Synthesis of endothiopeptides and their cyclization to 1,3-thiazol- 5(4H)-imines

Article abstract of DOI:10.1002/(SICI)1522-2675(19991110)82:11<1899::AID-HLCA1899>3.0.CO;2-M

Further investigations of the synthesis of endothio analogues of the segment 1-10 (8) of an apolar analogon of zervamicin IIA are described. The endothiodecapeptide Boc-Trp-Ile-Ala-Aib-Ile-Val-Aib-Leu-Aib-Ψ(CS)-Pro-OMe (10) has been prepared in good yield

Full text of DOI:10.1002/(SICI)1522-2675(19991110)82:11<1899::AID-HLCA1899>3.0.CO;2-M

Helvetica Chimica Acta ± Vol. 82 (1999)
1899
Synthesis of Endothiopeptides and Their Cyclization to 1,3-Thiazol-5(4H)-
imines
1
by Jürg Lehmann ) and Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
Further investigations of the synthesis of endothio analogues of the segment 1 ± 10 (8) of an apolar
analogon of zervamicin IIA are described. The endothiodecapeptide Boc-Trp-Ile-Ala-Aib-Ile-Val-Aib-Leu-
Aib-Y(CS)-Pro-OMe (10) has been prepared in good yield by our novel methodology. On the other hand, all
attempts to prepare endothio analogues of 8 with the thioamide group at position 3 (Alat) gave not the expected
linear endothiopeptides but led to epimerized 1,3-thiazol-5(4H)-imine derivatives as the main products. The
mixture of epimers of the thiazolimines 27, 30, and 31 have been separated by means of preparative HPLC, and
their structures have been established by 2D-NMR experiments.
Introduction. ± Peptides with backbone modifications have attracted considerable
interest in recent years [1]. Among them, endothiopeptides with one or more
thioamide groups replacing amide groups within the peptide chain play an important
role for several reasons (cf. refs. cited in [2 ± 4]). Endothiopeptides have hitherto been
prepared by the use of thionating reagents [5 ± 8] or via thioacylation [9 ± 16].
Unfortunately, most of these methods are accompanied by low yields or epimerization.
Other backbone-modified peptides of considerable interest are those containing a-
alkylated a-amino acids, e.g., a-aminoisobutyric acid (Aib) and isovaline (Iva).
Representatives are the naturally occurring peptaibols, which show antibiotic proper-
ties [17][18]. The twofold substitution at the C(a)-atom of these amino acids restricts
the conformational flexibility and stabilizes or induces helices (cf. [19 ± 24] and refs.
cited therein). With the ꢀazirine/oxazolone methodꢁ, we developed a convenient
synthetic access to such peptides, and 3-amino-2H-azirines proved to be useful synthons
for the introduction of a-alkylated a-amino acids (cf. [25 ± 28] and refs. cited therein).
Recently, we succeeded in combining these two types of backbone modifications by a
variation of the ꢀazirine/oxazolone methodꢁ [2 ± 4] (Scheme 1).
Reaction of a N-protected a-amino thio S-acid 1 with 2,2-dimethyl-3-(N-methyl-N-
phenylamino)-2H-azirine (2) yields a thiodipeptide amide of type 3. With ZnCl2 and
HCl in AcOH, 3 undergoes an unprecedented isomerization to give 4 without
epimerization (ca. 90% yield) [2]. The acid-catalyzed conversion of the endothiodi-
peptide 4 to 1,3-thiazol-5(4H)-one 5 and direct coupling with an amino compound 6
(e.g., a C-protected a-amino acid) leads to endothiopeptides of type 7 in satisfactory
yields without epimerization [3]. We have already demonstrated the usefulness of this
novel methodology by the synthesis of Boc-Trp-Ile-Ala-Aib-Ile-Val-Y(CS)-Aib-Leu-
1
)
Part of the Ph. D. thesis of J.L., Universität Zürich, 1998; present address: Department of Chemistry,
University of California at Berkeley, CA 94720 (USA).

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Helvetica Chimica Acta ± Vol. 82 (1999)
Scheme 1
CSA ˆ (Æ)-Camphor-10-sulfonic acid
Fig. 1. Apolar analogues of segment 1 ± 10 of Zervamicin IIA
Aib-Pro-OMe (9) [4], an endothio derivative of the apolar segment 1 ± 10 of the
zervamicin IIA-analogue 8 [29] (Fig. 1).
In the present work, we describe our further investigations in preparing other
endothio derivatives of 8. We intended to synthesize endothiodecapeptides 10 ± 12 to
show, on the one hand, the usefulness of our methodology and, on the other hand, to
solve their crystal structures, with the aim of further understanding the influence of the

Helvetica Chimica Acta ± Vol. 82 (1999)
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replacement of an amide group by a thioamide group with respect to the conformation
of the peptide.
Results and Discussion. ± The endothiodecapeptide 10 was prepared by coupling of
segment 1 ± 5 (13) with segment 6 ± 10 (14; Scheme 2).
Scheme 2
Segment 1 ± 5 (13) was synthesized by standard solution peptide methodology, by
which the Aib group was introduced via the ꢀazirine/oxazolone methodꢁ [2 ± 4], and
segment 6 ± 10 (18) was prepared as shown in Scheme 2: the N-protected amino acid
Boc-Leu-OH was transformed into the corresponding thioacid via reaction of its mixed
anhydride with H2S. The crude Boc-Leu-SH was then treated with the Aib-Pro synthon
methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (15) to afford the endothiotripep-
tide 16 in 71% yield, with respect to Boc-Leu-OH. The dipeptide Fmoc-Val-Aib-
N(Me)Ph (17) was prepared in quantitative yield by the reaction of Fmoc-Val-OH and
3-amino-2H-azirine 2. After the hydrolysis of 17 under the standard conditions of the
ꢀazirine/oxazolone methodꢁ (3m HCl, THF/H2O 1:1), Fmoc-Val-Aib-OH was coupled
with the terminal-N-deprotected 16 (2m HCl in THF/H2O 1:1) using 2-(1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as the cou-
pling reagent in the presence of 1-hydroxy-1H-benzotriazole (HOBt) and EtN(i-Pr)2,
leading to the endothiopentapeptide 18 in 93% yield, with respect to 16. Finally,
coupling of the pentapeptide 13 with the endothiopentapeptide 14, which was obtained
by treatment of 18 with Et2NH, with [(benzotriazol-1-yl)oxy]tris(pyrrolidino)phos-
phonium hexafluorophosphate (PyBOP) as the coupling reagent in the presence of
EtN(i-Pr)2, yielded the endothiodecapeptide 10 in 90% yield.

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Helvetica Chimica Acta ± Vol. 82 (1999)
The synthesis of the isomeric endothiodecapeptide 11, in which the amide group of
Ala is replaced by a thioamide group, was planned as depicted in Scheme 3.
Scheme 3
Segment 3 ± 5 (20), containing a N-terminal Fmoc protecting group, was synthe-
sized by our novel methodology, which has been described earlier [2][3]. Reaction of
Boc-Trp-OH and H-Ile-OMe with TBTU, in the presence of HOBt and EtN(i-Pr)2,
gave the corresponding dipeptide in 99% yield. Base-catalyzed hydrolysis led to 19, and
its coupling with 20 (TBTU, HOBt, and EtN(i-Pr)2) gave the endothiopentapeptide 21
in 71% yield. Segment 6 ± 10 (26) was prepared as shown in Scheme 3: treatment of Z-
Val-OH with the Aib synthon 2 yielded dipeptide 24 (94%). Hydrolysis of 24 under the
conditions of the ꢀazirine/oxazolone methodꢁ, followed by coupling of the crude
product with H-Leu-OMe, gave tripeptide 25 in 82% yield. Base-catalyzed hydrolysis
of 25 with LiOH, followed by the reaction with 3-amino-2H-azirine 15, led to
pentapeptide 26 in 92% yield, with respect to 24.
Unexpectedly, the coupling of peptide acid 22 with pentapeptide 23, which was
obtained via Pd-catalyzed hydrogenolytic cleavage of the Z protecting group of 26,
with PyBOP as the coupling reagent, did not lead to the endothiodecapeptide 11.
Rather, an epimeric mixture of 1,3-thiazol-5(4H)-imine derivative 27 was obtained in
76% yield (Scheme 4).

Helvetica Chimica Acta ± Vol. 82 (1999)
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Scheme 4
That the isolated product was the epimerized thiazolimine derivative 27 and not
the desired linear endothiodecapeptide 11 has been inferred from the following
‡
observations: i) The ESI-MS showed the [M ‡ Na] peak at m/z 1201, i.e., 18 mass units
below that of 11. ii) In the NMR spectra, peak doubling was observed, which did not
disappear at elevated temperature (1008), i.e., a mixture of conformers can be
excluded. Moreover, ROESY spectra showed no exchange of doubled peaks. iii)
Analytical HPLC showed two peaks in a ratio of 62 : 38, which were separated by
preparative HPLC. iv) The NMR spectra of the two separated substances display
following characteristics: in the 13C-NMR spectra, no peak at ca. 200 ppm, typical for
the linear endothiodecapeptide 11, could be detected. Furthermore, in the region of the
amide C-atoms, two singlets at too low and too high chemical shift, respectively, were
observed: the singlet at 165.1 ppm of the main epimer showed a long-range coupling
with the H-atoms at C(a) and C(b) of Ala, and the singlet at 179.5 ppm with the H-
1
atoms of Aib(2). In the H-NMR spectra, the signal of H-C(a) (Ile(2)) at 3.28 ppm
appears as a sharp singlet and, in addition, only eight NH groups could be evidenced. v)
That a mixture of epimers of 27 has been formed and not, as also conceivable, a mixture
of (Z)/(E)-isomers around the double bond between C(5) of the thiazole ring, and the
N-atom of the imine group, is supported by the following experiment: after separating
the two peaks by means of preparative reversed-phase HPLC, an aliquot of the

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Helvetica Chimica Acta ± Vol. 82 (1999)
evaporated fractions of the main peak was dissolved in MeCN, and (Æ)-camphor-10-
sulfonic acid (CSA) was added. Even after only a few minutes, the second isomer could
be detected again by means of analytical HPLC. After 1 h, both peaks were present in a
50 : 50 ratio. From this result, we concluded that the major compound of the original
epimeric mixture (62%) has the (S)-configuration at C(a) of Ala; under acid catalysis
the (S)/(R) ratio settled down to 50 : 50. vi) There is no prove whether the (Z) or the
(E)-configured imino group has been formed. However, as a result of the steric
interactions with the geminal Me groups at C(4) of the thiazole ring, it can be assumed
that the (Z)-configuration is preferred, as shown for simpler but comparable 1,3-thiazol-
5(4H)-imines (cf. [30][31]).
The preparation of the endothiopeptide 12, in which two different amide groups are
replaced by thioamide groups, was attempted according to Scheme 5: coupling of the
two endothiopeptides 22 and 28 was expected to give the endothiooctapeptide 29,
which, after C-terminal deprotection and treatment with the Aib-Pro synthon 15,
should lead to 12.
Scheme 5
The synthesis of segment 6 ± 8 (28) has already been published [4]. In a first
attempt, 22 and 28 were coupled using TBTU, HOBt, and EtN(i-Pr)2. After the usual
workup, the crude product could not be dissolved anymore and, therefore, could not be
purified and analyzed. Thus, the crude product was directly hydrolyzed (LiOH) and
treated with the Aib-Pro synthon 15. Again, we did not obtain the expected linear 12
but a mixture of epimers of the 1,3-thiazol-5(4H)-imine 30 (Fig. 2) in 48% yield with
Fig. 2. 1,3-Thiazol-5(4H)-imine 30 of the endodithiodecapeptide 12

Helvetica Chimica Acta ± Vol. 82 (1999)
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respect to Boc-Trp-Ile-Ala-Y(CS)-Aib-Ile-OMe (21). The two epimers were detected
in a ratio of 55 :45 (HPLC) and could be separated by preparative HPLC. In analogy to
the case of 27, it can be assumed that the major epimer, which has been formed in more
than 50% yield, contains Ala with the (S)-configuration.
In a second experiment, 22 and 28 were coupled with PyBOP as the coupling
reagent in the presence of EtN(i-Pr)2 (Scheme 6). After the usual workup, no solubility
problems arose, in contrast to the first attempt. A mixture of epimers of the 1,3-thiazol-
5(4H)-imine 31 was isolated in 60% yield with a (S)/(R) ratio of 66 :34. In addition, a
third product, presumably the desired linear endothiooctapeptide 29, was obtained in
14% yield2).
Scheme 6
A plausible mechanism for the formation of the thiazolimines 27, 30, and 31 is
shown in Scheme 7: nucleophilic attack of the S-atom of the thioamide group in A at the
C-atom of the neighboring amide group leads to the zwitterionic heterocycle B, which
yields the thiazolimine D after elimination of H2O.
To clarify whether the cyclization to the thiazolimines occurred after the formation
of the linear endothiopeptide, a solution of 29 in MeCN was stirred at 408 for several
‡
2
)
The structure of this product has not yet been established. The ESI-MS shows the [M ‡ Na] peak at m/z
1053, in accordance with structure 29.

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Helvetica Chimica Acta ± Vol. 82 (1999)
Scheme 7
days, but no thiazolimine could be detected by HPLC. Then, the coupling reagent
PyBOP was added to the solution. Surprisingly, after stirring for several days, even
under these conditions no cyclization occurred. Thus, it can be concluded that
thiazolimine formation must take place before or during the coupling of the two
segments. It is conceivable that, during the coupling, a conformation of the
endothiopeptide is formed that favors cyclization according to Scheme 7.
In conclusion, we described further attempts to synthesize endothio derivatives of
the segment 1 ± 10 of the apolar zervamicin IIA analogue 8. Surprisingly, in the two
cases with Alat, we obtained not the expected linear endothiopeptides, but a mixture of
epimers of thiazolimine derivatives. In our future work, we will try to answer several
questions in connection with this cyclization, e.g., which structure elements are
required for the thiazolimine formation, and is there a possibility to prevent this
cyclization or the epimerization of the thiazolimine derivatives.
We thank Dr. G. Hopp-Rentsch, Mrs. N. Walch, and Mr. M. Binder for NMR spectra, Mr. N. Bild and Dr. L.
Bigler for mass spectra, and Mrs. J. Kessler for elemental analyses. Financial support of this work by the Swiss
National Science Foundation and F. Hoffmann-La Roche AG, Basel, is gratefully acknowledged.
Experimental Part
1. General. See [2].
General Procedure 1 (GP 1). To a soln. of 1 equiv. of N-protected amino acid or N-protected peptide,
2 equiv. (3 equiv., when the hydrochloride of the terminal-C-protected amino acid was used) of EtN(i-Pr)2,
1 equiv. of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), and 1 equiv. of 1-
hydroxy-1H-benzotriazol (HOBt) in MeCN, 1.1 equiv. of terminal-C-protected amino acid or peptide was
added. The mixture was stirred at r.t., until the starting material was consumed (TLC). Then, the soln. was
diluted with CH2Cl2 and extracted 3 Â with 5% NaHCO3 and KHSO4 soln. The combined aq. phase was washed
with Et2O, and the combined org. phase dried (MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by chromatography (SiO2) or recrystallization.
General Procedure 2 (GP 2). To a soln. of 1 equiv. of N-protected amino acid or N-protected peptide,
1.1 equiv. of terminal-C-protected amino acid or peptide, and 1 equiv. of [1H-benzotriazol-1-yl)oxy]tris-

Helvetica Chimica Acta ± Vol. 82 (1999)
1907
(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) in CH2Cl2, 2 equiv. of EtN(i-Pr)2 (3 equiv., when the
hydrochloride of the terminal-C-protected amino acid was used) were added. The mixture was stirred at r.t. until
the starting material was consumed (TLC). Then, the soln. was diluted with CH2Cl2 and extracted 3 Â with 5%
NaHCO3 and KHSO4 soln. The combined aq. phase was washed with CH2Cl2 and the combined org. phase dried
(MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography (SiO2).
General Procedure 3 (GP 3). To a soln. of 1 equiv. of N-protected amino acid or N-protected peptide in
CH2Cl2, 1 equiv. of 2,2-dimethyl-3-(N-methyl-N-phenylamino)-2H-azirine (2) or methyl N-(2,2-dimethyl-2H-
azirin-3-yl)-l-prolinate (15) was added slowly. The soln. was allowed to reach r.t. and stirred until the starting
material was consumed (TLC). The mixture was washed with KHSO4 soln., the org. phase was dried (MgSO4),
filtered, and evaporated. The crude product was purified by chromatography (SiO2) or recrystallization.
General Procedure 4 (GP 4). To a soln. of 1 equiv. of terminal-C- and terminal-N-protected peptide in
THF/MeOH/H2O 3 :1:1, 2 ± 5 equiv. of LiOH ´ H2O were added, and the mixture was stirred at r.t. until the
starting material was consumed. The mixture was diluted with CH2Cl2 and washed with 5% KHSO4 soln. The
combined org. phase was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was dried
under high vacuum and used in the next reaction without further purification.
General Procedure 5 (GP 5). A soln. of 1 equiv. of peptide anilide in 3m HCl (THF/H2O 1 :1) was stirred at
r.t. until the starting material was consumed. Then, the mixture was diluted with H2O and extracted 3 Â with
CH2Cl2. The combined org. phase was dried (MgSO4), filtered, and evaporated. The crude product was dried
under high vacuum and used in the next reaction without further purification.
2. Methyl (2S)-1-{2-[(2S)-2-(2-{(2S)-2-[(2S,3S)-2-(2-{(2S)-2-[(2S,3S)-2-((2S)-{[(tert-Butoxy)carbonyl]ami-
no}-3-(indol-3-yl)propanamido)-3-methylpentanamido]propanamido}-2-methylpropanamido)-3-methylpentan-
amido]-3-methylbutanamido}-2-methylpropanamido)-4-methylpentanamido]-2-methylthiopropanoyl}pyrrolidine-
2-carboxylate (Boc-Trp-Ile-Ala-Aib-Ile-Val-Aib-Leu-Aib-Y(CS)-Pro-OMe; 10). (9H-Fluoren-9-yl)methyl
1-{(2S)-2-Methyl-1-[({1,1-dimethyl-2-[methyl(phenyl)amino]-2-oxoethyl}amino)carbonyl]propyl}carbamate
(Fmoc-Val-Aib-N(Me)Ph; 17). According to the GP 3 with Fmoc-Val (1.022 g, 3.012 mmol), CH2Cl2 (25 ml),
and 2 (0.528 g, 3.029 mmol); reaction time: 3 d. Chromatography (SiO2; AcOEt/hexane 1:1) gave 1.560 g
(100%) of 17 as a colorless, viscous oil, which solidified slowly. [a]D
ˆ
9.9 (c ˆ 1.06). IR: 3430m, 3355m,
3070m, 3010m, 2965m, 1875w, 1720s, 1680s, 1630s, 1595s, 1495s, 1455s, 1390m, 1370m, 1320m, 1270m, 1250m,
1
1170m, 1130m, 1025m, 860w. H-NMR (300 MHz): 7.77 ± 7.17 (m, 13 arom. H); 6.59 (s, NH); 5.52 (d, J ˆ 8.6,
NH); 4.45 ± 4.38 (m, CHCH2O); 4.24 (t, J ˆ 7.0, CHCH2O); 3.80 ± 3.78 (m, H C(a) (Val)); 3.26 (s, MeN); 1.49,
1.43 (2s, 2 Me (Aib)); 0.93 ± 0.87 (m, 2 Me (Val)). 13C-NMR (75.5 MHz): 173.0, 169.4 (2s, 2 CO); 156.1
(s, urethane-CO); 144.0, 143.8, 141.2, 129.4, 128.1, 127.6, 127.0, 125.0, 119.9 (18 arom. C); 66.8 (t, CHCH2O);
59.9 (d, C(a) (Val)); 58.5 (s, C(a) (Aib)); 47.1 (d, CHCH2O); 41.4 (q, MeN); 31.7 (d, C(b) (Val)); 25.9, 25.5
‡
(2q, 2 Me (Aib)); 19.0, 17.5 (2q, 2 Me (Val)). ESI-MS: 536 ([M ‡ Na] ). Anal. calc. for C31H35N3O4 (513.63):
C 72.49, H 6.87, N 8.18; found: C 72.20, H 6.87, N 7.70.
Methyl (2S)-1-{2-[(2S)-2-{[(tert-Butoxy)carbonyl]amino}-4-methylpentanamido]-2-methylthiopropanoyl}-
pyrrolidine-2-carboxylate (Boc-Leu-Aib-Y(CS)-Pro-OMe; 16). A soln. of Boc-Leu (3.088 g, 12.386 mmol) in
THF (25 ml) was cooled to 108 in an ice/salt bath. Then, N-methylmorpholine (NMM; 2.52 g, 24.91 mmol)
was added, followed by isobutyl carbonochloridate (1.697 g, 12.425 mmol). The mixture was stirred for 10 min,
then a slow stream of H2S was bubbled through the soln. for 1 h, and the resulting suspension was stirred for
another 2 h at 108. The mixture was diluted with Et2O and washed with 0.1m H3PO4 soln. The org. phase was
dried (MgSO4), filtered, and evaporated. The crude Boc-Leu-SH (0.102 g, ca. 0.412 mmol) was treated at 08
with 15, dissolved in CH2Cl2 (2.5 ml). The mixture was allowed to reach r.t., was stirred for 75 min, diluted with
CH2Cl2, and extracted with 5% KHSO4 soln. The combined aq. phase was washed with CH2Cl2, the combined
org. phase was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; AcOEt/hexane 1 : 3) gave 16
(0.121 g, 71%) as a colorless, thick oil, which solidified slowly. [a]D
ˆ
110.0 (c ˆ 0.992). IR: 3670w, 3435w,
3235w, 2985s, 1960s, 1870w, 1700s, 1500s, 1440s, 1385m, 1365s, 1165s, 1090w, 1050m, 1020w, 1005w, 970m, 915w,
870w. 1H-NMR (300 MHz): 7.78 (br. s, NH); 5.21 ± 5.18 (d, NH); 5.12 ± 5.09 (m, H C(2) (Pro)); 4.14 ± 4.07
(m, H C(a) (Leu)); 4.01 ± 3.84 (m, 2 H C(5) (Pro)); 3.72 (s, MeO); 2.24 ± 1.96 (m, 2 H C(3) (Pro),
2 H C(b) (Leu)); 1.79, 1.67 (2s, 2 Me (Aibt)); 1.75 ± 1.39 (m, 2 H C(4) (Pro) H C(g) (Leu)); 0.95 ± 0.91
(m, 2 Me (Leu)). 13C-NMR (75.5 MHz): 204.5 (s, CS (Aibt)); 171.0, 170.7 (2s, 2 CO); 155.6 (s, urethane CO);
79.7 (s, Me3C); 68.5 (d,C(2) (Pro)); 60.8 (s, C(a) (Aibt)); 53.2 (d, C(a) (Leu)); 52.7 (t, C(5) (Pro)); 52.1
(q, MeO); 41.1 (t, C(b) (Leu)); 28.2 (q, Me3C); 27.7 (t, C(3) (Pro)); 25.9 (t, C(4) (Pro)); 24.6 (q, 2 Me (Aibt));
‡
22.7, 22.0 (2q, 2 Me (Leu)). ESI-MS: 466 ([M ‡ Na] ). Anal. calc. for C21H37N3O5S (443.60): C 56.86, H 8.41,
N 9.41, S 7.23; found: C 56.36, H 7.99, N 9.33, S 7.18.

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Helvetica Chimica Acta ± Vol. 82 (1999)
Methyl (2S)-1-[2-((2S)-2-{2-[(2S)-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-3-methylbutanamido]-
2-methylpropanamido}-4-methylpentanamido)-2-methylthiopropanoyl]pyrrolidine-2-carboxylate (Fmoc-Val-
Aib-Leu-Aib-Y(CS)-Pro-OMe; 18). A soln. of 16 (42.6 mg, 0.096 mmol) in 2 ml of 2m HCl (THF/H2O 1 :1)
was stirred at r.t. for 17 h. The mixture was diluted with 5% NaHCO3 soln., and extracted 3 Â with CH2Cl2. The
combined org. phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was added to the
crude product obtained from 17 (55.2 mg, 0.109 mmol) according to GP 5, and the mixture was treated
according to GP 1 with EtN(i-Pr)2 (16.0 mg, 0.124 mmol), TBTU (31.3 mg, 0.103 mmol), and HOBt (16.1 mg,
0.105 mmol) in MeCN (2 ml); reaction time: 2 h. Chromatography (SiO2; AcOEt/hexane 2 : 1) gave 18
(62.6 mg, 93%) as a colorless, viscous oil, which solidified under high vacuum. [a]D
ˆ
39.2 (c ˆ 1.00). IR:
3690w, 3420w, 3345w, 3005w, 2960m, 2875w, 1710s, 1675s, 1515s, 1450m, 1425m, 1385w, 1365w, 1270m, 1165m,
1110w, 1045w, 1005w, 970w, 850w. 1H-NMR (300 MHz): 7.78 ± 7.27 (m, 10 arom. H, 1 NH); 6.92 (d, J ˆ 7.9,
NH); 6.63 (s, NH); 5.79 (br. s, NH); 5.07 ± 5.03 (m, H C(2) (Pro)); 4.48 ± 3.58 (m, CHCH2O, H C(a) (Val),
H
C(a) (Leu), 2 H C(5) (Pro)); 3.80 (s, MeO); 2.18 ± 0.75 (m, 2 H C(4) and 2 H C(3) (Pro), 2 H C(b)
(Leu), 2 Me (Val), 2 Me (Leu)); 1.78, 1.68, 1.57, 1.42 (4s, 2 Me (Aib), 2 Me (Aibt)). 13C-NMR (75.5 MHz):
204.8 (s, CS (Aibt)); 173.5, 171.4, 170.7, 169.1 (4s, 4 CO); 157.6 (s, urethane-CO); 143.4, 143.2, 141.2, 127.9,
127.1, 124.7, 124.6, 120.1 (12 arom. C); 68.2 (d, C(2) (Pro)); 67.4 (t, CHCH2O); 63.1 (d, C(a) (Val)); 61.2, 57.1
(2s, C(a) (Aib), C(a) (Aibt)); 53.0 (t, C(5) (Pro)); 52.2 (d, C(a) (Leu)); 52.0 (q, MeO); 46.8 (d, CHCH2O);
39.6 (t, C(b) (Leu)); 29.7, 25.1 (2d, C(b) (Val), C(g) (Leu)); 27.8, 27.2 (2t, C(3) and C(4) (Pro)); 29.4, 27.0,
25.8, 23.7, 23.3, 20.6, 19.0, 18.8 (8q, 2 Me (Aib), 2 Me (Aibt), 2 Me (Val), 2 Me (Leu)). ESI-MS: 722 ([M ‡
‡
Na] ).
Boc-Trp-Ile(1)-Ala-Aib(1)-Ile(2)-Val-Aib(2)-Leu-Aib(3)-Y(CS)-Pro-OMe (10). According to GP 4, Boc-
3
Trp-Ile-Ala-Aib-Ile-OMe ) (47.4 mg, 0.0676 mmol) was hydrolyzed with LiOH ´ H2O (15.1 mg, 0.360 mmol in
THF/H2O/MeOH 3 : 1 : 1 (5 ml) to give 13; reaction time: 17 h. A soln. of 18 (50.4 mg, 0.0672 mmol) in MeCN
(2 ml) was treated with Et2NH (0.2 ml), yielding 14. After stirring at r.t. for 1 h, the intensely yellow soln. was
concentrated, and the residue dried under high vacuum. The two crude products were coupled according to
GP 2 with PyBOP (38.1 mg, 0.0732 mmol) and EtN(i-Pr)2 (17.4 mg, 0.135 mmol) in CH2Cl2 (1 ml); reaction
time: 4.5 h. Chromatography (SiO2; AcOEt/hexane 10 : 1) gave 72.9 mg (90%) of 10 as a colorless, thick oil,
which solidified. [a]D
ˆ
14.3 (c ˆ 1.00). IR: 3660w, 3475w, 3315s, 2965m, 2875w, 1730m, 1660s, 1535s, 1460m,
1435m, 1385m, 1365m, 1275m, 1250m, 1165m, 1095w, 1045w, 1010w, 970w, 915w, 850w. 1H-NMR (600 MHz, cf.
Figs. 3 ± 6): 9.29 (s, H N(1) (Trp)); 7.77 (s, NH (Aibt)); 7.71 (d, J ˆ 4.3, NH (Ala)); 7.62 (d, J ˆ 4.8, NH (Val));
7.52 (d, J ˆ 7.9, H C(4) (Trp)); 7.46 (d, J ˆ 8.2, H C(7) (Trp)); 7.44 (s, NH (Aib(1))); 7.32 (s, NH (Aib(2)));
7.32 (d, J ˆ 6.2, H C(2) (Trp)); 7.24 (d, J ˆ 5.5, NH (Ile(2))); 7.23 (d, J ˆ 8.1, NH (Leu)); 7.20 (t, J ˆ 7.6,
H
C(6) (Trp)); 7.10 (t, J ˆ 7.6, H C(5) (Trp)); 6.30 (s, NH (Ile(1))); 5.48 (s, NH (Trp)); 5.07 ± 5.05
(m, H C(2) (Pro)); 4.40 ± 4.36 (m, H C(a) (Leu)); 4.25 (br. s, H C(a) (Trp)); 4.08 ± 4.02 (m, 1 H C(5)
(Pro), H C(a) (Ala)); 3.95 ± 3.88 (m, 1 H C(5) (Pro), H C(a) (Ile(2))); 3.68 (s, MeO); 3.61 ± 3.59
(m, H C(a) (Val)); 3.33 ± 3.22 (m, 2 H C(b) (Trp)); 2.23 ± 2.19 (m, H C(b) (Val)); 2.11 ± 1.98 (m, 2 H C(b)
(Leu), H C(g) (Leu), 1 H C(3) (Pro), 1 H C(4) (Pro)); 1.83 (s, Me(1) (Aibt)); 1.73 (s, Me(2) (Aibt));
1.615 (s, Me(1) (Aib(1))); 1.609 (s, Me(2) (Aib(2))); 1.64 ± 1.41 (m, H C(b) (Ile(1)), 2 H C(g) (Ile(2)));
1.55 (s, Me(2) (Aib(1)); 1.53 (s, Me(1) (Aib(2))); 1.45 (d, J ˆ 6.4, Me (Ala)); 1.43 (s, Me3C); 1.36 ± 1.32
(m, 1 H C(g) (Ile(1))); 1.10 ± 1.06 (m, 1 H-C(g) (Ile(1))); 1.08 (d, J ˆ 6.7, Me(2) (Val)); 1.04 (d, J ˆ 6.8,
Me(1) (Val)); 1.01 (d, J ˆ 6.9, Me(b1) (Ile(2))); 0.95 (t, J ˆ 7.3, Me(d) (Ile(2))); 0.95 (d, J ˆ 6.4, Me(2) (Leu));
0.88 (d, J ˆ 6.4, Me(1) (Leu)); 0.85 (t, J ˆ 7.3, Me(d) (Ile(1))); 0.68 ± 0.67 (d, J ˆ 6.8, Me(b1) (Ile(1))).
13C-NMR (150.9 MHz, cf. Figs. 3 ± 6): 205.2 (s, CS (Aibt)); 176.0 (s,CO (Aib(1))); 175.0 (s, CO (Aib(2))); 174.1
(s, CO (Trp)); 173.9 (s, CO (Ile(2))); 173.6 (s, CO (Ala)); 172.7 (s, CO (Val)); 172.0 (s,CO (Ile(1))); 171.9
(s, CO (Leu)); 171.7 (s, CO (Pro)); 157.2 (s, urethane-CO); 136.8 (s, C(3a) (Trp)); 127.1 (s, C(7a) (Trp)); 124.4
(d, C(2) (Trp)); 122.4 (d, C(6) (Trp)); 119.7 (d, C(5) (Trp)); 118.3 (d, C(4) (Trp)); 111.9 (d, C(7) (Trp)); 108.4
(s, C(3) (Trp)); 81.7 (s, Me3C); 68.3 (d, C(2) (Pro)); 63.4 (d, C(a) (Val)); 61.4 (s, C(a) (Aibt)); 60.9 (d, C(a)
(Ile(2))); 59.6 (d, C(a) (Ile(1))); 57.1 (s, C(a) (Aib(2))); 56.9 (d, C(a) (Trp)); 56.8 (s, C(a) (Aib(1))); 53.3
(t, C(5) (Pro)); 52.7 (d, C(a) (Leu)); 52.1 (d, C(a) (Ala)); 52.0 (q, MeO); 40.1 (t, C(b) (Leu)); 35.9 (d, C(b)
(Ile(2))); 35.8 (d, C(b) (Ile(1))); 29.9 (q, Me(1) (Aibt)); 29.1 (d, C(b) (Val)); 28.2 (q, Me3C); 28.0 (2t, C(3) and
C(4) (Pro)); 27.50 (q, Me(1) (Aib(1))); 27.49 (q, Me(1) (Aib(2))); 27.4 (q, Me(2) (Aibt)); 27.3 (t, C(b) (Trp));
26.0 (t, C(g) (Ile(2))); 25.2 (t, C(g) (Ile(1))); 25.1 (d, C(g) (Leu)); 23.5 (q, Me(2) (Leu)); 23.4 (q, Me(2)
(Aib(2))); 23.1 (q, Me(2) (Aib(1))); 20.9 (q, Me(1) (Leu)); 19.8 (q, Me(2) (Val)); 19.2 (q, Me(1) (Val)); 16.5
3
)
For the preparation of Boc-Trp-Ile-Ala-Aib-Ile-OMe, see [4].

Helvetica Chimica Acta ± Vol. 82 (1999)
1909
Fig. 3. 1H-TOCSY Spectrum of 10 (CDCl3, 600 MHz; 10.0 ± 0.0 ppm)
Fig. 4. 1H-DQF-COSY Spectrum of 10 (CDCl3, 600 MHz; 2.5 ± 0.0 ppm)
(q, Me (Ala)); 15.8 (q, Me(b1) (Ile(2))); 15.6 (q, Me(b1) (Ile(1))); 11.8 (q, Me(d) (Ile(2))); 11.4 (q, Me(d)
‡
(Ile(1))). ESI-MS: 1219 ([M ‡ Na] ), 621 ([M ‡ 2Na]2‡).
3. Attempted Synthesis of Methyl (2S)-1-{2-[(2S)-2-(2-{(2S)-2-[(2S,3S)-2-(2-{(2S)-2-[(2S,3S)-2-((2S)-{[(tert-
Butoxy)carbonyl]amino}-3-(indol-3-yl)propanamido)-3-methylpentanamido]propanethioamido}-2-methylpropan-

1910
Helvetica Chimica Acta ± Vol. 82 (1999)
Fig. 5. 13C,1H-HSQC Spectrum of 10 (CDCl3, 600 MHz; 5.5 ± 0.0 and 70.0 ± 0.0 ppm, resp.)
Fig. 6. 13C,1H-HMBC ꢀLonge-rangeꢁ spectrum of 10 (CDCl3, 600 MHz; 9.5 ± 0.5 and 210 ± 5.0 ppm, resp.)
amido)-3-methylpentanamido]-3-methylbutanamido}-2-methylpropanamido)-4-methylpentanamido]-2-methyl-
propanoyl}pyrrolidine-2-carboxylate (Boc-Trp-Ile-Ala-Y(CS)-Aib-Ile-Val-Aib-Leu-Aib-Pro-OMe; 11). Methyl
N-[(tert-Butoxy)carbonyl]-l-tryptophanyl-l-isoleucinate (Boc-Trp-Ile-OMe; 19). According to GP 1 with Boc-
Trp (2.020 g, 6.636 mmol), EtN(i-Pr)2 (1.923 g, 14.878 mmol), TBTU (2.065 g, 6.858 mmol), HOBt (1.006 g,
6.575 mmol), and Ile-OMe ´ HCl (1.258 g, 6.925 mmol) in MeCN (50 ml); reaction time: 2.5 h. Chromatography
(SiO2; AcOEt/hexane 1 : 2) gave 2.818 g (99%) of 19 as a colorless, viscous oil, which solidified under high
vacuum. [a]D ˆ ‡5.4 (c ˆ 0.99). IR: 3480m, 3425m, 3005m, 2970m, 2935m, 2880w, 1735s, 1705s, 1675s, 1490s,
1455m, 1440m, 1420s, 1390m, 1370m, 1340m, 1300w, 1165s, 1090w, 1060w, 1010w, 860w, 810w. 1H-NMR
(300 MHz): 8.39 (s, NH); 7.66 ± 7.04 (m, 5 arom. H); 6.35 (d, NH); 5.22 (br. s, NH); 4.47 ± 4.42 (m, H C(a)
(Trp), H C(a) (Ile)); 3.61 (s, MeO); 3.32 ± 3.14 (m, 2 H C(b) (Trp)); 1.89 ± 0.94 (m, H C(b) (Ile), 2 H C(g)
(Ile)); 1.43 (s, Me3C); 0.86 ± 0.81 (t, J ˆ 7.3, Me(d) (Ile)); 0.74 (d, J ˆ 6.9, Me(b1) (Ile)). 13C-NMR (75.5 MHz):
171.6, 171.4, (2s, 2 CO); 155.5 (s, urethane-CO); 136.2, 127.4, 123.2, 122.1, 119.6, 118.7, 111.1, 110.4 (8 arom. C);
80.0 (s, Me3C); 56.5, 55.2 (2d, C(a) (Trp), C(a) (Ile)); 51.8 (q, MeO); 37.7 (d, C(b) (Ile)); 28.2 (q, Me3C); 28.0

Helvetica Chimica Acta ± Vol. 82 (1999)
1911
‡
(t, C(b) (Trp)); 25.0 (t, C(g) (Ile)); 15.1, 11.4 (2q, Me(d) (Ile), Me(b1) (Ile)). CI-MS: 432 (89, [M ‡ 1] ), 377
(6), 376 (33), 333 (19), 332 (100), 314 (6), 117 (5). Anal. calc. for C23H33N3O5 (431.52): C 64.17, H 7.49, N 9.76;
found: C 63.50, H 7.65, N 9.67.
Methyl (2S,3S)-2-(2-{(2S)-2-[(2S,3S)-2-((2S)-{[(tert-Butoxy)carbonyl]amino}-3-(indol-3-yl)propanamido)-
3-methylpentanamido]propanethioamido}-2-methylpropanamido)-3-methylpentanoate (Boc-Trp-Ile-Ala-Y(CS)-
Aib-Ile-OMe; 21). According to GP 4, 19 (75.1 mg, 0.174 mmol) was hydrolyzed with LiOH ´ H2O (15.1 mg,
4
0.360 mmol) in 4 ml of THF/MeOH/H2O 3 : 1 : 1. To a soln. of Fmoc-Ala-Y(CS)-Aib-Ile-OMe ) (84.1 mg,
0.156 mmol), Et2NH (0.3 ml) was added, and the mixture was stirred at r.t. After 45 min, the intensely yellow
soln. was concentrated, and the residue was dried under high vacuum. The two crude products were coupled
according to GP 1 with EtN(i-Pr)2 (21.7 mg, 0.168 mmol), TBTU (52.0 mg, 0.173 mmol), and HOBt (27.1 mg,
0.177 mmol) in MeCN (3 ml); reaction time: 2.5 h. Chromatography (SiO2; AcOEt/hexane 3 : 1) gave 21 as a
colorless, thick oil, which solidified under high vacuum. [a]D
ˆ
10.1 (c ˆ 0.971. IR: 3675w, 3475w, 3315m,
2965m, 2935w, 2880w, 1735m, 1670s, 1515s, 1455m, 1435m, 1370m, 1275m, 1160m, 1095w, 1070w, 1010w, 920w,
850w. 1H-NMR (300 MHz): 9.14 (s, NH); 8.47 (s, NH); 7.52 ± 7.05 (m, 5 arom. H, 1 NH); 6.79 (d, J ˆ 8.0, NH);
6.20 (d, J ˆ 5.2, NH); 5.25 (d, J ˆ 2.6, NH); 4.61 ± 3.98 (m, 2 H C(a) (Ile), H C(a) (Alat)); 3.61 (s, MeO);
3.25 ± 3.18 (m, 2 H C(b) (Trp)); 1.99 ± 0.58 (m, 2 H C(b) (Ile), 4 H C(g) (Ile), 2 Me(d) (Ile), 2 Me(b1)
(Ile)); 1.77, 1.73 (2s, 2 Me (Aib)); 1.35 (s, Me3C). 13C-NMR (75.5 MHz): 207.9 (s, CS (Alat)); 173.4, 173.3,
172.1, 170.8 (4s, 4 CO); 156.8 (s, urethane-CO); 136.6, 127.0, 123.9, 122.3, 119.6, 118.3, 111.7, 108.6 (8 arom. C);
81.4 (s, Me3C); 60.9 (s, C(a) (Aib)); 59.3, 58.4, 57.4, 56.5 (4d, C(a) (Trp), C(a) (Ile), C(a) (Alat)); 51.7
(q, MeO); 40.2, 37.0 (2d, 2 C(b) (Ile)); 28.1 (q, Me3C); 27.3 (t, C(b) (Trp)); 26.5, 23.8 (2q, 2 Me (Aib)); 25.3,
24.5 (2t, 2C(g) (Ile)); 20.5, 15.5, 15.5, 11.7, 11.2 (5q, 2 Me(g) (Ile), 2 Me(b1) (Ile), Me (Alat)). ESI-MS: 739
‡
([M ‡ Na] ). Anal. calc. for C36H56N6O7S (431.52): C 60.31, H 7.87, N 11.72, S 4.47; found: C 59.89, H 7.76,
N 11.29, S 4.49.
Benzyl
N-{(1S)-2-Methyl-1-[({1,1-dimethyl-2-[methyl(phenyl)amino]-2-oxoethyl}amino)carbonyl]pro-
pyl}carbamate (Z-Val-Aib-N(Me)Ph; 24). According to GP 3 with Z-Val (1.310 g, 5.27 mmol), CH2Cl2
(50 ml) and azirine 2 (1.00 g, 5.74 mmol). Chromatography (SiO2; AcOEt/hexane 1:1.5) led to 2.081 g
(94%) of 24 as a viscous oil, which solidified slowly. [a]D ˆ ‡10.0 (c ˆ 1.00). IR: 3690w, 3430m, 3360m, 2970m,
2875w, 1720s, 1680s, 1630s, 1595s, 1495s, 1455s, 1390m, 1370m, 1270m, 1170w, 1120m, 1095m, 1025m, 925w.
1H-NMR (300 MHz): 7.39 ± 7.17 (m, 10 arom. H); 6.55 (s, NH (Aib)); 5.46 (d, J ˆ 8.2, NH (Val)); 5.14 ± 5.12
(m, CH2O); 3.79 ± 3.75 (m, H C(a) (Val)); 3.25 (s, MeN); 2.06 ± 2.01 (m, H C(b) (Val)); 1.47, 1.43 (2s, 2 Me
(Aib)); 0.90 (2d, J ˆ 6.8, 2 Me (Val)). 13C-NMR (75.5 MHz): 173.0, 169.5 (2s, 2 CO); 156.2 (s, urethane CO);
144.2, 136.5, 129.4, 128.4, 128.1, 128.0, 127.9 (12 arom. C); 66.9 (t, CH2O); 60.0 (d, C(a) (Val)); 58.6 (s, C(a)
(Aib)); 41.4 (q, MeN); 31.6 (d, C(b) (Val)); 25.9, 25.6 (2q, 2 Me (Aib)); 19.1, 17.5 (2q, 2 Me (Val)). ESI-MS:
‡
448 ([M ‡ Na] ). Anal. calc. for C24H31N3O4 (425.52): C 67.69, H 7.29, N 9.87; found: C 67.82, H 7.36, N 9.82.
Methyl (2S)-2-[2-((2S)-{[(Benzyloxy)carbonyl]amino}-3-methylbutanamido)-2-methylpropanamido]-4-
methylpentanoate (Z-Val-Aib-Leu-OMe; 25). According to GP 4, 24 (1.00 g, 2.35 mmol) was hydrolyzed in
30 ml of 3m HCl (THF/H2O 1:1). The crude product was treated according to GP 1 with Leu-OMe ´ HCl
(0.500 g, 2.590 mmol), EtN(i-Pr)2 (0.909 g, 7.033 mmol), TBTU (0.750 g, 2.490 mmol), and HOBt (0.370 g,
2.418 mmol) in MeCN (20 ml); reaction time: 17 h. Chromatography (SiO2; AcOEt/hexane 1 : 1.5) gave 0.895 g
(82%) 25 as a colorless, thick oil, which solidified slowly. [a]D
ˆ
8.6 (c ˆ 1.03). IR: 3695w, 3430m, 3360m,
3010m, 2965m, 2875w, 1715s, 1680s, 1630s, 1595s, 1495s, 1455s, 1390m, 1370m, 1270m, 1170m, 1120m, 1090m,
1
1025m, 910m, 845w. H-NMR (300 MHz): 7.35 ± 7.32 (m, 5 arom. H); 6.93 (d, J ˆ 7.9, NH); 6.59 (s, NH); 5.38
(d, J ˆ 8.0, NH); 5.16 ± 5.05 (m, CH2O); 4.58 ± 4.55 (m, H C(a) (Leu)); 3.90 ± 3.85 (m, H C(a) (Val)); 3.70
(s, MeO); 2.11 ± 1.52 (m, 2 Me (Val), 2 H C(b) (Leu), H C(g) (Leu)); 1.57, 1.52 (2s, 2 Me (Aib)); 0.97 ± 0.90
(m, 2 Me (Val), 2 Me (Leu)). 13C-NMR (75.5 MHz): 173.7, 173.2, 170.9 (3s, 3 CO); 156.4 (s, urethane CO);
136.0, 128.4, 128.1, 127.9 (6 arom. C); 67.0 (t, CH2O); 60.9 (d, C(a) (Val)); 57.3 (s, C(a) (Leu)); 52.0 (q, MeO);
41.1 (t, C(b) (Leu)); 30.7 (d, C(b) (Val)); 24.7 (d, C(g) (Leu)); 25.6, 24.4, 22.7, 21.8, 19.0, 17.9 (6q, 2 Me (Aib),
‡
2 Me (Leu), 2 Me (Val)). ESI-MS: 486 ([M ‡ Na] ). Anal. calc. for C24H37N3O6 (463.57): C 62.18, H 8.04,
N 9.06; found: C 62.04, H 8.13, N 8.89.
Methyl (2S)-1-(2-{(2S)-2-[2-((2S)-{[(Benzyloxy)carbonyl]amino}-3-methylbutanamido)-2-methylpropan-
amido]-4-methylpentanamido}-2-methylpropanoyl)pyrrolidine-2-carboxylate (Z-Val-Aib-Leu-Aib-Pro-OMe;
26). According to GP 4, 25 (0.203 g, 0.437 mmol) was hydrolyzed with LiOH ´ H2O (41.3 mg, 0.984 mmol) in
5 ml of THF/MeOH/H2O 3 : 1 : 1; reaction time: 15 h. The crude product was treated according to GP 3 with
4
)
For the preparation of Fmoc-Ala-Y(CS)-Aib-Ile-OMe, see [3].

1912
Helvetica Chimica Acta ± Vol. 82 (1999)
azirine 15 (94.7 mg, 0.483 mmol) in 5 ml of CH2Cl2. Chromatography (SiO2; AcOEt) led to 0.259 g (92%) of 26
as a colorless, viscous oil, which solidified under high vacuum. [a]D
ˆ
58.5 (c ˆ 1.00). IR: 3690w, 3425m, 3350s,
3010m, 2960s, 2930m, 2875m, 1740s, 1715s, 1595s, 1675s, 1630s, 1515s, 1470s, 1455s, 1440s, 1415s, 1385m, 1365s,
1270s, 1170s, 1095m, 1005w, 910w, 825w. 1H-NMR (300 MHz): 7.60 (s, NH); 7.37 ± 7.27 (m, 5 arom. H); 7.13
(d, J ˆ 8.3, NH); 7.05 (s, NH); 6.50 (d, J ˆ 2.9, NH); 5.15 ± 5.03 (m, CH2O); 4.50 ± 3.47 (m, H C(a) (Val),
H
C(a) (Leu), H C(2) (Pro), 2 H C(5) (Pro)); 3.67 (s, MeO); 2.32 ± 1.20 (m, H C(b) (Val), H C(g)
(Leu), 2 H C(3) and 2 H C(4) (Pro)); 1.59, 1.56, 1.50, 1.42 (4s, 4 Me (Aib)); 1.07 ± 0.82 (m, 2 Me (Val), 2 Me
(Leu)). 13C-NMR (75.5 MHz): 174.0, 173.3, 172.4, 172.0, 171.4 (5s, 5 CO); 157.7 (s, urethane CO); 135.9, 128.2,
127.6 (6 arom. C); 66.9 (t, CH2O); 63.8, 60.4 (2d, C(2) (Pro), C(a) (Val)); 57.0, 56.5 (2s, C(a) (Aib)); 52.0
(d, C(a) (Leu)); 51.8 (q, MeO); 48.2 (t, C(5) (Pro)); 39.7 (t, C(b) (Leu)); 29.5 (d, C(b) (Val)); 27.8, 25.7 (2t,
C(3) and C(4) (Pro)); 25.1 (d, C(g) (Leu)); 27.3, 24.9, 24.3, 23.5, 23.3, 20.6, 19.3, 19.0 (8q, 4 Me (Aib), 2 Me
‡
(Val), 2 Me (Leu)). ESI-MS: 668 ([M ‡ Na] ). Anal. calc. for C33H51N5O8 (645.79): C 61.37, H 7.96, N 10.84;
found: C 61.29, H 8.23, N 10.02.
Methyl
(2S)-1-(2-{(2S)-2-[2-((2S)-2-{(2S,3S)-2-[(2-{(R/S)-1-[(2S,3S)-2-((2S)-{[(tert-Butoxy)carbonyl]-
amino}-3-(indol-3-yl)propanamido)-3-methylpentanamido]ethyl}-4,5-dihydro-4,4-dimethyl-1,3-thiazol-5-yli-
den)amino]-3-methylpentanamido}-3-methylbutanamido)-2-methylpropanamido]-4-methylpentanamido}-2-
methylpropanoyl)pyrrolidine-2-carboxylate (27). To a soln. of 26 (21.7 mg, 0.0336 mmol) in 2 ml of MeOH,
2 mg of Pd/C were added, and the suspension was stirred under H2 (balloon) for 5 min to give 23. Then, the
mixture was filtered over Celite, concentrated, and dried under high vacuum. According to GP 4, 21 (21.2 mg,
0.0296 mmol) was hydrolyzed with LiOH ´ H2O (2.5 mg, 0.0596 mmol) in 0.5 ml of THF/H2O/MeOH 3 : 1 : 1
yielding 22; reaction time: 18 h. The two crude products were coupled according to GP 2 with PyBOP (17.4 mg,
0.0334 mmol) and EtN(i-Pr)2 (5 ml, 0.03 mmol) in CH2Cl2 (0.5 ml); reaction time: 4 h. Chromatography (SiO2;
AcOEt/MeOH 30 : 1) gave a mixture of two epimers of 27 in a (S)/(R) ratio of 62 : 38 (27.0 mg, 76%). The
epimers were separated by prep. HPLC (Bischoff, Spherisorb ODS2, 5 mm, MeCN/H2O 70 : 30, 3.6 ml/min). The
following data are those of the epimer with the (S)-configuration of Ala. [a]D ˆ ‡4.5 (c ˆ 0.730). IR: 3475w,
3335m, 2995w, 2960m, 2935w, 2875w, 1740m, 1665s, 1500s, 1455m, 1440m, 1415w, 1365m, 1265m, 1170s, 1010w,
915w, 855w. 1H-NMR (600 MHz; 1H-TOCSY, 1H-DQF-COSY, 13C,1H-HSQC, 13C,1H-HMBC): 8.59 (s, H N(1)
(Trp)); 7.55 (d, J ˆ 8.0, H C(4) (Trp)); 7.33 (d, J ˆ 8.1, H C(7) (Trp)); 7.23 (s, NH (Aib(3))); 7.13 ± 7.03
(m, H C(2), H C(5), H C(6) (Trp), NH (Val), NH (Leu)); 6.80 (s, NH (Ala)); 6.27 (d, J ˆ 8.2, NH
(Ile(1))); 6.21 (s, NH (Aib(2))); 5.04 (s, NH (Trp)); 4.73 ± 4.68 (m, H C(a) (Ala)); 4.47 ± 4.45 (m, H C(2)
(Pro)); 4.33 ± 4.30 (m, H C(a) (Trp)); 4.20 ± 4.18 (m, H C(a) (Ile(1))); 3.67 ± 3.57 (m, H C(a) (Val),
1 H C(5) (Pro)); 3.52 ± 3.48 (m, 1 H C(5) (Pro)); 3.28 (d, J ˆ 3.3,
H C(a) (Ile(2))); 3.23 ± 3.15
(m, 2 H C(b) (Trp)); 2.13 ± 2.08 (m, H C(b) (Val)); 2.03 ± 1.97 (m, 1 H C(3) (Pro)); 1.93 ± 1.64
(m, 2 H C(4) (Pro), H C(b) (Ile(1)), H C(b) (Ile(2)), 2 H C(b) (Leu)), 1 H C(3) (Pro)); 1.58 ± 1.41
(m, H C(g) (Leu), 1 H C(g) (Ile(2))); 1.48 (s, Me(2) (Aib(2))); 1.47 (s, Me(2) (Aib(3))); 1.45 (s, Me(1)
(Aib(3))); 1.41 (s, Me(2) (Aib(1))); 1.39 (s, Me(1) (Aib(1))); 1.37 (s, Me(1) (Aib(2))); 1.35 (s, Me3C); 1.34
(d, J ˆ 3.2, Me (Ala)); 1.28 ± 1.20 (m, 1 H C(a) (Ile(1)), 1 H C(g) (Ile(2))); 0.97 (d, J ˆ 6.8, Me(1) (Val));
0.95 ± 0.94 (d, J ˆ 6.8, Me(2) (Val)); 0.94 ± 0.84 (m, 1 H C(g) (Ile(1)), 1 H C(g) (Ile(2))); 0.88 (d, J ˆ 6.7,
Me(2) (Leu)); 0.82 (d, J ˆ 6.8, Me(1) (Leu)); 0.81 (t, J ˆ 6.8, Me(d) (Ile(2))); 0.75 (t, J ˆ 7.3, Me(d) (Ile(1)));
0.70 (d, J ˆ 6.8, Me(b1) (Ile(1))). 13C-NMR (150.9 MHz): 179.5 (s, thiazole C(5)); 173.8 (s, CO (Aib(2))); 173.7
(s, CO (Pro)); 173.6 (s, CO (Ile(2))); 172.5 (s, CO (Aib(3))); 172.0 (s, CO (Trp)); 171.3 (s, CO (Leu)); 170.9
(s, CO (Val)); 170.8 (s, CO (Ile(1))); 165.1 (s, thiazole C(2)); 156.4 (s, urethane CO); 136.6 (s, C(3a) (Trp));
127.5 (s, C(7a) (Trp)); 123.6 (d, C(2) (Trp)); 122.5 (d, C(6) (Trp)); 119.9 (d, C(5) (Trp)); 118.8 (d, C(4) (Trp));
111.7 (d, C(7) (Trp)); 110.0 (s, C(3) (Trp)); 83.3 (s, thiazole C(4)); 80.9 (s, Me3C); 78.5 (d, C(a) (Ile(2))); 61.5
(d, C(a) (Val)); 60.8 (d, C(2) (Pro)); 58.1 (d, C(a) (Ile(1))); 57.6 (s, C(a) (Aib(2))); 56.8 (s, C(a) (Aib(3)));
55.9 (d, C(a) (Trp)); 53.0 (d, C(a) (Leu)); 52.2 (q, MeO); 49.0 (d, C(a) (Ala)); 48.3 (t, C(5) (Pro)); 40.2
(d, C(b) (Ile(2))); 39.6 (t, C(b) (Leu)); 36.5 (d, C(b) (Ile(1))); 29.7 (d, C(b) (Val)); 28.5 (q, Me3C); 28.2
(t, C(3) (Pro)); 27.9 (q, Me(1) (Aib(1)); 27.3 (t, C(b) (Trp)); 27.0 (q, Me(1) (Aib(2))); 26.8 (q, Me(2)
(Aib(1))); 26.2 (t, C(4) (Pro)); 25.8 (t, C(g) (Ile(2))); 25.5 (d, C(g) (Leu)); 25.4 (q, Me(1) (Aib(3))); 24.7
(q, Me(2) (Aib(3))); 24.6 (q, Me(2) (Aib(2))); 23.7 (q, Me(2) (Leu)); 21.3 (q, Me(1) (Leu)); 19.6 (q, Me(1)
(Val)); 18.9 (q, Me (Ala)); 18.6 (q, Me(2) (Val)); 16.1 (q, Me(b1) (Ile(2))); 15.8 (q, Me(b1) (Ile(1))); 12.1
‡
(q, Me(d) (Ile(2))); 11.8 (q, Me(d) (Ile(1))). ESI-MS: 1201 ([M ‡ Na] ).
4. Attempted Synthesis of Methyl (2S)-1-{2-[(2S)-2-(2-{(2S)-2-[(2S,3S)-2-(2-{(2S)-2-[(2S,3S)-2-((2S)-{[(tert-
Butoxy)carbonyl]amino}-3-(indol-3-yl)propanamido)-3-methylpentanamido]propanethioamido}-2-methylpropan-
amido)-3-methylpentanamido]-3-methylbutanethioamido}-2-methylpropanamido)-4-methylpentanamido]-2-meth-
ylpropanoyl}pyrrolidine-2-carboxylate
(Boc-Trp-Ile-Ala-Y(CS)-Aib-Ile-Val-Y(CS)-Aib-Leu-Aib-Pro-OMe;

Helvetica Chimica Acta ± Vol. 82 (1999)
1913
12). Methyl (2S)-2-[2-((2S)-2-{(2S,3S)-2-[(2-{(R/S)-1-[(2S,3S)-2-((2S)-{[(tert-Butoxy)carbonyl]amino}-3-(indol-
3-yl)propanamido)-3-methylpentanamido]ethyl}-4,5-dihydro-4,4-dimethyl-1,3-thiazol-5-yliden)amino]-3-methyl-
pentanamido}-3-methylbutanamido)-2-methylpropanamido]-4-methylpentanoate (31). According to GP 4, 21
(33.6 mg, 0.0468 mmol) was hydrolyzed with LiOH ´ H2O (4.0 mg, 0.095 mmol) in 0.5 ml of THF/MeOH/H2O
5
3 : 1 : 1 to give 22; reaction time: 17 h. To a soln. of Fmoc-Val-Y(CS)-Aib-Leu-OMe ) in MeCN (2 ml), Et2NH
(0.2 ml) was added, and the soln. was stirred at r.t., yielding 28. After 50 min, the intensely yellow soln. was
concentrated, and the residue was dried under high vacuum. The two crude products were coupled according to
GP 2 with PyBOP (26.3 mg, 0.0505 mmol) and EtN(i-Pr)2 (8.6 ml, 0.05 mmol) in CH2Cl2 (1 ml); reaction time:
4.5 h. Chromatography (SiO2; AcOEt/hexane 3 : 1) gave 35.7 mg (74%) of a mixture of three substances in a
ratio of 53 : 28 : 19 (HPLC), which were separated by prep. HPLC (Bischoff, Spherisorb ODS2, 5 mm, MeCN/
H2O 70 : 30, 10.0 ml/min). The physical data showed that the first two main products were the epimers of
6
thiazolimine 31, and that the last, smallest peak corresponds to the linear endothiooctapeptide 29 ). The
following data are those of the epimer of 31 with (S)-configuration at Ala. [a]D ˆ ‡26.6 (c ˆ 1.05). IR: 3695w,
3480w, 3380w, 2965s, 2935m, 2875w, 1735m, 1665s, 1505s, 1455s, 1420m, 1370m, 1170s, 1095w, 1010w, 925w.
1H-NMR (600 MHz; 1H-TOCSY, 1H-DQF-COSY, 13C,1H-HSQC, 13C,1H-HMBC): 8.37 (s, H N(1) (Trp));
8.25 (s, NH (Aib(2))); 7.65 (d, J ˆ 7.9, H C(4) (Trp)); 7.37 (d, J ˆ 8.4, NH (Valt)); 7.36 (d, J ˆ 8.5, H C(7)
(Trp)); 7.19 (t, J ˆ 7.4, H C(6) (Trp)); 7.12 (t, J ˆ 7.4, H C(5) (Trp)); 7.07 (d, J ˆ 1.8, H C(2) (Trp)); 6.72
(d, J ˆ 6.9, NH (Ala)); 6.48 (d, J ˆ 7.7, NH (Leu)); 6.44 (d, J ˆ 8.3, NH (Ile(1))); 5.10 (br. d, NH (Trp)); 4.79 ±
4.75 (m, H C(a) (Ala)); 4.55-4.51 (m, H C(a) (Leu)); 4.44 (br. d, H C(a) (Trp)); 4.25 ± 4.23 (m, H C(a)
(Ile(1)), H C(a) (Valt)); 3.71 (s, MeO); 3.29 ± 3.21 (m, H C(a) (Ile(2)), 2 H C(b) (Trp)); 2.22 ± 2.16
(m, H C(b) (Valt)); 1.98 ± 1.91 (m, H C(b) (Ile(2))); 1.86 ± 1.79 (m, H C(b) (Ile(1))); 1.72 (s, Me(1)
(Aib(2))); 1.68 (s, Me(2) (Aib(2))); 1.66 ± 1.49 (m, 2 H C(b) (Leu), H C(g) (Leu), 1 H C(g) (Ile(2)));
1.49 (s, Me(1) (Aib(1))); 1.45 (s, Me(2) (Aib(1))); 1.42 (s, Me3C); 1.39 (d, J ˆ 6.9, Me (Ala)); 1.36 ± 1.22
(m, 1 H C(g) (Ile(1)), 1 H C(g) (Ile(2))); 1.00 (d, J ˆ 6.7, Me(1) (Valt)); 0.98 (d, J ˆ 6.7, Me(2) (Valt));
1.00 ± 0.94 (m, 1 H C(g) (Ile(1))); 0.91 (t, J ˆ 8.0, Me(d) (Ile(2))); 0.90 (d, J ˆ 7.3, Me(b1) (Ile(2))); 0.89
(d, J ˆ 4.9, Me(1) (Leu)); 0.89 (d, J ˆ 6.2, Me(2) (Leu)); 0.82 (t, J ˆ 7.3, Me(d) (Ile(1))); 0.77 (d, J ˆ 6.8,
Me(b1) (Ile(1)). 13C-NMR (75.5 MHz): 202.4 (s, CS (Valt)); 177.4 (s, thiazole C(5)); 173.5 (s, CO (Leu)); 172.5
(s, CO (Aib(1))); 171.6 (s, CO (Aib(2))); 170.3 (s, CO (Ile(1))); 164.7 (s, thiazole C(2)); 156.4 (s, urethane
CO); 136.4 (s, C(3a) (Trp)); 127.5 (s, C(7a) (Trp)); 123.3 (d, C(2) (Trp)); 122.3 (d, C(6) (Trp)); 119.9 (d, C(5)
(Trp)); 118.9 (d, C(4) (Trp)); 111.3 (d, C(7) (Trp)); 110.5 (s, C(3) (Trp)); 83.9 (s, thiazole C(4)); 80.6
(s, Me3C); 79.5 (d, C(a) (Ile(2))); 66.4 (d, C(a) (Val)); 60.5 (s, C(a) (Aib(2))); 57.9 (d, C(a) (Ile(1))); 55.3
(d, C(a) (Trp)); 52.3 (q, MeO); 51.3 (d, C(a) (Leu)); 48.9 (d, C(a) (Ala)); 41.2 (t, C(b) (Leu)); 39.8 (d, C(b)
(Ile(2))); 36.8 (d, C(b) (Ile(1))); 33.2 (d, C(b) (Val)); 28.3 (q, Me3C); 27.5 (q, Me(2) (Aib(1))); 27.5 (t, C(b)
(Trp)); 27.0 (q, Me(1) (Aib(1))); 25.4 (t, C(g) (Ile(2))); 25.2 (q, Me(2) (Aib(2))); 24.8 (d, C(g) (Leu)); 24.6
(t, C(g) (Ile(1))); 23.1 (q, Me(1) (Aib(2))); 22.9 (q, Me(2) (Leu)); 22.0 (q, Me(1) (Leu)); 19.6 (q, Me (Ala));
19.3 (q, Me(2) (Val)); 18.8 (q, Me(1) (Val)); 16.0 (q, Me(b1) (Ile(2))); 15.4 (q, Me(b1) (Ile(1))); 11.9 (q, Me(d)
‡
(Ile(2))); 11.4 (q, Me(d) (Ile(1))). ESI-MS: 1035 ([M ‡ Na] ).
Methyl
(2S)-1-(2-{(2S)-2-[2-((2S)-2-{(2S,3S)-2-[(2-{(R/S)-1-[(2S,3S)-2-((2S)-{[(tert-Butoxy)carbonyl]-
amino}-3-(indol-3-yl)propanamido)-3-methylpentanamido]-1-methylethyl}-4,5-dihydro-4,4-dimethyl-1,3-thia-
zol-5-yliden)amino]-3-methylpentanamido}-3-methylbutanethioamido)-2-methylpropanamido]-4-methylpentan-
amido}-2-methylpropanoyl)pyrrolidine-2-carboxylate (30).
A
soln. of Fmoc-Val-Y(CS)-Aib-Leu-OMe5
(48.5 mg, 0.0855 mmol) in MeCN (2 ml) was treated with Et2NH (0.2 ml) and stirred at r.t., yielding 28. After
55 min, the intensely yellow soln. was concentrated and dried under high vacuum. According to GP 4, 21
(43.2 mg, 0.0602 mmol) was hydrolyzed with LiOH ´ H2O (7.2 mg, 0.172 mmol) in 2 ml of THF/MeOH/H2O
3 : 1 : 1 to give 22; reaction time: 17 h. The two crude products were coupled according to GP 1 with EtN(i-Pr)2
(10.0 mg, 0.0774 mmol), TBTU (20.0 mg, 0.0663 mmol), and HOBt (10.6 mg, 0.0693 mmol) in MeCN (2 ml);
reaction time: 19 h. Because the precipitated crude product could not be dissolved anymore, it was hydrolyzed
without further purification according to GP 4 with LiOH ´ H2O (5.1 mg, 0.122 mmol) in 1.5 ml of THF/MeOH/
H2O 3 : 1 : 1; reaction time: 20 h. The crude product was treated according to GP 3 with azirine 15 (15 mg,
0.076 mmol) in CH2Cl2 (2 ml); reaction time: 3.5 h. Chromatography (SiO2; AcOEt) led to 35.2 mg (48%) of a
mixture of epimers of 30 in a (S)/(R) ratio of 55 : 45. The two epimers were separated by prep. HPLC (Bischoff,
5
)
)
For the preparation of Fmoc-Val-Y(CS)-Aib-Leu-OMe, see [3].
The ESI-MS of this product showed a peak at m/z 1053 ([M ‡ Na] ); the molecular weight of the linear
octaendothiopeptide 29 is 1030.
‡
6

1914
Helvetica Chimica Acta ± Vol. 82 (1999)
Spherisorb ODS2, 5 mm, MeCN/H2O 70 : 30, 8.0 ml/min). The following data are those of 30 with the (R)-
configuration of Ala. [a]D ˆ ‡10.6 (c ˆ 0.50). IR: 3475w, 3340m, 3000w, 2960m, 2935w, 2870w, 1740m, 1670s,
1505s, 1415m, 1365m, 1280w, 1170s, 1005w, 925w, 855w. 1H-NMR (600 MHz; 1H-TOCSY, 1H-DQF-COSY,
13C,1H-HSQC, 13C,1H-HMBC): 8.46 (br. s, H N(1) (Trp)); 7.90 (br. s, NH (Aib(2))); 7.65 (d, J ˆ 8.0, H C(4)
(Trp)); 7.40 (d, J ˆ 8.1, H C(7) (Trp)); 7.30 (br. s, NH (Valt)); 7.20 (t, J ˆ 7.7, H C(6) (Trp)); 7.13 (t, J ˆ 7.8,
H
C(5) (Trp)); 7.11 ± 7.06 (m, H C(2) (Trp), NH (Ile(2)), NH (Aib(3)), NH (Ala)); 6.86 (br. d, J ˆ 7.7, NH
(Leu)); 6.32 (d, J ˆ 8.1, NH (Ile(1))); 5.11 (d, J ˆ 5.3, NH (Trp)); 4.82 ± 4.77 (m, H C(a) (Ala)); 4.54 (dd, J ˆ
3.4, 8.8, H C(2) (Pro)); 4.40 ± 4.37 (m, H C(a) (Leu)); 4.29 ± 4.27 (m, H C(a) (Ile(1))); 4.23 ± 4.21
(m, H C(a) (Valt)); 3.77 ± 3.71 (m, 1 H C(5) (Pro), MeO); 3.55 ± 3.50 (m, 1 H C(5) (Pro)); 3.31 ± 3.25
(m, H C(a) (Ile(2)), 2 H C(b) (Trp)); 2.49 ± 2.42 (m, H C(b) (Valt)); 2.11 ± 1.97 (m,1 H C(3) (Pro),
1 H C(4) (Pro)); 1.94 ± 1.77 (m, H C(b) (Ile(1)), H C(b) (Ile(2)), 1 H C(4) (Pro), 1 H C(3) (Pro),
1 H C(b) (Leu)); 1.77 (s, Me(1) (Aib(2))); 1.68 ± 1.37 (m,1 H C(b) (Leu), H C(g) (Leu), 1 H C(g)
(Ile(2)), 1 H C(g) (Ile(1))); 1.60 (s, Me(2) (Aib(2))); 1.56 (s, Me(1) (Aib(3))); 1.55 (s, Me(2) (Aib(3))); 1.51
(s, Me(1) (Aib(1))); 1.46 (s, Me(2) (Aib(1))); 1.44 (d, J ˆ 4.6, Me (Ala)); 1.42 (s, Me3C); 1.32 ± 1.23
(m, 1 H C(g) (Ile(2))); 1.05 (d, J ˆ 6.8, Me(1) (Valt)); 0.99 ± 0.93 (m, 1 H C(g) (Ile(1))); 0.93 (d, J ˆ 7.4,
Me(2) (Valt)); 0.92 (d, J ˆ 6.8, Me(2) (Leu)); 0.90 (t, J ˆ 7.5, Me(d) (Ile(2))); 0.88 (d, J ˆ 6.6, Me(1) (Leu),
Me(b1) (Ile(2))); 0.83 (t, J ˆ 7.3, Me(d) (Ile(1))); 0.77 (d, J ˆ 6.9, Me(b1) (Ile(1))). 13C-NMR (150.9 MHz):
201.8 (s, CS (Valt)); 179.2 (s, thiazole C(5)); 173.5 (2s, CO (Pro), CO (Ile(2))); 172.4 (s, CO (Aib(2))); 172.1
(s, CO (Aib(3))); 171.9 (s, CO (Trp)); 171.0 (s, CO (Leu)); 170.8 (s, CO (Ile(1))); 164.6 (s, thiazole C(2)); 156.4
(s, urethane CO); 136.6 (s, C(3a) (Trp)); 127.5 (s, C(7a) (Trp)); 123.5 (d, C(2) (Trp)); 122.6 (d, C(6) (Trp));
120.1 (d, C(5) (Trp)); 118.9 (d,C(4) (Trp)); 111.6 (d, C(7) (Trp)); 110.3 (s, C(3) (Trp)); 83.3 (s, thiazole C(4));
81.0 (s, Me3C); 79.0 (d, C(a) (Ile(2))); 68.2 (d, C(a) (Valt)); 61.2 (s, C(a) (Aib(2))); 60.9 (d, C(2) (Pro)); 58.3
(d, C(a) (Ile(1))); 57.1 (s, C(a) (Aib(3))); 56.1 (d, C(a) (Trp)); 53.1 (d, C(a) (Leu)); 52.2 (q, MeO)); 49.3
(d, C(a) (Ala)); 48.4 (t, C(5) (Pro)); 40.6 (t, C(b) (Leu)); 40.2 (d, C(b) (Ile(2))); 36.8 (d, C(b) (Ile(1))); 32.1
(d, C(b) (Valt)); 28.5 (q, Me3C)); 28.1 (t, C(3) (Pro)); 27.9 (q, Me(2) (Aib(1))); 27.9 (t, C(b) (Trp)); 27.0
(q, Me(1) (Aib(1))); 26.8 (q, Me(2) (Aib(2))); 26.2 (t, C(4) (Pro)); 25.7 (t, C(g) (Ile(2))); 25.3 (d, C(g)
(Leu)); 25.1 (q, Me(2) (Aib(1))); 24.7 (t and q, C(g) (Ile(1)), Me(1) (Aib(3))); 23.6 (q, Me(2) (Leu), Me(1)
(Aib(2))); 21.4 (q, Me(1) (Leu)); 20.2 (q, Me(1) (Valt)); 18.9 (q, Me (Ala)); 17.5 (q, Me(2) (Valt)); 16.1
(q, Me(b1) (Ile(2))); 15.8 (q, Me(b1) (Ile(1))); 12.1 (q, Me(d) (Ile(2))); 11.9 (q, Me(d) (Ile(1))). ESI-MS: 1217
‡
([M ‡ Na] ), 620 ([M ‡ 2Na]2‡).
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Received July 22, 1999