Tetrahedron: Asymmetry 25 (2014) 362–372

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Tetrahedron: Asymmetry

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Base-promoted diastereoselective addition of nitromethane andnitroethane to N-tert-butylsulfinyl imines: synthesis of N-protecteda-amino acids and amino ketones

0957-4166/$ - see front matter � 2014 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetasy.2014.01.010

⇑ Corresponding authors. Tel.: +34 965903548; fax: +34 965 903549.E-mail addresses: foubelo@ua.es (F. Foubelo), yus@ua.es (M. Yus).

M. Jesús García-Muñoz, Haythem K. Dema, Francisco Foubelo ⇑, Miguel Yus ⇑Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain

a r t i c l e i n f o

Article history:Received 16 December 2013Accepted 10 January 2014

Dedicated to Professor Max Malacria on theoccasion of his 65th birthday.

a b s t r a c t

The reaction of N-tert-butylsulfinyl imines with nitromethane or nitroethane in the presence of NaHCO3

under solvent-free reaction conditions gave b-nitro amine derivatives with reasonable levels of diastere-oselectivity. Enantioenriched N-tert-butylsulfinyl protected a-amino acids or a-amino ketones are acces-sible upon oxidation of the adducts derived from nitromethane or nitroethane, respectively.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction

The addition of an organometallic compound1 or an active C–Hnucleophile to an imine is of great synthetic interest because inthis reaction together with a new functionality (the amino group),a C–C bond is formed. Thus, if the additions are carried out in astereoselective fashion, enantioenriched amines, or amine deriva-tives, would be produced. These compounds are valuable targetsfor synthetic organic chemists because of their importance in agro-chemicals, fine chemicals, and pharmaceuticals. Among the reac-tions of imines with active C–H nucleophiles, the nitro-Mannich(also known as aza-Henry) reaction,2 in which a nitronate anionis involved, has received much attention over the last decade,and as a consequence of this, new methodologies are constantlyemerging. The resulting b-nitroamine compounds, known as ni-tro-Mannich adducts, bearing vicinal nitrogen-containing func-tionalities in different oxidation states, are versatileintermediates that can be easily transformed into a wide range ofinteresting multifunctionalized molecules, such as 1,2-diamines3

and a-aminocarbonyl compounds, via reduction of the nitro groupor performing a Nef-type oxidation reaction, respectively.4 Impor-tantly, enantiomerically pure b-nitroamine compounds have beenaccessed through both metal-based and organic catalysis.5 Otherstrategies to reach these compounds involve the use of chiral imi-nes, such as N-tert-butylsulfinyl derivatives,6 which have foundhigh applicability in synthesis as electrophiles because both enan-tiomers are accessible via large-scale processes7 and because thechiral auxiliary can be easily removed under acidic conditions. Inaddition, practical processes for recycling the tert-butylsulfinylgroup upon deprotection of N-tert-butanesulfinyl amines have also

been reported.8 In this context, we described the diastereoselectivecoupling of dimethyl malonate with N-(tert-butyl)sulfinyl iminesunder solvent-free conditions and using NaHCO3 as a base pro-moter. The resulting dimethyl 2-(1-aminoalkyl)malonates wereeasily transformed successively to b-amino esters and the corre-sponding b-lactams with high enantiomeric purity.9 Continuingour interest in this topic, we herein report our first approach tothe base-mediated coupling of nitroalkanes and chiral N-(tert-butyl)sulfinyl imines under mild reaction conditions. Consideringthe nitro-Mannich reaction using sulfinyl imines as electrophiles,in 2005, García Ruano, Cid et al. reported the asymmetric reactionof N-p-toluene sulfinyl aldimines and ketimines with nitromethaneand nitroethane. They found opposite facial selectivity dependingon the reaction conditions (Scheme 1).10 However, to the best ofour knowledge, there is only one report involving the nitro-Man-nich reaction of an N-tert-butylsulfinyl aldimine, which Lu et al.used in one step of their synthesis of the antiviral oseltamivir(Scheme 1).11 More recently, Liu reported on the nitro-Mannichreaction of chiral fluoroalkyl a,b-unsaturated N-tert-butylsulfinylketimines and nitromethane in the presence of 0.2 equiv of anhy-drous potassium carbonate (Scheme 1).12

2. Results and discussion

In order to determine the best reaction conditions for the cou-pling of nitromethane 2a and chiral N-tert-butanesulfinyl imines1, we took imine (R)-1c (derived from 3-phenylpropanal) as themodel compound. Sodium iodide has recently been successfullyused as a promoter of the condensation of bromonitromethanewith imines,13 and also in the reaction of dimethyl malonate withchiral imines 1.9 Unfortunately, no reaction occurred when 2 equivof nitromethane 2a and imine (R)-1c were treated with 1 equiv ofsodium iodide in THF at room temperature for 72 h (Table 1, entry

H

O

Me

Me

N

OH

SOt-Bu

MeNO2

NaOH, 4Å MS, 23 ºC

O

Me

Me

HN

OH

SOt-Bu

NO2

(86%, 10:1 dr)

O

Me

Me

AcHN

NH2

CO2Et

oseltamivir

R1 R2

NS

O

t-Bu

MeNO2

K2CO3 (0.2 equiv), 23 ºC, 3 h R1 R2

HN NO2

St-Bu O

R1 = CF3, CF2Cl, CF2HR2 = Ph, 4-MeOC6H4, 4-ClC6H4, 1-naphthyl, n-C8H18

(54-95%, 95:5 dr)

N

R1R2

S

O

TolCH3NO2

NaOH, 4Å MS40 ºC, 24 h

CH3NO21 M TBAF/THF

23 °C, 1 hNH

R1

R2S

O

TolNO2

NH

R1

R2S

O

TolNO2

R1 = aryl, alkyl, vinylR2 = H, aryl, alkyl

(56-99%, 74:26-62:38 dr) (25-90%, 85:15-97:3 dr)

(10)

(11)

(12)

Scheme 1.

Table 1Optimization of the reaction conditions with nitromethane 2a

reactionconditions

+H

NS

t-Bu

O

(R)-1c

CH3NO2Ph

HNS

t-Bu

O

PhNO2

3c2a

Entry Reaction conditionsa Conversionb (%) drc

1 CH3NO2 (2 equiv), NaI (1.1 equiv), THF (1 mL), 23 �C, 72 h 0 —2 CH3NO2 (3 equiv), NaI (1.1 equiv), 23 �C, 72 h 0 —3 CH3NO2 (3 equiv), NaI (1.1 equiv), 60 �C, 72 h 0 —4 CH3NO2 (3 equiv), NaHCO3 (2 equiv), 23 �C, 72 h 28 90:105 CH3NO2 (3 equiv), NaHCO3 (2 equiv), 60 �C, 72 h 95 92:86 CH3NO2 (2 equiv), NaHCO3 (2 equiv), THF (1 mL), 60 �C, 72 h 70 73:277 CH3NO2 (2 equiv), 2 M NaOH/H2O (1.1 equiv), THF (1 mL), 23 �C, 72 h 0 —8 CH3NO2 (280 equiv, 3 mL), NaOH (5 equiv), 4 Å MS (40 mg), 40 �C, 24 h 84 93:79 CH3NO2 (145 equiv, 1 mL), 1 M TBAF/THF (0.2 equiv), 23 �C, 1 h 100 30:70

a All reactions were carried out using 0.2 mmol of aldimine (R)-3c.b Conversion is given based on the disappearance of the starting (R)-3c by 1H NMR.c The diastereomeric ratio was determined by 1H NMR.

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372 363

1). The same result was obtained under solvent free reaction con-ditions but using 3 equiv of nitromethane 2a and 1 equivalent ofsodium iodide for 3 days at both room temperature and 60 �C (Ta-ble 1, entries 2 and 3). Switching from sodium iodide to sodiumbicarbonate as a base under solvent free conditions led to a lowconversion (28%) and relatively high diastereoselectivity (90:10,Table 1, entry 4) of the expected b-nitroamine derivative 3c. Theconversion was dramatically improved upon when the sodiumbicarbonate mediated coupling was performed at 60 �C instead ofroom temperature (from 28 to 95%); furthermore, a slightly higherdiastereomeric ratio was also achieved (Table 1, entry 5). Con-versely, a lower conversion and diastereoselectivity were obtainedwhen the reaction was performed in THF solution at 60 �C (Table 1,

entry 6). The reaction did not take place in THF at room tempera-ture when a stronger base, such as a 2 M aqueous solution of so-dium hydroxide, was used (Table 1, entry 7). At this point, wedecided to apply to chiral N-tert-butylsulfinyl imine (R)-1c, thesame reaction conditions that García Ruano reported in the highlyeffective asymmetric nitro-Mannich reaction of nitromethane 2awith N-p-toluenesulfinyl imines.10 Thus, the reaction of (R)-1c ina large excess of nitromethane 2a (reagent and solvent) with 5equiv of sodium hydroxide in the presence of 4 Å molecular sievesat 40 �C for 24 h led to 84% conversion and a 93:7 diastereomericratio (Table 1, entry 8). Complete conversion and a significantlylower and reversed diastereoselectivity were obtained when a1 M THF solution of tetrabutylammonium fluoride (TBAF) was used

364 M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372

at room temperature for 1 h, instead of the combination of sodiumhydroxide in the presence of 4 Å molecular sieves (Table 1, entry9).

In order to broaden the scope of the sodium bicarbonate pro-moted nitro-Mannich reaction we applied the optimized condi-tions depicted in Table 1, entry 5, to different N-tert-butylsulfinylaldimines 1. When chiral alkyl aldimines 1 were used, b-nitro-amine derivatives 3 were obtained in moderate to good yieldsand with high diastereomeric ratios (Table 2, entries 1–6). Enantio-meric nitro amine derivatives 3 were accessed through this meth-

Table 2Preparation of b-nitroamine derivatives 3

+R H

NS

t-Bu

O

1

CH3NO2NaHCO

2a (3 equiv)

Aldimine 1

Entry No. R No.

1 (R)-1a CH3(CH2)7 3a

2 (R)-1b i-Pr 3b

3 (R)-1c Ph(CH2)2 3c

4 (S)-1a CH3(CH2)7 ent-3a

5 (S)-1b i-Pr ent-3b

6 (S)-1c Ph(CH2)2 ent-3c

7 (S)-1d Ph ent-3d

8 (R)-1e 2-Benzofuryl 3e

a All products were >95% pure (GLC and/or 300 MHz 1H NMR).b Isolated yield after column chromatography of the major diastereoisomer (silica gelc The diastereomeric ratio was determined by 1H NMR.

odology, depending exclusively on the configuration of the sulfuratom of the starting aldimine (Table 2, compare entries 1 and 4,2 and 5, and 3 and 6). However, in the case of aromatic aldimine(S)-1d derived from benzaldehyde, the expected reaction productent-3d was isolated in 28% yield and lower diastereoselectivitywhen compared with the other aldimines (Table 2, entry 7). A pos-sible explanation for the low yield could be that a retro nitro-Man-nich reaction could occur to a significant extent for this aldimineunder basic conditions. Taking into account the aforementioned re-sults, heteroaromatic aldimine (S)-1e produced the expected

R

HNS

t-Bu

O

NO2

3

3 (2 equiv), 60 ºC, 72 h

b-Nitroamine derivative 3a

Structure Yieldb (%) drc

HNS

t-Bu

O

Me NO27( )

63 93:7

HNS

t-Bu

O

Me NO2

Me

75 90:10

HNS

t-Bu

O

PhNO2

78 92:8

HNS

t-Bu

O

Me NO2( )7

67 92:8

HNS

t-Bu

O

Me NO2

Me

72 90:10

HNS

t-Bu

O

PhNO2

82 91:9

Ph

HNS

t-Bu

O

NO2

28 61:39

HNS

t-Bu

O

NO2

O

66 72:28

, hexane/EtOAc) based on the starting aldimine 1.

Me

NS

t-Bu

O

Me

Me

NS

t-Bu

O

Me

(R)-1f

(R)-1g

HNS

t-Bu

O

NO2MeMe

HNS

t-Bu

O

NO2Me

Me

3f (70%, 92:8dr)

3g(35%, 96:4 dr)

Figure 1.

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372 365

reaction product in high yield, although with moderate diastere-oselectivity (Table 2, entry 8).

The N-tert-butylsulfinyl ketimines also reacted with nitrometh-ane 2a under the optimized reaction conditions. Thus, ketiminesderived from butanone (R)-1f (obtained as an 85:15 E:Z isomericmixture) and 2-heptenone (R)-1g (obtained as an 83:17 E:Z iso-meric mixture) were converted into the b-nitroamine derivatives

Table 3Preparation of N-tert-butylsulfinyl protected a-amino acids 4

R1

HNS

t-Bu

O

NO2

3

NaNO2 (5 equiv), A

DMF, 45 ºR2

b-Nitroamine derivative 3

Entry No. R1 R2

1 3a CH3(CH2)7 H

2 ent-3b i-Pr H

3 3c Ph(CH2)2 H

4 3f CH3(CH2)4 Me

5 3g Et Me

a All products were >95% pure (GLC and/or 300 MHz 1H NMR).b Isolated yield after acid–base extraction based on the starting b-nitroamine derivati

3f and 3g, respectively, in a reasonable yield for 3f and a modestisolated yield in the case of 3g [starting ketimine (R)-1g was themajor component of the resulting reaction mixture]. However,both reaction products were obtained with excellent diastereose-lectivities (Fig. 1). The diastereomeric ratios exceeded the E:Z iso-meric ratios of the starting ketimines. We have previouslyobserved that the indium-mediated allylation14 and propargyla-tion15 of N-tert-butylsulfinyl methyl alkyl ketimines proceeded inan almost diastereoselective fashion.

In order to show the potential synthetic usefulness of theseb-nitroamine derivatives 3, some of them were transformed intoN-tert-butylsulfinyl protected a-amino acids 4 upon treatmentwith sodium nitrite and acetic acid in dimethylformamide (DMF)at 45 �C for 12 h (Table 3).16 After base-acid extraction, pure com-pounds 4 were obtained in reasonable yields (no column chroma-tography purification was needed). Remarkably, this methodologyallowed the synthesis of a-amino acid derivatives 4 with thenitrogen bonded to a quaternary stereocenter, as in the case ofb-nitroamines 3f,g derived from ketimines (R)-1g and (R)-1f,respectively (Table 3, entries, 4 and 5). It is noteworthy that thisvariant of the Nef oxidation of primary nitroalkanes proceedsunder mild acidic conditions which are compatible with theN-tert-butanesulfinamide acid sensitive functionality.

cOH (6 equiv)

C, 12 h R1

HNS

t-Bu

O

O

4OH

R2

a-Amino acid derivative 4a

No. Structure Yieldb (%)

4aHN

St-Bu

O

Me O7

OH

( )50

ent-4bHN

St-Bu

O

Me O

Me OH

68

4cHN

St-Bu

O

PhO

OH

56

4fHN

St-Bu

O

Me OMe

OH

40

4gHN

St-Bu

O

OMe

Me

OH

46

ve 3.

366 M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372

In addition, the nitro group could be reduced to an amino groupby using sodium borohydride in the presence of nickel dichloridehexahydrate.17 This transformation was exemplified by transform-ing compound ent-3b into ent-5b, which after subsequent protec-tion of the free amino group with benzyloxycarbonyl chloride(CbzCl) under basic conditions produced 1,2-diamino derivativeent-6b in 52% overall yield, based on the starting nitro compoundent-3b (Scheme 2). Vicinal diamine derivative ent-6b could betransformed with complete chemoselectivity involving the aminofunctionalities because the protecting groups could be removedunder different reaction conditions: an acid medium for the tert-butylsulfinyl unit and a catalytic hydrogenation for the benzyloxy-carbonyl group.

We also studied the more challenging reaction of these chiralN-tert-butylsulfinyl imines 1 with nitroethane 2b, due to theformation of two stereogenic centers. We found that what weconsidered the optimal reaction conditions for the addition ofnitromethane 2a to our model ketimine (R)-1c worked equally aswell with nitroethane 2b. Thus, the reaction of (R)-1c with 3 equivof nitroethane 2b in the presence of 2 equiv of sodium bicarbonateat 60 �C for 72 h led to a conversion of 93% (83% isolated yield aftercolumn chromatography) with good facial diastereoselectivity(90:10). On the other hand, the reaction of (R)-1c in a large excessof nitroethane 2b with 5 equiv of sodium hydroxide in the pres-ence of 4 Å molecular sieves at 45 �C for 24 h led in this case to alow conversion (23%) although with high facial diastereoselectivity(95:5 dr) (Table 4, entry 2). Conversion was greatly improved uponwhen working at a higher temperature for longer reaction time,but in this case the diastereoselectivity diminished significantly(Table 4, entry 3). A lower and reverse facial selectivity was alsoobserved when the reaction was carried out in a large excess ofnitroethane 2b in the presence of a substoichiometric amount ofa 1 M THF solution of TBAF (Table 4, entry 4). Considering the ste-reogenic center bearing the nitro group, an almost 1:1 mixture ofepimers was obtained in all cases.

The addition of nitroethane 2b to aldimines 1 proceeded wellunder the reaction conditions shown in Table 4, entry 1. Unfortu-

NiCl2·6H2O, NaBH4

-5 ºC, MeOH, 15 minHN

St-Bu

O

Me NO2

Me

ent-3b

HNS

O

Me

Me

ent-5b

Scheme

Table 4Optimization of the reaction conditions with nitroethane 2b

rco

+H

NS

t-Bu

O

(R)-1c

EtNO2Ph

2b

Entry Reaction conditionsa

1 EtNO2 (3 equiv), NaHCO3 (2 equiv), 60 �C, 72 h2 EtNO2 (280 equiv, 3 mL), NaOH (5 equiv), 4 Å MS (40 mg3 EtNO2 (280 equiv, 3 mL), NaOH (5 equiv), 4 Å MS (40 mg4 EtNO2 (145 equiv, 1 mL), 1 M TBAF/THF (0.2 equiv), 23 �C

a All reactions were carried out using 0.2 mmol of aldimine (R)-1c.b Conversion is given based on the disappearance of the starting (R)-1c by 1H NMR.c The diastereomeric ratio was determined by 1H NMR and refers to the facial selecti

nately, the reaction did not take place under the optimized reac-tion conditions with ketimines. In these reactions, twostereogenic centers are generated, and the diastereomeric ratiosshown in Table 5 refer to the facial selectivity. With regard tothe second stereogenic center, an almost 1:1 mixture of epimerswas always obtained, probably due to the reaction conditions (pro-longed reaction times in the presence of a base), considering thatan acidic proton remains in 7, so epimerization could take placerapidly. The sterically congested aldimine (R)-1b derived from iso-butyraldehyde along with aromatic aldimine (R)-1d derived frombenzaldehyde performed poorly to produce the expected reactionproducts 7b and 7d in only 26% and 27% yield, respectively,although with excellent diastereoselectivity in the case of the ali-phatic imine (Table 5, entries 2 and 4). Compared to (R)-1d, theyield obtained was much higher for the aromatic aldimine (R)-1j,derived from o-bromobenzaldehyde, while both performed simi-larly regarding the diastereoselectivity (Table 5, entry 7). Unfortu-nately, it was not possible to separate, after columnchromatography the two pair of epimers for aromatic derivatives7d and 7j (Table 5, entries 4 and 7).

In order to establish the utility of the obtained b-nitroaminederivatives 7, some of them were transformed from an epimericmixture into a single isomer upon oxidation by treatment withpotassium hydroxide in methanol, followed by the addition ofpotassium permanganate and magnesium sulfate at 0 �C(Table 6).18 In this way, the N-tert-butylsulfinyl protected a-aminoketones 8 were obtained in moderate yields. It is worth mentioningthat these mild reaction conditions prevent epimerization at thestereogenic center adjacent to the carbonyl group.

The configuration of the newly created stereogenic center in b-nitroamine derivatives 3 and 7 was determined by comparing thespecific rotation of ent-4b {configuration (SS,S), mp 125–128 �C,½a�23

D ¼ þ84:2 (c 1.07, CHCl3)}, with that provided in the literaturefor its enantiomer (RS,R)-N-tert-butylsulfinyl-2-amino-3-methylb-utanoic acid (D-N-tert-butylsulfinylvaline) {configuration (RS,R),mp 124–126 �C, ½a�23

D ¼ �98:2 (c 1.12, CHCl3)}.19 They exhibitedidentical 1H and 13C NMR spectra, and specific rotations with oppo-

t-Bu

NH2NaOH/H2O, CH2Cl2

0 ºC, 30min

CbzCl HNS

t-Bu

O

Me NHCbz

Me

ent-6b

2.

eactionnditions HN

St-Bu

O

PhNO2

7cMe

* *

Conversionb (%) drc

93 (83) 90:10), 45 �C, 24 h 23 95:5), 60 �C, 96 h 93 82:18, 1.5 h 98 36:64

vity.

Table 5Preparation of b-nitroamine derivatives 7

+

R H

NS

t-Bu

O

1

EtNO2

R

HNS

t-Bu

O

NO2

7

NaHCO3 (2 equiv), 60 ºC, 72 h

2b (3 equiv) Me

Aldimine 1 b-Nitroamine derivative 3a

Entry No. R No. Structure Yieldb (%) drc

1 (R)-1a CH3(CH2)7 7aHN

St-Bu

O

Me NO2

Me7( )

66 80:20

2 (R)-1b i-Pr 7bHN

St-Bu

O

Me NO2

Me Me

26 >98:2

3 (R)-1c Ph(CH2)2 7cHN

St-Bu

O

PhNO2

Me

83 90:10

4 (R)-1d Ph 7d

Ph

HNS

t-Bu

O

NO2

Me

27d 42:22:20:16e

5 (R)-1h i-Bu 7hHN

St-Bu

O

NO2Me

Me

Me

57 89:11

6 (R)-1i Bn 7iHN

St-Bu

O

Ph NO2

Me

59 90:10

7 (R)-1j 2-BrC6H4 7j

HNS

t-Bu

O

NO2

BrMe

51d 31:28:24:17e

a All products were >95% pure (GLC and/or 300 MHz 1H NMR).b Isolated yield after column chromatography of the major pair of epimers (silica gel, hexane/EtOAc) based on the starting aldimine 1.c Diastereomeric ratio was determined by 1H NMR and refers exclusively to face selectivity.d Isolated yield after column chromatography of the four diastereoisomers (silica gel, hexane/EtOAc) based on the starting aldimine 1.e Diastereomeric ratio was determined by 1H NMR and refers to the four possible diastereoisomers.

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372 367

site sign. In order to explain the stereochemical pathway of thenucleophilic addition of the proposed sodium nitronate intermedi-ates to chiral N-tert-butanesulfinyl imines 1, a six-membered ringmodel I, with a four-membered metallacycle, in which sodium ischelated both by the oxygen and the nitrogen atoms of the iminemoiety, is proposed (Fig. 2). Here, we assume that the nucleophilicattack for both nitromethane and nitroethane occurs to the Si-faceof the imine unit for (RS)-isomers (Table 2, entries 1–3 and 8; Fig. 1

and Table 5) and to the Re-face in the case of (SS)-derivatives (Ta-ble 2, entries 4–7).

3. Conclusion

We have reported that a direct nitro-Mannich-type reaction ofnitromethane 2a or nitroethane 2b and N-tert-butylsulfinyl imines1 could be performed under solvent-free conditions in the pres-

Table 6Preparation of N-tert-butylsulfinyl protected a-amino ketones 8

R

HNS

t-Bu

O

NO2

7

2. KMnO4 (0.7 equiv), MgSO4 (0.7 equiv)0 ºC, 4 h R

HNS

t-Bu

O

O

8MeMe

1. MeOH, KOH (1 equiv), 0 ºC, 45 min

b-Nitroamine derivative 7 a-Amino ketone derivatives 8

Entrya No. R No. Structure Yieldb (%)

1 7a CH3(CH2)7 8aHN

St-Bu

O

Me O7

Me

( )44

2 7b i-Pr 8bHN

St-Bu

O

Me O

Me Me

10

3 7c Ph(CH2)2 8cHN

St-Bu

O

PhO

Me

52

4 7h i-Bu 8hHN

St-Bu

O

O

Me

Me

Me39

5 7i PhCH2 8iHN

St-Bu

O

Ph O

Me

40

a All products were >95% pure (GLC and/or 300 MHz 1H NMR).b Isolated yield after column chromatography (silica gel, hexane/EtOAc) based on the starting b-nitroamine derivative 7.

I

O

N

NNa

O

H

H

R

H

SO

MeMe

Me

(RS: Si-face attack)

_+

‡

Figure 2.

368 M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372

ence of NaHCO3. Aldimines and ketimines reacted in a highly dia-stereoselective fashion with nitromethane 2a, while nitroethane2b reacted exclusively with aldimines to produce an almost 1:1mixture of epimers of b-nitroamine derivatives 7. The configura-tion of the newly created stereogenic center at the carbon atomof the imine group was determined by the configuration of the sul-fur atom of the starting chiral imine. Enantiomerically pure a-ami-no acids and a-amino ketones can be easily obtained from thesenitro-Mannich products.

4. Experimental

4.1. General

(RS)-tert-Butanesulfinamide and its enantiomer were a gift fromMedalchemy (>99% ee by chiral HPLC on a Chiracel AS column,90:10 n-hexane/i-PrOH, 1.2 mL/min, k = 222 nm). TLC was per-formed on silica gel 60 F254, using aluminum plates and visualizedwith phosphomolybdic acid (PMA) stain. Flash chromatographywas carried out on handpacked columns of silica gel 60 (230–400mesh). Melting points are uncorrected. Optical rotations weremeasured using a polarimeter with a thermally jacketted 5 cm cellat approximately 20 �C and concentrations (c) are given in g/100 mL. Infrared analyses were performed with a spectrophotom-eter equipped with an ATR component; wavenumbers are given incm�1. Low-resolution mass spectra (EI) were obtained at 70 eV;and fragment ions in m/z with relative intensities (%) in parenthe-ses. High-resolution mass spectra (HRMS) were also carried out inthe electron impact mode (EI) at 70 eV and on an apparatusequipped with a time of flight (TOF) analyzer and the samples wereionized by ESI techniques and introduced through an ultra-highpressure liquid chromatographer (UPLC) model. 1H NMR spectrawere recorded at 300 or 400 MHz for 1H NMR and 75 or

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372 369

100 MHz for 13C NMR, using CDCl3 as the solvent and TMS as inter-nal standard (0.00 ppm). The data are being reported as: s = singlet,d = doublet, t = triplet, q = quartet, p = pentet, h = heptet, m = mul-tiplet or unresolved, br s = broad signal, coupling constant(s) inHz, integration. 13C NMR spectra were recorded with 1H-decou-pling at 100 MHz and referenced to CDCl3 at 77.16 ppm. DEPT-135 experiments were performed to assign CH, CH2, and CH3.

4.2. General procedure for the synthesis of N-tert-butylsulfinylimines 1

To a solution of (R)- or (S)-tert-butanesulfinamide (0.605 g,5 mmol) and the corresponding carbonyl compound (4.5 mmol)in dry THF (20 mL) under argon at 23 �C was slowly added titaniumtetraethoxide (2.005 g, 1.885 mL, 9 mmol). The reaction mixturewas then stirred for 12 h at the same temperature for the alde-hydes and at 76 �C for 5 h for the ketones. The resulting mixturewas hydrolyzed with brine (30 mL), extracted with ethyl acetate(3 � 15 mL), dried over anhydrous MgSO4, and evaporated(15 Torr). The residue was purified by column chromatography(silica gel, hexane/ethyl acetate) to yield pure compounds 1. Imines1a,20 1b,21 1c,22 1d,23 1f,14 1g,14 1h,24 1i,23 and 1j,25 were charac-terized by comparison of their physical and spectroscopic datawith those reported in the literature. The physical, spectroscopic,and analytical data for imine 1e follow.

4.2.1. (RS)-N-(tert-Butylsulfinyl)benzofuran-2-ylmethanimine 1eWhite solid; mp 125–127 �C (hexane/CH2Cl2); ½a�23

D þ 3:9 (c1.03, CH2Cl2); Rf 0.55 (hexane/EtOAc: 1/1); IR m (KBr) 2971, 2962,2922, 1599, 1292, 1127, 1081, 953, 834, 764, 691 cm�1; dH 8.57(s, 1H), 7.72–7.67 (m, 1H), 7.60 (dd, J = 8.4, 0.8 Hz, 1H), 7.48–7.42(m, 1H), 7.34–7.28 (m, 2H), 1.30 (s, 9H); dC 156.2, 151.5 (C),150.9, 127.9 (CH), 127.5 (C), 123.8, 122.7, 115.3, 112.2 (CH), 58.3(C), 22.6 (CH3); LRMS (EI) m/z 193 (M+�C4H8, 32%), 145 (62), 144(31), 143 (100), 131 (74), 118 (19), 115 (36), 114 (17), 106 (13),90 (13), 89 (27), 88 (18), 77 (16), 63 (25), 62 (15), 57 (26), 56(11), 51 (13); HRMS (ESI): Calculated for C13H16NO2S (M++H)250.0902, found 250.0891.

4.3. General procedure for the synthesis of b-nitroamine deriv-atives 3 and 7

A heterogeneous mixture of nitromethane 2a (186 mg,0.165 mL, 3.0 mmol) or nitroethane 2b (225 mg, 0.213 mL,3.0 mmol), NaHCO3 (118 mg, 2.0 mmol), and the correspondingN-tert-butylsulfinyl imine 3 (1.0 mmol) was stirred at 60 �C for72 h. The resulting mixture was hydrolyzed with water (10 mL),acidified with 2 M hydrochloric acid (3 mL), extracted with EtOAc(3 � 15 mL), dried over anhydrous MgSO4, and evaporated(15 Torr). The residue was purified by column chromatography(silica gel, hexane/ethyl acetate) to yield pure compounds 3 and7. Yields for compounds 3 are given in Table 2 and Figure 1, andfor compounds 7 in Table 5. Physical and spectroscopic data follow.

4.3.1. (R,RS)-N-(tert-Butylsulfinyl)-1-nitrodecan-2-amine 3aWhite solid; mp 56–57 �C (hexane/CH2Cl2); ½a�23

D ¼ �33 (c 1.21,CH2Cl2); Rf 0.62 (hexane/EtOAc: 1/1); IR m (KBr) 3136, 2949, 2922,2854, 1554, 1378, 1364, 1042 cm�1; dH 4.72–4.64 (m, 2H), 4.12 (d,J = 9.3 Hz, 1H), 3.82–3.76 (m, 1H), 1.69–1.54 (m, 2H), 1.49–1.24 (m,12H), 1.23 (s, 9H), 0.88 (t, J = 6.7 Hz, 3H); dC 79.6 (CH2), 56.1 (C),54.9 (CH), 32.8, 31.5, 29.1, 28.9, 28.2, 25.5 (CH2), 22.4 (CH3), 22.2(CH2), 13.8 (CH3); LRMS (EI) m/z 187 (M+�t-BuSON, 40%), 170(17), 143 (28), 140 (25), 129 (77), 95 (35), 90 (33), 81 (46), 69(58), 57 (69), 55 (100); HRMS (ESI): Calculated for C14H31N2O3S(M++H) 307.2055, found 307.2049.

4.3.2. (R,RS)-N-(tert-Butylsulfinyl)-3-methyl-1-nitrobutan-2-amine 3b

White solid; mp 39–40 �C (hexane/CH2Cl2); ½a�23D ¼ �61 (c 1.23,

CH2Cl2); Rf 0.49 (hexane/EtOAc: 1/1); IR m (KBr) 3157, 2962, 2925,2871, 1555, 1469, 1379, 1042 cm�1; dH 4.75 (d, J = 5.1 Hz, 2H), 4.12(d, J = 8.5 Hz, 1H), 3.60–3.53 (m, 1H), 1.91 (h, J = 6.7 Hz, 1H), 1.25(s, 9H), 1.00 (d, J = 6.7 Hz, 3H), 0.99 (3H, d, J = 6.8, CH3); dC 77.7(CH2), 60.6 (CH), 56.3 (C), 30.7 (CH), 22.4, 19.1, 18.2 (CH3); LRMS(EI) m/z 220 (M+, 1%), 132 (12), 119 (25), 90 (10), 69 (21), 57(100); HRMS (ESI): Calculated for C9H21N2O3S (M++H) 237.1273,found 237.1264.

4.3.3. (R,RS)-N-(tert-Butylsulfinyl)-1-nitro-4-phenylbutan-2-amine 3c

Colorless oil; ½a�23D ¼ �24 (c 1.14, CH2Cl2); Rf 0.55 (hexane/

EtOAc: 1/1); IR m (film) 3298, 3026, 2955, 2923, 2854, 1550,1375, 1240, 1045 cm�1; dH 7.31–7.26 (m, 2H), 7.22–7.14 (m, 3H),4.71 (dd, J = 13.0, 4.8 Hz, 1H), 4.61 (dd, J = 13.0, 5.3 Hz, 1H), 4.21(d, J = 9.4 Hz, 1H), 3.80–3.74 (m, 1H), 2.86–2.79 (m, 1H), 2.72–2.65 (m, 1H), 1.97–1.86 (m, 2H), 1.25 (s, 9H); dC 140.1 (C), 128.5,128.2, 126.0, (CH), 79.6 (CH2), 56.3 (C), 54.2 (CH), 34.6, 31.6(CH2), 22.4 (CH3); LRMS (EI) m/z 179 (M+�t-BuSON, 12%), 136(15), 131 (21), 104 (73), 91 (100), 90 (62), 77 (18), 65 (17); HRMS(ESI): Calculated for C14H23N2O3S (M++H) 299.1429, found299.1429.

4.3.4. (S,SS)-N-(tert-Butylsulfinyl)-1-nitrodecan-2-amine ent-3aPhysical and spectroscopic data were found to be same as for

3a. ½a�23D ¼ þ31 (c 1.08, CH2Cl2).

4.3.5. (S,SS)-N-(tert-Butylsulfinyl)-3-methyl-1-nitrobutan-2-amine ent-3b

Physical and spectroscopic data were found to be same as for3b. ½a�23

D ¼ þ59 (c 1.25, CH2Cl2).

4.3.6. (S,SS)-N-(tert-Butylsulfinyl)-1-nitro-4-phenylbutan-2-amine ent-3c

Physical and spectroscopic data were found to be same as for3c. ½a�23

D ¼ þ25 (c 1.70, CH2Cl2).

4.3.7. (S,SS)-N-(tert-Butylsulfinyl)-2-nitro-1-phenylethanamineent-3d

Yellow oil; ½a�23D ¼ þ94 (c 0.44, CH2Cl2); Rf 0.56 (hexane/EtOAc:

1/1); IR m (KBr) 3201, 3060, 3025, 2978, 2960, 2924, 1551, 1455,1376, 1243, 1046 cm�1; dH 7.42–7.33 (m, 5H), 5.10–5.06 (m, 1H),4.85 (dd, J = 13.4, 7.3 Hz, 1H), 4.78 (dd, J = 13.4, 4.6 Hz, 1H), 4.45(d, J = 5.0 Hz, 1H), 1.25 (s, 9H); dC 136.1 (C), 129.1, 129.0, 127.3(CH), 80.0 (CH2), 56.8 (CH), 56.2 (C), 22.5 (CH3); LRMS (EI) m/z165 (M+�t-BuSO, 41%), 150 (10), 117 (41), 106 (49), 104 (90), 91(29), 77 (61), 57 (100), 51 (32); HRMS (ESI): Calculated for C12H19-

N2O3S (M++H) 271.1116, found 271.1112.

4.3.8. (S,RS)-N-(tert-Butylsulfinyl)-1-(2-benzofuryl)-2-nitroethan-amine 3e

Yellow oil; ½a�23D ¼ �61:9 (c 1.66, CH2Cl2); Rf 0.32 (hexane/

EtOAc: 1/1); IR m (KBr) 3193, 2976, 2957, 2917, 1554, 1454,1376, 1253, 1051, 812, 750 cm�1; dH 7.60–7.49 (m, 1H), 7.49–7.40 (m, 1H), 7.38–7.27 (m, 1H), 7.27–7.20 (m, 1H), 6.78 (t,J = 0.9 Hz, 1H), 5.31–5.21 (m, 1H), 5.10 (dd, J = 13.8, 6.0 Hz, 1H),4.99 (dd, J = 13.8, 5.2 Hz, 1H), 4.50 (d, J = 8.2 Hz, 1H), 1.27 (s, 9H);dC 155.0, 151.9, 127.5, (C), 125.0, 123.8, 121.4, 111.3, 105.9 (CH),77.2 (CH2), 56.7 (C), 52.6 (CH), 22.5 (CH3); LRMS (EI) m/z 206 (M+-

�C4H8SO, 0.5%), 189 (73), 146 (49), 142 (31), 131 (15), 119 (19),118 (100), 115 (54), 114 (17), 113 (11), 89 (31), 88 (10), 77 (17),63 (26), 62 (12); HRMS (ESI): Calculated for C14H19N2O4S (M++H)311.1066, found 311.1055.

370 M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372

4.3.9. (R,RS)-N-(tert-Butylsulfinyl)-2-methyl-1-nitrobutan-2-amine 3f

Yellow oil; ½a�23D ¼ �89:0 (c 1.24, CH2Cl2); Rf 0.23 (hexane/

EtOAc: 1/1); IR m (KBr) 3208, 2977, 2873, 1547, 1458, 1374, 1248,1051, 939, 735 cm�1; dH 4.69 (d, J = 12.1 Hz, 1H), 4.50 (d,J = 12.1 Hz, 1H), 4.23 (s, 1H), 1.76–1.62 (m, 1H), 1.44 (s, 3H), 1.25(s, 9H), 0.96 (t, J = 7.4 Hz, 3H); dC 83.7 (CH2), 57.3, 56.1 (C), 31.9(CH2), 22.62, 22.54, 7.67 (CH3); LRMS (EI) m/z 180 (M+�C4H8,6%), 119 (27), 118 (9), 69 (27), 57 (100), 55 (8); HRMS (ESI): Calcu-lated for C9H21N2O3S (M++H) 237.1273, found 237.1262.

4.3.10. (R,RS)-N-(tert-Butylsulfinyl)-2-methyl-1-nitroheptan-2-amine 3g

Yellow oil; ½a�23D ¼ �52:3 (c 1.28, CH2Cl2); Rf 0.33 (hexane/

EtOAc: 1/1); IR m (KBr) 3218, 2956, 2931, 2869, 1548, 1457,1374, 1048, 940 cm�1; dH 4.67 (d, J = 12.1 Hz, 1H), 4.49 (d,J = 12.0 Hz, 1H), 4.22 (s, 1H), 1.74–1.55 (m, 2H), 1.44 (s, 3H),1.41–1.26 (m, 6H), 1.24 (s, 9H), 0.89 (t, J = 6.6 Hz, 3H); dC 83.9(CH2), 57.2, 56.1 (C), 39.1, 31.8 (CH2), 23.2 (CH3), 22.9 (CH2), 22.6(CH3), 22.4 (CH2), 13.9 (CH3); LRMS (EI) m/z 222 (M+�C4H8, 1%),178 (8), 151 (10), 135 (28), 114 (34), 70 (25), 57 (100), 56 (12),55 (13); HRMS (ESI): Calculated for C12H27N2O3S (M++H)279.1742, found 279.1732.

4.3.11. (2R⁄,3R,RS)-N-(tert-Butylsulfinyl)-2-nitroundecan-3-amine7a

Diastereomeric mixture (1:1); colorless wax; Rf 0.36 (hexane/EtOAc: 1/1); IR m (KBr) 3215, 2947, 2924, 2855, 1546, 1457, 1390,1363, 1048 cm�1; dH 5.01 (qd, J = 6.9, 2.9 Hz, 1H), 4.85 (qd, J = 6.8,4.6 Hz, 1H), 4.23 (d, J = 9.7 Hz, 1H), 3.96 (d, J = 8.7 Hz, 1H), 3.61–3.49 (m, 1H), 3.49–3.40 (m, 1H), 1.64 (d, J = 6.9 Hz, 3H), 1.56 (d,J = 6.9 Hz, 3H), 1.54–1.42 (m, 4H), 1.39–1.17 (m, 42H), 0.88 (t,J = 6.7 Hz, 6H); dC 86.4, 85.6, 60.2, 59.4 (CH), 56.6, 56.5 (C), 32.8,31.7, 29.7, 29.3, 29.1, 29.0, 28.9 (CH2), 22.7, 22.7 (CH3), 22.6(CH2), 16.0, 15.2, 14.1 (CH3); LRMS (EI) m/z 216 (M+�C4H8SO,9%), 187 (25), 170 (17), 168 (10), 143 (32), 142 (81), 140 (17),111 (10), 110 (11), 104 (19), 103 (44), 97 (28), 96 (17), 95 (19),84 (18), 83 (32), 82 (16), 81 (23), 71 (49), 70 (21), 69 (59), 68(13), 67 (23), 64 (15), 58 (12), 57 (95), 56 (97), 55 (100), 54 (16),53 (12); HRMS (ESI): Calculated for C15H33N2O3S (M++H)321.2212, found 321.2198.

4.3.12. (3R,4R⁄,RS)-N-(tert-Butylsulfinyl)-2-methyl-4-nitropen-tan-3-amine 7b

Diastereomeric mixture (1:1); white solid, mp 88–91 �C (hex-ane/CH2Cl2); Rf 0.28 (hexane/EtOAc: 1/1); IR m (KBr) 3120, 2967,2902, 2873, 1545, 1454, 1390, 1359, 1008, 864 cm�1; dH 4.95(qd, J = 6.9, 4.1 Hz, 1H), 4.76 (p, J = 6.8 Hz, 1H), 4.43 (d,J = 8.1 Hz, 1H), 3.67 (d, J = 9.8 Hz, 1H), 3.56–3.46 (m, 1H), 3.12(td, J = 7.9, 4.0 Hz, 1H), 1.93–1.82 (m. 1H), 1.81–1.72 (m, 1H),1.69 (d, J = 6.8 Hz, 6H), 1.29 (s, 9H), 1.28 (s, 9H), 1.02 (d,J = 6.7 Hz, 3H), 1.00-0.95 (m, 6H), 0.88 (d, J = 6.7 Hz, 3H); dC

85.2, 83.7 64.9, 64.8 (CH), 57.1, 56.9 (C), 32.3, 29.5 (CH), 23.0,22.9, 21.2, 20.2, 18.9, 18.1, 16.5, 16.3 (CH3); LRMS (EI) m/z 194(M+�C4H8, 4%), 146 (11), 119 (39), 83 (26), 76 (10), 57 (100),56 (21), 55 (10); HRMS (ESI): Calculated for C10H23N2O3S(M++H) 251.1429, found 251.1423.

4.3.13. (3R,4R⁄,RS)-N-(tert-Butylsulfinyl)-4-nitro-1-phenylpentan-3-amine 7c

Diastereomeric mixture (1:1), white wax; Rf 0.28 (hexane/EtOAc: 1/1); IR m (KBr) 3222, 3026, 2976, 2957, 1544, 1455, 1390,1363, 1048, 699 cm�1; dH 7.37–7.06 (m, 10H), 5.04 (qd, J = 6.9,2.8 Hz, 1H), 4.85 (qd, J = 6.8, 4.9 Hz, 1H), 4.40 (d, J = 10.1 Hz, 1H),4.10 (d, J = 10.0 Hz, 1H), 3.63–3.51 (m, 1H), 3.42 (tt, J = 10.4,2.8 Hz, 1H), 2.94–2.81 (m, 2H), 2.74–2.53 (m, 2H), 1.95–1.81 (m,

4H), 1.63 (d, J = 6.9 Hz, 3H), 1.47 (d, J = 6.9 Hz, 3H), 1.31 (s, 9H),1.28 (s, 9H); dC 140.3 (C), 128.6, 128.6, 128.4, 128.3, 126.4, 126.3,86.3 85.7, 59.4, 58.6 (CH), 56.7, 56.6 (C), 34.9, 31.9, 31.4 (CH2),22.8, 22.7, 16.3, 15.3 (CH3); LRMS (EI) m/z 208 (M+�C4H8SO,0,6%), 206 (11), 145 (19), 144 (11), 133 (15), 132 (26), 117 (14),115 (10), 105 (26), 104 (57), 103 (15), 91 (100), 77 (18), 65 (17),57 (13), 56 (14); HRMS (ESI): Calculated for C15H25N2O3S (M++H)313.1586, found 313.1584.

4.3.14. (2R⁄,3R,RS)-N-(tert-Butylsulfinyl)-5-methyl-2-nitrohexan-3-amine 7h

Diastereomeric mixture (1:1), white solid, mp 74–76 �C (hex-ane/CH2Cl2); Rf 0.27 and 0.29 (hexane/EtOAc: 1/1); IR m (KBr)3229, 2958, 2927, 2870, 1545, 1456, 1388, 1364, 1036, 899 cm�1;dH 5.05 (qd, J = 6.8, 2.6 Hz, 1H), 4.84 (qd, J = 6.8, 4.5 Hz, 1H), 4.29(d, J = 10.1 Hz, 1H), 3.91 (d, J = 9.6 Hz, 1H), 3.74–3.60 (m, 1H),3.58–3.42 (m, 1H), 1.90–1.70 (m, 2H), 1.64 (d, J = 6.9 Hz, 3H),1.55 (d, J = 6.9 Hz, 3H), 1.51–1.41 (m, 2H), 1.26 (s, 9H), 1.25 (s,9H), 0.94 (d, J = 1.2 Hz, 3H), 1.02–0.95 (m, 2H), 0.92 (d, J = 1.2 Hz,3H), 0.90 (d, J = 2.2 Hz, 3H), 0.88 (d, J = 2.2 Hz, 3H); dC 86.6, 85.9,58.6, 57.5 (CH), 56.7, 56.5 (C), 41.6, 38.5 (CH2), 24.3, 24.2 (CH),23.4, 23.2, 22.7, 22.7, 21.2, 21.0, 15.8, 15.3 (CH3); LRMS (EI) m/z208 (M+�C4H8, 5%), 160 (7), 133 (44), 97 (15), 57 (100), 56 (11),55 (15); HRMS (ESI): Calculated for C11H25N2O3S (M++H)265.1586, found 265.1584.

4.3.15. (2R,3R⁄,RS)-N-(tert-Butylsulfinyl)-3-nitro-1-phenylbutan-2-amine 7i

Diastereomeric mixture (1:1), yellow oil; Rf 0.23 (hexane/EtOAc: 1/1); IR m (KBr) 3227, 3055, 3026, 2981, 2951, 2868,1545, 1455, 1390, 1241, 1045 746, 700 cm�1; dH 7.45–7.08(m, 10H), 4.92 (qd, J = 6.9, 3.7 Hz, 1H), 4.83 (qd, J = 6.9, 3.9 Hz,1H), 4.11 (d, J = 8.8 Hz, 2H), 3.94–3.84 (m, 1H), 3.84–3.74 (m,1H), 2.95–2.80 (m, 3H), 2.78–2.65 (m, 3H), 1.69 (d, J = 3.5 Hz,3H), 1.67 (d, J = 3.5 Hz, 3H), 1.10 (s, 9H), 1.08 (s, 9H); dC

136.5, 136.5 (C), 129.4, 129.3, 128.7, 128.6, 127.0, 126.9, 85.8,84.1, 61.1, 61.0 (CH), 56.5 (C), 39.6, 36.7 (CH2), 22.4, 22.4,16.5, 15.2 (CH3); LRMS (EI) m/z 194 (M+�C4H8SO, 0.8%), 119(15), 118 (15), 117 (12), 103 (11), 92 (12), 91 (100), 65 (10);HRMS (EI): Calculated for C14H23N2O3S (M++H) 299.1429, found299.1428.

4.4. General procedure for the synthesis of a-amino acid deriv-atives 4

Solid NaNO2 (207 mg, 3.0 mmol) was added to a stirred solutionof compound 3 or 7 (0.50 mmol) and AcOH (150 mg, 0.143 mL,2.50 mmol) in a 7:1 mixture of DMF and water (1.25 mL) at23 �C. The reaction was heated at 45 �C for 12 h, after which itwas quenched with a 2 M NaOH water solution (10 mL) and ex-tracted with CH2Cl2 (2 � 15 mL). The aqueous layer was acidifiedwith 2 M hydrochloric acid (12 mL) and extracted with EtOAc(3 � 15 mL), dried over anhydrous MgSO4, and evaporated(15 Torr) to give pure compounds 4. Yields are given in Table 3.Physical and spectroscopic data follow.

4.4.1. (R,RS)-N-(tert-Butylsulfinyl)-2-aminodecanoic acid 4aColorless oil; ½a�23

D ¼ �20:2 (c 2.26, CHCl3); Rf 0.75 (MeOH/CH2-

Cl2: 2/1); IR m (KBr) 3143, 2947, 2920, 2852, 1721, 1467, 1213,1034, 900, 694 cm�1; dH 9.89 (br s, 1H), 4.48 (d, J = 7.6 Hz, 1H),3.87 (dd, J = 12.3, 6.8 Hz, 1H), 1.85–1.72 (m, 1H), 1.71–1.58 (m,1H), 1.24–1.29 (m, 12H), 1.26 (s, 9H), 0.88 (t, J = 6.5 Hz, 3H); dC

174.9 (C), 58.7 (CH), 56.6 (C), 34.0, 31.8, 29.3, 29.1, 29.0, 25.1(CH2), 22.7 (CH3), 22.6 (CH2), 14.0 (CH3); LRMS (EI) m/z 187 (M+-

�C4H8SO, 0.4%), 131 (10), 75 (43), 57 (100); HRMS (ESI): Calculatedfor C14H30NO3S (M++H) 292.1946, found 292.1935.

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372 371

4.4.2. (S,SS)-N-(tert-Butylsulfinyl)-2-amino-3-methylbutanoicacid ent-4b

White solid; mp 125–128 �C (hexane/CH2Cl2); ½a�23D ¼ þ84:2 (c

1.07, CHCl3); Rf 0.69 (MeOH/CH2Cl2: 1/1); IR m (KBr) 3269, 2958,2929, 2872, 1721, 1384, 1257, 1024, 1014 cm�1; dH 4.45 (d,J = 7.9 Hz, 1H), 3.72 (dd, J = 7.8, 5.0 Hz, 1H), 2.16–2.05 (m, 1H),1.31 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); dC

173.9 (C), 64.0 (CH), 56.9 (C), 32.1 (CH), 22.85, 19.3, 17.2 (CH3);LRMS (EI) m/z 165 (M+�C4H8, 17%), 119 (42), 105 (10), 72 (33),57 (100), 56 (27).

4.4.3. (R,RS)-N-(tert-Butylsulfinyl)-2-amino-4-phenylbutanoicacid 4c

White solid; mp 88–90 �C (hexane/CH2Cl2); ½a�23D ¼ �19:8 (c

1.00, CHCl3); Rf 0.55 (MeOH/CH2Cl2: 1/1); IR m (KBr) 3168,3021, 2957, 2928, 2864, 1724, 1455, 1245, 1210, 1105, 1036,901, 759, 700 cm�1; dH 7.36–7.07 (m, 5H), 6.61 (br s, 1H),4.51 (d, J = 8.0 Hz, 1H), 3.97–3.84 (m, 1H), 2.81–2.60 (m, 2H),2.21–2.05 (m, 1H), 2.04–1.90 (m, 1H), 1.30 (s, 9H); dC 174.3,140.8 (C), 128.5, 128.4, 126.2, 58.4 (CH), 56.8 (C), 35.8, 31.5(CH2), 22.8 (CH3); LRMS (EI) m/z 178 (M+�C4H9SO, 0.6%), 164(31), 132 (9), 117 (40), 91 (48), 77 (9), 65 (9), 57 (100); HRMS(ESI): Calculated for C14H22NO3S (M++H) 284.1320, found284.1307.

4.4.4. (R,RS)-N-(tert-Butylsulfinyl)-2-amino-2-methylbutanoicacid 4f

Yellow oil; ½a�23D ¼ �70:1 (c 0.79, CH2Cl2); Rf 0.71 (MeOH/CH2-

Cl2: 1/2); IR m (KBr) 3180, 3055, 2980, 2939, 1726, 1460, 1367,1265, 1008, 733 cm�1; dH 9.26 (br, 1H), 4.71 (s, 1H), 1.91–1.67(m, 2H), 1.57 (s, 3H), 1.27 (s, 9H), 0.88 (t, J = 7.4 Hz, 3H); dC

176.5, 62.1, 56.4 (C), 33.1 (CH2), 23.3, 22.8, 8.12 (CH3); LRMS (EI)m/z 161 (M+�C2H4O2, 0.5%), 160 (10), 159 (97), 103 (52), 88 (15),75 (12), 74 (61), 70 (79), 57 (100); HRMS (ESI): Calculated for C9-

H20NO3S (M++H) 222.1164, found 222.1152.

4.4.5. (R,RS)-N-(tert-Butylsulfinyl)-2-amino-2-methylheptanoicacid 4g

Colorless oil; ½a�23D ¼ �20:6 (c 1.77, CH2Cl2); Rf 0.76 (MeOH/CH2-

Cl2: 1/2); IR m (KBr) 3173, 3046, 2956, 2929, 2871, 1721, 1525,1460, 1151, 1025, 874, 735 cm�1; dH 8.21 (br s, 1H), 4.69 (s, 1H),1.83–1.68 (m, 2H), 1.58 (s, 3H), 1.24–1.32 (m, 15H), 0.88 (t,J = 6.8 Hz, 3H); dC 176.7, 61.7, 56.4 (C), 40.3, 31.8 (CH2), 23.5(CH3), 23.3 (CH2), 22.8 (CH3), 22.4 (CH2), 13.9 (CH3); LRMS (EI)m/z 207 (M+�C4H8, 0.5%), 201 (28), 145 (17), 112 (10), 89 (100),74 (15), 57 (37); HRMS (ESI): Calculated for C12H26NO3S (M++H)264.1633, found 264.1624.

4.5. (S,SS)-N1-(Benzyloxycarbonyl)-N2-(tert-butylsulfinyl)-3-methylbutane-1,2-diamine ent-6b

To a solution of compound ent-3b (160 mg, 0.68 mmol) andNiCl2�6H2O (161.4 mg, 0.68 mmol) in dry MeOH (5 mL) under ar-gon at �5 �C was slowly added NaBH4 (128.8 mg, 2.31 mmol).The mixture was stirred at the same temperature for 25 min,quenched with a saturated NaHCO3 aqueous solution (5 mL),and filtered through Celite. The filtrate was concentrated undervacuum (15 Torr), and extracted with EtOAc (3 � 15 mL), driedover anhydrous MgSO4, and evaporated (15 Torr) to give103.5 mg of crude diamine derivative ent-5b as a brown oil(0.5 mmol, 74% yield). Next, a solution of ent-5b (103 mg,0.50 mmol) in CH2Cl2 (2 mL) was added to a 2 M NaOH aqueoussolution (1.25 mL) at 0 �C. Next, CbzCl (0.128 mg, 0.106 mL,0.75 mmol) was added slowly to the reaction mixture and thesystem was allowed to reach 23 �C over 1 h. The reaction wasquenched with brine (10 mL), extracted with EtOAc (3 � 15 mL),

dried over anhydrous MgSO4, and evaporated (15 Torr) to give88 mg (0.26 mmol, 52% overall yield) of compound ent-6b. Color-less oil; ½a�23

D ¼ þ56 (c 1.04, CH2Cl2); Rf 0.41 (hexane/EtOAc: 1/1);IR m (KBr) 3290–3245, 3057, 3035, 2960, 2928, 2872, 1705, 1535,1264, 1042, 1027 cm�1; dH 7.38–7.25 (m, 5H), 6.32 (br s, 1H),5.15–5.06 (m, 2H), 3.55–3.48 (m, 1H), 3.40 (d, J = 7.7 Hz, 1H),3.13–3.06 (m, 2H), 1.81–1.73 (m, 1H), 1.24 (s, 9H), 0.94 (d,J = 6.8 Hz, 3H), 0.91 (3H, d, J = 6.8, CH3); dC 157.2 (C), 136.7 (C),128.3, 127.8, 127.7 (CH), 66.5 (CH2), 63.7 (CH), 56.25 (C), 44.35(CH2), 31.8 (CH), 22.8, 19.5, 17.6 (CH3); LRMS (EI) m/z 205 (M+-

�BnOCO, 7%), 176 (11), 91 (100), 72 (44), 65 (13), 55 (10); HRMS(ESI): Calculated for C17H29N2O3S (M++H) 431.1899, found341.1885.

4.6. General procedure for the synthesis of a-amino ketone deriv-atives 8

To a solution of the corresponding b-nitroamine derivative 7(0.4 mmol) in MeOH (2.8 mL) was added dropwise a freshly pre-pared solution of KOH (26.4 mg, 0.4 mmol) in MeOH (4 mL) underargon at 0 �C. After stirring for an additional 15 min, a solution ofKMnO4 (42.4 mg, 0.27 mmol) and MgSO4 (35.4 mg, 0.30 mmol) inwater (6 mL) was added dropwise. Next, the reaction mixturewas stirred for approximately 3 h at 0 �C and then filtered over alayer of Celite using EtOAc (25 mL). The organic layer was washedwith brine (2 � 15 mL), dried with anhydrous MgSO4, and evapo-rated (15 Torr) to give pure compounds 8. Yields are given in Ta-ble 6. Physical and spectroscopic data follow.

4.6.1. (R,RS)-N-(tert-Butylsulfinyl)-3-aminoundecan-2-one 8aWhite wax; ½a�23

D ¼ �146:7 (c 1.07, CH2Cl2); Rf 0.37 (hexane/EtOAc: 1/2); IR m (KBr) 3257, 2923, 2855, 1714, 1458, 1362,1078 cm�1; dH 4.53 (d, J = 5.2 Hz, 1H), 4.04 (dt, J = 6.9, 4.7 Hz,1H), 2.25 (s, 3H), 1.91–1.71 (m, 1H), 1.73–1.51 (m, 1H), 1.23–1.29 (m, 21H), 0.88 (t, J = 6.7 Hz, 3H); dC 206.9 (C), 63.0 (CH),55.8 (C), 32.7, 31.7, 29.3, 29.2, 29.1 (CH2), 26.9 (CH3), 24.5 (CH2),22.6 (CH3), 22.5 (CH2), 14.03 (CH3); LRMS (EI) m/z 189(M+�C4H9–COCH3, 32%), 142 (100), 140 (34), 84 (13), 83 (12), 70(25), 69 (27), 57 (18), 56 (41), 55 (36); HRMS (ESI): Calculatedfor C15H32NO2S (M++H) 290.2154, found 290.2163.

4.6.2. (R,RS)-N-(tert-Butylsulfinyl)-3-amino-4-methylpentan-2-one 8b

Yellow oil; ½a�23D ¼ �136:0 (c 0.23, CH2Cl2); Rf 0.36 (hexane/

EtOAc: 1/2); IR m (KBr) 3252, 2960, 2924, 2871, 2854, 1714, 1463,1364, 1287, 1070 cm�1; dH 4.53 (d, J = 6.3 Hz, 1H), 3.91 (dd,J = 6.4, 3.4 Hz, 1H), 2.26 (s, 3H), 2.23–2.14 (m, 1H), 1.28 (s, 9H),1.04 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H); dC 207.0 (C), 68.4(CH), 56.3 (C), 30.9 (CH3), 27.6 (CH), 22.9, 20.3, 15.9 (CH3); LRMS(EI) m/z 163 (M+�C4H8, 33%), 145 (13), 120 (100), 112 (15), 103(16), 102 (16), 85 (12), 72 (20), 62 (24), 57 (100), 56 (16); HRMS(ESI): Calculated for C10H22NO2S (M++H) 220.1371, found220.1362.

4.6.3. (R,RS)-N-(tert-Butylsulfinyl)-3-amino-5-phenylpentan-2-one 8c

White wax; ½a�23D ¼ �99:2 (c 1.00, CH2Cl2); Rf 0.26 (hexane/

EtOAc: 1/2); IR m (KBr) 3262, 2955, 2925, 2859, 1713, 1455,1361, 1062, 735, 699 cm�1; dH 7.38–7.07 (m, 5H), 4.63 (d,J = 5.4 Hz, 1H), 4.12–4.01 (m, 1H), 2.77–2.54 (m, 2H), 2.22 (s, 3H),2.19–2.08 (m, 1H), 2.00–1.85 (m, 1H), 1.31 (s, 9H); dC 206.6,140.6 (C), 128.6, 128.4, 126.3, 62.5 (CH), 56.0 (C), 34.6, 30.9(CH2), 26.9, 22.7 (CH3); LRMS (EI) m/z 176 (M+�C4H9SO, 12%),175 (100), 158 (13), 143 (10), 132 (75), 130 (22), 117 (21), 115(48), 91 (48), 77 (11), 65 (11); HRMS (EI): Calculated forC11H13NO (M+�C4H10OS) 175.0997, found 175.1002.

372 M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372

4.6.4. (R,RS)-N-(tert-Butylsulfinyl)-3-amino-5-methylhexan-2-one8h

White solid, mp 63–66 (hexane/CH2Cl2); ½a�23D ¼ �168:5 (c 0.79,

CH2Cl2); Rf 0.36 (hexane/EtOAc: 1/2); IR m (KBr) 3262, 2958, 2929,2870, 1707, 1359, 1170, 1040, 887 cm�1; dH 4.50 (d, J = 6.9 Hz, 1H),4.07–3.90 (m, 1H), 2.26 (s, 3H), 1.91–1.75 (m 1H), 1.57–1.34 (m,2H), 1.26 (s, 9H), 0.97 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H);dC 207.7 (C), 62.1 (CH), 56.0 (C), 42.2 (CH2), 27.1 (CH3), 24.5 (CH),23.3, 22.7, 21.4 (CH3); LRMS (EI) m/z 177 (M+�C4H8, 24%), 134(100), 117 (10), 116 (15), 78 (20), 71 (11), 57 (50); HRMS (EI): Cal-culated for C7H15NO2S (M+�C4H8) 177.0823, found 177.0848.

4.6.5. (R,RS)-N-(tert-Butylsulfinyl)-3-amino-4-phenylbutan-2-one8i

Yellow oil; ½a�23D ¼ �122:0 (c 1.04, CH2Cl2); Rf 0.27 (hexane/

EtOAc: 1/2); IR m (KBr) 3255, 2950, 2924, 2860, 1714, 1456, 1362,1060, 733, 699 cm�1; dH 7.36–7.11 (m, 5H), 4.47 (d, J = 6.6 Hz,1H), 4.25 (ddd, J = 8.5, 6.8, 4.9 Hz, 1H), 3.11 (dd, J = 14.0, 5.7 Hz,1H), 2.87 (dd, J = 14.0, 7.6 Hz, 1H), 2.21 (s, 3H), 1.14 (s, 9H); LRMS(EI) m/z 211 (M+�C4H8, 5%), 120 (100), 91 (18), 57 (49); HRMS(ESI): Calculated for C14H22NO2S (M++H) 268.1371, found268.1364.

Acknowledgements

We thank the Spanish Ministerio de Ciencia e Innovación (GrantNo. CTQ2007-65218, Consolider Ingenio 2010-CSD-2007-00006and CTQ2011-24165), the Generalitat Valenciana (Grant No. PRO-METEO/2009/039 and FEDER) and the University of Alicante forgenerous and continuous financial support.

References

1. For reviews, see: (a) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–2569; (b) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr. Org. Chem.2005, 9, 1315–1392; (c) Petrini, M.; Torregiani, E. Synthesis 2007, 159–186.

2. For a review, see: Noble, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887–2939.3. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151–153.4. Ono, N. The Nitro Group in Organic Synthesis; John Wiley & Sons: New York,

2001.5. Marqués-López, E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J. Org. Chem. 2009,

2401–2420.6. For recent reviews, see (a) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc.

Chem. Res. 2008, 41, 831–840; (b) Ferreira, F.; Botuha, C.; Chemla, F.; Pérez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162–1186; (c) Robak, M. A. T.; Herbage, M.A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600–3740.

7. (a) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317–1320; (b) Weix, D. A.;Ellman, J. A. Org. Synth. 2005, 82, 157–165.

8. (a) Wakayama, M.; Ellman, J. A. J. Org. Chem. 2009, 74, 2646–2650; (b)Aggarwal, V. K.; Barbero, N.; McGarrigle, E. M.; Mickle, G.; Navas, R.; Suárez, J.R.; Unthank, M. G.; Yar, M. Tetrahedron Lett. 2009, 50, 3482–3484.

9. Dema, H. K.; Foubelo, F.; Yus, M. Helv. Chim. Acta 2012, 95, 1790–1798.10. (a) García Ruano, J. L.; Topp, M.; López-Cantarero, J.; Alemán, J.; Remuiñán, M.

J.; Cid, M. B. Org. Lett. 2005, 7, 4407–4410; (b) García Ruano, J. L.; López-Cantarero, J.; De Haro, T.; Alemán, J.; Cid, M. B. Tetrahedron 2006, 62, 12197–12203.

11. Weng, J.; Li, Y.-B.; Wang, R.-B.; Li, F.-Q.; Liu, C.; Chan, A. S. C.; Lu, G. J. Org. Chem.2010, 75, 3125–3128.

12. Zhang, F.; Liu, Z.-J.; Liu, J.-T. Org. Biomol. Chem. 2011, 9, 3625–3628.13. Rodríguez-Solla, H.; Concellón, C.; Alvarado, N.; Soengas, R. G. Tetrahedron

2012, 68, 1736–1744.14. Sirvent, J. A.; Foubelo, F.; Yus, M. Chem. Commun. 2012, 48, 2543–2545.15. García-Muñoz, M. J.; Zacconi, F.; Foubelo, F.; Yus, M. Eur. J. Org. Chem. 2013,

1287–1295.16. Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1997, 62, 234–235.17. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29, 1159–1161.18. Steliou, K.; Poupart, M.-A. J. Org. Chem. 1985, 50, 4971–4973.19. Reddy, L. R.; Gupta, A. P.; Liu, Y. J. Org. Chem. 2011, 76, 3409–3425.20. Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2008, 19, 2484–

2491.21. (a) Mukade, T.; Dragoli, D. R.; Ellman, J. A. J. Comb. Chem. 2003, 5, 590–596; (b)

Tanuwidjaja, J.; Peltier, H. M.; Lewis, J. C.; Schenkel, L. B.; Ellman, J. A. Synthesis2007, 3385–3391.

22. Schenkel, L. B.; Ellman, J. A. Org. Lett. 2004, 6, 3621–3624.23. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64,

1278–1284.24. Nielsen, L.; Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup, T. J. Org. Chem.

2007, 72, 10035–10044.25. Sirvent, J. A.; Foubelo, F.; Yus, M. Eur. J. Org. Chem. 2013, 2461–2471.