Cyclisation of meta-phenylene-bis-alanine derivatives

Article abstract of DOI:10.1039/a805350b

The cyclisation of a meta-phenylene-bis-alanine derivative with several different spacer moieties was investigated. A large difference in the ease of cyclisation was observed depending on which path of cyclisation was chosen. NMR studies indicate that the closed-loop molecules adopt folded conformations with the loop directly above the aromatic ring plane.

Full text of DOI:10.1039/a805350b

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Cyclisation of meta-phenylene-bis-alanine derivatives
Andreas Ritzén and Torbjörn Frejd*
Organic Chemistry 1, Department of Chemistry, Lund University, PO Box 124, SE-221 00,
Lund, Sweden
Received (in Cambridge) 9th July 1998, Accepted 20th August 1998
The cyclisation of a meta-phenylene-bis-alanine derivative with several different spacer moieties was investigated.
A large difference in the ease of cyclisation was observed depending on which path of cyclisation was chosen. NMR
studies indicate that the closed-loop molecules adopt folded conformations with the loop directly above the aromatic
ring plane.
Introduction
CO2R1
CO2R1
Noncoded amino acid derivatives are attracting increasing
NHCO
CO2Bn
NHR4
NHCO
interest for several reasons, one of which is the occurence of
such structures in a number of antibiotics of the vancomycin
and biphenomycin classes.1–4 In addition, the possibility of
making modified peptides using such derivatives is widely rec-
ognised.5 Bis-armed amino acids of the phenylalanine type and
their derivatives were synthesised in 1951 by Burckhalter et al.
via alkyaltion of bis-benzylic bromides with ethyl acetamido-
cyanoacetate.6 Since then several groups have developed alter-
native routes and a number of new structures have appeared in
the literature including optically active derivatives.7–13 For some
time we have been working on synthetic methods for optically
active aromatic bis-alanine derivatives carrying protecting
groups useful for peptide synthesis.14–21 In this report we wish to
present aspects of the loop formation of meta-phenylene-bis-
alanine derivatives.
iii
R
R
–
CO2
+
H3N
ZHN
NHR4
6a-f
4a-f
i, ii
v or vi
CO2R1
NHR2
CO2R3
NHR4
CO2R1
NHCO
CONH
NHR4
CO2R1
NHBoc
CONH
NHR4
R: see Table 1
R
3
7a-f
iii, iv
i, vi
We are currently investigating a tris-amino acid 1, which we
plan to use for the construction of synthetic host molecules for
molecular recognition (Scheme 1). A concave host 2 can be
3: R1 = Me, R2 = Boc,
R3 = Bn, R4 = Ac
4–7: R1 = Me, R4 = Ac
CO2But
O
C
H
N
R
RO2C
NHR′
5a, b
OC
X
NH
X
CO2R
NHR′
Scheme 2 Reagents: i, TFA; ii, ZHN–R–CO2H, TEA, DCC, HOBt,
THF; iii, 5% Pd/C, H2 1 atm, EtOH; iv, HClؒH2N–R–CO2But, DIEA,
DCC, HOBt, THF; v, DPPA, NaHCO3, DMF; vi, HATU, DIEA,
DMF.
HN
OC
CO
NH
R′HN
HN
X
CO
CO2R
acids to form 4 and 5, Scheme 2, which are then cyclised. In
principle, the cyclisation can occur in two ways: using an amine
nucleophile either on the coupled amino acid, path a, or on the
aromatic core, path b. It is not a priori evident that both direc-
tions will be equally successful. We reasoned that on steric
grounds, the amino group of an amino acid without substitu-
ents α to nitrogen would be a better nucleophile than the amino
group of the phenylalanine-like core. The difference would be
expected to be small, and easily overridden by conformational
effects, but we decided to try path a first.
C
O
N
H
1
2
Scheme 1
envisaged where three loops are formed around the edges of 1
by linking the C- and N-terminals with various tethers. Since
cyclisations leading to this type of system are not straight-
forward, we decided to investigate these cyclisations using a
bis-amino acid model system, Scheme 2. In a recent publication
by Travins and Etzkorn,22 a very similar cyclised bis-amino
acid system was constructed for use as a turn subunit in a helix–
turn–helix motif for incorporation in a short synthetic peptide.
This prompted us to communicate our hitherto obtained
results.
To make the open-chain precursors, we needed a bis-armed
phenylalanine derivative 3 with two blocking groups, R1 and
R4, stable to all reaction conditions applied, and two orthog-
onal protecting groups, R2 and R3. This would ensure that the
same core could be used for both directions of cyclisation.
Furthermore, the blocking groups should not complicate the
1
NMR spectra, so groups giving singlets in H NMR would be
Results and discussion
preferred. Finally, it is well-known that Nα-carbamate protect-
ing groups suppress racemisation of a C-terminal residue better
than amides in most peptide couplings.5 If R4 is a carbamate,
For maximum flexibility, we adopted a strategy where a com-
mon core derivative 3 is coupled to various protected amino
J. Chem. Soc., Perkin Trans. 1, 1998, 3419–3424
3419

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Table 1 Yield of cyclisation products 7a–f
the proximal stereogenic centre would be less prone to racemis-
ation during the cyclisation reaction following path a, than if
R4 is an amide. While this would be beneficial for this cyclis-
ation reaction leading to 2, Scheme 1, the corresponding amine
would necessarily be part of an amide, and thus be more prone
to racemisation. In conclusion, when path a is followed a
carbamate at R4 could mask racemisation in the model system
that would later become a problem in the cyclisation leading to
2. For this reason, the N-acetyl blocking group was chosen.
A very convenient route to optically active amino acids is via
the corresponding didehydro derivatives, which are hydrogen-
ated with a chiral, nonracemic Rh()–bisphosphine catalyst.
The development of highly efficient ligands, such as DuPHOS†
has led to ees of >98% for a large variety of substituted
phenylalanines.23
For the synthesis of didehydrophenylalanine derivatives, we
have earlier used the Heck–Jeffery reaction between aromatic
halides and 2-amidoacrylates or 2-carbamatoacrylates.14,16,18
This method tolerates a variety of protecting groups in the
acrylate, which is readily available in multigram quantities in
three steps from -serine, typically in 70% overall yield. The
commercial availability of a number of aromatic halides
enables the synthesis of many different substituted aromatic
didehydroamino acids via this route.
Chain R
Precursor
Product
Yield(%)
CH2
(CH2)2
(CH2)3
(CH2)4
5a, 6a
5b, 6b
6c
7a
7b
7c
7d
7e
7f
ND,a 82,b 16c
ND,a 36b
24a
6d
29a
(CH2)5
6e
6f
50c
(S)-N α(Boc)Lysd
50c
ND = not detected. a DPPA, path a. b HATU, path b. c HATU, path a.
d Replaces CO–R–NHZ in 4, CO–R–NH3ϩ in 6 and CO–R–NH in 7.
The final hydrogenation worked well with (S,S)-Me-
DuPHOS as a ligand giving 3 in 98% yield with a dr (diastereo-
meric ratio) of 95:5 as determined by H NMR. Changing
1
to (S,S)-Et-DuPHOS improved the dr to у99.5:0.5. The
enantiomers of 3 could be separated using HPLC on a chiral
(R,R)-Whelk-O1 column, but only one peak could be detected
for the product from the Et-DuPHOS hydrogenation, thus
establishing у98% ee. The absolute configuration was assigned
as (S,S)-3 based on the fact that the (S,S) enantiomer of the
ligand in all examined cases gives the S amino acid.23
We initially synthesised several open-chain derivatives 6a–f
on which to try the cyclisation according to path a, Scheme 2.
The results are summarized in Table 1. Compound 6e was also
synthesised as a racemic, 1:1 mixture of diastereomers for use
as reference material in the dr estimation by NMR spectro-
scopy. The diastereomers of 6e could be partially separated
using flash chromatography.
We chose to try DPPA as cyclisation agent first, since it is
known to suppress epimerisation,5,27 and had been previously
used by our group in a synthesis of a biphenomycin analogue.17
Addition of a 0.1–0.2% solution of 6 in DMF to a suspension
of DPPA and NaHCO3 in DMF, using a syringe pump over 60
h, gave a moderate yield of the cyclised products 7c and 7d.
Some epimerisation of the C-terminal residue, ca. 10%, was
also observed. No cyclised product could be isolated in the
short-chain cases 6a and 6b, but since the reactions were
performed on a small scale, typically 20 mg, a <10% yield may
have passed undetected.
An alternative method, the condensation of a phosphonyl-
glycine derivative with an aromatic aldehyde in a Horner–
Wadsworth–Emmons reaction, was developed by Schmidt
et al.,24,25 and has previously been used by us19,20 and also by
Travins and Etzkorn.22 The Schmidt method generally gives
somewhat higher yields in the coupling step, but at the cost of
five–seven steps for the synthesis of most of the phosphonyl-
glycines.
The synthesis of the core derivative 3 is based on the Heck–
Jeffery method (Scheme 3). Starting with 3-bromoiodobenzene,
Heck = Pd(OAc)2,
NaHCO3, Bu4NCl
CO2Me
NHBoc
CO2Bn
NHAc
8
9
I
CO2Me
NHBoc
Heck
Heck
DMF
57%
DMF
63%
We next tried HATU as cyclisation reagent, since it has been
shown to be fast, versatile, and usually suppresses epimerisation
of C-terminal residues in cyclisation reactions.28 In a typical
procedure, the deprotected amino acid (1 mM in DMF) was
treated with HATU (1.1 equiv.) and DIEA (3 equiv.) for 1 h at
room temp. For the cyclisations of 6e and 6f, cyclised products
were formed in fair yields, but there was still ca. 10% epimeris-
ation of the core C-terminal. We next attempted to cyclise 6a
with HATU, which gave a modest 16% yield of the cyclised
product 7a. Interestingly, no C-terminal epimerisation was evi-
dent from the 1H NMR of 7a. To try to improve the yields, we
then changed the direction of cyclisation from path a to path b,
Scheme 2. A high yield of the shortest-chain derivative 7a and a
moderate yield of the next shortest-chain one, 7b, was obtained
with HATU. These two derivatives, unlike the others, 7c–7f, are
insoluble or sparingly soluble in CHCl3, and just by washing the
crude product with water and CHCl3 a fairly pure product was
obtained.
Br
Br
10
CO2Me
NHBoc
CO2Bn
NHAc
CO2Me
NHBoc
NHAc
CO2Bn
{Rh(COD)[(S,S)-Et-
DuPHOS]}OTf
H2, 2.5 bar
MeOH
98%
3
11
Scheme 3
two successive Heck–Jeffery reactions with olefins 8 and 9 gave
the doubly unsaturated derivative 11. Both couplings were
highly Z-selective, as expected for this method,14,18 and 11 was
obtained as the single stereoisomer (Z,Z) after chromatography
and recrystallisation. The stereochemistry of both 10 and 11
was confirmed by NOE measurements.20 The stereochemistry
3
In all cases, the monomeric formulation of the cyclised prod-
ucts 7a–f was confirmed by MS. In no case could more than a
few percent of cyclodimerised material be detected.
may alternatively be determined by measuring the JCH coup-
ling constant between the vinylic proton and the ester carbonyl
carbon in a proton-coupled 13C NMR experiment.26 However,
this coupling constant could not be determined for 10 and 11
due to line broadening of the carbonyl carbon peaks.
It is interesting at this point to compare our results with those
obtained by Travins and Etzkorn.22 In their work, path b was
chosen in the cyclisation of a derivative very similar to our
deprotected 5a, and a high yield of cyclised product, 80%, was
obtained after reaction with DPPA for 7 d. Although Travins
and Etzkorn never tried path a, our results suggest that for 7a,
there is indeed a large difference in ease of cyclisation between
these two paths. Computer modelling will be required to pin-
† List of abbreviations: DIEA = N,N-diisopropylethylamine, DPPA =
diphenylphosphoryl azide, DuPHOS = 1,2-bis(2,5-dialkylphosphol-
ano)benzene, HATU = O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetrameth-
yluronium hexafluorophosphate, HOBt = 1-hydroxybenzotriazole,
TEA = triethylamine.
3420
J. Chem. Soc., Perkin Trans. 1, 1998, 3419–3424

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1-{(Z)-2-(Acetylamino)-2-[(benzyloxy)carbonyl]ethenyl}-3-{(Z)-
2-[(tert-butoxycarbonyl)amino]-2-(methoxycarbonyl)ethenyl}-
benzene 11
The reaction was carried out analogously to the one described
for 10 above, using 10 (3.56 g, 10 mmol), methyl 2-
(acetamido)acrylate 9 (2.63 g, 12 mmol), Pd(OAc)2 (0.11 g, 0.50
mmol), Bu4NCl (2.78 g, 10 mmol), and NaHCO3 (2.10 g, 25
mmol) in DMF (15 ml). The reaction temperature was ϩ85 ЊC,
and the flash chromatography was performed using heptane–
EtOAC 2:3 as eluent (TLC Rf 0.24). The analytically pure
product was obtained as white needles (2.81 g, 57%) by dis-
solution in EtOAc (20 ml) followed by precipitation by slow
addition of heptane (50 ml), mp 115–118 ЊC; δH(ϩ55 ЊC) 1.38
(9 H, s), 2.08 (3 H, br s), 3.86 (3 H, s), 5.28 (2 H, s), 6.22 (1 H, br
s), 7.07 (1 H, br s), 7.21 (1 H, s), 7.35–7.49 (9 H, m) and 7.64
(1 H, s); δC 23.55, 28.21, 52.90, 67.80, 81.41, 125.05, 125.23,
128.55, 128.61, 128.81, 129.29, 130.29, 130.70, 131.01, 131.50,
134.17, 134.63, 135.64, 152.91, 165.25, 166.07 and 169.16;
HRMS (FABϩ): C27H31N2O7 (M ϩ H); Found: m/z, 495.2141.
Calc.: m/z, 495.2131.
Fig. 1
point the exact cause for this.29 In retrospect, the large differ-
ence between path a and b is perhaps not unexpected in view of
results from cyclisation of tetra- to hexapeptides.5,29
A noteworthy feature of the 1H NMR spectra of the cyclised
derivatives with an odd number of methylene groups in the
loop, is the large chemical shift difference of the protons of the
central methylene group, see Fig. 1. These protons resonate at
up to 1 ppm apart from each other, with one signal at very
low shift. This is most readily explained by assuming that a
folded conformation is adopted, where one of the protons is
positioned closely above the aromatic ring.
1-{(2S)-2-(Acetylamino)-2-[(benzyloxy)carbonyl]ethyl}-3-{(2S)-
2-[(tert-butoxycarbonyl)amino]-2-(methoxycarbonyl)ethyl}-
benzene 3
With the successful construction and cyclisation of this
model system at hand, we will try to extend it to also include the
tris-armed receptor 2. These results will be reported in due
course.
Compound 11 (1.00 g, 2.02 mmol) and {Rh(COD)[(S,S)-Et-
DuPHOS]}ϩOTfϪ (5 mg, 7 µmol) were dissolved in MeOH (10
ml) which had been deoxygenated by N2 bubbling for 30 min.
The solution was hydrogenated at 40 psi for 6 h at room temp.
after which the solvent was removed on a rotary evaporator.
The residue was passed through a plug of silica using EtOAc as
eluent to remove the catalyst. After evaporation of the solvent,
the analytically pure product was obtained as an oil that crystal-
lised on standing. To get a more easily handled product, crystal-
lisation from EtOAc–heptane was performed, which gave the
product as white, fluffy needles (0.99 g, 98%), mp 90–93 ЊC; [α]D22
ϩ34 (c 1.6, CHCl3); ee у98% by HPLC (Merck (R,R)-Whelk-
O1 4.6 × 250 mm; n-hexane–propan-2-ol 80:20 ϩ0.25% HOAc
at 1.0 ml minϪ1; tR 18.5 (S,S)-3, 20.1 (R,R)-3 min; dr у99.5:0.5
by 1H NMR; δH 1.42 (9 H, s), 2.01 (3 H, s), 2.97–3.11 (4 H, m),
3.71 (3 H, s), 4.53–4.57 (1 H, m), 4.90–4.97 (2 H, m), 5.14 (1 H,
d, J 12), 5.20 (1 H, d J 12), 5.97 (1 H, br d, J 7.6), 6.81 (1 H, s),
6.87 (1 H, d, J 7.7), 6.99 (1 H, d, J 7.7), 7.13 (1 H, t, J 7.7) and
7.32–7.40 (5 H, m); δC 23.50, 28.70, 38.06, 38.71, 52.67, 53.46,
54.85, 67.67, 80.44, 128.44, 128.52, 129.00, 129.08, 129.19,
130.75, 135.55, 136.44, 136.74, 155.46, 170.21, 171.86 and
172.71; HRMS (FABϩ): C27H35N2O7 (M ϩ H); Found: m/z,
499.2438. Calc.: m/z, 499.2444.
Experimental
All reactions were carried out under an inert atmosphere of dry
N2. TLC was performed using Merck Silica Gel 60 coated glass
plates with the same eluent as in the corresponding flash chrom-
atography, unless otherwise noted. Me-DuPHOS and Et-
DuPHOS were purchased from Strem Chemicals, and HATU
was purchased from PerSeptive Biosystems. All commercial
materials were used without further purification unless other-
wise noted. The Rh hydrogenation catalysts were synthesised
according to the published procedure.23 Protected amino acids
were either commercially available or synthesised via standard
procedures.30 Olefins 814 and 931 were synthesised according to
the published procedures. NMR spectra were recorded on a
Bruker DRX400 spectrometer operating at 400 MHz for pro-
ton and 75 MHz for carbon-13 experiments, and using CDCl3
as solvent unless otherwise noted. J Values are given in Hz. [α]D
Values are given in units 10Ϫ1 deg cm2 gϪ1
.
Methyl (Z)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]-
The (R,R) isomer was prepared analogously using (R,R)-Me-
DuPHOS as ligand, and a racemic sample was prepared as a
1:1 mixture of diastereomers by hydrogenation using DPPE
as ligand. The methyl ester resonance at δH 3.7 was used to
measure the dr, since two baseline-separated singlets, one
corresponding to each diastereomer, were seen in the spectrum
of a 1:1 diastereomeric mixture of 3.
prop-2-enoate 10
1-Bromo-3-iodobenzene (3.8 ml, 30 mmol), methyl 2-[(tert-
butoxycarbonyl)amino]acrylate 8 (7.0 ml, 36 mmol), Pd(OAc)2
(0.34 g, 1.5 mmol), Bu4NCl (8.3 g, 30 mmol), and NaHCO3 (6.3
g, 75 mmol) were mixed in DMF (30 ml) in a screwcap vessel,
and a few crystals of hydroquinone were added to prevent
polymerisation of the olefin. The mixture was stirred at ϩ60 ЊC
for 18 h, and was then allowed to cool to room temp. It was
diluted with EtOAc (200 ml) and washed with half-saturated
brine (4 × 200 ml). The organic phase was dried over MgSO4,
the solvents were removed on a rotary evaporator, and the resi-
due was purified by flash chromatography (heptane–EtOAc
4:1; TLC Rf 0.33 using heptane–EtOAc 3:1). The analytically
pure product was obtained as white needles (6.78 g, 63%) by
recrystallisation from EtOAc–heptane, mp 103–105 ЊC; δH 1.41
(9 H, s), 3.86 (3 H, s), 6.40 (1 H, br s), 7.17 (1 H, s), 7.22 (1 H, t,
J 7.8), 7.41–7.43 (2 H, m) and 7.68 (1 H, t, J 1.8); δC(ϩ40 ЊC)
28.31, 52.86, 81.44, 122.71, 125.61, 128.05, 128.47, 130.02,
132.03, 132.35, 136.68, 152.46 and 165.87; HRMS (FABϩ):
C15H19BrNO4 (M ϩ H); Found: m/z, 356.0490. Calc.: m/z,
356.0497.
Deprotection and general coupling, path a
Compound 3 (0.20 g, 0.40 mmol) was dissolved in TFA (5 ml)
and kept for 15 min at room temp. after which the TFA was
removed on a rotary evaporator. The residue was washed with
ether to remove the last traces of TFA, and vacuum-dried. The
resulting white solid was dissolved in dry THF (3 ml) and the
Z-protected amino acid (0.40 mmol), TEA (0.14 ml, 1.0 mmol),
and HOBt (61 mg, 0.40 mmol, monohydrate) were added. The
resulting solution was cooled on an ice-bath under N2 and DCC
(87 mg, 0.42 mmol) was added. After stirring for 1 h at 0 ЊC
followed by 16 h at room temp. the reaction mixture was filtered
to remove the separated dicyclohexylurea. The filtrate was
evaporated to dryness, dissolved in EtOAc (5 ml) and the solu-
J. Chem. Soc., Perkin Trans. 1, 1998, 3419–3424
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tion washed with saturated aqueous NaHCO3 (3 ml). After
brief drying over Na2SO4 the solution was chromatographed
using heptane–EtOAc–acetone 2:7:1 as eluent (TLC Rf 0.2–
0.3) after which the pure product 4a–f was obtained as a white
solid.
3.08 (4 H, m), 3.13–3.18 (2 H, m), 3.70 (3 H, s), 4.82–4.93 (2 H,
m), 5.03 (1 H, br t, J 7), 5.08 (2 H, s), 5.09–5.15 (2 H, m), 5.98
(1 H, d, J 8.0), 6.16 (1 H, d, J 7.8), 6.82 (1 H, s), 6.88 (1 H, d,
J 7.6), 6.94 (1 H, d, J 7.7), 7.14 (1 H, t, J 7.6) and 7.28–7.37
(10 H, m); δC 23.14, 25.16, 26.28, 29.66, 36.18, 37.89, 37.99,
40.92, 52.54, 52.97, 53.32, 66.67, 67.37, 128.21, 128.24, 128.27,
128.64, 128.73, 128.80, 128.88, 130.29, 135.21, 136.28, 136.37,
136.82, 156.60, 170.06, 171.69, 172.35 and 172.65; HRMS
(FABϩ): C36H44N3O8 (M ϩ H); Found: m/z, 646.3134. Calc.:
m/z, 646.3128.
1-{(2S)-2-(Acetylamino)-2-[(benzyloxy)carbonyl]ethyl}-3-
{(2S)-2-[(2-{[(benzyloxy)carbonyl]amino}acetyl)amino]-2-
(methoxycarbonyl)ethyl} benzene 4a. Yield 67%; mp 38–41 ЊC;
[α]D22 ϩ30 (c 1.5, CHCl3); δH 1.93 (1 H, s), 2.95–3.12 (4 H, m),
3.71 (3 H, s), 3.74–3.91 (2 H, m), 4.80–4.84 (1 H, m), 4.90–4.94
(1 H, m), 5.08–5.18 (4 H, m), 5.88 (1 H, br t, J 7), 6.32 (1 H, br
d, J 7.6), 6.61 (1 H, br d, J 7.2), 6.82 (1 H, s), 6.89 (1 H, d, J 7.6),
6.94 (1 H, d, J 7.2), 7.12 (1 H, t, J 7.6) and 7.28–7.37 (10 H, m);
δC 23.04, 37.55, 38.02, 44.56, 52.61, 53.12, 53.34, 67.21, 67.44,
128.08, 128.15, 128.32, 128.61, 128.66, 128.71, 128.80, 128.88,
130.29, 135.22, 136.10, 136.35, 136.49, 156.82, 169.16, 170.22
and 171.86; HRMS (FABϩ): C32H36N3O8 (M ϩ H); Found:
m/z, 590.2500. Calc.: m/z, 590.2502.
1-{(2S)-2-(Acetylamino)-2-[(benzyloxy)carbonyl]ethyl}-3-
{(2S)-2-[(6-{[(benzyloxy)carbonyl]amino}-2-(2S)-{[tert-butoxy-
carbonyl]amino}hexanoyl)amino]-2-(methoxycarbonyl)ethyl}-
benzene 4f. Yield 50%; mp 133–135 ЊC; [α]D22 ϩ19 (c 0.26,
CHCl3); δH(ϩ55 ЊC) 1.33–1.63 (14 H, m), 1.75–1.85 (1 H, m),
1.97 (3 H, s), 3.00–3.20 (6 H, m), 3.70 (3 H, s), 4.02–4.09 (1 H,
m), 4.78–4.84 (1 H, m), 4.88–4.96 (2 H, m), 5.10 (2 H, s), 5.12–
5.22 (2 H, m), 5.23–5.28 (1 H, m), 6.21 (1 H, br s), 6.43 (1 H, br
s), 6.85 (1 H, br s), 6.91–6.96 (2 H, m), 7.14 (1 H, t, J 7.6) and
7.29–7.39 (10 H, m); δC 22.77, 23.06, 28.53, 29.70, 32.14, 37.88,
38.20, 40.87, 52.45, 53.15, 53.60, 54.92, 66.85, 67.51, 80.35,
128.24, 128.50, 128.68, 128.85, 128.97, 130.51, 135.55, 136.29,
136.73, 137.07, 155.84, 156.76, 170.09, 171.89 and 172.06;
HRMS (FABϩ): C41H53N4O10 (M ϩ H); Found: m/z, 761.3769.
Calc.: m/z, 761.3762.
1-{(2S)-2-(Acetylamino)-2-[(benzyloxy)carbonyl]ethyl}-3-
{(2S)-2-[(3-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-2-
(methoxycarbonyl)ethyl}benzene 4b. Yield 60%; mp 99–101 ЊC;
[α]D22 ϩ31 (c 1.6, CHCl3); δH 1.95 (3 H, s), 2.36–2.40 (2 H, m),
2.93–3.11 (4 H, m), 3.37–3.43 (2 H, m), 3.70 (3 H, s), 4.78–
4.84 (1 H, m), 4.88–4.94 (1 H, m), 5.06 (2 H, s), 5.10–5.18
(2 H, m), 5.50 (1 H, br t, J 7), 6.21–6.27 (2 H, m), 6.83 (1 H, s),
6.87 (1 H, d, J 7.5), 6.94 (1 H, d, J 7.6), 7.12 (1 H, t, J 7.6) and
7.28–7.37 (10 H, m); δC 23.05, 35.88, 37.21, 37.75, 37.96, 52.54,
53.17, 53.24, 66.70, 67.38, 128.09, 128.17, 128.34, 128.58,
128.60, 128.69, 128.78, 128.84, 130.13, 135.24, 136.29, 136.43,
136.71, 156.58, 170.04, 171.27, 171.72 and 172.15; HRMS
(FABϩ): C33H38N3O8 (M ϩ H); Found: m/z, 604.2657. Calc.:
m/z, 604.2659.
Deprotection and general coupling, path b
Compound 3 (0.50 g, 1 mmol) was dissolved in 99.5% ethanol
(10 ml) and 5% Pd on carbon (50 mg) was added. After
stirring for 3 h at room temp. under hydrogen at atmos-
pheric pressure, the catalyst was removed by filtration through
Celite. The solvent was removed on a rotary evaporator,
and EtOAc was added and evaporated to remove residual
ethanol. After storage in vacuum overnight, the free acid 1-[(2S)-
2-(acetylamino)-2-carboxyethyl]-3-{(2S)-2-[(tert-butoxycarb-
onyl)amino]-2-(methoxycarbonyl)ethyl}benzene was obtained
as a white powder (0.42 g, >100%) that retained a small amount
of EtOAc, but was otherwise pure. The NMRs had to be
recorded at elevated temperature in DMSO, since at ordinary
temperatures the different rotamers around the carbamate
interconvert slowly on the NMR time scale, thus complicating
the spectra. It is known32 that the occurence of free carboxylic
acids stabilises the minor rotamer of the carbamate. Data for
the free acid: mp 60–63 ЊC; δH(DMSO-d6, ϩ70 ЊC) 1.34 (9 H, s),
1.80 (3 H, s), 2.82–3.06 (4 H, m), 3.61 (3 H, s), 4.15–4.26 (1 H,
m), 4.41–4.50 (1 H, m), 6.85 (1 H, br s), 7.04–7.12 (3 H, m),
7.18 (1 H, t, J 7.8) and 7.84 (1 H, d, J 8.0); δC 21.98, 27.81,
36.50, 36.63, 51.26, 53.10, 54.97, 78.13, 126.82, 127.66, 129.49,
137.00, 137.35, 154.82, 168.86, 172.05 and 172.54; HRMS
(FABϩ): C20H29N2O7 (M ϩ H); Found: m/z, 409.1978. Calc.:
m/z, 409.1975.
1-{(2S)-2-(Acetylamino)-2-[(benzyloxy)carbonyl]ethyl}-3-
{(2S)-2-[(4-{[(benzyloxy)carbonyl]amino}butanoyl)amino]-2-
(methoxycarbonyl)ethyl}benzene 4c. Yield 61%; mp 135–
137 ЊC; [α]D23 ϩ26 (c 1.6, CHCl3); δH 1.72–1.79 (2 H, m), 1.95
(3 H, s), 2.16–2.21 (2 H, m), 2.97–3.10 (4 H, m), 3.12–3.18 (2 H,
m), 3.70 (3 H, s), 4.80–4.92 (2 H, m), 5.07 (2 H, s), 5.09–5.16
(2 H, m), 5.24 (1 H, br t, J 7), 6.13 (1 H, br d, J 7.8), 6.31 (1 H,
br d, J 7.6), 6.84–6.88 (2 H, m), 6.94 (1 H, d, J 7.6), 7.12 (1 H, t,
J 7.6) and 7.28–7.37 (10 H, m); δC 23.15, 26.07, 33.42, 37.77,
38.09, 40.35, 52.56, 53.17, 53.39, 66.80, 67.45, 128.25, 128.30,
128.67, 128.76, 128.84, 128.91, 130.26, 135.26, 136.36, 136.49,
136.79, 156.95, 170.13, 171.73, 172.33 and 172.46; HRMS
(FABϩ): C34H40N3O8 (M ϩ H); Found: m/z, 618.2793. Calc.:
m/z, 618.2815.
1-{(2S)-2-(Acetylamino)-2-[(benzyloxy)carbonyl]ethyl}-3-
{(2S)-2-[(5-{[(benzyloxy)carbonyl]amino}pentanoyl)amino]-2-
(methoxycarbonyl)ethyl}benzene 4d. Yield 50%; mp 91–94 ЊC;
[α]D23 ϩ34 (c 1.6, CHCl3); δH 1.22–1.28 (2 H, m), 1.42–1.49 (2 H,
m), 1.96 (3 H, s), 2.11–2.21 (2 H, m), 2.95–3.18 (6 H, m), 3.70
(3 H, s), 4.81–4.92 (2 H, m), 5.07 (2 H, s), 5.09–5.16 (2 H, m),
5.21 (1 H, br t, J 7), 6.11 (1 H, br d, J 7.7), 6.23 (1 H, br d,
J 7.7), 6.83 (1 H, s), 6.87 (1 H, d, J 7.4), 6.94 (1 H, d, J 7.6), 7.13
(1 H, t, J 7.6) and 7.28–7.36 (10 H, m); δC 22.61, 23.06, 29.34,
35.67, 37.81, 37.92, 40.51, 52.48, 53.04, 53.33, 66.63, 67.34,
128.12, 128.15, 128.23, 128.60, 128.68, 128.77, 128.84, 130.30,
135.22, 136.31, 136.39, 136.82, 156.70, 170.08, 171.68, 172.27
and 172.59; HRMS (FABϩ): C35H42N3O8 (M ϩ H); Found:
m/z, 632.2992. Calc.: m/z, 632.2972.
This material (204 mg, 0.50 mmol) was used directly in the
coupling reaction. After dissolution in dry THF (3 ml), the
amino acid ester hydrochloride (0.50 mmol), DIEA (0.22 ml,
1.3 mmol), and HOBt (77 mg, 0.50 mmol, monohydrate) were
added. The resulting solution was cooled on an ice-bath under
N2 and DCC (109 mg, 0.53 mmol) was added. The reaction
conditions and work-up were as for the general coupling follow-
ing path a above.
1-{(2S)-2-(Acetylamino)-2-[({2-[(tert-butoxycarbonyl)]-
methyl}amino)carbonyl]ethyl}-3-{(2S)-2-[(tert-butoxycarbonyl)-
amino]-2-(methoxycarbonyl)ethyl}benzene 5a. Yield 64%; mp
61–64 ЊC; [α]D22 ϩ20 (c 1.5, CHCl3); δH(ϩ50 ЊC) 1.39 (9 H, s), 1.44
(9 H, s), 1.96 (3 H, s), 2.94–3.11 (4 H, m), 3.70 (3 H, s), 3.84
(2 H, br s), 4.49 (1 H, br s), 4.65–4.71 (1 H, m), 5.12 (1 H, br d,
J 7.6), 6.32 (1 H, br d, J 7.6), 6.46 (1 H, br s), 6.99 (1 H, d,
J 7.5), 7.03 (1 H, s), 7.08 (1 H, d, J 7.7) and 7.19 (1 H, t, J 7.6);
δC 23.24, 28.15, 28.44, 38.39, 42.09, 52.42, 54.47, 54.76,
1-{(2S)-2-(Acetylamino)-2-[(benzyloxy)carbonyl]ethyl}-3-
{(2S)-2-[(6-{[(benzyloxy)carbonyl]amino}hexanoyl)amino]-2-
(methoxycarbonyl)ethyl}benzene 4e. Yield 49%; mp 95–97 ЊC;
[α]D22 ϩ35 (c 1.5, CHCl3); δH 1.25–1.32 (2 H, m), 1.43–1.49 (2 H,
m), 1.53–1.61 (2 H, m), 1.97 (3 H, s), 2.12–2.16 (2 H, m), 2.96–
3422
J. Chem. Soc., Perkin Trans. 1, 1998, 3419–3424

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80.02, 82.36, 128.03, 128.19, 128.89, 130.43, 136.67, 136.99,
155.29, 168.68, 170.34, 171.28 and 172.47; HRMS (FABϩ):
C26H40N3O8 (M ϩ H); Found: m/z, 522.2798. Calc.: m/z,
522.2815.
(3 H, s), 2.21–2.25 (2 H, m), 2.88–2.99 (4 H, m), 3.17–3.25 (2 H,
m), 3.73 (3 H, s), 4.49–4.53 (1 H, m), 4.65–4.69 (1 H, m), 7.12–
7.19 (3 H, m) and 7.30 (1 H, t, J 7.6); δC(ϩ40 ЊC) 22.44, 22.52,
26.52, 35.06, 36.97, 38.02, 39.63, 53.50, 54.59, 56.85, 127.98,
128.41, 129.30, 130.48, 137.31, 138.73, 173.83, 174.33, 176.44
and 178.09; HRMS (FABϩ): C20H30N3O6 (M ϩ H); Found:
m/z, 408.2135. Calc.: m/z, 408.2135.
1-{(2S)-2-(Acetylamino)-2-[({3-[(tert-butoxycarbonyl)]ethyl}-
amino)carbonyl]ethyl}-3-{(2S)-2-[(tert-butoxycarbonyl)amino]-
2-(methoxycarbonyl)ethyl}benzene 5b. Yield 74%; mp 55–58 ЊC;
[α]D22 ϩ26 (c 1.5, CHCl3); δH 1.40 (9 H, s), 1.42 (9 H, s), 1.99 (3 H,
s), 2.26–2.37 (2 H, m), 2.89–3.01 (2 H, m), 3.06–3.11 (2 H, m),
3.35–3.41 (2 H, m), 3.74 (3 H, s), 4.53–4.59 (2 H, m), 5.09 (1 H,
br d, J 8.3), 6.23–6.26 (2 H, m), 6.98–7.07 (3 H, m), 7.21 (1 H, t,
J 7.5); δC 23.36, 28.25, 28.47, 35.02, 35.17, 38.65, 38.78, 52.53,
54.85, 80.14, 81.30, 128.17, 129.01, 130.35, 136.79, 137.06,
155.22, 170.04, 170.76, 171.61 and 172.41; HRMS (FABϩ):
C27H42N3O8 (M ϩ H); Found: m/z, 536.2974. Calc.: m/z,
536.2972.
1-[(2S)-2-(acetylamino)-2-carboxyethyl]-3-{(2S)-2-[(6-
aminohexanoyl)amino]-2-(methoxycarbonyl)ethyl}benzene 6e.
Yield 92%; mp 170–173 ЊC; δH(D2O, ϩ40 ЊC) 1.10–1.19 (2 H,
m), 1.43–1.61 (4 H, m), 1.92 (3 H, s), 2.21 (2 H, t, J 7.3), 2.85–
3.00 (4 H, m), 3.15–3.27 (2 H, m), 3.76 (3 H, s), 4.39–4.43 (1 H,
m), 4.68–4.73 (1 H, m), 7.12–7.19 (3 H, m) and 7.31 (1 H, t,
J 7.5); δC 22.48, 25.15, 25.36, 26.93, 35.59, 36.95, 38.19, 39.84,
53.51, 54.48, 57.06, 127.90, 128.31, 129.29, 130.54, 137.32,
138.90, 173.73, 174.38, 177.02 and 178.67; HRMS (FABϩ):
C21H32N3O6 (M ϩ H); Found: m/z, 422.2290. Calc.: m/z,
422.2291.
Second deprotection, path a
Compound 4 (100 mg) was dissolved in ethanol and 5% Pd on
carbon (50 mg) was carefully added. The mixture was stirred
under 1 atm of H2 for 16 h. Sometimes the free amino acid
precipitated, and was in those cases dissolved by addition of a
small amount of water. The catalyst was removed by filtration
through Celite, the filtrate was evaporated, and the residue was
recrystallised by dissolution in ethanol or methanol followed by
precipitation by the addition of ether. After centrifugation and
drying, compound 6 was obtained as a white powder that
retained some solvents. It was used immediately in the ring-
closing experiments.
1-[(2S)-2-(acetylamino)-2-carboxyethyl]-3-{(2S)-2-{6-amino-
2-(2S)-[(tert-butoxycarbonyl)amino]hexanoyl}amino]-2-
(methoxycarbonyl)ethyl}benzene 6f. Yield 82%; mp 118–121 ЊC;
δH(D2O, ϩ40 ЊC) 1.24–1.69 (15 H, m), 1.95 (3 H, s), 2.94–3.08
(4 H, m), 3.18–3.26 (2 H, m), 3.75 (3 H, s), 3.94 (1 H, br s), 4.54–
4.59 (1 H, m), 4.73–4.77 (1 H, m), 7.14–7.21 (3 H, m) and 7.33
(1 H, t, J 7.5); δC 22.31, 22.56, 26.83, 28.14, 31.26, 37.01, 37.50,
39.77, 53.50, 54.29, 55.29, 55.58, 82.16, 128.29, 128.39, 129.45,
130.49, 137.15, 138.08, 157.63, 173.86, 174.19, 175.18 and
176.63; HRMS (FABϩ): C26H41N4O8 (M ϩ H); Found: m/z,
537.2920. Calc.: m/z, 537.2924.
1-[(2S)-2-(Acetylamino)-2-carboxyethyl]-3-{(2S)-2-[(2-amino-
acetyl)amino]-2-(methoxycarbonyl)ethyl}benzene 6a. Yield 73%;
mp 193–196 ЊC; δH(D2O, ϩ40 ЊC) 1.95 (3 H, s), 2.94 (1 H, dd,
J 8.2 and 13.7), 3.04 (1 H, dd, J 8.9 and 14.1), 3.14 (1 H, dd,
J 5.5 and 13.8), 3.24 (1 H, dd, J 5.4 and 14.1), 3.77 (3 H, s),
3.77–3.85 (2 H, m), 4.44 (1 H, dd, J 5.5 and 8.0), 4.80 (1 H, dd,
J 5.4 and 8.8), 7.12 (1 H, s), 7.15 (1 H, d, J 7.6), 7.19 (1 H, d,
J 7.8) and 7.33 (1 H, t, J 7.6); δC 22.44, 37.04, 38.08, 40.86,
53.60, 54.71, 56.91, 127.95, 128.66, 129.33, 130.43, 137.04,
138.74, 167.36, 173.81, 173.83 and 178.20; HRMS (FABϩ):
C17H24N3O6 (M ϩ H); Found: m/z, 366.1664. Calc.: m/z,
366.1665.
Cyclisation with DPPA, path a
Using a syringe pump, a solution of 6 (20–30 mg) in DMF (10–
20 ml) was added to a stirred suspension of DPPA (0.10 ml) and
NaHCO3 (0.10 g) in DMF (20 ml) over a period of 60 h at room
temp. After this time, the reaction mixture was evaporated to
dryness and the residue was partitioned between water and
CHCl3 (1ϩ1 ml). The organic layer was dried over MgSO4 and
purified by flash chromatography or HPLC (SiO2, CHCl3–
MeOH 20:1) to yield the cyclised product 7 as a white solid.
Second deprotection, path b, and cyclisation with HATU, path a
and b
1-[(2S)-2-(Acetylamino)-2-carboxyethyl]-3-{(2S)-2-[(3-
aminopropanoyl)amino]-2-(methoxycarbonyl)ethyl}benzene 6b.
Yield 48%; mp 181–183 ЊC; δH(D2O) 1.91 (3 H, s), 2.59–2.68
(2 H, m), 2.88 (1 H, dd, J 8.7 and 13.9), 2.98 (1 H, dd, J 9.3 and
13.9), 3.11–3.16 (3 H, m), 3.21 (1 H, dd, J 5.3 and 13.9), 3.73
(3 H, s), 4.39 (1 H, J 5.0 and 8.7), 4.72 (1 H, dd, J 5.4 and 9.2),
7.11–7.17 (3 H, m) and 7.29 (1 H, t, J 7.7); δC 22.16, 31.90,
35.75, 36.76, 37.89, 53.30, 54.39, 56.85, 127.68, 128.36, 129.08,
130.23, 136.94, 138.57, 172.29, 173.56, 173.98 and 178.50;
HRMS (FABϩ): C18H26N3O6 (M ϩ H); Found: m/z, 380.1821.
Calc.: m/z, 380.1822.
In the case of path b, protected amino acid 5 (0.10 mmol) was
first dissolved in TFA (1 ml) and the solution was stored under
N2 at room temp. for 2 h. After this time, the solution was
evaporated to dryness and the residue was washed with ether to
remove traces of TFA. After brief vacuum drying, the depro-
tected amino acid was obtained as a white powder, which was
immediately used in the cyclisation reaction.
The deprotected amino acid so prepared (path b), or separ-
ately prepared as 6 (path a), was dissolved in DMF (100 ml) to
make a solution 1 mM in amino acid. HATU (42 mg, 0.11
mmol) and DIEA (52 µl, 0.30 mmol) were added which caused
the solution to turn yellow. After 1 h at room temp. the reaction
mixture was evaporated to dryness and worked up as described
for DPPA above, except in the cases of 7a and 7b which are
insoluble in CHCl3. For these two derivatives, a simple filtration
of the added CHCl3–water mixture was sufficient to isolate the
compounds in fairly pure states. Recrystallisation from DMF–
ether did not significantly improve purity.
1-[(2S)-2-(Acetylamino)-2-carboxyethyl]-3-{(2S)-2-[(4-
aminobutanoyl)amino]-2-(methoxycarbonyl)ethyl}benzene
6c.
Yield 45%; mp 112–114 ЊC; δH(D2O) 1.77–1.86 (2 H, m), 1.92
(3 H, s), 2.26–2.36 (2 H, m), 2.79–3.00 (4 H, m), 3.14–3.26 (2 H,
m), 3.73 (3 H, s), 4.45–4.49 (1 H, m), 4.68–4.72 (1 H, m), 7.12–
7.19 (3 H, m) and 7.30 (1 H, t, J 7.7); δC(ϩ50 ЊC) 22.51, 23.44,
32.74, 37.10, 37.90, 39.44, 53.63, 54.72, 56.34, 128.17, 128.60,
129.44, 130.55, 137.46, 138.60, 174.10, 174.38, 175.30 and
177.39; HRMS (FABϩ): C19H28N3O6 (M ϩ H); Found: m/z,
394.1976. Calc.: m/z, 394.1978.
Methyl (3S,9S)-9-(acetylamino)-5,8-dioxo-4,7-diazabicyclo-
[9.3.1]pentadeca-1(15),11,13-triene-3-carboxylate 7a. Yield 16%
(path a) and 82% (path b) respectively; mp >350 ЊC (decomp.);
δH(DMSO-d6) 1.85 (3 H, s), 2.72–2.91 (3 H, m), 3.02–3.09 (2 H,
m), 3.67 (3 H, s), 4.07–4.13 (1 H, m), 4.22–4.28 (1 H, m), 4.35–
4.41 (1 H, m), 6.80 (1 H, s), 7.04–7.09 (2 H, m), 7.16–7.19 (1 H,
1-[(2S)-2-(Acetylamino)-2-carboxyethyl]-3-{(2S)-2-[(5-
aminopentanoyl)amino]-2-(methoxycarbonyl)ethyl}benzene 6d.
Yield 75%; mp 136–140 ЊC; δH(D2O) 1.44–1.54 (4 H, m), 1.91
J. Chem. Soc., Perkin Trans. 1, 1998, 3419–3424
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m), 7.64 (1 H, d, J 8.7), 7.99 (1 H, d, J 7.4) and 8.08–8.11 (1 H,
m); δC 22.54, 36.14, 38.61, 42.97, 52.07, 52.11, 54.70, 127.03,
127.63, 128.58, 132.08, 135.70, 136.49, 168.30, 168.82, 170.80
and 171.26; HRMS (FABϩ): C17H22N3O5 (M ϩ H); Found:
m/z, 348.1571. Calc.: m/z, 348.1559.
Methyl
(3S,6S,13S)-13-(acetylamino)-6-[(tert-butoxycarb-
onyl)amino]-5,12-dioxo-4,11-diazabicyclo[13.3.1]nonadeca-
1(19),15,17-triene-3-carboxylate 7f. Yield 50%; mp 193–195 ЊC;
δH Ϫ0.26 to Ϫ0.11 (1 H, m), 0.87–0.99 (1 H, m), 1.22–1.37 (3 H,
m), 1.48 (9 H, s), 1.68–1.77 (1 H, m), 2.05 (3 H, s), 2.51–2.57
(1 H, m), 2.66–2.73 (1 H, m), 2.84–2.89 (1 H, m), 3.22–3.26
(1 H, m), 3.36–3.41 (1 H, m), 3.83 (3 H, s), 4.10 (1 H, br s), 4.51–
4.57 (1 H, m), 4.66 (1 H, d, J 6.8), 5.09–5.16 (1 H, m), 6.20 (1 H,
br s), 6.51 (1 H, d, J 7.6), 6.88–6.95 (3 H, m), 7.10 (1 H, t, J 7.6)
and 7.50 (1 H, s); δC 19.87, 23.62, 25.22, 27.85, 28.44, 37.36,
40.01, 40.35, 52.78, 52.92, 54.35, 56.37, 81.18, 128.39, 128.47,
128.55, 130.47, 137.01, 137.75, 155.48, 169.48, 170.66, 171.49
and 172.17; HRMS (FABϩ): C26H39N4O7 (M ϩ H); Found:
m/z, 519.2824. Calc.: m/z, 519.2819.
Methyl
(3S,10S)-10-(acetylamino)-5,9-dioxo-4,8-diaza-
7b.
bicyclo[10.3.1]hexadeca-1(16),12,14-triene-3-carboxylate
Yield 36%; mp >350 ЊC (decomp.); δH(DMSO-d6) 1.84 (3 H, s),
2.01–2.08 (1 H, m), 2.61–2.85 (5 H, m), 3.00–3.06 (1 H, m),
3.25–3.30 (1 H, m), 3.68 (3 H, s), 4.11–4.16 (1 H, m), 4.42–4.48
(1 H, m), 6.90 (1 H, s), 7.07–7.11 (2 H, m), 7.23 (1 H, t, J 7.6),
7.55–7.59 (1 H, m), 8.02 (1 H, d, J 7.5) and 8.27 (1 H, d, J 9.5);
δC 23.36, 34.56, 36.59, 37.69, 40.43, 52.94, 54.02, 56.51, 128.01,
128.38, 129.49, 131.62, 137.60, 138.33, 169.43, 170.45, 171.49
and 172.73; HRMS (FABϩ): C18H24N3O5 (M ϩ H); Found:
m/z, 362.1717. Calc.: m/z, 362.1716.
Acknowledgements
We thank the Swedish Natural Research Council, the Crafoord
Foundation, the Knut and Alice Wallenberg Foundation, and
the Royal Physiographic Society for economic support.
Methyl
(3S,11S)-11-(acetylamino)-5,10-dioxo-4,9-diaza-
bicyclo[11.3.1]heptadeca-1(17),13,15-triene-3-carboxylate 7c.
Yield 24%; dr 87:13; mp >280 ЊC (decomp.); δH 1.00–1.10 (1 H,
m), 1.75–1.83 (2 H, m), 2.03 (3 H, s), 1.23–1.30 (1 H, m), 2.60–
2.70 (2 H, m), 2.95–3.03 (2 H, m), 3.25–3.32 (1 H, m), 3.44–3.50
(1 H, m), 3.83 (3 H, s), 4.48–4.55 (1 H, m), 5.25–5.32 (1 H, m),
5.80 (1 H, d, J 9), 6.33 (1 H, d, J 8), 6.93 (1 H, d, J 8), 7.03 (1 H,
d, J 8), 7.17 (1 H, t, J 8) and 7.25 (1 H, s); δC 22.86, 23.58, 35.15,
39.15, 40.08, 40.37, 51.63, 52.94, 55.68, 128.69, 128.87, 129.26,
129.34, 136.31, 137.67, 169.45, 169.99, 172.56 and 174.03;
HRMS (FABϩ): C19H26N3O5 (M ϩ H); Found: m/z, 376.1871.
Calc.: m/z, 376.1872.
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PCT/GB93/01170 (Chem. Abstr., 1994, 121, 281231e).
14 A.-S. Carlström and T. Frejd, Synthesis, 1989, 414.
15 A.-S. Carlström and T. Frejd, J. Org. Chem., 1990, 55, 4175.
16 A.-S. Carlström and T. Frejd, J. Org. Chem., 1991, 56, 1289.
17 A.-S. Carlström and T. Frejd, J. Chem. Soc., Chem. Commun., 1991,
1216.
Methyl
(3S,12S)-12-(acetylamino)-5,11-dioxo-4,10-diaza-
7d.
bicyclo[12.3.1]octadeca-1(18),14,16-triene-3-carboxylate
Yield 29%; mp 240–260 ЊC (decomp.); δH 0.80–0.93 (1 H, m),
1.23–1.33 (1 H, m), 1.36–1.53 (2 H, m), 2.03 (3 H, s), 2.12–2.20
(2 H, m), 2.68–2.77 (1 H, m), 2.80–2.88 (1 H, m), 3.13–3.18
(1 H, m), 3.30–3.36 (1 H, m), 3.83 (3 H, s), 4.56–4.65 (1 H, m),
5.13–5.22 (1 H, m), 6.23 (1 H, br d, J 7), 6.55 (1 H, d, J 10), 6.61
(1 H, d, J 8), 7.04–7.08 (2 H, m) and 7.16–7.24 (2 H, m); δC
21.82, 23.43, 27.37, 34.98, 38.45, 39.04, 39.42, 52.63, 52.83,
55.29, 127.97, 128.17, 128.73, 131.43, 136.68, 136.86, 169.94,
170.82, 172.93 and 173.03; HRMS (FABϩ): C20H28N3O5
(M ϩ H); Found: m/z, 390.2033. Calc.: m/z, 390.2029.
18 A.-S. Carlström and T. Frejd, Acta Chem. Scand., 1992, 46, 163.
19 B. Basu and T. Frejd, Acta Chem. Scand., 1996, 50, 316.
20 B. Basu, S. K. Chattopadhyay, A. Ritzén and T. Frejd, Tetrahedron:
Asymmetry, 1997, 8, 1841.
21 A. Ritzén, B. Basu, S. K. Chattopadhyay, F. Dossa and T. Frejd,
Tetrahedron: Asymmetry, 1998, 9, 503.
22 J. M. Travins and F. A. Etzkorn, J. Org. Chem., 1997, 62, 8387.
23 M. J. Burk, J. E. Feaster, W. A. Nugent and R. L. Harlow, J. Am.
Chem. Soc., 1993, 115, 10125.
24 U. Schmidt, A. Lieberknecht, U. Schanbacher, T. Beuttler and
J. Wild, Angew. Chem., Int. Ed. Engl., 1982, 21, 770.
25 U. Schmidt, A. Lieberknecht and J. Wild, Synthesis, 1984, 53.
26 E. P. Prokof ’ev and E. I. Karpeiskaya, Tetrahedron Lett., 1979, 737.
27 T. Shioiri, K. Ninomiya and S.-i. Yamada, J. Am. Chem. Soc., 1972,
94, 6203.
Methyl
(3S,13S)-13-(acetylamino)-5,12-dioxo-4,11-diaza-
7e.
bicyclo[13.3.1]nonadeca-1(19),15,17-triene-3-carboxylate
Yield 50%; mp 255–258 ЊC; δH Ϫ0.23 to Ϫ0.08 (1 H, m), 0.86–
0.98 (1 H, m), 1.08–1.35 (3 H, m), 1.45–1.58 (1 H, m), 1.86–1.94
(1 H, m), 2.05 (3 H, s), 2.22–2.29 (1 H, m), 2.51 (1 H, t, J 13),
2.69 (1 H, t, J 12), 2.80–2.87 (1 H, m), 3.24 (1 H, dd, J 3.8 and
12.6), 3.40 (1 H, dd, J 3.6 and 13.2), 3.56–3.66 (1 H, m), 3.84
(3 H, s), 4.50–4.56 (1 H, m), 5.19–5.26 (1 H, m), 5.99 (1 H, d,
J 9.6), 6.26 (1 H, br d, J 5.6), 6.54 (1 H, d, J 7.6), 6.89–6.95 (2 H,
m), 7.09 (1 H, t, J 7.6) and 7.51 (1 H, s); δC 20.41, 23.06, 23.64,
25.77, 34.75, 36.63, 40.15, 40.42, 52.75, 52.92, 56.55, 128.43,
128.46, 128.76, 130.34, 136.94, 137.67, 169.41, 170.49, 172.32
and 172.78; HRMS (FABϩ): C21H30N3O5 (M ϩ H); Found:
m/z, 404.2173. Calc.: m/z, 404.2185.
28 A. Ehrlich, H.-U. Heyne, R. Winter, M. Beyermann, H. Haber,
L. A. Carpino and M. Bienert, J. Org. Chem., 1996, 61, 8831.
29 F. Cavelier-Frontin, G. Pèpe, J. Verducci, D. Siri and R. Jacquier,
J. Am. Chem. Soc., 1992, 114, 8885.
( )-(S*,R*)-7e. δH 0.19–0.31 (1 H, m), 0.78–0.90 (1 H, m),
1.03–1.16 (1 H, m), 1.22–1.33 (1 H, m), 1.34–1.47 (2 H, m),
1.95–2.01 (1 H, m), 2.12 (1 H, s), 2.18–2.26 (1 H, m), 2.68–2.81
(2 H, m), 2.87–2.95 (1 H, m), 3.25–3.40 (3 H, m), 3.89 (3 H, s),
4.85–4.99 (2 H, m), 5.88 (1 H, d, J 10), 6.05 (1 H, br t, J 6), 6.95
(1 H, d, J 8), 7.03–7.09 (2 H, m) and 7.15 (1 H, t, J 8).
30 M. Bodanszky and A. Bodanszky, The Practise of Peptide Synthesis,
Springer-Verlag, Berlin, 1984.
31 S. Gladiali and L. Pinna, Tetrahedron: Asymmetry, 1991, 2, 623.
32 D. Marcovici-Mizrahi, H. E. Gottlieb, V. Marks and A. Nudelman,
J. Org. Chem., 1996, 61, 8402.
Paper 8/05350B
3424
J. Chem. Soc., Perkin Trans. 1, 1998, 3419–3424