalyzed asymmetric hydrogenation of N-Boc b- derivative (2S,3S,4R,5R,6S)-696 in 84% yield, which by catalytic keto-c-aminoester 713 by [RuCl (p-cymene)]/(S)-SYNPHOS, 414)], hydrogenation of the azide function using Pd/C, produced the con- 2 afforded the N-Boc b-hydroxy-c-amino esters (2R,3R,4S)-714 and formationally restricted sugar derived c-amino acid (2S,3R,4S)-715 in 55% yield and 2:1 diastereoisomeric ratio. The (2S,3S,4R,5R,6S)-697 in quantitative yield, used for the preparation N,O-dimethylation of (2R,3R,4S)-714 using LiHMDS and MeOTf at of a/c-glycopeptides (Scheme 188). 20 °C in THF and hexamethylphosphoramide (HMPA), gave the dimethylated derivative (2R,3R,4S)-716 in 45% yield, which by 4. Stereoselective synthesis of azacyclic c-amino acids saponification with LiOH, produced the N-Boc Dolaproine 176 5 (2R,3R,4S)-712 in 59% yield (Scheme 194). 4.1. Synthesis of N; Cc derivatives 5 4.2. Synthesis of N; Cb derivatives The enantioselective intermolecular c-addition to allenoates 698a–f catalyzed by the spirophosphine (S)-310 in cyclopentyl Asymmetric organocatalytic addition reactions of monothioma- methyl ether (CPME), gave the a,b-unsaturated c-amino esters lonates to nitrostyrenes is another key step for the synthesis of (R)-699a–f in 44–68% yield and 88–94% enantiomeric excess conformationally restricted c-amino acids. For example, the addi- (Scheme 189).139 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1049

R R (S)-310 (10 mol%) NH N CO2t-Bu CO t-Bu 2,4-dimethoxyphenol R1 2 R1 CPME 698a-f (R)-699a-f

CO t-Bu N 2 N CO2t-Bu N CO2t-Bu PMP PMP H (R)-699a; 68%; 91% e.e. (R)-699b; 60%; 94% e.e. (R)-699c ; 55%; 90% e.e.

MeO F3C

N CO2t-Bu N CO2t-Bu N CO2t-Bu H H H (R)-699d; 44%; 89% e.e. (R)-699e ; 44%; 88% e.e. (R)-699f; 67%; 88% e.e.

Scheme 189.

O O H 1. Meldrum's acid O O Me N DMAP, DCC NH H BF3K OH O N N 2. NaBH4, AcOH TBAI 29% Boc O CH Cl /H O Boc OH O O 2 2 2 (S)-703 (S,R,S)-710; 94:6 d.r. (S)-700 (S)-701 89% NaH/MeI H O, py 76% 96% 2 DMF 116 oC Me Me RuO /H O O OH 2 2 H N MeCN/CCl N N 4 Boc OMe O 75% Boc OMe OH (2R,3R,4S)-712 (S,R,S)-711 O N-Boc Dolaproine (Dap) (S)-702 Scheme 193. Scheme 190.

Me H2 Me Me H (S)-414 (3 mol%) OEt OEt OEt OEt N N2CHCO2Et N + N [RuCl2(p-cymene) N N O SnCl2, CH2Cl2 Boc Boc O O O O 55% OH O OH O 91% Boc Boc Boc (S)-703 (S)-704 713 (2R,3R,4S)-714 2:1 (2S,3R,4S)-715

THF , 4 o C 1. LiHMDS, HMPA 8 45% THF, -78 oC NaBH -7 2. MeOTf, -20 oC OEt OEt N + N Me Me LiOH Boc OH O Boc OH O OH OEt N EtOH/H2O N (3R,4S)-705; 58% (3S,4S)-706; 42% 59% Boc OMe O Boc OMe O (2R,3R,4S)-712 (2R,3R,4S)-716 Scheme 191. N-Boc Dolaproine

Scheme 194. H N Boc O S (S)-703 NO R NO tion of monothiomalonate 717 to the 2-bromo-b-nitrostyrene 116e Cl SmI2 N S O O 74% Boc OH O O catalyzed by epiquinidine thiourea (eQDTU) 718 followed by the (S)-438 (S,R,S)-707 addition of TFA and subsequent treatment with DIPEA, afforded the c-nitrothioester (R)-719 in quantitative yield and 97% enan- 96% LiOH, H O 2 2 tiomeric excess, which by reduction of the nitro group with zinc/

AcOH followed by treatment with TiCl3, gave the c-lactam (R)- R OH c N S 720 in 91% yield. Protection of the amino group in the -lactam Boc OH O (R)-720 with (Boc)2O followed by the MeONa-mediated ring open- (3R,4S)-708 ing, produced the N-Boc b-substituted c-amino ester (R)-721 in 96% yield and 95% enantiomeric excess. Cyclization of (R)-721 (R)-438 238 H S OH through an intramolecular Buchwald-Hartwig coupling using N N S catalytic amounts of Pd(OAc)2/DPEphos and Cs2CO3, provided the Boc O Boc OH O indolin-3-yl acetic acid derivative (R)-722a in 96% yield and 95% (3S,4S)-709 (S)-703 enantiomeric excess, considered as a conformationally restricted c Scheme 192. diprotected -amino acid. The indolin-3-yl acetic acid derivatives 1050 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

OO 1. 718 (1 mol%) SPMP PhMe, -50 oC + NO2 PMBO SPMP NO2 2. TFA/CH2Cl2 Br 3. PIDEA/CH2Cl2 717 Br 116e 99% PMB = 4-methoxybenzyl (R)-719; 97% e.e. PMP = 4-methoxyphenyl 1. Zn, AcOH 91% 2. TiCl3

O CO2Me CO2Me Pd(OAc)2 1. (Boc)2O/Et3N DPEphos NHBoc DMAP, r.t. N H 2. MeONa/MeOH N Cs2CO3 o o PhMe, 100 C CH2Cl2, 5 C Boc Br Br 96% 96% (R)-722a; 95% e.e. (R)-721; 95% e.e. (R)-720

CO2Me CO2Me CO2Me Cl O

N F N O N Boc Boc Boc (R)-722b; 77%, 95% e.e. (R)-722c; 74%, 96% e.e. (R)-722d; 69%, 91% e.e.

CO2Me CO2Me CO2Me F3C BocHN

N N N Boc Boc Boc (R)-722e; 80%, 94% e.e. (R)-722f; 68%, 95% e.e. (R)-722g; 53%

CF3

S PPh2 PPh2 F3C N NH H O N N DPEphos OMe eQDTU; 718

Scheme 195.

(R)-722b–g were obtained under identical conditions with moder- treatment with 1,2-ethanedithiol/BF3OEt2, produced the dithiolane ate to good enantiomeric excess and 53–80% overall yield from the (7S,9R)-733 in 91% yield. Catalytic hydrogenation of (7S,9R)-733 appropriate substituted-b-nitrostyrenes (Scheme 195).239 using excess of Ra-Ni followed by saponification with NaOH and On the other hand, the addition of a-methyl monothiomalonate purification on a Dowex resin, afforded the trifluoromethyl piperi- 723 to the 2-bromo-b-nitrostyrene 116e in the presence of cat- dine c-amino acid (2S,6R)-734 in 88% yield (Scheme 197). alytic amounts of epi-cinchonine urea catalyst (eCNU) 724, pro- The reaction of pipecolic acid derivatives (2R,6R)-735a,b with duced the quaternary c-nitrothioester derivative 725 in an 11:1 the N,O-dimethylhydroxylamine hydrochloride and isopropyl diastereoisomeric ratio and >98% enantiomeric excess, which by magnesium chloride and subsequent reaction with methyl magne- reduction of the nitro group using zinc/AcOH, followed by treat- sium bromide, gave the methyl ketones (2R,6R)-736a,b. Enoliza- ment with TiCl3, produced the c-lactam (3R,4R)-726 in 86% yield. tion of (2R,6R)-736a,b with potassium hexamethyldisilazide Reduction of ester in the c-lactam (3R,4R)-726 with LiBH4/THF, (KHMDS) followed by the addition of N-(5-chloro-2-pyridyl)bis gave the alcohol (3S,4R)-727 in 60% yield as only diastereoisomer, (trifluoro-methanesulfonimide) (Comins’ reagent), followed by which by hydrolysis with HCl followed by the reaction with (Boc)2- smoothly carbonylation in the presence of Pd(dba)2/Ph3P, pro- O/NaHCO3 and subsequent treatment with MeI/K2CO3, furnished duced the a,b-unsaturated esters (2R,6R)-737a,b. Reduction of the N-Boc trisubstituted c-amino ester (2S,3R)-728 in 73% yield. the methyl esters in (2R,6R)-737a,b with DIBAL-H and subsequent

Protection of the alcohol group in (2S,3R)-728 with tert- cyclopropanation with ClCH2I/Et2Zn, furnished the cyclopropyl butyldimethylsilyl chloride (TBSCl) followed by the intramolecular derivatives (2R,6R)-738a,b, which by reaction with I2/Ph3P fol- Buchwald-Hartwig coupling in the presence of catalytic amounts lowed by treatment with n-Bu4NCN, gave the nitriles (2R,6R)- of Pd(OAc)2/DPEphos and Cs2CO3, gave the quaternary c-amino 739a,b. Finally, the reduction of cyano group in (2R,6R)-739a,b 239 ester (S,S)-729 in 91% yield (Scheme 196). with DIBAL-H and subsequent oxidation with NaCl2O/NaH2PO4, gave the c-amino acid derivatives (2R,6R)-740a,b (Scheme 198).241 6 242 4.3. Synthesis of N; Cc derivatives Finally, Ye et al. reported the synthesis of the imino sugar derivatives 744a,b. For this purpose, they carried out the reaction Canet et al.240 reported the asymmetric synthesis of triﬂuo- of the aldehydes 741a,b under Wittig conditions, obtaining the a, romethyl piperidine c-amino acid (2S,6R)-734. Thus, the reaction b-unsaturated esters 742a,b, in 92% and 96% yield, respectively, of enantiopure aminoketal (R)-730 with ethyl (E)-oxobutenoate as an inseparable mixture of E,Z-isomers, which by reduction of

731 under classical Mannich conditions, produced the cis-2,6-dis- the double bond with NaBH4/NiCl2, afforded the saturated esters ubstituted CF3 piperidine (8S,10R)-732 in 68% yield (85% 743a,b in 85% and 80% yield, respectively. Saponiﬁcation of the diastereoisomeric ratio) and 96% enantiomeric excess, which by methyl esters 743a,b with 1 N NaOH followed by the catalytic M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1051

OO PMBO C SPMP 724 (2 mol%) 2 + NO o 2 PMBO SPMP NO2 PhMe, -15 C Br Br 116e 723 725; 11:1 d.r.,>98% e.e.

1. Zn, AcOH 86% 2. TiCl3

O O HO HO CO2Me PMBO2C 1. conc. HCl N H LiBH4 N H NHBoc 2. (Boc)2O, NaHCO3 THF 3. MeI, K2CO3 60% Br Br 73% Br (2S,3R)-728 (3S,4R)-727 (3R,4R)-726

1. TBSCl/imidazole CF 3 91% 2. Pd(OAc)2/DPEphos o O Cs2CO3,PhMe,100 C

F3C N NH TBSO H N CO2Me N

N eCNU, 724 Boc (S,S)-729

Scheme 196.

H R Cbz R Cbz F3C N CO2Et BnO BnO CO2Et N N OHC OBn Ph P=CHCO Me OBn NH2 R' 3 2 R' OO 731 CHO THF CH=CHCO Me MgSO4 OO 2 CF3 OBn OBn p-TsOH, PhMe 741a; R = CH2OBn, R' = H 742a; 92% (R)-730 68% (8S,10R)-732 741b; R= H, R' = CH2OBn 742b; 96% 85% d.r.; 96% e.e. NaBH4 1,2-ethanedithiol 91% NiCl2.6H2O BF3OEt2,CH2Cl2 R H R Cbz BnO BnO H H N N 1. H2,Ra-Ni,MeOH 1. 1 N NaOH, MeOH OBn OBn CO H F C N CO2Et R' R' F3C N 2 2. 0.3 M NaOH 3 2. H2, Pd/C, MeOH CH2CH2CO2H CH2CH2CO2Me 3. 1 M HCl OBn OBn 4. Dowex, MeOH SS 744a; 80% 743a; 85% 743b; 80% (2S,6R)-734 88% 744b; 83% (7S,9R)-733 Scheme 199. Scheme 197.

hydrogenation using Pd/C, produced the c-amino acids 744a,b in 1. Me(OMe)NH.HCl OMe 80% and 83% yield, respectively (Scheme 199). R N i-PrMgCl, THF R N O 2. MeMgBr, THF O P P 5. Conclusions (2R,6R)- (2R,6R)-736a,b

735a; R = ethyl 1. KHMDS, THF 735b; R = cyclopropyl In this review we have tried to cover all the most important pro- 2. Comins' reagent c P=4-ClC6H4SO2 3. CO, n-Bu3N, Pd(dba)2, cedures that allow the synthesis of -amino acids and their deriva- Ph3P, LiCl, MeOH/MeCN tives. These procedures involve the stereoselective synthesis of the desired compounds or the racemic synthesis followed by resolu- O 1. DIBAL-H, THF tion procedures. The classiﬁcation of the strategies based on the R N OH R N OMe 2. ClCH2I, Et2Zn disconnection approach should allow the organic chemist to ﬁnd P P out the most valuable approach to synthesize their desired com- (2R,6R)-738a,b (2R,6R)-737a,b pound with the major enantioselectivity or diastereoselectivity. 1. I2/Ph3P, imidazole 2. n-Bu NCN, MeCN 4 Acknowledgements

1. DIBAL-H/CH2Cl2 OH The authors thank CONACYT-Mexico for ﬁnancial support via R N CN R N 2. NaClO2/NaH2PO4 O projects 181816 and 248868. Ministerio de Ciencia e Innovación– P t-BuOH/H2O P (2R,6R)-739a,b (2R,6R)-740a,b FEDER-Spain (grant CTQ2010-17436) and Gobierno de Aragón– FSE (research group E40). We thank José Luis Viveros Ceballos for Scheme 198. their valuable help. 1052 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

References K.; Chatterjee, S.; Aravinda, S.; Shamala, N.; Balaram, P. J. Am. Chem. Soc. 2007, 129, 4039–4048. 24. Ordóñez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3–99. 1. (a) Brown, K. M.; Roy, K. K.; Hockerman, G. H.; Doerksen, R. J.; Colby, D. A. J. 25. Gil, S.; Parra, M.; Rodríguez, P. Molecules 2008, 13, 716–728. Med. Chem. 2015, 58, 6336–6347; (b) Abdel-Halim, H.; Hanrahan, J. R.; Hibbs, 26. For the organocatalytic addition of acetaldehyde to b-nitrostyrene, see: D. E.; Johnston, G. A. R.; Chebib, M. Chem. Biol. Drug Des. 2008, 71, 306–327; (c) Ramachary, D. B.; Reddy, P. S.; Prassad, M. S. Eur. J. Org. Chem. 2014, 3076– Filip, M.; Frankowska, M. Pharmacol. Rep. 2008, 60, 755–770. 3081. 2. (a) Killam, K. F.; Bain, J. A. J. Pharmacol. Exp. Ther. 1957, 119, 255–262; (b) 27. Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 5608– Kardos, J.; Szabó, Z.; Héja, L. J. Med. Chem. 2016, 59, 777–787. 5609. 3. (a) Jensen, T. S. Eur. J. Pain 2002, 6, 61–68; (b) Dickenson, A. H.; Ghandehari, J. 28. Kong, D.; Li, M.; Wang, R.; Zi, G.; Hou, G. Org. Biomol. Chem. 2016, 14, 1216– Handb. Exp. Pharmacol. 2007, 177, 145–177. 1220. 4. Kalueff, A. V.; Nutt, D. J. Depression Anxiety 2007, 24, 495–517. 29. Brenna, E.; Gatti, F. G.; Manfredi, A.; Monti, D.; Parmeggiani, A. Catal. Sci. 5. Mulleners, W. M.; Chronicle, E. P. Cephalalgia 2008, 28, 585–597. Technol. 2013, 3, 1136–1146. 6. Lloyd, K. G.; Shemen, L.; Hornykiewicz, O. Brain Res. 1977, 127, 269–278. 30. Mitsunuma, H.; Matsunaga, S. Chem. Commun. 2011, 469–471. 7. Lanctôt, K. L.; Herrmann, N.; Mazzotta, P.; Khan, L. R.; Ingber, N. Can. J. 31. Moss, T. A.; Fenwick, D. R.; Dixon, D. J. J. Am. Chem. Soc. 2008, 130, 10076– Psychiatry 2004, 49, 439–453. 10077. 8. Zádori, D.; Geisz, A.; Vámos, E.; Vécsei, L.; Klivényi, P. Pharmacol. Biochem. 32. Paixao, M. W.; Nielsen, M.; Jacobsen, C. B.; Jorgensen, K. A. Org. Biomol. Chem. Behav. 2009, 94, 148–153. 2008, 6, 3467–3470. 9. (a) Pardridge, W. M. Annu. Rep. Med. Chem. 1985, 20, 305–313; (b) Shashoua, V. 33. Blakemore, D. C.; Bryans, J. S.; Carnell, P.; Carr, C. L.; Chessum, N. E. A.; Field, E.; Jacob, J. N.; Ridge, R.; Campbell, A.; Baldessarini, R. J. J. Med. Chem. 1984, 27, M. J.; Kinsella, N.; Osborne, S. A.; Warren, A. N.; Williams, S. C. Bioorg. Med. 659–664; (c) Meldrum, B. S.; Horton, R. W. In Epilepsy; Churchill Livingston: Chem. Lett. 2010, 20, 461–464. Edinburgh, 1974; pp 55–64. 34. Aguilera, J.; Gutiérrez-Abad, R.; Mor, À.; Moglioni, A. G.; Moltrasio, G. Y.; 10. Baxter, C. F.; Roberts, E. J. Biol. Chem. 1958, 233, 1135–1139. Ortuño, R. M. Tetrahedron: Asymmetry 2008, 19, 2864–2869. 11. (a) Froestl, W. Adv. Pharmacol. 2010, 58, 19–62; (b) Bowery, N. G.; Hill, D. R.; 35. (a) Moglioni, A. G.; García-Expósito, E.; Aguado, G. P.; Parella, T.; Branchadell, Hudson, A. L.; Doble, A.; Middlemiss, D. N.; Shaw, J.; Turnbull, M. Nature 1980, V.; Moltrasio, G. Y.; Ortuño, R. M. J. Org. Chem. 2000, 65, 3934–3940; (b) 283, 92–94. Moglioni, A. G.; Muray, E.; Castillo, J. A.; Álvarez-Larena, Á.; Moltrasio, G. Y.; 12. Olpe, H. R.; Demiéville, H.; Baltzer, V.; Bencze, W. L.; Koella, W. P.; Wolf, P.; Branchadell, V.; Ortuño, R. M. J. Org. Chem. 2002, 67, 2402–2410. Haas, H. L. Eur. J. Pharmacol. 1978, 52, 133–136. 36. For the application of (R,R,S)-41, see: Ospina, J.; Sorrenti, A.; Illa, O.; Pons, R.; 13. (a) Lal, R.; Sukbuntherng, J.; Tai, E. H. L.; Upadhyay, S.; Yao, F.; Warren, M. S.; Ortuño, R. M. Tetrahedron: Asymmetry 2013, 24, 713–718. Luo, W.; Bu, L.; Nguyen, S.; Zamora, J.; Peng, G.; Dias, T.; Bao, Y.; Ludwikow, 37. For the application of the c-lactam (R,R,S)-47, see: Aguilera, J.; Moglioni, A.; M.; Phan, T.; Scheuerman, R. A.; Yan, H.; Gao, M.; Wu, Q. Q.; Annamalai, T.; Mor, A.; Ospina, J.; Illa, O.; Ortuño, R. M. Tetrahedron 2014, 70, 6546–6553. Raillard, S. P.; Koller, K.; Gallop, M. A.; Cundy, K. C. J. Pharmacol. Exp. Ther. 38. Izquierdo, S.; Aguilera, J.; Buschmann, H. H.; García, M.; Torrens, A.; Ortuño, R. 2009, 330, 911–921; (b) Mann, A.; Boulanger, T.; Brandau, B.; Durant, F.; M. Tetrahedron: Asymmetry 2008, 19, 651–653. Evrard, G.; Heaulme, M.; Desaulles, E.; Wermuth, C. G. J. Med. Chem. 1991, 34, 39. Domingos, J. L. O.; Lima, E. C.; Dias, A. G.; Costa, P. R. R. Tetrahedron: 1307–1313. Asymmetry 2004, 15, 2313–2314. 14. For the synthesis and biological evaluation of novel Baclofen derivatives, see: 40. Richard, M.; Felten, A.-S.; Didierjean, C.; Ruiz-Lopez, M.; Chapleur, Y.; Xu, F.; Peng, G.; Phan, T.; Dilip, U.; Chen, J. L.; Chernov-Rogan, T.; Zhang, X.; Pellegrini-Moïse, N. Eur. J. Org. Chem. 2014, 7364–7376. Grindstaff, K.; Annamalai, T.; Koller, K.; Gallop, M. A.; Wustrow, D. J. Bioorg. 41. For the synthesis of cyclic sugar c-amino acids, see: (a) Risseeuw, M.; Med. Chem. Lett. 2011, 21, 6582–6585. Overhand, M.; Fleet, G. W. J.; Simone, M. I. Amino acids 2013, 45, 613–689; (b) 15. Dambrova, M.; Zvejniece, L.; Liepinsh, E.; Cirule, H.; Zharkova, O.; Veinberg, Rjabovs, V.; Turks, M. Tetrahedron 2013, 69, 10693–10710. G.; Kalvinsh, I. Eur. J. Pharmacol. 2008, 583, 128–134. 42. Tovar-Gudiño, E.; Morales-Nava, R.; Fernández-Zertuche, M. Can. J. Chem. 16. Zvejniece, L.; Vavers, E.; Svalbe, B.; Veinberg, G.; Rizhanova, K.; Liepins, V.; 2014, 48, 45–48. Kalvinsh, I.; Dambrova, M. Pharmacol. Biochem. Behav. 2015, 137, 23–29. and 43. Oba, M.; Saegusa, T.; Nishiyama, N.; Nishiyama, K. Tetrahedron 2009, 65, 128– references therein. 133. 17. Lapin, I. CNS Drug Rev. 2001, 7, 471–481. 44. Chang, M.-Y.; Sun, P.-P.; Chen, S.-T.; Chang, N.-C. Tetrahedron Lett. 2003, 44, 18. (a) Belliotti, T. R.; Capiris, T.; Ekhato, I. V.; Kinsora, J. J.; Field, M. J.; Heffner, T. 5271–5273. G.; Meltzer, L. T.; Schwarz, J. B.; Taylor, C. P.; Thorpe, A. J.; Vartanian, M. G.; 45. (a) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307–5309; (b) Wise, L. D.; Ti, Z.-S.; Weber, M. L.; Wustrow, D. J. J. Med. Chem. 2005, 48, 2294– Hayashi, Y.; Sakamoto, D.; Okamura, D. Org. Lett. 2016, 18, 4–7. 2307; (b) Silverman, R. B. Angew. Chem., Int. Ed. 2008, 47, 3500–3504; (c) 46. For the synthesis and application of c-lactams, see: Lebedev, A. Chem. Gajraj, N. M. Int. Anesthesia Res. Soc. 2007, 105, 1805–1815. Heterocycl. Compd. 2007, 43, 673–684. 19. (a) Al-Majed, A. Proﬁles Drug Subst. Excip. Relat. Methodol. 2010, 35, 309–345. 47. Jensen, K. L.; Poulsen, P. H.; Donslund, B. S.; Morana, F.; Jorgensen, K. A. Org. and references therein; (b) Tolman, J. A.; Faulkner, M. A. Expert Opin. Lett. 2012, 14, 1516–1519. Pharmacother. 2009, 10, 3077–3089; (c) Jung, M. J.; Lippert, B.; Metcalf, B. 48. Maltsev, O. V.; Kucherenko, A. S.; Beletskaya, I. P.; Tartakovsky, V. A.; Zlotin, S. W.; Bohlen, P.; Schechter, P. J. J. Neurochem. 1977, 29, 797–802. G. Eur. J. Org. Chem. 2010, 2927–2933. 20. (a) Karila, L.; Gorelick, D.; Weinstein, A.; Noble, F.; Benyamina, A.; Coscas, S.; 49. Felluga, F.; Gombac, V.; Pitacco, G.; Valentin, E. Tetrahedron: Asymmetry 2005, Blecha, L.; Lowenstein, W.; Martinot, J. L.; Reynaud, M.; Lepine, J. P. Int. J. 16, 1341–1345. Neuropsychopharmacol. 2008, 11, 425–438; (b) Peng, X.-Q.; Li, X.; Gilbert, J. G.; 50. Veverková, E.; Bilka, S.; Baran, R.; Šebesta, R. Synthesis 2016, 48, 1474–1482. Pak, A. C.; Ashby, C. R., Jr.; Brodie, J. D.; Dewey, S. L.; Gardner, E. L.; Xi, Z.-X. 51. Akagawa, K.; Kudo, K. Angew. Chem., Int. Ed. 2012, 51, 12786–12789. Drug Alcohol Depend. 2008, 97, 216–225. 52. Guo, X.-T.; Shen, J.; Sha, F.; Wu, X.-Y. Synthesis 2015, 47, 2063–2072. 21. (a) Zoidis, G.; Sandoval, A.; Pineda-Farias, J. B.; Granados-Soto, V.; Felix, R. 53. Leyva-Pérez, A.; García-García, P.; Corma, A. Angew. Chem., Int. Ed. 2014, 53, Bioorg. Med. Chem. 2014, 22, 1797–1803; (b) Lebedyeva, I. O.; Ostrov, D. A.; 8687–8690. Neubert, J.; Steel, P. J.; Patel, K.; Sileno, S. M.; Goncalves, K.; Ibrahim, M. A.; 54. (a) Poe, S. L.; Kobašlija, M.; McQuade, D. T. J. Am. Chem. Soc. 2007, 129, 9216– Alamry, K. A.; Katritzky, A. R. Bioorg. Med. Chem. 2014, 22, 1479–1486. and 9221; see also: (b) Li, X.; Li, X.; Peng, F.; Shao, Z. Adv. Synth. Catal. 2012, 354, references therein. 2873–2885. 22. For representative papers, see (a) Shi, Y.; Teng, P.; Sang, P.; She, F.; Wei, L.; Cai, 55. Baschieri, A.; Bernardi, L.; Ricci, A.; Suresh, S.; Adamo, M. F. A. Angew. Chem., J. Acc. Chem. Res. 2016, 49, 428–441; (b) Wani, N. A.; Kant, R.; Gupta, V. K.; Int. Ed. 2009, 48, 9342–9345. Aravinda, S.; Rai, R. J. Pept. Sci. 2016, 22, 208–213; (c) Rodríguez-Vázquez, N.; 56. Camps, P.; Muñoz-Torrero, D.; Sánchez, L. Tetrahedron: Asymmetry 2004, 15, Amorín, M.; Alfonso, I.; Granja, J. R. Angew. Chem., Int. Ed. 2016, 55, 4504– 2039–2044. 4508; (d) Konda, M.; Kauffmann, B.; Rasale, D. B.; Das, A. K. Org. Biomol. Chem. 57. (a) Moccia, M.; Cortigiani, M.; Monasterolo, C.; Torri, F.; Del Fiandra, C.; Fuller, 2016, 14, 4089–4102; (e) Grison, C. M.; Robin, S.; Aitken, D. J. Chem. Commun. G.; Kelly, B.; Adamo, M. F. A. Org. Process Res. Dev. 2015, 19, 1274–1281; (b) 2016, 7802–7805; (f) Winiecka, I.; Jaworski, P.; Mazurek, A. P.; Marszałek, D.; Moccia, M.; Wells, R. J.; Adamo, M. F. A. Org. Biomol. Chem. 2015, 13, 2192– Goldnik, A.; Sokulski, D. J. Pept. Sci. 2016, 22, 106–115; (g) Vasudev, P. G.; 2195. Chatterjee, S.; Shamala, N.; Balaram, P. Chem. Rev. 2011, 111, 657–687. 58. Yao, Q.; Wang, Z.; Zhang, Y.; Liu, X.; Lin, L.; Feng, X. J. Org. Chem. 2015, 80, 23. For representative papers, see: (a) Byun, B. J.; Kang, Y. K. Biopolymers 2013, 5704–5712. 101, 87–95; (b) Basuroy, K.; Dinesh, B.; Reddy, M. B. M.; Chandrappa, S.; 59. Monge, D.; Martín-Zamora, E.; Vázquez, J.; Alcarazo, M.; Álvarez, E.; Raghothama, S.; Shamala, N.; Balaram, P. Org. Lett. 2013, 15, 4866–4869; (c) Fernández, R.; Lassaletta, J. M. Org. Lett. 2007, 9, 2867–2870. Lengyel, G. A.; Eddinger, G. A.; Horne, W. S. Org. Lett. 2013, 15, 944–947; (d) 60. Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442–4443. Kang, Y. K.; Byun, B. J. Biopolymers 2012, 97, 1018–1025; (e) Bouillière, F.; 61. Wang, J.; Li, W.; Liu, Y.; Chu, Y.; Lin, L.; Liu, X.; Feng, X. Org. Lett. 2010, 12, Thetiot-Laurent, S.; Kouklovsky, C.; Alezra, V. Amino Acids 2011, 41, 687–707; 1280–1283. (f) Blanco, S.; López, J. C.; Mata, S.; Alonso, J. L. Angew. Chem., Int. Ed. 2010, 49, 62. For the phase-transfer-catalyzed asymmetric conjugate cyanation of 9187–9192; (g) Vasudev, P. G.; Chatterjee, S.; Shamala, N.; Balaram, P. Acc. alkylidenemalonates with KCN, see: Liu, Y.; Shirakawa, S.; Maruoka, K. Org. Chem. Res. 2009, 42, 1628–1639; (h) James, W. H., III; Müller, C. W.; Buchanan, Lett. 2013, 15, 1230–1233. E. G.; Nix, M. G. D.; Guo, L.; Roskop, L.; Gordon, M. S.; Slipchenko, L. V.; 63. Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.; Gellman, S. H.; Zwier, T. S. J. Am. Chem. Soc. 2009, 131, 14243–14245; (i) Shibasaki, M. Tetrahedron 2007, 63, 5820–5831. Chatterjee, S.; Vasudev, P. G.; Raghothama, S.; Ramakrishnan, C.; Shamala, N.; 64. Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, Balaram, P. J. Am. Chem. Soc. 2009, 131, 5956–5965; (j) Vasudev, P. G.; Ananda, 4722–4724. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1053

65. García-García, P.; Ladépêche, A.; Halder, R.; List, B. Angew. Chem., Int. Ed. 2008, 102. For the resolution of alkyl (±)-3-cyano-5-methylhexanoates using 47, 4719–4721. immobilized lipase PS from Pseudomonas cepacia, see: Zheng, R.-C.; Li, A.-P.; 66. Bae, H. Y.; Song, C. E. ACS Catal. 2015, 5, 3613–3619. Wu, Z.-M.; Zheng, J.-Y.; Zheng, Y.-G. Tetrahedron: Asymmetry 2012, 23, 1517– 67. Liu, J.-M.; Wang, X.; Ge, Z.-M.; Sun, Q.; Cheng, T.-M.; Li, R.-T. Tetrahedron 2011, 1521. 67, 636–640. 103. For the synthesis of (S)-3-cyano-5-methylhexanoic acid from (S)-Pregabalin 5, 68. (a) Bassas, O.; Huuskonen, J.; Rissanen, K.; Koskinen, A. M. P. Eur. J. Org. Chem. see: Zagami, M.; Binda, M.; Piccolo, O.; Straniero, V.; Valoti, E.; Pallavicini, M. 2009, 1340–1351; (b) Kataja, A. O.; Koskinen, A. M. P. Arkivoc 2010, ii, 205– Tetrahedron Lett. 2012, 53, 6075–6077. 223. 104. Martinez, C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L. Org. Process 69. Baran, R.; Veverková, E.; Škvorcová, A.; Šebesta, R. Org. Biomol. Chem. 2013, 11, Res. Dev. 2008, 12, 392–398. 7705–7711. 105. Wells, A. S.; Wong, J. W.; Michels, P. C.; Entwistle, D. A.; Fandrick, K.; Finch, G. 70. Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583–11592. L.; Goswami, A.; Lee, H.; Mix, S.; Moody, T. S.; Pang, L.; Sato, R. K.; Turner, N. J.; 71. Bae, H. Y.; Some, S.; Lee, J. H.; Kim, J.-Y.; Song, M. J.; Lee, S.; Zhang, Y. J.; Song, Watson, T. J. Org. Process Res. Dev. 2016, 20, 594–601. C. E. Adv. Synth. Catal. 2011, 353, 3196–3202. 106. YiTao, D.; PeiYuan, Y.; Jie, R.; Chao, H.; Qian, L.; Jing, Y.; JinHui, F.; QiaQing, W.; 72. Jin, H.; Kim, S. T.; Hwang, G.-S.; Ryu, D. H. J. Org. Chem. 2016, 81, 3263–3274. DunMing, Z. Sci. Chin. Chem. 2014, 57, 1164–1171. 73. Tsakos, M.; Kokotos, C. G.; Kokotos, G. Adv. Synth. Catal. 2012, 354, 740–746. 107. (a) Muratake, H.; Ito, A.; Toda, T.; Suzuki, H.; Fukasawa, H.; Tsuda, M.; Inoue, 74. Massolo, E.; Benaglia, M.; Genoni, A.; Annunziata, R.; Celentano, G.; Gaggero, K.; Sugiyama, K.; Shudo, K. Bioorg. Med. Chem. Lett. 2012, 22, 7602–7604; (b) N. Org. Biomol. Chem. 2015, 13, 5591–5596. Fukasawa, H.; Muratake, H.; Ito, A.; Suzuki, H.; Amano, Y.; Nagae, M.; 75. Xu, Y.; Kaneko, K.; Kanai, M.; Shibasaki, M.; Matsunaga, S. J. Am. Chem. Soc. Sugiyama, K.; Shudo, K. ACS Chem. Neurosci. 2014, 5, 525–532. 2014, 136, 9190–9194. 108. Felluga, F.; Pitacco, G.; Valentin, E.; Venneri, C. D. Tetrahedron: Asymmetry 76. Borisova, T.; Pozdnyakova, N.; Shaitanova, E.; Gerus, I.; Dudarenko, M.; 2008, 19, 945–955. Mironets, R.; Haufe, G.; Kukhar, V. Bioorg. Med. Chem. 2015, 23, 4316–4323. 109. Felluga, F.; Ghelfi, F.; Pitacco, G.; Roncaglia, F.; Valentin, E.; Venneri, C. D. 77. Deng, J.; Duan, Z.-C.; Huang, J.-D.; Hu, X.-P.; Wang, D.-Y.; Yu, S.-B.; Xu, X.-F.; Tetrahedron: Asymmetry 2010, 21, 2183–2191. Zheng, Z. Org. Lett. 2007, 9, 4825–4828. 110. Ghislieri, D.; Gilmore, K.; Seeberger, P. H. Angew. Chem., Int. Ed. 2015, 54, 678– 78. Deng, J.; Hu, X.-P.; Huang, J.-D.; Yu, S.-B.; Wang, D.-Y.; Duan, Z.-C.; Zheng, Z. J. 682. Org. Chem. 2008, 73, 6022–6024. 111. Montoya-Balbás, I. J.; Valentín-Guevara, B.; López-Mendoza, E.; Linzaga- 79. Fryszkowska, A.; Fisher, K.; Gardiner, J. M.; Stephens, G. M. Org. Biomol. Chem. Elizalde, I.; Ordoñez, M.; Román-Bravo, P. Molecules 2015, 20, 22028–22043. 2010, 8, 533–535. 112. Rodríguez, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron Lett. 2007, 48, 4305– 80. (a) Debarge, S.; McDaid, P.; O’Neill, P.; Frahill, J.; Wong, J. W.; Carr, D.; Burrell, 4308. A.; Davies, S.; Karmilowicz, M.; Steflik, J. Org. Process Res. Dev. 2014, 18, 109– 113. Hinton, T.; Chebib, M.; Johnston, G. A. R. Bioorg. Med. Chem. Lett. 2008, 18, 121; For the asymmetric bioreduction of b-cyanoacrylate esters using Ene- 402–404. reductases, see: (b) Winkler, C. K.; Clay, D.; Davies, S.; O’Neill, P.; McDaid, P.; 114. (a) Otsuka, M.; Obata, K.; Miyata, Y.; Tanaka, Y. J. Neurochem. 1971, 18, 287– Debarge, S.; Steflik, J.; Karmilowicz, M.; Wong, J. W.; Faber, K. J. Org. Chem. 295; (b) García-Flores, E.; Farías, R. Stereotact. Funct. Neurosurg. 1997, 69, 243– 2013, 78, 1525–1533; (c) Winkler, C. K.; Clay, D.; Turrini, N. G.; Lechner, H.; 246. Kroutil, W.; Davies, S.; Debarge, S.; O’Neill, P.; Steflik, J.; Karmilowicz, M.; 115. (a) Zhu, J.; Ma, D. Angew. Chem., Int. Ed. 2003, 42, 5348–5351; (b) Qureshi, A.; Wong, J. W.; Faber, K. Adv. Synth. Catal. 2014, 356, 1878–1882. Colin, P. L.; Faulkner, D. Tetrahedron 2000, 56, 3679–3685; (c) Sasaki, S.; 81. Brenna, E.; Crotti, M.; Gatti, F. G.; Monti, D.; Parmeggiani, F.; Powell, R. W., III; Hamada, Y.; Shiori, T. Synlett 1999, 453–455; (d) Schmidt, E. W.; Faulkner, D. J. Santangelo, S.; Stewart, J. D. Adv. Synth. Catal. 2015, 357, 1849–1860. Tetrahedron 1998, 54, 3043–3056; (e) Bewley, C. A.; Debitus, C.; Faulkner, D. J. 82. Han, F.; Chen, J.; Zhang, X.; Liu, J.; Cun, L.; Zhu, J.; Deng, J.; Liao, J. Tetrahedron J. Am. Chem. Soc. 1994, 116, 7631–7636. Lett. 2011, 52, 830–833. 116. (a) Ong, J.; Bexis, S.; Marino, V.; Parker, D. A. S.; Kerr, D. I. B.; Froestl, W. Eur. J. 83. Yasukawa, T.; Suzuki, A.; Miyamura, H.; Nishino, K.; Kobayashi, S. J. Am. Chem. Pharmcol. 2001, 412, 27–37; (b) Falch, E.; Hedegaard, A.; Nielsen, L.; Jensen, B. Soc. 2015, 137, 6616–6623. R.; Hjeds, H.; Krogsgaard-Larsen, P. J. Neurochem. 1986, 47, 898–903. 84. Shao, C.; Yu, H.-J.; Wu, N.-Y.; Tian, P.; Wang, R.; Feng, C.-G.; Lin, G.-Q. Org. Lett. 117. Zhang, W.; Jiang, S.-K.; Wu, Y.-L.; Guo, C.-X.; Zhang, H.-F.; Sugiyama, H.; Chen, 2011, 13, 788–791. X.-L. ChemBioChem 2012, 13, 47–50. 85. Yu, H.-J.; Shao, C.; Cui, Z.; Feng, C.-G.; Lin, G.-Q. Chem. Eur. J. 2012, 18, 13274– 118. Sanyal, I.; Shukla, B.; Barman, P. D.; Banerjee, A. K. Tetrahedron Lett. 2013, 54, 13278. 2637–2640. 86. Yang, X.-F.; Ding, C.-H.; Li, X.-H.; Huang, J.-Q.; Hou, X.-L.; Dai, L.-X.; Wang, P.-J. 119. Ivšic´, T.; Dokli, I.; Rimac, A.; Hameršak, Z. Eur. J. Org. Chem. 2014, 631–638. J. Org. Chem. 2012, 77, 8980–8985. 120. Sahin, E.; Kishali, N.; Kelebekli, L.; Mete, E.; Secen, H.; Altundas, R.; Kara, Y. 87. Brodzka, A.; Koszelevski, D.; Cwiklak, M.; Ostaszewski, R. Tetrahedron: Org. Prep. Proced. Int. 2007, 39, 509–522. Asymmetry 2013, 24, 427–433. 121. Shaitanova, E. N.; Gerus, I. I.; Belik, M. Y.; Kukhar, V. P. Tetrahedron: 88. Blakemore, D. C.; Bryans, J. S.; Carnell, P.; Chessum, N. E. A.; Field, M. J.; Asymmetry 2007, 18, 192–198. Kinsella, N.; Kinsora, J. K.; Osborne, S. A.; Williams, S. C. Bioorg. Med. Chem. 122. Pallavicini, M.; Bolchi, C.; Binda, M.; Ferrara, R.; Fumagalli, L.; Piccolo, O.; Lett. 2010, 20, 362–365. Valoti, E. Tetrahedron: Asymmetry 2008, 19, 1637–1640. 89. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, 123. (a) Deniau, G. P.; Slawin, A. M. Z.; Lebl, T.; Chorki, F.; Issberner, J. P.; van A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124. 1307–131. Mourik, T.; Heygate, J. M.; Lambert, J. J.; Etherington, L. A.; Sillar, K. T.; 90. Mujahid, M.; Muthukrishnan, M. Chirality 2013, 25, 965–969. O’Hagan, D. ChemBioChem 2007, 8, 2265–2274; (b) Clift, M. D.; Ji, H.; Deniau, 91. Murtagh, L.; Dunne, C.; Gabellone, G.; Panesar, N. J.; Field, S.; Reeder, L. M.; G. P.; O’Hagan, D.; Silverman, R. B. Biochemistry 2007, 46, 13819–13828. Saenz, J.; Smith, G. P.; Kissick, K.; Martínez, C.; Van Alsten, J. G.; Evans, M. C.; 124. For evaluation of both enantiomers of 3F-GABA on GABAC receptors, see: (a) Franklin, L. C.; Nanninga, T.; Wong, J. Org. Proccess Res. Dev. 2011, 15, 1315– Yamamoto, I.; Deniau, G. P.; Gavande, N.; Chebib, M.; Johnston, G. A. R.; 1327. O’Hagan, D. Chem. Commun. 2011, 7956–7958. 92. Sekiyama, T.; Hatsuya, S.; Tanaka, Y.; Uchiyama, M.; Ono, N.; Iwayama, S.; 125. For conformational study of 3F-GABA, see: (a) Cao, J.; Bjornsson, R.; Bühl, M.; Oikawa, M.; Suzuki, K.; Okunishi, M.; Tsuji, T. J. Med. Chem. 1998, 41, 1284– Thiel, W.; van Mourik, T. Chem. Eur. J. 2012, 18, 184–195; (b) O’Hagan, D. 1298. Future Med. Chem. 2011, 3, 189–195. 93. Ok, T.; Jeon, A.; Lee, J.; Lim, J. H.; Hong, C. S.; Lee, H.-S. J. Org. Chem. 2007, 72, 126. Friestad, G. K.; Banerjee, K. Org. Lett. 2009, 11, 1095–1098. 7390–7393. 127. Reddy, L. R.; Prasad, K.; Prashad, M. J. Org. Chem. 2012, 77, 6296–6301. 94. Hamersak, Z.; Stipetic, I.; Avdagic, A. Tetrahedron: Asymmetry 2007, 18, 1481– 128. For the synthesis of N-tert-butanesulfinyl c-aryl c-amino esters by a highly 1485. diastereoselective Rh-catalyzed boronic acid addition to enantiopure 95. Park, S. E.; Nam, E. H.; Jang, H. B.; Oh, J. S.; Some, S.; Lee, Y. S.; Song, C. E. Adv. sulfinylimines, see: Ramachandran, P. V.; Mitsuhashi, W.; Biswas, B. Org. Synth. Catal. 2010, 352, 2211–2217. Chem. Front. 2015, 2, 885–889. 96. Yang, H.-J.; Xiong, F.-J.; Chen, X.-F.; Chen, F.-E. Eur. J. Org. Chem. 2013, 4495– 129. Saavedra, C. J.; Boto, A.; Hernández, R. Org. Lett. 2012, 14, 3542–3545. 4498. 130. Chin, J.; Kwon, S. H.; Kim, H.; Chin, P.; So, S. M.; Kim, B. M. Eur. J. Org. Chem. 97. Ji, L.; Ma, Y.; Li, J.; Zhang, L.; Zhang, L. Tetrahedron Lett. 2009, 50, 6166–6168. 2014, 725–730. 98. Yan, L.-J.; Wang, H.-F.; Chen, W.-X.; Tao, Y.; Jin, K.-J.; Chen, F.-E. ChemCatChem 131. Xue, Z.-Y.; Liu, L.-X.; Jiang, Y.; Yuan, W.-C.; Zhang, X.-M. Eur. J. Org. Chem. 2016, 8, 2249–2253. 2012, 251–255. 99. For the preparation of (R)-3-(4-chlorophenyl)glutaric acid monoamide 210 by 132. Appayee, C.; Fraboni, A. J.; Brenner-Moyer, S. E. J. Org. Chem. 2012, 77, 8828– enzymatic desymmetrization of 3-(4-chlorophenyl)glutarimide, see: Nojiri, 8834. M.; Hibi, M.; Shizawa, H.; Horinouchi, N.; Yasohara, Y.; Takahashi, S.; Ogawa, J. 133. Wei, Z. Y.; Knaus, E. E. Synlett 1994, 345–346. Appl. Microbiol. Biotechnol. 2015, 99, 9961–9969. 134. Shen, L.-T.; Sun, L.-H.; Ye, S. J. Am. Chem. Soc. 2011, 133, 15894–15897. 100. Jung, J.-H.; Yoon, D.-H.; Kang, P.; Lee, W. K.; Eum, H.; Ha, H.-J. Org. Biomol. 135. Chen, X.-Y.; Xia, F.; Cheng, J.-T.; Ye, S. Angew. Chem., Int. Ed. 2013, 52, 10644– Chem. 2013, 11, 3635–3641. 10647. 101. For the resolution of (±)-111b and derivatives, see: (a) Xu, F.; Chen, S.; Xu, G.; 136. Gnamm, G.; Franck, G.; Miller, N.; Stork, T.; Brödner, K.; Helmchen, G. Wu, J.; Yang, L. Biotechnol. Bioprocess Eng. 2015, 20, 473–487; (b) Lia, X.-J.; Synthesis 2008, 20, 3331–3350. Zhenga, R.-C.; Maa, H.-Y.; Huanga, J.-F.; Zhenga, Y.-G. J. Biotechnol. 2014, 188, 137. Sharma, A.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 17983–17989. 29–35; (c) Zheng, R.-C.; Wang, T.-Z.; Fu, D.-J.; Li, A.-P.; Li, X.-J.; Zheng, Y.-G. 138. Bao, H.; Tambar, U. K. J. Am. Chem. Soc. 2012, 134, 18495–18498. Appl. Microbiol. Biotechnol. 2013, 97, 4839–4847; (d) Zheng, R.-C.; Li, A.-P.; 139. (a) Lundgren, R. J.; Wilsily, A.; Marion, N.; Ma, C.; Chung, Y. K.; Fu, G. C. Angew. Wu, Z.-M.; Zheng, J.-Y.; Zheng, Y.-G. Tetrahedron: Asymmetry 2012, 23, 1517– Chem., Int. Ed. 2013, 52, 2525–2528; for the synthesis of a, b-unsaturated c- 1521; (e) Mukherjee, H.; Martinez, C. A. ACS Catal. 2011, 1, 1010–1013. 1054 M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055

amino esters bearing pyrrolidine ring, see: (b) Takahashi, K.; Haraguchi, N.; 182. Kavitha, N.; Kumar, V. P.; Chandrasekhar, S. Tetrahedron Lett. 2013, 54, 2128– Ishihara, J.; Hatakeyama, S. Synlett 2008, 671–674. 2130. 140. Zhou, Y.-Y.; Wang, L.-J.; Li, J.; Sun, X.-L.; Tang, Y. J. Am. Chem. Soc. 2012, 134, 183. Duschmal, J.; Wennemers, H. Chem. Eur. J. 2012, 18, 1111–1120. 9066–9069. 184. Kotkar, S. P.; Chavan, V. B.; Sudalai, A. Org. Lett. 2007, 9, 1001–1004. 141. Burgos, P. O.; Fernández, I.; Iglesias, M. J.; García-Granada, S.; López, O. F. Org. 185. Mathieu, L.; Bonnel, C.; Masurier, N.; Maillard, L. T.; Martinez, J.; Lisowski, V. Lett. 2008, 10, 537–540. Eur. J. Org. Chem. 2015, 2262–2270. 142. Nasopoulou, M.; Georgiadis, D.; Matziari, M.; Dive, V.; Yiotakis, A. J. Org. Chem. 186. Hu, X.-G.; Lawer, A.; Peterson, M. B.; Iranmanesh, H.; Ball, G. E.; Hunter, L. Org. 2007, 72, 7222–7228. Lett. 2016, 18, 662–665. 143. Kumar, M. G.; Mali, S. M.; Gopi, H. N. Org. Biomol. Chem. 2013, 11, 803–813. 187. Ghosh, A. K.; Bischoff, A.; Cappiello, J. Eur. J. Org. Chem. 2003, 821–832. 144. For the synthesis of (S)-322c, see: Fu, Y.; Xu, B.; Zou, X.; Ma, C.; Yang, X.; Mou, 188. (a) Hui, H.; Dequn, S. Prog. Chem. 2015, 27, 1260–1274; (b) Fang, Z.; Song, Y.; K.; Fu, G.; Lu, Y.; Xu, P. Bioorg. Med. Chem. Lett. 2007, 17, 1102–1106. Zhan, P.; Zhang, Q.; Liu, X. Future Med. Chem. 2014, 6, 885–901. 145. Kulkarni, S. J.; Pedduri, Y.; Chittiboyina, A. G.; Avery, M. A. J. Org. Chem. 2010, 189. Duke, R. K.; Chebib, M.; Balcar, V. J.; Allan, R. D.; Mewett, K. N.; Johnston, G. A. 75, 3113–3116. R. J. Neurochem. 2000, 75, 2602–2610. 146. Mali, S. M.; Bandyopadhyay, A.; Jadhav, S. V.; Kumar, M. G.; Gopi, H. N. Org. 190. (a) Kang, Y. K.; Lee, J. Y. New J. Chem. 2015, 39, 3241–3249; (b) Lee, J. H.; Park, Biomol. Chem. 2011, 9, 6566–6574. H. S.; Kang, Y. K. New J. Chem. 2015, 39, 4640–4646. 147. Soto-Cairoli, B.; de Pomar, J. J.; Soderquist, A. J. Org. Lett. 2008, 10, 333–336. 191. Sugeno, Y.; Ishikawa, Y.; Oikawa, M. Synlett 2014, 987–990. 148. Mou, K.; Xu, B.; Ma, C.; Yang, X.; Zou, X.; Lü, Y.; Xu, P. Bioorg. Med. Chem. Lett. 192. Oikawa, M.; Sugeno, Y.; Ishikawa, Y.; Tukada, H. Synlett 2013, 886–888. 2008, 18, 2198–2202. 193. Nakada, K.; Yoshikawa, M.; Ide, S.; Suemasa, A.; Kawamura, S.; Kobayashi, T.; 149. Jadhav, S. V.; Misra, R.; Singh, S. K.; Gopi, H. N. Chem. Eur. J. 2013, 19, 16256– Masuda, E.; Ito, Y.; Hayakawa, W.; Katayama, T.; Yamada, S.; Arisawa, M.; 16262. Minami, M.; Shuto, S. Bioorg. Med. Chem. 2013, 21, 4938–4950. 150. Paliwal, S.; Reichard, G. A.; Shah, S.; Wrobleski, M. L.; Wang, C.; Stengone, C.; 194. Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53–58. Tsui, H.-C.; Xiao, D.; Duffy, R. A.; Lachowicz, J. E.; Nomeir, A. A.; Varty, G. B.; 195. Aitken, D. J.; Bull, S. D.; Davies, I. R.; Drouin, L.; Ollivier, J.; Peed, J. Synlett 2010, Shih, N.-Y. Bioorg. Med. Chem. Lett. 2008, 18, 4168–4171. 2729–2732. 151. Kand, D.; Chauhan, D. P.; Lahiri, M.; Talukdar, P. Chem. Commun. 2013, 3591– 196. Rodríguez-Soria, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron 2008, 64, 2750– 3593. 2754. 152. Raj, I. V. P.; Sudalai, A. Tetrahedron Lett. 2008, 49, 2646–2648. 197. Roggen, H.; Kehler, J.; Stensbol, T. B.; Hansen, T. Bioorg. Med. Chem. Lett. 2007, 153. Emmett, M. R.; Grover, H. K.; Kerr, M. A. J. Org. Chem. 2012, 77, 6634–6637. 17, 2834–2837. 154. Ramachandran, P. V.; Biswas, D. Org. Lett. 2007, 9, 3025–3027. 198. Alliot, J.; Gravel, E.; Pillon, F.; Buisson, D.-A.; Nicolas, M.; Doris, E. Chem. 155. Juncosa, J. I.; Groves, A. P.; Xia, G.; Silverman, R. B. Bioorg. Med. Chem. 2013, 21, Commun. 2012, 8111–8113. 903–911. 199. (a) Tamiya, J.; Dyck, B.; Zhang, M.; Phan, K.; Fleck, B. A.; Aparicio, A.; Jovic, F.; 156. Katritzky, A. R.; Tao, H.; Jiang, R.; Suzuki, K.; Kirichenko, K. J. Org. Chem. 2007, Tran, J. A.; Vickers, T.; Grey, J.; Foster, A. C.; Chen, C. Biorg. Med. Chem. Lett. 72, 407–414. 2008, 18, 3328–3332; (b) Vickers, T.; Dyck, B.; Tamiya, J.; Zhang, M.; Jovic, F.; 157. Schneider, S.; Ftouni, H.; Niu, S.; Schmitt, M.; Simonin, F.; Bihel, F. Org. Biomol. Grey, J.; Fleck, B. A.; Aparicio, A.; Johns, M.; Jin, L.; Tang, H.; Fosterd, A. C.; Chem. 2015, 13, 7020–7026. Chen, C. Biorg. Med. Chem. Lett. 2008, 18, 3230–3235. 158. Kawasoko, C. Y.; Foletto, P.; Rodrigues, O. E. D.; Dornelles, L.; Schwab, R. S.; 200. (a) Sakai, M.; Ishikawa, Y.; Takamizawa, S.; Oikawa, M. Tetrahedron Lett. 2013, Braga, A. L. Org. Biomol. Chem. 2013, 11, 5173–5183. 54, 5911–5912; (b) Sakai, M.; Tanaka, K.; Takamizawa, S.; Oikawa, M. 159. Ping, W.; Chunhua, M.; Senhan, X.; Yingxia, L.; Yanjun, Z.; Wei, Z. Chin. J. Org. Tetrahedron 2014, 70, 4587–4594. Chem. 2016, 36, 191–195. 201. Nakagawa, Y.; Chanthamath, S.; Shibatomi, K.; Iwasa, S. Org. Lett. 2015, 17, 160. (a) Shon, M.; Shanmugavel, R.; Shin, G.; Mathew, S.; Lee, S.-H.; Yun, H. Chem. 2792–2795. Commun. 2014, 12680–12683; (b) athew, S.; Nadarajan, S. P.; Chung, T.; Park, 202. Aitken, D. J.; Drouin, L.; Goretta, S.; Guillot, R.; Ollivier, J.; Spiga, M. Org. H. H.; Yun, H. Enzyme Microb. Technol. 2016, 87–88, 52–60. Biomol. Chem. 2011, 9, 7517–7524. 161. Pandya, B. A.; Dandapani, S.; Duvall, J. R.; Rowley, A.; Mulrooney, C. A.; Ryba, 203. Gajcy, K.; Pekala, J.; Frackowiak-Wojtasek, B.; Librowski, T. Tetrahedron: T.; Domdrowski, M.; Harton, M.; Young, D. W.; Marcaurelle, L. A. Tetrahedron Asymmetry 2010, 21, 2015–2020. 2011, 67, 6131–6137. 204. Kobayashi, T.; Suemasa, A.; Igawa, A.; Ide, S.; Fukuda, H.; Abe, H.; Arisawa, M.; 162. Zhang, M.-L.; Chen, L.; You, Y.; Wang, Z.-H.; Yue, D.-F.; Zhang, X.-M.; Xu, X.-Y.; Minami, M.; Shuto, S. ACS Med. Chem. Lett. 2014, 5, 889–893. Yuan, W.-C. Tetrahedron 2016, 72, 2677–2682. 205. (a) André, V.; Vidal, A.; Ollivier, J.; Robin, S.; Aitken, D. J. Tetrahedron Lett. 163. (a) Hunter, L.; Jolliffe, K. A.; Jordan, M. J. T.; Jensen, P.; Macquart, R. B. Chem. 2011, 52, 1253–1255; (b) André, V.; Gras, M.; Awada, H.; Guillot, R.; Robin, S.; Eur. J. 2011, 17, 2340–2343; (b) Yamamoto, I.; Jordan, M. J. T.; Gavande, N.; Aitken, D. J. Tetrahedron 2013, 69, 3571–3576. Doddareddy, M. R.; Chebib, M.; Hunter, L. Chem. Commun. 2012, 829–831; (c) 206. Awada, H.; Robin, S.; Guillot, R.; Yazbeck, O.; Naoufal, D.; Jaber, N.; Hachem, Patel, A. R.; Hu, X.-G.; Lawer, A.; Ahmed, Md. I.; Au, C.; Jwad, R.; Trinh, J.; A.; Aitken, D. J. Eur. J. Org. Chem. 2014, 7148–7155. Gonzalez, C.; Hannah, E.; Bhadbhade, M. M.; Hunter, L. Tetrahedron 2016, 72, 207. Aguilera, J.; Moglioni, A. G.; Moltrasio, G. Y.; Ortuño, R. M. Tetrahedron: 3305–3317. Asymmetry 2008, 19, 302–308. 164. Raghavan, B.; Balasubramanian, R.; Steele, C. J.; Sackett, L. D.; Fecik, A. R. J. 208. (a) Aguilera, J.; Cobos, J. A.; Gutiérrez-Abad, R.; Acosta, C.; Nolis, P.; Illa, O.; Med. Chem. 2008, 51, 1530–1533. Ortuño, R. M. Eur. J. Org. Chem. 2013, 3494–3503; (b) Gutiérrez-Abad, R.; 165. Dömling, A.; Beck, B.; Eichelberger, U.; Sakamuri, S.; Menon, S.; Chen, Q.-Z.; Carbajo, D.; Nolis, P.; Acosta-Silva, C.; Cobos, J. A.; Illa, O.; Royo, M.; Ortuño, R. Lu, Y.; Wessjohann, L. A. Angew. Chem., Int. Ed. 2006, 45, 7235–7239. M. Amino Acids 2011, 41, 673–686; For applications, see: (c) Gorrea, E.; 166. Pando, O.; Dörner, S.; Preusentanz, R.; Denkert, A.; Porzel, A.; Richter, W.; Carbajo, D.; Gutiérrez-Abad, R.; Illa, O.; Branchadell, V.; Royo, M.; Ortuño, R. Wessjohann, L. Org. Lett. 2009, 11, 5567–5569. M. Org. Biomol. Chem. 2012, 10, 4050–4057. 167. Zhu, Y.; Khumsubdee, S.; Schaefer, A.; Burgess, K. J. Org. Chem. 2011, 76, 7449– 209. (a) Guiliano, M. W.; Maynard, S. J.; Almeida, A. M.; Reidenbach, A. G.; Guo, L.; 7457. Ulrich, E. C.; Guzei, I. A.; Gellman, S. H. J. Org. Chem. 2013, 78, 12351–12361; 168. Becker, D.; Kazmaier, U. J. Org. Chem. 2013, 78, 59–65. (b) Guo, L.; Zhang, W.; Reidenbach, A. G.; Giuliano, M. W.; Guzei, I. A.; 169. Cella, R.; Venturoso, R. C.; Stefani, H. A. Tetrahedron Lett. 2008, 49, 16–19. Spencer, L. C.; Gellman, S. H. Angew. Chem., Int. Ed. 2011, 50, 5843–5846. 170. Telle, W.; Kelter, G.; Fiebig, H.-H.; Jones, P. G.; Lindel, T. Beilstein J. Org. Chem. 210. Enders, D.; Wang, C.; Bats, J. W. Angew. Chem., Int. Ed. 2008, 47, 7539–7542. 2014, 10, 316–322. 211. Singh, R.; Vince, R. Chem. Rev. 2012, 112, 4642–4686. 171. For the synthesis of (S)-c-amino b-keto esters, see also: Katritzky, R. A.; Wang, 212. Cai, C.; Kang, F.-A.; Beauchamp, D. A.; Sui, Z.; Russell, R. K. Tetrahedron: Z.; Hall, D. C. ARKIVOC 2008, x, 26–36. Asymmetry 2013, 24, 651–656. 172. (a) Bandyopadhyay, A.; Agrawal, N.; Mali, S. M.; Jadhav, S. V.; Gopi, H. N. Org. 213. Rodríguez-Vázquez, N.; Salzinger, S.; Silva, L. F.; Amorín, M.; Granja, J. R. Eur. J. Biomol. Chem. 2010, 8, 4855–4860; (b) Bandyopadhyay, A.; Malik, A.; Kumar, Org. Chem. 2013, 3477–3493. M. G.; Gopi, H. N. Org. Lett. 2014, 16, 294–297. 214. (a) Zhu, S.; Ren, L.; Yu, S.; Gong, C.; Song, D.; Zheng, G. Bioorg. Med. Chem. Lett. 173. For recent advances in the diastereoselective Reformatsky-type reaction, see: 2014, 24, 4899–4902; (b) Assaf, Z.; Eger, E.; Vitnik, Z.; Fabian, W. M. F.; Choppin, S.; Ferreiro-Medeiros, L.; Barbarotto, M.; Colobert, F. Chem. Soc. Rev. Ribitsch, D.; Guebitz, G. M.; Faber, K.; Hall, M. ChemCatChem 2014, 6, 2517– 2013, 42, 937–949. 2521; (c) Yin, J.-G.; Gong, Y.; Zhang, X.-Y.; Zheng, G.-W.; Xu, J.-H. Catal. Sci. 174. Nelson, C. G.; Burke, T. R., Jr. J. Org. Chem. 2012, 77, 733–738. Technol. 2016, 6, 6305–6310. 175. Segade, Y.; Montaos, M. A.; Rodríguez, J.; Jiménez, C. Org. Lett. 2014, 16, 5820– 215. Forró, E.; Fülöp, F. Eur. J. Org. Chem. 2008, 5263–5268. 5823. 216. Winkler, M.; Knall, A. C.; Kulterer, M. R.; Klempier, N. J. Org. Chem. 2007, 72, 176. Mordant, C.; Reymond, S.; Tone, H.; Lavergne, D.; Touati, R.; Hassine, B. B.; 7423–7426. Ratovelomanana-Vidal, V.; Genet, J.-P. Tetrahedron 2007, 63, 6115–6123. 217. Zheng, C.; Cao, G.; Xia, M.; Feng, H.; Glenn, J.; Anand, R.; Zhang, K.; Huang, T.; 177. Yoo, D.; Song, J.; Kang, M. S.; Kang, E.-S.; Kim, Y. G. Tetrahedron: Asymmetry Anlai Wanga, A.; Ling Kong, L.; Li, M.; Galya, L.; Hughes, R. O.; Devraj, R.; 2011, 22, 1700–1704. Morton, P. A.; Rogier, D. J.; Covington, M.; Baribaud, F.; Shin, N.; Scherle, P.; 178. For the synthesis of ethyl derivative (2R,3S,4S)-455, see: Fu, Y.; Xu, B.; Zou, X.; Diamond, S.; Yeleswaram, S.; Vaddi, K.; Newton, R.; Hollis, G.; Friedman, S.; Ma, C.; Yang, X.; Mou, K.; Fu, G.; Lu, Y.; Xu, P. Bioorg. Med. Chem. Lett. 2007, 17, Metcalf, B.; Xue, C.-B. Bioorg. Med. Chem. Lett. 2011, 21, 1442–1446. 1102–1106. 218. Kothandaraman, S.; Donnely, K. L.; Butora, G.; Jiao, R.; Pasternak, A.; Morriello, 179. Kumar, M. G.; Gopi, H. N. Org. Lett. 2015, 17, 4738–4741. G. J.; Goble, S. D.; Zhou, C.; Mills, S. G.; MacCoss, M.; Vicario, P. P.; Ayala, J. M.; 180. Ghosh, A. K.; Shurrush, K.; Kulkarni, S. J. Org. Chem. 2009, 74, 4508–4518. DeMartino, J. A.; Struthers, M.; Cascieri, M. A.; Yang, L. Bioorg. Med. Chem. Lett. 181. Noole, A.; Pehk, T.; Järving, I.; Lopp, M.; Kanger, T. Tetrahedron: Asymmetry 2009, 19, 1830–1834. 2012, 23, 188–198. 219. Eagles, J. B.; Hitchcock, S. R. Tetrahedron: Asymmetry 2010, 21, 519–523. M. Ordóñez et al. / Tetrahedron: Asymmetry 27 (2016) 999–1055 1055

220. Kamlet, A. S.; Préville, C.; Farley, K. A.; Piotrowski, D. W. Angew. Chem., Int. Ed. 231. Guo, L.; Chi, Y.; Almeida, A. M.; Guzei, I. A.; Parker, B. K.; Gellman, S. H. J. Am. 2013, 52, 10607–10610. Chem. Soc. 2009, 131, 16018–16020. 221. (a) Kiss, L.; Forró, E.; Sillanpää, R.; Fülöp, F. Tetrahedron 2010, 66, 3599–3607; 232. Badland, M.; Bains, C. A.; Howard, R.; Laity, D.; Newman, S. D. Tetrahedron: (b) Kiss, L.; Forró, E.; Sillanpää, R.; Fülöp, F. Synthesis 2010, 153–160. Asymmetry 2010, 21, 864–866. 222. Pinto, A.; Tamborini, L.; Pennacchietti, E.; Coluccia, A.; Silvestri, R.; Cullia, G.; 233. Karlsson, S. Org. Process Res. Dev. 2016, 20, 1336–1340. De Micheli, C.; Conti, P.; De Bias, D. J. Enzyme Inhib. Med. Chem. 2016, 31, 295– 234. Prazeres, V. F. V.; Castedo, L.; González-Bello, C. Eur. J. Org. Chem. 2008, 3991– 301. 4003. 223. Kiss, L.; Nonn, M.; Fülöp, F. Synthesis 2012, 1951–1963. 235. Pilgrim, S.; Kociok-Kohn, G.; Lloyd, M. D.; Lewis, S. E. Chem. Commun. 2011, 224. Risseeuw, M. D. P.; Overhand, M.; Fleet, G. J. W.; Simone, M. I. Tetrahedron: 4799–4801. Asymmetry 2007, 18, 2001–2010. 236. Franconetti, A.; Jatunov, S.; Borrachero, P.; Gómez-Guillén, M.; Cabrera- 225. Le, H. V.; Hawker, D. D.; Wu, R.; Doud, E.; Widom, J.; Sanishvili, R.; Liu, D.; Escribano, F. Org. Biomol. Chem. 2013, 11, 676–686. Kelleher, N. L.; Silverman, R. B. J. Am. Chem. Soc. 2015, 137, 4525–4533. 237. Gondo, C. A.; Bode, J. W. Synlett 2013, 1205–1210. 226. Szakonyi, Z.; Balazs, A.; Martinek, T. A.; Fülöp, F. Tetrahedron: Asymmetry 238. (a) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35–37; (b) Anderson, J. C.; 2010, 21, 2498–2504. Noble, A.; Tocher, D. A. J. Org. Chem. 2012, 77, 6703–6727. 227. Guo, L.; Zhang, W.; Guzei, I. A.; Spencer, L. C.; Gellman, S. H. Org. Lett. 2012, 14, 239. Kolarovic, A.; Käslin, A.; Wennemers, H. Org. Lett. 2014, 16, 4236–4239. 2582–2585. 240. Jatoi, W. B.; Desiront, A.; Job, A.; Troin, Y.; Canet, J.-L. J. Fluorine Chem. 2013, 228. Guilano, M. W.; Maynard, S. J.; Almeida, A. M.; Guo, L.; Guzei, I. A.; Spencer, L. 145, 8–17. C.; Gellman, S. H. J. Am. Chem. Soc. 2014, 136, 15046–15053. 241. McBriar, D. M.; Clader, W. J.; Chu, I.; Del Vecchio, R. A.; Favreau, L.; Greenlee, 229. Xu, Y.; Lin, L.; Kanai, M.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2011, W. J.; Hyde, L. A.; Nomeir, A. A.; Parker, E. M.; Pissarnitski, D. A.; Song, L.; 133, 5791–5793. Zhang, L.; Zhao, Z. Bioorg. Med. Chem. Lett. 2008, 18, 215–219. 230. (a) Nodes, W. J.; Nutt, D. R.; Chippindale, A. M.; Cobb, A. J. A. J. Am. Chem. Soc. 242. Zhang, G.-L.; Zheng, X.-J.; Zhang, L.-H.; Ye, X.-S. MedChemComm 2011, 2, 909– 2009, 131, 16016–16017; (b) Nodes, W. J.; Shankland, K.; Rajkumar, S.; Cobb, 917. A. J. A. Synlett 2010, 3011–3014.