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Contribution

A reliable and easy method for synthesis of nitrogen-containing compounds :

Ns-strategy and with high-activity trityl type resin

Toshiyuki KanLaboratory of Synthetic and Medical Chemistry,

School of Pharmaceutical Sciences, University of Shizuoka,

Tohru FukuyamaLaboratory of Synthetic Natural Products Chemistry

Graduate School of Pharmaceutical Sciences, University of Tokyo

1. Introduction

Nitrogen-containing compounds are important chemicalentities, many of which show unique bioactivity. In view ofthis their efficient synthesis is an important issue in thedevelopment of pharmaceutically active molecule. However,the handling of highly-polar nitrogen-containing compoundsis often problematic, and furthermore the propensity of basicnitrogen compounds to undergo oxidation limits the scopeof reaction conditions to which these compounds may besubmitted. Accordingly, judicious choice of protectinggroups for nitrogen-containing groups is an essential partof the planning of any synthesis involving multiplefunctionalities.1) We found that nitrobenzenesulfonyl (Ns)group acts as an active group for the alkylation andsucceeded in developing a synthetic procedure involvingof the secondary amines by means of this method (Ns-strategy).2) Furthermore, the Ns group can be removedunder mild conditions. Since we presented this method, ithas been widely adopted by many chemists and we havealso utilized the process in the total synthesis of bioactivenatural products.3) In the course of applying the presentmethodology to the synthesis of the polyamine toxin, wealso succeeded in developing a solid phase procedureusing trityl resins with much higher loading values thanthose typically available commercially.4) The correspond-ing solid phase route using this resin represents asignificant methodological advance, since no purificationsteps are required in its execution. In the present articles,we introduce an operationally simple and convenientprocess for the synthesis of nitrogen-containing compoundsbased on these methodologies.

2. Synthesis of secondary amines from primary

amines

The selective monoalkylation of amines is a non-trivialprocess and thus no single effective method for theygeneration of secondary amines from the primary analoguehas been established. Scheme 1 shows a number ofrepresentative methods for the synthesis of secondaryamines and the problems inherent in each approach. Forexample, the alkylation of primary amine 1 with an alkylhalide or sulfonate ester not only affords the desiredsecondary amine 2 but frequently also the corresponding,tertiary amine 3 and quarternary ammonium salt 4 arisingfrom over-alkyation. Likewise, the formation of secondaryamine 5 by reductive amination of aldehydes or ketoneswith a suitable reducing agent such as NaBH3CN canproduce tertiary amine 6 as a by-product when theintermediate secondary amine 5 generated in the reactionis sufficiently sterically unencumbered to undergocondensation with a second equivalent of the carbonylcompound and subsequent reduction. Although thesynthesis of secondary amines via reduction of the relatedalkylamide obtained by acylation of the correspondingprimary amine with a strong reducing agent such as LiAlH4and BH3 is reliable, the harsh conditions required precludeits application to the synthesis of polyfunctional compounds.Recently, the Mitsunobu reaction5) involving toluenesulfone(Ts) amide 8a or trifluoroacetoamide 8b has beendeveloped. However, since strong basic conditions arerequired for the deprotection (9a,b→2), its scope ofapplication is limited to those compounds which are stabletowards alkaline media.

* For convenience, 2-nitro, 4-nitro, and 2,4-dinitro derivatives of nitrobenzenesulfonate will be abbreviated as Ns, pNs and DNs,respectively.

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Scheme 1. Conversion of primary amines to correspondingsecondary amines.

2.1 2-or 4-Nitrobenzenesulfonamide 2)

Sulfonamides are a reliable class of nitrogen protectinggroups as they are stable under both strong acidic or themore usual basic conditions. Furthermore, sulfonamidescarry the advantage that they do not suffer from linebroadening in the 1H NMR, which is often seen in therelated carbamates and amides. One drawback howeveris the severe conditions necessary for the removal oftoluenesulfonyl (Ts) and methanesulfonyl (Ms) groups whichare the most commonly used analogues. We have shownthat the related nitrobenzenesulfonamides (Ns) can beconverted into the corresponding amine under very mild

R2 X

baseR1 NH2 R1 N R1 N R1 N

R2

R2

R2

H

R2

R2

R2

X

1 2 3 4

R2 CHO

reductiveamination

R1 NH2 R1 N R1 NH

1 5 6

R2R2

R2

R2 CO2H

condensationR1 NH2 R1 N

H

1 7

R2

O

reductionR1 N

H

5

R2

R2 OH

Mitsunobuconditions

R1HN R1 N

R2

P

9a: P = Ts9b: P = CF3CO

deprotectionR1 N

R2

H

2

P

8a: P = Ts8b: P = CF3CO

OMe

NH2

OMe

NHR

primary amine: 10 secondary amine: 15

SO2ClX

Y

SR'X

Y

a; X = NO2, Y = Hb; X = H, Y = NO2c; X = NO2, Y = NO2

(Ns)(pNs)(DNs)

11

Base

SO2,

OMe

HNSO2

X

Y

OMe

NSO2

X

Y

OMe

NSO2

X

Y

R RR'S

12 13 14

RXor

ROH

R'S

conditions. In Scheme 2, the reaction of p-methoxybenzylamine (10) is shown as a representative example of the“Ns strategy” in which the Ns group is used both as aprotecting and activating group for the synthesis ofsecondary amines from primary amines.

** Although there is no problem about 2-nitrobenzenesulfonamide, complications due to competing side reactions were reported inthe deprotection of 4-nitro derivative: P.G.M. Northuis, Tetrahedron Lett., 1998, 39, 3889.

Scheme 2. Conversion of primary amines to correspondingsecondary amines via Ns-strategy.

Accordingly, primary amine 10 is allowed to react with 2-nitrobenzenesulfonyl chloride (NsCl) 11a in the presenceof a base affording sulfonamide 12a. The alkylation of thisN-mono-substituted sulfonamide 12a proceeds readily withan akyl halide (R-X) or the related (R-OH)6) under Mitsunobuconditions to produce N-di-substituted sulfonamide 13a.Nitrobenzenesulfonamide, which has a small pKa acts asan activating group in the alkylation, and therefore theMitsunobu reaction which is relatively difficult with Ts amide,proceeds smoothly. When a soft nucleophilic agent (Nu-)such as PhSH acts on 13a in the presence of a base,Meizenheimer complex 14a is formed by the nucleophilicaddition of the thiolate anion to an aromatic ring and then itis converted to secondary amine 15 via the elimination ofSO2. As mentioned above, the Ns group can be removedunder mild conditions and it is also stable under strongacidic and basic conditions. Thus, it is a protecting groupfor primary or secondary amines, that survives varioussynthetic reactions. Furthermore, we confirmed thatracemization does not take place these series of reaction.We generally use inexpensive NsCl 11a extensively in ourlaboratory although 4-nitrobenzenesulfonyl chloride(pNsCl:11b) offers similar reactivity to that of 11a.** (TokyoChemical Industry Co., Ltd. NsCl: N0142, pNsCl: N0144).

2.2 2,4-Dinitrobenzenesulfonamide (DNs) 7)

2,4-Dinitrobenzenesulfonamide (DNs) group hasalkylation ability equal to that of Ns group, but it has adisadvantage that it is unstable when heated for prolongedperiods in the presence of a base. However, it is possibleto remove only the DNs group selectively since it can becleaved under milder conditions than those required for theremoval of the Ns group. As shown in Scheme 3, the DNsgroup of diamine 16, protected by two nitrobenzene-sulfonyl groups, could be selectively removed under theconditions of HSCH2CO2H, Et3N, affording secondaryamine 17 in quantitative yield. In addition, this process hasan advantage that 2,4-dinitrophenylthioacetate, formed asby-product, can be removed is removed by separation ofthe diethyl ether and saturated aqueous sodiumbicarbonate solution.

Scheme 3. Selective deprotection of DNs group.

BnN N

PMB

DNsNs

BnN N

PMB

HNs

HSCH2CO2HEt3N

CH2Cl2(99%)16 17

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3. Synthesis of protected primary amines (N-Carboalkoxynitrobenzenesulfonamide)

The introduction of a nitrogen atom to alkyl halide oralcohol by nucleophilic substituting reaction to synthesizeprimary amines is a useful reaction. Although the Gabrielsynthesis9) and azide methods have been developed, thereare few general methods for the synthesis of protectedprimary amines directly. Recently, the Mitsunobu reactionwith respect to TsNHBoc by Weinreb et al. and the improvedMitsunobu reaction concerning TsNH2 by Tsunoda10) et al.have been reported. We thought that it was possible todevelop more useful nitrogen nucleophilic agent byutilizing the characteristics of the Ns group. In NsNH2 whichcan be easily prepared from ammonium (NH3) and NsCl11a, conversion to the carbamate proceeds in thepresence of Et3N and a catalytic amount of DMAP, givingthe Boc derivative of 19a as a crystalline solid. Thesulfonamide 19a so obtained undergoes smooth alkylationwith alkyl halide and Mitsunobu reaction with alcohols. Asa representative example, the reaction of 19a individuallywith (-)-ethyl lactate 20 is shown in Scheme 4. It ispossible to remove the Ns group and Boc group selectivelyfrom 21, which itself was obtained under the usualMitsunobu reaction conditions. This means that thereaction of thiol with 21 promotes the deprotection of theNs group, to afford N-Boc alanine derivative 22. Further,the removal of the Boc group from 21 is proceeds underacidic conditions facilitating the conversion to Ns-amide 23.Primary amines are produced by removing the Boc groupof 22, and 23 can be converted to secondary amine viaNs-strategy. In addition, it is possible to synthesize Allocderivative 19b and the Cbz derivative 19c of N-Ns-sulfonamide in the same way, Sulfonamide 18 and 19a-c,which act as crystalline ammonium equivalents, arecommercially available from Tokyo Chemical Industry Co.,Ltd.

olefin methathesis process. However, there are fewstudies on the use of direct nitrogen nucleophilic agents inthe synthesis of the heterocycles. Accordingly, we appliedthe alkylation of Ns group to such intramolecular reactions.We found that they displayed usefulness in the cyclizationof eight, nine and ten-membered rings - a process that istypically difficult to perform. When Cs2CO3 acts on halide24, synthesized from sulfonamide 18, in the presence ofn-Bu4NI, the cyclization proceeded smoothly givingheterocycle 25. In the same way, alcohol 26 was cyclisedunder Mitsunobu conditions, affording 25 was obtained. Itshould be noted that cyclization precursors 24 and 26 haveno substituents that especially promote the cyclisation andfurthermore, the present reaction does not require the highdilution conditions.

Scheme 4. Alkylation and deprotection of N-Boc-Ns-amides.

4. Intramolecular alkylation (synthesis of medium-sized ring compounds)

Recently, many studies on the synthesis of large ormedium-sized ring compounds, have been reported using

NsNH2

HN

Ns R

EtO2C OH

Me

Boc2O, Et3NDMAP (0.1 eq)

CH2Cl2

(95%)

DEAD, PPh3

benzene

(91%)21

18 19a: R = Boc19b: R = Alloc19c: R = Cbz

20

EtO2C NBoc

Me

Ns

EtO2C NH2

MeTFA

22

EtO2C NH

Boc

MeHSCH2CO2K2CO3

DMF

TFA

(100%)

Ns-strategyEtO2C NH

Me

R23

EtO2C NH

Ns

Me21

(94%)

Scheme 5. Construction of medium-sized rings.

5. Synthesis of natural products, polyamine toxin

Recently, a number of natural products having polyaminechain have been isolated with the aid of microanalysistechnology. Most of them are often obtained in extremelysmall amounts from natural source and have strongbioactivity. Accordingly they have attracted a good deal ofsynthetic interest but there are have been few satisfactoryapproaches to the construction of the secondary amineportions. We reasoned that the efficient synthesis can bepossibly by means of Ns-strategy and launched studies onthe synthesis of the natural polyamines.

5.1 Selective protection of diamines

Diamines in which two amino groups are distinguishedfrom each other are not only useful elements for thesynthesis of polyamines, but also useful compounds thatcan be used as linkers of probe molecules etc. However,the monocarbamation of symmetric diamines generallyproceed in low yield and reactions are notoriously difficultto purify.13) We have found that Ns protection of diamineson one of the terminal nitrogens selectively. As shown inScheme 6, monosulfonylation was carried out selectivelyby adding NsCl slowly to 1,3-diaminopropane at lowtemperature. The isolation of monosulfonylated diamine 27can be performed by neutralizing the hydrochloride withNaOEt, filtering off NaCl, evaporation of solvents andremoving excess of unreacted diamines under reducedpressure. In addition, it is possible to obtain monosulfonylspecies 28 and 29 from both diamines having n=2, 3 inhigh yield. These diamine derivatives (n=1-5) are alsocommercially available from Tokyo Chemical Industry Co.,Ltd.

NsHN

Br

n

NsN

n

NsHN

HO

n

Cs2CO3n-Bu4NI

DEADPPh3

n = 1: 62%n = 2: 64%n = 3: 66%

n = 1: 59%n = 2: 57%n = 3: 62%

24 25 26

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Scheme 6. Selective mono-nosylation of diamines.

5.2 Total synthesis of HO-416b 5)

It is known that certain polyamines isolated from thepoison gland of spiders specifically inhibits the excitatoryglutamic acid receptor.14) This receptor is expected toprovide targets lead-compounds for the development ofmedicines and agrichemicals since it is closely associatedwith the memory of brain nervous cells and the learningmechanism.15) We postulated that the simple synthesis ofpolyamines could be performed via Ns-strategy andlaunched the studies of synthesizing HO-416b (30)16)

isolated from Holoena curta.

For the right fragment, diamine 33 made by Boc-protectionof 27 to Boc was used as starting material. Treatment ofthis with an excess of 1,3-dibromopropane gave bromide34, which was then alkylated with sulfonamide 35 to give36. While the coupling with 32 can be also performed byMitsunobu reaction, we utilized the alkylation of halide dueto the ease of purification of the reaction. After mesylation(Ms) of alcohol 36, the intermediate so obtained wasconverted to iodine 37 to in preparation for the couplingwith 32. The reaction proceeded smoothly along under basiccondit ion giving couple compound 38 which wasdeprotected to give primary amine 39.

H2N NH2n H2N NHnNs

NsCl (11a), EtOH-20 °C;

NaOEt

27: n = 1 (83% from NsCl)28: n = 2 (77% from NsCl)29: n = 3 (87% from NsCl)

Fig. 1. Structure of HO-416b (30).

As shown in Scheme 7, a convergent method for thesynthesis consisting of the separate construction of the rightand left fragments which are subsequently brought togetherwas envisaged. The left fragment 32 was synthesized bythe condensation of indoleacetic acid 31 and diamine 28.

NH

HN

NH

NH

O

NH

NH2

HO-416b (30)

NH

OH

ONH

HN

O

NH

Ns

PivCl, Et3N;

28, Et3N, DMAP(97%)

31 32

HN NH

RNs

Br Br

K2CO3

(97%)

N NH

BocNs

Br

3427: R = H33: R = Boc

(99%)

Boc2O, Et3N

HO NH

Ns

N NH

BocNs

N

36: X = OH37: X = I

1) MsCl, Et3N2) NaI, 2-butanone

Ns

X34, Cs2CO3

n-Bu4NI

(86%)35

32 + 37

N NH

RNs

N

Ns

N

Ns

HN

NH

O

Cs2CO3 (94%)

38: R = Boc39: R = H

SOCl2, MeOH(96%)

(98%)

Scheme 7. Total synthesis of HO-416b (30).

Removal of the Ns groups from 39 subsequently gaveHO-416b (30). However, whilst the removal of the Ns groupproceeded without incident, the isolation and purificationof 30 was problematic. Generally, reversed-phase HPLCand ion-exchange resin are used for the purification ofwater-soluble polyamines. However, we thought thatexcess reagents and nitrobenzene derivatives producedas by-products could be removed by washing, if thedeprotection of Ns group was performed on solid phase,so that the purification process was not necessary. Initiallywe examined the relatively expensive 2-chlorotrityl resin40 as a support for primary amine 39, however loadinglevels were not sufficiently high for efficient reaction. Inorder to improve loading we designed resin 42 havingreaction point far from the polymers (Scheme 8). Thereagent may be readily prepared by conversion of tritylalcohol 41 to the corresponding chloride, after alkylation ofinexpensive Merrifield resin with p-hydroxytrityl alcohol.Resin 42 has high reactivity since trityl cation at thereaction site is stabilized by oxygen atom at the para-position. In addition, this resin can be recovered,regenerated by rechlorination and reused repeatedlyrepeatedly. Compound 41, a stable precursor of resin 42,is also available commercially from Tokyo ChemicalIndustry Co., Ltd.

Scheme 8. Synthesis of trityl-type resin (42).

As shown in Scheme 9, 39 was supported on the solidphase prepared just prior to the utilization by i-Pr2NEt. Thedeprotection of Ns group on the solid phase was performedunder the condition of (HSCH2CH2OH, DBU). Afterwashing out excess of reagents, the resin was dried andthen cut out with (1%, TFA-CH2Cl2). Removal of solventgave the TFA salt of pure HO-416b (30). In this way,isolation of high-polar polyamine could be carried withoutneed for purification by performing the last deprotection onsolid phase.

Cl

P

X

O

Cl

P

Cl P

OH

HO

40

41: R = OH42: R = Cl

SOCl2

K2CO3

Merrifield resin

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Scheme 9. Completion of total synthesis of HO-416b (30).

5.3 Total synthesis of 18 membered-ring

polyamine, Lipogrammistin-A (43) 17)

A number of natural products including plant alkaloidshaving large cyclic polyamine structures are known.18)

Although many synthetic approaches to these targets havebeen described the construction of the large ring structuralelement has proved problematic. Accordingly, we reasonedthat the intramolecular alkylation of Ns group, which hadproved to be effective for the synthesis of mediummembered-ring, could also be useful in the synthesis oflarge membered-ring amine and launched the synthesis ofLipogrammsitin-A (43).

Finally, all of three Ns groups were deprotected andreacted with 2-methylbutanoic acid to achieve the totalsynthesis of Lipogrammistin-A (43).

N NH2

Ns

N

Ns

N

Ns

HN

NH

O

NH

NH2NH

NH

HN

NH

O

39

1) 42, i-Pr2NEt2) HSCH2CH2OH, DBU3) TFA

HO-416b (30) (68%, 3 steps)

NH O

HN

N

N O

O

Lipogrammistin-A (43)

Fig. 2. Structure of Liprogrammistin-A (43).

Lipogrammistin-A (43) is a polyaminetoxin isolated fromthe skin of Grammsitidae the structure of which has beendetermined by a collaborative research of Tachibana,Fusetani et al.19) This compound has a distinctivestructure composed of β-amino acid having 18-membered-ring macrolactam and a long fatty chain. A diagram of ourtotal synthesis involving intramolecular alkylkation of Nsgroup as the key step is shown in Scheme 10. β-Aminoacid derivative 45 was synthesized from the knownoptically-active carboxylic acid 44 20) via 6 steps using aWittig reaction as the central step. Coupling of sulfonamide45 and alcohol 46 was performed by Mitsunobu reaction toobtain 47. Since it was found that basic hydrolysis ofmethyl ester 47 was accompanied by β-elimination ofalkylsulfonamide, the corresponding allyl ester was usedwhich could then be deprotected with Pd catalyst withoutcompromising the integrity of the sulfonamide. Carboxylicacid and diamine derivative 27 were condensed accordingto mixed acid anhydride method to form cyclic precursor48. 18-Membered-ring construction, which is a key in theprocess, was achieved under (Cs2CO3, n-Bu4NI) condition.

Scheme 10. Total synthesis of Lipogrammistin-A (43).

5.4 Total synthesis of Ephedradine A (50) 21)

Encouraged by the good results obtained during thetotal synthesis of Lipogrammistin-A (43), our attentionturned to the total synthesis study of Ephedradine A (50)which is considered to be a more complicated structure.Ephedradine A (50) is a spermine alkaloid, isolated as theactive ingredient of, Chinese traditional drug Ephedra sinicaStapfe. This compound has been known since ancient timesalthough its structure was only determined in 1979 by Hikinoat Tohoku University.22) The only synthetic approach to thetarget was conducted by Wasserman in 1985, although theirwork concentrated on the preparation of the O-methylderivative. The most challenging point of the synthesis of50 is generally accepted to be the construction of twomacrolactam rings in the presence of dihydobenzofuranring which is unstable to acid and β-amino acid derivativewhich is unstable to base. On the other hand, since Ns-strategy can be used to promote the cyclization anddeprotection under mild conditions, it is possible toconstruct amine structure using this approach aftersynthesizing core part 52 as optically-active compound asshown in Fig. 3.

Lipogrammistin-A (43)

HO2C CO2Me

NHCbz

CO2Me

NHNs

C8H176 steps

44 45

46DEAD, PPh3

1) Ti(Oi-Pr)4, allyl alcohol2) Pd(PPh3)4, pyrrolidine

3) PivCl, Et3N;27, Et3N

CO2Me

NNs

C8H17

NsN

Br

47

HO NNs

Br

46

NNs

C8H17

NsN

Br

HN

O

NNsH

R

R =

48

Cs2CO3, n-Bu4NI

(86%)

NNs

NsN

HN

O

NNs

R

49

2 steps

Fig. 3. Structure of (-)-Ephedradine A (50).

O

OR

H

H

N

O

NH

HNH

NH

O

O

OBn

H

H

N

O

OAc

CO2Me

NsHN OTBDPS

52(−)-Ephedradine A (Orantine): R = H (50)O-Methylorantine: R = Me (51)

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The optically-active dihydrobenzofuran ring of advancedintermediate 52, shown in Scheme 11, was synthesized bychiral C-H insertion reaction.24) Subsequently, β-amino esterwas constructed by using Sharpless chiral aminohydroxylation reaction25) as the key step. After introducingthe alcohol fragment 53 to sulfonamide 52 via the Mitsunobureaction, protection group on nitrogen atom was convertedto Cbz group to obtain 54. Desilylation followed bycondensation of the corresponding alcohol with NsNH2 (18),and removal of TBDPS gave the key cyclic precursor 55.Closure of the 16-membered ring using DEAD and PPh3proceeded smoothly to give 56 in good yield. Subsequently,the acetoxy group of 56 was converted to azide and thenthe methyl ester was converted to pentafluorophenyl(PfpOH) ester 57. Subsequent Staudinger reaction26) of 57with PPh3 proceeded without incident to produce imino-phospholane 58 which was united brought together byintramolecular aza-Wittig reaction with the active esteraffording imino ether 59. Hydrolysis of this compound wasperformed to give to macrolactam 60. Finally, simultaneousremoval of the Ns groups of 60 along with the benzyl groupand Cbz group using BCl 3 accomplished the totalsynthesis of Ephedradine A (50 ). The present totalsynthesis revealed power and functional group toleranceof the Ns-strategy and allowed us to demonstrate newchemistry for the creation of amido bond.27)

Scheme 11. Total synthesis of (-)-Ephedradine A (50).

OH

H

R

O

NsHNH

Ar

CO2Me

OH

H

R

O

CbzNH

Ar

CO2Me

OTBS

N

OAcOTBDPS

R =1)

DEAD, PPh3

2) KOH, PhSH3) Cbz-Cl, Et3N

(80%)

HO OTBS53

5254

CbzNH CO2Me

NHNs

OH

H

N

O

OAcHO

Ar

OBnAr =

DEAD, PPh3

1) CSA, MeOH2) 18

3) HF(79%)

PPh3, DEAD

(77%)

CbzNH CO2Me

OH

H

N

O

OAc

Ar

NNs

5655

CbzNH CO2Pfp

OH

H

N

O

N3

Ar

NNs

57

1) K2CO32) MsCl, Et3N3) NaN3

4) LiOH5) PfpOH

(71%)

PfpOH = pentafluorophenol

H

N

O

NNs

NPfpO

OPPh3

CbzN

58

PPh3

H

N

O

NCbzN

59

N

Ns

PfpO

H

N

O

NCbzN

60

NH

Ns

OH Ar

HO

H2O

(73%)

1) KOHPhSH

2) BCl3

(73%)

50

WSCD

6. Solid phase synthesis by highly active trityltype resin (42)

The trityl type resin 42 developed by us has not only ahigh loading efficiency of amines, but also permitsalkylation of Ns amide and alkyl halide, and amidationreaction as well as the reaction with secondary amine onsolid phase. This discovery opened the door to newcombinatorial procedures described below.

6.1 Solid phase synthesis of PhTX-343 (61)

Polyamines such as spermine and spermidine arephysiologically active substances ubiquitous in livingsystems and a number of compounds containing them arealso known.29) Therefore, an easy method for synthesizingvarious compounds are strongly desired. This process canbe facilitated by using a reaction sequence utilizing resin42 which does not require purification in the final step. Ifalkylation on solid phase is realized, it would lead to asuccessful combinatorial synthesis of the desiredcompounds could be realized. In order to demonstratedthe efficacy of our methodology, we launched thesynthesis of a spermine derivative, philanthotoxin-343(PhTX-343: 61).30) The outline of the synthesis is shown inScheme 12. After linking diaminopropane to resin 42,

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the free amine was protected with Ns group to prepare Ns-amide 62. Subsequently protected spermine derivative 62could be readily synthesised by alkylation of sulfonamidewith dibromobutane in an iterative sequence. According tothis process, it is possible to combine various diaminesand halides and it is also easy to perform Mitsunobureaction with alcohols. Thus, it is easy to synthesize alibrary of polyamine chains having different length. Inaddition, facile removal from 64 gave the correspondingterminal amine which could be readily alkylated or acylated.Hence, it is a useful intermediate for the synthesis ofspermine-linked compounds. In the synthesis of PhTX-343(61), tyrosine derivative was introduced to 64 and Ns groupwas removed and the compound cleaved from the solidphase to achieve the total synthesis via nine steps fromthe resin 42 and in a total yield of 75%. Fig. 4 shows1H NMR of the material obtained simply by removal ofsolvent after the final step. In the present synthesis, it waspossible to obtain a pure product as shown in Fig. 4 usinga sequence which did not require purification at any stage.In this way, we succeeded in developing the revolutionarysynthesizing process by combining our solid phase 42 withNs-strategy.

Scheme 12. Solid-phase synthesis of PhTX-343 (61).

H2NHN

NH

NH

O

NH

O

OHPhTX-343 (61)

ClHN NHNs

HN

NsN

NNs

NH

R

H2N NH2 BrBr

NsHN NHAlloc

K2CO3

K2CO3

1)

2)

i-Pr2NEt

2) NsCl, collidine

1)

PNPO

O

NH

O

OAc

1)

2) K2CO3, MeOH3) HSCH2CH2OH, DBU4) TFA

61

63: R = Alloc64: R = H Pd(PPh3)4, pyrrolidine

42 62

Fig. 4. 1H NMR spectra of synthetic PhTX-343 (61).

6.2 Parallel synthesis of dipeptide type γ-secretase inhibitor DAPT derivative 31)

In our laboratory, we have conducted research on thedevelopment of a γ-secretase inhibitor32) important to theretardation of the onset of Alzheimer’s disease and theclarification of its function, as a collaborative researchproject of the laboratory for several years.33) As a part ofthe research, we have performed structure-activity studieson DATP (65) 34) reported by Elan Co., Ltd. Group as aninhibitor by the group of Elan Co., Ltd., and discoveredalmost equal activity of the compound, of which C-terminalt-Bu ester is converted to amide to that of 65.

Fig. 5. Structure of DAPT (65).

F

F

HN

O Me

NH

O Ph

CO2t-Bu

N-[N-(3,5-difluorophenylacetyl)-L-alanyl]-(S)-phenylglycine-tert-butyl ester (DAPT 65)

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Accordingly, we attempted the parallel synthesis on solidphase with resin 42 in order to synthesize a range of DAPT(65) amide compounds bearing various C-terminalsubstituents. After supporting dipeptide 66 on solid phaseresin, the allyl ester was removed to afford carboxylic acid67. The condensation of carboxylic acid 67 with variouskinds of amines 68 a-o progressed smoothly using DOC inthe presence of an excess of HOBt. Subsequent cleavagefrom the solid phase resin was carried out under acidiccondition, and the phenyl acetic acid segment wassubsequently introduced according to the active estermethod. Accordingly, we succeeded in obtainingderivatives 69 a-o having amide, which were converted fromC-terminal of DAPT (65) only by filtering and washingcrystals of crude products after the reaction.

F

F

HN

O Me

NH

O Ph

H2N

Me

NH

O Ph

CO2Allyl

66

1) 42, i-Pr2NEt

2) Pd(PPh3)4pyrrolidine

HN

Me

NH

O Ph

CO2H

67

1) RNH2 (68a-o)DCC, HOBt

2) TFA3) 3,5-F2C6H3CH2CO2Pfp

i-Pr2NEt

HN

O

R

69a-o

R = n-C7H15 (a), CH2Ph (b), CHPh2 (c), CH2C6H4-o-OMe (d), CH2C6H4-m-OMe (e), CH2C6H4-p-OMe (f), CH2C6H4-o-Cl (g), CH2C6H4-m-Cl (h),CH2C6H4-p-Cl (i), CH2C6H4-o-Br (j), CH2C6H4-m-Br (k), CH2C6H4-p-Br (l), CH2C6H4-p-F (m), CH2C6H4-p-CO2Me (n), CH2C6H4-p-Bz (o).

Scheme 13. Parallel synthesis of DAPT derivatives (69a-o).

In general, the solid phase synthesis of peptiderepresented by the Merrifield method is performed bylinking the C-terminal to the solid phase, and repeating thecondensation and deprotection with N-protected aminoacid. On the contrary, according to the present syntheticprocess, the condensation proceeds without epimerizationat the α-position in using N-acylamino acids whose N-terminal is linked. Thus, it is possible to extend the peptidechain from N-terminal to C-terminal. Further, due to thefact that amido DAPT derivative 69o had the activity 30times stronger activity than DAPT (65) itself, this techniquewas efficacious in the development of the probe.

F

F

HN

O Me

NH

O PhHN

O

HN

HN

O

NHHN

S

O

HH

8 3

Biotin-tagCross-linking group Linker

H2N

O

NHN

O

NHHN

S

O

HH

n 3

O

70: n = 8

71

6.3 Solid phase synthesis of photoaffinity probe 35)

In recent studies on familial Alzeheimer’s disease,presenilin (PS) was cloned as one of genes causing thedisease. Later, it was revealed that γ-secretase itself is ahuge complex mainly composed of membrane proteinproduced by the Ps gene.36) The photoaffinity labelingmethod is one of a few effective analytical methods,although the biochemical analysis of membrane proteaseis difficult.37) For the probe synthesis, it is necessary tointroduce a photoreactive group which is cross-linked withcompounds having a strong affinity with protein (highactivity) by exposure to light. Benzophenone is a frequentlyused photoreactive group for the photoaffinity labeling.Thus, it was preferable to increase the activity of thederivative 69o showing higher activity than DAPT (65).Further, the adoption of the biotin tag makes it possible torealize the easy detection and purification of protein byusing the high biotin affinity with avidin. Accordingly, wesynthesized photoreactive benzophenon and biotin, andsimultaneously synthesized solid phase resin 70 into whichthey could be readily introduced.

We used mono Ns diamine synthesized according to theprocess above mentioned as linker. After it was linked tobenzophenone by Mitsunobu reaction and condensed withbiotin and then secondary amine was by deprotection ofNs group. The secondary amines so obtained were

Scheme 14. Solid-phase synthesis of photoaffinity probe (71).

10

number 128

supported on solid phase resin 42 so as to succeed insynthesizing benzophenone-biotin unit type solid phaseresin 70 having an amino group reactive with ligand at theterminal. Subsequently, after condensation of carboxylicacid derivative of DAPT(65) and amine 70, we achievedthe synthesis of photoaffinity probe 71 by cleavage fromthe solid phase under acidic conditions. In this case,complicated purification process was not necessarysimilarly with the cases of the synthesis of 30 and 61. Inaddition, it is often difficult to purify the compounds to whichbiotin is introduced because they become insoluble inorganic solvent. We believed that this synthetic strategy isalso of great significance from this point of view. In fact, wehave succeeded in detection of 23 and 26 kDa proteinsderived from presenilin, that disappear in the presence ofDAPT (65) in the photoaffinity-labeling experiment with theprobe 71.38,39)

7. Conclusion

For many pharmacologically active compounds such aspharmaceutical products medicines functioning withinliving body, solubility becomes an important and seriousproblem because the environment in which they functionis aqueous. In general, compounds having nitrogen atomexist in many medicines because they show high solubilityin water. However, as outlined in the current report it isgenerally acknowledged by synthetic chemists that thegeneration of compounds containing nitrogen atom is

often problematic. We believe that use of the Ns groupoffers a potential solution to these problems and havedeveloped a wide range of protocols which utilize it. In theprocess, we have shown that the Ns group worked both onthe protection (defence) and on the activation of thealkylation (attack). Thus, the total synthesis of somenatural products and the contribution to the developmentof drugs such as those of Alzeheimer’s disease could berealized. In conclusion, we hope and expect that thechemistry introduced in the present contributed article iswill be widely used in the chemical community.

The studies referenced in the present article wereconducted at the Laboratory of Natural Products SyntheticChemistry, Graduate School of Pharmaceutical Sciences,University of Tokyo. We express our sincere thanks toself-sacrificing efforts of all the students, described in thereferences. In addition, the research on γ-serectase,introduced in the last section of the report was carried outin collaboration with the Laboratory of Neurophotology andNeuroscience Laboratory of Rational Medical Science,Graduate School of Pharmaceutical Sciences, Universityof Tokyo. We would also like to thank Professor TakeshiIwatsubo and Professor Hideaki Natsukari for giving to usa chance of taking on studies in fields other than totalsynthesis.

Reference

1) T. W. Green, P. G. Wuts, “Protective Groups in OrganicSynthesis” 3rd ed., John Wiley and Sons, Inc., New York,1998, p. 494.

2) (a) T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett.,1995, 36, 6373. (b) W. Kurosawa, T. Kan, T. Fukuyama, Org.Synth., 2002, 79, 186.

3) Review articles on Ns-strategy, T. Kan, T. Fukuyama, YukiGosei Kagaku Kyokaishi (J. Synth. Org Chem. Jpn.), 2001,59, 779; (b) T. Kan, T. Fukuyama, Chem. Commun., 2004,353.

4) (a) Y. Hidai, T. Kan, T. Fukuyama, Tetrahedron Lett., 1999,40, 4711. (b) Y. Hidai, T. Kan, T. Fukuyama, Chem. Pharm.Bull., 2000, 48, 1570.

5) (a) J. R. Henry, L. R. Marcint, M. C. McIntosh, P. M. Scola, G.D. Harris, S. M. Weinreb, Tetrahedron Lett., 1989, 30, 5709.(b) T. Tsunoda, J. Otsuka, Y. Yamashita, S. Ito, Chem. Lett.,1994, 539.

6) Review articles on Mitsunobu reaction: (a) O. Mitsunobu,Synthesis, 1981, 1. (b) D. L. Hughes, Org. React., 1992, 42,335.

7) T. Fukuyama, M. Cheung, C.-K. Jow, Y. Hidai, T. Kan,Tetrahedron Lett., 1997, 38, 5831.

8) T. Fukuyama, M. Cheung, T. Kan, Synlett, 1999, 1301.

9) Review articles on Gabriel method: M. S. Gibson, R. W.Bradshaw, Angew. Chem., Int. Ed., 1968, 7, 919.

10) (a) T. Tsunoda, H. Yamamoto, K. Goda, S. Ito, TetrahedronLett., 1996, 37, 2457. (b) Current review articles on the methodof Tsunoda et al.: TCIMAIL, 2004, number123, 2.

11) (a) T. Kan, H. Kobayashi, T. Fukuyama, Synlett, 2002, 697.(b) T. Kan, A. Fujiwara, H. Kobayashi, T. Fukuyama,

Tetrahedron, 2002, 58, 6267.12) Review articles on natural polyamine: A. Guggisberg, M.

Hesse, “The Alkaloids”, Vol. 50, eds. by Cordell G. A., BrossiH. S., Academic Press, New York, 1998, p. 219.

13) W. J. Fiedler, M. Hesse, Helv. Chim. Acta, 76, 1511 (1993).14) Review articles on spider venom (isolation, decision of

structure, synthesis): A. Schafer, H. Benz, W. Fiedler, A.Guggisberg, S. Bienz, M. Hesse, “The Alkaloids”, Vol. 45, ed.by Cordell G. A., Academic Press, New York, 1994, p. 1.

15) Review articles on spider venom (pharmacology): A. L.Mueller, R. Roeloffs, H. Jackson, “The Alkaloids”, Vol. 46,eds. by Cordell G. A., Brossi H. S., Academic Press, NewYork, 1994, p. 63.

16) G. B. Quistad, C. C. Reuter, W. S. Skinner, P. A. Dennis, S.Suwanrumpha, E. W. Fu, Toxicon., 1991, 29, 329.

17) A. Fujiwara, T. Kan, T. Fukuyama, Synlett, 2000, 1667.

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18) Review articles on cyclic polyamines: A. Guggiserberg, M.Hesse, “The Alkaloids”, Vol. 22, 1983, p. 85.

19) (a) H. Onuki, K. Tachibana, N. Fusetani, Tetrahedron Lett.,1993, 34, 5609. (b) H. Onuki, K. Ito, Y. Kobayashi, N.Matsumori, K. Tachibana, N. Fusetani, J. Org. Chem., 1998,63, 3925.

20) M. Ohno, S. Kobayashi, T. Iimori, Y.-F. Wang, T. Izawa, J.Am. Chem. Soc., 1981, 103, 2405.

21) W. Kurosawa, T. Kan, T. Fukuyama, J. Am. Chem. Soc., 2003,125, 8112.

22) (a) M. Tamada, K. Endo, H. Hikino, C. Kabuto, TetrahedronLett., 1979, 20, 873. (b) P. Dätwyler, H. Bosshardt, S. Johne,M. Hesse, Helv. Chim. Acta, 1979, 62, 2712.

23) H. H. Wasserman, R. K. Brunner, J. D. Buynak, C. G. Carter,T. Oku, R. P. Robinson, J. Am. Chem. Soc., 1985, 107, 519.

24) W. Kurosawa, T. Kan, T. Fukuyama, Synlett, 2003, 1028.25) G. Li, H. H. Angert, K. B. Sharpless, Angew. Chem. Int. Ed.,

1996, 35, 2813.26) H. Staudinger, J. Meyer, Helv. Chim. Acta, 1919, 2, 635.27) H. Fuwa, Y. Okamura, Y. Morohashi, T. Tomita, T. Iwatsubo,

T. Kan, T. Fukuyama, H. Natsugari, Tetrahedron Lett., 2004,45, 2323.

28) T. Kan, H. Kobayashi, T. Fukuyama, Synlett, 2002, 1338.29) Review articles on polyamines and their coupled body: (a) G.

Karigiannis, D. Papaioannou, Eur. J. Org. Chem., 2000, 65,1841. (b) V. Kuksa, R. Buchan, Synthesis, 2000, 1189.

30) A. T. Eldefrawi, M. E. Eldefrawi, K. Konno, N. A. Mansour, K.Nakanishi, E. Oltz, P. N. Usherwood, Proc. Natl. Acad. Sci.USA, 1988, 85, 4910.

31) T. Kan, Y. Tominari, K. Rikimaru, Y. Morohashi, H. Natsugari,T. Tomita, T. Iwatsubo and T. Fukuyama, Bioorg. Med. Chem.Lett., 2004, 14, 1983.

32) Recent review art icles on secretase: M. S. Wolfe,Nature. Rev. Drug. Discov., 2002, 1, 859.

33) Y. Takahashi, I. Hayashi, Y. Tominari, K. Rikimaru, Y.Morohashi, T. Kan, H. Natsugari, T. Fukuyama, T. Tomita, T.Iwatsubo, J. Bio. Chem., 2003, 278, 18664.

34) H. F. Dovey, V. John, J. P. Anderson, L. Z. Chen, P. de SaintAndrieu, L. Y. Fang, S. B. Freedman, B. Folmer, E. Goldbach,E. J. Holsztynska, K. L. Hu, K. L. Johnson-Wood, S. L.Kennedy, D. Kholodenko, J. E. Knops, L. H. Latimer, M. Lee,Z. Liao, I. M. Lieberburg, R. N. Motter, L. C. Mutter, J. Nietz,K. P. Quinn, K. L. Sacchi, P. A. Seubert, G. M. Shopp, E. D.Thorsett, J. S. Tung, J. Wu, S. Yang, C. T. Yin, D. B. Schenk,P. C. May, L. D. Altstiel, M. H. Bender, L. N. Boggs, T. C.Britton, J. S. Clemens, D. L. Czilli, D. K. Dieckman-MacGinty,J. J. Droste, K. S. Fuson, B. D. Gitter, P. A. Hyslop, E. M.Johnstone, W. Y. Li, S. P. Little, T. E. Mabry, F. D. Miller, J. E.Audia, J. Neurochem, 2001, 76, 173.

35) T. Kan, Y. Tominari, Y. Morohashi, H. Natsugari, T. Tomita, T.Iwatsubo, T. Fukuyama, Chem. Commun., 2003, 2244.

36) N. Takasugi, T. Tomita, I. Hayashi, M. Niimura, Y. Takahashi,G. Thinakaram, T. Iwastubo, Nature, 2003, 422, 438.

37) Review articles on photoaffinity labeling: (a) F. Kotozyba-Hilbert, I. Kapfer, M. Goeldner, Angew. Chem., Int. Ed. Engl.,1995 , 34, 1296. (b) G. Dorman, G. D. Prestwich,Biochemistry, 1994, 33, 5661.

38) Y. Morohashi, T. Kan, Y. Tominari, H. Fuwa, Y. Okamura, N.Watanabe, H. Natsugari, T. Fukuyama, T. Iwatsubo, T. Tomita,J. Biol. Chem., 2006, 281, 14670.

39) H. Fuwa, Y. Takahashi, Y. Konno, N. Watanabe, H. Miyashita,M. Sasaki, H. Natsugari, T. Kan, T. Fukuyama, T. Tomita, T.Iwatsubo, ACS Chemical Biology, 2007, 2, 408.

(Received Jan. 2008)

Introduction of authors

Toshiyuki KanProfessor, Laboratory of Synthetic Organic and Medicinal Chemistry, School of Pharmaceutical Science, University of

Shizuoka

[Brief career history] 1986, Graduated from Undergraduate School, Faculty of Science, Department of Chemistry, HokkaidoUniversity. 1993, Completed doctoral course of Research Faculty of Science (supervisor, Professor Haruhisa Shirahama).1993-1996, Scientist of Suntory Institute for Bioorganic Research. 1996, Assistant Professor of Faculty of PharmaceuticalScience, the University of Tokyo. 2004, Associate Professor of Graduate School of Pharmaceutical Science, since 2005,Present post, 2002, Incentive award from the Society of Synthetic Organic Chemistry, Japan. 2004, PharmaceuticalResearch Vision Award from the Pharmaceutical Society of Japan.[Specialty] Synthetic organic chemistry, Chemical Biology

Tohru FukuyamaProfessor, Graduate School of Pharmaceutical Science, University of Tokyo

[Brief career history] 1971, Graduated from school of Agricultural, Department of Agricultural Chemistry, NagoyaUniversity. 1977, Ph.D from Department of Chemistry, Harvard University. 1977-1978, Postdoctoral Fellow of GraduateSchool of Harvard University. 1978, Assistant Professor, Department of Chemistry, Rice University. 1982, AssociateProfessor of Rice University. 1988, Professor of Rice University. 1995, Professor, Faculty of Pharmaceutical Sciences,University of Tokyo. Since 1997, Present post. 1993, Arthur C.Cope Scholar Award from American Chemical Society.2002, Academic Award from the Society of Synthetic Organic Chemistry, Japan. 2003, Senior Award from InternationalSociety of Heterocyclic Chemistry. 2004, Arthur C. Cope Award from American Chemical Society. 2006, PharmaceuticalSociety of Japan Award.[Specialty] Synthetic organic chemistry

12

number 128

TCI Related Compounds of Contribution

Nitorbenzenesulfonyl Compounds

[4+2] Cycloadditions

D3211 3,6-Di-4-pyridyl-1,2,4,5-tetrazine (1) 1g 5g

xylene, reflux, 7 h

NNR1

R1

N

N N

NR1R1

CH2Cl2, 0 °C, 5 h

R1 = 4-pyridylR2 R2

R2R2R2R2

N NR1R1

R2 R2CH2Cl2, r.t., 24 h

R2 = H, Me

NH

NH

N

N

R1

R1

1

R2R2

1a)

1b)

Tetrazine 1 is known as a useful diene in [4+2] cycloadditions. For example, 5H-pyridazino-[4,5-b]indole was obtained in reaction of 1 with indole as a dienophile.1a) With a cyclopropene, a tetracyclicaliphatic azo compound which is a versatile starting compound for a thermolysis and photolysis reactionscan be obtained.1b)

References1) [4+2] Cycloadditions of 1,2,4,5-tetrazines and dienophiles

a) M. Takahashi, H. Ishida, M. Kohmoto, Bull. Chem. Soc. Jpn., 1976, 49, 1725.b) J. Sauer, P. Bäuerlein, W. Ebenbeck, C. Gousetis, H. Sichert, T. Troll, F. Utz, U. Wallfahrer, Eur. J. Org. Chem.,

2001, 2629.

p.3-4X=NO2, Y=H: NsCl (11a)

25g, 500g [N0142]X=H, Y=NO2: pNsCl (11b)

5g, 25g [N0144]

X

SO2Cl

Y

p.4-5X=NO2, Y=H: NsNH2 (18)

5g, 25g [N0705]X=H, Y=NO2 5g, 25g [N0697]

X

SO2NH2

Y

p.4-5R=Boc (19a) 1g, 5g [B2303]R=Alloc (19b) 5g [A1632]

R=Cbz (19c) 5g [C1757]

p.6 Diamine derivativesn=1 25ml, 500ml [D0114]n=2 25g, 500g [D0239]n=3 5ml, 25ml [D0108]n=4 25g, 500g [D0095]n=5 5g, 25g [D0094]n=6 25g [D0107]n=7 5g, 25g [D0106]n=8 25g [D0085]n=9 1g, 5g [D2075]n=10 25g, 500g [D0091]

n=0 1g [A1627]n=1 (27) 1g [A1628]n=2 (28) 1g [A1630]n=3 •HCl 1g [A1661]n=4 •HCl 1g [A1662]

p.7 Resins (41)4-Benzyloxytrityl Alcohol Resin,cross-linked with 1% DVB (200-400 mesh) (1.4-1.6 mmol/g) 1g [B2368]

NO2

SO2NHR

H2N NH2n

nSO2NH

NO2

NH2O

OH

P

13

number 128

Fluorinated Bifunctional Synthetic Block

F0465 Ethyl Fluoro(phenylthio)acetate (1) 1g

Useful Iodonium Compound

Fluoroacetate 1 has an ethoxycarbonyl group, phenyltiho group and fluorine atom on the samecarbon atom and is used as a monofluorinated synthetic block. For example, Wong et al. reported on asynthetic method using 1 for fluorocyclopropane derivative 4 which is a key framework toward thesynthesis of mGluR 2 receptor agonist MGS0028. Since the phenylthio group and ethoxycarbonyl groupof 1 may be separately elaborated, 1 is expected to be of significant use in a variety of fields.

ReferencesA. Wong, C. J. Welch, J. T. Kuethe, E. Vazquez, M. Shaimi, D. Henderson, I. W. Davies, D. L. Hughes, Org. Biomol.Chem., 2004, 2, 168.

PhS CO2Et

F

EtO2C F

OtBu

O

EtO2C F

O

N2

i) ii) iii) iv) v) vi) vii)

O

H

H

F

CO2Et1

2 3 4

i) tBuOCl/tBuOH, ii) NaH, DMAc, iii) BrCH2CH2CH2CO2tBu, iv) TFA, v) oxalyl chloride, vi) CH2N2/ether

vii) Cu(OTf)2-chiral bisoxazoline ligand, optical resolution by preparative HPLC

1

CH2Cl2, r.t., 1 h Y. 95%

CH2Cl2, r.t., 10 min

1

Y. 93%

2

OH

O I

N I PF6

H2N H2N I

B2359 Bis(2,4,6-trimethylpyridine)iodonium(I) Hexafluorophosphate (1)

1g 5g

Iodonium salt 1 is a useful reagent for the construction of oxygen-containing heterocycles withconcomitant introduction of an iodine atom. For example, the iodonium salt 1 electrophilically reacts withunsaturated alcohols and carboxylic acids to give cyclic ethers1a) and lactones, respectively.1b) In theanalogous reactions with phenols or anilines, iodinated compounds can be obtained in high yield by adirect iodination.1c)

References1) The reactions using bis(2,4,6-trimethylpyridine)iodonium hexafluorophosphate

a) Y. Brunel, G. Rousseau, J. Org. Chem., 1996, 61, 5793.b) B. Simonot, G. Rousseau, J. Org. Chem., 1994, 59, 5912.c) Y. Brunel, G. Rousseau, Tetrahedron Lett., 1995, 36, 8217.

14

number 128

Useful Coupling Reagent

D3262 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3 H)-one (DEPBT) (1) 5g

The coupling reagent 1 was developed by Ye et al. and can be used to form peptides with minimalracemization. Ye et al, make comparison with the reactivity of various kind of coupling reagents includingBOP with 1 by amide bond formation with Boc-Ser(Bzl)-OH and benzylamine as a model. According totheir study, 1 shows minimum racemization with very high yield among the reagents, and is an excellentcoupling reagent.

References1) A new coupling reagent with remarkable resistance to racemization

H. Li, X. Jiang, Y.-H. Ye, C. Fan, T. Romoff, M. Goodman, Org. Lett., 1999, 1, 91.Y.-H. Ye, H. Li, X. Jiang, Biopolymers, 2005, 80, 172.

2) Synthesis of cyclopentapeptidesY.-C. Tang, X.-M. Gao, G.-L. Tian, Y.-H. Ye, Chem. Lett., 2000, 826.

NN

N

O

O P

O

OEt

1 (2eq.), DIEA (2eq.)

Y. >99% L : D ratio = 96 : 4CH2Cl2, 20 °C, 60 min

PhCH2NH2Boc Ser(Bzl)Boc Ser(Bzl)

OEt

NHCH2PhOH

DIANANE-Salen Ligand - for Asymmetric Nozaki-Hiyama-Kishi Reaction -

B2652 (1R,2R,4R,5R)-2,5-Bis(3,5-di- tert -butyl-2-hydroxybenzylideneamino)- bicyclo[2.2.1]heptane (1a) 100mg

B2653 (1S,2S,4S,5S)-2,5-Bis(3,5-di- tert -butyl-2-hydroxybenzylideneamino)- bicyclo[2.2.1]heptane (1b) 100mg

DIANANE-Salen ligand 1 is a useful reagent for the asymmetric Nozaki-Hiyama-Kishi (NHK)reaction as a ligand for transition metal complexes. Such complexes can be used as highly enantioselectivecatalysts to obtain chiral secondary alcohols in high enantiopurity.

ReferencesA. Berkessel, D. Menche, C. A. Sklorz, M. Schröder, I. Paterson, Angew. Chem. Int. Ed., 2003, 42, 1032.I. Paterson, H. Bergmann, D. Menche, A. Berkessel, Org. Lett., 2004, 6, 1293.

+ii) Hydrolysis

R1CHO R2XCrCl3 (0.1 eq.), 1b (0.1 eq.)Mn, TMSCl

R1 R2

OH

NN

tBu

tBu OH HO

tBu

tBu

*

2 3 4

R2X = allyl, vinyl halides

R1 = Ph, R2X = allyl bromideY. 72% (R)- 90%ee

i)

15

number 128

Imidazolium Iodides

E0556 1-Ethyl-3-methylimidazolium Iodide (1) 5g 25gM1440 1-Methyl-3-propylimidazolium Iodide (2) 5gB2708 1-Butyl-3-methylimidazolium Iodide (3) 5g

Solar-cells for converting a solar energy into an electrical energy are an important eco-friendlytechnologies. In recent years, research using ionic liquids as non-volatile, nonflammable and electro-chemically stable electrolytes of dye-sensitized solar cells has been widely described. Especially, imidazoliumiodides are most widely used. Improving the durability of devices by gelation of imidazolium iodides is animportant area of investigation.

References1) Novel and efficient ionic liquid electrolytes for dye-sensitized solar cells

a) K. Hara, T. Nishikawa, M. Kurashige, H. Kawauchi, T. Kashima, K. Sayama, K. Aika, H. Arakawa, Solar EnergyMaterials & Solar Cells, 2005, 85, 21.

b) S. Chengwu, D. Songyuan, W. Kongjia, P. Xu, G. Li, Z. Longyue, H. Linhua, K. Fantai, Solar Energy Materials &Solar Cells, 2005, 86, 527.

c) S. Sakaguchi, H. Ueki, T. Kato, T. Kado, R. Shiratuchi, W. Takashima, K. Kaneto, S. Hayase, J. Photochem. Photobiol.A: Chem., 2004, 164, 117.

N

R

I

NCH3

R = 1EtPr 2Bu 3

Magnetic Ionic Liquid

B2672 1-Butyl-3-methylimidazolium Tetrachloroferrate (1) 5g

Ionic liquids are salts composed of cations such as imidazolium ions, pyridinium ions and anionssuch as BF4−, PF6

− and are liquid at relatively low temperatures. Their characteristic properties include;(1) essentially no vapor pressure, (2) non-flammability, (3) high thermal stability, (4) relatively low viscos-ity, (5) liquid state over extended temperature ranges, (6) high ionic conductivity. Applications of ionicliquids with these features are being vigorously explored in various fields.

Recently, Hamaguchi et al. reported that 1-butyl-3-methylimidazolium tetrachloroferrate (1) ismagnetic ionic liquid. Traditional magnetic fluids have had problems of volatility and phase separation.The new magnetic ionic liquid overcomes these problems, and is expected to be applied to many fields,including the use as a sealing agent for the motor axis.

ReferencesS. Hayashi, H. Hamaguchi, Chem. Lett., 2004, 33, 1590.

FeCl4N

(CH2)3CH3

NCH3

1