amino acids, peptides and proteins in organic chemistry (origins and synthesis of amino acids) ||...

9Synthetic Approaches to a;b-Diamino AcidsAlma Viso and Roberto Fern�andez de la Pradilla

9.1Introduction

The discovery ofa,b-diamino acids among natural products, either in the native stateor as fragments of complex molecules, has stimulated interest in these molecules.Their structural complexity, having two vicinal chiral centers, represents a currentchallenge for synthetic organic chemists, especially the synthesis of enantiopurematerials. Therefore, this chapter will provide a general overview of the existingmethodology for the synthesis of aliphatic a,b-diamino acids and their simplederivatives, esters or amides [1]. Within this context, in recent years a number ofsynthetic routes of variable length, yield, and complexity have been reported.Figure 9.1 gathers some representative routes that can be classified into two maincategories: methods that require construction of the carbon backbone, and methodsthat start from the basic carbon skeleton and introduce the C�N bonds modifyingthe nature of the functional groups.

9.2Construction of the Carbon Backbone

The search for new methodology to form C�C bonds is critical for the developmentof organic synthesis. The established methods to build the carbon skeleton ofa,b-diamino acids can be classified with respect to the C�C bond formed in thekey step and therefore the following section has been organized accordingly(Figure 9.1).

9.2.1Methods for the Formation of the Cb�Cc Bond

9.2.1.1 Reaction of Glycinates and Related Nucleophiles with ElectrophilesThe Mannich reaction of glycinates and imines is a fundamental solution withinthe plethora of available methods. This strategy can be applied to the synthesis

Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.1 – Origins and Synthesis of Amino Acids.Edited by Andrew B. HughesCopyright � 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32096-7

j411

of 3-amino-b-lactams [2]; nevertheless the use of suitably functionalized precursorscan circumvent the cyclization [3]. In a recent example high syn diastereoselectivities(>90 : 10) are obtained when the glycinate 2 is generated in situ under reductiveconditions from an a-iminoester 1 and TiI4. In these examples the relative stereo-chemistry of the final diamino esters 3 depends on the nature of the substituentsof the imine counterpart with a complete reversal to the anti isomer when the iminecontains a triple bond [4]. N-(p-Toluenesulfonyl)-a-chloroaldimines 5 can also act aselectrophiles affording racemic g-chloro-a,b-diamino esters 6 upon reaction withbenzophenone imine glycinate 4 with low syn/anti diastereoselectivity. After separa-tion, both diastereoisomers were efficiently cyclized by treatment with K2CO3 tob,g -aziridino a-amino ester derivatives 7a,b [5]. Substoichiometric amounts of Lewisacids such as Zn(OTf)2 allow for the smooth reaction of benzophenone imineglycinates and enamines, but again low diastereomeric ratios are produced [6](Scheme 9.1).Asymmetric versions of this strategy involving chiral glycinates are found in the

literature. The enantiopure Ni(II) complex of benzophenone a-imino glycinate andthe aluminum enolate of a chiral oxazinone derived from glycine have been used forthe synthesis of fluorinated 2,3-diamino acids (98%d.e.) [7] and capreomycidine [8],respectively. Chiral imines can participate as inductors of asymmetry in theMannichprocess. Recently, Yadav et al. have reported the one-pot synthesis of 4-aminoperhydropyrimidines 10 upon a Biginelli reaction. Upon microwave irradiationand in the presence of a Ce(III) salt, D-xylose and D-glucose react with ureas 8and thioureas generating aldose-derived C¼N species that are attacked in situ by an1,3-oxazol-5-one 9 and finally evolve to the perhydropyrimidine 10 diastereoselec-tively (Scheme9.2) [9]. p-Toluenesulfinimines 11 canparticipate as chiral inductors inthe BF3�Et2O-mediated addition of lithiated a-imino glycinates to afford enantiopure

XCO2H

NH2

CO2R

CO2RX

"N "

CO2R

N

CO2R

NR R

RR

NR

R

NZR

CO2R

RHN NHR

X Y "CO2H"

C-N bond formationC-C bond formation

a

b

bc

R

O

OH

H2N

NH2

bc

c'

Rb'

ab

c

Figure 9.1 Representative routes towards a,b-diamino acids.

412j 9 Synthetic Approaches to a,b-Diamino Acids

4,5-trans 4-carbomethoxyN-sulfinylimidazolidines 12 (Scheme 9.2). Interestingly inthe absence of BF3�Et2O, enolates derived from phenylalanine, alanine, and leucinetreated with lithium diisopropylamide (LDA) provide imidazolidines 12a containingquaternary centerswith endo stereocontrol andexcellent diastereofacial discrimination

N

R

SOpTolR1

N

Ph

OMeO

NHN

Ph

R CO2Me

S

O

pTol

NHP

RCO2Me

NH2

O

OEtN

NPh

p-TolOS

NHSOpTol

PhCO2Et

NCPh2

anti (33:1)

LDA,(a)conditions:andReagents − BFthenºC78 3·Et2O, − H(b)rt.toºC78 3PO4, THF-H2 rt,O,H(c)%68-84 3PO4, MeOH-H2 THFLDA,(d)%.59-65rt,O, − H(e)ºC.78 2 THFO-LDA, − ºC.78

(a)

Ph

Ph

NHSOpTol

PhCO2Et

NCPh2

syn

(d) (e)

(33:1)

+

12ref

BFno 3.Et2 BFO 3

.Et2O

orNHN

Ph

RCO2Me

R1

STol

O

p

Raryl,=R 1 Bn,= i MeBu, arylalkyl,=R 11and10refs

D-Xylose N

OPh

O+H2N NH2

OMW

saltCe(III) NN

OH

OH

OH

O

O

H

BzNH

95:59ref

(c)or(b)

+

=P pTolSO, H

8 910

11 12a 1312b

4 11a14b 14a

Scheme 9.2 Mannich reaction of chiral imines and glycinates.

thenandseparation(b)THF.LDA,(a)conditions:andReagents K2CO3, acetone

Ph

Ph N

O

OEt NTs

Cl

+(a)

CO2Et

NHTs

NCl

anti:syn, 2:1

Ph

Ph

CO2Et

TsN

N Ph

Ph

CO2Et

TsN

N Ph

Ph

(b)

5ref

EtO

O

NTs

NAr

R

Ph,=R c-Hex, alkyne

+ TiI4 CO2EtR

NHAr

NHTs

94:6 syn =R c-Hex99:1 syn Ph=R99:1 anti alkyne=R

4ref

or

NTs

HO

EtOTiI3

TiI3

1

2

3

7b7a654

Scheme 9.1 Mannich reaction of imines and glycinates.

9.2 Construction of the Carbon Backbone j413

of the chiral sulfiminine [10]. Subsequently, enantiopure syn N-sulfinyl-a,b-diaminoesters 13 can be selectively producedunder acidic conditionsmodulated by choosing anon-nucleophilic solvent [tetrahydrofuran (THF) :H2O versus MeOH] to preservethe sulfinamide moiety and thus achieve different degrees of functionalization atthe amino groups [11]. A parallel strategy has been addressed by the group of Davis inthe synthesis of syn and anti a,b-diamino esters recently used in the total synthesisof (�)-agelastatin A and (þ )-CP-99 994. Diastereoselectivity in the addition tosulfinimine 11a was completely controlled by the nitrogen protecting groupsof the glycinate that provide different geometries, (E) versus (Z), respectively, forthe enolate transition state. In addition, a thorough study has demonstrated that forthe N-benzhydrylglycinate 4 a small amount of H2O is crucial in preventing theretro-Mannich reaction of the kinetic anti isomer 14a thus yielding complete antidiastereoselectivity, while in the absence ofH2O the addition provides syn isomers 14bexclusively (Scheme 9.2) [12]. Double diastereoselection has also been applied for theasymmetric synthesis of b-carboline-containing a,b-diamino esters with fairly goodresults [13].Asymmetric catalysis also constitutes a useful tool in the synthesis of a,b-diamino

esters (Scheme9.3). In this context, chiral Lewis acid-stabilized benzophenone iminoglycinate enolates (from 15), generated in the presence of CuClO4 and a chiraloxazoline 17, react with a group ofN-sulfonyl imines 16 to afford, as major products,syn a,b-diamino esters 18 with good enantiomeric excesses (88–97%). Interestingly,the aliphatic nature of N-sulfonyl imines is crucial to reach a good syn : antidiastereoselectivity (>95 : 5) [14]. A parallel approach has been reported by Willisto provide enantioenriched antia,b-diamino acid derivatives 21 asmajor products byusing an oxazolidinone 19 as nucleophilic partner and a C-2 symmetric bis(oxazo-line) 20 as ligand in the presence of Mg(ClO4)2 [15]. In contrast, the system CuOTf/(R,R)-Me-DuPhos has been used for the catalytic direct-type Mannich reaction ofaliphatic aldehydes, secondary amines, and benzophenone imine glycinates, provid-ing low diastereo- and enantioselectivities [16]. Similarly, phase-transfer-catalyzedMannich reaction has been examined using chiral quaternary ammonium salts.For this purpose, catalytic amounts of an N-spiro C-2-symmetric chiral quaternaryammonium salt 24 have been used to produce enantiomerically enriched syn-diamino succinates 25 [64%d.e.; 91% e.e. (syn)] from benzophenone imine glyci-nate 22 and a-iminoester 23, in the context of the synthesis of a precursor ofstreptolidine [17]. Alternatively, syn a,b-diamino ester derivatives 28 havebeen generated from N-Boc imines 26 using a tartrate-derived diammonium salt[(S,S)-TaDiAS] 27 with excellent syn : anti ratio and moderate enantiomericexcesses [18].Imines are also susceptible to nucleophilic addition of nitroalkanes (Scheme 9.4).

Recently, the group of Jørgensen has developed one of themost efficient protocols forthe synthesis of a,b-diamino esters 32, the catalytic enantioselective aza-Henryreaction between imino ester 23 and nitro compounds 29. The reaction proceedsat room temperature with high anti : syn diastereoselectivity (from 77 : 23 to 95 : 5)and enantiomeric excess values above 95% for the major anti b-nitro-a-aminoesters 31, in the presence of base and a copper complex based on a chiral bisoxazoline


ligand [19]. Furthermore, the use of base can be avoided using silyl nitronates 30instead of nitro compounds [20]. Recently, Johnston et al. have reported theenantioselective Brønsted acid catalyzed addition of nitroacetates 33 to aromaticN-Boc imines 34 using chiral trans-1,2-cyclohexane diamine derived quinolinium

N NSO2pTol

R1N=CPh2

CO2MeR1

NHTs

R1 = alkyl, aryl

3,4,5-F3C6H2

3,4,5-F3C6H2

N

N

P-(2,4,6-MeC6H2)2

O

CO2Me

Br

ref 14

O

NOO

N

PhPh

ref 15

ref 17

O

O

4-F-C6H4

4-F-C6H4

N

N

Me C6H4-4-Me

C6H4-4-Me

Me C6H4-4-Me

C6H4-4-Me

BF4

BF4

ref 18

Ph

Ph

15

10% CuClO4

THF, 4Å MS

10% 17

16

17

R1 = Arsyn:anti ,61:39-84:16R1 = alkylsyn:anti > 95:5ee (syn)= 88-97%

18

NSO2pTol

Ph16a

N O

OO

SCN +

19

10% Mg(ClO4)2

10% 20

20

N O

OO

TsN N

Ph

S21

anti :syn, 88:12ee (anti) = 96%

CH2Cl2, DIPEA

4Å MS

N CO2tBu

Ph

Ph

H

NPMP

O

OEt+

NH2

CO2tBuEtO2C

NHPMPa) −20 ºC, 2% 24mesytilene,17% NaOH aq

b) 1N HCl, THF22 23 25

syn:anti, 82:18ee (syn)= 91%

NBoc

MeO

Cs2CO3, PhF,10% 27, −45 ºC

NH2

CO2tBu

NHPMP

26

MeO

syn:ant i, 99:1ee (syn)= 82%

2724

28

22 +

Scheme 9.3 Chiral catalysts for the enantioselective Mannich reaction.


salts (35). After reduction of the resulting nitro compound the best results are 12 : 1anti : syn ratio and 93%e.e. for the major anti diaminoester 36 [21].The reactions between glycinates and electrophiles other than imines have also

been employed to build the Cb�Cc bond; however, these protocols need additionalsteps to transform the primary adduct into the final a,b-diamino acid. For thispurpose, halogenated electrophiles like dibromomethane [22] and N-bromo-methylphthalimide [23] have been successfully employed. Esters such as ethylformate have been submitted to the addition of ethyl hippurate to give (�)-quisqualicacid, further submitted to enzymatic resolution [24], and aldehydes have beendemonstrated to be valuable intermediates in the multistep synthesis of L-capreo-mycidine [25]. Amide acetals are also useful electrophiles in these reactions [26].In particular, an enantioselective synthesis of a,b-diaminopropionic acid derivatives40 has been achieved by condensation of hippuric acid 37 with dimethylformamidedimethyl acetal, 38 followed by treatment with NH4OAc inMeOHand then acylationof the resulting enamide. The a,b-dehydro a,b-diamino ester 39 was submittedto a remarkably efficient asymmetric hydrogenation using (R,R)-EtDuPhos-Rh(I)complex that provides a,b-diamino esters in yields above 99% and enantiomericexcesses of 99% (Scheme 9.5) [27].

9.2.1.2 Dimerization of GlycinatesIn some instances dimerizations of glycinates and related compounds [28] have beenused for the synthesis of diamino succinates. Early attempts entailing photodimer-ization or treatment with sodium hydride of ethyl N-acetyl malonate and 2-acetoxyglycinate [29] led to equimolecular mixtures of diastereoisomers. Alternatively,

RO2N

O

OEtNPMP

CO2EtR

NO2

NHPMP

CO2EtR

NH2

NHPMP

anti:syn, 77:23-95:5(anti)ee 95-99%=

Et(a)conditions:andReagents 3 Cu(OTf)N, 2 CuPF(b)ºC.0orrt, 6, − Ni,Raney(c)THF.ºC,100H2 Tol,(d)80%., − ºC,78 35 NaBH(e)mol).(5% 4 CoCl, 2.

NCuXn

N

O O

Ph Ph

(c)

benzylalkyl,=R

CO2tBu

NO2

2019,refs

+ 35

35 :

(d)

(e)

CO2tBu

2-Np

NHBoc

NH2

anti:syn 12:1 21ref(anti)ee 93%:

HN

HN N

N

9-Anth

H OTf

N

R

OTMSO

or

mol)(20%

NBoc

29

23

(a)

(b) 30

31

363433

32

Scheme 9.4 Enantioselective aza-Henry reactions.


the oxidative dimerization of a chiral Ni(II) complex derived from a-imino alaninateoccurs by treatment with nBuLi followed by addition of pentyl iodide or MnO2 toafford after acidic hydrolysis (�)-(2S,3S)-2,3-dimethyl-2,3-diaminosuccinic acid [30].In another example, a highly diastereoselective oxidative dimerization of glycinateshas been reported by enolization (tBuLi, LDA, or sBuLi) and treatment with iodine toafford racemic syn (threo) diamino succinates (syn : anti >98 : 2) in high yield [31].Recently, a highly diastereoselective route that relies on the coupling of a-ethylthio-glycinate 41 and a-acyliminoglycinate 42 mediated by PPh3 to provide selectively agood yield of (Z)-dehydrodiamino succinate 43 that can be readily converted to the (E)isomer 44 under basic conditions has been described. The cis-selective catalytichydrogenation of both (Z)- and (E)-dehydrodiamino acids allows for the efficientand diastereoselective synthesis of anti and syn orthogonally protected diaminosuccinates 45 and 46 [32]. Finally, enantioselective catalysis has also been applied tothe synthesis of diamino succinates 48. Indeed, a 2-acetoxy imino glycinate 47 wassubmitted to a palladium-mediated p-azaallylic substitution using the benzophenonea-iminoglycinate 15 derived sodium enolate as nucleophile and chiral phosphineligands. Unfortunately, although the yields are fairly good, diastereomeric ratios(dl :meso) are moderate and enantiomeric excess values for the dl pair are low(Scheme 9.6) [33].

9.2.1.3 Through Cyclic IntermediatesCycloaddition reactions, one of the most useful tools for the construction of C�Cbonds, have also been used in the synthesis of a,b-diamino acids. In this context,imines and related compounds containingC¼Nbonds can undergo stereocontrolledcycloaddition with a number of species that render cyclic precursors of a,b-diaminoacids.Among these cyclic precursors are 2-alkoxycarbonyl aziridines, readily available by

Lewis acid-mediated [2 þ 1] cycloaddition of imines and alkyl diazoacetates [34].Studies on this process comprise the use of Lewis acids [35], metal complexes basedon Cu(I) and chiral oxazolines [36], Rh(II) and sulfur ylides [37], boron-basedcatalysts [38], and chiral phase-transfer catalysts [39]. Alternatively, 1,3,5-triazines,N-methoxymethylanilines, and 2-amino nitriles can be used as source of iminesin the presence of the Lewis acid [40]. In particular, SnCl4 and 2-amino nitrilesderived from 1-(R or S)-phenylethylamine 50, provide in situ formation of the

(a)-(c) (d)

ee = 99%

CO2H

NH

PhO

CO2MeNH

Ph

ONH

OMe

CO2MeAcHN

NHCOPh

Reagents and conditions: (a) Tol, reflux. (b) NH4OAc, MeOH, rt. (c) MeCOCl, base, CH2Cl2-Et2O. (d) (R,R)-EtDuPhos-Rh (I), H2, 60-90 psi, 15-60 h.

ref 27Me2NCH(OMe)2+

40393837

Scheme 9.5 Enantioselective hydrogenation of an a,b-dehydro a,b-diamino ester.


iminium ion in the reaction with diazoacetate 49. In this example, aziridine 51 isobtained with complete cis selectivity and with moderate diastereoselectivity relativeto the chiral auxiliary. A further three-step sequence transformed the 2-ethoxycar-bonyl aziridine 51 into the corresponding enantiopure free a,b-diamino acid[syn-(2R,3S)- diaminobutanoic acid (Dab)] (Scheme 9.7) [[40]b].3-Amino-b-lactams are valuable precursors to a,b-diamino acid derivatives. These

intermediates are available by the [2 þ 2] ketene–imine cycloaddition, also referredto as the Staudinger reaction. Using a suitable amino ketene equivalent or anotherketene equivalent such as 2-acetoxyacetyl chloride allows for straightforward intro-duction of an amino group at C-3 after b-lactam formation [41]. The preparation ofamino taxol side-chain precursors has been addressed using this strategy [42].

CN

Me NH

Ph

Me

N2

N

Me CO2Et

CO2Et (a)

100% cis, dr = 66:34

Me Ph

CO2HMe

NH2

NH2

(2S,3R)-Dab

Reagents and conditions: (a) SnCl4, CH2Cl2, rt. (b) TMSN3, BF3·OEt2. (c) H2, Pd-C, (Boc)2O. (d) 6 N HCl.

+(b)-(d)

2 HClref 40b

515049

Scheme 9.7 a,b-diamino acids through aziridines.

OtBuO

NHR1

EtSOMe

R2NR1HN CO2

tBu

R2HN CO2Me

R1HN CO2tBu

MeO2C NHR2

R1 RBoc= 2 Cbz=R1 R= 2 = (S)-BocNHCH(Me)-CO

CO2tBu

MeO2C

NHR1

CO2tBu

MeO2C

NHR1

R2HNR2HN

SO(a)conditions:andReagents 2Cl2, CH2Cl2, PPh(b)ºC.0 3 Et(c). 3 THF,N, − ºC,78Et(d)61%. 2 [Rh(COD)Cl](e)52%.ºC,70MeOH,NH, 2 Hbar,90dppf, 2, ºC.80toluene,

Pd(OAc)(f) 2, (R)-BINAP,MeCN, 77%.NaH,h,24

CO2tBu

N OAc

OMeO

N

Ph

Ph Ph

Ph

Ph2CN CO2tBu

tBuO2C NCPh2

(f) syn:anti 48:52=(syn)ee 47%=

(d)(a),(b)

O

(e)(e)

32ref

33ref

(c)

41

42

4443

4645

481547

Scheme 9.6 Diaminosuccinates through dimerization of glycinates.


Alternatively, 3-azido b-lactams are available from azido ketenes and this approachwas employed in the total synthesis of dimeric diketopiperazine antibiotic (�)-593A [43]. A more straightforward route to enantiopure a,b-diamino acids has beenreported using chiral Evans–Sj€ogren acid chloride 52 and imine 53. The resulting cis-3-amido-4-styryl-b-lactam 54 can be then alkylated diastereoselectively at C-3 (55),furnishing after complete removal of protecting groups and b-lactam cleavage(3 steps), free (S,R)-a-methyl-a,b-diamino acids 56 (Scheme 9.8) [44]. Alternatively,the cis b-lactam 54 can undergo epimerization to the trans isomer and further acidichydrolysis afforded anti (R,R)-a,b-diamino acids in good yield [45]. The highlyefficient transformation of enantiopure N-Boc-protected 3-amino-b-lactams 57into a-alkyl-a,b-diamino acid residues 58 incorporated as part of a peptide backbonehas also been developed by the group of Palomo. Indeed, upon treatment with(S)-phenylalanine or (S)-valinemethyl esters and sodiumazide or potassium cyanide,b-lactams afforded dipeptides (Scheme 9.8) [46].Carboxyimidazolines and imidazolidines are cyclic analogs of a,b-diamino

acids, easily accessible via [3 þ 2] cycloaddition of imines and azomethine ylides [47].The palladium-mediated synthesis of imidazolines reported by Arndtsen can be heldin this category [48]. Within this context, the group of Harwood reported that chiralazomethine ylides 61 generated in situ from (5S)-phenylmorpholin-2-one 59 in thepresence of aromatic aldimines 60 and pyridinium p-toluenesulfonate canundergo cycloaddition with excess of imine to give imidazolidines 62 as singleproducts. Finally, hydrogenolysis under acidic conditions released the correspondingenantiopure syn a,b-diamino acids in excellent yields 63 (Scheme 9.9) [49].Another remarkable example of this approach is the reaction of methyl isocyanoa-cetate 64 with N-sulfonyl imines 16 [R ( aryl, (E)-styryl] catalyzed by transition metalcomplexes such as AuCl(NCc-hex) to give racemic cis-imidazolines 65 with high

N

O O

PhCl

N

R2

R1N

O R1

N R2

O

Ph

O

NO R1

R2AuxN

R3

(a) (b) steps3 CO2HPh

NH2

H2N Me

R1 RBn,= 2 styryl= R3 Me=

Et(a)conditions:andReagents 3 CHN, 2Cl2, − NaNDMF,(c)MeI.LHMDS,(b)rt.toºC78 3, 10-rth.10-14rt,DMF,,KCN(d)h.14

O

98%=de

44ref

NO Boc

NHR2

R1R3

O

CO2MeNH

BocHN

R4O

NH

R1 R2

O

R3(d)or(c)

57a R1 RH,= 2 = i RPr, 3 CbzLeu=57b R1 R= 2 RMe,= 3 OBn= R4 = i BnPr,

(S)-H2NCH(R4)CO2Me+ 46ref

545352 55 56

58

Scheme 9.8 a,b-Diamino acids through b-lactams.


diastereoselectivity. cis-Imidazolines were readily converted into anti a,b-diaminoacids 67 or their methyl esters and can be isomerized (R1¼Ph) into the thermody-namically more stable trans isomer 66 by treatment with Et3N leading to thecorresponding syn a,b-diamino acids or esters 68 (Scheme 9.9) [50]. Interestingly,RuH2(PPh3)4 as catalyst and CH2Cl2/MeOH 1 : 3 as solvent, provide oppositediastereoselectivity (trans) for the cycloaddition [51]. Furthermore, in the presenceof Au(I) salts and a chiral ferrocenylphosphine ligand 69, cis imidazolines (R1¼ aryl)were obtained as optically pure materials (96–99%e.e.) and were then converted toanti diamino esters (2R,3R) using a parallel procedure [52].

9.2.2Methods in Which the Ca�Cb Bond is Formed

9.2.2.1 Nucleophilic Synthetic Equivalents of CO2RConstruction of the Ca�Cb bond is another key approach in the synthesis ofa,b-diamino acids. In fact, the carboxylic group is introduced into the molecule bymeans of a synthetic equivalent as a nucleophile or electrophile and then additionalmanipulation to give the carboxylic group is usually needed. Within this context,nitrocompounds have been employed as nucleophiles to form the Ca�Cb bond [53].

O

HN

O

Ph

N

Ar

Bn O

N

O

Ph

Ar

(a)

O

N

O

Ph

NAr

Ar(b)

NH2

ArCO2H

NH2

100:0=de

TFA,(b)reflux.toluene,PPTS,(a)conditions:andReagents MeOH-H 2 Pd(OH)(10:1),O 2, H2 bar.5,(c -hexNC);AuCl(c) RuHtrans.cis:89:11-95:5 2(PPh3)4 AuCl·SMetrans:cis.13:87-5:95; 2, ferrocenyl

(4R,5S)phosphine; Et(d)96%-99%.=eecis, 3 CHN, 2Cl2, HCl,orH=RforHClN6(e)reflux.Me.=RforMeOH

Bn

H

OMeO

NC

N

R1

Ts NTsN

R1 CO2Me

NTsN

R1 CO2Me

(c)

(d)

NHTs

R1 CO2R2

NHTs

R1 CO2R2

NH2·HCl NH2·HCl

(e)Fe

PPh2

PPh2

Me

NMe

N

R2 MeH,=

styrylaryl,=R

R2 MeH,=

50-52refs

49ref

(e)

)( 2

6362616059

66651664

67 68

69

Scheme 9.9 a,b-Diamino acids through imidazolidines and imidazolines.


Jackson et al. have developed a new route to enantiopure anti a,b-diamino acidsbased on the stepwise condensation of (p-tolylthio)nitromethane 71 and a-aminoaldehydes 70 (Scheme 9.10). The resulting nitroalkenes 72 were submitted tonucleophilic epoxidation and diastereoselective epoxide cleavage using NH3 torender a,b-diamino thioesters that were transformed in two steps into differentiallyprotected anti a,b-diamino acids 73 [54]. The use of terminal alkynes as syntheticequivalents of the carboxylic acidmoiety is well documented in organic synthesis andhas been applied to the synthesis of a,b-diamino acids (Scheme 9.10). The group ofMerino has demonstrated that addition of lithium trimethylsilylacetylide to a-aminonitrones 74, takes place with a high degree of diastereocontrol (>95 : 5) to give synpropargylhydroxylamines 75. In contrast, changing protecting groups in the startingnitrone allows for an inversion of the diastereoselectivity (76, anti : syn, 85 : 15). Then,removal of the trimethylsilyl group,O-acylation, alkyne oxidation with RuCl3/NaIO4,and esterification provide syn and anti a,b-diamino esters 77 and 78, respectively.Pyrrolidinyl glycinates have been produced with this approach [55]. A close strategycan be carried out using 2-lithiofuran instead of lithium trimethylsilylacetylide in theaddition to the nitrone [56].The Bucherer–Bergs reaction of a-amido ketones, potassium cyanide, and ammo-

nium carbonate produced hydantoins in good yields that, after cleavage of theprotecting carbamate and saponification, rendered a-alkyl a,b-diamino acids [57],

NHFmoc

R CNO2

STol(a)

FmocHN

R NO2

STol NHFmoc

RCO2H

NHBoc R = Me, Bn, iPr

(b-c)

4 steps

i.(a)conditions:andReagents tBuOK, t MeSOii.BuOH-THF; 2Cl, iPr2EtN,CH2Cl2, i.(b)69-80%.LiOOt NHii.toluene;Bu, 3, Boci.(c)35-57%. 2 Hii.97-99%;THF,O, 2O2 LiCCTMS,(d)63-91%.NaOH,,THF, −80 ºC, 68-97%. (e) Bu4NF, THF, rt, 70-80 %. (f) Ac2O, pyr, 1 h, rt. (g) RuCl3-NaIO4, MeCN, rt. (h) CH2N2, Et2O, 72-76% (3 steps).

O

Href 54

L-serine

NO

Bn

OR1

NR2

(d)NBnOH

ON

TMS

NBnOH

OTBDPSBocHNor

TMS

Boc Boc

(e)-(h)

NBnOAc

O

N

MeO2C

NBnOAc

OTBDPS

BocHN

MeO2C

Boc

syn:anti > 95:5 syn:anti = 15:85

ref 56(e)-(h)

7170 72 73

74

7675 78

77

Scheme 9.10 Introduction of the carboxylate as nucleophile.


aswell asa,b-diamino acids derived fromproline [58] and pipecolic acid [59] that haveserved as monomers for assembling, by solid-phase synthesis, larger molecularentities with a well-defined secondary structure in solution. On the other hand,the Strecker reaction, involving addition of cyanide to a-amino imines providesefficient access to a,b-diamino nitriles that have been transformed into differenta,b-diamino acid derivatives. This strategy was employed to synthesize peptidicenalapril analogs containing an a,b-diamino acid residue, as inhibitors of theangiotensin-converting enzyme [60], as well as for the synthesis of octapeptideangiotensin II analogs containing an a,b-diamino acid unit [61]. AsymmetricStrecker reactions have been carried out using chiral imines generated fromenantiopure (R)-a-phenylethylamine with moderate diastereoselectivity [62]. Incontrast, a,b-aziridinosulfinimines [63] and glucopyranose-derived aldimines [64]provide, with high diastereocontrol, amino nitriles that have been used in thesynthesis of a,b-diamino acids. The Strecker methodology has been used in thetotal synthesis of enantiopure dysibetaine and related compounds (Scheme9.11) [65].In fact, an enantiopure bicyclic d-lactam 79 was used as precursor of an N-acylimi-nium ion for the highly diastereoselective addition of trimethylsilyl cyanide (80).After diastereoselective lactamhydroxylation atC-4 (81, diastereomeric ratio> 80 : 1),hydrogenolysis, acidic hydrolysis and esterification, hydroxymethyl lactam 82 wasproduced. Substitution of the side-chain hydroxyl group was effected by means ofazide displacement onto a mesylate derivative and then suitable manipulation of thefunctional groups afforded natural (2S,4S)-dysibetaine. Within the context of theStrecker protocol, the modular synthesis of syn a,b-diamino esters has beenreported via sequential addition of cyanocuprates and cyanide. The key intermediate

SnClTMSCN,(a)conditions:andReagents 4, HCl.N6(c)81%.THF,toluene,MoOPH,KHMDS,(b)65%.CH(d) 2N2, Et2 NaNii.MsCl-Pyr;i.(e)steps.2over59%O, 3 H(f)steps.2over28%DMF,, 2, MeOH.Pd-C,

MeI,i.(g) iPr2 (h)61%.550A,Dowexii.THF;EtN, i BFLiCl,BuCuCNMgBr, 3·Et2 THF.BuLi,TsCl,(i)THF.O,BFTMSCN,(k)THF.BuLi,BnSH,(j) 3·Et2 CHO, 2Cl2.

NO

OOH

Ph

NO

OCN

Ph

(a) N

O

OCN

Ph

HO

(c-d)(b) NH

O

HO

CO2Me

OH(e-g) N

HO

HO

CO2

NMe3

(S)-dysibetaine81, 80:1=dr80, :0100=dr 65ref

NAcAcN

O

steps5NRHN

O

(h)-(j)

MeO OMe

NHTsN

O

Bu OMe

NHTsN

O

Bu CNi iNHTs

BuCO2Me

NHBoc

steps4(k)

=R

OMeO

i

(MAC)66ref

79 82

8786858483

Scheme 9.11 Diastereoselective Strecker reaction in the synthesis of a,b-diamino acids.


enantiopure dimethoxyimidazolidinone 84, generated in five steps from a nonchiralimidazolone 83, underwent nucleophilic addition of isobutylcyanocuprate to anin situ generated acyliminium ion followed by introduction of a tosyl group andremoval of the chiral auxiliary (MAC) to afford anN-tosylmethoxyimidazolidinone 85that was submitted to diastereoselective Lewis acid mediated addition of cyanotri-methylsilane (86). Finally, four steps, including acidic hydrolysis of the cyanidegroup and imidazolidinone cleavage, rendered the enantiopure syn a,b-diaminoester 87 in good yield (Scheme 9.11) [66].Finally, the multicomponent Ugi condensation has been used as the key step

for the assembly of piperazine-2-carboxamides (Scheme 9.12). This one-pot proce-dure consists of reaction between a mono-N-alkylethylenediamine, an a-chloroace-taldehyde, an isocyanide, and a carboxylic acid to give piperazine carboxamides in avery efficient manner. Furthermore, access to enantiopure piperazines is alsopossible using a,a-dichloroacetaldehyde that allows for the isolation of 88 thatcyclizes to tetrahydropyrazine 89. Asymmetric hydrogenation of the latter inthe presence of Rh-2,20-Bis(diphenylphosphino)1,10-binaphthyl (BINAP) catalystprovides the enantiopure piperazine 90, a fragment of the HIV protease inhibitorindinavir [67].

9.2.2.2 Electrophilic Synthetic Equivalents of CO2R and Other ApproachesIn contrast to the approaches above, the introduction of the carboxylic group as anelectrophile has been scarcely explored. An example developed by the group ofSeebach starts from a glycine-derived imidazolidinone (R)-[2-tert-butyl-3-methyl-4-imidazolidinone (BMI)] (Scheme 9.13). Deoxygenation using lithium triethylbor-ohydride in combinationwith lithiumborohydride rendered an acylimidazolidine 91that upon directed metallation with tBuLi followed by trapping with CO2 diaster-eoselectively afforded carboxyimidazolidines 92 (diastereomeric ratio> 98 : 2).Subsequent diastereocontrolled alkylation using alkyl halides 93 and then acidichydrolysis allowed for the isolation of a number of enantiopure free a-alkyla,b-diamino acids 94. In addition, since (S)-(BMI) is equally accessible the enantio-meric a,b-diamino acids are also available. A parallel approach has been used in thesynthesis of 2-carboxypiperazines by the group of Quirion [68]. Finally, [2 þ 2]ketene–imine cycloadditions have been applied to form the Ca�Cb bond of

NHBoc

NH2

(a)N

CHO

NHBoc

NHtBu

O

Cl (b)

N

N

CHO

Boc

NH tBu

O

(c),(d)

NH

N

Boc

NH But

O

rt,days,2MeOH,ºC,50toluene,(a)conditions:andReagents Etthen 3 (~100%).rt,h,3N,KO(b) t [(R)-BINAP(COD)Rh]OTf,MeOH,(c)60%.h,3THF,Bu, H2, aqueous(d)atm.100

NH2NH2, 91%.ºC,100

HCO2H, tBuNCCl2CHCHO

67ref89 9088

Scheme 9.12 Multicomponent Ugi reaction for piperazine-2-carboxamides.


a,b-diamino acids with the oxidative treatment of b-lactams as a crucial step ofthis strategy (Scheme 9.13). In particular, enantiopure 3-hydroxy-4-(aminoalkyl)b-lactams 97, readily available from acid chlorides 96 and optically pure a-aminoimines 95, were efficiently submitted to an oxidative cycloexpansion protocol usingTEMPO (2,2,6,6-tetramethylpiperidinooxy) that provides N-carboxy anhydrides 98without epimerization. Ensuing esterification rendered enantiopure differentiallyprotected syn a,b-diamino esters 99 [69].

9.2.3Methods in Which the CbCb0 or CcCc0 Bonds are Formed

The number of routes to introduce carbon substituents on the diamino acid skeletonis considerably smaller than the number of approaches found for the abovedisconnections. Some of these methods are based on alkylation of asparagine oraspartic derivatives [70]. Within this family of methods, the group of Merino hasreported an effective route for the diastereoselective synthesis of syn or anti a,b-diamino esters based on nucleophilic additions of Grignard reagents to nitronesprepared from L-serine. The authors have observed different diastereoselectivitiesdepending on the protecting groups of the substrates [71]. Similarly, addition ofallylmagnesium bromide to Garner�s aldehyde derived imine 100 has recently beenapplied to the synthesis of 2-piperidinyl glycinate 101 (Scheme 9.14) [72]. Finally, in areport from the group of Snider, the total synthesis of (�)- and (()-dysibetaine hasbeen addressed using as a key step the intramolecular cleavage of an oxirane to build apyrrolidinone ring (Scheme 9.14). Initial N-acylation of ethyl amino(cyano)acetate

N

N

OtBu

Me

Boc

N

N

tBu

Me

Boc

N

N

tBu

Me

BocCO2R

1

N

N

tBu

Me

Boc

CO2MeR2

HO2C NHMe

H2NR2

(c)(b)(a)

(R)-BMI98:2>drR1 MeH,=

LiBH(a)conditions:andReagents 4 LiBHEtcat., 3 TMEDA,(b)90%.min,90reflux,THF,, tBuLi,Et2O, − COthenmin30ºC,70 2 CHthenh3, 2N2 (c)84%. iPr2 THF,NH, nBuLi, − min,20rt,toºC60R2 CHTFA,i.(d)60-86%.h,12X, 2Cl2 50Dowexiii.h;1rt,NaOH,N2ii.h;14, X (e)60-75%.8,

NaHCOcat.,TEMPONaOCl, 3 KH, 2PO4-K2HPO4 CHKBr,, 2Cl2 rt,TMSCl,MeOH,(f)92%.ºC,0,80%.reflux,MeOH,orh24

(d)

68aref

Cl O

OBn

NO R3

HOR4

NHBocH

NO

O

OR3

R4

NHBoc

(e)

NR3

NHBoc

R2

R3 RBnAr,PMP,= 4 PhMe,=

(f) CO2Me

NHR3

R4

NH2

69ref

94939291

95 99989796

Scheme 9.13 Introduction of Ca through electrophilic reagents.


with (R)-glycidic acid gave a glycinamide 102 that underwent intramolecularalkylation upon treatment with NaOEt to give a 45 : 55 mixture of diastereomerichydroxy pyrrolidinones 103 that was readily separated after silylation. Subsequenthydrogenation of the cyano group, followed by permethylation and saponificationrendered (R,R)-dysibetaine and (S,R)-epidysibetaine, respectively [73].

9.3Introduction of the Nitrogen Atoms in the Carbon Backbone

9.3.1From Readily Available a-Amino Acids

Natural a-amino acids are key starting materials for the synthesis of a,b-diaminoacids. Indeed, a plethora of synthetic approaches can be found through the literatureconsisting of the manipulation of functional groups that already exist in availablea-amino acids with the additional advantage of using enantiopure startingmaterials.Most of these methods are already reviewed [1] and only illustrative examples aregathered herein.Serine, threonine, and allo-threonine have been frequently submitted to conver-

sion of the alcohol into an amine, and by far the most studied approach is theMitsunobu reaction (for a recent example, see [74]). However, a suitable combinationof protecting groups at the acid, the a-nitrogen as well as the newly introducedb-nitrogen should be chosen to prevent undesired side-reactions such as b-elimina-tion, aziridine formation, and so on, and to ensure a reasonable yield of thea,b-diamino acid derivative [75]. The synthesis ofb-pyrazol-1-yl-L-alanine [76] analogs

Garner'saldehyde

N

NBocO

(b)-(c)(a)

CH(a)conditions:andReagents 2=CHCH 2 THF:EtMgBr, 2O, − NEtTsCl,(b)ºC.30 3, CH2Cl2 (c).DCC(e)ºC.0acetone,reagent,Jones'(d)rt.5%,catGrubbs' (g)THF.NaOEt,(f)EtOAc.,

CH2,6-lutidine,TBSOTf, 2Cl2 PtOseparation;(h). 2, H2 Hi.(i)HCl.EtOH,, 2 HPd-C,CO, 2 ii.;NaHCO 3, ºC.55MeOH,550A,Dowex(j)THF.MeI,

EtO

O

CN

O

CO2H

NH2(e)

NC NH

EtO2C

O

O

(f),(g)

NH

OTBDMS

CNEtO2C

O NH

OH

O2CO N

H

OH

O2CO

(R,R)-dysibetaine

(h)-(j)

NMe3

NMe3

72ref

45:55dr:(S,R)-epidysibetaine

73ref

HN

NBocO

NTs

HO2C

NHBoc(99:1)100 101

102 103

Scheme 9.14 Examples of formation of CcCc0 and CbCb0 bonds.

9.3 Introduction of the Nitrogen Atoms in the Carbon Backbone j425

of willardine [77] as well as enantiopure 2-carboxypiperazine derivatives [78] havebeen addressed using Mitsunobu protocols. In contrast, the direct nucleophilicsubstitution on suitably protected b-tosyl serine [79] and threonine [80] derivatives oreven on b-chloroalanine [81] is less documented. A recent and simple exampledescribes N,N-dibenzyl-O-methylsulfonyl serine methyl ester 104 as a suitableprecursor of a,b-diamino esters 105ab by reaction with nitrogen nucleophiles viaregioselective (C-2) opening of a transient aziridinium ion (Scheme9.15) [82]. Finally,there are a few reports inwhich the hydroxymethyl group of L-serine is converted intothe new carboxylic group in the target a,b-diamino acid [83]. In many of theseexamples the Garner�s aldehyde obtained from L-serine is an essential syntheticintermediate [84].Aside from using b-hydroxy amino acids, a common approach to L-2,3-diamino-

propionic acid involves either a Curtius rearrangement of free L-aspartic acid or aHofmann reaction of an L-asparagine derivative [85,86]. The main side-products inthese reactions are imidazolidinones [87]; however, a clever use of the reagents canprovide orthogonally protected L-2,3-diaminopropionic acid [88]. Within this generalapproach, L-aspartic acid has been used as starting material for the preparation of akey intermediate for the synthesis of (þ )-biotin [89]. Indeed, an enantiopure b-hydroxymethyl asparagine derivative 106, prepared fromN-Cbz-L-aspartic acid infivesteps, was submitted to Hofmann rearrangement to afford cyclic urea 107 with noepimerization. Removal of the protecting group (Bom) by hydrogenation led tobicyclic g-lactone 108 that was submitted toN-benzylation followed by treatmentwithKSAc to furnish thiolactone intermediate 109 (Scheme 9.15).

OHO

HO2CNHCbz

OH2N

HO2CNHCbz

BOMO

HN NCbz

CO2H

O

BOMO

(b)RN NR

O

X O

(c)

(d)

HN NH

O

(+)-biotin

SCO2H

4

Reagents and conditions: (a) MeCN, 80 ºC. (b) NaOCl, NaOH, H2O, 70%. (c) H2, Pd(OH)2-C, MeOH, 80%. (d) i. BnBr, NaH, DMF, 84%; ii. KSAc, DMF, 92%.

5 steps108, X = O, R = H

109, X = S, R = Bn ref 89

CO2Me

OMs

Bn2N

+ R1R2NH(a) CO2Me

Bn2N

CO2Me

NBn2

R1R2N

ref 82

R1R2NH =X

NH

NH

HN

CO2Me

NR1R2

Bn2N

+

X = O, NBn, S, CH2 CO2MePh

37-92% 0-10%104 105ab

106 107

Scheme 9.15 Serine and aspartic derivatives as starting materials.


9.3.2From Allylic Alcohols and Amines

Optically pure allylic alcohols and amines are valuable precursors to a,b-diaminoacids. The key step in these approaches is the internal delivery of a nitrogen atomfrom the group attached to the hydroxy or amino group to the unsaturated C�Cbond [90]. Consequently, the degree of diastereoselectivity in the intramoleculartransfer is crucial for efficient access to the target molecules. An approach to a taxolside-chain analog illustrates thismethodology (Scheme 9.16) [91]. Enantiopure epoxycarbamate 110 was prepared from cinnamyl alcohol via Sharpless asymmetricepoxidation and was then treated with sodium hydride to produce an oxazolidinone111 with complete inversion of stereochemistry at the epoxide carbon. Activation ofthe hydroxyl group as a methanesulfonate ester 112 and further displacement usingpotassium phthalimide with undesired retention of configuration, gave the antioxazolidinone 113. In contrast, when themesylate was treatedwith sodiumazide andchlorotrimethylsilane (TMSCl), the syn oxazolidinone 114 was produced exclusivelythat was transformed into the target syn a,b-diamino acid derivative in five steps.Alternatively, other approaches rely on sigmatropic rearrangements for the construc-tion of the C�Nbond [92]. Recently, a stereocontrolled route to anti- and syn-2,3-Dabs

OBzHN

O

O

PhOR1

Ph

HNO

O

NPth

Ph

HNO

O

N3

Ph

HNO

O(a) (d)or(c)

111, R1 H=112, R1 Ms=

(b)

NHBz

PhCO2H

NHBocsteps5

sidetaxolanalogchain

LiOH,ii.88%;reflux,THF,NaH,i.(a)conditions:andReagents H2 NEtMsCl,(b)%.85rt,THF,O, 3,NaN(c)%.89 3 CCli.(e)%.79DMF,KPhthalimide,(d)64%.DMF,TMSCl,, 3 CHCONCO, 2Cl2 ii..

K2CO3, PPhi.(f)MeOH. 3, CBr4, NEt3, CH2Cl2 BuBnOH,ii.. 3 CHDDQ,i.(g)93%.SnOBn, 2Cl2, H2O.CClii. 3 CHCONCO, 2Cl2 Kiii.. 2CO3, PPh(h)MeOH. 3, CBr4, Et3 CHN, 2Cl2, %.70-77

91ref

OR

PMBO

O

PMBO

CN

PMBO

NCO

RO

NHCbz

(e)H,=R 115CONH=R 2

(f)

PMB,=R 118CONH=R 2

(g)

(h)NHCbzN

O

CO2H

H2N

NH22HCl

(2R,3R)-Dab

steps6

93ref

or

inversionretention114113110

119117116

Scheme 9.16 a,b-Diamino acids from allylic alcohols.


has been reported that entails two consecutive [3,3]-sigmatropic rearrangementswithcomplete transfer of chirality from the C�Obonds in the startingmaterial to the newC�N bonds. Thus, the starting anti allyl diol 115, available in four steps from L-lacticacid methyl ester, was transformed into an allyl cyanate 116 that underwentrearrangement to an allyl isocyanate 117 captured with benzylic alcohol to providea benzyloxy carbamate 118. The remaining allyl alcohol is again transformedinto a cyanate that suffered the second [3,3]-sigmatropic rearrangement to yieldcis-4-propenyl imidazolidinone 119. Finally, a six-step sequence that includesoxidative cleavage of the propenyl chain rendered anti-(2R,3R)-Dab. Through asimilar sequence, the syn allyl diol provides enantiopure syn-(2R,3S)-Dab(Scheme 9.16) [93].

9.3.3From Halo Alkanoates

One of the most efficient routes found among the earlier endeavors to synthesizethese compounds consists of treating a,b-dibromo propionates 120 or succinates121 with amines (Scheme 9.17). Following this approach meso, dl-2,3-diamino-succinic acid derivatives [94] and 2-carboxypiperazines can be readily obtained [95].However, when ammonia is used as the nucleophile, racemic methoxycarbonylaziridines, readily resolved by enzymatic means, were produced. This protocol hasbeen used for the synthesis of enantiopure 2,3-diaminopropionic acid [96] and ofVLA-4 antagonists containing an a,b-diamino acid residue [97]. Besides, sequentialintroduction of the nitrogen nucleophiles has also been reported using ethyl b-bromo a-hydroxy propanoate as starting material [98]. Alternatively, a facile routefor the synthesis of a,b-diamino acids has been reported by reaction of 2-methoxycarbonyl aziridine 122, with chiral (þ )-a-methylbenzylisocyanate 123 inthe presence of sodium iodide to produce a mixture of diastereomeric imidazo-lidinones 124 (65 : 35), by means of initial iodide-mediated aziridine opening.After separation and acidic cleavage both enantiomers of 2,3-diaminopropionicacid are available. a-Alkyl-a,b-diamino acids are also available by this approach

Br R2

Br CO2R1

BnNH2

BnHN CO2H

BnHN CO2H

120, R1 REt,= 2 H=121, R1 RH,= 2 CO= 2H

dl- or meso

N

N

R3

R3

CO2Et

R3HN

NHR3

Ph NCO

MeN

NO

Ts

PhMe

MeO2CNaI

65:35=dr

Dpr

N

MeO2C

Ts

95and94refs

99ref

123122 124

Scheme 9.17 a,b-Diamino acids from halo and aziridino alkanoates.


(Scheme 9.17) [99]. Similarly, the group of Ha has examined the TMSCl-mediatedring expansion of enantiopure aziridine-2-carboxylates with achiral isocyanates. Inthese reactions, imidazolidin-2-one-4-carboxylates are obtained regio- and stereo-specifically in good yields [100].

9.3.4From Alkenoates

Aside from the above examples, it could be easily envisioned that enantioselectivediamination of a,b-unsaturated acids would be the shorter route to a,b-diaminoacids; however, the direct asymmetric diamination of olefins is a reaction compara-tively less studied than the related dihydroxylation process. In fact, the stoichiometricosmium mediated diamination of a chiral cinnamate 125 with bis(tert-butylimido)dioxoosmium(VIII) provides an osmaimidazolidinone 126 in excellent diastereo-meric ratio (94 : 6). Subsequent reaction with tert-butylamine and ZnCl2 provides anamide that was submitted to osmium removal with sodium borohydride furnishingan a,b-diamino amide 127 in good yield (Scheme 9.18). Furthermore, the synthesisof enantioenriched osmaimidazolidinones 129 (enatiomeric ratio> 90 : 10) fromachiral N-alkenoyl oxazolidinones 128 has been accomplished using a 10% TiTAD-DOLate (TADDOL¼ 4,5-bis[hydroxy(diphenyl)methyl]-2,2-dimethyl-1,3-dioxolane)

O

OR*Ph

NOs

N Ph

CO2R*O

O

OsO NtBu

O NtBu94:6=dr

NHtBu

PhCONHtBu

NHtBu(b),(c)

(a)

(b)ºC.THF,-15(a)conditions:andReagents tBuNH2, ZnCl2 NaBH(c). 4, 95%.rt,EtOH,TsNCl(e)ºC.5Tol,Ti-TADDOLate,(d) 2, FeClMeCN, 3·PPh3 70HCl,N6(f)63%.(cat.),

92%.ºC,

tBu

tBu

R

O

N O

ON

OsN R

CO

O

tBu

tBu

N O

OO

COPh,H,Me,=R 2Me(d) 101ref

95:591:9-=er

PhCO2Me (e)

NTsN

Ph CO2Me

CHCl2

(tr ans)de 95%>

(f)Ph

CO2Me

NHCOCHCl2

NHTs

(-)-8-phenylmenthol=R*OH

refs102-103

125126 127

128

129

130

131 132

Scheme 9.18 Direct diamination of a,b-unsaturated esters and amides.


as enantioselective catalyst [101]. Within the same context, the group of Li hasreported the first direct electrophilic diamination ofa,b-unsaturated esters 130usingN,N-dichloro 2-nitrobenzenosulfonamide (2-NsNCl2) in acetonitrile [102]. The pro-cess takes place with complete anti diastereoselectivity and the use of acetonitrile iscrucial since amolecule of solvent is apparently responsible for delivering the secondnitrogen atom to the final racemic anti a,b-diamino ester. Alternatively, in thepresence of Rh(II), Fe(III), or Mn(IV) catalysts trans imidazolines 131 are producedthat can be readily transformed into syn a,b-diamino esters 132 upon acidichydrolysis (Scheme 9.18) [103].Different groups have envisioned that a,b-diamino acid derivatives could

be prepared efficiently by aminohydroxylation of a,b-unsaturated esters [104,105].The group of Sharpless has outlined a short and highly versatile route to a series ofa,b-diamino esters from an 87 : 13 mixture of regioisomeric anti amino hydroxypropanoates 133, prepared from a trans glycidic ester and a secondary amine(Scheme 9.19). Subsequent mesylation of the mixture provided exclusively theb-chloroamino ester 134 in quantitative yield via in situ chloride attack to anaziridinium ion. Regeneration of the aziridinium ion followed by in situ reactionwith a wide range of nitrogen nucleophiles took place with excellent yields andregioselectivities, furnishing racemic anti a,b-diamino esters 135 as major pro-ducts. Furthermore, the starting mixture of anti amino hydroxy propanoatesunderwent a one-pot procedure, mesylation and nucleophilic attack of the amine,to give diamino esters 135 through the aziridinium ion in an extremely efficientmanner [106].A different approach takes advantage of the Michael acceptor character of

a,b-unsaturated acid derivatives to nitrogen nucleophiles. In particular, a,b-dehydroalanine derivatives have resulted extremely useful starting materials con-taining the a-nitrogen [107,108]. In addition, the reaction of vinyl triflates derivedfrom a-keto esters with secondary amines has been recently examined as anefficient route to a,b-diamino acid derivatives. However, the low stereoselectivies

EtMsCl,(a)conditions:andReagents 3 CHN, 2Cl2, R(b)94-99%.ºC,0 1R2 KNH, 2CO3, 72-99%.MeCN,

PhCO2Et

OH

NR2

PhCO2Et

NR2

OH

+

133 (87:13),

HR2N

PhCO2Et

Cl

PhCO2Et

NR2

Cl

PhCO2Et

NR2

NR1R2(a)

=regioselectivity92:8-100:0

R1R2 NH=NH 3,nBuNH2, PhNH2,

tBuNH2

NHPhN NH,NH

NNH2,,

OHN NPhHN Bn2NHNH

2,,,R2 =NH

106ref

(b)

135134

Scheme 9.19 a,b-Diamino esters from aminohydroxy alkanoates.


represent a severe drawback for this route [109]. Alternatively, when the startinga,b-unsaturated ester does not have a pre-existing nitrogen atom in the molecule,the synthesis of the a,b-diamino acid requires two steps, Michael addition of anamine to introduce the b-nitrogen and subsequent amination of an enolate tointroduce the a-nitrogen. The groups of Seebach and Davies have independentlyexamined the above methodology [110]. In particular, Davies showed that additionof chiral secondary lithium amide 136 was crucial to obtain b-amino esters 137with complete diastereocontrol. Further diastereoselective trapping of the enolatewith trisylazide (138, anti, >95%d.e.) followed by Staudinger reaction andhydrolysis of the iminophosphorane intermediate led after four more steps toenantiopure anti a,b-diamino acid, (2S,3S)-Dab. In contrast, after anti a-hydrox-ylation of the enolate using chiral (�)-(camphorsulfonyl)oxaziridine and displace-ment of the mesylate with sodium azide a 66 : 33 mixture of syn azide 139 andtrans oxazolidinone 140 was obtained. After separation, hydrogenation and acidicdeprotection, enantiopure syn a,b-diamino acid (2R,3S)-Dab was also available(Scheme 9.20) [110b].

9.3.5Electrophilic Amination of Enolates and Related Processes

The diastereoselective electrophilic amination of b-amino enolates provides anefficient access to a,b-diamino acid derivatives of diverse structures. N-Sulfonylazides have been used as electrophiles for the introduction of a nitrogen atom at C-3of b-lactams within the synthesis of an analog of rhodopeptin B5 and also for theamination of piperidinyl acetic acid derivatives, in a study focused on the synthesis ofanalogs of streptolutin as enantiopure materials [111]. Furthermore, this approachhas been successfully employed for the diastereocontrolled synthesis of 2,3-diamino

Ph NBn

Me

Li Me

tBuO2C(a)

MeCO2

tBu

NBnPh

Me

MeCO2

tBu

NBnPh

Me

NH2

steps4Me

CO2H

NH2

NH2

(2S,3S)-Dab

THF,(a)conditons:andReagents − THF,LDA,i.(b)ºC.78 − THF,trisylazide,ii.ºC;78 − HOAc,iii.ºC;78THF, − PPh(c)32%.rt,toºC78 3, HTHF, 2 THF,LDA,i.(d)91%.rt,O, − (ii.ºC;78 −)-

EtMsCl,i.(e)(camphorsulfonyl)oxaziridine. 3 CHN, 2Cl2, NaNii.rt. 3, 55%.DMF,

95%>de

MeCO2

tBu

NHBoc

OH

MeCO2

tBu

NHBoc

N3

(b),(c)

OHN

O

Me CO2tBu

MeCO2H

NH2

NH2

HCl·2(2R,3S)-Dab

(66:33)

(d)

+

(e)

steps2

110bref

137136

138

140139

Scheme 9.20 a,b-Diamino acids via Michael addition of chiral amines.


succinates [112] and for the synthesis of orthogonally protected units in thepreparation of somatostatin analogs [113]. Alternatively, the electrophilic aminationof b-amino acids can be performed with di-tert-butylazodicarboxylate as electro-phile [114]. In addition, the group of Cativiela found that 2-cyano propanoates 141containing an isobornyloxy group as a chiral auxiliary (R�) can be converted into 2-amino-2-cyano propanoates 142 with moderate to good diastereoselectivites upontreatment with lithium hexamethyldisilazane and O-(diphenylphosphinyl)hydroxyl-amine as the source of electrophilic nitrogen (Scheme 9.21). Separation and suitablemanipulation of the functional groups resulted in a-substituted a,b-diaminoacids [115].Finally, a recent and interesting example was brought to light by the group of

Wardrop in the total synthesis of (�)-dysibetaine (Scheme 9.22) [116]. The syntheticroute commenced from an a,b-unsaturated ester 143 readily converted into anenantiopure a-silyloxy methoxylamide 144 in four steps that entail Sharplessasymmetric dihydroxylation and regioselective reduction of the b-hydroxyl group.Subsequent generation of an N-acylnitrenium ion using phenyliodine(III) bis(tri-fluoroacetate) promoted spirocyclization to afford an spirodienone 145 as an insepa-rable 9 : 1 mixture of C-5 epimers. The mixture was converted into an azido g-lactam146 through a sequence that entails ozonolysis and methanosulfonate displacementwith azide. Further removal of the silyl group, hydrogenation of the azide, permethy-lation and ester hydrolysis finally furnished (�)-dysibetaine.

CHPIFA,(a)conditions:andReagents 2Cl2 MeOH,, − toºC78 − EtMsCl,(b)99%.ºC,30 3 CHN, 2Cl2,NaN(c)87%.ºC,0 3, 63%.ºC,80DMF,

Ar

CO2Me

MeO

OMe

OTIPS

O

HN OMeN

O

O

OMe

TIPSO

MeONH

OTIPSO

MeO2C P

NH

OHO

O2C NMe3

(−)-dysibetaine

steps4

(a)

(b,c)

steps3 steps3

9:1=dr

116ref

OH=PN=P 3, 146

143

144 145

Scheme 9.22 Total synthesis of (�)-dysibetaine.

R CO2R*

CN =R*OH

(C6H11)2NO2S

HO(a)

CN

H2NR

CO2R* H2NCO2H

H2N R

(b-d)

PhLiHMDS,(a)conditions:andReagents 2P(O)ONH2, THF, − (b)60-70%.rt,toºC78H(c)separation. 2, Rh-Al2O3, MeOH-NH3, 90-95%.MeOH,KOH,(d)83%-quantitative.

benzylalkyl,=R 70:30-80:20=dr115ref

141 142

Scheme 9.21 a,b-Diamino acids through electrophilic amination.


9.3.6From b-Keto Esters and Related Compounds

The use of b-keto esters as precursors to a,b-diamino acid derivatives is alsodocumented in the literature. For instance, enantioenriched alkoxycarbonyl azir-idines were prepared by an asymmetric Neber reaction to generate disubstitutedazirines followed by reduction with sodium borohydride [117]. In another recentreport, ethyl acetoacetatewas transformed infive steps into (E) and (Z)a,b-unsaturateda,b-diamino esters (147 and 148) that can be thermally or photochemically inter-converted. The key process in this report is the highly enantioselective hydrogenationusing (R,R)- or (S,S)-MeDuPhos-Rh(I) triflate as chiral catalyst that provides indepen-dently all four isomersofa,b-diaminobutanoic acidderivatives ingreater than95%e.e.(Scheme 9.23) [118]. A bisferrocenyl phosphine has also been used as chiral ligand inthe asymmetric hydrogenation ofa,b-dehydro-a,b-diamino esters catalyzedby aRh(I)complex [119].Similarly, thecatalytic enantioselectivehydrogenationof 2-carboxamidetetrahydropyrazines using [(R)-BINAP(COD)Rh]OTf (COD¼ cyclooctadiene) af-forded orthogonally protected carboxamide piperazines (99%e.e.), which are valuableintermediates in the synthesis of indinavir [120].

9.4Conclusions

The development of short, general, and efficient synthetic routes to a,b-diaminoacids is a focus of current chemical research. a,b-Diamino acids are becominguseful tools in many areas and the need for these molecules demands not onlyapplication of existingmethodology, but discovery of new strategies that contribute tothe advance of organic synthesis. This overview brings to light that in spite of theincreasing number of approaches to these diamino acids, there are still manychallenges. Future endeavors in this area will provide new routes and applicationsof these fascinating molecules.

OMe

CO2Et

MeAcHN

COBzHN 2Et

Me

NHAc

CO2Et

NHBz

Me

NHAc

CO2Et

NHBz

NHAcMe

COBzHN 2Et

Me

NHAc

CO2Et

NHBzMe

NHAc

CO2Et

NHBz

(a)-(e)

(S,S)-cat (R,R)-cat (S,S)-cat(R,R)-catee96% ee98%

NaNO(a)conditions:andReagents 2 THF.Al(Hg),(b)81%.ºC,0HOAc,aqueous,NH(d)steps).(263%BzCl,(c) 4 CHpyr,AcCl,(e)81%.MeOH,OAc, 2Cl2-Et2O.

hυ or ∆

ee96%

cat:Rh(I)-MeDuPhos

ee98%

118ref

148147

Scheme 9.23 a,b-Diamino esters by catalytic enantioselective hydrogenation.

9.4 Conclusions j433

9.5Experimental Procedures

9.5.1(SS,2R,3S)-(þ )-Ethyl-2-N-(diphenylmethyleneamino)-3-N-(p-toluenesulfinyl)-amino-3-phenylpropanoate (14b) [12a]

O

OEtN

N PhS

Ph

Ph

NH

PhCO2Et

S

O

pTol

NCPh2

O

p-Tol

1. LDA

2.

4 11a 14b

In a 50-ml, one-necked, round-bottomed flask equipped with amagnetic stirring bar,rubber septum and argon balloon was placed N-(diphenylmethylene)glycine ethylester (4) (0.302 g, 1.13mmol), in water-free THF (8ml, purified through columnspacked with activated alumina and supported copper catalyst). The solution wascooled to �78 �C and LDA (0.56ml, 2.0M in heptane/THF/ethylbenzene fromAldrich) was added dropwise. The red-brown solution was stirred at �78 �C; thecolor slowly changed to yellowwithin 40min and the solution became slightly turbid.After stirring for 60min, sulfinimine (S)-(þ )-11a [121] (0.055 g, 0.23mmol) inanhydrous THF (1.6ml) at �78 �C was added dropwise via a cannula. The reactionmixture was stirred at�78 �C for 30min, quenched by addition of saturated aqueousNH4Cl (3ml), stirred for 5min, and warmed to room temperature. The phases wereseparated and the aqueous phase was extracted with EtOAc (3� 5ml). The combinedorganic phases were washed with brine (10ml), dried (Na2SO4), and concentrated.Chromatography (20% EtOAc in hexanes) afforded 0.099 g (86%) of a clear oil (14b).½a�20D ¼ þ 182 (c 0.4, CHCl3); infrared (IR) (neat): 3281, 3058, 1738, 1093 cm�1; 1H-nuclear magnetic resonance (NMR) (CDCl3) d 1.18 (t, J¼ 7.2Hz, 3 H), 2.42 (s, 3 H),4.13 (m, 2H), 4.18 (d, J¼ 3.6Hz, 1H), 5.08 (m, 1H), 5.75 (d, J¼ 7.2Hz, 1H), 6.50 (d,J¼ 7.2Hz, 2 H), 7.20–7.60 (m, 17 H); 13C-NMR d 14.4, 21.7, 60.9, 61.8, 71.3, 126.2,127.5, 127.8, 127.9, 128.4, 128.6, 128.6, 128.9, 129.3, 129.8, 131.1, 136.2, 139.1, 140.8,141.5, 142.7, 169.8, 173.1. High-resolution mass spectroscopy (MS) calculated forC31H30N2O3SLi (M þ Li): 517.2137; found: 517.2146.

9.5.2Synthesis of Ethyl (2R,3R)-3-amino-2-(4-methoxyphenyl)aminopentanoate 32avia Asymmetric aza-Henry Reaction [20]

PMP

N

CO2Et

TMSO

N

Et

O

30a

+

23

cat (20 mol%)

THF, −100 ºC

NO2

EtCO2Et

NHPMP31a

H2, RaNi

EtOH

NH2

EtCO2Et

NHPMP32a

O

N N

OPh

Ph

Ph

PhCuPF6

cat


Ethyl (2R,3R)-2-(4-methoxyphenyl)amino-3-nitropentanoate 31a To a flame-driedSchlenk tube was added CuPF6�4MeCN (11.8mg, 0.040mmol, 20% mol) and2,20-methylenebis[(4R,5S)-4,5-diphenyl-2-oxazoline] (20.2mg, 0.044mmol, 22mol%) under N2. The mixture was stirred in vacuum for 1 h, then anhydrous THF(2.0ml) was added and the resulting solution was stirred for 1 h. To this solution wasadded ethyl a-(4-methoxyphenyl)iminoacetate 23 (39mg, 0.2mmol, available fromethyl glyoxylate and p-methoxyaniline in CH2Cl2/4A

�MS/room temperature) [19].

The solution was cooled to�100 �Cusing an ether/liquid N2 cooling bath. A solutionof trimethylsilyl propanenitronate [122] 30a (42mg, 0.3mmol) in THF (1.0ml) wasadded over 1 h using a syringe pump. The reaction was left to warm to �20 �Covernight and quenchedwith EtOH (0.5ml). The crudematerial was purified byflashchromatography using CH2Cl2/pentane 1 : 1 as eluent. The product was isolated in68% yield with a diastereomeric ratio of 10 : 1 favoring the title compound. Theenantiomeric excess was 97% for the major erythro isomer and 88% for the minorthreo isomer detected by high-performance liquid chromatography using an ODcolumn (hexane/iPrOH, 97 : 3). 31a: ½a�20D ¼ �25:7 (c 0.017, CHCl3);

1H-NMR(CDCl3) d 0.97 (dd, J¼ 7.2, 7.2Hz, 3 H), 1.20 (dd, J¼ 7.2, 7.2Hz, 3 H), 1.9–1.3(bs, 1 H), 1.93 (ddq, J¼ 14.8, 7.2, 4.0Hz, 1 H), 2.16 (ddq, J¼ 14.8, 10.0, 7.2Hz, 1 H),4.13 (dq, J¼ 11.2, 7.2Hz, 1 H), 3.68 (s, 3 H), 4.18 (dq, J¼ 11.2, 7.2Hz, 1 H), 4.41(d, J¼ 5.6Hz, 1 H), 4.65 (ddd, J¼ 10.0, 5.6, 4.0Hz, 1 H), 6.58 (d, J¼ 8.8Hz, 2 H),6.72 (d, J¼ 8.8Hz, 2 H); 13C-NMR d 10.6, 14.0, 23.1, 55.6, 60.7, 62.4, 90.3, 114.9,116.2, 139.6, 153.7, 170.0; mass (time-of-flight electrospray þ ve): m/z 319; high-resolution MS calculated for C14H20N2O5Na: 319.1270; found: 319.1263.

Ethyl (2R,3R)-3-amino-2-(4-methoxyphenyl)aminopentanoate 32a Ethyl (2R,3R)-2-(4-methoxyphenyl)amino-3-nitropentanoate 31a (74mg, 0.25mmol) was dissolved inEtOH (3.6ml) and Raney nickel (100mg) was added. The reaction was treated withH2 at 1 atm and left for 48 h. The catalyst wasfiltered off and the crudewas purified byflash chromatography in 20% EtOAc/CH2Cl2 to yield the title compound 53.0mg,80% yield. 32a: ½a�20D ¼ �23:0 (c 0.026, CHCl3);

1H-NMR (CDCl3) d 1.02 (dd, J¼ 7.2,7.2Hz, 3 H), 1.23 (t, J¼ 7.2Hz, 3 H), 1.35 (ddq, J¼ 14.0, 8.8, 7.2Hz, 1 H); 1.55–1.35(br, 3 H), 1.62 (ddq, J¼ 14.0, 7.2, 4.4Hz, 1 H), 2.97 (ddd, J¼ 8.8, 4.4, 4.4Hz, 1 H),3.73 (s, 3 H), 3.97 (d, J¼ 4.4Hz, 1 H), 4.16 (q, J¼ 7.2Hz, 2 H); 6.65 (d, J¼ 8.8Hz, 2H), 676 (d, J¼ 8.8Hz, 2 H); 13C-NMR d 11.2, 14.5, 28.1, 55.5, 55.9, 61.1, 62.6, 115.0,115.6, 141.4, 153.0, 173.3; mass (time-of-flight electrospray, þ ve): m/z 289; high-resolution MS calculated for C14H22N2O3Na: 289.1528; found: 289.1528.

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