A concise synthesis of photoactivatable 4-aroyl-L-phenylalanines

Article abstract of DOI:10.1016/S0960-894X(00)00344-9

An efficient preparation of the title compounds from 4-iodo-L-phenylalanines using a carbonylative Stille cross-coupling reaction as the key-step is described. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00344-9

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1815±1818
A Concise Synthesis of Photoactivatable
4-Aroyl-L-phenylalanines
Enrico Morera and Giorgio Ortar*
Dipartimento di Studi Farmaceutici e Centro di Studio per la Chimica del Farmaco del C.N.R.,
Á
Universita 'La Sapienza', 00185 Rome, Italy
Received 10 March 2000; revised 24 May 2000; accepted 15 June 2000
AbstractÐAn ecient preparation of the title compounds from 4-iodo-l-phenylalanines using a carbonylative Stille cross-coupling
reaction as the key-step is described. # 2000 Elsevier Science Ltd. All rights reserved.
The use of benzophenone (BP) photophores in biochem-
istry has increased considerably during the past 10 years,
owing to their advantages over previously employed diazo-
ester, azide, and diazirine probes.1 In particular, the devel-
opment of 4-benzoyl-l-phenylalanine (BPA, 1a),2 a BP-
containing amino acid, brought a signi®cant advance in
the application of photoanity labeling to the study of
peptide±protein interactions.
In recent years, a wide variety of structurally modi®ed
phenylalanine derivatives have been synthesized in
enantiopure forms exploiting transition metal-catalyzed
reactions.7 The introduction of an aroyl moiety in a
phenylalanine derivative by a palladium-catalyzed reac-
tion would provide a conceptually simple and straight-
forward approach to 4-aroylphenylalanines. We now
report on such a conversion which is based on a carbon-
ylative Stille reaction8 as well on the availability of 4-
iodo-l-phenylalanine derivatives such as 3a.7y1
The original report on BPA has involved a non-selective
preparation of the dl-form followed by an enzymatic
resolution.2 A similar strategy has been adopted also in
the preparation of tritiated BPAs.3 More recently, the
synthesis and the use of (RS)-4-(4-hydroxybenzoyl)phe-
nylalanine (rac-HBPA, 2), a photoreactive amino acid
also amenable to radioiodination, have been described.4
Eventually, enantioselective syntheses of S- and R-
enantiomers of HBPA (2a,b) and of (S)-Boc-N-methyl-
4-benzoylphenylalanine (1b) have been accomplished
using Schollkopf and Oppolzer chiral auxiliary reagents,
respectively.5,6
Aryl iodides can be carbonylatively coupled with organo-
stannanes to a€ord ketones, but the number of exam-
ples in the literature is limited, due to the versatility of
aryl tri¯ates in this strategy.8 Our attempt at coupling
the tyrosine tri¯ate derivative 3b7a,b with C6H5SnBu3
9
under conditions developed by Stille (CO, PdCl2/dppf,
LiCl, DMF)10 has proven, however, to be surprisingly
unsuccessful and 3b was recovered practically unchan-
ged after 24 h at 90 ꢀC. In contrast, the reaction of
iodide 3a with tributylphenyltin under atmospheric CO
*Corresponding author. Tel.:+39-6-49913612; fax:+39-6-491491; e-mail: giorgio.ortar@uniroma1.it
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00344-9

1816
E. Morera, G. Ortar / Bioorg. Med. Chem. Lett. 10 (2000) 1815±1818
Scheme 1.
Scheme 2.
pressure in the presence of PdCl2/2PPh3 proceeded
smoothly to give the 4-benzoyl derivative 3c in 88%
yield.11 Repetition of the procedure with 4-t-BuOCO
prepared in two di€erently protected forms (7a,b)
through standard solution phase techniques20 and sub-
jected to carbonylative cross-coupling reaction with
C6H5SnBu3. Smooth conversions to the BPA-containing
peptides 8a,b21 were accomplished in 96 and 88% iso-
lated yields, respectively (Scheme 2).
OC6H4SnBu3 a€orded 3d in 87% yield.13 Removal of
12
the ester group of 3c with NaOH/MeOH/H2O at room
temperature and complete deprotection of 3d (NaOH/
MeOH/H2O, rt, then TFA/CH2Cl2, rt) a€orded almost
quantitatively 1c and 2a, respectively, whose physical data,
in particular optical rotations, were in good agreement
with the values reported in literature.14 The carbonylative
coupling of 3a with phenylboronic acid C6H5B(OH)2
according to Suzuki (CO, PdCl2/2PPh3, K2CO3, dioxane,
80 ꢀC)15 was also explored but resulted in a lower yield of
3c (64%) and a longer reaction time (18 h).
References and Notes
1. (a) Kotzyba-Hibert, F.; Kapfer, I.; Goeldner, M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1296. (b) Dorman, G.; Pre-
stwich, G. D. Biochemistry 1994, 33, 5661.
2. Kauer, J. C.; Erickson-Viitanen, S.; Wolfe Jr., H. R.;
DeGrado, W. F. J. Biol. Chem. 1986, 261, 10695.
A number of interesting reports have already appeared
in the literature on synthetic work concerning covalent
linkages between aromatic side chains of two amino-
acids with the aim at investigating conformationally
restricted analogues of bioactive peptides.7y,16 On this
basis, a 4,40-bis(alanyl)benzophenone, which could act as
a photoactivatable bis(phenylalanine) analogue, has been
synthesized in the di€erentially protected form 617 in 80%
yield by carbonylative coupling between N-Fmoc-4-
iodo-l-phenylalanine benzyl ester (4)18 and N-Boc-4-
trimethylstannyl-l-phenylalanine methyl ester (5)7o
(Scheme 1).
3. Dorman, G.; Olszewski, J. D.; Prestwich, G. D.; Hong, Y.;
Ahern, D. G. J. Org. Chem. 1995, 60, 2292.
4. Wilson, C. J.; Husain, S. S.; Stimson, E. R.; Dangott, L. J.;
Miller, K. W.; Maggio, J. E. Biochemistry 1997, 36, 4542.
5. Fauq, A. H.; Ziani-Cherif, C.; Richelson, E. Tetrahedron:
Asymmetry 1998, 9, 2333.
6. Karoyan, P.; Sagan, S.; Clodic, G.; Lavielle, S.; Chassaing,
G. Bioorg. Med. Chem. Lett. 1998, 8, 1369.
7. (a) Yao, Z.-J.; Gao, Y.; Burke Jr., T. R. Tetrahedron:
Asymmetry 1999, 10, 3727. (b) Campbell, A. D.; Raynham, T.
M.; Taylor, R. J. K. Tetrahedron Lett. 1999, 40, 5263. (c)
Hudgens, T. L.; Turnbull, K. D. Tetrahedron Lett. 1999, 40,
2719. (d) Firooznia, F.; Gude, C.; Chan, K.; Marcopulos, N.;
Satoh, Y. Tetrahedron Lett. 1999, 40, 213. (e) Shakespeare, W.
C.; Bohacek, R. S.; Narula, S. S.; Azimioara, M. D.; Yuan, R.
W.; Dalgarno, D. C.; Madden, L.; Bot®eld, M. C.; Holt, D. A.
Bioorg. Med. Chem. Lett. 1999, 9, 3109. (f) Firooznia, F.;
Gude, C.; Chan, K.; Satoh, Y. Tetrahedron Lett. 1998, 39,
3985. (g) Ritzen, A.; Basu, B.; Wallberg, A.; Frejd, T. Tetra-
hedron: Asymmetry 1998, 9, 3491. (h) Ritzen, A.; Basu, B.;
Chattopadhyay, S. K.; Dossa, F.; Frejd, T. Tetrahedron:
Asymmetry 1998, 9, 503. (i) Morera, E.; Ortar, G.; Varani, A.
Synth. Commun. 1998, 28, 4279. (j) Malan, C.; Morin, C. J.
Org. Chem. 1998, 63, 8019. (k) Jackson, R. F. W.; Moore, R.
J.; Dexter, C. S. J. Org. Chem. 1998, 63, 7875. (l) Nakamura,
The presence of the BPA moiety in a peptide renders it
light-sensitive. Special precautions are therefore to be
taken during synthesis of BPA-containing probes and
dithioketal formation for temporary protection followed
by regeneration with Hg(OCOCF3)2 or AgNO3 has been
suggested.19 In this view, it would be advantageous to
introduce the benzoyl moiety at a late stage, i.e., into
the fully coupled peptide. To demonstrate the feasibility
of this approach, we have extended our methodology to
the model peptide Ala-4-I-Phe-Leu. The tripeptide was

E. Morera, G. Ortar / Bioorg. Med. Chem. Lett. 10 (2000) 1815±1818
1817
H.; Fujiwara, M.; Yamamoto, Y. J. Org. Chem. 1998, 63,
7529. (m) Ritzen, A.; Frejd, T. J. Chem. Soc., Perkin Trans. 1
1998, 3419. (n) Lai, J. H.; Marsilje, T. H.; Choi, S.; Nair, S.
A.; Hangauer, D. G. J. Peptide Res. 1998, 51, 271. (o) Morera,
E.; Ortar, G. Synlett 1997, 1403. (p) Satoh, Y.; Gude, C.;
Chan, K.; Firooznia, F. Tetrahedron Lett. 1997, 38, 7645. (q)
Dunn, M. J.; Jackson, R. F. W. Tetrahedron 1997, 53, 13905.
(r) Kayser, B.; Altman, J.; Beck, W. Tetrahedron 1997, 53,
2475. (s) Crisp, G. T.; Gore, J. Tetrahedron 1997, 53, 1523. (t)
Walker, M. A.; Kaplita, K. P.; Chen, T.; King, H. D. Synlett
1997, 169. (u) Fretz, H. Tetrahedron Lett. 1996, 37, 8475. (v)
Rajagopalan, S.; Radke, G.; Evans, M.; Tomich, J. M. Synth.
Commun. 1996, 27, 1431. (w) Christensen, J. W.; Peterson, M.
L.; Saneii, H. H.; Healy, E. T. In Peptides: Chemistry, Struc-
ture and Biology; Kaumaya, P. T. P., Hodges, R. S., Eds.;
May¯ower Scienti®c: Kingswinford, UK, 1996; pp 141±143.
(x) Sengupta, S.; Bhattacharyya, S. Tetrahedron Lett. 1995, 36,
4475. (y) Lei, H.; Stoakes, M. S.; Herath, K. P. B.; Lee, J.;
Schwabacher, A. W. J. Org. Chem. 1994, 59, 4206. (z) Burk,
M. J.; Lee, J. R.; Martinez J. P. J. Am. Chem. Soc. 1994, 116,
10847. (aa) Franz, R. G.; Weinstock, J.; Calvo, R. R.; Sama-
nen, J.; Aiyar, N. Org. Prep. Proced. Int. 1994, 26, 533. (ab)
Shieh, W.-C.; Carlson, J. A. J. Org. Chem. 1992, 57, 379. (ac)
Hartman, G. D.; Halczenko, W. Synth. Commun. 1991, 21,
2103. (ad) Tilley, J. W.; Sarabu, R.; Wagner, R.; Mulkerins,
K. J. Org. Chem. 1990, 55, 906. (ae) Jackson, R. F. W.;
Wythes, M. J.; Wood, A. Tetrahedron Lett. 1989, 43, 5941.
(af ) Petrakis, K. S.; Nagabhushan, T. L. J. Am. Chem. Soc.
1987, 109, 2831.
(300 MHz, CDCl3) d 1.35 (9H, s, t-Bu), 3.07 (1H, m, CHH),
3.25 (1H, m, CHH), 4.54 (1H, m, a-CH), 5.35 (1H, m, NH),
7.29±7.75 (9H, m, ArH), 8.05 (1H, br s, CO2H); 13C NMR d
28.25, 37.97, 54.85, 80.19, 128.16, 129.29, 129.88, 130.23,
132.31, 136.01, 137.42, 141.62, 155.56, 175.89, 196.40. 2a (TFA
salt): wax; [a]2D0 5 ꢀ (c 0.2, MeOH:H2O=3:1 by volume) [lit.5
[a]2D0 5.5 ꢀ (c 0.2, MeOH:H2O=3:1 by volume)]; IR (KBr)
3171, 1640, 1606, 1586, 1524, 1380, 1315, 1282, 1256,
1
1174 cm
;
1H NMR (300 MHz, disodium salt, D2O) d 2.92
(1H, dd, J=13.9, 7.5 Hz, CHH), 3.08 (1H, dd, J=13.9, 5.2 Hz,
CHH), 3.56 (1H, m, a-CH), 6.62, 7.70 (4H, ABq, J=8.8 Hz,
ArH), 7.38, 7.60 (4H, ABq, J=8.2 Hz, ArH); 13C NMR d
43.54, 60.07, 121.75, 124.66, 131.86, 132.34, 137.46, 139.60,
145.29, 177.87, 184.86, 201.39.
15. Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki, A.;
Miyaura, N. J. Org. Chem. 1998, 63, 4726.
16. Carlstrom, A.-S.; Frejd, T. J. Org. Chem. 1990, 55, 4175
and references therein.
17. 6: mp 159±161 ꢀC; [a]D20+27 ꢀ (c 2.0, CHCl3); IR (CHCl3)
3431, 1738, 1711, 1650, 1608, 1500, 1279, 1178 cm 1; 1H NMR
(300 MHz, CDCl3) d 1.42 (9H, s, t-Bu), 3.20 (4H, m, bb0-CH2),
3.74 (3H, s, CO2Me), 4.20 (1H, t, J=6.8 Hz, FmocCH), 4.41
(1H, dd, J=10.5, 6.8 Hz, FmocCHH), 4.48 (1H, dd, J=10.5,
6.8 Hz, FmocCHH), 4.65 (1H, m, a-CH), 4.76 (1H, m, a0-CH),
5.05 (1H, d, J=8.4 Hz, NH), 5.13, 5.21 (2H, ABq, J=11.9 Hz,
CH2Ph), 5.34 (1H, d, J=8.1 Hz, N0H) 7.06±7.77 (21H, m,
ArH); 13C NMR d 28.29, 38.21, 38.44, 47.21, 52.38, 54.26,
54.62, 66.96, 67.52, 80.19, 120.04, 124.99, 127.10, 127.78,
128.71, 128.75, 129.32, 130.29, 134.87, 136.35, 140.59, 141.12,
141.37, 143.68, 143.78, 155.03, 155.51, 171.02, 172.01, 195.75.
18. Obtained in 78% overall yield from 4-iodo-l-phenylala-
nine by N-protection with Fmoc-ONSu/Na2CO3/DMF±H2O,
rt followed by esteri®cation with BnBr/NaHCO3/Bu4NCl/
8. Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic
Reactions; Wiley: New York, 1997; Vol. 50, pp 36±42.
9. C6H5SnBu3 is commercially available from Sigma-Aldrich.
10. Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1988,
110, 1557.
CH2Cl2/H2O, rt. 4: mp 157±160 ꢀC; [a]D20 4 ꢀ (c 2.0, CHCl3);
1
11. A mixture of 3a (405 mg, 1 mmol), C6H5SnBu3 (404 mg,
1.1 mmol), PdCl2 (9 mg, 0.05 mmol), and PPh3 (26 mg,
0.10 mmol) in dry DMF (4 mL) was purged with carbon
monoxide for 5 min and then stirred under a CO balloon at
90 ꢀC for 5 h. The reaction mixture was then diluted with
AcOEt (100 mL) and stirred at room temperature with a satu-
rated aqueous KF solution (1 mL) for 30 min. The precipitate
was removed by ®ltration and the organic phase was washed
three times with water, dried (Na2SO4), and evaporated. The
residue (548 mg) was chromatographed on silica gel (17 g)
using hexane:AcOEt=8:2 as eluent to give 336 mg (88%) of
3c: oil; [a]2D0+51 ꢀ (c 2.0, CHCl3); IR (CHCl3) 3435, 1741,
1710, 1656, 1499, 1367, 1279, 1165 cm 1; 1H NMR (300 MHz,
CDCl3) d 1.42 (9H, s, t-Bu), 3.12 (1H, dd, J=13.8, 6.6 Hz,
CHH), 3.24 (1H, dd, J=13.8, 5.4 Hz, CHH), 3.73 (3H, s,
CO2Me), 4.65 (1H, m, a-CH), 5.15 (1H, d, J=7.8 Hz, NH),
7.25±7.79 (9H, m, ArH); 13C NMR d 28.24, 38.33, 52.29,
54.20, 79.95, 128.15, 129.18, 129.82, 130.21, 132.24, 136.15,
137.49, 141.08, 154.89, 171.85, 196.08.
IR (CHCl3) 3428, 1719, 1509, 1342, 1183 cm
;
1H NMR
(300 MHz, CDCl3) d 3.03 (2H, m, b-CH2), 4.19 (1H, t,
J=6.9 Hz, FmocCH), 4.33±4.49 (2H, m, FmocCH2), 4.67 (1H,
m, a-CH), 5.08, 5.18 (2H, ABq, J=12.0 Hz, CH2Ph), 5.28
(1H, m, NH), 6.68, 7.76 (4H, ABq, J=7.3 Hz, 4-I-ArH), 7.24±
7.56 (13H, m, ArH); 13C NMR d 37.72, 47.17, 54.53, 66.92,
67.44, 92.63, 120.03, 124.99, 127.09, 127.76, 128.71, 128.74,
131.34, 134.84, 135.18, 137.59, 141.35, 143.65, 143.81, 155.48,
171.01.
19. Breslav, M.; Becker, J.; Naider, F. Tetrahedron Lett. 1997,
38, 2219.
20. 7a: (a) N-Boc-4-I-Phe-OH, H-Leu-OMe.HCl, i-BuOCOCl,
NMM, CH2Cl2, rt; (b) SOCl2, MeOH, 45 ꢀC; (c) Ac-Ala-OH,
TEA, HOBt, EDC, DMF, rt, 78% overall yield; mp 248±250 ꢀC;
[a]2D0 52ꢀ (c 0.5, CHCl3); IR (CHCl3) 3425, 1740, 1659, 1504,
1371, 1277cm 1; 1H NMR (300 MHz, CDCl3:CD3OD=3:1 by
volume) d 0.92 (6H, t, J=6.8 Hz, CH(CH3)2), 1.26 (3H, d,
J=7.2 Hz, CHCH3), 1.60 (3H, m, CH2CH(CH3)2), 1.95 (3H, s,
CH3CONH), 2.91 (1H, dd, J=13.8, 7.9Hz, CHHAr), 3.10 (1H,
dd, J=13.8, 6.0 Hz, CHHAr), 3.71 (3H, s, CO2Me), 4.31 (1H,
m, a-CH Ala), 4.48 (1H, m, a-CH Leu), 4.59 (1H, m, a-CH 4-
I-Phe), 6.98, 7.59 (4H, ABq, J=8.2 Hz, ArH); 13C NMR d
17.57, 21.66, 22.49, 22.86, 24.95, 37.30, 40.80, 51.11, 52.43,
54.08, 92.20, 131.61, 136.47, 137.54, 164.42, 171.16, 171.55,
173.30. 7b: (a) N-Fmoc-4-I-Phe-OH, H-Leu-OtBu.HCl, i-Bu-
OCOCl, NMM, CH2Cl2, rt; (b) piperidine, DMF, rt; (c) N-Fmoc-
Ala-OH, i-BuOCOCl, NMM, CH2Cl2, rt, 75% overall
12. Obtained in 74% overall yield from 4-iodophenol by
sequential O-derivatization ((Boc)2O/pyridine/THF, rt) and
stannylation according to Azizian, H.; Eaborn, C.; Pidcock,
A. J. Organomet. Chem. 1981, 215, 49.
13. 3d: oil; [a]2D0+36 ꢀ (c 2.0, CHCl3); IR (CHCl3) 3438, 1754,
1
1710, 1657, 1601, 1501, 1370, 1274, 1147 cm
;
1H NMR
(300 MHz, CDCl3) d 1.42 (9H, s, BocNH), 1.58 (9H, s, BocO),
3.12 (1H, dd, J=13.5, 6.1 Hz, CHH), 3.23 (1H, dd, J=13.5,
5.7 Hz, CHH), 3.74 (3H, s, CO2Me), 4.64 (1H, m, a-CH), 5.07
(1H, d, J=8.1 Hz, NH), 7.24±7.84 (8H, m, ArH); 13C NMR d
27.65, 28.25, 38.36, 52.32, 54.18, 80.03, 84.10, 121.01, 129.24,
130.14, 131.42, 134.83, 136.08, 141.11, 151.06, 154.04, 154.87,
171.81, 194.90.
yield; mp 170±172 ꢀC; [a]D20 22ꢀ (c 1.0, CHCl3); IR (CHCl3)
1
3421, 1722, 1666, 1520, 1501, 1369, 1151 cm
;
1H NMR
(300 MHz, CDCl3) d 0.87 (6H, br s, CH(CH3)2), 1.32 (3H, d,
J=6.9 Hz, CHCH3), 1.44 (9H, s, t-Bu), 1.52 (3H, m,
CH2CH(CH3)2), 2.97 (1H, dd, J=13.8, 6.3 Hz, CHHAr), 3.05
(1H, dd, J=13.8, 6.5 Hz, CHHAr), 4.22 (2H, m, a-CH Ala
and FmocCH), 4.40 (3H, m, a-CH Leu and FmocCH2), 4.68
(1H, m, a-CH 4-I-Phe), 5.42 (1H, d, J=5.7 Hz, FmocNH),
14. 1c: mp 85±88 ꢀC; [a]D20+18.5 ꢀ (c 2.0, EtOH) [lit.2 mp 91±
92 ꢀC; [a]D20+18.5 ꢀ (c 1.03, EtOH)]; IR (CHCl3) 3435, 3281,
1703, 1657, 1607, 1497, 1367, 1279, 1164 cm
1
;
1H NMR

1818
E. Morera, G. Ortar / Bioorg. Med. Chem. Lett. 10 (2000) 1815±1818
6.47 and 6.72 (2H, m, amidic NHs), 6.92, 7.76 (4H, ABq,
J=8.0 Hz, 4-I-ArH), 7.26±7.60 (8H, m, FmocArH); 13C NMR
d 18.45, 22.11, 22.68, 24.85, 28.00, 37.58, 41.65, 47.13, 50.64,
51.57, 53.95, 67.21, 82.07, 92.51, 120.04, 125.07, 127.12,
127.78, 131.44, 135.88, 137.59, 141.35, 143.75, 156.01, 169.72,
171.54, 172.15.
53.96, 54.04, 128.31, 129.36, 129.98, 130.21, 132.56, 135.99,
137.46, 141.91, 170.71, 170.98, 172.91, 173.10, 196.97. 8b: mp
174±175 ꢀC; [a]D20 25ꢀ (c 1.0, CHCl3); IR (CHCl3) 3417, 1722,
1659, 1607, 1498, 1278, 1150 cm
1
;
1H NMR (300 MHz,
CDCl3) d 0.89 (6H, br s, CH(CH3)2), 1.34 (3H, d, J=6.3 Hz,
CHCH3), 1.43 (9H, s, t-Bu), 1.55 (3H, m, CH2CH(CH3)2),
3.12 (1H, dd, J=13.2, 6.0 Hz, CHHAr), 3.23 (1H, dd, J=13.2,
6.6 Hz, CHHAr), 4.18 (2H, m, a-CH Ala and FmocCH), 4.38
(3H, m, a-CH Leu and FmocCH2), 4.76 (1H, m, a-CH Bpa),
5.42 (1H, br s, FmocNH), 6.46 and 6.80 (2H, m, amidic NHs),
7.26±7.76 (17H, m, ArH); 13C NMR d 18.46, 22.10, 22.64,
24.85, 27.94, 38.02, 41.65, 47.09, 50.68, 51.57, 54.02, 67.16,
82.04, 119.99, 125.01, 127.08, 127.74, 128.23, 129.34, 129.94,
130.41, 132.31, 136.28, 137.60, 141.29, 143.73, 156.01, 169.66,
171.52, 172.18, 196.21.
21. 8a: mp 232±235 ꢀC; [a]D20 54ꢀ (c 0.5, CHCl3); IR (CHCl3)
1
3421, 1738, 1658, 1607, 1513, 1279 cm 1; H NMR (300MHz,
CDCl3:CD3OD=10:1 by volume) d 0.91 (6H, s, CH(CH3)2),
1.27 (3H, d, J=6.9Hz, CHCH3), 1.60 (3H, m, CH2CH(CH3)2),
1.94 (3H, s, CH3CONH), 3.06 (1H, dd, J=13.8, 8.4 Hz,
CHHAr), 3.28 (1H, dd, J=13.9, 5.8 Hz, CHHAr), 3.70 (3H, s,
CO2Me), 4.39 (1H, m, a-CH Ala), 4.52 (1H, m, a-CH Leu),
4.70 (1H, m, a-CH Bpa), 7.32±7.79 (9H, m, ArH); 13C NMR d
17.85, 21.70, 22.69, 22.76, 24.82, 37.66, 40.90, 50.92, 52.31,