Pseudoaxially disubstituted cyclo-β3-tetrapeptide scaffolds

Article abstract of DOI:10.1016/S0040-4020(00)00666-9

An N,N-disubstituted cyclo-β³-tetrapeptide, identified as a potential molecular scaffold, has been synthesised on a multigram scale from β-homophenylalanine by employing a nosylate-based protection strategy. C₂-Symmetric derivatives containing pseudoaxial, combinatorially addressable functionalities have been prepared from the parent cyclopeptide. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00666-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7947±7958
Pseudoaxially Disubstituted Cyclo-b3-tetrapeptide Scaffolds
*
*
Â
Á
Á
Peter W. Sutton, Adrian Bradley, Jaume Farras, Pedro Romea, Felix Urpõ and Jaume Vilarrasa
 Á
Departament de Quõmica Organica, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
Received 22 May 2000; revised 28 June 2000; accepted 20 July 2000
AbstractÐAn N,N-disubstituted cyclo-b3-tetrapeptide, identi®ed as a potential molecular scaffold, has been synthesised on a multigram
scale from b-homophenylalanine by employing a nosylate-based protection strategy. C2-Symmetric derivatives containing pseudoaxial,
combinatorially addressable functionalities have been prepared from the parent cyclopeptide. q 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
Furthermore, such compounds might also be amenable to
standard peptide methodology. These calculations were
further con®rmed by the synthesis and three-dimensional
structure elucidation of a C2-symmetric prototype 1 (Fig.
1) which may be seen as a tetramer of b-homophenylalanine
(b3-hPhe).7
Performing reactions in a highly selective and ef®cient
manner has been a long-term goal for organic chemists,
which is nowadays being fuelled by the need to devise
synthetically clean processes to give access to a vast array
of complex structures.1 This challenge has been accelerated
by the development of new concepts and methods2 and, in
particular, has led to intensive research into the discovery of
synthetic catalysts.2b,3 In this context we, as part of a colla-
borative effort,4 have embarked on a project to generate new
families of catalysts based on a con®gurationally rigid,
chiral scaffold with conveniently oriented functional
handles for subsequent diversi®cation through the use of
combinatorial chemistry.4±6
Initially, cyclo-b3-tetrapeptide 1 was prepared in suf®cient
amounts to elucidate its structure and physical properties.
However, as we needed to obtain 1 on a larger scale in order
to perform further chemistry, it became necessary to opti-
mise the synthetic route. Herein, we report an improved
synthesis that allows the preparation of 1 on a multigram
scale and the functionalisation of the N-allyl moieties so as
to facilitate direct attachment of appendages.
We have reported recently the evaluation of a range of
polyamide macrocycles derived from a-, b-, and g-amino
acids by means of molecular mechanics.6 From this study
N,N-disubstituted cyclo-(S,S,S,S)-b3-tetrapeptides were
recognised as suitable targets, possessing a rigid framework,
pseudoaxially located functionality on the nitrogen atoms
and a potential point of attachment to a solid support.
Results and Discussion
The previously described route leading to 1 is based on the
cyclisation of a linear b3-tetrapeptide which in turn is
obtained by a Boc protection strategy from (S)-phenyl-
alaninol (2), readily prepared from l-phenylalanine (see
Figure 1. Drawing of compound 1 and of its X-ray crystal structure (side view, with phenyl groups omitted for clarity).
Keywords: amino acids and derivatives; aziridines; macrocycles; b3-peptides; sulfonamides.
* Corresponding authors. Tel. 134-93-402-1248; fax: 134-93-339-78-78; e-mail: furpi@qo.ub.es; e-mail: promea@qo.ub.es
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00666-9

7948
P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
Scheme 1. (a) Boc2O, THF, H2O, 17 h; (b) TsCl, pyridine, CHCl3, 1 h; (c) NaCN, DMF, 558C, 22 h; (d) NaOH, H2O2, MeOH, H2O, 6 h; (e) (MeO)2CHNMe2,
MeOH, 7 h; (f) 1 M LiOH, dioxane, 20 h, then Amberlyst-15 resin (H1 form); (g) KHMDS, DMF, 2208C, 5 min then allyl iodide, 2208C, 45 min; (h) TFA,
CH2Cl2, 1 h then Amberlyst A-26 resin (Cl2 form); (i) PyBroP, HOAt, EtiPr2N, CH2Cl2, 16 h; (j) TFA, CH2Cl2, 2 h; (k) 1 M LiOH, dioxane, 23 h, then
Amberlyst-15 resin (H1 form); (l) PyBroP, EtiPr2N, CH2Cl2, 23 h; (m) 1 M LiOH, MeOH, 20 h, then 0.5 M citric acid; (n) C6F5OH, EDC´HCl, CH2Cl2, 15 h;
(o) i: TFA, CH2Cl2, 3 h; ii: EtiPr2N, MeCN, 708C, addition over 12 h plus further heating for 4 h.
Scheme 1).8 Although it constitutes a highly convergent and
versatile approach to tetralactam 1, it was considered that it
could be improved; with this purpose two issues were
addressed.
Scheme 1) proved to be problematic in two steps: (i) basic
hydrolysis of the nitrile 5 directly to the acid 8 was low
yielding and a longer route had to be taken via the amide
6 (49% over three steps); (ii) the allylation of the methyl
ester 7 turned out to be troublesome and required very
precise conditions to give acceptable yields of 9 (see
Scheme 1).9 Facing both problems, as appealing alternatives
to the use of the Boc group we turned our attention to the
sulfonyl-like protecting groups due to their stability to both
acidic and basic media, the milder conditions required for
their N-alkylation, and the current availability of smooth
deprotection procedures.10 Thus, phenylalaninol (2) was
converted in a high yielding one-pot procedure to the aziri-
dine 19 (see Scheme 3) by reaction with excess of p-nitro-
benzenesulfonyl chloride (NsCl) and pyridine followed by a
basic work up. The nosyl aziridine 19 reacted with cyanide
ion with complete regioselectivity,11 to afford the nitrile
which, without puri®cation, was hydrolysed under acidic
Firstly, the possibility of shortening the synthesis by way of
a one-pot dimerisation and cyclisation via the crude penta-
¯uorophenyl ester 17 was studied. Unfortunately, the cyclic
dipeptide 18 (see Scheme 2) was obtained in 74% yield
(57% from 13) instead of 1, when the above-mentioned
process was carried out under dilute conditions; at higher
concentrations, without slow addition of the activated
dipeptide, mixtures of 18 and 1 were formed, but the
cyclo-b3-tetrapeptide 1 was never isolated in a synthetically
useful yield (see Scheme 2 and Table 1).
Secondly, evaluation of the N-protecting groups was
addressed. The previously reported Boc-based route (see
Scheme 2. (a) i: C6F5OH, EDC´HCl, CH2Cl2, 15 h; ii: TFA, CH2Cl2, 2 h; (b) EtiPr2N, MeCN, 708C, 15 h.

P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
Table 1. One-pot dimerisation and cyclisation of 17
7949
®rst portion was subjected to a basic hydrolysis and the
second one treated with mercaptoacetic acid and DBU, to
give the acid 24 (88%) and the amino ester 25 (91%) respec-
tively.12 Treatment of 24 with thionyl chloride followed by
addition of 25 gave a complex mixture. Therefore, 24 and
25 were coupled using EDC/HOAt methodology to give the
linear tetrapeptide 26 in good yield after chromatographic
puri®cation.13 Removal of the Ns protecting group followed
by hydrolysis of the ester 27 and cyclisation of the crude
product under high dilution conditions (0.004 M), at 708C in
the presence of PyBroP, HOAt and EtiPr2N, afforded the
target macrolactam 1 in 35% yield (over two steps).14
Thus, the macrocycle 1 was prepared in 10% overall yield
(12 steps from phenylalaninol) with just two chromato-
graphic puri®cations required.
[M]
Reaction time (h)
Yieldsa (%)
18
1
0.002b
0.1c
1c
15
4
19
14
74
30
20
23
±
12
21
18
2c
a Yields are given for puri®ed products.
b Cyclisation performed by the slow addition over 12 h of a dilute solu-
tion of the activated ester 17 to a solution of EtiPr2N in MeCN at 708C.
c EtiPr2N added dropwise to a solution of the activated ester 17 in MeCN
at 708C.
conditions to the acid 20. It should be stressed that the
b-amino acid 20 can be readily prepared in quantities up
to 30 g (64% from phenylalaninol in three steps) without
need for chromatographic puri®cation or use of special
equipment. The acid 20 was esteri®ed and the resulting
methyl ester 21 converted, in one pot, into the N-allyl
amino ester 22 (86%) by treatment with allyl bromide and
potassium carbonate followed by the addition of mercapto-
acetic acid and DBU in order to remove the p-nitroben-
zenesulfonyl group.10 Thiophenol and b-mercaptoethanol
proved to be equally successful regarding the cleavage of
the sulfonamide, but they require the use of chromato-
graphic puri®cation to remove the thioether formed as co-
product that, in the former case, can be easily extracted with
a dilute NaHCO3 solution.10
Having developed a route to the tetralactam 1 that enabled
us to routinely access gram scale quantities, we turned our
attention to the modi®cation of the allyl substituents. We
were particularly interested in the preparation of scaffold
systems containing either amine or acid functionalities to
which appendages might be attached through stable amide
bonds. Also, a scaffold containing two independently
addressable side chains was deemed highly desirable.
It was envisioned that amino derivatives of the tetralactam 1
might be obtained by conversion of the carbon±carbon
double bonds into the corresponding hydroxy groups.
Hydroboration of 1 gave no identi®able products under a
variety of standard reaction conditions. However, ozonoly-
sis followed by sodium borohydride reduction smoothly
afforded the C2-symmetric diol 28 in 74% yield (see Scheme
5). The diol 28 was converted, by a standard two step pro-
cedure, into the diazide 29 in 66% yield. The diazide 29
The two b3-amino acid building blocks 20 and 22 were
coupled using a thionyl chloride activation procedure to
afford the dipeptide 23 in 98% yield which was subse-
quently split into two portions as shown in Scheme 4. The
Scheme 3. (a) p-NsCl, CH2Cl2, pyridine, 10 h, then 2 M KOH; (b) i: NaCN, MeCN, H2O, 16 h. ii: 37% HCl, AcOH, re¯ux, 4 h; (c) PTSA, MeOH, re¯ux, 20 h;
(d) allyl bromide, K2CO3, DMF, 18 h, then HSCH2COOH, DBU, 3 h.
Scheme 4. (a) i: SOCl2, re¯ux, 1 h; ii: 22, THF, pyridine, 2 h; (b) 1 M LiOH, MeOH, 20 h then 0.5 M citric acid; (c) HSCH2COOH, DBU, DMF, 16 h;
(d) EDC´HCl, HOAt, CH2Cl2, 20 h; (e) i: 1 M LiOH, MeOH, 16 h, then 2 M HCl; ii: PyBroP, HOAt, EtiPr2N, MeCN, 708C, 4 h.

7950
P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
Scheme 5. (a) O3, CH2Cl2, 2788C, 40 min, then NaBH4, MeOH, 2208C, 40 min; (b) i: MsCl, Et3N, CH2Cl2, 16 h; ii: NaN3, DMF, 22 h; (c) 1 M Me3P, THF,
2208C, 5 min, then Boc-ON, 18 h; (d) TBDPSCl, imidazole, CH2Cl2, 2.5 h; (e) i: O3, CH2Cl2, 2788C, 1 h, then NH2CONH2´H2O2, DBU, 2208C, 16 h; ii:
PTSA, MeOH, re¯ux, 16 h.
failed to give the desired diamine by catalytic hydrogena-
tion (Pd/C), but the Boc-protected diamine 30, also a
C2-symmetric compound, was readily obtained in high
yield by treatment with trimethyl phosphine and Boc-
ON.15 Alternatively, 28 was desymmetrised by treatment
with 1.3 equiv. of TBDPSCl in CH2Cl2 to afford the mono-
silyl ether 31 (43%) together with the disilyl ether 32 (24%)
and the unreacted diol 28 (8%). Finally, ozonolysis followed
by an oxidative treatment cleanly produced the correspond-
ing diacid (83% yield), which was characterised as its
dimethyl ester 33.
spectra were recorded on a Varian Unity Inova 500 spec-
trometer; chemical shifts (d) are quoted in ppm and
referenced to internal TMS for H NMR and CDCl3 (d
1
77.0), DMSO-d6 (d 39.7) or CD3OD (d 49.0) for 13C
NMR; data are reported as follows: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; br, broad; where appro-
priate, 2D techniques were also used to assist in structure
elucidation. Low resolution mass spectra (LRMS) were
performed by the Servei d'Espectrometria de Masses,
Universitat de Barcelona. High resolution mass spectra
(HRMS) were obtained from the Centro de Apoio Cienti®co
Tecnoloxico a Investigacion (C.A.C.T.I.), Universidad de
Vigo. Elemental analyses were obtained by the Servei de
In conclusion, we have synthesised the prototype of a new
family of scaffolds that is readily accessible on a multigram
scale employing a sulfonamide-based protection strategy.
Furthermore, it may be readily derivatised to incorporate
functionalities to which catalytic appendages might be
directly attached. The adaptation of this methodology to
the solid support and the generation of libraries of catalysts
are subjects of further investigation in our laboratories.
Á
Microanalisi (CID-CSIC, Barcelona). Flash chroma-
tography was performed on SDS silica gel (35±70 mm).
Analytical thin-layer chromatography was carried out on
Merck Kieselgel 60 F254 plates. The following solvents
and reagents were puri®ed and dried according to standard
procedures: THF, CH2Cl2, MeOH, MeCN, Et3N, EtiPr2N
and pyridine. All other reagents were used as received.
The following known compounds were prepared by litera-
ture procedures: (S)-2-tert-butoxycarbonylamino-3-phenyl-
1-propanol (3),16 (S)-2-tert-butoxycarbonylamino-3-phenyl-
1-propyl p-toluenesulfonate (4),17 and (S)-3-tert-butoxy-
carbonylamino-4-phenylbutanenitrile (5).17
Experimental
Melting points were taken on an Electrothermal apparatus
and have not been corrected. Speci®c rotations were deter-
mined at 208C on a Perkin±Elmer 241 MC polarimeter. IR
spectra were recorded on either a Perkin-Elmer 681 or a
Nicolet 510 FT spectrometer and only the more representa-
(S)-3-tert-Butoxycarbonylamino-4-phenylbutanamide (6).
A solution of NaOH (16.47 g, 410 mmol) and 33% w/v
H2O2 (8.5 mL, 82 mmol) in H2O (100 mL) was added to a
stirred solution of 5 (10.74 g, 41 mmol) in MeOH (200 mL).
After 6 h, the resulting white precipitate was ®ltered,
washed with H2O until neutral pH and dried in vacuo over
P4O10 to afford 6 (6.71 g, 58%) as a white powder: Rfˆ0.15
(CH2Cl2/MeOH 20:1); mp 125±1298C; [a]Dˆ218.96
1
tive frequencies (cm21) are reported. H NMR (200 MHz)
and 13C NMR (50.3 MHz) spectra were recorded on a
Varian Gemini 200 spectrometer; 1H NMR (300 MHz)
and 13C NMR (75.4 MHz) spectra were recorded on a
1
Varian Unity Plus 300 spectrometer; H NMR (500 MHz)

P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
7951
(cˆ2.6 in CHCl3); IR (KBr): n 3400, 3357, 3197, 2981,
at 08C under N2. The solution was stirred at room tempera-
ture for 1 h. The volatiles were removed by distillation
under reduced pressure and the residue re-dissolved in
CH2Cl2 (20 mL). An excess of Amberlyst A-26 (Cl2
form) was added and the resulting mixture was stirred for
1 h and ®ltered. The solvent was removed by distillation
under reduced pressure to afford 10 (1.56 g, 100%) as a
colourless oil: [a]Dˆ23.55 (cˆ0.9 in CHCl3); IR (®lm):
1
1692, 1650, 1530, 1167; H NMR (DMSO-d6, 200 MHz)
d 7.31±7.20 (5H, m, ArH), 4.07 (1H, m, CHNH), 2.84
(2H, m, CH2Ar), 2.37 (2H, m, CH2CO), 1.38 (9H, s,
C(CH3)3); 13C NMR (DMSO-d6, 50.3 MHz) d 172.9,
155.3, 139.5, 129.8, 128.6, 126.5, 78.1, 49.9, 40.6, 40.1,
28.9; LRMS (CI, NH3) m/z (%): [M]1 278 (100); HRMS
(FAB): calcd for [M1H]1 C15H23N2O3: 279.1709; found:
279.1708.
1
n 2958, 2900±2200, 1739, 1673, 1202; H NMR (CDCl3,
200 MHz) d 7.33±7.20 (5H, m, ArH), 6.00 (1H, m,
CH2CHvCH2), 5.45 (2H, m, CH2CHvCH2), 3.71 (3H,
m, CHNH and CH2CHvCH2), 3.61 (3H, s, OCH3), 3.36
(1H, dd, Jˆ13.8, 4.5 Hz, CHaHbAr), 2.90 (2H, m, CHaHbAr
and CHaHbCO), 2.70 (1H, dd, Jˆ17.7, 5.1 Hz, CHaHbCO);
13C NMR (CDCl3, 50.3 MHz) d 170.7, 135.2, 129.2, 128.9,
127.7, 127.4, 123.8, 55.0, 52.1, 48.0, 36.8, 34.4; LRMS
(FAB) m/z (%): [M2Cl]1 234 (100), 160 (33), 117 (19).
Methyl (S)-3-tert-butoxycarbonylamino-4-phenylbutano-
ate (7). N,N-Dimethylformamide dimethyl acetal (10 mL,
75.4 mmol) was added dropwise to a stirred suspension of 6
(6.71 g, 24.0 mmol) in dry MeOH (60 mL). After 7 h a
0.5 M aqueous solution of citric acid (200 mL) was added
and the resulting white precipitate ®ltered, washed with H2O
(200 mL) and dried in vacuo to afford 7 (6.39 g, 91%) as a
white powder: mp 53.0±54.08C (lit.18 mp 54.5±55.58C);
[a]Dˆ29.58 (cˆ2.4 in CHCl3) (lit.18 [a]Dˆ210 (cˆ0.99
in CHCl3)).
Methyl N-tert-butoxycarbonyl-(S)-b3-homophenylalanyl-
N-allyl-(S)-b3-homophenylalaninate [Boc-b3-hPhe-N-
allyl-b3-hPhe-OMe] (11). Dry EtiPr2N (2.5 mL,
14.4 mmol), HOAt (328 mg, 2.4 mmol) and PyBroP
(2.566 g, 5.5 mmol) were added consecutively to a stirred
solution of 8 (702 mg, 2.4 mmol) and 10 (792 mg,
2.9 mmol) in dry CH2Cl2 (3 mL) at 08C under N2. The
resulting mixture was stirred at room temperature for
16 h. A 0.5 M aqueous solution of citric acid (10 mL) was
added and the mixture extracted with CH2Cl2 (3£10 mL).
The organic portions were combined, dried (MgSO4) and
the solvent removed by distillation under reduced pressure.
The residue was puri®ed by ¯ash chromatography (hexanes/
EtOAc 7:3) to afford 11 (827 mg, 68%) as a glassy solid:
Rfˆ0.30 (hexanes/EtOAc, 7:3); mp 87±898C (from EtOAc/
hexanes); [a]Dˆ237.89 (cˆ1.4 in CHCl3); IR (KBr): n
3417, 2979, 1739, 1701, 1653, 1507, 1028; 1H NMR
(CDCl3, 200 MHz; 2:1 rotamers ratio) d 7.40±6.88 (10H,
m, ArH), 5.85 and 5.34 (1H, m, CH2CHvCH2, ratio 1:2),
5.61 (1H, d, Jˆ8.0 Hz, NH), 5.15 and 4.95 (2H, m,
CH2CHvCH2, ratio 1:2), 4.54 and 4.30 (1H, m, allylNCH,
ratio 2:1), 4.17 and 3.61 (3H, m, HNCH and CH2CHvCH2),
3.41 and 3.37 (3H, s, OCH3, ratio 2:1), 3.14±2.04 (8H, m,
2£CH2Ar, CH2CO2 and CH2CON), 1.41 and 1.37 (9H, s,
C(CH3)3, ratio 2:1); 13C NMR (CDCl3, 50.3 MHz; asterisk
denotes the minor rotamer) d 171.9, 171.7p, 171.1p, 170.8,
155.2, 138.7p, 138.6, 138.0, 136.9p, 134.5p, 133.5, 129.3±
128.3, 127.0±126.2, 117.4, 116.2p, 78.9, 78.8p, 56.5p, 55.9,
51.9p, 51.8, 50.4, 49.5, 48.9p, 44.0, 40.3, 40.0, 39.8p, 38.7,
37.3p, 36.8, 36.1, 35.6p, 28.4; LRMS (CI, NH3) m/z (%):
[M1H]1 495 (100), 297 (10), 280 (12), 279 (15); HRMS
(FAB): calcd for [M]1 C29H38N2O5: 494.2781; found:
494.2762.
(S)-3-tert-Butoxycarbonylamino-4-phenylbutanoic acid
[Boc-b3-hPhe-OH] (8). A 1 M aqueous solution of LiOH
(62 mL, 62 mmol) was added to a stirred solution of 7
(1.83 g, 6.3 mmol) in dioxan (160 mL). After 20 h, the
resulting solution was ®ltered through a bed of Amberlyst-
15 resin (H1 form) and the solvent removed by vacuum
distillation to afford 8 (1.60 g, 92%) as a white solid, similar
in all respects to a commercially available sample (Fluka
Chemie AG).
Methyl (S)-3-(N-allyl-N-tert-butoxycarbonylamino)-4-phenyl-
butanoate [Boc-N-allyl-b3-hPhe-OMe] (9). A 0.5 M solu-
tion of KHMDS in toluene (18 mL, 9 mmol) was added
dropwise to a stirred solution of 7 (2.50 g, 8.5 mmol) in
dry DMF (75 mL) at 2208C under N2. After 5 min allyl
iodide (1.5 mL, 16.5 mmol) was quickly added and the
resulting solution stirred for further 45 min. It was then
poured into a 0.5 M aqueous solution of citric acid
(150 mL) which was extracted with CH2Cl2 (3£100 mL).
The organic portions were combined, washed with H2O
(5£100 mL) and brine (100 mL), dried (MgSO4), and the
solvent removed by distillation under reduced pressure. The
residue was puri®ed by ¯ash chromatography (hexanes/
EtOAc 9:1) to afford 9 (2.20 g, 77%) as a colourless oil:
Rfˆ0.16 (hexanes/EtOAc 10:1); [a]Dˆ235.71 (cˆ0.91 in
1
CHCl3); IR (®lm): n 2977, 1740, 1694, 1366, 1171; H
NMR (CDCl3, 200 MHz) d 7.31±7.19 (5H, m, ArH), 5.58
(1H, m, CH2CHvCH2), 5.04 (2H, m, CH2CHvCH2), 4.21
(1H, m, CHNH), 3.63 (3H, s, OCH3), 3.62 (2H, m,
CH2CHvCH2), 2.95 (3H, m, CH2Ar and CHaHbCO), 2.56
(1H, m, CHaHbCO), 1.44 (9H, s, C(CH3)3); 13C NMR
(CDCl3, 50.3 MHz; 1:1 rotamers ratio) d 171.9, 171.5,
154.8, 154.5, 138.3, 134.9, 129.1, 128.2, 126.3, 116.4,
115.8, 79.9, 79.3, 56.9, 56.2, 51.4, 50.2, 49.9, 39.6, 38.7,
38.2, 37.4, 28.2; LRMS (CI, NH3) m/z (%): [M1NH4]1 351
(13), [M1H]1 334 (100), 278 (18); HRMS (EI): calcd for
[M]1 C19H27NO4: 333.1940; found: 333.1940.
TFA´H-b3-hPhe-N-allyl-b3-hPhe-OMe (12). Tri¯uoro-
acetic acid (0.60 mL, 7.8 mmol) was added dropwise to a
stirred solution of 11 (395 mg, 0.78 mmol) in dry CH2Cl2
(1 mL) at 08C under N2. The solution was stirred at room
temperature for 2 h. Concentration under reduced pressure
afforded the crude product 12 (407 mg, 100%). An analyti-
cal sample of the free amine was prepared, as a colourless
oil, by chromatographic puri®cation (CH2Cl2/MeOH 9:1):
Methyl (S)-3-allylamino-4-phenylbutanoate hydro-
chloride [HCl´H-N-allyl-b3-hPhe-OMe] (10). Tri¯uoro-
acetic acid (4.40 mL, 57.5 mmol) was added dropwise to a
stirred solution of 9 (1.92, 5.8 mmol) in dry CH2Cl2 (8 mL)
1
IR (®lm): n 3379, 3027, 2950, 1737, 1642, 1438, 1210; H
NMR (CDCl3, 300 MHz; 2:1 rotamers ratio) d 7.32±7.00
(10H, m, ArH), 5.81 and 5.47 (1H, m, CH2CHvCH2, ratio

7952
P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
1:2), 5.04 (2H, m, CH2CHvCH2), 4.46 (1H, m, allylNCH),
4.16 (dd, Jˆ16.2, 7.3 Hz) and 3.75±3.33 (m) (3H, HNCH
and CH2CHvCH2), 3.57 and 3.53 (3H, s, OCH3, ratio 2:1),
3.05 (dd, Jˆ15.4, 8.1 Hz), 2.94±2.46 (m), 2.32 (dd, Jˆ16.2,
4.1 Hz) and 2.15 (dd, Jˆ16.2, 8.0 Hz) (8H, 2£CH2Ar,
CH2CO2 and CH2CON), 1.66 (2H, br d, Jˆ16.0 Hz, NH2);
13C NMR (CDCl3, 75.4 MHz; asterisk denotes the minor
rotamer peaks) d 172.6, 172.1p, 172.0, 171.1p, 139.0p,
138.9, 138.2, 137.0p, 134.7p, 133.9, 129.2±128.4, 126.8±
126.3, 117.4, 116.6p, 56.7, 55.5, 54.5, 52.0, 51.6, 50.4,
49.8, 48.7, 43.9, 43.6, 41.4, 40.4, 39.7, 38.6, 37.4, 36.8;
LRMS (ES) m/z (%): [M]1 394 (25), 377 (12), 363 (18),
303 (100); HRMS (FAB): calcd for [M]1 C24H30N2O3:
394.2256; found: 394.2240.
C18; H2O (10.045% TFA): MeCN (10.036% TFA);
10±100% of MeCN in 330 min; 1 mL/min): trˆ26.2 min.
Boc-b3-hPhe-N-allyl-b3-hPhe-b3-hPhe-N-allyl-b3-hPhe-
OH (15). A 1 M aqueous solution of LiOH (1.4 mL,
1.4 mmol) was added to a stirred solution of 14 (123 mg,
0.14 mmol) in MeOH (3 mL). After 20 h the resulting
solution was diluted with EtOAc (20 mL), washed with a
0.5 M aqueous solution of citric acid (2£20 mL) and H2O
(20 mL), dried (MgSO4) and the solvent removed by
vacuum distillation to afford 15 (95 mg, 78%) as a colour-
less oil which was used without further puri®cation:
Rfˆ0.11 (CH2Cl2/MeOH 20:1); [a]Dˆ242.47 (cˆ2.0 in
CHCl3); IR (®lm): n 3318, 2971, 2864, 1711, 1642, 1455,
1
1171, 1088; H NMR (CDCl3, 500 MHz; mixture of rota-
Boc-b3-hPhe-N-allyl-b3-hPhe-OH (13). A 1 M aqueous
solution of LiOH (6.0 mL, 6 mmol) was added to a stirred
solution of 11 (302 mg, 0.6 mmol) in dioxane (30 mL). After
23 h the resulting solution was ®ltered through a bed of
Amberlyst-15 resin (H1 form) and the solvent removed by
vacuum distillation to afford 13 (291 mg, 99%) as a colour-
less oil: Rfˆ0.55 (CH2Cl2/MeOH 9:1); [a]Dˆ241.21
(cˆ0.1 in CHCl3); IR (®lm): n 3333, 2977, 2621, 1707,
1636, 1595, 1169; 1H NMR (CDCl3, 500 MHz; 1:1 rotamers
ratio) d 7.33±6.85 (10H, m, ArH), 5.86, 5.50 and 5.36 (2H,
m, CH2CHvCH2 and NH), 5.15 and 4.95 (2H, m,
CH2CHvCH2), 4.50 and 4.24 (1H, m, allylNCH), 4.14,
3.72, 3.62 and 3.49 (3H, m, HNCH and CH2CHvCH2),
3.07±1.92 (8H, m, 2£CH2Ar, CH2CO2 and CH2CON),
1.39 and 1.30 (9H, s, C(CH3)3); 13C NMR (CDCl3,
75.4 MHz) d 175.4, 174.4, 172.5, 171.7, 156.4, 155.8,
138.5, 138.1, 137.2, 134.6, 133.3, 129.4±128.4, 127.0±
126.3, 117.6, 116.8, 80.5, 79.3, 56.9, 56.3, 50.6, 49.7,
49.3, 44.2, 41.0, 40.5, 40.0, 38.6, 37.5, 36.9, 36.2, 36.1,
28.4; LRMS (ES) m/z (%): [M]1 480 (25), 407 (14), 389
(63), 289 (100); HRMS (FAB): calcd for [M]1 C28H36N2O5:
480.2624; found: 480.2613.
mers) d 7.32±7.05 (18H, m, ArH), 6.96±6.81 (3H, m, ArH
and NH), 5.93±5.71 and 5.54±4.84 (7H, m, 2£
CH2CHvCH2 and 2£CH2CHvCH2 and NH), 4.64±3.44
(8H, m, 2£allylNCH, 2£HNCH and 2£CH2CHvCH2),
3.24±1.89 (16H, 4£CH2Ar, CH2CO2 and 3£CH2CON),
1.40±1.29 (9H, m, C(CH3)3); 13C NMR (CDCl3,
75.4 MHz) d 174.3±169.1, 156.7±154.8, 138.6±137.1,
135.0±133.3, 129.9±128.4, 127.9±126.1, 118.1±116.4,
80.2±78.5, 57.2±56.5, 51.9±47.1, 44.3, 44.1, 40.9±35.0,
28.3; LRMS (ES) m/z (%): [M1H]1 844 (10), 795 (100);
HRMS (FAB): calcd for [M1H]1 C51H63N4O7: 843.4697;
found: 843.4698.
Boc-b3-hPhe-N-allyl-b3-hPhe-b3-hPhe-N-allyl-b3-hPhe-
OC6F5 (16). A solution of penta¯uorophenol (12 mg,
65 mmol) and EDC´HCl (15 mg, 78 mmol) in dry CH2Cl2
(2 mL) was added dropwise to a stirred solution of 15
(41 mg, 47 mmol) in dry CH2Cl2 (2 mL) at 08C under N2.
The mixture was stirred at room temperature for 15 h,
washed with a 0.5 M aqueous solution of citric acid
(5 mL) and brine (5 mL) and dried (MgSO4). The solvent
was removed by distillation under reduced pressure to afford
16 (38 mg, 78%) as a colourless oil which was used without
further puri®cation: Rfˆ0.56 (CH2Cl2/MeOH 20:1); IR
(®lm): n 3247, 2971, 2869, 1788, 1709, 1645, 1522, 1454,
1175, 1086; 1H NMR (CDCl3, 200 MHz; mixture of
rotamers) d 7.60±6.80 (20H, m, ArH), 5.96±4.80 (6H, m,
2£CH2CHvCH2 and 2£CH2CHvCH2), 4.54±3.92 (4H, m,
2£allylNCH and 2£HNCH), 3.80±1.80 (20H, 2£
CH2CHvCH2, 4£CH2Ar, CH2CO2 and 3£CH2CON),
1.39±1.29 (9H, m, C(CH3)3); LRMS (ES) m/z (%):
[M1H]1 1009 (75), 905 (100), 743 (20), 547 (17); HRMS
(FAB): calcd for [M1H]1 C57H62F5N4O7: 1009.4539;
found: 1009.4547.
Boc-b3-hPhe-N-allyl-b3-hPhe-b3-hPhe-N-allyl-b3-hPhe-
OMe (14). Dry EtiPr2N (0.30 mL, 1.73 mmol) was added to
a stirred solution of 13 (283 mg, 0.57 mmol), 12 (354 mg,
0.58 mmol) and PyBroP (408 mg, 0.87 mmol) in dry
CH2Cl2 (2 mL) at 08C under N2. The resulting mixture
was stirred at room temperature for 24 h and the solvent
was removed by distillation under reduced pressure. The
residue was puri®ed by ¯ash chromatography (CH2Cl2/
MeOH 20:1) to afford 14 (161 mg, 35%) as a colourless
oil: Rfˆ0.13 (CH2Cl2/MeOH 20:1); [a]Dˆ239.69 (cˆ1.6
in CHCl3); IR (®lm): n 3245, 2970, 2869, 1710, 1646, 1454,
1
1177, 1084; H NMR (CDCl3, 300 MHz; mixture of rota-
mers) d 7.35±7.08 (18H, m, ArH), 7.03±6.88 (2H, m, ArH),
5.84 and 5.48±4.83 (6H, m, 2£CH2CHvCH2 and
2£CH2CHvCH2), 4.70±3.93 and 3.80±3.32 (11H, m,
2£allylNCH, 2£HNCH, 2£CH2CHvCH2 and OCH3),
3.17±2.04 (16H, 4£CH2Ar, CH2CO2 and 3£CH2CON),
1.40, 1.37 and 1.33 (9H, s, C(CH3)3); 13C NMR (CDCl3,
75.4 MHz) d 172.1±170.9, 169.8, 168.5, 156.5, 138.8±
137.5, 137.1, 136.8, 135.0, 134.1, 137.0, 130.0±128.2,
126.8±125.6, 117.5±115.8, 79.7±78.3, 56.5±55.4, 51.8,
51.7, 50.0, 49.4, 48.5, 47.6, 47.0, 43.8, 40.5±35.0, 28.3;
LRMS (MALDI-TOF) m/z: [M1K]1 895.7, [M1Na]1
879.7; HRMS (FAB): calcd for [M1H]1 C52H65N4O7:
857.4853; found: 857.4827. HPLC (250£4 mm Nucleosil
Cyclo-(N-allyl-b3-hPhe-b3-hPhe-N-allyl-b3-hPhe-b3-hPhe)
(1). Tri¯uoroacetic acid (30 mL, 0.39 mmol) was added
dropwise to a stirred solution of 16 (38 mg, 37 mmol) in
dry CH2Cl2 (1 mL) at 08C under N2. The resulting mixture
was stirred at room temperature for 3 h. The solvent was
removed by distillation under reduced pressure and the
residue was added in dry MeCN (4 mL) over a period of
12 h to a stirred solution of dry EtiPr2N (10 mL, 58 mmol) in
dry MeCN (20 mL) at 708C under N2. After stirring for
further 4 h the solvent was removed by distillation under
reduced pressure. The residue was dissolved in EtOAc
(10 mL), washed with a 0.5 M aqueous solution of citric
acid (2£5 mL), a 0.1 M aqueous solution of NaOH

P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
7953
(2£5 mL) and H2O (5 mL), dried (MgSO4) and the solvent
removed by distillation under reduced pressure. The residue
was puri®ed by ¯ash chromatography (CH2Cl2/MeOH 50:1)
to afford the tetralactam 1 (17 mg, 62%) as a colourless
foam: Rfˆ0.24 (CH2Cl2/MeOH 50:1); mp 162±1638C
(from CH2Cl2/pentane); [a]Dˆ254.56 (cˆ1.0 in CHCl3);
IR (KBr): n 3404, 3064, 2957, 1653, 1505, 1382, 1214;
1H NMR (CDCl3, 500 MHz) d 7.63 (1H, d, Jˆ10.0 Hz,
NH), 7.30±7.16 (10H, m, ArH), 5.14 (1H, m,
CH2CHvCH2), 4.88 (2H, m, CH2CHvCH2), 4.45 (1H,
m, HNCH), 3.70 (1H, m, allylNCH), 3.33 (4H, m,
CH2CHvCH2, allylNCHCHaHbAr, CHaHbCONH), 3.11
(1H, dd, Jˆ13.5, 7.5 Hz, allylNCHCHaHbAr), 3.03 (2H,
m, HNCHCH2Ar), 2.33 (1H, dd, Jˆ13.0, 5.0 Hz,
CHaHbCONH), 2.30 (1H, dd, Jˆ17.0, 2.5 Hz, CHaHbCON-
allyl), 2.03 (1H, dd, Jˆ17.0, 4.0 Hz, CHaHbCONallyl);
13C NMR (CDCl3, 75.4 MHz) d 171.9, 170.1, 138.6,
138.5, 132.4, 129.3, 129.2, 128.6, 128.5, 126.7, 126.5,
118.2, 63.9, 55.7, 46.7, 40.1, 39.8, 38.7, 35.6; HRMS
(FAB): calcd for [M1H]1 C46H53N4O4: 725.4067; found:
725.4079.
(S)-N-p-Nitrobenzenesulfonyl-2-benzylaziridine
(19).
p-Nitrobenzenesulfonyl chloride (4.44 g, 20.0 mmol) was
added in one portion to a stirred suspension of 2 (1.01 g,
6.7 mmol) in dry CH2Cl2 (5 mL) and dry pyridine (2.2 mL)
at 08C. The resulting mixture was stirred at room tempera-
ture for 10 h, diluted with CH2Cl2 (100 mL) and washed
with 2 M HCl (2£100 mL), which was subsequently
extracted with CH2Cl2 (20 mL). The organic portions were
combined and shaken with a 2 M aqueous solution of KOH
(3£100 mL), which was subsequently extracted with
CH2Cl2 (20 mL). The organic portions were combined,
washed with H2O (100 mL), dried (MgSO4) and the solvent
removed by distillation under reduced pressure to afford 19
(2.02 g, 95%) as a brown crystalline solid that was used
without further puri®cation: Rfˆ0.54 (CH2Cl2); mp 130±
1338C (from acetone/hexanes); [a]Dˆ20.56 (cˆ6.8 in
1
CHCl3); IR (KBr): n 3107, 2925, 1530, 1345, 1165; H
NMR (CDCl3, 300 MHz) d 8.16 (2H, AA0BB0, JAB
ˆ
8.7 Hz, ArH), 7.88 (2H, AA0BB0, JABˆ8.7 Hz, ArH),
7.13±7.06 (3H, m, ArH), 6.99±6.96 (2H, m, ArH), 3.07±
2.94 (2H, m, NCHaHb and CHaHbAr), 2.89 (1H, d, Jˆ
6.6 Hz, CHaHbAr), 2.48 (1H, dd, Jˆ13.8, 7.8 Hz, NCH),
2.31 (1H, d, Jˆ4.2 Hz, NCHaHb); 13C NMR (CDCl3,
75.4 MHz) d 150.4, 143.5, 136.9, 129.0, 128.7, 128.5,
126.7, 124.0, 42.8, 37.65, 33.4; LRMS (FAB) m/z (%):
[M1H]1 319 (100), 246 (24), 215 (47). Anal. Calcd for
C15H14N2O4S: C, 56.59; H, 4.43; N, 8.80; S, 10.07.
Found: C, 56.41; H, 4.43; N, 8.80; S, 9.88.
Cyclo-(N-allyl-b3-hPhe-b3-hPhe) (18). A solution of
penta¯uorophenol (146 mg, 0.79 mmol) and EDC´HCl
(169 mg, 0.92 mmol) in dry CH2Cl2 (5 mL) was added drop-
wise to a stirred solution of 13 (291 mg, 0.59 mmol) in dry
CH2Cl2 (10 mL) at 08C under N2. The mixture was stirred at
room temperature for 15 h, washed with a 0.5 M aqueous
solution of citric acid (15 mL) and H2O (15 mL) and dried
(MgSO4). The solvent was removed by distillation under
reduced pressure and the residue dissolved in dry CH2Cl2
(2 mL). Tri¯uoroacetic acid (0.35 mL, 4.57 mmol) was
added dropwise to the stirred solution at 08C under N2 and
the resulting mixture was stirred at room temperature for
2 h. The solvent was removed by distillation under reduced
pressure, the residue dissolved in dry MeCN (20 mL) and
added, over a period of 12 h, to a stirred solution of dry
EtiPr2N (0.20 mL, 1.16 mmol) in dry MeCN (180 mL) at
708C under N2. After stirring for 3 h the solvent was
removed by distillation under reduced pressure. The residue
was dissolved in EtOAc (100 mL), washed with a 0.5 M
aqueous solution of citric acid (2£50 mL), a 0.1 M aqueous
solution of NaOH (2£50 mL) and H2O (50 mL), dried
(MgSO4) and the solvent removed by distillation under
reduced pressure. The residue was puri®ed by ¯ash chroma-
tography (CH2Cl2/MeOH 20:1) to afford 18 (122 mg, 57%)
as a white solid: Rfˆ0.20 (CH2Cl2/MeOH 20:1); mp 185±
1868C (from CH2Cl2/hexane); [a]Dˆ226.93 (cˆ1.0 in
CHCl3); IR (KBr): n 3215, 3020, 2910, 1665, 1635, 1400,
(S)-3-(p-Nitrobenzenesulfonyl)amino-4-phenylbutanoic
acid (20). NaCN (25.50 g, 0.52 mol) was added in one
portion to a suspension of 19 (53.83 g, 169 mmol) in
MeCN (750 mL) and H2O (200 mL) and the resulting
mixture stirred vigorously at room temperature for 16 h.
The ®nal solution was diluted with EtOAc (400 mL),
washed successively with a saturated aqueous solution of
NH4Cl (3£400 mL) and H2O (400 mL), dried (MgSO4) and
the solvent removed by distillation under reduced pressure
to afford the crude nitrile as a dark brown viscous oil. Then,
37% HCl (1000 mL) and glacial AcOH (250 mL) were
consecutively added to the crude nitrile and the resulting
mixture heated at re¯ux for 4 h. After cooling, the solution
was extracted with CH2Cl2 (4£400 mL), dried (MgSO4) and
the solvent removed by distillation under reduced pressure.
The residual solid was powdered and washed with hexanes
(500 mL) to afford 20 (40.98 g, 67%) as a cream coloured
solid: Rfˆ0.16 (CH2Cl2/MeOH 20:1); mp 164±1688C (from
CH2Cl2/hexanes); [a]Dˆ241.3 (cˆ1.0 in EtOH); IR (KBr):
1
n 3233, 3150±2400, 1767, 1533, 1150; H NMR (DMSO-
1
1355; H NMR (CDCl3, 300 MHz, d 7.35±7.24 (6H, m,
d6, 300 MHz) d 8.19 (2H, d, Jˆ8.7 Hz, ArH), 7.77 (2H, d,
Jˆ8.4 Hz, ArH), 7.14±7.00 (5H, m, ArH), 3.68 (1H, m,
NCH), 2.69 (1H, dd, Jˆ13.5, 5.4 Hz, CHaHbAr), 2.60
(1H, dd, Jˆ13.5, 7.8 Hz, CHaHbAr), 2.33 (2H, d, Jˆ
6.3 Hz, CH2CO); 13C NMR (DMSO-d6, 75.4 MHz) d
171.9, 149.2, 147.0, 137.8, 129.3, 128.3, 127.8, 126.3,
124.4, 52.9, 41.0, 40.3; LRMS (FAB) m/z (%): [M1H]1
365 (100). Anal. Calcd for C16H16N2O6S: C, 52.70; H,
4.43; N, 7.69; S, 8.69. Found: C, 52.74; H, 4.41; N, 7.69;
S, 8.69.
ArH), 7.13±7.07 (4H, m, ArH), 5.91 (1H, br s, NH), 5.67
(1H, br s, CH2CHvCH2), 5.16 (2H, m, CH2CHvCH2),
4.39 (1H, m, CHaHbCHvCH2), 3.88 (1H, m, allylNCH),
3.82 (1H, m, HNCH), 3.28 (1H, m, CHaHbCHvCH2),
2.96±2.85 (4H, m, 2£CH2Ar), 2.65 (1H, t, Jˆ13.8 Hz,
CHaHbCONallyl), 2.46 (2H, m, CHaHbCONallyl and
CHaHbCONH), 2.36 (1H, m, CHaHbCONH); 13C NMR
(CDCl3, 75.4 MHz) d 171.6, 170.0, 136.2 (£2), 133.0,
129.3, 129.1, 128.8, 127.2, 127.1, 118.2, 56.7, 52.1, 50.9,
42.8, 41.0, 40.3; LRMS (FAB) m/z (%): [M1Na]1 385 (10),
[M1H]1 363 (100), 289 (10), 271 (47), 244 (42); HRMS
(FAB): calcd for [M1H]1 C23H27N2O2: 363.2073; found:
363.2056.
Methyl (S)-3-(p-Nitrobenzenesulfonyl)amino-4-phenyl-
butanoate (21). p-Toluenesulfonic acid (19.77 g,
104 mmol) was added in one portion to a stirred solution

7954
P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
of 20 (25.26 g, 69 mmol) in dry MeOH (200 mL). The
resulting solution was heated at re¯ux under N2 (allowing
pyridine (6.0 mL, 73.4 mmol) at 08C. The resulting solution
was stirred at room temperature for 2 h. The mixture was
diluted with EtOAc (50 mL), washed with an aqueous
solution of citric acid (2£50 mL) and brine (50 mL) and
dried (MgSO4). The solvent was removed by distillation
under reduced pressure to afford 23 (4.26 g, 98%) as an
orange oil. An analytical sample was prepared by chromato-
graphic puri®cation (hexanes/EtOAc 7:3) to afford a yellow
oil: Rfˆ0.18 (hexanes/EtOAc, 7:3); [a]Dˆ248.92 (cˆ1.2
in CHCl3); IR (®lm): n 3317, 3029, 1737, 1629, 1530, 1163;
1H NMR (CDCl3, 500 MHz; 1:1 rotamers ratio) d 8.11 and
8.08 (2H, AA0BB0, JABˆ9.0 Hz, ArH), 7.74 and 7.68 (2H,
AA0BB0, JABˆ9.0 Hz, ArH), 7.30±6.91 (10H, m, ArH),
6.25 and 6.00 (1H, d, Jˆ9.0 Hz, NH), 5.78 and 5.38 (1H,
m, CH2CHvCH2), 5.11 and 5.00 (2H, m, CH2CHvCH2),
4.56 and 4.24 (1H, m, allylNCH), 4.13 (dd, Jˆ16.0, 5.0 Hz)
and 3.76±3.52 (m) (3H, HNCH and CH2CHvCH2), 3.65
and 3.62 (3H, s, OCH3), 3.04 (dd, Jˆ13.5, 8.5 Hz), 2.92 (dd,
Jˆ13.5, 7.5 Hz), 2.84 (dd, Jˆ16.5, 9.0 Hz), 2.78 (d,
Jˆ7.5 Hz), 2.73±2.58 (m), 2.47 (dd, Jˆ17.0, 5.0 Hz),
2.43 (d, Jˆ4.5 Hz), 2.34 (dd, Jˆ14.0, 6.0 Hz), 2.08 (dd,
Jˆ16.5, 3.5 Hz) (8H, 2£CH2Ar, CH2CO2 and CH2CON);
13C NMR (CDCl3, 75.4 MHz) d 172.1, 171.8, 171.1,
170.9, 149.7, 149.6, 146.7, 146.6, 138.1, 138.0, 137.1,
134.3, 133.2, 129.6±126.8, 124.1, 124.0, 117.6, 116.7,
56.1, 53.7, 53.4, 52.1, 51.9, 42.2, 41.0, 40.6, 39.7, 38.7,
37.5, 37.3, 36.8, 36.5; HRMS (FAB): calcd for [M1H]1
C30H34N3O7S: 580.2117; found: 580.2107.
Ê
the condensing methanol to pass through a bed of 3 A
molecular sieves) for 20 h, cooled and quenched with H2O
(100 mL) to afford a white precipitate. The solvent was
removed by ®ltration and the residue thoroughly washed
with H2O (4£100 mL) and dissolved in CH2Cl2 from
which the remaining H2O was extracted. The solution was
dried (MgSO4) and the solvent removed by distillation
under reduced pressure to afford 21 (23.50 g, 90%) as a
creamy solid: Rfˆ0.15 (CH2Cl2); mp 95±968C (from
CH2Cl2/hexanes); [a]Dˆ246.94 (cˆ1.0 in CHCl3); IR
1
(KBr): n 3271, 1723, 1524, 1333, 1160; H NMR (CDCl3,
300 MHz) d 8.15 (2H, AA0BB0, JABˆ9.0 Hz, ArH), 7.76
(2H, AA0BB0, JABˆ9.0 Hz, ArH), 7.17±7.10 (3H, m,
ArH), 7.00±6.96 (2H, m, ArH), 5.49 (1H, br d, Jˆ9.0 Hz,
NH), 3.81 (1H, m, NCH), 3.68 (3H, s, OCH3), 2.85 (1H, dd,
Jˆ13.8, 6.3 Hz, CHaHbAr), 2.76 (1H, dd, Jˆ13.8, 8.4 Hz,
CHaHbAr), 2.66 (1H, dd, Jˆ16.5, 5.4 Hz, CHaHbCO), 2.60
(1H, dd, Jˆ16.5, 5.1 Hz, CHaHbCO); 13C NMR (CDCl3,
75.4 MHz) d 171.6, 150.0, 146.0, 136.6, 129.1, 128.7,
128.0, 127.0, 124.1, 52.8, 51.9, 40.8, 38.8; LRMS (FAB)
m/z (%): [M1Na]1 401 (12), [M1H]1 379 (100), 305 (81);
HRMS (FAB): calcd for [M1H]1 C17H19N2O6S: 379.0964;
found: 379.0975.
Methyl
(S)-3-allylamino-4-phenylbutanoate
(22).
Anhydrous K2CO3 (3.33 g, 24.0 mmol) was added in one
portion to a stirred solution of 21 (4.07 g, 10.8 mmol) and
allyl bromide (1.10 mL, 12.7 mmol) in moist DMF
(100 mL) at room temperature. After 18 h, mercaptoacetic
acid (1.65 mL, 23.7 mmol) was added followed by DBU
(16.0 mL, 107.1 mmol) and the mixture stirred for further
3 h. The resulting suspension was diluted with EtOAc
(200 mL) and washed with a saturated aqueous solution of
NaHCO3 (3£150 mL) which was subsequently extracted
with EtOAc (200 mL). The organic portions were
combined, dried (MgSO4) and the solvent removed by
distillation under reduced pressure to afford 22 (2.15 g,
86%) as an orange oil: Rfˆ0.53 (CH2Cl2/MeOH, 20:1);
[a]Dˆ28.34 (cˆ0.9 in CHCl3); IR (®lm): n 3334, 2952,
1739, 1438, 1200; 1H NMR (CDCl3, 200 MHz) d 7.29±7.10
(5H, m, ArH), 5.83 (1H, m, CH2CHvCH2), 5.14 (2H, m,
CH2CHvCH2), 3.65 (3H, s, OCH3), 3.29 (3H, m, NCH and
CH2CHvCH2), 2.85 (1H, dd, Jˆ13.4, 6.0 Hz, CHaHbAr),
2.70 (1H, dd, Jˆ13.4, 7.2 Hz, CHaHbAr), 2.40 (2H, d,
Jˆ6.4 Hz, CH2CO); 13C NMR (CDCl3, 50.3 MHz) d
172.5, 138.3, 136.5, 129.2, 128.3, 126.2, 115.8, 55.2, 51.4,
49.5, 40.4, 38.4; LRMS (CI, NH3) m/z (%): [M1H]1 234
(100); HRMS (FAB): calcd for [M1H]1 C14H20NO2:
234.1494; found: 234.1496.
Ns-b3-hPhe-N-allyl-b3-hPhe-OH (24). A 1 M aqueous
solution of LiOH (250 mL, 250 mmol) was added to a
stirred solution of 23 (13.53 g, 23 mmol) in MeOH
(300 mL). After 20 h the solution was diluted with EtOAc
(600 mL) and washed with a 0.5 M aqueous solution of
citric acid (2£100 mL) which was subsequently extracted
with EtOAc (300 mL). The organic portions were
combined, washed with brine (300 mL), dried (MgSO4)
and the solvent removed by distillation under reduced
pressure to afford 24 (12.07 g, 91%) as a light brown
foam. An analytical sample was prepared by chromato-
graphic puri®cation (CH2Cl2/MeOH 10:1) to afford a yellow
oil: Rfˆ0.22 (CH2Cl2/MeOH 20:1); [a]Dˆ258.25 (cˆ1.4
in CHCl3); IR (®lm): n 3220, 3029, 1713, 1609, 1530, 1351,
1
1164; H NMR (CDCl3, 500 MHz; 1:1 rotamers ratio) d
8.10 and 8.03 (2H, AA0BB0, JABˆ9.0 Hz, ArH), 7.73 and
7.62 (2H, AA0BB0, JABˆ8.5 Hz, ArH), 7.28±7.16 (4H, m,
ArH), 7.09±7.03 (3H, m, ArH), 6.99 (1H, m, ArH), 6.91±
6.87 (2H, m, ArH), 6.26 and 6.14 (1H, d, Jˆ9.0 Hz, NH),
5.81 and 5.39 (1H, m, CH2CHvCH2), 5.15 and 4.99 (2H, m,
CH2CHvCH2), 4.59 and 4.28 (1H, m, allylNCH), 4.12 (dd,
Jˆ16.0, 5.0 Hz) and 3.76±3.53 (m) (3H, HNCH and
CH2CHvCH2), 3.02 (dd, Jˆ14.0, 8.5 Hz), 2.93 (dd,
Jˆ14.0, 7.5 Hz), 2.86 (dd, Jˆ16.0, 8.5 Hz), 2.75 (d, Jˆ
7.5 Hz), 2.73±2.61 (m), 2.51 (dd, Jˆ17.0, 4.5 Hz), 2.44
(d, Jˆ5.0 Hz), 2.29 (dd, Jˆ13.5, 5.5 Hz), 2.04 (dd, Jˆ
17.0, 4.0 Hz) (8H, 2£CH2Ar, CH2CO2 and CH2CON); 13C
NMR (CDCl3, 75.4 MHz) d 175.7, 174.6, 171.5, 171.1,
149.2, 149.1, 146.3, 146.2, 137.7, 137.5, 137.3, 136.8,
133.8, 133.0, 128.9±126.2, 123.8, 123.7, 117.6, 116.8,
55.9, 53.4, 53.2, 49.6, 44.1, 40.3, 39.2, 38.4, 37.9, 37.3,
36.5; LRMS (FAB) m/z (%): [M1H]1 566 (100), 548
(65); HRMS (FAB): calcd for [M1H]1 C29H32N3O7S:
566.1961; found: 566.1950.
Methyl N-(p-nitrobenzenesulfonyl)-(S)-b3-homophenyl-
alanyl-N-allyl-(S)-b3-homophenylalaninate [Ns-b3-hPhe-
N-allyl-b3-hPhe-OMe] (23). A stirred suspension of 20
(2.72 g, 7.5 mmol) (predried by co-evaporation with dry
toluene) in thionyl chloride (11.0 mL, 150.8 mmol) was
heated at re¯ux under N2. After 1 h the excess of thionyl
chloride was removed by distillation under reduced pressure
to afford the crude acid chloride as a light brown oil. The
acid chloride was dissolved in dry THF (15 mL) and added
dropwise to a stirred solution of 22 (1.92 g, 9.2 mmol)
(predried by co-evaporation with dry toluene) in dry

P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
7955
H-b3-hPhe-N-allyl-b3-hPhe-OMe (25). DBU (6.30 mL,
42.2 mmol) was added to a stirred solution of 23 (2.46 g,
4.2 mmol) and mercaptoacetic acid (0.70 mL, 10.1 mmol)
in DMF (50 mL). After 16 h the solution was diluted with
EtOAc (200 mL) and washed with a saturated aqueous
solution of NaHCO3 (3£100 mL) which was subsequently
extracted with EtOAc (100 mL). The organic portions were
combined, dried (MgSO4) and the solvent removed by
distillation under reduced pressure to afford 25 (1.46 g,
88%) as an orange oil. The physical and spectroscopic
data are identical to that of the free amine of 12.
3£CH2CON); 13C NMR (CDCl3, 75.4 MHz) d 171.9±
168.0, 138.0±136.0, 134.5±132.9, 128.6±127.5, 125.7±
125.5, 117.7±114.8, 55.3, 50.9, 49.6±48.7, 48.5, 47.2,
46.4, 43.5±42.0, 39.9±34.9; LRMS (FAB) m/z (%):
[M1Na]1 780 (10), [M1H]1 758 (100), 597 (12), 557
(10); HRMS (FAB): calcd for [M1H]1 C47H57N4O5:
757.4329; found: 757.4356.
Cyclo-(N-allyl-b3-hPhe-b3-hPhe-N-allyl-b3-hPhe-b3-hPhe)
(1). A 1 M aqueous solution of LiOH (21 mL, 21 mmol) was
added to a stirred solution of the tetrapeptide 27 (1.589 g,
2.1 mmol) in MeOH (42 mL). After 16 h the solution was
quenched with 2 M HCl (20 mL) and extracted with CH2Cl2
(2£100 mL). The organic fractions were combined, dried
(MgSO4) and the solvent removed by distillation under
reduced pressure to afford a light yellow oil, which was
®ltered through a plug of silica gel (CH2Cl2/MeOH 10:1)
to afford an oil (1.310 g). A portion of this crude material
(632 mg) was co-evaporated with dry toluene, dissolved in
dry MeCN (2.4 L) and stirred at 08C under N2. Dry EtiPr2N
(1.45 mL, 8.3 mmol), HOAt (226 mg, 1.7 mmol) and a
solution of PyBroP (0.792 g, 1.7 mmol) in dry MeCN
(100 mL) were added and the resulting mixture was heated
at 708C; after 2 h an additional solution of PyBroP (0.785 g,
1.7 mmol) in dry MeCN (100 mL) was added dropwise and
the solution stirred for further 2 h. The solvent was removed
by distillation under reduced pressure and the residue was
puri®ed by ¯ash chromatography (CH2Cl2/MeOH 10:1) to
afford pure tetralactam 1 (254 mg, 35% overall yield). The
physical and spectroscopic data are identical to that given
previously.
Ns-b3-hPhe-N-allyl-b3-hPhe-b3-hPhe-N-allyl-b3-hPhe-
OMe (26). HOAt (0.879 g, 6.46 mmol) and EDC´HCl
(0.915 g, 4.77 mmol) were added consecutively, as solids,
to a stirred solution of 24 (1.806 g, 3.20 mmol) and 25
(1.434 g, 3.65 mmol) in dry CH2Cl2 (25 mL) at 08C under
N2. The mixture was stirred at room temperature for 20 h,
diluted with CH2Cl2 (100 mL) and washed with a 0.5 M
aqueous solution of citric acid (2£100 mL), which was
subsequently extracted with CH2Cl2 (50 mL). The organic
portions were combined, dried (MgSO4) and the solvent
removed by distillation under reduced pressure. The residue
was puri®ed by ¯ash chromatography (CH2Cl2/MeOH 10:1)
to afford 26 (2.264 g, 75%) as an orange oil: Rfˆ0.15
(CH2Cl2/MeOH 10:1); [a]Dˆ233.81 (cˆ1.1 in CHCl3);
IR (®lm): n 3303, 3029, 2927, 1737, 1644, 1530, 1349,
1
1163; H NMR (CDCl3, 500 MHz; mixture of rotamers) d
8.15±8.03 (2H, m, ArH), 7.82±7.63 (2H, m, ArH), 7.29±
6.88 (20H, m, ArH), 6.43 (m), 6.35 (d, Jˆ7.5 Hz), 6.26 (d,
Jˆ8.0 Hz), 6.15 (d, Jˆ9.0 Hz), 6.08 (d, Jˆ9.0 Hz), 5.80
(m), 5.37 (m), 5.28 (m) and 5.20±4.90 (m) (8H, 2£NH,
2£CH2CHvCH2 and 2£CH2CHvCH2), 4.60 (m), 4.38
(m), 4.30 (m), 4.19±3.98 (m) and 3.75±3.52 (m) (11H,
2£allylNCH, 2£HNCH, 2£CH2CHvCH2 and OCH3),
3.08±2.24 (m), 2.18±2.07 (m), 2.01 (dd, Jˆ16.5, 4.0 Hz)
and 1.95 (dd, Jˆ16.5, 4.0 Hz) (16H, 4£CH2Ar, CH2CO2
and 3£CH2CON); 13C NMR (CDCl3, 75.4 MHz) d 172.2±
168.1, 149.6±149.3, 147.0±146.9, 138.9±136.9, 134.8±
133.3, 129.2±127.8, 126.7±126.4, 124.0±123.8, 118.0±
116.4, 56.5±55.5, 53.7±53.1, 52.1±51.5, 50.9±49.2, 48.1±
46.4, 44.5±43.4, 40.8±34.4; LRMS (FAB) m/z (%):
[M1Na]1 965 (48), [M1H]1 943 (100), 742 (27), 549
(65); HRMS (FAB): calcd for [M1H]1 C53H60N5O9S:
942.4112; found: 942.4145.
Cyclo-(N-(2-hydroxyethyl)-b3-hPhe-b3-hPhe-N-(2-
hydroxyethyl)-b3-hPhe-b3-hPhe) (28). Ozone was
bubbled through
a stirred solution of 1 (93 mg,
0.128 mmol) in dry CH2Cl2 (10 mL) at 2788C. After
40 min the solution was warmed to 2208C and NaBH4
(149 mg, 4.0 mmol) and dry MeOH (10 mL) added con-
secutively. After a further 40 min, the solvent was removed
by distillation under reduced pressure and the residue
diluted with EtOAc (20 mL), washed with H2O (2£
20 mL), dried (MgSO4) and the solvent removed by distil-
lation under reduced pressure to afford 28 (70 mg, 74%) as a
glassy solid: Rfˆ0.18 (CH2Cl2/MeOH 10:1); [a]Dˆ277.28
(cˆ1.1 in CHCl3); IR (®lm): n 3392, 2929, 1646, 1517,
1
1455, 1379; H NMR (CDCl3, 500 MHz) d 8.00 (1H, d,
H-b3-hPhe-N-allyl-b3-hPhe-b3-hPhe-N-allyl-b3-hPhe-
OMe (27). Neat DBU (0.80 mL, 5.35 mmol) was added to a
stirred solution of 26 (510 mg, 0.54 mmol) and mercapto-
acetic acid (80 mL, 1.15 mmol) in dry DMF (10 mL) under
N2. After 23 h the solution was diluted with EtOAc (50 mL)
and washed with a saturated aqueous solution of NaHCO3
(3£50 mL) which was subsequently extracted with EtOAc
(50 mL). The organic portions were combined, dried
(MgSO4) and the solvent removed by distillation under
reduced pressure to afford 27 (348 mg, 85%) as an orange
oil: Rfˆ0.22 (CH2Cl2/MeOH 10:1); IR (®lm): n 3305, 3029,
2927, 1737, 1642, 1495; 1H NMR (CDCl3, 300 MHz;
mixture of rotamers) d 7.30±6.93 (20H, m, ArH), 5.82,
5.37 and 5.18±4.93 (6H, m, 2£CH2CHvCH2 and
2£CH2CHvCH2), 4.54, 4.39, 4.29, 4.13, 3.68±3.50
and 3.41 (11H, 2£allylNCH, 2£HNCH, 2£CH2CHvCH2
and OCH3), 3.09±2.11 (16H, m, 4£CH2Ar, CH2CO2 and
Jˆ10.0 Hz, NH), 7.40±7.00 (10H, m, ArH), 4.47 (1H, m,
HNCH), 3.79 (1H, m, alkylNCH), 3.48 (2H, m, CHaHbOH
and CHaHbCONH), 3.40 (1H, dd, Jˆ13.5, 9.5 Hz,
alkylNCHCHaHbAr), 3.15 (1H, m, CHaHbOH), 3.06 (1H,
dd, Jˆ13.5, 7.0 Hz, HNCHCHaHbAr), 2.97 (3H, m,
alkylNCHCHaHbAr, HNCHCHaHbAr and CHaHbCH2OH),
2.44 (3H, m, CHaHbCONH, CHaHbCONalkyl and
CHaHbCH2OH), 2.11 (1H, dd, Jˆ18.0, 4.5 Hz, CHaHbCON-
alkyl); 13C NMR (CDCl3, 75.4 MHz) d 173.2, 171.2, 138.5,
138.4, 129.3, 129.1, 128.7, 128.6, 126.9, 126.6, 61.8, 60.5,
53.6, 47.0, 41.0, 40.2, 38.1, 35.3; LRMS (FAB) m/z (%):
[M1Na]1 755 (18), [M1H]1 733 (100), 715 (40); HRMS
(FAB): calcd [M1H]1 for C44H53N4O6: 733.3965; found:
733.3932.
Cyclo-(N-(2-azidoethyl)-b3-hPhe-b3-hPhe-N-(2-azido-
ethyl)-b3-hPhe-b3-hPhe) (29). Methanesulfonyl chloride

7956
P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
(90 mL, 1.16 mmol) was added to a stirred solution of 28
(207 mg, 0.28 mmol) in dry CH2Cl2 (25 mL) and dry Et3N
(0.20 mL, 1.44 mmol) under N2. After 16 h the mixture was
diluted with CH2Cl2 (50 mL) and washed with H2O
(2£50 mL) which was subsequently extracted with CH2Cl2
(25 mL). The organic portions were combined, dried
(MgSO4) and the solvent removed by distillation under
reduced pressure. NaN3 (118 mg, 1.82 mmol) was added
to a stirred solution of the residue dissolved in DMF
(10 mL) at room temperature under N2. After 22 h the
solvent was removed by distillation under reduced pressure
and the residue diluted with EtOAc (50 mL) and washed
with brine (2£50 mL) which was subsequently extracted
with EtOAc (25 mL). The organic portions were combined,
dried (MgSO4) and the solvent removed by distillation
under reduced pressure to afford 29 (147 mg, 66%) as an
off-white foam: Rfˆ0.70 (EtOAc); [a]Dˆ293.62 (cˆ1.1 in
CHCl3); IR (®lm): n 3402, 3027, 2927, 2101, 1659, 1503,
954 (41), [M1H]1 931 (28), 831 (100), 731 (34), 714
(27); HRMS (FAB): calcd for [M1H]1 C54H71N6O8:
931.5333; found: 931.5291.
Cyclo-[N-2-hydroxyethyl-b3-hPhe-b3-hPhe-N-2-(tert-
butyldiphenylsilyloxy)ethyl-b3-hPhe-b3-hPhe] (31) and
cyclo-[N-2-(tert-butyldiphenylsilyloxy)ethyl-b3-hPhe-b3-
hPhe-N-2-(tert-butyldiphenylsilyloxy)ethyl-b3-hPhe-b3-
hPhe] (32). Imidazole (30 mg, 0.44 mmol) and tert-butyl-
diphenylsilyl chloride (48 mL, 0.18 mmol) were added
consecutively to a stirred solution of 28 (103 mg,
0.14 mmol) in dry CH2Cl2 at 08C under N2 and the resulting
mixture was stirred at room temperature for 2.5 h. The solu-
tion was diluted with CH2Cl2 (20 mL) and washed with H2O
(2£10 mL), which was subsequently extracted with CH2Cl2
(10 mL). The organic portions were combined, dried
(MgSO4) and the solvent removed by distillation under
reduced pressure. The residue was puri®ed by ¯ash chroma-
tography (hexanes/EtOAc 3:1) to afford the disilyl ether 32
(41 mg, 24%) as a colourless oil: Rfˆ0.16 (hexanes/EtOAc,
3:1); [a]Dˆ216.43 (cˆ1.4 in CHCl3); IR (®lm): n 3396,
1
1377, 1263; H NMR (CDCl3, 500 MHz) d 7.66 (1H, d,
Jˆ10.0 Hz, NH), 7.30±7.18 (10H, m, ArH), 4.50 (1H, m,
HNCH), 3.54 (1H, m, alkylNCH), 3.40 (2H, m, alkyl-
NCHCHaHbAr and CHaHbCONH), 3.22 (1H, m, CHaHbN3),
3.06±2.84 (5H, m, HNCHCH2Ar, alkylNCHCHaHbAr,
CHaHbN3 and CHaHbCH2N3), 2.44 (1H, dd, Jˆ10.5,
4.5 Hz, CHaHbCH2N3), 2.39 (1H, dd, Jˆ17.5, 2.5 Hz,
CHaHbCONalkyl), 2.34 (1H, dd, Jˆ13.0, 4.5 Hz, CHaHb-
CONH), 2.28 (1H, dd, Jˆ17.5, 4.5 Hz, CHaHbCONalkyl);
13C NMR (CDCl3, 75.4 MHz) d 172.8, 169.5, 138.6, 138.5,
129.2, 129.1, 128.6, 128.4, 126.8, 126.5, 63.1, 50.2, 49.0,
46.7, 40.6, 40.2, 38.2, 35.1; LRMS (FAB) m/z (%):
[M1H]1 784 (100), 691 (16), 460 (30); HRMS (FAB):
calcd for [M1H]1 C44H51N10O4: 783.4095; found:
783.4120.
1
2930, 1648, 1513, 1111; H NMR (CDCl3, 500 MHz) d
7.46±7.00 (21H, m, ArH and NH), 4.15 (1H, m, CHNH),
3.51 (1H, m, alkylNCH), 3.20 (1H, dd, Jˆ13.5, 8.5 Hz,
CHaHbCONH), 3.16 (1H, dd, Jˆ13.0, 12.0 Hz, alkyl-
NCHCHaHbAr), 2.99±2.83 (6H, m, HNCHCH2Ar,
CH2OSi and CH2CH2OSi), 2.80 (1H, dd, Jˆ13.0, 9.0 Hz,
alkylNCHCHaHbAr), 2.24 (1H, dd, Jˆ13.5, 5.0 Hz,
CHaHbCONH), 1.83 (1H, dd, Jˆ17.5, 2.5 Hz, CHaHbCON-
alkyl), 1.50 (1H, dd, Jˆ17.5, 4.5 Hz, CHaHbCONalkyl),
0.93 (9H, s, C(CH3)3); 13C NMR (CDCl3, 75.4 MHz) d
171.9, 169.4, 138.6, 138.5, 135.6, 135.5, 133.1, 132.9,
129.9, 129.8, 129.3, 129.2, 128.6, 128.4, 127.8, 127.7,
126.7, 126.5, 64.0, 60.0, 53.3, 46.6, 40.0, 39.7, 38.7, 35.1,
26.8, 19.0; LRMS (FAB) m/z (%): [M1H]1 1210 (48), 1152
(17), 1132 (11), 954 (100), 862 (12); HRMS (FAB): calcd
for [M1H]1 C76H89N4O6Si2: 1209.6321; found: 1209.6281.
Later fractions, eluting with hexanes/EtOAc (1:1) afforded
the monosilyl ether 31 (59 mg, 43%), as a colourless oil:
Rfˆ0.31 (hexanes/EtOAc, 1:1); [a]Dˆ258.21 (cˆ1.18 in
Cyclo-[N-2-(tert-butoxycarbonyl)aminoethyl-b3-hPhe-
b3-hPhe-N-2-(tert-butoxycarbonyl)aminoethyl-b3-hPhe-
b3-hPhe] (30). A 1 M solution of Me3P in dry THF (53 mL,
53 mmol) was added to a stirred solution of 29 (19 mg,
24 mmol) in dry THF (0.5 mL) at 2208C under N2. After
5 min Boc-ON (13 mg, 53 mmol) was added and the result-
ing solution was stirred for further 15 min at 2208C and at
room temperature for 18 h. The ®nal solution was diluted
with CH2Cl2 (10 mL) and washed with H2O (2£10 mL)
which was subsequently extracted with CH2Cl2 (5 mL).
The organic fractions were combined and washed with a
2 M aqueous solution of KOH (2£10 mL) which was subse-
quently extracted with CH2Cl2 (5 mL). The organic
fractions were combined, washed with brine (10 mL),
dried (MgSO4) and the solvent removed by distillation
under reduced pressure. The residue was puri®ed by ¯ash
chromatography (EtOAc/hexanes 1:1) to afford 30 (20 mg,
80%) as a glassy solid: Rfˆ0.48 (hexanes/EtOAc, 1:1);
[a]Dˆ246.60 (cˆ1.5 in CHCl3); IR (®lm): n 3400, 3342,
2996, 2950, 1817, 1715, 1663, 1510, 1263; 1H NMR
(CDCl3, 500 MHz; mixture of rotamers) d 8.03 (m), 7.95
(d, Jˆ10.0 Hz) and 7.79 (m) (1H, NH), 7.32±6.97 (10H, m,
1
CHCl3); IR (®lm): n 3398, 2933, 1646, 1510, 1079; H
NMR (CDCl3, 500 MHz; asterisk denotes signals associated
with the N-(2-hydroxyethyl)-b3-hPhe-b3-hPhe portion of
the molecule) d 7.79 (1H, d, Jˆ10.0 Hz, NH), 7.61 (1H,
d, Jˆ10.0 Hz, NHp), 7.46±6.95 (30H, m, ArH), 4.33 (1H, m,
CHNH), 4.14 (1H, m, CHNHp), 3.78 (1H, m, alkylNCHp),
3.57±3.41 (2H, m, alkylNCH and CHaHbOp), 3.40±3.31
(2H, m, alkylNCHCHaHbArp and CHaHbCONHp), 3.28±
3.20 (2H, m, alkylNCHCHaHbAr and CHaHbCONH),
3.11 (1H, m, CHaHbOp), 3.03±2.76 (11H, m, CH2O,
CH2N, CHaHbNp, HNCHCH2Ar, HNCHCH2Arp, alkyl-
NCHCHaHbAr and alkylNCHCHaHbArp), 2.40±2.25 (4H,
m, CHaHbCONHp, CHaHbCONH, CHaHbCONalkyl and
CHaHbNp), 1.76 (1H, dd, Jˆ17.5, 4.5 Hz, CHaHbCON-
alkyl), 1.65 (1H, dd, Jˆ17.5, 3.0 Hz, CHaHbCONalkylp),
1.52 (1H, dd, Jˆ17.5, 4.0 Hz, CHaHbCONalkylp), 0.89
(9H, s, C(CH3)3); 13C NMR (CDCl3, 75.4 MHz) d 173.2,
172.0, 171.1, 169.6, 138.7, 138.5, 138.4, 135.6, 135.5,
132.9, 132.8, 129.8, 129.3, 129.1, 128.7, 128.6, 128.5,
128.4, 127.7, 127.6 (£2), 126.9, 126.7, 126.6, 64.2, 61.8,
60.8, 59.8, 53.8, 53.1, 46.9, 46.8, 40.9, 40.3 (£2), 39.6, 38.7,
38.0, 34.8, 34.7, 26.7, 18.8; LRMS (FAB) m/z (%):
[M1Na]1 994 (15), [M1H]1 972 (77), 716 (59), 664
t
ArH), 4.58±4.30 (2H, m, BuOCONH and HNCH), 3.63
(1H, m, alkylNCH), 3.40, 3.11±2.36, 2.18 and 2.06 (12H,
m, 2£CH2Ar, 2£CH2CON, CH2CH2NH and CH2CH2NH),
1.42±1.20 (9H, m, C(CH3)3); 13C NMR (CDCl3, 75.4 MHz)
d 173.0, 169.9, 155.6, 138.5, 138.4, 129.3, 129.1, 128.8,
128.5, 127.0, 126.6, 79.2, 61.4, 52.2, 47.0, 40.7, 40.3,
38.7, 38.3, 35.9, 28.4; LRMS (FAB) m/z (%): [M1Na]1

P. W. Sutton et al. / Tetrahedron 56 (2000) 7947±7958
7957
(70), 648 (100); HRMS (FAB): calcd for [M1H]1
C60H71N4O6Si: 971.5143; found: 971.5096. Further elution
using CH2Cl2/MeOH (20:1) afforded recovered diol 28
(8 mg, 8%) as a glassy solid. The physical and spectroscopic
data are identical to that given previously.
138.8, 138.3p, 136.9p, 129.3±128.5, 126.9±126.4, 65.7p,
57.5, 54.0, 52.4p, 52.3, 47.7p, 46.6, 43.3p, 40.5p, 39.8,
39.7, 39.2p, 39.1p, 38.5, 35.0, 32.7p; 13C NMR (CD3OD,
75.4 MHz) d 172.2, 172.1, 172.0, 139.8, 138.9, 130.5,
130.3, 129.7, 127.7, 127.6, 59.1, 52.5, 50.0, 44.3, 41.1,
39.3, 38.9, 33.5; LRMS (FAB) m/z: [M1Na]1 811 (100),
[M1H]1 789 (90), 757 (16), 729 (14), 697 (20), 663 (33),
647 (33); HRMS (FAB): calcd [M1H]1 for C46H53N4O8:
789.3863; found: 789.3829.
Cyclo-[N-(methoxycarbonylmethyl)-b3-hPhe-b3-hPhe-
(33).
N-(methoxycarbonylmethyl)-b3-hPhe-b3-hPhe]
Ozone was bubbled through a stirred solution of the tetra-
lactam 1 (0.15 g, 0.21 mmol) in dry CH2Cl2 (15 mL) at
2788C. After 1 h the solution was warmed to 2208C,
DBU (0.12 mL, 0.80 mmol) and urea-hydrogen peroxide
addition compound (80 mg, 0.86 mmol) added consecu-
tively and the resulting mixture was stirred at room tempera-
ture for 16 h. The mixture was diluted with CH2Cl2 (50 mL)
and washed with 2 M HCl (2£25 mL) which was subse-
quently extracted with CH2Cl2 (25 mL). The organic
portions were combined, dried (MgSO4) and the solvent
removed by distillation under reduced pressure to afford
the crude diacid (130 mg, 83%) as a white solid. p-Toluene-
sulfonic acid (100 mg, 0.54 mmol) was added to the solid
dissolved in dry MeOH (10 mL) and the resulting solution
heated at re¯ux for 16 h, cooled and the solvent removed by
distillation under reduced pressure. The residue was diluted
with CH2Cl2 (40 mL) and washed with a saturated aqueous
solution of NaHCO3 (2£20 mL) which was subsequently
extracted with CH2Cl2 (20 mL). The organic portions were
combined, dried (MgSO4) and the solvent removed by
distillation under reduced pressure to afford 33 (100 mg,
62%) as a white solid. An analytical sample was prepared
by chromatographic puri®cation (CH2Cl2/MeOH 40:1) to
afford a white solid: Rfˆ0.33 (CH2Cl2/MeOH 40:1);
[a]Dˆ274.14 (cˆ1.3 in CH2Cl2); IR (®lm): n 3409,
Acknowledgements
We thank the European Union TMR programme for support
(ERBFMRX-CT96-0011) including postdoctoral research
fellowships to A. B. (1997) and to P. W. S. (1998±2000).
Â
Also, ®nancial support from the Ministerio de Educacion y
Cultura (PM95-0061) and from the Direccio General de
Â
Recerca, Generalitat de Catalunya (1998SGR00040) is
gratefully acknowledged.
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3333, 2927, 1750, 1650, 1513, 1204; H NMR (CDCl3,
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