Heterospirocyclic N-(2H-azirin-3-yl)-L-prolinates: New dipeptide synthons

Article abstract of DOI:10.1002/1522-2675(20001108)83:11<2961::AID-HLCA2961>3.0.CO;2-S

The synthesis of methyl N-(1-aza-6-oxaspiro[2.5]oct-1-en-2-yl)-L-prolinate (1e) has been performed by consecutive treatment of methyl N-[(tetrahydro-2H-pyran-4-yl)thiocarbonyl]-L-prolinate (5) with COCl₂, 1.4-diazabicyclo[2.2.2]octane (DABCO), and NaN₃ (Scheme 1). As the first example of a novel class of dipeptide synthons, 1e has been shown to undergo the expected reactions with carboxylic acids and thioacids (Scheme 2). The successful preparation of the nonapeptide 16, which is an analogue of the C-terminal nonapeptide of the antibiotic Trichovirin I IB, proved that 1e can be used in peptide synthesis as a dipeptide building block (Scheme 3). The structure of 7 has been established by X-ray crystal-structure analysis (Figs. 1 and 2).

Full text of DOI:10.1002/1522-2675(20001108)83:11<2961::AID-HLCA2961>3.0.CO;2-S

Helvetica Chimica Acta ± Vol. 83 (2000)
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Heterospirocyclic N-ꢀ2H-Azirin-3-yl)-l-prolinates:
New Dipeptide Synthons
by Giovanni Suter1), Svetlana A. Stoykova2), Anthony Linden, and Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
The synthesis of methyl N-(1-aza-6-oxaspiro[2.5]oct-1-en-2-yl)-l-prolinate (1e) has been performed by
consecutive treatment of methyl N-[(tetrahydro-2H-pyran-4-yl)thiocarbonyl]-l-prolinate (5) with COCl2, 1,4-
diazabicyclo[2.2.2]octane (DABCO), and NaN3 (Scheme 1). As the first example of a novel class of dipeptide
synthons, 1e has been shown to undergo the expected reactions with carboxylic acids and thioacids (Scheme 2).
The successful preparation of the nonapeptide 16, which is an analogue of the C-terminal nonapeptide of the
antibiotic Trichovirin I 1B, proved that 1e can be used in peptide synthesis as a dipeptide building block
(Scheme 3). The structure of 7 has been established by X-ray crystal-structure analysis (Figs. 1 and 2).
1. Introduction. ± Extensive studies on the use of 2H-azirin-3-amines (ˆ 3-amino-
2H-azirines) 1 proved them to be versatile synthons for a,a-disubstitued a-amino acids
(2,2-disubstituted glycines) in peptide synthesis [1 ± 8]. Thus, the reaction of peptide
acids with 1a and 1b leads to peptide amides with a backbone extended by a 2-
methylalanine (aminoisobutyric acid, Aib) and an (S)-2-methylphenylalanine
(Phe(Me)) moiety, respectively. After the selective acid-catalyzed hydrolysis of the
terminal amide bond, the extended peptide acid is obtained, which can then be used for
further ꢀazirine couplingꢁ or for segment condensation.
Some years ago, we designed methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate
(1c) as a synthon for the dipeptide unit Aib-Pro. This building block has been used to
1
)
)
Diploma thesis of G.S., Universität Zürich, 1999.
Part of the projected Ph.D. thesis of S.A.S., Universität Zürich.
2

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prepare segments of the peptaibol antibiotics Trichovirin I 1B and I 4A [9]3) and in the
synthesis of endothiopeptides with a C-terminal Aib-Pro unit [7]. Aminoazirines of
type 1d have been shown to be synthons for heterocyclic a-amino acids [12].
Incorporated in tripeptides of the type Z-Aib-Xaa-Aib-N(Ph)Me, Z-Phe-Xaa-Val-
OMe, and Asp-d-Ala-Xaa-OMe, they behave like Aib and some other a,a-
disubstituted a-amino acids that are known to stabilize secondary structures such as
b-turns and a or 310 helices (cf. [13 ± 15] and refs. cit. therein)4).
In the present paper, we report the synthesis of methyl N-(1-aza-6-oxaspiro[2.5]oct-
1-en-2-yl)-l-prolinate (1e), the first example of heterospirocyclic N-(2H-azirin-3-yl)-l-
prolinates, which are expected to be new dipeptide synthons. In this novel azirine
derivative, the structural elements of 1c and 1d are combined, and the question arose as
to whether or not this sterically congested compound can be of use in peptide synthesis.
2. Results and Discussion. ± The precursor for the preparation of 1e was the
thioamide 5 (Scheme 1). As the method of Villalgordo and Heimgartner [18], used by
Strässler for the synthesis of 1d [12], is limited to N-alkyl-N-phenyl amides, methyl N-
[(tetrahydro-2H-pyran-4-yl)carbonyl]-l-prolinate (4) was converted to 5 by thionation
with Lawesson reagent. In analogy to the procedure described in [9], consecutive
treatment of a solution of the latter in CH2Cl2 and catalytic amounts of DMF with
COCl2, evaporation of the solvent, dissolution of the residue in THF, addition of 1,4-
diazabicyclo[2.2.2]octane (DABCO), filtration, and reaction with NaN3 gave azirine 1e
in 74% yield as a yellow oil.
Scheme 1
3
)
)
For an alternative synthesis of Trichovirin I 4A, see [10][11].
Other 2,2-disubstituted glycines, e.g., 2,2-diethyl- and 2,2-dipropylglycine [16], as well as 2-butyl-2-
ethylglycine [17], prefer planar conformations of the peptide backbone.
4

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For the chemical characterization of 1e, the reaction with PhCOSHacid was
performed in CH2Cl2 at 08 ! room temperature. After chromatographic workup, the
N-benzoylated endothiodipeptide 6 was obtained in 79% yield (Scheme 2). The
analogous reaction of 1e with PhCOOHunder similar conditions proceeded more
slowly and with lower yield. After chromatography, dipeptide 7 was isolated in 28%
yield. Its structure was established by X-ray crystal-structure analysis (Figs. 1 and 2).
Scheme 2
The asymmetric unit in the structure of 7 contains one peptide and one H2O
molecule. The torsion angles f(C(3)ÀC(2)ÀN(1)ÀC(9)) and f(N(1)ÀC(2)ÀC(3)À
N(4)) of the tetrahydro-2H-pyran-4-yl (Thp) residue are 52.8(3) and 39.9(4)8,
respectively. They are close to the values expected for an amino acid in a b-turn of
type I or III. The Thp ring adopts a chair conformation, and the pyrrolidine ring of Pro
shows a half-chair conformation twisted on C(22)ÀC(23) (Fig. 1).
The amide NHforms an intermolecular H-bond with the C ˆO group that lies
between the six- and five-membered rings of a neighboring molecule (N(1) ´´´ O(3'):
3.115(3) Š, angle: 1538). This interaction links the molecules into infinite one-
dimensional chains that run parallel to the x-axis and have a graph set motif [20] of
C(5). The H2O molecule forms an intermolecular H-bond with each of two different
molecules of 7, thereby forming infinite one-dimensional chains of alternating peptide
and H2O molecules, which run parallel to the z-axis and have a graph set motif of
C22(10). The acceptor atoms are the amide O-atom (O(9)) and the Thp O-atom (O(18))
(O ´´´´ O distances in these H-bonds: 2.850(3) and 2.799(3) Š, resp., angles: 1548 each).
The combination of all H-bonding interactions links the peptide and H2O molecules
into infinite two-dimensional networks which lie in the xz-plane (Fig. 2).
With the aim of testing the utility of 1e as a dipeptide synthon (Thp-Pro) in peptide
synthesis, the reaction with Z-protected l-alanine (Z-Ala) was carried out in CH2Cl2.

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Fig. 1. ORTEP Plot [19] of the molecular structure of 7 (with 50% probability ellipsoids)
After the addition of Z-Ala-OHat 0 8, the mixture was stirred overnight at room
temperature. Chromatographic purification gave tripeptide Z-Ala-Thp-Pro-OMe (8a)
in 89% yield as a colorless foam (Scheme 2).
The strategy for the synthesis of the nonapeptide 16, which is an analogue of the C-
terminal nonapeptide of the antibiotic peptaibol Trichovirin I 1B (cf. [9][10]), is shown
in Scheme 3. Key steps in this synthesis are the reactions coupling Z-Val-OHand Z-
Leu-OHwith azirine 1e to give the tripeptides Z-Val-Thp-Pro-OMe (8b) and Z-Leu-
Thp-Pro-OMe (8c), respectively. After recrystallization, 8b was obtained in 71% yield
as pale yellow crystals, whereas 8c was purified by column chromatography (73%;
colorless foam). Saponification of 8b and 8c with LiOH´ H 2O in THF/MeOH/H2O
gave the tripeptide acids 9b and 9c in 93 and 77% yield, respectively.
Next, the Z-protected tripeptide 9b was reacted with 2,2,N-trimethyl-N-phenyl-2H-
azirin-3-amine (1a) to give Z-Val-Thp-Pro-Aib-N(Me)Ph (10; 71% yield). Depro-
tection of the NH2 group by catalytic hydrogenation yielded 11, which was coupled to
Z-Ser(tBu)-OHwith
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-
fluorophosphate (HATU) in MeCN to yield 82% of Z-Ser(tBu)-Val-Thp-Pro-Aib-
N(Me)Ph (12) as a pale yellow oil. Selective hydrolysis of the C-terminal amide group

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Fig. 2. Packing diagram of dipeptide 7
under the conditions described by Wipf [21] (3n HCl in THF/H2O 1:1, room
temperature) gave, after 1 h, the acid 13 in 81% yield, contaminated with 10 ± 15% of
the starting material 12.
The synthesis of the segment H-Leu-Thp-Pro-Leuol (15) was performed by
coupling 9c to Leuol with HATU/HOBt/Et3N in MeCN to give Z-Leu-Thp-Pro-Leuol
(14) in 81% yield, which then was deprotected by catalytic hydrogenation leading to 15
in 95% yield.
The two segments, pentapeptide 13 and tetrapeptide 15, were coupled by the
HATU/HOBt method in MeCN. The expected nonapeptide Z-Ser(tBu)-Val-Thp-Pro-
Leu-Thp-Pro-Leuol (16; Scheme 4) was obtained in 73% yield as a white foam. Based
on the 1H- and 13C-NMR spectra, there are two conformers present in CDCl3 solution.
It is worth mentioning that the acid-catalyzed hydrolysis of the pentapeptide amide
12 for 1 h gave the peptide acid 13 with the (tert-butoxy)-protected side chain of Ser in
high yield. When the hydrolysis was performed under the same conditions, but for 48 h,
Z-Ser-Val-Thp-Pro-Aib-OH( 13a) with deprotected Ser was obtained in 80% yield.
This product was coupled with 15 (HATU/HOBt) to give 16a in 71% yield (Scheme 5).

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Scheme 3
Scheme 4

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Scheme 5
In conclusion, the studies presented show that spirocyclic N-(2H-azirin-3-yl)pro-
linates of type 1e can be prepared according to previously reported protocols. It is
important to transform the N-acylated prolinate 4 into the corresponding thioamide 5
because of the low reactivity of 4 in the reaction with COCl2 (Scheme 1). In the
reactions with PhCOOH, PhCOSH, and N-protected a-amino acids, 1e behaves like
other 2H-azirin-3-amines (ˆ 3-amino-2H-azirines) that have been extensively used as
building blocks for a,a-disubstituted glycines in peptide synthesis. The novel amino-
azirine 1e has been shown to be a synthon for the dipeptide N-[(4-aminotetrahydro-
2H-pyran-4-yl)carbonyl]-l-proline (Thp-Pro). As a model, the nonapeptide Z-
Ser(tBu)-Val-Thp-Pro-Aib-Leu-Thp-Pro-Leuol (16) was prepared according to a
combination of the azirine/oxazolone method and segment coupling with HATU/
HOBt (Schemes 3 ± 5).
We thank the analytical units of our institute for spectra and analyses, and the Swiss National Science
Foundation, the Stiftung für wissenschaftliche Forschung an der Universität Zürich, and F. Hoffmann-La Roche
AG, Basel, for financial support.
Experimental Part
1. General. See [22]. M.p. determined on a Büchi 510 instrument; uncorrected. Unless otherwise stated, IR
spectra in KBr on a Perkin-Elmer 1600 Series FT-IR spectrometer, NMR spectra in CDCl3 on Bruker-ARX-300,
DRX-500, and AMX-600 spectrometers (1H: 300, 500, and 600 MHz; 13C: 75.5, 125.8, and 150.9 MHz).
Multiplicities of the C-atoms determined with DEPT technique. MS on a Finnigan MAT SSQ-700 (EI (70 eV),
CI with NH3) and Finnigan MAT TSQ-700 (ESI) instrument or a Hewlett-Packard HP-5971/HP-5890 Series II
(GC/MS) combination.
2. Synthesis of Methyl >S)-N->1-Aza-6-oxaspiro[2.5]oct-1-en-2-yl)prolinate (1e). 2.1. Methyl >S)-N-
[>Tetrahydro-2H-pyran-4-yl)carbonyl]prolinate (4). To cooled MeOH(17 ml) was slowly added SOCl
2
(3.7 ml) keeping the temp. below 08. Then, (S)-proline (5.42 mg, 47.0 mmol) was added, and the mixture was

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heated under reflux for 1 h. Excess MeOHwas evaporated, the sticky pale yellow residue was dissolved in
AcOEt (17 ml), Et3N (2.2 ml) and tetrahydro-2H-pyran-4-carbonyl chloride (3; 5.00 g, 33.6 mmol) [12] were
added at 08, and the mixture was heated to 558 for 2 h. After evaporation of AcOEt, the residue was dissolved in
CH2Cl2, the soln. was washed with sat. NaCl soln., dried (MgSO4), CH2Cl2 was evaporated, and the residue was
distilled (bulb-to-bulb, 1808/7 ´ 10À2 mbar): 7.24 g (89%) of 4. Pale yellow oil. IR (neat): 2955s, 2848m, 1745vs,
1642vs, 1435vs, 1387m, 1357s, 1311m, 1280m, 1240m, 1198s, 1175s, 1130s, 1088s, 1038w, 1015w, 985m, 959w, 915w,
886w, 820w, 779w. 1H-NMR (600 MHz, 2D): 4.48 (dd, J ˆ 8.5, 4.2, CH(a)(Pro)); 4.02 (dt, J ˆ 11.5, 3.0, 2 Heq of
CH2(2), CH2(6)(Thp)); 3.75 (s, MeO); 3.72 ± 3.68, 3.62 ± 3.57 (2m, CH2(d)(Pro)); 3.44 (td, J ˆ 11.6, 3.0, 2 Hax of
CH2(2), CH2(6)(Thp)); 2.69 ± 2.64 (m, CH(4)(Thp)); 2.22 ± 2.15 (m, 1 Hof CH 2(b)(Pro)); 2.13 ± 2.07 (m, 1 H of
CH2(g)(Pro)); 2.04 ± 1.97 (m, 1 H of CH 2(b), 1 Hof CH 2(g)(Pro)); 1.94 ± 1.83 (m, 2 Hax of CH2(3),
CH2(5)(Thp)); 1.72, 1.62 (2 br. d, J ˆ 13.6, 2 Heq of CH2(3), CH2(5)(Thp)). 13C-NMR (150.9 MHz): 173.1,
172.7 (2s, 2 CˆO); 67.1, 66.9 (2t, C(2), C(6)(Thp)); 58.6 (d, C(a)(Pro)); 52.0 (q, MeO); 46.6 (t, C(d)(Pro)); 39.5
(d, C(4)(Thp)); 28.9 (t, C(b)(Pro)); 28.4, 28.2 (2t, C(3), C(5)(Thp)); 24.8 (t, C(g)(Pro)). GC/MS: Retention
.
‡
time (tR) 11.9 min; 241 (M ), 223, 213, 198, 182, 171, 152, 138, 124, 113, 96, 85, 70, 55. Anal. calc. for C12H19NO4
(241.29): C 59.74, H7.94, N 5.80; found: C 59.60, H8.22, N 5.72.
2.2. Methyl >S)-N-[>Tetrahydro-2H-pyran-4-yl)thiocarbonyl]prolinate (5). To a soln. of 4 (6.00 g,
24.8 mmol) in abs. toluene (70 ml) was added Lawesson reagent (12.13 g, 30.0 mmol), and the mixture was
stirred unter reflux for 2 h. After cooling to r.t., the mixture was filtered (Celite), the solvent evaporated, and the
crude product was purified by chromatography (SiO2; hexane/AcOEt 1:1) and distillation (bulb-to-bulb, 1908/
7 ´ 10À2 mbar): 2.89 g (45%) of 5. Pale yellow solid. M.p. 94 ± 958. IR: 2958s, 2922m, 2878m, 2850m, 2768m,
2700w, 1739vs, 1476vs, 1450vs, 1394m, 1362m, 1322m, 1239s, 1081m, 1015m, 985m, 972m, 925m, 902m, 874m,
783s, 748w. 1H-NMR (300 MHz): 5.07 (dd, J ˆ 8.5, 8.2, CH(a)(Pro)); 4.04 (dt, J ˆ 11.5, 3.4, 2 Heq of CH2(2),
CH2(6)(Thp)); 3.96 ± 3.82 (m, CH2(d)(Pro)); 3.73 (s, MeO); 3.47 (td, J ˆ 11.7, 2.0, 2 Hax of CH2(2),
CH2(6)(Thp)); 2.93 (tt, J ˆ 11.3, 3.5, CH(4)(Thp)); 2.37 ± 1.98 (m, CH2(b)(Pro), CH2(g)(Pro), 2 Hax of
CH2(3), CH2(5)(Thp)); 1.72, 1.58 (2 br, d, J ˆ 13.5, 2 Heq of CH2(3), CH2(5)). 13C-NMR (75.5 MHz): 205.6
(s, CˆS); 170.9 (s, CˆO); 67.4, 67.2 (2t, C(2), C(6)(Thp)); 65.1 (d, C(a)(Pro)); 52.2 (q, MeO); 50.1
(t, C(d)(Pro)); 46.7 (d, C(4)(Thp)); 32.2, 31.9 (2t, C(3), C(5)(Thp)); 28.6 (t, C(b)(Pro)); 24.6 (t, C(g)(Pro)).
.
‡
GC/MS: tR 15.0 min; 257 (M ), 242, 224, 214, 200, 182, 168, 154, 128, 114, 99, 85, 70, 55. Anal. calc. for
C12H19NO3S (257.35): C 56.01, H7.44, N 5.44, S 12.46; found: C 56.07, H7.51, N 5.49, S 12.35.
2.3. Azirine 1e. In a dried two-neck round-bottom flask, a soln. of 5 (2.91 g, 12.2 mmol) in CH2Cl2 (15 ml)
and 3 drops of DMF was cooled to 08. After slow addition of 7.3 ml of a COCl2 soln. in toluene (2m, 14.6 mmol),
the mixture was stirred at r.t. for 15 min, and the solvent was evaporated. The residue was dissolved in THF
(30 ml), DABCO (1.64 g, 14.6 mmol) was added, and the mixture was stirred at r.t. for 40 min. The solid was
removed by filtration under Ar and washed with THF. To the pale yellow soln. was added NaN3 (2.38 g,
36.6 mmol), the mixture was stirred at r.t. overnight, filtered through a Celite pad, and the solvent was
evaporated. The residue was dissolved in AcOEt, the soln. was washed with sat. aq. NaHCO3 and NaCl soln., the
org. layer was dried (MgSO4) and evaporated. Purification by CC (SiO2; hexane/AcOEt 1:9) gave 1e: 2.16 g
(74%). Yellow oil. IR (neat): 3457w, 2955m, 2910m, 2849m, 2754w, 2696w, 2349w, 1773s, 1743s, 1688m, 1659m,
1565w, 1461m, 1437m, 1384m, 1349m, 1282s, 1235s, 1072m, 1029m, 1002m, 967. 1H-NMR (300 MHz): 4.42 ± 4.31
(br. s, CH (a)(Pro)); 3.99 ± 3.91 (m, 2 Hof CH 2(5), CH2(7)(Thp)); 3.74 (s, MeO); 3.72 ± 3.68 (m, 2 Hof CH 2(5),
CH2(7)); 3.67 ± 3.56 (m, CH2(d)(Pro)); 2.38 ± 2.02 (m, CH2(b), CH2(g)(Pro)); 1.91 ± 1.85, 1.78 ± 1.64 (m, 4 H of
CH2(4), CH2(8)). 13C-NMR (75.5 MHz): 164.7 (s, CˆO); 67.4 (t, C(5), C(7)); 52.4 (q, MeO); 36.0 (t, C(4),
C(8)); 30.2 (t, C(b)(Pro)); 23.9 (t, C(g)(Pro)); C(a) and C(d) of Pro could not be localized. GC/MS: tR
.
‡
11.6 min; 238 (M ), 207, 195, 179, 168, 149, 138, 128, 110, 96, 82, 70, 53.
3. Reactions of 1e with PhCOSH, PhCOOH, and Amino Acids. 3.1. General Procedure 1 (GP 1). To a soln.
of the acid (0.2 ± 0.3 mmol) in dry CH2Cl2 (5 ml) at 08, a soln. of ca. 0.9 mol-equiv. of 1e in CH2Cl2 (5 ml) was
added dropwise. The mixture was stirred at r.t. for 6 ± 16 h, the solvent was evaporated, and the residue was
purified by CC (SiO2; AcOEt).
3.2. Methyl >S)-N-{[4->Benzoylamino)tetrahydro-2H-pyran-4-yl]thiocarbonyl}prolinate (6). According to
GP 1, PhCOSH(32 mg, 0.231 mmol) and 1e (50 mg, 0.210 mmol), stirring for 14 h: 64 mg (79%) of 6. Pale
yellow solid. M.p. 185 ± 1878. IR: 3369m, 2955m, 2854m, 1741s, 1646s, 1601m, 1579w, 1522m, 1488m, 1423m,
1346m, 1283s, 1248s, 1206s, 1149s, 1105m, 1077m, 1002m, 931m, 884m, 805m, 765m, 717m, 662m. 1H-NMR
(300 MHz): 7.81 (d, J ˆ 7.4, 2 arom. H); 7.57 ± 7.44 (m, 3 arom. H); 6.65 (br. s, NH); 5.19 (br. d, J ˆ 6.6,
CH(a)(Pro)); 4.14 ± 3.93 (m, 2 Hof CH 2(2), CH2(6)(Thp)); 3.78 ± 3.61 (m, 5 H); 3.71 (s, MeO); 3.06 ± 2.95
(m, 1 H); 2.42 ± 1.94 (m, 6 H ). 13C-NMR (75.5 MHz): 203.5 (s, CˆS); 171.1 (s, OÀCˆO); 165.5 (s, PhCˆO);
133.5 (s, 1 arom. C); 132.0, 128.9, 126.9 (3d, 5 arom. CH); 68.6 (d, C(a)(Pro)); 64.2, 62.9 (2t, C(2), C(6)(Thp));

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61.6 (s, C(4)(Thp)); 52.4 (t, C(d)(Pro)); 52.1 (q, MeO); 35.9, 34.6, 27.4, 25.9 (4t, 4 CH2). CI-MS: 378 (19), 377
‡
(100, [M ‡ 1] ), 353 (17), 346 (12), 345 (62). Anal. calc. for C19H24N2O4S ´ 1/2 H2O (385.48): C 59.20, H6.28,
N 7.27, S 8.32; found: C 59.22, H6.46, N 7.21, S 8.09.
3.3. Methyl >S)-N-{[4->Benzoylamino)tetrahydro-2H-pyran-4-yl]carbonyl}prolinate (7). According to
GP 1, PhCOOH(29 mg, 0.231 mmol) and 1e (50 mg, 0.210 mmol), stirring for 14 h: 21 mg (28%) of 7.
Colorless solid. M.p. 198 ± 2008. IR: 3349m, 2958m, 2856m, 1748s, 1639m, 1617vs, 1579m, 1527m, 1489m, 1419m,
1360m, 1299m, 1252m, 1206s, 1163s, 1108m, 1081m, 940w, 848m, 806m, 779w, 720m, 666w. 1H-NMR (300 MHz):
7.81 ± 7.78 (m, 2 arom. H); 7.57 ± 7.46 (m, 3 arom. H); 6.43 (br. s, NH); 4.64 (br. s, CH a( )(Pro)); 4.14 ± 3.31
(m, 6 H); 3.72 (s, MeO); 2.71 ± 2.64 (m, 1 H); 2.30 ± 2.23 (m, 1 H); 2.12 ± 1.76 (m, 6 H ).13C-NMR (75.5 MHz):
173.1, 170.1 (2s, 2 CˆO); 165.8 (s, PhCˆO); 133.5 (s, 1 arom. C); 132.0, 128.8, 126.8 (3d, 5 arom. CH); 64.5, 62.9
(2t, C(2), C(6)(Thp)); 60.6 (d, C(a)(Pro)); 56.9 (s, C(4)(Thp)); 52.0 (q, MeO); 47.6, 33.0, 32.8, 27.5, 25.7 (5t,
‡
5 CH2). ESI-MS: 399 (100, [M ‡ K] ). Anal. calc. for C19H24N2O5 ´ H2O (360.41): C 60.30, H6.39, N 7.40; found:
C 60.20, H6.80, N 7.26.
Suitable crystals for the X-ray crystal-structure determination were grown from DMSO.
3.4. Methyl >S)-N->{4-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-1-oxopropyl)amino]tetrahydro-2H-pyran-
4-yl}carbonyl)prolinate (Z-Ala-Thp-Pro-OMe, 8a). According to GP 1, Z-Ala (66 mg, 0.294 mmol) and 1e
(70 mg, 0.294 mmol), stirring for 6 h: 121 mg (89%) of 8a. White foam. IR: 3341m, 3303m, 3063m, 2957m,
2878m, 2848m, 1719vs, 1685s, 1605s, 1541s, 1428m, 1394m, 1361m, 1298m, 1253m, 1218m, 1163m, 1143m, 1109m,
1026m, 988w, 840w, 782w, 738m, 697m. 1H-NMR (300 MHz): 7.36 ± 7.31 (m, 5 arom. H); 6.92 (br. s, NH(Thp));
5.57 (d, J ˆ 7.0, NH(Ala)); 5.13, 5.06 (AB, J ˆ 12.1, PhCH2); 4.55 ± 4.51 (m, CH (a)(Pro)); 4.28 ± 4.24
(m, CH (a)(Ala)); 3.91 ± 3.45 (m, CH2(2), CH2(6)(Thp), CH2(d)(Pro)); 3.69 (s, MeO); 2.46 ± 2.42 (m, 1 H of
CH2(3) or CH2(5)(Thp)); 2.10 ± 1.74 (m, 3 Hof CH 2(3) and CH2(5)(Thp), CH(b)(Val), CH2(b)(Pro),
CH2(g)(Pro)); 1.38 (d, J ˆ 7.1, Me(Ala)). 13C-NMR (75.5 MHz): 173.0 (s, MeOCˆO); 171.0, 169.9 (2s, 2 CˆO);
156.3 (s, PhCH2OCˆO); 136.0 (s, 1 arom. C); 128.5, 128.3, 128.0 (3d, 5 arom. CH); 67.1 (t, PhCH2); 64.1, 62.7
(2t, CH2(2), CH2(6)(Thp)); 60.5 (d, CH (a)(Pro)); 56.5 (s, C(4)(Thp)); 51.9 (q, MeO); 50.4 (d, CH (a)(Ala));
47.3 (t, CH2(d)(Pro)); 32.5, 32.2 (2t, CH2(3), CH2(5)(Thp)); 27.6 (t, CH2(b)(Pro)); 25.7 (t, CH2(g)(Pro)); 17.8
‡
(q, Me(Ala)). ESI-MS: 484 ([M ‡ Na] ). Anal. calc. for C23H31N3O7 ´ H2O (461.52): C 57.61, H6.52, N 8.76;
found: C 57.27, H6.60, N 8.62.
3.5. Methyl >S)-N->{4-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-3-methyl-1-oxobutyl)amino]tetrahydro-2H-
pyran-4-yl}carbonyl)prolinate (Z-Val-Thp-Pro-OMe, 8b). According to GP 1, Z-Val (1.340 g, 5.33 mmol), 1e
(1.155 g, 4.85 mmol), 100 ml of dry CH2Cl2, stirring for 16 h, purification by recrystallization from Et2O: 1.686 g
(71%). Pale yellow crystals. M.p. 189 ± 1928. IR: 3416m, 3284s, 3034m, 2961m, 2876m, 2843m, 1751s, 1716s,
1673s, 1619vs, 1542m, 1504m, 1420m, 1359m, 1285m, 1219s, 1110m, 1024m, 984w, 920w, 825w, 775m, 699m, 670m.
1H-NMR (600 MHz, 2D): 7.37 ± 7.30 (m, 5 arom. H); 6.55 (br. s, NH(Thp)); 5.49 (br. d, J ˆ 8.9, NH(Val)); 5.12,
5.06 (AB, J ˆ 12.1, PhCH2); 4.55 ± 4.51 (m, CH (a)(Pro)); 3.99 ± 3.97 (m, CH (a)(Val)); 3.96 ± 3.90, 3.78 ± 3.61
(2m, CH2(2), CH2(6)(Thp)); 3.71 (s, MeO); 3.59 ± 3.50, 3.46 ± 3.41 (2m, CH2(d)(Pro)); 2.53 (br. s, 1 Hof CH 2(3)
or CH2(5)(Thp)); 2.15 ± 2.10 (m, 1 Hof CH 2(3) or CH2(5)(Thp)); 2.13 ± 2.08 (m, CH (b)(Val)); 2.05 ± 1.97
(m, 1 Hof CH 2(b)(Pro)); 1.93 ± 1.82 (m, 2 Hof CH 2(3) and CH2(5)(Thp)); 1.88 ± 1.83 (m, 1 Hof CH 2(g)(Pro));
1.81 ± 1.76 (m, 1 Hof CH 2(b)(Pro)); 1.70 ± 1.64 (m, 1 Hof CH 2(g)(Pro)); 1.09 ± 1.06 (2d, J ˆ 6.8, 2 Me).
13C-NMR (150.9 MHz): 173.0 (s, MeOCˆO); 170.2, 169.7 (2s, 2 CˆO); 156.5 (s, PhCH2OCˆO); 136.0
(s, 1 arom. C); 128.5, 128.2, 127.8 (3d, 5 arom. CH); 67.0 (t, PhCH2); 64.4, 62.8 (2t, CH2(2), CH2(6)(Thp)); 60.4
(d, CH (a)(Val), CH(a)(Pro)); 56.7 (s, C(4)(Thp)); 51.9 (q, MeO); 47.3 (t, CH2(d)(Pro)); 32.7, 32.5 (2t, CH2(3),
CH2(5)(Thp)); 30.6 (d, CH (b)(Val)); 27.6 (t, CH2(b)(Pro)); 25.7 (t, CH2(g)(Pro)); 19.3, 18.0 (2q, 2 Me(Val)).
‡
ESI-MS: 512 (100, [M ‡ Na] ).
3.6. Methyl >S)-N->{4-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-4-methyl-1-oxopentyl)amino]tetrahydro-
2H-pyran-4-yl}carbonyl)prolinate (Z-Leu-Thp-Pro-OMe, 8c). According to GP 1, Z-Leu (0.91 g, 6.3 mmol),
1e (1.50 g, 6.9 mmol), 100 ml of dry CH2Cl2, stirring for 14 h: 2.31 g (73%) of 8c. White foam. IR: 3313m,
3035m, 2957m, 2871m, 2399w, 1745s, 1693s, 1664s, 1621s, 1536s, 1442m, 1409m, 1366m, 1244m, 1214m, 1162m,
1109m, 1043m, 843m, 781m, 740m, 698m, 613m. 1H-NMR (300 MHz): 7.39 ± 7.29 (m, 5 arom. H); 6.74, 5.38
(2 br., s, 2 NH); 5.13, 5.07 (AB, J ˆ 12.4, PhCH2); 4.55 ± 4.41 (m, CH (a)(Pro)); 4.21 ± 4.13 (m, CH (a)(Leu));
3.94 ± 3.41 (m, CH2(2), CH2(6)(Thp), CH2(d)(Pro)); 3.70 (s, MeO); 2.49 ± 1.46 (m, CH2(3), CH2(5)(Thp),
CH2(d)(Pro), CH2(g)(Pro), CH2(b)(Leu), CH(g)(Leu)); 0.94 (t, J ˆ 6.1, 2 Me(Leu)). 13C-NMR (75.5 MHz):
173.1 (s, MeOCˆO); 170.8, 169.8 (2s, 2 CˆO); 156.5 (s, PhCH2OCˆO); 135.9 (s, 1 arom. C); 128.5, 128.3, 128.0
(3d, 5 arom. CH); 67.2 (t, PhCH2); 64.2, 62.7 (2t, CH2(2), CH2(6)(Thp)); 60.4 (d, CH (a)(Pro)); 56.5
(s, C(4)(Thp)); 53.4 (d, CH (a)(Leu)); 51.9 (q, MeO); 47.3 (t, CH2(d)(Pro)); 40.4 (t, CH2(b)(Leu)); 32.5

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(t, CH2(3), CH2(5)(Thp)); 27.6 (t, CH2(b)(Pro)); 25.7 (t, CH2(g)(Pro)); 24.6 (d, CH (g)(Leu)); 22.7, 21.9 (2q,
‡
2 Me(Leu)). ESI-MS: 526 (100, [M ‡ Na] ).
4. Synthesis of the Nonapeptide Z-Ser>tBu)-Val-Thp-Pro-Aib-Leu-Thp-Pro-Leuol (16). 4.1. General
Procedures. General Procedure 2 (GP 2). To a soln. of the Z-protected peptide methyl ester in THF/MeOH/
H2O 3 :1:1 was added LiOH´ H 2O (4 mol-equiv.), and the mixture was stirred at r.t. After completion of the
reaction (TLC), 1m HCl was added until pH 1 was reached, and the org. solvent was evaporated. The residue
was extracted with CH2Cl2, the org. phases were dried (MgSO4), evaporated, and the residue was dried under
h.v.
General Procedure 3 (GP 3). To a soln. of 1.1 mol-equiv. of the Z-protected amino or peptide acid in MeCN
were added Et3N (3 equiv.), 1-hydroxy-1H-benzotriazole (HOBt, 1 equiv.), and O-(7-azabenzotriazol-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 1 equiv.). A soln. of the amino component (1 equiv.)
in MeCN was added dropwise, and the mixture was stirred at r.t. After completion of the reaction (TLC), the
solvent was evaporated, the residue dissolved in CH2Cl2, the soln. was washed with 1m HCl, sat. NaHCO3, and
NaCl soln., dried (MgSO4), evaporated, and purified by CC (SiO2).
General Procedure 4 (GP 4). The Z-protected peptide was dissolved in MeOH, Pd/C (10%) was added as a
catalyst, and the mixture was stirred under H2. The suspension was filtered through Celite, the filtrate was
evaporated, and the residue was dried under h.v.
4.2. >S)-N->{4-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-3-methyl-1-oxobutyl)amino]tetrahydro-2H-pyran-
4-yl}carbonyl)proline (Z-Val-Thp-Pro-OH, 9b). According to GP 2, 8b (1.500 g, 3.06 mmol), LiOH´ H 2O
(12.26 mmol), 1 h. After acidification and addition of CH2Cl2, 9b precipitated. The solid was filtered, washed
with cold H2O, and dried at 608 under h.v.: 1.361 (93%) of 9b. Colorless solid. M.p. 131 ± 1338. IR: 3455m, 2954m,
2848m, 2349w, 1773s, 1743s, 1688m, 1658m, 1565m, 1535w, 1437m, 1349m, 1298m, 1235m, 1172m, 1071m, 1029m,
‡
967m, 917w, 890w, 811m. ESI-MS: 498 (100, [M ‡ Na] ).
4.3. 2->{[>2S)-1->{4-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-3-methyl-1-oxobutyl)amino]tetrahydro-2H-
pyran-4-yl}carbonyl)pyrrolidin-2-yl]carbonyl}amino)-2,N-dimethyl-N-phenylpropanamide (Z-Val-Thp-Pro-
Aib-N(Me)Ph, 10). According to GP 1, 9b (889 mg, 1.87 mmol), 2,2,N-trimethyl-N-phenyl-2H-azirin-3-amine
(1a; 358 mg, 2.06 mmol), stirring for 24 h: 1.686 g (71%) of 10. Colorless foam. M.p. 81 ± 828. 1H-NMR
(600 MHz, 2D): 7.48 ± 7.30 (m, 10 arom. H, 2 NH); 5.81 (br. s, NH(Val)); 5.14, 5.08 (AB, J ˆ 12.1, PhCH2);
4.52 ± 4.46 (m, CH (a)(Pro)); 3.95 ± 3.89 (m, CH (a)(Val)); 3.79 ± 3.73 (m, 3 Hof CH 2(2), CH2(6)(Thp)); 3.59 ±
3.50, 3.46 ± 3.39 (2m, CH2(d)(Pro)); 3.44 ± 3.37 (m, 1 Hof CH (2) or CH2(6)(Thp)); 3.34 (s, MeN); 2.40 ± 2.33
2
(m, 1 H of CH 2(3) or CH2(5)(Thp)); 2.05 ± 2.02 (m, CH (b)(Val)); 2.00 ± 1.94 (m, 1 H of CH 2(3) or
CH2(5)(Thp)); 1.90 ± 1.84 (m, CH2(b)(Pro)); 1.81 ± 1.68 (m, 2 H of CH 2(3), CH2(5)(Thp)); 1.76 ± 1.64
(m, CH2(g)(Pro)); 1.53, 1.49 (2s, 2 Me(Aib)); 1.02 ± 0.90 (m, 2 Me(Val)). 13C-NMR (150.9 MHz): 173.7, 171.2,
170.8, 169.8 (4s, 4 CˆO); 156.6 (s, PhCH2OCˆO); 145.6, 136.0 (2s, 2 arom. C); 128.9, 128.5, 128.3, 128.0, 127.2,
126.8 (6d, 10 arom. CH); 67.2 (t, PhCH2); 63.7, 62.7 (2t, CH2(2), CH2(6)(Thp)); 61.9 (d, CH (a)(Pro)); 61.0
(d, CH (a)(Val)); 57.1 (s, C(a)(Aib)); 56.8 (s, C(4)(Thp)); 47.7 (t, CH2(d)(Pro)); 40.3 (q, MeN); 31.9 (t, CH2(3),
CH2(5)(Thp)); 29.6 (d, CH (b)(Val)); 27.8, 26.3 (2q, 2 Me(Aib)); 27.6 (t, CH2(b)(Pro)); 25.6 (t, CH2(g)(Pro));
‡
19.6, 18.2 (2q, 2 Me(Val)). ESI-MS: 672 (100, [M ‡ Na] ). Anal. calc. for C35H47N5O7 (649.79): C 64.70, H7.29,
N 10.78; found: C 64.33, H7.50, N 10.78.
4.4. 2->{[>2S)-1->{4-[>>2S)-2-Amino-3-methyl-1-oxobutyl)amino]tetrahydro-2H-pyran-4-yl}carbonyl)pyr-
rolidin-2-yl]carbonyl}amino)-2,N-dimethyl-N-phenylpropanamide (H-Val-Thp-Pro-Aib-N(Me)Ph, 11). Ac-
cording to GP 4, 10 (700 mg, 1.079 mmol), MeOH(25 ml), Pd/C (175 mg): 521 mg (94%) of 11. Colorless
foam. M.p. 138 ± 1448. 1H-NMR (300 MHz): 8.33, 7.54 (2 br. s, 2 NH); 7.41 ± 7.20 (m, 5 arom. H); 4.60 ± 4.56
(m, CH (a)(Pro)); 3.91 ± 3.87 (m, CH (a)(Val)); 3.83 ± 3.69 (m, 3 Hof CH 2(2), CH2(6)(Thp)); 3.65 ± 3.53
(m, CH2(d)(Pro)); 3.50 ± 3.43 (m, 1 Hof CH 2(2) or CH2(6)(Thp)); 3.35 (s, MeN); 3.27 (m, NH2); 2.55 ± 2.46
(m, 1 Hof CH 2(3) or CH2(5)(Thp)); 2.36 ± 2.31 (m, CH (b)(Val)); 2.13 ± 1.65 (m, 3 Hof CH 2(3), CH2(5)(Thp),
CH2(b)(Pro), CH2(g)(Pro)); 1.49 (br. s, 2 Me(Aib)); 1.00, 0.82 (2d, J ˆ 6.9, 2 Me(Val)). 13C-NMR (75.5 MHz):
173.7, 173.6, 170.8, 170.7 (4s, 4 CˆO); 145.8 (s, 1 arom. C); 128.6, 127.3, 126.6 (3d, 5 arom. CH); 63.9, 62.5 (2t,
CH2(2), CH2(6)(Thp)); 62.1 (d, CH (a)(Pro)); 59.5 (d, CH (a)(Val)); 57.2 (s, C(a)(Aib)); 56.1 (s, C(4)(Thp));
47.6 (t, CH2(d)(Pro)); 40.2 (q, MeN); 32.2, 32.0 (2t, CH2(3), CH2(5)(Thp)); 30.6 (d, CH (b)(Val)); 27.8
(t, CH2(b)(Pro)); 26.7, 25.7 (2q, 2 Me(Aib)); 25.6 (t, CH2(g)(Pro)); 19.5, 15.9 (2q, 2 Me(Val)). ESI-MS: 538
‡
(100, [M ‡ Na] ). Anal. calc. for C27H41N5O5 ´ H2O (515.66): C 60.77, H7.74, N 13.12; found: C 61.09, H8.06,
N 13.01.
4.5. 2-{[>>2S)-1-{[4->{>2S)-2-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-3->tert-butoxy)-1-oxopropyl)ami-
no]-3-methyl-1-oxobutyl}amino)tetrahydro-2H-pyran-4-yl]carbonyl}pyrrolidin-2-yl)carbonyl]amino}-2,N-di-
methyl-N-phenylpropanamide (Z-Ser(tBu)-Val-Thp-Pro-Aib-N(Me)Ph, 12). According to GP 2, 11 (350 mg,

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0.679 mmol), Z-Ser(tBu)-OH(221 mg, 0.747 mmol), Et 3N (0.35 ml, 2.45 mmol), HOBt (92 mg, 0.679 mmol),
HATU (259 mg, 0.679 mmol), MeCN (4 ml); CC (CH2Cl2/MeOH9 :1): 396 mg (82%) of 12. Pale yellow oil.
1H-NMR (600 MHz, 2D): 7.66 (br. s, NH); 7.38 ± 7.19 (m, 10 arom. H); 6.86, 5.76, 5.65 (3 br. s, 3 NH); 5.15, 5.06
(AB, J ˆ 12.2, PhCH2); 4.51 ± 4.47 (m, CH (a)(Pro)); 4.29 ± 4.25 (m, CH (a)(Ser)); 4.21 ± 4.14 (m, CH2(b)(Ser));
3.85 ± 3.80 (m, CH (a)(Val)); 3.80 ± 3.68 (m, CH2(2), CH2(6)(Thp)); 3.65 (s, MeN); 3.52 ± 3.40
(m, CH2(d)(Pro)); 2.49 ± 2.44 (m, 1 Hof CH 2(3) or CH2(5)(Thp)); 2.49 ± 2.46 (m, CH (b)(Val)); 2.02 ± 1.80
(m, 3 Hof CH 2(3), CH2(5)(Thp)); 1.90 ± 1.75 (m, CH2(b)(Pro)); 1.71 ± 1.67 (m, CH2(g)(Pro)); 1.49, 1.45 (2s,
2 Me(Aib)); 1.19 (s, (Me)3C); 0.97, 0.90 (2d, J ˆ 6.6, 2 Me(Val)). 13C-NMR (150.9 MHz): 173.7, 171.3, 171.0,
170.6, 170.4 (5s, 5 CˆO); 156.8 (s, PhCH2OCˆO); 145.8, 135.8 (2s, 2 arom. C); 128.9, 128.6, 128.4, 127.7, 127.2,
126.7 (6d, 10 arom. CH); 74.1 (s, (Me)3C); 67.2 (t, PhCH2); 63.8, 62.7 (2t, CH2(2), CH2(6)(Thp)); 62.0
(d, CH (a)(Pro)); 61.1 (d, CH (a)(Val)); 58.6 (d, CH (a)(Ser)); 57.1 (s, C(a)(Aib)); 56.9 (s, C(4)(Thp)); 56.0
(t, CH2(b)(Ser)); 47.8 (t, CH2(d)(Pro)); 40.2 (q, MeN); 31.7 (t, CH2(3), CH2(5)(Thp)); 29.3 (d, CH (b)(Val));
27.8 (t, CH2(b)(Pro)); 27.3 (q, Me3C); 26.5 (q, 2 Me(Aib)); 25.7 (t, CH2(g)(Pro)); 17.4, 17.2 (2q, 2 Me(Val)).
‡
ESI-MS: 815 (100, [M ‡ Na] ). Anal. calc. for C42H60N6O9 ´ H2O (792.98): C 62.20, H7.46, N 10.36; found:
C 61.91, H7.60, N 10.24.
4.6. 2-{[>>2S)-1-{[4->{>2S)-2-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-3->tert-butoxy)-1-oxopropyl)ami-
no]-3-methyl-1-oxobutyl}amino)tetrahydro-2H-pyran-4-yl]carbonyl}pyrrolidin-2-yl)carbonyl]amino}propanoic
Acid (Z-Ser(tBu)-Val-Thp-Pro-Aib-OH, 13). To a soln. of 12 (140 mg, 0.176 mmol) in THF (1 ml) at 08, 6m aq.
HCl (1 ml) was added, and the mixture was stirred at r.t. for 1 h. Then, 4m HCl (1 ml) was added, and the
mixture was extracted with CH2Cl2. The org. layer was dried (MgSO4) and filtered, the solvent was evaporated,
and the residue was dried under h.v.: 101 mg (81%) 13. White foam. 1H-NMR (300 MHz): 7.55 (br. s, NH );
7.29 ± 7.19 (m, 5 arom. H, NH); 5.74, 5.64 (2 br. s, 2 NH); 5.22 ± 5.06 (m, PhCH2); 4.45 (br. s, CH a( )(Pro));
4.23 ± 4.13 (m, CH (a)(Ser), CH2(b)(Ser)); 3.84 ± 3.49 (m, CH (a)(Val), CH2(2), CH2(6)(Thp), CH2(d)(Pro));
2.45 ± 2.32 (m, 1 Hof CH 2(3) or CH2(5)(Thp), CH(b)(Val)); 2.08 ± 1.63 (m, 3 Hof CH 2(3), CH2(5)(Thp),
CH2(b)(Pro), CH2(g)(Pro)); 1.48 (br. s, 2 Me(Aib)); 1.13 (s, Me3C); 1.01 ± 0.73 (m, 2 Me(Val)). ESI-MS: 726
‡
(100, [M ‡ Na] ).
4.7. >S)-N->{4-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-4-methyl-1-oxopentyl)amino]tetrahydro-2H-pyran-
4-yl}carbonyl)prolinate (Z-Leu-Thp-Pro-OH, 9c). According to GP 2, 8c (1.000 g, 1.98 mmol), LiOH´ H 2O
(334 mg, 7.94 mmol), 1 h: 747 mg (77%) of 9c. White foam. M.p. 90 ± 938. 1H-NMR (300 MHz): 7.58 (br. s, NH );
7.36 ± 7.29 (m, 5 arom. H); 6.07 (br. s, NH); 5.14 ± 5.02 (m, PhCH2); 4.52 ± 4.48 (m, CH (a)(Pro)); 4.28 ± 4.26
(m, CH (a)(Leu)); 3.90 ± 3.44 (m, CH2(2), CH2(6)(Thp), CH2(d)(Pro)); 2.25 ± 1.54 (m, CH2(3), CH2(5)(Thp),
CH2(b)(Pro), CH2(g)(Pro), CH2(b)(Leu), CH(g)(Leu)); 0.98 ± 0.86 (m, 2 Me(Leu)). 13C-NMR (75.5 MHz):
174.4, 172.3, 161.3 (3s, 3 CˆO); 156.7 (s, PhCH2OCˆO); 136.0 (s, 1 arom. C); 128.4, 128.2, 127.9 (3d,
5 arom. CH); 67.1 (t, PhCH2); 63.5, 63.1 (2t, CH2(2), CH2(6)(Thp)); 61.2 (d, CH (a)(Pro)); 56.5 (s, C(4)(Thp));
53.5 (d, CH (a)(Leu)); 47.8 (t, CH2(d)(Pro)); 40.4 (t, CH2(b)(Leu)); 32.0, 31.7 (2t, CH2(3), CH2(5)(Thp)); 27.3,
25.7 (2t, CH2(b)(Pro), CH2(g)(Pro)); 24.6 (d, CH (g)(Leu)); 22.7, 21.8 (2q, 2 Me(Leu)). ESI-MS: 512 (100,
‡
[M ‡ Na] ). Anal. calc. for C25H35N3O7 ´ 1/2H2O (489.57): C 60.22, H7.08, N 8.43; found: C 60.00, H7.40,
N 8.16.
4.8. >S)-N->{4-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-4-methyl-1-oxopentyl)amino]tetrahydro-2H-pyran-
4-yl}carbonyl)-N-[1->hydroxymethyl)-3-methylbutyl]prolinamide (Z-Leu-Thp-Pro-Leuol, 14). According to
GP 3, 9c (400 mg, 0.817 mmol), l-Leucinol (106 mg, 0.899 mmol), Et3N (0.35 ml, 2.45 mmol), HOBt (114 mg,
0.817 mmol), HATU (314 mg, 0.817 ml), MeCN (4 ml); CC (CH2Cl2/MeOH9 :1): 391 mg (81%) of 14. Pale
yellow oil. 1H-NMR (600 MHz, 2D): 7.56 (br. s, NH(Leuol)); 7.48 ± 7.28 (m, 5 arom. H); 6.99 (d, J ˆ 9.3,
NH(Leu)); 6.45 (br. s, NH(Thp)); 5.12, 5.06 (AB, J ˆ 12.3, PhCH2)); 4.32 ± 4.29 (m, CH (a)(Pro)); 4.15 ± 4.10
(m, CH (a)(Leu)); 4.14 ± 4.08 (m, CH (a)(Leuol)); 3.84 ± 3.79 (m, 1 Hof CH 2(2) or CH2(6)(Thp)); 3.77 ± 3.67
(m, 2 Hof CH 2(2) or CH2(6)(Thp)); 3.55 ± 3.45 (m, CH2OH); 3.53 ± 3.47 (m, 1 Hof CH 2(2) or CH2(6)(Thp));
3.51 ± 3.45, 3.40 ± 3.34 (2m, CH2(d)(Pro)); 2.46 ± 2.40 (m, 1 H of CH 2(3) or CH2(5)(Thp)); 2.27 ± 2.22
(m, CH (b)(Pro)); 1.90 ± 1.76 (m, 3 Hof CH 2(3), CH2(5)(Thp)); 1.87 ± 1.81 (m, 1 Hof CH 2(g)(Pro)); 1.72 ±
1.67 (m, CH (g)(Leuol)); 1.71 ± 1.65 (m, 1 Hof CH 2(g)(Pro)); 1.65 ± 1.58 (m, CH2(b)(Leu)); 1.56 ± 1.42
(m, CH (g)(Leu)); 1.42 ± 1.35, 1.16 ± 1.10 (2m, CH2(b)(Leuol)); 1.01 ± 0.85 (m, 2 Me(Leu), 2 Me(Leuol)).
13C-NMR (150.9 MHz): 173.2, 172.5, 171.9 (3s, 3 CˆO); 156.6 (s, PhCH2OCˆO); 136.4 (s, 1 arom. C); 128.4,
128.1, 127.9 (3d, 5 arom. CH); 67.0 (t, PhCH2); 65.4 (t, CH2OH); 64.1, 62.3 (2t, CH2(2), CH2(6)(Thp)); 63.8
(d, CH (a)(Pro)); 56.7 (s, C(4)(Thp)); 54.1 (d, CH (a)(Leu)); 49.9 (d, CH (a)(Leuol)); 48.4 (t, CH2(d)(Pro));
39.7 (t, CH2(b)(Leu)); 39.2 (t, CH2(b)(Leuol)); 31.9, 31.5 (2t, CH2(3), CH2(5)(Thp)); 28.8 (t, CH2(b)(Pro));
26.0 (t, CH2(g)(Pro)); 24.9 (d, CH (g)(Leu)); 24.79 (d, CH (g)(Leuol)); 23.1, 22.6 (2q, 2 Me(Leu)); 22.1, 21.7
(2q, 2 Me(Leuol)).

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4.9. >S)-N->{4-[>>2S)-2-Amino-4-methyl-1-oxopentyl)amino]tetrahydro-2H-pyran-4-yl}carbonyl)-N-[1-
>hydroxymethyl)-3-methylbutyl]prolinamide (H-Leu-Thp-Pro-Leuol, 15). According to GP 4, 14 (300 mg,
0.509 mmol), MeOH(15 ml), Pd/C (50 mg): 216 mg (95%) of 15. White foam. 1H-NMR (300 MHz): 8.41 (br. s,
NH(Thp)); 7.12 (d, J ˆ 9.1, NH(Leuol)); 4.39 ± 4.34 (m, CH (a)(Pro)); 4.06 ± 3.95 (m, CH (a)(Leu)); 3.84 ± 3.21
(m, CH (a)(Leuol), CH2(2), CH2(6)(Thp), CH2OH, CH2(d)(Pro)); 2.68 (br. s, NH2); 2.47 ± 2.38 (m, 1 H of
CH2(3) or CH2(5)(Thp)); 2.28 ± 2.22 (m, CH2(b)(Pro)); 1.93 ± 1.12 (m, 3 H of CH 2(3), CH2(5)(Thp),
CH2(g)(Pro), CH2(b)(Leuol), CH(g)(Leuol), CH2(b)(Leu), CH(g)(Leu)); 0.92 ± 0.80 (m, 2 Me(Leu), 2 Me-
(Leuol)). 13C-NMR (75.5 MHz): 175.4, 172.4, 171.8 (3s, 3 CˆO); 65.4 (t, CH2OH); 63.9, 62.3 (2t, CH2(2),
CH2(6)(Thp)); 63.7 (d, CH (a)(Pro)); 56.2 (s, C(4)(Thp)); 52.9 (d, CH (a)(Leu)); 49.9 (d, CH (a)(Leuol)); 48.4
(t, CH2(d)(Pro)); 43.7 (t, CH2(b)(Leu)); 39.1 (t, CH2(b)(Leuol)); 31.8 (t, CH2(3), CH2(5)(Thp)); 28.8
(d, CH2(b)(Pro)); 25.9 (t, CH2(g)(Pro)); 24.9, 24.7 (2d, CH (g)(Leu), CH2(g)(Leuol)); 23.2, 23.1, 22.1, 21.3
‡
(4q, 2 Me(Leu), 2 Me(Leuol)). ESI-MS: 455 (100, [M ‡ 1] ).
4.10. Z-Ser(tBu)-Val-Thp-Pro-Aib-Leu-Thp-Pro-Leuol (16). According to GP 3, 13 (78 mg, 0.110 mmol),
15 (50 mg, 0.110 mmol), Et3N (0.05 ml, 0.330 mmol), HOBt (16 mg, 0.121 mmol), HATU (38 mg, 0.121 mmol),
MeCN (2 ml); CC (AcOEt/MeOH9 :1): 92 mg (73%) of 16. Colorless foam. 1H-NMR (500 MHz, 2D): 7.96
(br. s, NH (Aib)); 7.64 (brs., NH (Thp)); 7.41 m( , NH(Val)); 7.38 ± 7.29 (m, 5 arom. H); 7.08 ± 7.02
(m, NH(Leuol)); 6.88 (d, J ˆ 8.9, NH(Leu)); 5.98 (br. s, NH(Thp)); 5.76 (d, J ˆ 3.9, NH(Ser)); 5.15, 5.04
(AB, J ˆ 12.4, PhCH2); 4.44 (t, J ˆ 7.5, CH(a)(Pro1)); 4.41 ± 4.32 (m, CH (a)(Leu)); 4.38 ± 4.30 (m, CH (a)-
(Val)); 4.33 ± 4.27 (m, CH (a)(Ser)); 4.26 ± 4.15 (m, CH (a)(Pro2)); 4.12 ± 4.03 (m, CH (a)(Leuol)); 4.11 ± 4.01
(m, 1 Hof CH 2(2) or CH2(6)(Thp)); 3.94 ± 3.86 (m, 1 Hof CH 2(d)(Pro2)); 3.93 ± 3.67 (m, 3 Hof CH 2(2),
CH2(6)(Thp)); 3.84 ± 3.79 (m, 1 H of CH 2(b)(Ser)); 3.78 ± 3.67 (m, 1 H of C H2OH); 3.72 ± 3.59
(m, CH2(d)(Pro1)); 3.67 ± 3.63 (m, 1 Hof CH 2(b)(Ser)); 3.63 ± 3.54 (m, 2 Hof CH 2(2) or CH2(6)(Thp));
3.58 ± 3.49 (m, 1 H of C H2OH); 3.55 ± 3.46 (m, 1 H of CH 2(d)(Pro2)); 2.61 ± 2.46 (m, 3 H of CH 2(3),
CH2(5)(Thp)); 2.40 ± 2.33 (m, CH (b)(Val)); 2.35 ± 2.22 (m, 1 Hof CH 2(b)(Pro2)); 2.34 ± 2.23 (m, 1 H of
CH2(b)(Pro1)); 2.18 ± 2.10 (m, 1 Hof CH 2(3) or CH2(5)(Thp)); 2.05 ± 1.79 (m, 3 Hof CH 2(3), CH2(5)(Thp));
2.03 ± 1.94 (m, 1 H of CH 2(g)(Pro2)); 1.89 ± 1.80 (m, 1 H of CH 2(g)(Pro1)); 1.84 ± 1.75 (m, 1 H of
CH2(b)(Pro1)); 1.80 ± 1.69 (m, 1 Hof CH 2(g)(Pro2)); 1.78 ± 1.67 (m, 1 Hof CH 2(g)(Pro1)); 1.78 ± 1.62
(m, CH2(b)(Leu)); 1.76 ± 1.62 (m, 1 Hof CH 2(b)(Pro2)); 1.73 ± 1.65 (m, CH (g)(Leu)); 1.66 ± 1.59 (m, 1 H of
CH2(3) or CH2(5)(Thp)); 1.66 ± 1.57 (m, CH (g)(Leuol)); 1.60 ± 1.49 (m, 1 Hof CH 2(b)(Leuol)); 1.47, 1.53 (2s,
2 Me(Aib)); 1.29 ± 1.20 (m, 1 H of CH 2(b)(Leuol)); 1.20, 1.19 (2s, Me3C, 2 conformers); 1.05 ± 0.95
(m, 2 Me(Leu)); 0.98 ± 0.93, 0.89 ± 0.83 (2m, 2 Me(Val)); 0.92 ± 0.85 (m, 2 Me(Leuol)). 13C-NMR (125.8 MHz,
2 conformers): 175.7, 175.6, 174.5, 174.4, 174.0, 173.9, 172.9, 172.6, 172.2, 171.9, 171.6 (11s, 8 CˆO); 157.6, 157.0
(2s, PhCH2OCˆO); 136.4, 136.1 (2s, 1 arom.. C); 129.2, 129.1, 129.0, 128.7, 128.1, 127.8 (6d, 5 arom. CH); 74.9,
74.5 (2s, Me3C); 67.9, 67.4 (2t, PhCH2); 65.1 (d, CH (a)(Pro2)); 64.9 (t, CH2(d)(Pro2)); 64.6, 64.3, 63.3, 63.1 (4t,
2 CH2(2), 2 CH2(6)(Thp)); 64.1 (d, CH (a)(Pro1)); 61.7 (t, CH2(d)(Pro1)); 61.4 (d, CH (b)(Ser)); 59.3
(d, CH (a)(Val)); 57.4 (s, C(a)(Aib)); 57.3, 57.2 (2s, 2 C(4)(Thp)); 56.6 (d, CH (a)(Ser)); 53.0, 52.9 (2d,
2 CH (a)(Leu)); 50.3 (d, CH (a)(Leuol)); 49.0 (t, CH2OH); 40.8 (t, CH2(b)(Leu)); 39.7 (t, CH2(b)(Leuol));
33.1, 32.2, 31.9, 31.7 (4t, 2 CH2(3), CH2(5)(Thp)); 29.8, 29.7 (2d, CH (b)(Val)); 29.5 (t, CH2(b)(Pro1)); 29.1
(t, CH2(b)(Pro2)); 27.8 (q, Me3C); 27.6, 23.6 (2q, 2 Me(Aib)); 26.7 (t, CH2(g)(Pro1)); 26.5 (t, CH2(g)(Pro2));
25.3 (d, CH (g)(Leuol)); 25.2 (d, CH (g)(Leu)); 23.4, 22.7 (2q, 2 Me(Leuol)); 21.0, 19.9 (2q, 2 Me(Leu)); 18.0,
‡
17.9 (2q, 2 Me(Val)). ESI-MS: 1163 (100, [M ‡ Na] ).
5. Synthesis of the Nonapeptide Z-Ser-Val-Thp-Pro-Aib-Leu-Thp-Pro-Leuol (16a). 5.1. 2-{[>>2S)-1-{[4-
>{>2S)-2-[>>2S)-2-{[>Benzyloxy)carbonyl]amino}-3-hydroxy-1-oxopropyl)amino]-3-methyl-1-oxobutyl}ami-
no)tetrahydro-2H-pyran-4-yl]carbonyl}pyrrolidin-2-yl)carbonyl]amino}propanoic Acid (Z-Ser-Val-Thp-Pro-
Aib-OH, 13a). To a soln. of 12 (195 mg, 0.301 mmol) in THF (1 ml) at 08 was added 6m aq. HCl (1 ml), and
the mixture was stirred at r.t. for 48 h. Then, 4m aq. HCl (1 ml) was added, the mixture was extracted with
CH2Cl2, the org. phase was dried (MgSO4), evaporated, and the residue was dried under h.v.: 127 mg (80%) of
13a. Colorless foam.
5.2. Z-Ser-Val-Thp-Pro-Aib-Leu-Thp-Pro-Leuol (16a). According to GP 3, 13a (85 mg, 0.131 mmol), 15
(50 mg, 0.110 mmol), Et3N (0.05 ml, 0.330 mmol), HOBt (16 mg, 0.121 mmol), HATU (38 mg, 0.121 mmol),
MeCN (2 ml); CC (AcOEt/MeOH9 :1): 85 mg (71%) of 16a. White foam. 1H-NMR (300 MHz): 8.17 ± 7.39
(br. s, 4 NH); 7.37 ± 7.12 (m, 5 arom. H, NH); 6.82 (br. s, NH); 5.80 (br. s, NH); 5.13, 5.02 (AB, J ˆ 12.6, PhCH2);
4.51 ± 4.47 (m, CH (a)(Pro1)); 4.44 ± 3.37 (m, CH (a)(Leu), CH(a)(Val), CH(a)(Ser), CH(a)(Pro2), CH(a)-
(Leuol), 2 CH2(2)(Thp), 2 CH2(6)(Thp), CH2(d)(Pro2), CH2(d)(Ser), CH2(d)(Pro1), CH2OH(Leuol), 3 H of
CH2(3), CH2(5)(Thp)); 2.42 ± 1.52 (m, CH (b)(Val), CH2(b)(Pro1), CH2(b)(Pro2), 5 Hof CH 2(3),
CH2(5)(Thp), CH2(g)(Pro1), CH2(g)(Pro2), CH2(b)(Leu), CH(g)(Leu), CH(g)(Leuol), 1 Hof

Helvetica Chimica Acta ± Vol. 83 (2000)
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CH2(b)(Leuol)); 1.46, 1.42 (2s, 2 Me(Aib)); 1.19 ± 1.09 (m, 1 Hof CH 2(b)(Leuol)); 0.95, 0.93 (2s, 2 Me(Leu));
‡
0.89 ± 0.77 (m, 2 Me(Val), 2 Me(Leuol)). ESI-MS: 1107 (100, [M ‡ Na] ).
6. Crystal-Structure Determination of 7 (see Table and Figs. 1 and 2)5). All measurements were made on a
Rigaku AFC5R diffractometer using graphite-monochromated MoKa radiation (l 0.71069 Š) and a 12-kW
rotating anode generator. The w/2q scan mode was employed for data collection.
The intensities were corrected for Lorentz and polarization effects, but not for absorption. Data collection
and refinement parameters are given in the Table, views of the molecule and the molecular packing are shown in
Figs. 1 and 2. The structure was solved by direct methods using SIR92 [23], which revealed the positions of all
non-H-atoms. The asymmetric unit contains one peptide and one H2O molecule. The enantiomer used in the
refinement was based on the known (S)-configuration of l-proline. The non-H-atoms were refined anisotropi-
cally. The H-atoms of the peptide molecule were fixed in geometrically calculated positions (d(CÀH) ˆ 0.95 Š),
while those of H2O were fixed in the positions indicated by a difference-electron-density map. Each H-atom was
assigned a fixed isotropic-displacement parameter with a value equal to 1.2Ueq of the atom to which it was
bonded. Refinement of the structure was carried out on F using full-matrix least-squares procedures, which
minimized the function Sw(j Fo jÀj Fc j )2. A correction for secondary extinction was applied. Neutral-atom-
scattering factors for non-H-atoms were taken from [24a] and the scattering factors for H-atoms from [25].
Anomalous dispersion effects were included in Fc [26]; the values for f ' and f '' were those of [24b], and the
values of the mass attenuation coefficients were those of [24c]. All calculations were performed using the teXsan
crystallographic software package [27].
Table. Crystallographic Data of Compound 7
Crystallized from
DMSO
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
C19H24N2O5 ´ H2O
378.42
colorless, irregular prism
0.40 Â 0.45 Â 0.46
173(1)
]
Crystal system
Space group
orthorhombic
P212121
Z
4
Reflections for cell determination
25
2q Range for cell determination [8]
37 ± 40
Unit-cell parameters a [Š]
11.628(3)
18.466(4)
8.956(3)
1923.1(7)
1.307
b [Š]
c [Š]
V [Š3]
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
2q(max) [8]
]
0.0974
55
Total reflections measured
Symmetry independent reflections
Reflections used [I > 2s(I)]
Parameters refined
2996
2879
2282
245
Final R
0.0433
0.0399
wR (w ˆ [s2(Fo) ‡ (0.005Fo)2]À1
)
Goodness of fit
Secondary extinction coefficient
Final Dmax/s
D1 (max; min) [e Š
1.958
5(1) Â 10À7
0.0001
À3
]
0.24; À0.29
5
)
Crystallographic data (excluding structure factors) for structure 7 reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-
145100. Copies of the data can be obtained, free of charge, on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: ‡44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).

2974
Helvetica Chimica Acta ± Vol. 83 (2000)
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Received July 5, 2000