V d . 18 No. 4 CHINESE JOURNAL OF CHEMETRY 2ooo

Highly efficient synthesis of peptides by rational utilization of novel coupling reagents

Keywords ty, no- amino acid

Peptide, oouplmg V t , d t i o n , reactivi-

The chemical synthesis of peptide is necessary and effective means to study s t ruc~-ac t iv i ty relationship (SAR) , elucidate structures and acquire ample quanti- ties of compwnds unavailable h natural sources or fermentation, especially for the peptidebased medicines and phamvrceuticals in reducing their toxicities or en- hancing their activities, selectivities or bioavailabilities by syntheticmanipulation. To meet the needs for peptide synthesis, many chemical methods for the peptide syn-

thesis have been developed, which in m t cases involve activation of the carkmylic acid components in the pep- tide couphg reactions by the formation of anhydrides, acid azidea , acid halides or active esters in advance, or- by the in s i t u activation of the &xylic acids by cou-

pling reagents. Because the couphng reagents are conve- nient to use and often show high efficiency, they have developed very rapidly in the past decades. In this ac- count, the exploited peptide coupling reagents are re- viewed and the rational selection of the coupling reagents, as well as the mechanisms for the collphg re-

of Sciences, Shmghui 200032, Chinu

actions is discussed.

Coupling reagents used for the synthesis of peptide containing only coded amino acid residues

Received Dccember23, 1999; acczpted March21, u)oo.

Project s u p p a d by the National Natural Science Foundation d China.

Synthesis of d e d small or medium peptides using conventional coupling reagents has becone routine. ?he most corrmylnly used couplmg reagents are the carbodi- irnides 1-3 shown in Scheme 1. These carbodiimides pmmote the fonnation of the amide bond by forming the correspondmg intennediates of the 0-acylisourea and symmetric anhydride, which subsequently underp aminolysis with the amino component to give product. However, the coupling of protected peptide segments us- ing the carbodiimides alone pm& with extensive racemization of the C-terminal amino acid of the segment besides other well-known side reactions. Such memiza- tion can be d r a m a t i d y reduced by the addition of the additives4-7, which intercept the above two interme- diates to form the corresponding active esters. The esters react rapidly with amino components to di amides.

Among the additives, HOSu was the first used in peptide synthesis. However it was gradually replaced by HOBt due to the better 'clcemization-suppmsing ability and much higher reactivity of the latter. HOOBt can suppress the racemktion more &ciendy than the HOBt does. Nevertheless it has not been used as broadly as HOBt because it produces an azide by-product dunng coupling. HOAt is the most efficient additive up to now, which can effectively promote the fonnation of sterically hindered amide bonds and dramatically suppress the

Vol. 18 No. 4 2aK) Chinese Joumal of Chemistry 457

racemization because of the presence of an anchimeric assistance effect.

0

4 HOSu 5 HOBt

One of the most significant developments in peptide coupling reagents is the successful exploitation of HOBt- based phosphonium and uronium salts. Subsequent to the first phosphonium salt BOP, designed by Castm,' a series of HOBt-derived onium type coupling reagents, such as PyBOP, HBTU , HBPyU, HBPipU and HBMDU (Scheme 2 ) , have been developed and applied to the peptide synthesis both in solution and solid phase. The

6 HOOBt 7 HOAt

previously predominant cabdiimide reagents are gradu- ally replaced by the more efficient onium salts. Among these onium salts, HOBt-derived urrxlium type reagents are shown to be somewhat more efficient than the come- sponding phosphonium analogues. Furthermore, H s b U was proved to be the most efficient among HOBt-derived uronium salts, of course more efficient than phosphoni- um salts based upon HOBt .

8 BOP 9 PyBOP 10 HBTU

I1 HBPyU 12 HBPipU 13 HBMDU

The mechanism of these phosphonium and mnium by the oxyanion of HOBt to afford the benzotriezolyl ester salts mediated coupling reactions is proposed as shown in 16, releasing the by-product 17 or 20. It is also pro- Scheme 3. "he cadmylate ion of the carboxyl comp- posed that all the intermediates, the acyloxyonium salt nent attacks the onium salt 14 or 18 to form the corre- 15 or 19, the active ester 16, the amino acid anhydride sponding unstable acyloxyuronium salt 15 or my- and 5(4H)-oxtmlone may react with amino component loxyphosphonium salt 19, which is subsequently attacked to give the final product. However, the benzotriazolyl

458 Peptide mupling reagents L I & x u

ester 16 is widely regarded as the main active i n t e d - ate. ?he racemization of products is mainly caused by the intnunolecular deprotonation of the a-CH of the ac-

tive ester 16 and the tautomerimtion or enolization of 5- (4H)-oxazolone under basic reaction conditions.

14

R 1 0,-

18

' 0 - I (D N

Although HOBt-derived phosphonium and uronium

salts demonshate hgh efficiency in peptide synthesis, the racanization is still a problem. For example, Young's tests show that the racemktion of products were 25.4% and 39.8 % , respectively, using HBTU or BOP as a cwplulg reagent.' To further suppress the racemization and enhance the couphg efficiency, a se- ries of HOBt-based immonium salts, such as BOW, BDMP and BPMP shown in Scheme 4, have been devel- oped. Similar to the urrmium/aminium salt HBTU, reagent BOMl crystallized in the N-substituted form 21, rather than the isomeric 0-substituted fom as shown by the X-ray analysis. The X-ray data for those analogous BDMP and BPMP as well as the umnium salts HBMDU and HBPyU have not been available yet. Therefore the structural representations are arbitrarily drawn as the 0-substituted f o m . Similar isomerization was also observed in the active ester 16, and could be explained by molecular orbital calculation using semi- empirid method P M ~ .4

These immoniurn !ype reagents show extremely high

I i:n N - + 16

R1, 1 ,R1 N N I I R' R'

17

R L o I

+

20

reactivity, very low racemization and good yields for the couplings shown in Table 1 and Fig. 1. It is obvious that, b0th.h terms of mtivity and racemization, the HOBt-based immonium salts are superior to the &urn salts H B e U and HAPyU, which are widely &ed as the most effective wents so far developed. Using BO- MI as coupling reagent and NMM as base, the model coupling reaction can be accomplished within 5 min even at - 709: (Entry 13) .5 The half-reaction time of t h ~ HOBt-based immonium salts is less than 20 min even at - 10°C in with sterically hindered 2,6-lutidine as base, while the half time of reaction ( t m ) of the car-

salts are more than 120 min under the same reaction conditions.3

The relatively low reactivity of HBPyU and HAPyU is mainly due to the lower susceptivity of the cxubocation in these uronium/aminium salts towards the attack of the cmbaxylate anion than that in the inmonium salts. 'Ihe two substituted amino groups of the uroNurn/aminium

salts provide two equal mnance structures to s t & i

bodiimida, HOBt-derived Uranium and p h o ~ p h h ~ m

P'P L'Z 8'M 8'06 O'ZP I'E 9'1 I> Z'H Z'P9 I'M O'S E'Z 0'2 1'69 6'L9 9'6P P'S E'Z 8'1 Z'% L'I8 9'LE E'S Z'Z 6'1 E'S6 9'68 0'1s

O'E I> E'68 1-68 9'LS L.1 S'P 0'98 S'EL 1.19

8'8 I'E 01 P'E6 1-01 EP'9 E'E 6P E'8L Z'II P'Z

6'€1 L'S I> 9'66 9'66 1-66 9'PI ozI< 1-91 6z'E O'Z 9'6 EZ P'98 P'tE O'PI

0'81 6'L I' 9'66 9'66 6'86 5-01 6'8 I> S'66 S'66 E'L6 E'E 8'6 I> E'66 E'66 S-S6 9'6E 9'6 I> 6'86 2-16 1'08 Z'IE 8'L EE P'EL 8.52 K'6

m rn rn m m bZ€D m m m ma

da ma ma ma ma ma

m

8'9 I8 8'€9 E'ZI LE'P .m

OI - 01 - OI - OI - OI - OL - 01 - 01 - OI - n 01 - n n n n n n 01 -

81 LI 91 SI PI €1

ZI 11 01

6 8

L

9 5 P E Z I

dROa 9z dWOS SZ dwae vz

dWde CZ

(H3 nne I

0 // 'H3

P-

460 Peptide couplmg reagents U & X u

301

10

0 20 40 60 80 100 120

Reaction time (min)

campanson d react;v;ty of innnomum salts with mm-

urn salts ( A BPMP , 0 BDMP, BOhfl, HBPyU , rHAFyU, + ZGF-OBt, o ZGF-Oh, m HBPyU). Reaction wnditions: T, - l o r , bese, 2,6-1~t idk . Sd., THF. subseate d o : N- protected amino acid: amino acid eater h-oxide: coupling -:base = 1:1.1:1.1:3 (mol).

The efficiency of these imrnonium salts was further demonstmted by the s u d synthesis of a series of oligopeptides and biologically active peptides, such as Lx-enkephalin, both in solution and solid phase. These immonium salts have also been employed in the synthesis of esters with excellent yields, especially the active esters such as benzotriazolyl , pentafluomphenyl, and succinimidyl esters, which are often used in the synthesis of Lactones and lactams .'

Coupling reagents for nonribcrsomal peptide

ed amino acid residues containing N - a l l ~ ~ h t e d or Ca, Ca-disubstitut-

N-alkyl amino or imino acid residues in peptides, such as MeVal and Pro, exhibit reduced preference for t m conformation, which may lead to the biologically relevant etum structures. The abridgment of i n k - and intermolecular hydrogen bonds in peptide containing N- &yl amino acid residues further affect the secondary and tertiary structures of the peptide. As for C,, C,- &substituted amino acids, such as Aib, they can rigidify the peptide backbone h u g h the formation of helixes

and ptums, the organized structures mponsible for the interesting biological activity of the peptaiboh. The structurally unwd, no* peptide containing N-alkylated or C,, C,-disubstituted amino acid m i dues, which are mainly isolated frwn fungi, bacteria, marine sponges and other lower animal fonns, usually exhibit a variety of activities including antitumor, antivi- ral antiinflammatory and immunosuppressive actions. These peptides or their analogues derived by SAR studies can be used as drug or leadmg compounds in drug de- velopment. The chemical synthesis of these compounds is thmfore necessary and valuable. Unfortunately, the incorporation of noncoded amino acids, especially steri- cally hindered N-methylated or C,,C,-diakylated amino acids, into peptides could not be satisfactorily achieved using the conventional DCCYHOBt or HOBt-derived oni-

um type coupling reagents. Although the reactivity of the N-methyl amino components should be higher than that of the primary amines in &2 reactions in view of the electronic effect, the steric hindrance of these secandary amines greatly outweighs their e n h a n d nucleophilicity

tion time, undesired side reactions, and extensive d o n . Fo~tunately, this pmblem has been suc-

cessfully circumvented with the exploitation of the new additive HOAP and HOAt derived umnium, phosphoni- urn and irmnonium type coupling reagents, such as I-LATU, HAPyU, HAPipU, HAMDU, AOP, PyAOP and AOMP (Scheme 5 ) .3*10 Just like HOBt-derived oni-

urn reagents, HOAt-based mnium salts are also more reactive than corresponding phosphonium analogues. HAPyU is shown to be the most efficient among these durn salts.

Phosphonium type reagents are more suitable than the unmium salts in solid phase peptide synthesis be- cause HOAt-derived uronium salts may react with amino groups to fonn undesired guanidino derivatives under the conditions c o m n l y employed in peptide synthesis. Such side reactions partly terminate peptide chain don- gation and may be a serious pmblem during the much slower activation of h i n d d amino acids, N,-pmtected peptide segments, or cah0xyl.i~ acids involved in cy- clization steps. lo The yields for coupling using immonium salt AOMP am usually poor because in the presence of a

base AOMP decomposes before the activation of N-pm- tected amino acid is achieved.

and re~dts in low 00upling rates, 1- to extend RSC-

Vol. 18 No. 4 2000 China Journal of Chemistry 46 1

scbaae5

V

2a ~ A O P 29 HATU 30 HAPyU 27 AOP

31 HAPipU 32 HAMDU 33 AOMP

Althaugh the HOAt-based coupling reagents men- tioned above are shown ta be very efficient for the con- struction of hindered peptides, they am very expensive and scale up is thus difficult. For these reasons another class of coupling resgents, halogenated mnium and phosphonium salts, such as PyClU, TFFH, BTFFH, PyBroP and PyCloP, become impoaant in the synthesis of hindered peptides (Scheme 6). For instance, TFFH shows high efficiency during the synthesis of peptide containing Aib or N-methyl amino acid residues, and can be used both in solution and solid phase. l1 The main intermediate of the TFFH or BTFFH mediated coupling reactions is the N,-pmtected amino acid fluoride. In the case of PyClU and PyCloP, the intermediate 5(4H)-ox- azolone is also formed besides the‘corresponh N,-pm-

tected amino acid chloride, resulting in mre s i N c a n t racemizBtion than TFFH or BTFFH. PyBroP is also a powerful reagent for the formation of hind& amide bonds via corresponding acid bromide intermediate. The main disadvantage of using these halogmated onium d t s is that the racemhion of products is more serious than using HOAt-based onium reagents, especially for seg- ment condensation. BOP-Cl demonstrated low racemiza- tion and high reactivity due to its intramolecdu general

base catalysis by the oxazolinane &yl of the mixed phosphorous anhydride active intermediates .. However, as it reacts with primary amines under the d y used reaction conditions, the acid components mupt, be pre-activated. Consequently, the coupLng reaction can

not be carried out in a m p o t m~nner.”

34 PyClU 35 TFFH 36 BTFFH 37 PyBroP 38 B O P 4

To tackle above problems, we have developed a se- BTFFH and BOP-CI. Ihe coupling could be ~cco111-

ries of halogenated reagents for peptide synthesis plished within 2 min under the adopted reaction condi- (Scheme 7) . Table 2 and Fig. 2 show that 2 - b d a - tions. “he coupling yield a d d be further impmed if mlium salt13 BEhiT and 2-halopyridinim salts BEP, the base was added siowly. As shown in Table 2, the FJP, BEPH and FEPH are much more reactive than the d t i o n of p&ct using 2-halopy1idinium or 2- commonly used halogenated reagents PyBmP, F’yClU, halothimlium salts as coupling reagents was much lower

462 Peptide coupling magea~ts U & x u

than using other halcgenated coupling reagents (except BOP-CI) . If HOAt was added as an additive, the ntcemizab'on can be further s u p p d due to its an- chuneric assistance effect. Fig. 3 also demonstrates the high reactivity of thiazolium and pyridinium type cou- p h q reagents in the coupling of s t e r i d y hindemxi N-

39 PyClOPP 40 CMBI

43 FEP 44 BEPH

methyl amino acids. Their hqgh efficiency was further proved by the succesafd synthesis of the extensively N- methylated irmnunosuppreasive cyclic undecapeptide Cy- cloaporin 0 (60) in -23% overall yield and the protected pentapeptide moiety of Dolastatin 15 in 57.7 % o v d yield.

41 BEMT 42 BEP

45 FEPH 46 CMMM

- w W r c a g a d Yield (%)' t'A (mill) D-imnn content (96)

1 P L S d 6.10 79 22.3 2 Bop-Cl 5.34 - 9 0 d 4.13 3 CMBI 19.7 92 16.8

4 pyau 5 . 6 4 > 120 33.2 5 BlFRI 9.35 49 25.9 6 CMMM 2.31 > 120 31.4

2.72 7 BEMT 45.9 -' 8 BEMF 84.3 < 2' 1.33 9 FEP 75.6 < 2' 2.33 10 FFPH 67.7 < 2' 2.08 1 1 BEP 50.8 < 2' 4.59 12 BEPH 52.3 < 2' 4.56 13 w 86.7 <2' I .54 14 BEF 75.9 < 2' 1.42

a Model d m : ZGly-&OH + Vd-OCH~*HCPZGly-PVal-OC&. rmditiar~~: Sd. CH&(lO Vd); tanp.

-109:; bmeDIEA. bReectiontimt=2min. 'HOAt(lequiv.)wmedQdanan&tive. d'IhetvlvaluedBOP-CI ca~ot be evaluated acxrurately due to irs poop dubility in ' l h e CotIpliOg d a w . wtw. acormplshed within2min.

The proposed mechanism of the couplug mt ions with the amino companent to give pduc t and release the mediated by the pyridinium type reagents is as follows: by-product N-ethyl-4-pyxidone 48. Alternatively, 47 First the carboxylic acid is activated by the 2-halopy1i- may be converted, on a crmpetitive basis, into the cor- dinium salt3 due to the formation of an unstable my- respondmg acid halide before being transformed into the loxypyridinium salt intermediate 47, which in turn reacts dipeptide by aminolysis. A small amount of 5(4H)-oxa-

Vol. 18 No. 4 20oO 463

m.

20 40 60 80 100 120

Reaction time (min)

90

.8.0

70

60 h c 50 I!

40

30

20

10

Or 60 120 180 240 300 3k Reaction time (min)

~ O I E and ~ylrnnehic anhydride of Boc-Vd-OH e- exated M mimr active intermediatee during co~pling.lbe former was also very liable to d t i m due to its tau- tnmerizaticm and enolieatian (Fig. 4) . Similarly, the

/ D" I-

R= 2. F m . Boc R1= OBd. OFm. OBu' R". R1 = Mino acid side c h i n

RZ, R' = €I, Me, dLyl R4 =Me. U, Ed. Bu! et d.

464 Peptide coupling reagents L I & M J

coupling reagents for cyclic peptide synthesis

The structural features of cyclic peptides, i . e . the

of cw arm& bonds, confer greater stability to pmteolytic enzymes, which can increase bioavailability and thera- peutic potential. Furthemre, cyclic structums reduce the conformational freedom of the peptide and often re- sult m high receptor bin+ affinities by reducing unfa-

vorable entropic effects. For these reasons, the cyclic peptides often make promising l m h g compounds for drug discovery. Therefore, chemical syntheses of these cyclic peptide or peptidomimetic derived by SAR studies are very useful and sgdicative.

For the synthesis of macrocyclic peptide, the ring d~~~~nnection plays an important role towards the peptide macfOcyc1ization reactions. h p e r d i ~ c o ~ e ~ t i o n can in- cram cyclizaton rates and suppress such side-reactions as dimenzation, oligrmerization, and racemization of the C-terminal residue. h e guidelines for ring dixonnec- boa have been well studied and reviewed, l4 and there- fore are not covered in this a c m t . Another important factor affecting peptide macrocyclizations is the rational selection of couphg methods. Although the mixed anhy- dnde and active eater methods sometimes give good re- sults, macmlactamization using coupling q n t s is still of pra+cal importance. Among the comnrlnly used cou- p l i y reagents, HOAt-derived uronium/aminium salts, such as HAPyU , TAPipU and HTAU, have been shown

absence of polar C- and N-termini and 8 high p f ~ p d ~ n

n

61 TAPipU 52 DEPBT

Besides the two imprtant factors affecting the re-

nection and selection of couplq method, other factors such as soluti4 cancentration, base, additives, d o of substmtes, temperature and reaction time, also affect these mecrolactamizetion reactions. For complex target

r i q p , d e l reactions must be done to help to optimize reaction procedure and conditions, and predict cycliza-

sults of peptide ntecnJcyclizatim reactions, ring discon-

to be very efficient in terms of reaction speed and low

and immonium salts also demonstrate good pexfomance in peptide macrocyclization, but usually result in rela- tively high racemidon than the HOAt-derived aria-

logues, especially for the cycl&on of the peptide that do not con& tum-inducing units such as Gly, Fro, or N - a k y l amino acid residues. The active intermediates of the macrocyclizations using these HOBt- or HOAt- based anium salts a' the benzotriazolyl or 7-azabenzotri- mly l esters of the acid terminals. Using onium salts HAPyU or BDMP, we have achieved the macrocycliza- tion of the undecapeptide H-D-Ala-MeLeu-Mebu- MeVal-MeLeu-Nva-Sar-MeLu-Val-MeLeu-&-OH to givi immunosuppressive cyclic peptide Cyclosporin 0 in 84% and 68% yield, respectively. ?he cyclization of pentapeptide Leu-enkephalin was also realized by using HBP~U to give cycio-Leu-enkephalin in nearly guantita- tive yield.

Reagent DEF'BT demonstrates high efficiency in peptide coupling and macrocyclizatim . l6 Elicited by the good results of pentanuomphenyl ester method for cyclic peptide sytithesis, we designed and synthesized reagent

FDPP" and FDP (Scheme 8) . Reagent F'DW not only demonstrated high efficiency in oligopeptide and bioac- tive peptide synthesis, but also gave better results in peptide macrolactamizetion than other q e n t s , such as DPPA and DEPC.19 Reagent BOP-Cl was also pmved to be effective for peptide cyclization, especially when the N-terminal was hindered amiw acid residues."

racemizati~n extent. H O B t - , M u r ~ n i ~ m , p h ~ p h o n ' ~

53 FDP 54 FDPP

tion results.

The development of coupling magents has signifi- cantly pmnoted the efficient synthesis of peptide. Re-

provide better choice for the synthesis of coded peptide cently developed HOBt-hed Lnmoni~m type reagents

Vol. 18 No. 4 2000 Chine Joumal of chemistry 465

with low or neghgble racemization. For s ter idy hin- dered noNibosamal peptide synthesis, 2-halopyridinium

MT, should be the most prefemd candidates besides HOAt-bmed onium salb, especially for the prepadon of peptide on large scale. As for the macmlactamization

and BOP-Cl have been shown to be efficient to promote the mwrocyclization reactions. These guidelines my vtuy for the synthesis of different peptide sequence. be- muse many facton influence peptide chain elongations or cyclizations. These gemeral d e s may prwide usefui ref- erences during the rational selection of coupkng reagerrts for the efficient synthesis af peptide or peptidomimetics targets.

and 2-halothiaZoli~m salts, such BS BEP, FEP'md BE-

of peptide, HOAt-based oni~m dte, FDPP, DEPBT

References and notes

1.

2.

3. 4.

5 . 6. 7. 8. 9.

10.

11 ./

12.

13. 14. IS.

16.

CaetFO, B . ; Dmmoy, J . R . ; Evin, G . ; Sclve, C . , Te- tnzhedun h. , 1219(1975). C h , S.Q.; Xu, J . C . , T e t m h e d r o n h . , 33, 647

I i , P.; Xu, J . C . , T*b.,41, 72l(UXX)). Anders, E.; Kaht&y, A . R . ; Malboea, N . ; Stevum, J . , J . Org. (%ma., 57, 3698(1992). Ii, P.; Xu, J . C . , T - h . , 40, m(1999). Ii, P.; Xu, J . C . , J . Prp. Ra., 55, llO(2oOo). Ii, P.; Xu, J . C . , Gem: L&., 1163(1999). Ii, P.; Xu, J . C . , Gin. J . Gem., 18, 85(2oOo).

(1992).

cprp;nO, L . A . , J . Am. Own. Soc., 115.4397 (1993).

Albedcio, F. ; BaGu, J . M . ; a-Fabsm, A . i +, S. A . , J . Org. chsn., 63, %78(1998). catp;lo, L.A.; El-Fthm, A., J . Am. Chan. Soc.,

117, 5401(1995). V ~ d e r A u m r a , C . ; AnteMis, M.J .O. , Int. J . Pep. PtDteinRa., 29, 574(15%7). Ii, P.; Xu, J . C . , T- I!&. , 40, 8301(1999). Wenger, R.M., Hdu. Chim. Auu., 67, 502(1984). h, S.Q.; Xu, J . C . , Gin. chan. h., 4, 847

Ii, H.; Jiang, X.; Ye, Y.H.; Fan, C . X . ; Romoff, T.; Goodman, M., elpkktt., 1, 91(1999).

(1993).

466 Peptide coupling reagents L I & x u

17. then, S. Q.; Xu, J . C . , TeaPhcdron h., 32, 6711 19. Deng, J. G . ; Hamada, Y . ; Sbitiri, T. , TetmhedTon

18. C h , S . Q . ; Xu, J . C . , Chin. 1. Qlan., l3, 175 20. Iahiwata.H.;SMle,H.;Kigoshi,H.;Yamada,K., 1. (1991). La., 37, 2261(19%).

(1995). Org. Qlan., 59, 4712(1994).

Pmp LI w88 born in Hailin, China in 1972. He received his B.S . degree (1994) and M.S. (1997) at Dalian University dTedurology & the direction d M. Zuwwg Wu. As a Ph. D. candidate, He is cunently

shdying at Sangbai Institute of Organic chemistry (SICK), Chineae Acsdemy dSciences under the supervi- sion dRd. Jiecheng XU. His research intuarts are the deign and gntheas of novel peptide coupling rragents

a8 dl 88 the total +a of bidogidy active peptidea and peptidomimica. (E-mail: Lipeng@ pub. sioc . ac. cn)

M. JiecbesgXU pduntcdfnm the department dChemietry, Nanjing Univemity in 1955 and achieved hit^ greduate studies at the Shan&ai Institute of Orgamc cbemiatry, Chinese Academy dSciences in 1%2. He waa appointed aeeociate Roaeasor in 1977, Pmfeasor in 1986. He waa a viniting echoler at the Univdty dTexae at Austin for the period of19&0-1982. He engaged in the total synthesis Or Gystalline Bwine Insulin and waa the c+racipient d the National Natural Science A d . China in 1982. He received the Cathay Award in 1996, whichwaa epMsored by the H . H . Liu Education Foundaton, and the QiuShi Scientific and Technalogicsl Award in 1997. His research intercats focus b m d y on peptide chemishy, synthesis of biologically active pep tides, developing new peptide cmphng reagents, as well as the design and synthesis dpeptuhmbica. ( E - d : Xj&q@ pub. sioc. ac. cn)

(E9912181 SONG, J . P . ; DONG, L.J.)