Indian Journal of Chemistry Vol. 43B, October 2004, pp. 2 152-2 158

Homologation of a-amino acids to ,B-amino acids: 9-Fluorenylmethyl chloroformate as a carboxyl group activating agent for the synthesis of Na

_

protected aminoacy ldiazomethanes

Kantharaju & Vommina V Suresh Babu*

Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India

E-mail :hariccb@rediffmail.com

Received 16 July 2003; accepted (revised) 16 December 2003

An efficient and stereospecific homologation of urethane-protected a-amino acids to ,B-amino acids by Arndt-Eister! approach using an equimolar mixture of Fmoc-/Boc-/Z-a-amino acid and 9-tluorenylmethyl ch loroformate for the acylation of diazomethane synthesizing the key intermediates Fmoc-/Boc-/Z-a-aminoacyldiazo-methanes as crysta lli ne solids is described. They are then converted to the corresponding ,B-amino acids using silver benzoatell ,4-dioxane-water under microwave irradiation. All the protected ,B-amino acids prepared have been obtained in good yield as well as purity.

IPC: Int.Ct.7 C 07 C 229/00

Oligomers of ,B-amino acids (,B-peptides) are an important class of unnatural polymers, which are known to adopt a large variety of different secondary structures both in solution as well as in solid state l

-3.

Thus, ,B-peptide helices4.5, as demonstrated by NMR

and CD spectral techniques, are very stable in methanol solution on heating even at 100°C6

. T hey also form other structures like hairpins(pleated sheet­turn-pleated sheet)7-9, antiparallel pleated sheets lO

, etc .

More importantly, ,B-peptides are emerging as a new class of promising peptidomimetics II. They are resistant against the degradation by proteolytic enzymes such as pepsin, elastase, carboxypeptidase A, pronase or protease 20S 12.13. Thus, ,B-peptides have been demonstrated to have the potential to form a new platform technology and that a place in the design of stable enzyme inhibitors and in generating molecules with selectivity between closely related enzymes.

The mixed anhydride method using isobutyl ch loroformate or ethyl chloroformate for the acti­vation of the carboxyl moiety is a well-studied approach for the synthesis of peptides in solution l4

.

Some very new, promising methodology with special emphasis on catalytic, enzymatic and chemical process for the large scale synthesis of ,B-amino acids is also well documented I5.16. The first successful route for the homologation of the commercially avail able,

crystalline, optically pure t-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) and 9-f1uorenylmethoxy­carbonyl (Fmoc)-a-amino acids to the corresponding

,B-amino acids by the Arndt-Eistert method in a two step process I7.18. The use of isobutyl chloroformate or ethyl chloroformate l9

-21 method is emp loyed, under

careful conditions, for the synthesis of a-aminodiazo­ketones derivatives with moderate to good yields. In recent years, we as well as others, have demonstrated the utility of pentafluorophenyl esters22 , acid f1uorides23 , acid ch lorides24 , coupling agents like BOC2025, p-toluenesulfonyl-chloride26. 9-Fluorenyl­methyl chloroformate (Fmoc-CI), a popu lar reagent used for the introduction of Fmoc group27-29, is a crystalline solid and commercially avai lable. However, its utility for the activation of the carboxyl group, to the best of our knowledge is not reported so far. Recently, we have employed it as a coupling agent for the synthesis of peptides' o. This paper demonstrates the use of Fmoc-CI for the homologa­

tion of a-amjno acids to ,B-amino acids. The present study demonstrates the utility of Fmoc­

Cl in the preparation of a-aminoacyldiazomethane derivatives, starting from the corresponding urethane

protected a-amino acids, through Arndt-Ei st~rt

methodology. In a typical procedure, to a solution of

NG-urethane protected amino acid (L mmole) in dry

KANTHARAJU el al.: HOMOLOGATION OF a-AMINO ACIDS TO ,B-AMINO ACIDS 2 153

THF (5 mL) maintained at - 15°C, was added equi­molar quantiti es of Fmoc-CI and N-methylmorpholine (NMM) and stirred at the same temperature for 10 min . Then, the diazomethane solution in dry ether was added and stirring continued at the same temperature, till the yellow colour persisted. The progress of the reaction, as monitored by TLC and IR, was found to be complete in about I hr. The IR analysis of an aliquot of the reaction mixture studied, ten minutes after the addition of Fmoc-CI, had a peak at 1822 cm' ! which clearly indicates that the reac tio n proceeds via mixed anhydride of the type 2. At the end of the reaction , the peak correspo nding to mixed anhydride disappeared complete ly and a strong peak at aro und 2 107 cm' ! corresponding to di azoketones 3 was present. Routine work-up of the reaction mixture resulted 111 the isolation of the diazomethane derivatives in good yield as well as purity. It is important to note that the side product, 9-f1 uorenylmethanol could be eas ily and complete ly removed by recrysta lli zation us ing ethyl acetate­hexane (I :3) mixture . The Fmoc-/Boc-/Z­aminoacy ldiazomethanes synthesized by thi s method were subjected to Wolff rearrangement empl oy ing catalytic amount of s il ver benzoate, 1,4-dioxane and

.. . d' . 3 ! 32 Th water uSll1g microwave IlTa Jatlon ' . e rearrange-ment was fast and complete in about 1 min . The

corresponding ,B-homolog ues were obtai ned in good yield as we ll as purity. The co mparison of the

determined spec ific rotati ons of the pairs of 3bHalo25

(c I, CHCb -32.2) [reported33: c I , CHCI.1 -32.0]}

and 4b Ha]o25 (c I, CHCI3 -21.1 ) [reported33: c I,

CHCb -2 1.0]} ; 3c Halo"5 (c I, CHCI3 +32 .3) [reported33

: c I, CHCI3 +32. I]} and 4c {[alD25 (c 1,

CHCb +21 .0) [reported33: c 1, CHCIJ +21 .2]} have

been found to be in agreement with the reported va lues. ]n addi tion, the HPLC ana lys is of 3e (R, for L­

isomer 17.48 min , R, for racemic mixture 17.44 and 18. 18 min) and 4e (R, fo r L-isomer 15.42 min, R, fo r racemic mixture 15.36 and 16. 12 min ) derived from Fmoc-L-Va l-OH and comparison with the analysis of racemic mi xture specificall y prepared to test the poss ihle extent of racem izati on revealed that both acy lation of diazomethane using Fmoc-C1 and Wolff rearrangement proceed stereospeci fically.

Thus, Fmoc-CI , a commonly used reagent fo r the protection of the Fmoc group in peptide synthes is, can also conveniently be used for the homologation of urethane protected a-ami no ac ids to ,B-amino ac ids with good yield and without racemi zation .

Experimental Section Solvents and reagents were purified by standard

procedures and were distilled prior to use. The melting points were determined using a Leitz-Wetzler apparatus and are uncorrected . Optical rotations were measured on a AA-1O polarimeter operating at the sodium D line . Infrared spectra were recorded o n a Nicolet model impact 400D Ff-IR spectrometer (neat, CHCb as solvent). TLC was carried out on precoa1ed s ilica gel plates using solvent systems: (i) ethyl acetate:hexane, (35:65 , v/v) , (ii ) chloroform: methanol : acetic acid (45:2: 1, v/v) and (iii ) chloro­form:methanol (9: 1, v/v) and Rr values are designated as RJA, RJB and RIC, respecti vely . E lemental analysi's was carried out on a Perkin-Elmer Analyzer. The samples were dried for 24 hr under vacuum prio r to analysis. HPLC analysis was performed with a Waters LC-3000 system consi sting of a 484 tunable absorbance UV detector and a Millipore 745 data

modulae using a C18 Bondapak (3.9 x 300 mm, 10 /-l) and chiralcel OD (4 .6 x 250 mm, 10 /-l) columns with a linear gradient of water (0 . 1 % TFA) and acetonitrile (0.1 % TFA) with acetonitril e from 20 to 90% ('ver 25 min . !H NMR spectra were recorded on a Bruker AMX-400 MH z spectrometer using tetramethyl sil ane as inte rnal standard , the measurements were carried o ut at 298K, sample soluti ons in deuterochloroform. LG domestic microwave oven operat ing at 2450 MH z freque ncy at its 60% power was used fo r microwave irradiation . The d iazometh ane so lu tio n in dry ether was prepared fro m di aza ld fo llowi ng the reported procedures34

.35

. The concentration o f diazomethane soluti on was est imated by back -titration using benzo ic acid solution 36 .

General procedure for the preparation of N a_

pl-otected aminoacyldiazomethanes 3a-o. To an ice-co ld solu tion of ~ -protected amino ac id ( I mmole) in dry THF (5 mL) was added NMM (0.11 mL, I mmo le) and the mixture stirred at - 15°C for a few min. Then a soluti on of Fmoc-CI ( I mmole) in dry T HF (5 mL) was added and stirred at the same temperature for abo ut 10 min. The react io n mixture was treated w ith a saturated solution o f diazomethane in dry eth er unt il th e ye llow co lour o f diazomethane persisted and stirred for 30 min at O°e. The mixture was al lowed to warm to room temperature and stirred fo r an addit iona l I hr. The progress of the react ion was monitored by TLC and IR . Afte r the comple ti o n of react ion, the excess diazomethane was decomposed by the addition of a few drops of acetic acid. The mixture was washed

2154 INDIAN 1. CHEM., SEC B, OCTOBER 2004

with an aqueous NaHC03 solution (25 mL x 3), 5% HCl (25 mL x 3) or 5% citric acid sol ution (in case of Boc-protected derivatives) and brine. It was dried over anhydrous Na2S04 and evaporated under reduced pressure. The resu lti ng residue was crystal­lized using EtOAc-hexane (l :3) to yield the title compounds 3a-o as crystall ine solids (Scheme I). The physical constants of the compounds are given in Table I .

Fmoc-L-glycyldiazomethane 3a: Light yellow solid; Anal. Calc. for C, sH, sN30 3: C, 67.28; H, 4.57; N, 13.10. Found: C, 67.30; H, 4 .60; N, 13 .02%; IR (neat, CHCb): 2104 (CHN2), 1690 cm-' (urethane) ; 'H NMR (0, COCl3): 2.7 (2H, t), 4.25 (lH, t), 4.60 (2H, d), 5.42 (lH, d), 5.5 (lH, d), 7.24-7 .8 (8H, m).

Fmoc-L-alanyldiazomethane 3b: Light yellow solid ; Anal. Calc. for C' 9H17N30 3: C, 68 .05; H, 5.11; N, 12.54. Found: C, 68 .16; H, 5.28; N, 12.49%; IR (neat, CHCb): 2106 (CHN2), 1698 cm-' (urethane); 'H NMR (0, COCl3): 1.32 (3H, d) , 4.2 (2H, br), 4.42 (2H, d), 5.3 (lH, s), 5.4 (lH, br) ,7.3-7.9 (8H, m) .

Fmoc-D-alanyldiazomethane 3c: Light yellow solid; Anal. Calc. for C'9H17N30 3: C, 68.05; H, 5.11; N, 12.54. Found: C, 68 .18; H, 5.08 ; N, 12.29%; IR (neat, CHCb): 2106 (CHN2), 1702 cm-' (urethane) ;

THF ,NMM, Fmoc-CI.

-15 °C

1a-o

RHO

X"-N>C1--oH A

4a-o

x = Fmoc-/Boc-/Z group

X a Fmoc

b/c Fmoc d Fmoc e Fmoc f Fmoc g Fmoc h Fmoc I Fmoc

1,4 - Dioxane-Water

M.W

R H C H) C H(C H)CH2C H) CH(CH)2 CH2C6Hs C6HS

(CH2)4NHBoc (CH2h COOB'u

'H NMR (0, COCb): 1.32 (3H, d), 4.2 (2H, br), 4.42 (2H, d), 5.3 (lB, s) , 5.4 (lH, br) ,7.3-7.9 (8H, m) .

Fmoc-L-isoleucyldiazomethane 3d : Light yellow solid; Anal. Calc. for C22H23N30 3: C , 69.72; H, 6.08; N, 11.04. Found: C, 70.0; H, 6.14; N, 11.14%; IR (neat, CHCI3): 2105 (CHN2), 1700 cm- ' (urethane) ; 'H NMR (0, COCl3): 0.93 (6H, d), 1.44 (2H, m), 1.84 (2H, m), 4 .23 (lH, m), 4.42 (2H, m), 5.3 (lH, br) , 5.35 (lH, br), 7.3-7.8 (8H, m).

Fmoc-L-valyldiazomethane 3e: Light yellow solid; Anal. Calc. for C2,H2,N30 3: C, 69.41 ; H, 5.81 ; N, 11.56. Found: C, 69 .56; H, 5.86: N, 11.69%; IR (neat, CHCb): 2105 (CHN2), 1702 cm-' (urethane); 'H NMR (0, CDCl3): 0.90 (6H, d) , J .75 (lH, m), 4 .25 (2H, m), 4.45 (2H, m), 5.3 (lH, s), 5.4 (lH, d), 7.3-7.9 (8H, m) .

Fmoc-L-phenylalanyldiazomethane 3f: Light yellow solid; Anal. Calc. for C2sHn N30 3: C, 72.60; H, 5.60; N, 10.18 . Found: C, 71.88; H, 5.56; N, 10.21 %; IR (neat, CHCb): 2108 (CHN2), 1704 cm-' (urethane); 'H NMR (0, COCl3): 2.6 (2H, m), 4.2 (2H, m), 4 .5 (2H, d) , 5.2 (lH, s), 5.4 (IH, br), 7.2-7.8 (13H, m) .

Fmoc-L-phenylglycinyldiazomethane 3g: Light ye llow solid; Anal. Calc . for C24H '9NJ0 3: C, 72.50;

2a-o 1 CH2N2 - Et20

X"X/HN2

A ~ 3a-o

X R j Fmoc CH2COO B'u k Boc (CH2»)C H)

Boc CH(CH) CH2C H) m Z (C H2)2CH) n Z C6HS

0 Z CH2C6 Hs

Scheme I - Synthesis o f N-protected ,B-amino ac ids

KANTHARAJU el af.: HOMOLOGATION OF a-AMINO ACIDS TO ,B-AMINO AC IDS 2155

Table I - Physical data of Fmoc-/Boc-/Z-a-aminodiazoketones 3a-o

SI. Compd Yie ld

No. 3a-o (%)

a Fmoc-Gly-DAM 9 1

b Fmoc-Ala-DAM 88

c Fmoc-o-Ala-DAM 86

d Fmoc-lIe-DAM 84

e Fmoc-Val-DAM 90

f Fmoc-Phe-DAM 88

g Fmoc-Phg-DAM 86

h Fmoc-Lys(NEBoc)-DAM 84

Fmoc-Gl u(O'B u)- DAM 78

j Fmoc-Asp(O'Bu)-DAM 82

k Boc-Val-DAM 90

Boc-lIe-DAM 86

m Z-Nva-DAM 86

n Z-o-Phg-DAM 84

0 Z-Phe-DAM 88

H, 4.81; N, 10.57. Found : C, 71.90; H, 4.55 ; N, 10.69%; IR (neat, CHCI3): 2107 (CHN2), 1698 cm" (urethane); 'H NMR (6, CDCI3): 4.22 (2H, m), 4.5 (2H, d), 5.1 (lH, s), 6.05, (lH, br), 7.2-7 .8 (l3H, m) .

Fmoc-L-Iysyl(e-Boc)diazomethane 3h: Light yellow solid; Anal. Calc. for C27H32N40 s: C, 65.80; H, 6.54; N, 11.37. Found: C, 64.82; H, 6.56; N, 11.41 %; IR (neat, CHCI3): 2106 (CHN2), 1692 cm" (urethane); 'H NMR (6, CDCb): 1.3 (9H, s), 2.22 (8H, m), 4.16 (2H, t) , 4.24, (2H, d), 5.25 (lH, s), 5.63 (lH, br), 6.0, (lH, br), 7.2-7 .8 (8H, m).

Fmoc-L-glutamyl(OIBu)diazomethane 3i: Light yellow solid; Anal. Calc. for C2sH27N30 s: C, 65.86; H, 5.79; N, 9.30. Found: C, 66.80; H, 6.06; N, 9.35%; IR (neat, CHCI3): 2112 (CHN2), 1696 cm" (urethane) ; 'H NMR (6, CDCI3): 1.44 (9H, s), 1.79 (lH, m), 2.1 (lH, m), 2.4 (2H, m), 4.2 (2H, d), 4.4 (lH, br), 5.0 (lH, m), 5.4-5.6 (2H, d), 7.2-7 .8 (8H, m).

Fmoc-L-aspartyl(OIBu)diazomethane 3j: Li ght yellow solid; Anal. Calc . for C24H2SN30 S: C, 66.18; H, 5.78; N, 9.65. Found: C, 66.02; H, 5.55; N, 9.45%; IR (neat, CHCI3): 2112 (CHN2), 1702 cm-' (urethane) ; 'H NMR (6, CDCb): 1.4 (9H, s), 2.0 (lH, m), 2.4 (2H, m), 4.3 (2H, d), 4.4-4.5 (l H, m), 5.4-5.6 (2H, d), 7.2-7 .8 (8H, m).

Boc-L-valyldiazomethane 3k: Light yellow solid; Anal. Calc. for CIIH'9N30 3: C, 54.75 ; H, 7.93; N, 17.41. Found: C, 54.58; H, 7.89; N, 17.32%; IR (neat,

m.p. RLvalue [a]o25

"c RIA Rfo (c=I ,CHCI3)

108-10 0.60 0.86

110-12 0.59 0.85 -32.0

112-13 0.60 0.82 +32.(

143-44 0.70 0.82 -46d

123-25 0.68 0.82 -23.0

136-37 0.61 0.78 +16.1

148-49 0.64 0.80 -32.0

95-96 0.52 0.69 -26.8

137-38 0.51 0.74 -25.8

71-73 0.62 0.78 -26.4

61-62 0.72 0.8 1 -30.2

86-88 0.68 0.78 -42.0

114-16 0.70 0.81 -33 .2

82-84 0.70 0.78 +36.2

8 1-82 0.68 0.79 -42.0

CHCI3): 2107 (CHN2), 1694 cm" (urethane); 'H NMR (6, CDCI3): 0.92 (6H, d) , 1.32 (9 H, s), 1.75 (tH, m), 4.21 (lH, br), 5.2 (lH, s), 5.42 (lH, br).

BOC-L-isoleucyldiazomethane 31: Light yellow solid ; Anal. Calc. for C' 2H2,N30 3: C, 56.45 ; H, 8.28; N, 16.45. Found: C, 56.58 ; H, 8.34; N, 16.48%; IR (neat, CHCb): 2108 (CHN2), 1688 cm-' (urethane); 'H NMR (6, CDCb): 0.93 (6H, d), 1.44 (2H, m), 1.84 (2 H, m), 4.13 (l H, m) , 4.42 (l H, m), 5.3 (l H, br), 5.35 (lH, br), 7.3-7 .8 (8H, m) .

Z-norvalyldiazomethane 3m: Light yellow solid ; Anal. Calc. for C'4H 17N30 3: C, 58 .29; H, 5.29; N, 16.99. Found: C, 57.98; H, 5.24; N, 16.88%; IR (neat, CHCI3): 2112 (CHN2), 1708 cm-' (urethane); 'H NMR (6, CDCI3): 0.9-2.0 (7H, m), 2.4 (lH, d), 3.75 (lH, m), 5.1 (2H, s), 5.6 (lH, br) , 7.2 (5H, m).

Z-D-phenylglycinyldiazomethane 3D: Light yellow solid; Anal. Calc. for C 17H,sN30 3: C, 65.01; H, 4.88; N, 13.58. Found: C, 65.84; H, 4.72; N, 13.75%; IR (neat, CHCI3): 2108 (CHN2), 1710 cm-' (urethane); 'H NMR (6, CDCb): 4.5 (lH, br), 5.01 (2H, s), 5.24 (l H, s), 5.4 (I H, br) , 7.25 (IOH, m).

Z-L-phenylalanyldiazomethane 30: Light yellow solid; Anal. Calc. for C' SH' 7N30 3: C,56.86; H, 5.29; N, 12.99. Found: C, 56.3 ; H, 5.8; N, 13.28%; IR (neat, CHCb): 2107 (CHN2), 1712 cm-' (urethane); 'H NMR (6, CDCI3): 3.0 (2H, d) , 4.5 (lH, m), 5.1 (2H, s), 5.2 (lH, s), 5.4 (lH, d), 7.2-7.5 (lOH, m).

2156 INDIAN J. CHEM., SEC B, OCTOBER 2004

Table II - Physical data of Fmoc-/Boc-/Z-,B-homoamino acids 4a-o

SI Compd Yield No. 4a-o (%)

a Fmoc-,B-HGly 78

b Fmoc-,B-HAla 82

c Fmoc-,B-DHAla 80

d Fmoc-,B-HIIe 80

e Fmoc-,B-HVal 78

f Fmoc-,B-HPhc 80

g Fmoc-,B-HPhg 82

h Fmoc-,B- Hlys(£ Soc) 75

Fmoc-,B-HGlu(O'Bu) 78

Fmoc-,B-HAsp(O'Bu) 76

k Boc-,B-HVal 88

Boc-,B-Hlle 80

m Z-,B-HNva 79

n Z-,B-D-HPhg 84

0 Z-,B-HPhe 85

General procedure for the synthesis of N­protected ,B-homoamino acids 4a-o. A suspension of Fmoc-/Boc-/Z-a-aminoacyldiazomethane (1 mmole) , silver benzoate (20 mg, 0.08 mmole) in 1,4-dioxane 00 mL) and water (5 mL) was irradiated to microwaves till the completion of the rearrangement. The remaining solvent was filtered and evaporated under reduced pressure. The resulting residue was red issolved in 10% aq ueous Na2C03 solution (20 mL). It was washed with ether (2 x 30 mL) and acidified to pH 2 using 10% HCI (or citric acid in case of Boc- derivatives) and extracted using ethyl acetate (3 x 25 mL) . The combined organic layer was washed with water (2 x 20 mL), dried over anhydrous Na2S04. T he solvent was removed in vacuo and a crude material was crystallized from n-hexane-ethyl acetate to get the title compounds 4a-o in good yield. The physical constants of 4a-o are given in Table II.

Fmoc-L-p-homoglycine 4a: White solid; Anal. Calc. for C lsH17N04: C, 69.45 ; H, 5.46; N, 4.50. Found: C, 69.5 I; H, 5.42; N, 4.58%; IR (neat, CHCI3): 3340,1692 em-I; IH NMR (£5, COCl3): 2.75 (2H, t), 3.45 (2H, m), 4.25 (1.H, t), 4.59 (2H, d), 5.5 (lH, br), 7.2-7.8 (8H, br) .

Fmoc-L-p-homoalanine 4b: White solid; Anal. Calc. for CI9HI9N04: C, 70.14; H, 5.89; N, 4.30.

m.p. Rlvalue [a]o25 °C RrA RrB (c= I,CHCI ))

148-50 0.60 0.76

96-98 0.58 0.75 -2 1.0

97-99 0.60 0.74 +21.2

98-100 0.65 0.74 +16.8

153-54 0.59 0.77 -36.2

110- 12 0.62 0.75 -26.0

182-84 0.60 0.78 -22.0

95-96 0.67 0.80 -18.2

58-60 0.69 0.75 - 11.4

82-83 0.68 0.76 +0.3 (c= 1.9,MeOH)

65-66 0.62 0.71 -20.3

85-86 0.65 0.74 -24.0

82-83 0.67 0.63 -29 .1

86-88 0.68 0.72 +1 8.8

84-85 0.67 0.60 -36.0

Found: C, 70.30; H, 5.72; N, 4.52%; IR (neat, CHCI3): 3324, 1688 cm'l; IH NMR «(), CDCb): 1.10 (3H, d), 2.31 (I H, d), 2.45 (l H, d) , 3.85 (l H, m), 4. 1-4.3 (3H, m), 7 .3-7 .8 (8H, m) .

Fmoc-D-p-homoalanine 4c: White solid; Anal. Calc. for CI9HI 9N04: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.34; H, 5.69; N, 4.50%; IR (neat, CHCI3): 3322, 1696 cm· l; IH NMR (£5, COCb): 1.08 (3H, d), 2.35 (I H, d), 2.45 (I H, d), 3.6 (l H, m), 4.2-4.28 (3H, m), 7.3-7.8 (8H, m) .

Fmoc-L-p-homoisoleucine 4d: White solid; Anal. Calc. for C22H2SN04: C, 72.0; H, 6.86; N, 3.82. Found: C, 71.78; H, 6.68; N, 3.78%; IR (neat, CHCh): 3324, 1698 em-I; IH NMR (£5, COCl3): 0.83 (6H, m), 1.34 (2H, m), 1.47 (lH, m), 2.31 (2H, d) , 3.5 (lH, m), 4.2 (1 H, t) , 4.25 (2H, m), 5.4 (lH, br), 7.2-7.8 (8H, m) .

Fmoc-L-p-homovaline 4e: White solid; Anal. Calc . for C21H23N04: C, 70.14; H, 5.89; N, 4.20. Found: C, 71.24; H, 6.38; N, 3.78%; IR (neat, CHCI3): 3334, 1698 cm' I; IH NMR (£5, COCl3): 0.85 (6H, d), 1.75 (lH, m), 2.3 (2H, d), 4.2 (2H, m), 4.3 (2H, m), 5.4 (lH, br), 7 .3-7.8 (8H, m) .

Fmoc-L-p-homophenylalanine 4f: White solid; Anal. Calc. for C2sH23N04: C, 75 .05 ; H, 5.58 ; N, 3.70. Found: C, 74.81; H, 5.78; N, 3.49%; IR (neat, CHCh): 3342,1704 em-I; IH NMR (£5, CDCh): 2.52

KANTHARAJU et al.: HOMOLOGATION OF a-AMINO ACIDS TO ,B-AMINO ACIDS 2157

(2H, m), 2.71 (2H, d), 3.6 (lH, m), 4.1 (lH, m), 4.2 (2H, m), 5.3 (l H, br), 7.3-7.8 (l3H, m).

Fmoc-L-p-homophenylglycine 4g: White solid; Anal. Calc. for C24H2,N04: C, 74.58 ; H, 5.49; N, 3.99. Found: C, 74.40; H, 5.45; N, 3.61 %; IR (neat, CHCI)): 3338,1702 em" ; 'H NMR (6, CDCh): 2.5 (2H, d), 4.25 (2H, m), 4.4 (2H, d) , 5.85 (lH, br) , 7.2-7.8 (13H, m).

Fmoc-L-p-(E-Boc)homolysine 4h: White solid; Anal. Calc. for C27H)4N20 6: C, 64.6; H, 6.53; N, 5.38. Found: C, 64.38; H, 6.54; N, 5.34%; IR (neat, CHCI)): 3400, 3450,1702, 1692 em"; 'H NMR (6, CDCb): 1.45 (9H, s), 2.2 (8H, m), 2.32 (2H, d) 2.45, (lH, d) , 4.2 (lH, t) , 4.35 (2H, d), 5.65 (2H, br) , 7.25-7.8 (8H, m).

Fmoc-L-p-homoglutamic acid (OIBu) 4i: White solid; Anal. Calc. for C2sH29N06: C, 68 .32; H, 6.65; N, 3.19. Found: C, 68.28; H, 6.7; N, 3.2%; IR (neat, CHCb): 3430, 1714 em" ; 'H NMR (6, CDCh): 1.4 (9H, s), 2.4 (4H, m), 2.6 (2H, d), 3.8-4.4 (4H, m), 5.6 (1 H, d), 7.2-7.8 (8H, m) .

Fmoc-L-p-homoaspartic acid (OIBu) 4j: White solid; Anal. Calc. for C24H27 N06: C, 67.76; H, 6.35; N, 3.29. Found: C, 67.68; H, 6.44; N, 3.42%; IR (neat, CHCI)): 3328, 1704 em"; 'H NMR (6, CDCh): 1.43 (9H, s), 2.67 (4H, m), 4.2-4.4 (4H, m), 6.5 (l H, br), 7.2-7.8 (8H, m).

BOC-L-p-homovaline 4k: White solid; Anal. Calc. for C ll H2,N04: C, 57.37 ; H, 9.19; N, 6.08. Found: C, 57.20; H, 9.22; N, 6.23%; IR (neat, CHCh): 3346, 1688 em" ; 'H NMR (6, CDCI)): 0.94 (6H, d), 1.32 (9H, s), 1.72 (lH, m), 2.5 (2H, d), 4.2 (lH, br), 5.4 (lH, br).

BOC-L-p-homoisoleucine 41: White solid; Anal. Calc. for C'2H23N04: C, 58.99; H, 9.48; N, 5.73. Found: C, 58.85; H, 9.52; N, 5.68%; IR (neat, CHCI)): 3340, 1692 em" ; 'H NMR (6, CDCh): 0.90 (6H, m), 1.32 (llH, m), 1.5 (lH, m), 2.35 (2H, d), 3.5 (lH, m), 5.4 (lH, br).

Z-L-p-homonorvaline 4m: White solid; Anal. Calc. for C'4H'9N04: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.19; H, 7.18; N, 18.0%; lR (neat, CHCI)): 3346, 1696 em"; 'H NMR (6, CDCh): 1.1-1.3 (7H, m), 2.6 (2H, d), 3.9 (l H, d), 5.1 (2H, s), 5.8 (lH, br), 7.2 (5H, m).

Z-D-p-homophenylglycine 4n: White solid; Anal. Calc. for C'7H17N04: C, 68.44; H, 5.74; N, 4.95. Found: C, 68.24; H, 5.34; N, 5.06%; IR (neat, CHCI)): 3340, 1692 em"; 'H NMR (6, CDCI)): 2.5 (2H, d), 4.2 (lH, m), 5.01 (2H, s), 5.46, (lH, br), 7.25 (lOH, s).

Z-L-p-homophenylalanine 40: White solid; Anal. Calc. for C, sH'9N04: C, 69.21; H, 6.13; N, 4.48. Found: C, 68.92; H, 6.18; N, 4.35 %; IR (neat, CHCI)): 3340, 1690 em"; 'H NMR (6, CDCI)): 2.6 (2H, d), 3.0 (2H, d) , 4.2 (lH, m), 5.0 (2H, s), 5.3 (IH, br), 7.25 (lOH, m) .

Acknowledgements Authors thank the Department of Science and

Technology, Govt. of India for financial assistance. One of the authors (VVSB) thanks Department of Biotechnology, Govt. of India for an overseas associateship. Author (KR) thanks KSVN trust, Bangalore for their kind help.

References I Seebach D & Matthews J L, Chern ComlllLln, 1997,2015. 2 Cheng R P, Gellman S H & DeGrado W F, Chem Rev, 101 ,

2001,3219. 3 Gellman S H, Acc Chern Res, 31,1998,173. 4 Lopenz-Carrasquero F, Aleman C & Munoz-Guerra S,

Biopolymer, 36, 1995,263. 5 Apella D H,Christianson L A, Klein D A, Powell D R, Huang

X, Barchi J J & Gellman S H, Nature , 387, 1997, 38 1. 6 Gademann K, Jaun B, Seebach D, Perozzo R, Scapozza L &

Folkers G, Helv Chirn Acta, 82, 1999, l. 7 Nowick J S, Smith E M, Ziller J W & Shaka A J,

Tetrahedron, 58, 2002, 727. 8 Smith C K & Regan L, Acc Chem Res, 30, 1997, 153. 9 Miwa J H, Patel A K, Vivatrat N, Popek S M & Meyer AM ,

Org Lett, 3, 2001, 3373. 10 Krauthauser S, Christianson L A, Powell DR & Gellman S H,

JAm Chem Soc, 119, 1997,11719. II Steer D L, Lew R A, Perlmutter P, Smith A I & Aguilar M I,

Lett in Peptide Science. 8, 2002, 241. 12 Hintermann T & Seebach D, Chimia , 50, 1997, 244. 13 Gademann K, Hintermann T & Schreiber J V, CLi rr Med

Chem, 6, 1999,905. 14 Benoiton N L, HOLiben-weyl lIlethods of organic chemistry,

synthesis of peptides and peptidol11il11itics, Vol. 22a, edited by E Goodman, A Felix, L Moroder & C Toniolo (New York), 2002,443.

15 Ahmed F, Abdel-Magid, Cohen J H & MarynanoFr C A, Curl' Med Chel11, 6, 1999,955.

16 Juaristi E & Lopez-Ruiz H, CLirr Med Chern, 6, 1999, 983. 17 Cole D C, Tetrahedron, 32, 1994,9517. 18 Ye T & Anthony McKervey M, Chem Rev, 94,1994,1091. 19 Plucinska K & Liberek, Tetrah edron, 43, 1987, 3509. 20 Muller A, Vogt C & Sewald N, Synthesis, 1998, 837. 21 Ellmerer-Muller E P, Brossner D, Nas louh N, Tako A, Helv

Chim Acta. 59, 1998,81. 22 Suresh Babu V V, Gopi H N & Ananda K, J Pept Res, 53 ,

1999,308. 23 Suresh Babu V V, Gopi H N & Ananda K, J Pept Res, 55 ,

2000,289. 24 Leggio A, Liguori A, Procopio A & Sindona G, J Chem Soc

Perkin TrailS 1, 1997, J 969. 25 Vasanthakumar G R, Patil B S & Suresh Babu V V, J Chem

Soc Perkin TrailS I, 2002, 2087.

2158 INDIAN J. CH EM. , SEC B, OCTOBER 2004

26 Yasanthakumar G R & Suresh Babu Y Y, Synth COn/mull, 32, 2002,65 1.

27 Carpino L A & Han G Y, } Am Chem Soc, 92,1970,5748. 28 Carpino LA & Han G Y, } Org G em, 37,1972,3404. 29 Carpino L A, Beyermann M, Wenschuh H & Bienert M, Acc

Chem Res, 29, 1996,268 . 30 Tantry S J, Yasanthakumar G R & Suresh Babu Y Y, Lett in

Peptide Science, (in press). 31 Patil B S, Yasanthakumar G R & Suresh Babu Y Y, Lett in

Peptide Science, 9,2003,231.

32 Kantharaju, Palil B S & Suresh Babu Y Y, (communicated). 33 Ananda K & Suresh Babu Y Y, Indian} Chem, 38B, 1999,418. 34 Furniss B S, Hannaford A J , Smith P W G & Tatcheli A R,

Vogel's text book of practical organic chemistlY, Fifth edn ., (Longmann , UK), 1994,430.

35 Caution: The preparation of diazomethane solution should be carried out only in a fume cupboard with a powerful ex haust system.

36 Arndt F, Organic Synthesis Colin, Vol.2 (Wiley, New York) , 1943, 165.