Synthesis of cyclic peptides by photochemical decarboxylation of N-phthaloyl peptides in aqueous solution

Article abstract of DOI:10.1002/hlca.200290027

The synthesis of a variety of cyclic peptides from N-phthaloyl-protected di-, tri-, tetra-, and pentapeptides with different aminocarboxylic acid tethers by photodecarboxylation - initiated by intramolecular electron transfer - has been explored in aqueous media. The progress and the chemoselectivity of the follow-up processes after CO₂ extrusion were traced by the respective pH/time-profiles, as well as by the overall change in pH after completion of the reaction. The competition between cyclization and simple oxidative decarboxylation depends on spacer length and geometry, H-bonding interaction between the electron accepting phthalimide C=O groups and amide H-atoms, as well as the geometric reorganization coupled with the radical combination step and the formation of the lactam rings. With progressing reaction, hydrolysis of the phthalimide chromophore becomes an increasingly important side reaction due to the constant increase in pH. The use of phosphate-buffered aqueous media consequently improved the cyclization yields. The ground-state interactions between amide groups and the terminal COO^- group with the imide C=O groups were studied for the model system [N-(phthaloyl)glycyl]sarcosine (1) by NMR spectroscopy where the amide (E/Z)-equilibrium depends on the presence of carboxylate vs. free carboxylic acid, demonstrating the role of H-bonding and metal coordination.

Full text of DOI:10.1002/hlca.200290027

Helvetica Chimica Acta Vol. 85 (2002)
4561
Synthesis of Cyclic Peptides by Photochemical Decarboxylation of
N-Phthaloyl Peptides in Aqueous Solution
by Axel G. Griesbeck*, Thomas Heinrich1), Michael Oelgemˆller2), Arne Molis, and Axel Heidtmann
Institut f¸r Organische Chemie der Universit‰t zu Kˆln, Greinstr. 4, D-50939 Kˆln
(tel.: ‡492214703083; fax: ‡492214705057; e-mail: griesbeck@uni-koeln.de)
This paper is dedicated to Professor Dieter Seebach on the occasion of this 65th birthday
The synthesis of a variety of cyclic peptides from N-phthaloyl-protected di-, tri-, tetra-, and pentapeptides
with different aminocarboxylic acid tethers by photodecarboxylation initiated by intramolecular electron
transfer has been explored in aqueous media. The progress and the chemoselectivity of the follow-up processes
after CO2 extrusion were traced by the respective pH/time-profiles, as well as by the overall change in pH after
completion of the reaction. The competition between cyclization and simple oxidative decarboxylation depends
on spacer length and geometry, H-bonding interaction between the electron accepting phthalimide CˆO groups
and amide H-atoms, as well as the geometric reorganization coupled with the radical combination step and the
formation of the lactam rings. With progressing reaction, hydrolysis of the phthalimide chromophore becomes
an increasingly important side reaction due to the constant increase in pH. The use of phosphate-buffered
aqueous media consequently improved the cyclization yields. The ground-state interactions between amide
groups and the terminal COOÀ group with the imide CˆO groups were studied for the model system [N-
(phthaloyl)glycyl]sarcosine (1) by NMR spectroscopy where the amide (E/Z)-equilibrium depends on the
presence of carboxylate vs. free carboxylic acid, demonstrating the role of H-bonding and metal coordination.
1. Introduction. In the last years, we have elaborated the synthetic applicability of
the intramolecular photoinduced decarboxylation of electronically excited phthali-
mides, originally described in 1991 [1]. In a first attempt to evaluate the scope and
limitation of this reaction with respect to the dimension of a flexible hydrocarbon chain
linking the electron acceptor with the electron donor (phthalimide and carboxylate,
respectively), we discovered that macrocyclic amines can be prepared in high yields
even without the use of dilution conditions (Scheme 1) [2]. The intermolecular version
of this reaction was subsequently discovered and proceeds with high efficiency and
Scheme 1. Photoinduced Electron-Transfer Decarboxylation/Cyclization Reaction of w-Phthalimido-substituted
Alkylcarboxylates with Divergent Linker Chains L1 and L2 and Spacer Functional Groups X
1
)
)
Part of the Ph.D. Thesis, University of Cologne, 2002.
New address: Bayer CropScience K.K., 9511-4 Yuki, Yuki-City, Ibaraki 307-001, Japan.
2

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Helvetica Chimica Acta Vol. 85 (2002)
flexibility when potassium alkylcarboxylates are used as the electron-donor compo-
nents and N-alkylated phthalimides as the acceptors [3]. Laser flash photolysis studies
revealed that triplet-excited states are responsible for the photochemistry of the
electronically excited phthalimides, with a substantial participation of the second
excited triplet state T2 [4]. From the results of time-resolved conductivity measure-
ments, we concluded that the intramolecular photoinduced electron transfer (PET) [5]
step is complete within less than 20 ns [6].
Substrates with a thioether moiety as the internal functional group X in Scheme 1
are prone to one-electron oxidation at the S-atom. This primary PET is followed by
decarboxylation in case of mercaptoacetic acid derivatives [7]. This approach
(Scheme 2,a D ˆ S, Y ˆ COÀ2 ) to medium-sized and macrocyclic thioethers is analogous
to the a-trialkylsilyl pathway developed by Yoon and Mariano (D ˆ O, S, or NR; Yˆ
SiR3) [8]. The principal difference between these two approaches is the position and
the function of the primary electron donor: in Scheme 2,a, the primary electron donor is
part of the spacer, and a biradical is generated by mesolytic3) cleavage of an a-CY bond
(Yˆ H, CO2, SiR3, SnR3); in Scheme 2,b, as a consequence of PET, the primary
electron donor D is converted to a leaving group and, thus, does not become part of the
new ring structure. We have recently applied this PET decarboxylation to the synthesis
of benzopyrrolizidines [10], macrocyclic lactones, and benzodiazepines [11].
Scheme 2. Pathways a) and b) to Biradicals Initiated by Photoinduced Electron-Transfer of Phthalimides in the
Presence ofElectron-Donor Groups (D)
We now report the application of this new type of photo-initiated biradical
generation for the synthesis of various cyclopeptides from terminally N-phthaloyl-
protected peptides and discuss the influence of ground-state properties on the
efficiency of the cyclization step [12].
2. Results and Discussion. 2.1. Mechanistic Studies on Electron-Transfer Geo-
metries. In Scheme 3, the possible pathways for the PET decarboxylation are
summarized, taking into account different conformational situations in the ground
states, electronically excited states, radical ions, as well as the precyclization states (i.e.,
the 1,n-biradical or biradical anion, respectively). Among numerous conformational
3
)
The term mesolytic was introduced by Maslak et al. [9].

Helvetica Chimica Acta Vol. 85 (2002)
4563
Scheme 3. General Mechanistic Pathways for Photodecarboxylations
local minima, only two states are discussed here: the remote conformations Ia IIIa,
where radical combination is geometrically impossible, and the proximate conforma-
tions Ib IIIb, which are likely to preceed the biradical combination.
It appears obvious, by chemical intuition, that the proximate states should favor
also the electron-transfer step due to the distance dependence of this reaction. Taking
into account the relatively long lifetimes of the T1 state (in the microsecond range),
conformational rearrangement at this stage is possible, however, less feasible at the
stage of the short-lived T2 state. From time-resolved laser flash conductivity studies
with the tranexamic acid derivative B, we concluded that the PET is rapid and should
proceed at the stage of the chair conformer and, preferentially, via the T2 state [6]. The
distance for electron transfer is ca. 6 7 ä, and subsequent extrusion of CO2, chair-boat
interconversion, and biradical combination are all time-delayed. Thus, the photo-
chemistry of this conformationally flexible but ground-state-remote substrate is
initiated at the acceptor side of Ia, proceeds via the biradical anion IIIa to give the
cyclization product IVb [2][6]. The 4-aminobenzoic acid derivative A cannot adopt a
proximate conformation, but the photoinduced decarboxylation still proceeds, how-
ever, with clean formation of N-phthaloyltoluidine (F) (oxidative decarboxylation
product IVa in Scheme 3). In order to be readily comparable, the model substrates A
and B, as well as the more-elaborate substrates C E, possess identical numbers of
linker atoms: in A C five C-atoms separate the phthalimide from the carboxylate
group, while D and E exhibit an additional (Z)-configured amide functionality.
The e-aminocaproic acid derived substrate C, upon PET, gives the corresponding
cyclization product H in high yields (Scheme 4) [1][2]. Due to the conformationally
flexible hydrocarbon chain, both the remote and proximate states Ia,b can be involved
in the excitation and electron transfer steps. A U-shaped conformation Ib is present in
the anthranilic acid derivatives of type D, which were investigated as precursors to the
benzodiazepines I [11]. These substrates efficiently photocyclize only when substituted
amino acids are applied (R=H). The parent substrate (R ˆ H) gives rise to complete

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Helvetica Chimica Acta Vol. 85 (2002)
O
O
COO
N
O
N
COO
O
A
C
B
D
O
O
COO
N
N
O
O
O
R
HN
COO
O
N
O
O
HN
E
COO
oxidative decarboxylation. This behavior can be rationalized by assuming the presence
of a H-bond between the amide NH and one of the imide CˆO groups. Likewise, open-
chain [N-(phthaloyl)glycyl]-b-alanin (E) decomposes to J, and no cyclization product
could be observed.
Whether the reaction of E ! J is really due to an internal H-bond deactivation was
investigated by comparison with the corresponding transformation of 1 (Scheme 5).
This substrate, when irradiated in aqueous acetone, gave upon 50% conversion the d-
lactam 2 in 20% yield besides simple photodecarboxylation. Additionally, this substrate
enabled us to observe by NMR spectroscopy a competing cooperative phenomenon,
i.e., a potassium-mediated donor-acceptor interaction (corresponding to Ib in Scheme 3).
In acetone/D2O solution, the (Z)-isomer of the free acid 1 dominated with ca. 75%
relative proportion. When 0.5 equiv. of K2CO3 was added, the (E)/(Z)-ratio changed
from 1:3 to 0.9 :1, indicating that noncovalent interactions operate in favor of the (E)-
isomer (Fig. 1).
The assumption of a metal-chelate facilitating the electron transfer step is
reasonable and in analogy to H-bonding interactions in w-phthalimido-containing
alkylcarboxylates as detected by X-ray analyses and cyclic voltammetry [13]. From
these results and by comparing photochemical behavior with ground-state properties,
we conclude that, in the case of N-(phthaloyl)dipeptides (and higher homologues
thereof), an appreciable amount of proximate conformation Ib exists in the ground
state, which favorably conducts both the PET and the cyclization steps after electronic
excitation. This type of PET-promoting interaction can compete with intramolecular H-
bonds or exist independently when the linker chain is long and flexible enough to
enable both types of interactions. Thus, we expected a pronounced influence of the
amino acid structure and the total peptide length on the electron transfer as well as the
cyclization efficiency.

Helvetica Chimica Acta Vol. 85 (2002)
4565
Scheme 4. Photolysis ofthe Model Substrates A E in Aqueous Acetone at 300 nm
Scheme 5. (E/Z)-Equilibrium ofthe Peptide Bond of N-(Pht)Gly-Sar (1) and Subsequent Photoreaction
2.2. Reactivity Studies of N-Phthaloyl-Protected Dipeptides. In a first series of
photochemically active dipeptides, we prepared compounds 3a f (N(Pht)Gly-AA2)
with increasing chain length of the second amino acid (AA2) component. The diglycine
and the glycyl-b-alanine substrates 3a,b (not shown) have already been described as

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Helvetica Chimica Acta Vol. 85 (2002)
Fig. 1. 1H-NMR Spectrum ofpeptide 1 in (D6)acetone/D2O as the potassium salt (upper spectrum) and the free
acid (lower spectrum). The red color refers to signals arising from the (Z)-isomer, blue signals belong to the
corresponding (E)-isomer of 1 with respect to the peptide bond.
photochemically active but only gave decomposition and simple decarboxylation
products [2]. From the elongated starting materials 3c 3f, however, we obtained the
lactams 4c 4f in medium yields through photolysis in H2O in the presence of small
amounts of acetone and 0.5 equiv. of K2CO3 (Scheme 6). The eight- and ten-membered
lactams 4c,d could be isolated in 48% and 69% yield, respectively, without detection of
simple decarboxylation products. In contrast to these two reactions, the more-
elongated substrates 3e,f gave, in addition to the desired 15- and 16-membered lactams
4e,f, the simple oxidative decarboxylation products 5e,f, respectively.
With a second series of substrates (6a c), we investigated the influence of the
hydrocarbon chain-length of the N-terminal amino acid on the efficiency of the
reaction (Scheme 7). These substrates were of special interest for another (mecha-
nistic) reason: the arrangement of amide bond and the terminal COOH group
corresponds to the situation shown in Scheme 2,a, i.e., the primary electron transfer can
also involve oxidation of the amide N-atom followed by decarboxylation. Analysis of
the relative rate of decarboxylation (vide infra) and the yields of the cyclization
products 7a c revealed, however, that this approach is not superior to the unmediated
direct one-electron oxidation of the carboxylate anion in contrast to the results
obtained from the mercaptoacetic acid derivatives [7].
Next, the tripeptides 8a d were investigated (Scheme 8). These substrates differ in
the position of the diglycine motif within the sequence. Here, no substantial effects
were detected from the terminal glycyl electron donor group (in 8a,b) in comparison
with an elongated terminal amino acid spacer (in 8c,d).
Similar to the diglycine derivative, the homologous triglycine substrate was
reluctant in the photocyclization step and yielded solely its decarboxylation product in

Helvetica Chimica Acta Vol. 85 (2002)
4567
Scheme 6
Scheme 7
28% yield. Likewise, as described for the N-protected glycylsarcosine 1, incorporation
of sarcosine as the second amino acid component led to peptide 10, which was
photocyclized in 35% yield to the nine-membered tricyclic system 11 (Scheme 9).
Following the above approach, we also investigated two tetrapeptide derivatives, N-
phthaloyl-protected Gly-Sar-Gly-Gly (12) and Gly-Pro-Gly-Gly (14), respectively.
Except for small amounts of decarboxylation and hydrolysis products (vide infra), the
cyclopeptides 13 and 15 were formed in 31 and 44% yields, respectively (Scheme 10).
Only one diastereoisomeric product was obtained from the chiral substrate 14, which
we assigned the trans-configuration based on 1H-NMR analysis and by comparison with
benzodiazepines obtained stereoselectively by a similar approach [11].

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 8
Scheme 9
Finally, to evaluate the limitations of this cyclization protocol, we investigated the
photochemistry of the phthaloyl-protected pentapeptide Gly-Pro-Gly-Pro-Gly (16).
Here, the proline residues were incorporated to avoid a deactivating H-bond (as for the
corresponding oligo glycines) and, additionally, to induce a hairpin structure that might
facilitate the donor/acceptor approach (Scheme 11).
The pH/time profile showed a constant increase in pH during the photolysis of 16 in
a H2O/acetone 4 :1, as well as a desymmetrization of the NMR-pattern of the
phthalimide electrophore. The resulting product 17 had the expected molecular weight
(as shown by high-resolution MS), but consisted of an inseparable mixture of at least
four isomers, most probably diastereoisomers with different amide-bond configurations
of the prolyl residues, a known phenomenon for flexible, proline-containing peptides
and cyclopeptides [14].
2.3. Analysis ofthe pH-Proifle as an Analytical Tool . In our recent time-resolved
conductivity study, we detected a rapid conductivity increase after the laser pulse,
which slowly decays when the reaction is initiated at low or neutral pH. Correspond-
ingly, we used the pH/time profile to follow the course of the reaction [15]. To obtain
tentative information about the nature of the photoreaction, it was sufficient to
measure and compare the changes in pH after a constant reaction time for different

Helvetica Chimica Acta Vol. 85 (2002)
4569
Scheme 10
Scheme 11
substrates. The values given in the Table show pH-changes after constant irradiation
times (3 h) at identical initial substrate concentrations (10 mm).
Table. Representative pH-Changes (DpHhn) upon Irradiation ofAqueous Solutions ofSelected Oligopeptides
The substrates were irradiated for 3 h at l ˆ 300 nm at an initial pH of 6.8 7.3.
.
Entry
Peptidea)
DpHhn
DpHcontrol
1
2
3
4
5
6
7
8
9
(Pht)Gly-Gly
(Pht)e-Acs-Gly (6b)
(Pht)Gly-Gly-Gly
(Pht)Gly-Gly-e-Acs (8b)
(Pht)e-Acs-Gly-Gly (8c)
(Pht)Gly-Sar-Gly (10)
(Pht)Gly-Gly-Gly-Gly
(Pht)Gly-Sar-Gly-Gly (12)
(Pht)Gly-Pro-Gly-Gly (14)
‡ 0.34
‡ 2.60
À 1.88
‡ 1.30
‡ 2.20
‡ 2.03
‡ 0.54
‡ 1.85
‡ 2.90
À 0.42
0.00
À 0.53
À 0.16
‡ 0.17
‡ 0.13
À 0.29
À 0.21
‡ 0.12
a) (Pht) ˆ N-Phthaloyl.

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Helvetica Chimica Acta Vol. 85 (2002)
All oligoglycine derivatives (Entries 1, 2, and 7 in the Table) showed a significant
decrease in pH under control conditions, indicating thermal hydrolysis with formation
of the corresponding phthalic monoacid. This hydrolysis was photochemically
accelerated with triglycine (Entry 3). The two other substrates, di- (Entry 1) and
tetraglycine (Entry 7) underwent decarboxylation without cyclization, which is
indicated by a small increase in pH. An efficient cyclization corresponds to a strong
increase in pH (1.5 to 2.5 units), resulting from the protonation of the alkoxide formed
after PETand biradical combination. With increasing pH, however, thermal hydrolysis
starts to interfere, and substantial amounts of nonabsorbing phthalic monoacid is
formed as a product. To suppress this unwanted side reaction, we performed the
cyclization in phosphate-buffer solution (pH 7.0) and, in the case of 6b, indeed detected
a 20% increase in the yield of 7b to 80%. It can be safely expected that this change in
reaction conditions will generally improve the yields of these reactions.
3. Conclusions.
Photodecarboxylation cyclization is an attractive route to
synthetic cyclic oligopeptides that can potentially mimic conformational motifs of
bioactive oligopeptides [16], and are, thus, currently investigated as peptidomimetics
[17], pharmaceutically active low-molecular-weight peptide analogues [18], or artificial
arrays with defined nanostructures [19]. The classical pathways to these target
structures are numerous and take advantage of the highly developed techniques in
peptide synthesis [20]. Nevertheless, due to the observation that most of these
compounds are macrocyclic polylactams, the fundamental restrictions in (thermal)
macrocyclization chemistry have to be considered [21]. Photochemical macrocycliza-
tions constitute an alternative class of reactions that are often controlled by excited-
state rather than ground-state properties [22]. The advantage of the concept described
herein is its simplicity and the obvious applicability to polypeptide structures where
distinct peptide motifs [23] can be incorporated into cyclic systems (Scheme 12).
Scheme 12. Photodecarboxylation/Cyclization Concept for Peptide Motifs
In the course of our investigations, we were repeatedly confronted with the question
of donor/acceptor geometries (cf. Scheme 3). The electron transfer is expected to be
fast due to the lifetime properties of the excited phthalimide triplet states, which is in
good agreement with time-resolved conductivity measurements [6] and the observation
that no dimers were obtained during photolysis even at relatively high concentrations
up to 50 mm. Thus, we assume that there are already ground-state donor/acceptor
interactions that facilitate electron transfer and subsequent biradical combination. The
geometric prerequisites for electron transfer are, however, less stringent compared to
biradical combination. Electron transfer can be conducted via a p-system as, e.g., in
substrate A (Scheme 4). Obviously, subsequent bond-formation is prohibited here.
But, also in polyglycine substrates that are PET-reactive, bond-formation seems to be

Helvetica Chimica Acta Vol. 85 (2002)
4571
prohibited. Due to the linker geometry, a H-bond interaction between the phthalimide
chromophore and a proximate secondary amide can generate an unfavorable situation.
If this H-bond is excluded, biradical combination reactivity is restored (e.g.,
N(Pht)Gly-Gly vs. N(Pht)Gly-Sar or N(Pht)Ala-Pro [24]). Alternatively, by elongat-
ing the second amino acid component, the electron-donating carboxylate can −return×
to the electron acceptor and consequently CÀC bond-formation starts to compete with
other processes (Fig. 2). Analogously, approach-favoring linkers like the ortho-
phenylene group in substrates of type D (Scheme 4) are unfavorable when the second
amino acid component spatially separates the donor from the acceptor. In this case, the
electron transfer is followed by an −exit× process (decarboxylation, second electron
transfer, and protonation leading to −simple× decarboxylation) [25]. Naturally, −return×
and −exit× geometries take into account neither solvent effects nor the exact structure of
the amphiphilic substrates in aqueous solutions, which might additionally influence the
geometry of the electronic ground and excited states.
Acc
linker
Acc
HOOC
COOH
Return geometry
Exit geometry
O
N
O
N
O
O
HN
O
O
HOOC
HN
COOH
Fig. 2. −Return× and −exit× geometries in N-Phthaloylpeptides
This research project has been financially supported by the Deutsche Forschungsgemeinschaft, the Fonds
der Chemischen Industrie, Degussa AG, Bayer AG, and Merck KGaA.
Experimental Part
General. Substrates, reagents and products for/of peptide syntheses are abbreviated by standard amino-acid
terminology; Pht ˆ phthaloyl, Sarˆ sarcosine, b-Ala ˆ b-alanine, g-Aba ˆ g-aminobutyric acid, e-Aca ˆ e-
aminocaproic acid, Auda ˆ 11-aminoundecanoic acid. Column chromatography (CC) was performed on Merck
silica gel 60 (230 mesh) with AcOEt/petroleum ether (PE) mixtures. Melting points (m.p.): B¸chi 535 melting
point apparatus; uncorrected. IR: Perkin-Elmer Paragon-1000 spectrophotometer; in cmÀ1 1H-NMR and
.
13C-NMR: Bruker AC-250, DPX-300, and DRX-500; in CDCl3, (D6)DMSO, (D6)acetone, and (CF3)COOD
(TFA); coupling constants J in Hz, chemical shifts d in ppm relative to Me4Si as internal standard; carbon
multiplicities determined by DEPT. Electron-impact mass spectroscopy (EI-MS): Finnigan MAT-8200 and
MAT-312. Electrospray-ionization mass spectra (ESI-MS) were recorded with methanolic peptide samples at
concentrations of ca. 3 Â 10À8 mol mlÀ1 and at 3.6 kV. Elemental analyses: Elementar Vario EL Rayonet.
Irradiation experiments: chamber photoreactors RPR-208 (8  3000 ä lamps, ca. 800 W, l ˆ 300 Æ 10 nm) and
RPR-100 (16  3500 ä lamps, ca. 400 W, l ˆ 350 Æ 20 nm), and immersion-wall reactors (l > 280 nm).
Synthesis ofUnfunctionalized N-Phthaloyl-containing Peptides. All substrates were synthesized following
published routes by coupling reactions of the appropriate N-phthaloylamino acids with the corresponding amino
acid benzyl esters following the DCC/HOBt (dicyclohexylcarbodiimide/1-hydroxy-1H-benzotriazole) protocol

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Helvetica Chimica Acta Vol. 85 (2002)
[2][11b][25]. Subsequent hydrogenolysis of the benzyl ester groups were performed in MeOH with Pd ¥ C under
a H2 atmosphere (standard pressure and temp.).
General Procedure (GP) for the Photolysis of N-Phthaloyl Peptides. Preparative photolyses were performed
in Pyrex vessels containing 20 40 ml of solvent while purging with a stream of N2 and cooling to 158 in H2O/
acetone mixtures. In exploratory experiments, photolyses with continous pH and sequential NMR control were
performed in 2 ml of a D2O/(D6)acetone. Preparative photolyses were performed until completion was
indicated by thin-layer chromatography (TLC). The resulting soln. was extracted with CH2Cl2 (3 Â 20 ml); the
aq. phase was acidified to pH 1 and extracted with AcOEt (3 Â 20 ml). The combined org. phases were dried,
the solvent was evaporated, and the residue was purified by CC.
(N-Phthaloylglycyl)sarcosine (1). Following the GP, starting from 32.0 g (87.0 mmol) of N-(Pht)Gly-Sar-
OBn, 15.7 g (65%) of 1 was obtained as a colorless solid. M.p. 128 1298. 1H-NMR (300 MHz, CDCl3/
(D6)DMSO): 3.11 (s, Me); 3.97 (s, NCH2CO2); 4.48 (s, NCH2); 7.68 (m, 2 arom. H); 7.77 (m, 2 arom. H).
13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 35.0 (q, Me); 38.7 (t, NCH2); 49.1 (t, NCH2CO2); 122.8 (d, 2 arom.
CH); 131.6 (d, 2 Cq); 133.8 (s, 2 arom. CH); 165.8 (s, 2 CON); 167.2 (s, CONMe); 170.0 (s, CO2).
4-[(N-Phthaloylglycyl)amino]butyric Acid (3c). Following the GP, starting from 2.00 g (5.30 mmol) of
N(Pht)Gly-g-Abu-OBn, 1.40 g (91.5%) of 3c was obtained as a colorless solid. M.p. 213 2148. IR (CsI): 3297,
2930, 1778, 1729, 1714, 1658, 1461, 1421, 1089, 807, 722, 716, 676. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 1.60
(quint., CH2); 2.11 (t, 3J ˆ 7.3, CH2CO2); 3.04 (dt, 3J ˆ 5.1, 6.6, NHCH2); 4.11 (s, NCH2); 7.41 (t, 3J ˆ 5.1, NH);
7.53 (m, 2 arom. H); 7.65 (m, 2 arom. H). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 23.6 (t, CH2); 30.4
(t, CH2CO2); 32.9 (t, NHCH2); 37.7 (t, NCH2); 122.2 (d, 2 arom. CH); 131.2 (s, 2 arom. Cq); 133.1 (d, 2 arom.
H); 165.4 (s, 2 CON); 166.7 (s, CONH); 173.9 (s, CO2).
6-[N-(Phthaloylglycyl)amino]hexanoic Acid (3d). Following the GP, starting from 2.00 g (4.88 mmol) of
N-(Pht)Gly-e-Aca-OBn, 1.25 g (80.5%) of 3d was obtained as a colorless solid. M.p. 140 1418. IR: (CsI) : 3293,
2936, 1777, 1733, 1711, 1656, 1627, 1564, 1468, 1421, 1089, 803, 745, 716, 686. 1H-NMR (300 MHz, D2O/
(D6)acetone): 1.30 (m, CH2); 1.45 1.64 (m, 2 CH2); 2.22 (t, 3J ˆ 7.4, CH2CO2); 4.13 (t, 3J ˆ 7.4, NHCH2); 4.46
(s, NCH2); 7.88 (br. m, 4 arom. H). 13C-NMR: (75.5 MHz, D2O/(D6)acetone): 24.4 (t, CH2); 25.2 (t, 2 CH2); 30.0
(t, CH2CO2); 34.0 (t, NHCH2); 39.3 (t, NCH2); 124.1 (d, 2 arom CH); 131.6 (s, 2 arom Cq); 135.6 (d, 2 arom.
CH); 168.9 (s, 2 CON); 169.0 (s, CONH); 177.7 (s, CO2). Anal. calc. for C16H18N2O5 (318.1): C 60.37, H 5.70, N
8.80; found: C 60.76, H 5.82, N 7.11.
11-[N-(Phthaloylglycyl)amino]undecanoic Acid (3e). Following the GP, starting from 1.30 g (2.70 mmol)
of N-(Pht)Gly-Auda-OBn, 1.02 g (97%) of 3e was obtained as a colorless solid. M.p. 160 1628. 1H-NMR:
(300 MHz, CDCl3/(D6)DMSO): 1.20 1.56 (br. m, 8 CH2); 2.13 (t, 3J ˆ 7.4, CH2CO2); 3.37 (dt, 3J ˆ 6.2, 6.8,
NHCH2); 4.17 (s, NCH2); 7.72 (m, 2 arom. H); 7.80 (m, 2 arom. H); 7.94 (t, 3J ˆ 6.4, NH). 13C-NMR (75.5 MHz,
CDCl3/(D6)DMSO): 25.2 (t, CH2); 26.3 (t, CH2); 28.4 (t, CH2); 28.5 (t, CH2); 28.6 (t, CH2); 28.7 (t, CH2); 28.8
(t, CH2); 28.9 (t, CH2); 33.5 (t, CH2CO2); 33.3 (t, NHCH2); 38.8 (t, NCH2); 122.7 (d, 2 arom. CH); 133.7
(d, 2 Cq); 135.5 (d, arom. H); 167.2 (s, 2 CON); 172.4 (s, CONH); 174.6 (s, CO2).
N-(3-Phthalimidopropanoyl)glycine (6a). Following the GP, starting from 2.00 g (5.45 mmol) of N-(Pht)b-
Ala-Gly-OBn, 1.45 g (96%) of 6a was obtained as a colorless solid. M.p. 200 2028. 1H-NMR (300 MHz, CDCl3/
TFA): 2.87 (t, 3J ˆ 6.7, CH2CON); 4.06 (t, 3J ˆ 6.7, NCH2); 4.14 (d, 3J ˆ 5.2, NHCH2); 7.17 (br. t, NH); 7.77
(m, 2 arom. H); 7.85 (m, 2 arom. H). 13C-NMR (75.5 MHz, CDCl3/TFA): 32.5 (t, CH2CON); 34.4 (t, NHCH2);
41.5 (t, NCH2); 124.1 (d, 2 arom. CH); 131.1 (s, 2 Cq); 135.1 (d, 2 arom. CH); 169.7 (s, 2 CON); 174.9
(s, CONH); 175.0 (s, CO2).
N-(6-Phthalimidohexanoyl)glycine (6b). Following the GP, starting from 2.00 g (4.89 mmol) of N-(Pht)e-
Aca-Gly-OBn, 1.42 g (91%) of 6b was obtained as a colorless solid. M.p. 142 1448. IR: (CsI): 3301, 2940, 1774,
1722, 1647, 1547, 1460, 1439, 1075, 796, 723, 712, 622. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 1.30 (m, CH2);
1.58 (m, 2 CH2); 2.12 (t, 3J ˆ 7.4, CH2CO2); 3.56 (t, 3J ˆ 7.4, NHCH2); 3.73 (d, 3J ˆ 7.7, NCH2); 7.69 (m, 2 arom.
H); 7.75 (m, 2 arom. H). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 24.5 (t, CH2); 25.8 (t, CH2); 27.7 (t, CH2);
35.0 (t, CH2CO2); 37.1 (t, NCH2); 40.4 (t, NHCH2); 122.5 (d, 2 arom. CH); 131.4 (d, 2 arom. Cq); 133.6
(s, 2 arom. CH); 167.5 (s, 2 CON); 171.2 (s, CONH); 172.6 (s, CO2). Anal. calc. for C16H18N2O5 (318.1): C 60.37,
H 5.70, N 8.80; found: C 60.81, H 6.16, N 9.11.
N-(6-Phthalimidoundecanoyl)glycine (6c). Following the GP, starting from 2.00 g (4.18 mmol) of N-
1
(Pht)Auda-Gly-OBn, 1.55 g (96%) of 6c was obtained as a colorless solid. M.p. 83 848. H-NMR (300 MHz,
CDCl3): 1.24 1.29 (br. m, 6 CH2); 1.59 1.63 (m, 2 CH2); 2.27 (t, 3J ˆ 7.5, CH2CO2); 3.64 (t, 3J ˆ 7.2, NCH2); 4.05
(d, 3J ˆ 4.9, NHCH2); 6.44 (br. t, NH); 7.68 (m, 2 arom. H); 7.82 (m, 2 arom. H). 13C-NMR (75.5 MHz, CDCl3):
24.6 (t, CH2); 25.5 (t, CH2); 26.7 (t, CH2); 28.5 (t, CH2); 28.9 (t, CH2); 29.0 (t, CH2); 29.0 (t, CH2); 29.1 (t, CH2);

Helvetica Chimica Acta Vol. 85 (2002)
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36.1 (t, CH2CON); 38.1 (t, NHCH2); 41.5 (t, NCH2); 123.2 (d, 2 arom. CH); 132.1 (s, 2 arom. Cq); 133.9
(d, 2 arom. CH); 168.6 (s, 2 CON); 172.2 (s, CONH); 175.3 (s, CO2).
6-{[(N-Phthaloylglycyl)glycyl]amino}hexanoic Acid (8a). Following the GP, starting from 2.00 g
(4.30 mmol) of N-(Pht)Gly-Gly-e-Aca-OBn, 1.56 g (97%) of 8a was obtained as a colorless solid. M.p. 191
1928. IR: (CsI): 3318, 2927, 1775, 1721, 1707, 1684, 1634, 1562, 1469, 1426, 1090, 916, 716, 663. 1H-NMR
(300 MHz, CDCl3/(D6)DMSO): 1.21 1.40 (m, CH2); 1.45 (m, 2 CH2); 2.16 (t, 3J ˆ 7.4, CH2CO2); 3.05 (dt, 3J ˆ
6.2, 6.5, NHCH2); 3.71 (d, 3J ˆ 5.6, NHCH2CO); 4.30 (s, NCH2); 7.73 (t, 3J ˆ 5.3, NH); 7.79 (m, 2 arom. H); 7.85
(m, 2 arom. H); 8.52 (t, 3J ˆ 5.6, NH). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 24.2 (t, CH2); 25.9 (t, CH2);
28.8 (t, CH2); 33.6 (t, CH2CO2); 38.5 (t, NHCH2); 40.1 (t, NHCH2CO); 42.2 (t, NCH2); 123.0 (d, 2 arom. CH);
131.7 (d, 2 arom. Cq); 134.3 (s, 2 arom. CH); 166.4 (s, 2 CON); 167.4 (s, CONH); 168.2 (s, CONH); 174.4
(s, CO2).
11-{[(N-Phthaloylglycyl)glycyl]amino}undecanoic Acid (8b). Following the GP, starting from 2.00 g
(3.73 mmol) of N-(Pht)Gly-Gly-Auda-OBn, 1.55 g (93%) of 8b was obtained as a colorless solid. M.p. 170
1
1728. H-NMR (300 MHz, CDCl3/(D6)DMSO): 1.20 (br. m, 6 CH2); 1.38 1.48 (br. m, 4 CH2); 2.14 (t, 3J ˆ 7.4,
2 CH2CO2); 3.08 (dt, 3J ˆ 6.0, 6.8, 2 NHCH2); 3.73 (d, 3J ˆ 5.7, NHCH2CO); 4.30 (s, 2 NCH2); 7.72 (m, 2 arom.
H); 7.79 (m, 2 arom. H); 8.52 (t, 3J ˆ 5.6, NH); 8.79 (t, 3J ˆ 6.2, NH). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO):
23.5 (t, CH2); 25.4 (t, CH2); 27.6 (t, CH2); 27.8 (t, CH2); 27.9 (t, CH2); 28.0 (t, CH2); 28.8 (t, CH2); 32.7 (t, CH2);
33.6 (t, CH2CO2); 39.1 (t, NHCH2); 40.0 (t, NHCH2CO); 42.4 (t, NCH2); 121.9 (d, 2 arom. CH); 130.8
(d, 2 arom. Cq); 132.9 (s, 2 arom. CH); 165.5 (s, 2 CON); 166.3 (s, CONH); 167.8 (s, CONH); 173.9 (s, CO2).
Anal. calc. for C23H31N3O6 ¥ 0.5 H2O (454.2): C 60.78, H 7.10, N 9.25; found: C 60.29, H 7.51, N 9.12.
[N-(6-Phthalimidohexanoyl)glycyl]glycine (8c). Following the GP, starting from 2.00 g (4.59 mmol) of N-
(Pht)e-Aca-Gly-Gly-OBn, 1.64 g (95%) of 8c was obtained as a colorless solid. M.p. 158 1598. 1H-NMR
(300 MHz, CDCl3/(D6)DMSO): 1.30 (m, 2 CH2); 1.59 (m, 2 CH2); 2.14 (t, 3J ˆ 7.4, CH2CON); 3.56 (t, 3J ˆ 7.2,
NCH2); 3.78 (t, 3J ˆ 5.4, 2 NHCH2); 7.68 (m, 2 arom. H); 7.75 (m, 2 arom. H); 7.7 (t (obscured), 3J ˆ 5.4, 2 NH).
13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 24.5 (t, CH2); 26.9 (t, CH2); 27.7 (t, CH2); 34.3 (t, CH2CON); 37.1
(t, NCH2); 40.5 (t, NHCH2); 41.2 (t, NHCH2CO2); 65.9 (t, PhCH2); 12.7 (d, 2 arom. CH); 130.6 (d, 2 arom. Cq);
132.7 (s, 2 arom. CH); 166.7 (s, 2 CON); 169.1 (s, CONH); 169.5 (s, CONH); 171.8 (s, CO2).
[N-(11-Phthalimidoundecanoyl)glycyl]glycine (8d). Following the GP, starting from 2.00 g (3.55 mmol) of
N-(Pht)Auda-Gly-Gly-OBn, 1.38 g (58%) of 8d was obtained as a colorless solid. M.p. 180 1818. IR (CsI):
3411, 3376, 3336, 2928, 2851, 1698, 1667, 1631, 1530, 1467, 1401, 1088, 1018, 725. 1H-NMR (300 MHz, CDCl3/
(D6)DMSO): 1.20 (br. m, 6 CH2); 1.47 1.59 (br. m, 2 CH2); 2.12 (t, 3J ˆ 7.4, CH2CON); 3.56 (t, 3J ˆ 7.1, NCH2);
3.78 (d, 3J ˆ 5.7, 2 NHCH2); 7.70 (m, arom. H); 7.77 (m, 2 arom. H); 7.80 (t (partly obscured), 3J ˆ 5.6, NH); 8.05
(t, 3J ˆ 5.8, NH). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 24.4 (t, CH2); 25.0 (t, CH2); 26.2 (t, CH2); 27.9
(t, CH2); 28.5 (t, CH2); 28.6 (t, CH2); 28.7 (t, CH2); 33.3 (t, CH2); 35.3 (t, CH2CON); 37.2 (t, NCH2); 40.5
(t, NHCH2); 41. 9 (t, NHCH2CO2); 121.4 (d, 2 arom. CH); 130.3 (d, 2 Cq); 132.5 (d, 2 arom. CH); 167.6
(s, 2 CON); 169.1 (s, CONH); 169.6 (s, CONH); 173.6 (s, CO2). Anal. calc. for C23H31N3O6 ¥ 3 H2O (499.2): C
55.30, H 7.47, N 8.41; found: C 55.21, H 7.62, N 9.02.
[(N-Phthaloylglycyl)sarcosyl]glycine (10). Following the GP, starting from 2.10 g (5.00 mmol) of N-
(Pht)Gly-Sar-Gly-OBn, 1.30 g (78%) of 10 was obtained as a colorless solid. M.p. 69 708. IR (CsI): 3330, 2935,
1775, 1721, 1665, 1572, 1547, 1468, 1431, 1115, 958, 795, 716. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 2.88
(d, Me); 3.74 4.09 (m, MeNCH2, NHCH2); 4.51 (d, NCH2); 7.71 (m, arom. H); 7.79 (m, 2 arom. H); 7.96
(t, 3J ˆ 5.4, NH). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 35.0 (q, Me); 38.8 (t, NCH2); 41.0 (t, NHCH2); 50.2
(t, MeNCH2); 122.8 (d, 2 arom. CH); 131.6 (d, 2 arom. Cq); 133.8 (s, 2 arom. CH); 165.9 (s, 2 CON); 166.2
(s, CONMe); 167.1 (s, NHCO); 167.8 (s, CO2).
{[(N-Phthaloylglycyl)sarcosyl]glycyl}glycine (12). Following the GP, starting from 5.00 g (10.0 mmol) of N-
(Pht)Gly-Sar-Gly-Gly-OBn, 3.33 g (84.5%) of 12 was obtained as a yellowish solid. M.p. 96 978. IR (CsI):
3646, 3628, 3329, 2934, 2852, 1772, 1717, 1700, 1652, 1627, 1575, 1559, 1436, 1089, 959, 893, 717. 1H-NMR
(300 MHz, CDCl3/(D6)DMSO): 2.85 (s, Me); 3.72 4.11 (m, MeNCH2, 2 NHCH2); 4.52 (s, NCH2); 7.72
(m, 2 arom. H); 7.79 (m, 2 arom. H); 7.98 (t, 3J ˆ 5.6, NH); 8.14 (t, 3J ˆ 5.7, NH). 13C-NMR (75.5 MHz, CDCl3/
(D6)DMSO): 35.8 (q, Me); 38.9 (t, NCH2); 40.5 (t, NHCH2); 41.9 (t, NHCH2); 47.5 (t, MeNCH2); 122.8
(d, 2 arom. CH); 131.6 (d, 2 arom. Cq); 133.8 (s, 2 arom. CH); 166.1 (s, 2 CON); 167.2 (s, CONMe); 167.7
(s, NHCO); 168.1 (s, NHCO); 168.9 (s, CO2).
{[(N-Phthaloylglycyl)-l-prolyl]glycyl}glycine (14). Following the GP, starting from 6.90 g (14.0 mmol) of
N-(Pht)Gly-Pro-Gly-Gly-OBn, 2.95 g (51%) of 14 was obtained as a yellowish solid. M.p. 95 968. ‰aŠ2D0 : À 77.9
(c ˆ 1, MeOH). IR (CsI): 3808, 3328, 2935, 2362, 1777, 1721, 1659, 1650, 1562, 1547, 1536, 1449, 1090, 958, 717.
1H-NMR (300 MHz, CDCl3): 2.00 (m, 2 CH2); 3.55 3.93 (m, CH2, 2 NHCH2); 4.44 (s, NCH2); 4.38 4.50

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Helvetica Chimica Acta Vol. 85 (2002)
(m, CH); 7.40 (br. t, NH); 7.7 (t (partly obscured), NH); 7.66 (m, 2 arom. H); 7.77 (m, 2 arom. H). 13C-NMR
(75.5 MHz, CDCl3): 25.0 (t, CH2); 28.7 (t, CH2); 39.9 (t, CH2); 41.1 (t, NHCH2); 42.7 (t, NHCH2); 46.9
(t, NCH2); 61.1 (d, CH); 123.5 (d, 2 arom. CH); 131.8 (d, 2 arom. Cq); 134.2 (s, 2 arom. CH); 166.2 (s, 2 CON);
167.9 (s, CONH); 170.6 (s, CONH); 170.9 (s, CONCH); 171.9 (s, CO2). Anal. calc. for C19H20N4O7 (416.1): C
54.81, H 4.84, N 13.46; found: C 56.77, H 5.54, N 11.39.
({[(N-Phthaloylglycyl)-l-prolyl]glycyl}-l-prolyl)glycine (16). Following the GP, starting from 3.18 g
(5.3 mmol) of N-(Pht)Gly-Pro-Gly-Gly-OBn, 2.29 g (85%) of 16 was obtained as a yellow solid. M.p. 128
1308. 1H-NMR (300 MHz, CDCl3): 1.73 2.19 (m, 4 CH2); 3.30 4.07 (m, 8 H, 4 CH2); 4.31 4.62 (m, 2 NCH2);
7.68 (dd, J ˆ 8.5, 2 arom. H); 7.80 (dd, 3J ˆ 8.5, 2 arom. H). 13C-NMR (75.5 MHz, CDCl3): 24.6 (t, CH2); 24.5
(t, CH2); 28.7 (t, CH2); 28.8. (t, CH2); 39.8 (t, NCH2CO); 41.2 (t, NCH2CO); 42.1 (t, NCH2CO); 46.6 (t, NCH2);
46.7 (t, NCH2); 60.3 (d, NCH); 60.4 (d, NCH); 123.5 (d, 2 arom. CH); 132.0 (s, 2 arom. Cq); 134.2 (d, 2 arom.
CH); 162.7 (s, 2 NCO); 165.6 (s, CO); 167.8 (s, CO); 168.5 (s, CO); 171.7 (s, CO); 172.0 (s, COOH). ESI-HR-
‡
MS (peak matching, reference ion: PPG505, resolution >7000): 536.174 ([M ‡ Na] , C24H27N5O8Na; calc.:
536.176). Anal. calc. for C24H27N5O8 ¥ H2O (531.2): C 54.23, H 5.50, N 13.18; found: C 53.64, H 5.89, N 13.74.
1,10b-Dihydro-10b-hydroxy-2-methylpyrazino[2,1-a]isoindole-3,6(2H,4H)-dione (2). Following the gener-
al photolysis procedure, a mixture of 280 mg (1.00 mmol) of 1 and 70.0 mg (0.50 mmol) of K2CO3 in 100 ml of
H2O/acetone 1 :1 was irradiated for 18 h. After extraction with CH2Cl2, acidification of the aq. phase and
extraction with AcOEt, the crude product was purified by CC (AcOEt/hexane 10 :1), resulting in 74 mg (20%)
of 2 as a colorless oil (50% conversion). 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 2.78 (s, NMe); 3.19 (d, 2J ˆ
12.3, MeNCH2); 3.57 (d, 2J ˆ 12.3, MeNCH2); 3.68 (d, 2J ˆ 18.2, NCH2); 4.34 (d, 2J ˆ 18.2, NCH2); 6.48 (br.
s, COH); 7.22 7.56 (m, 4 arom. H). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 34.6 (q, NMe); 40.5
(t, MeNCH2); 56.7 (t, NCH2); 82.4 (s, COH); 121.5 (d, arom. CH); 123.0 (d, arom. CH); 129.5 (d, arom.
CH); 130.7 (s, arom. Cq); 131.9 (d, arom. CH); 144.8 (s, arom. Cq); 163.7 (s, CON); 168.6 (s, CONH).
4,5,6,6a-Tetrahydro-6a-hydroxy[1,4]diazocino[8,1-a]isoindole-2,11(1H,3H)-dione (4c). Following the gen-
eral photolysis procedure, a mixture of 116 mg (0.40 mmol) of 3c and 14.0 mg (0.10 mmol) of K2CO3 in 20 ml of
H2O/acetone 10 :1 was irradiated for 3 h. After extraction with CH2Cl2, acidification of the aq. phase, and
extraction with AcOEt, the crude product was purified by CC (MeOH/CH2Cl2 1:7), resulting in 46.8 mg (48%)
of 4c as a yellow oil. DpHcontrol ˆ À0.06; DpHhv ˆ ‡1.22. IR (CsI): 3387, 2957, 2357, 1652, 1578, 1551, 1497, 1295,
1150, 1049, 1026. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 1.47 1.57 (br. m, CH2); 2.26 (t, 3J ˆ 4.1, CH2COH);
3.09 3.21 (br. m, NHCH2); 3.88 (d, 3J ˆ 17.9, 1 H, NCH2); 4.79 (d, 3J ˆ 17.9, 1 H, NCH2); 6.21 (s, OH); 6.96
(t, 3J ˆ 7.1, NH); 7.34 (m, 1 arom. H); 7.43 (m, 1 arom. H); 7.45 (m, 1 arom. H); 7.93 (m, 1 arom. H). 13C-NMR
(75.5 MHz, CDCl3/(D6)DMSO): 32.3 (t, CH2); 37.2 (t, CH2COH); 39.8 (t, NHCH2); 40.4 (t, NCH2); 89.5
(s, COH); 121.3 (d, arom. CH); 122.7 (d, 1 arom. CH); 128.9 (d, arom. CH); 130.4 (d, arom. CH); 132.3
(s, 1 arom. Cq); 146.3 (s, arom. Cq); 168.4 (s, CON); 170.6 (s, CH2CO). Anal. calc. for C13H14N2O3 (246.1): C
63.40, H 5.73, N 11.38; found: C 62.96, H 5.51, N 11.67.
4,5,6,7,8,8a-Hexahydro-8a-hydroxy[1,4]diazecino[10,1-a]isoindole-2,13(1H,3H)-dione (4d). Following the
general photolysis procedure, a mixture of 130 mg (0.40 mmol) of 3c and 14.0 mg (0.10 mmol) of K2CO3 in
20 ml of H2O/acetone 10 :1 was irradiated for 3 h. After extraction with CH2Cl2, acidification of the aq. phase,
and extraction with AcOEt, the crude product was purified by CC (MeOH/CH2Cl2 1:5), resulting in 76.8 mg
(69%) of 4c as a yellow oil. DpHcontrol ˆ 0.0; DpHhV ˆ ‡2.60. IR (CsI): 3409, 2954, 2257, 1651, 1568, 1557, 1397,
1295, 1152, 1049, 1026, 1004, 824, 764. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 0.93 (m, CH2); 1.38 (m, CH2);
1.41 (m, 1 H, NHCH2CH2); 1.43 (m, 1 H, CH2); 1.79 (m, 1 H, CH2COH); 1.93 (m, 1 H, NHCH2CH2); 2.10
(m, 1 H, CH2COH); 3.71 (dt, 3J ˆ 11.3, 1 H, NHCH2); 3.75 (d, 3J ˆ 17.1, 1 H, NCH2); 4.49 (d, 3J ˆ 17.2, 1 H,
NCH2); 4.80 (dt, 3J ˆ 11.0, 1 H, NHCH2); 7.47 (m, arom. H); 7.51 (m, arom. H); 7.58 (m, arom. H); 7.71
(m, arom. H). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 22.1 (t, CH2); 23.6 (t, NHCH2CH2); 25.3 (t, CH2);
31.3 (t, CH2COH); 39.7 (t, NCH2); 67.0 (t, NHCH2); 91.5 (s, COH); 121.9 (d, arom. CH); 123.6 (d, arom. CH);
129.7 (d, arom. CH); 130.6 (s, arom. Cq); 132.8 (d, arom. CH); 146.0 (s, arom. Cq); 166.9 (s, CON); 169.0
(s, CH2CO). Anal. calc. for C15H18N2O3 (274.1): C 65.68, H 6.61, N 10.21; found: C 65.33, H 6.44, N 10.49.
3,4,5,6,7,8,9,10,11,12,13,13a-Dodecahydro-13a-hydroxy-1H-[1,4]diazacyclopentadecino[15,1-a]isoindole-
2,18- dione (4e) and N-Decyl-2,3-dihydro-1,3-dioxo-1H-isoindole-2-acetamide (5e). Following the general
photolysis procedure, a mixture of 155 mg (0.40 mmol) of 3e and 14.0 mg (0.10 mmol) of K2CO3 in 20 ml of
H2O/acetone 1:1 was irradiated for 5 h. After extraction with CH2Cl2, acidification of the aq. phase, and
extraction with AcOEt, the crude product was purified by CC (SiO2; MeOH/CH2Cl2 1:10), resulting in 34.4 mg
(26%) of 4e and 48.2 mg (35%) of 5e as oils. DpHcontrol ˆ ‡0.14; DpHhV ˆ ‡1.30.
Data of 4e: 1H-NMR (300 MHz, CDCl3): 1.10 1.69 (br. m, 8 CH2); 1.84 (m, 1 H, CH2COH); 1.88 (m, 1 H,
CH2COH); 3.36 (m, NHCH2); 3.90 (d, 3J ˆ 16.0, 1 H, NCH2); 4.15 (d, 3J ˆ 16.0, 1 H, NCH2); 7.45 7.55 (br.

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m, 4 arom. H). 13C-NMR (75.5 MHz, CDCl3): 24.2 (t, CH2); 24.6 (t, CH2); 25.0 (t, CH2); 26.2 (t, CH2); 26.3
(t, CH2); 26.5 (t, CH2); 28.6 (t, CH2); 35.5 (t, CH2); 36.8 (t, CH2COH); 39.1 (t, NHCH2); 43.5 (t, NCH2); 91.7
(s, COH); 122.2 (d, arom. CH); 123.4 (d, arom. CH); 129.5 (d, arom. CH); 130.1 (d, arom. CH); 132.1 (s, arom.
‡
Cq); 147.2 (s, arom. Cq); 167.9 (s, CON); 170.0 (s, CH2CO). ESI-MS: 367.3 (70, [M ‡ Na] ). Anal. calc. for
C20H28N2O3 (344.2): C 69.74, H 8.19, N 8.13; found: C 69.89, H 8.04, N 7.78.
1
Data of 5e: H-NMR (300 MHz, CDCl3): 1.06 (t, 3J ˆ 7.2, Me); 1.11 1.39 (br. m, 8 CH2); 2.06 (t, 3J ˆ 7.2,
NHCH2); 4.12 (s, NCH2); 7.64 (m, 2 arom. H); 7.70 (m, 2 arom. H). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO):
14.7 (q, Me); 25.3 (t, CH2); 27.2 (t, CH2); 29.5 (t, CH2); 29.6 (t, CH2); 29.7 (t, CH2); 29.8 (t, CH2); 29.8 (t, CH2);
34.6 (t, NHCH2CH2); 40.8 (t, NCH2); 60.6 (t, NHCH2); 123.8 (d, 2 arom. CH); 132.6 (s, 2 arom. Cq); 134.8
(s, 2 arom. CH); 168.3 (s, 2 CON); 175.9 (s, CH2CO).
4,5,6,7,8,9,10,11,12,13,14,14a-Dodecahydro-14a-hydroxy-[1,4]diazacyclohexadecino[16,1-a]isoindole-
2,19(1H ,3H)-dione (4f) and N-Undecyl-2,3-dihydro-1,3-dioxo-1H-isoindole-2-acetamide (5f). For procedure
and anal. data, see [2].
4,5-Dihydro-11b-hydroxy-1H-[1,4]diazepino[2,1-a]isoindole-3,7(2H,11bH)-dione (7a). Following the gen-
eral photolysis procedure, a mixture of 113 mg (0.40 mmol) of 6a and 28.0 mg (0.20 mmol) of K2CO3 in 20 ml of
H2O/acetone 10 :1 was irradiated for 5 h. After extraction with CH2Cl2, acidification of the aq. phase and
extraction with AcOEt, 22.3 mg (24%) of 7a was obtained as a yellow oil that could not be purified any further.
DpHcontrol ˆ ‡0.08; DpHhV ˆ ‡1.40. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 2.79 (m, CH2CON); 3.79
(m, NHCH2); 3.98 (m, NCH2); 7.34 (m, arom. H); 7.46 (m, 2 arom. H); 7.60 (m, arom. H). 13C-NMR
(75.5 MHz, CDCl3/(D6)DMSO): 36.0 (t, CH2CON); 37.1 (t, NHCH2); 40.0 (t, NCH2); 104.5 (s, COH); 121.2
(d, arom. CH); 122.5 (d, arom. CH); 128.1 (s, arom. Cq); 130.2 (d, arom. CH); 131.3 (d, arom. CH); 140.0
(s, arom. Cq); 168.0 (s, CON); 169.1 (s, CONH).
1,5,6,7,8,14b-Hexahydro-14b-hydroxy-[1,4]diazecino[2,1-a]isoindole-3,10(2H,4H)-dione (7b). Following
the general photolysis procedure, a mixture of 130 mg (0.40 mmol) of 6b and 28.0 mg (0.20 mmol) of K2CO3
in 20 ml of H2O/acetone 9 :1 was irradiated for 5 h. After extraction with CH2Cl2, acidification of the aq. phase,
and extraction with AcOEt, 65.8 mg (60%) of 7b was obtained after CC (MeOH/CH2Cl2 1:7) as a yellowish oil.
DpHcontrol ˆ À0.13; DpHhV ˆ ‡2.20. IR (CsI): 3288, 2933, 2256, 1770, 1703, 1699, 1694, 1661, 1652, 1634, 1563,
1557, 1470, 1398, 1301, 1153, 1055, 823, 764. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 0.94 1.62 (br. m, 3 CH2);
2.00 (m, CH2CON); 3.30 (m, NCH2); 3.51 (m, 1 H, NHCH2); 3.74 (m, 1 H, NHCH2); 6.54 (s, OH); 7.42 7.63
(m, 4 arom. H). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 24.4 (t, CH2); 25.2 (t, CH2); 25.8 (t, CH2); 33.3
(t, CH2CON); 36.2 (t, NCH2); 46.6 (t, NHCH2); 88.2 (s, COH); 121.6 (d, arom. CH); 122.2 (d, arom. CH); 129.1
(d, arom. CH); 131.0 (d, arom. CH); 131.5 (s, arom. Cq); 146.3 (s, Cq); 166.7 (s, CON); 174.7 (s, CONH). Anal.
calc. for C15H18N2O3 ¥ 1.5 H2O (301.1): C 59.79, H 7.02, N 9.30; found: C 60.24, H 6.84, N 8.94.
4,5,6,7,8,9,10,11,12,13-Decahydro-19b-hydroxy-1H-[1,4]diazacyclopentadecino[2,1-a]isoindole-3,15(2H,19bH)-
dione (7c). Following the general photolysis procedure, a mixture of 155 mg (0.40 mmol) of 6c and 28.0 mg
(0.20 mmol) of K2CO3 in 20 ml of H2O/acetone 1:1 was irradiated for 3 h. After extraction with CH2Cl2,
acidification of the aq. phase, and extraction with AcOEt, 41.3 mg (30%) of 7c was obtained as a yellowish oil
that could not be purified further. 1H-NMR (300 MHz, CDCl3): 1.20 1.32 (m, 6 CH2); 1.48 1.88 (m, 2 CH2);
2.26 (m, CH2); 3.34 (m, 3 H, NCH2, NHCH2); 4.10 (dd, 3J ˆ 13.8, 4.9, 1 H, NCH2); 6.02 (s, OH); 6.71 (br.
t, NH); 7.38 (dd, 3J ˆ 7.2, 1.9, arom. H); 7.52 (m, 3 arom. H). 13C-NMR (75.5 MHz, CDCl3): 24.5 (t, CH2); 24.7
(t, CH2); 25.7 (t, CH2); 25.8 (t, CH2); 26.2 (t, CH2); 26.4 (t, CH2); 26.6 (t, CH2); 27.1 (t, CH2); 35.3 (t, CH2CON);
40.1 (t, NCH2); 48.5 (t, NHCH2); 89.8 (s, COH); 122.0 (d, arom. CH); 122.9 (d, arom. CH); 129.7 (d, arom.
CH); 130.9 (s, arom. Cq); 132.5 (d, arom. CH); 146.2 (s, arom. Cq); 167.8 (s, CON); 176.3 (s, CONH).
3,4,7,8,9,10,11,11a-Octahydro-11a-hydroxy-1H-[1,4,7]triazacyclotridecino[13,1-a]isoindole-2,5,16(6H)-tri-
one (9a). Following the general photolysis procedure, a mixture of 150 mg (0.40 mmol) of 8a and 28.0 mg
(0.20 mmol) of K2CO3 in 20 ml of H2O/acetone 10 :1 was irradiated for 5 h. After extraction with CH2Cl2,
acidification of the aq. phase, and extraction with AcOEt, 67.6 mg (51%) of 9a was obtained after CC (MeOH/
CH2Cl2 1:7) as a yellowish oil. DpHcontrol ˆ À0.16; DpHhV ˆ ‡1.30. IR (CsI): 3680, 3509, 3482, 3245, 2946, 2851,
1746, 1703, 1699, 1422, 1048, 822, 771. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 1.02 1.23 (br. m, 3 CH2); 1.85
(m, CH2COH); 1.92 (m, CH2COH); 2.96 (m, 1 H, NHCH2); 3.12 (m, 1 H, NHCH2); 3.61 (m, NHCH2CO); 3.79
(m, 1 H, NCH2); 4.25 (s, NCH2); 7.21 (t, 3J ˆ 5.6, NH); 7.47 (m, arom. H); 7.48 (m, arom. H); 7.59 (m, arom. H);
7.66 (m, arom. H); 8.27 (t, 3J ˆ 6.3, NH). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 25.6 (t, CH2); 27.4 (t, CH2);
33.7 (t, NHCH2CH2); 37.1 (t, CH2COH); 39.8 (t, NHCH2); 41.6 (t, NCH2); 44.5 (t, NHCH2CO); 90.8 (s, COH);
122.2 (d, arom. CH); 123.0 (d, arom. CH); 129.5 (d, arom. CH); 130.7 (s, arom. Cq); 132.8 (d, arom. CH); 148.2
‡
(s, arom. Cq); 167.9 (s, CON); 169.5 (s, NCH2CO); 169.9 (s, NHCH2CO). ESI-MS: 354.2 ([70, [M ‡ Na] ). ESI-

4576
Helvetica Chimica Acta Vol. 85 (2002)
HR-MS (peak-matching, reference ion: PPG367, resolution >7000): 354.143 (calc.: 354.1430 (M) from the obs.
‡
‡
signal for C17H21N3O4Na ([M ‡ Na] )).
3,4,5,6,7,8,9,10,11,12,13,14,15,16,16a-Tetradecahydro-16a-hydroxy-[1,4,7]triazacyclooctadecino[18,1-a]iso-
indole-2,5,21(1H)-trione (9b). Following the general photolysis procedure, a mixture of 183 mg (0.40 mmol) of
8b and 28.0 mg (0.20 mmol) of K2CO3 in 20 ml of H2O/acetone 1:1 was irradiated for 3 h. After extraction with
CH2Cl2, acidification of the aq. phase, and extraction with AcOEt, 111 mg (69%) of 9b was obtained after CC
(MeOH/CH2Cl2 1:10) as a yellow oil. DpHcontrol ˆ À0.03; DpHhV ˆ ‡1.60. 1H-NMR (300 MHz, CDCl3/
(D6)DMSO): 0.80 (m, 1 H, CH2); 1.13 (m, 1 H, CH2); 0.95 1.25 (br. m, 6 CH2); 1.34 (m, 1 H, CH2); 1.37
(m, 1 H, CH2); 1.86 (m, 1 H, CH2COH); 1.96 (m, 1 H, CH2COH); 2.90 (m, 1 H, NHCH2); 3.41 (m, 1 H,
NHCH2); 3.68 (d, 3J ˆ 4.1, 1 H, NHCH2CO); 3.88 (d, 3J ˆ 6.0, 1 H, NHCH2CO); 3.94 (m, 1 H, NCH2); 4.09
(m, 1 H, NCH2); 6.13 (s, OH); 7.27 (dd, 3J ˆ 4.1, 2.8, NH); 7.40 (dd, 3J ˆ 7.2, 1.2, arom. H); 7.45 (m, arom. H);
7.51 (m, arom. H); 7.58 (t (partly obscured), NH); 7.66 (d, 3J ˆ 7.5, arom. H). 13C-NMR (75.5 MHz, CDCl3/
(D6)DMSO): 22.8 (t, CH2CH2COH); 23.4 (t, CH2); 25.4 (t, CH2); 25.8 (t, CH2); 26.8 (t, CH2); 26.9 (t, CH2); 27.9
(t, NHCH2CH2); 28.5 (t, CH2); 36.3 (t, CH2COH); 36.9 (t, NHCH2); 41.9 (t, NCH2); 42.0 (t, NHCH2CO); 90.4
(s, COH); 121.8 (d, arom. CH); 122.5 (d, arom. CH); 128.5 (d, arom. CH); 130.3 (s, arom. Cq); 131.8 (d, arom.
CH); 147.6 (s, arom. Cq); 167.6 (s, CON); 167.7 (s, NCH2CO); 168.5 (s, NHCH2CO). ESI-MS: 424.3 (100, [M ‡
‡
‡
Na] ). ESI-HR-MS (peak-matching, reference ion: PPG389, resolution >8000): 424.222 ([M ‡ Na] ,
C22H31N3O4Na; calc.: 424.221). Anal. calc. for C22H31N3O4 (401.2): C 65.81, H 7.78, N 10.47; found: C 64.97, H
7.08, N 10.11.
4,5,8,9,10,11-Hexahydro-17b-hydroxy-1H-[1,4,7]triazacyclotridecino[2,1-a]isoindole-3,6,13(2H,7H,17bH)-
trione (9c). Following the general photolysis procedure, a mixture of 154 mg (0.40 mmol) of 8c and 28.0 mg
(0.20 mmol) of K2CO3 in 20 ml of H2O/acetone 10 :1 was irradiated for 3 h. After extraction with CH2Cl2,
acidification of the aq. phase, and extraction with AcOEt, 55.7 mg (42%) of 9c resulted after CC (MeOH/
CH2Cl2 1:7) as a yellow oil. DpHcontrol ˆ ‡0.17; DpHhV ˆ ‡2.20. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 1.49
(m, CH2); 1.62 (m, CH2); 1.75 (m, CH2); 2.05 (m, 1 H, CH2CON); 2.15 (m, 1 H, CH2CON); 3.24 (dd, 1 H,
NHCH2CON); 3.37 (m, NCH2); 3.42 (dd, 1 H, NHCH2COH); 3.70 (dd, 1 H, NHCH2COH); 3.85 (dd, 1 H,
NHCH2CON); 6.55 (s, OH); 6.79 (d, 3J ˆ 6.6, NH); 7.44 (m, arom. H); 7.52 (m, arom. H); 7.52 (m, arom. H);
7.61 (m, arom. H); 8.51 (t, 3J ˆ 6.0, NH). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 22.7 (t, CH2); 24.5 (t, CH2);
26.7 (t, CH2); 35.8 (t, CH2CON); 38.0 (t, NCH2); 43.5 (t, NHCH2CON); 45.4 (t, NHCH2COH); 87.8 (s, COH);
121.1 (d, arom. CH); 122.1 (d, arom. CH); 129.1 (d, arom. CH); 131.0 (s, arom. Cq); 131.7 (d, arom. CH); 146.1
(s, arom. Cq); 167.5 (s, CON); 169.1 (s, NHCH2CO); 174.0 (s, CH2CON). Anal. calc. for C17H21N3O4 (331.2): C
61.62, H 6.39, N 12.68; found: C 60.87, H 6.42, N 12.70.
1,4,5,7,8,9,10,11,12,13,14,15,16,22b-Tetradecahydro-22b-hydroxy-1H-[1,4,7]triazacyclooctadecino[2,1-a]iso-
indole-3,6,18(2H)-trione (9d). Following the general photolysis procedure, a mixture of 183 mg (0.40 mmol) of
8d and 28.0 mg (0.20 mmol) of K2CO3 in 20 ml of H2O/acetone 5 :1 was irradiated for 5 h. After extraction with
CH2Cl2, acidification of the aq. phase, and extraction with AcOEt, 91.5 mg (57%) of 9d resulted after CC
(MeOH/CH2Cl2 1:1) as a yellow oil. DpHcontrol ˆ À0.12; DpHhV ˆ ‡2.00. IR (CsI): 3612, 3519, 3475, 3245, 2951,
2845, 1746, 1709, 1695, 1414, 1048, 822, 778. 1H-NMR: (300 MHz, CDCl3/(D6)DMSO): 0.98 1.07 (m, CH2);
1.17 1.25 (m, CH2 , CH2CH2CH2CON); 1.49 (m, CH2CH2CON); 1.60 (m, CH2); 1.78 (m, CH2); 2.10
(m, CH2CON); 3.18 (m, 1 H, NCH2); 3.34 (m, 1 H, NCH2); 3.42 (m, 1 H, NHCH2CON); 3.59 (m, 1 H,
NHCH2CON); 3.71 (m, 1 H, NHCH2COH); 3.74 (m, 1 H, NHCH2COH); 6.42 (s, OH); 7.01 (d, 3J ˆ 5.6, NH);
7.41 (m, arom. H); 7.49 (m, arom. H); 7.49 (m, arom. H); 7.54 (t, 3J ˆ 5.6, NH); 7.60 (m, arom. H). 13C-NMR
(75.5 MHz, CDCl3/(D6)DMSO): 24.2 (t, CH2CH2CH2CON); 25.7 (t, CH2); 26.0 (t, CH2CH2CON); 26.9
(t, CH2); 27.3 (t, CH2); 27.5 (t, CH2); 32.2 (t, CH2); 34.7 (t, CH2CON); 38.2 (t, NCH2); 42.4 (t, NHCH2CON);
43.2 (t, NHCH2COH); 88.4 (s, COH); 121.9 (d, arom. CH); 122.0 (d, arom. CH); 128.9 (d, arom. CH); 131.3
(d, arom. CH); 131.7 (s, arom. Cq), 145.6 (s, arom. Cq); 167.0 (s, CON); 168.9 (s, NHCH2CO); 172.9
‡
(s, CH2CON). ESI-MS: 424.3 (100, [M ‡ Na] ). ESI-HR-MS (peak matching, reference ion: PPG389,
‡
resolution >8000): 424.222 ([M ‡ Na] , C22H31N3O4Na; calc.: 424.2213). Anal. calc. for C22H31N3O4 (401.2): C
65.81, H 7.78, N 10.47; found: C 65.01, H 7.00, N 10.24.
4,5-Dihydro-13b-hydroxy-5-methyl-1H-[1,4,7]triazonino[2,1-a]isoindole-3,6,9(2H,7H,13bH)-trione (11).
Following the general photolysis procedure, a mixture of 133 mg (0.40 mmol) of 10 and 28.0 mg (0.20 mmol)
of K2CO3 in 20 ml of H2O/acetone 4 :1 was irradiated for 5 h. Extraction of the aq. phase gave 40.5 mg (35%) of
11 as a yellowish oil. DpHcontrol ˆ ‡0.13; DpHhV ˆ ‡2.03. IR (CsI): 3315, 2951, 2257, 1648, 1561, 1538, 1391, 1295,
1152, 1055, 1014, 893, 724. 1H-NMR (300 MHz, CDCl3/(D6)DMSO): 2.85 (s, NMe); 3.62 (m, MeNCH2); 3.85
4.28 (m, 4 H, NHCH2COH, NCH2); 7.34 7.69 (m, 4 arom. H). 13C-NMR (75.5 MHz, CDCl3/(D6)DMSO): 37.2
(q, NMe); 42.7 (t, NCH2); 51.4 (t, MeNCH2); 56.3 (t, NHCH2); 84.0 (s, COH); 122.8 (d, arom. CH); 124.0

Helvetica Chimica Acta Vol. 85 (2002)
4577
(d, arom. CH); 129.6 (d, arom. CH); 130.2 (s, arom. Cq); 130.9 (d, arom. CH); 144.3 (s, arom. Cq); 165.1
‡
(s, CON); 170.7 (s, CONMe); 171.8 (s, CONH). ESI-MS: 289.3 (80, [M ‡ H] ). ESI-HR-MS (peak matching,
‡
reference ion: PPG331, resolution >7000): 289.315 ([M ‡ H] , C14H15N3O4; calc.: 289.3146). Anal. calc. for
C14H15N3O4 (289.1): C 58.13, H 5.23, N 14.53; found: C 58.33, H 5.15, N 14.21.
1,4,5,7,8,16b-Hexahydro-16b-hydroxy-8-methyl-[1,4,7,10]tetraazacyclododecino[2,1-a]isoindole-
3,6,9,12(2H,10H)-tetraone (13). Following the general photolysis procedure, a mixture of 156 mg (0.40 mmol) of
12 and 28.0 mg (0.20 mmol) of K2CO3 in 20 ml of H2O/acetone 4 :1 was irradiated for 5 h. Extraction of the aq.
phase and subsequent CC (MeOH :CH2Cl2 1 :7) afforded 42.9 mg (31%) of 13 as a yellowish oil. DpHcontrol
ˆ
À0.21; DpHhV ˆ ‡1.85. IR (CsI): 3448, 2951, 2845, 2256, 1655, 1395, 1131, 699. 1H-NMR (300 MHz, CDCl3/
(D6)DMSO): 2.79 (s, NMe); 3.68 (s, MeNCH2); 3.86 4.24 (m, 2 NHCH2COH, NCH2); 7.4 (t (partly
obscured), NH); 7.6 (t (partly obscured), NH); 7.36 7.71 (m, 4 arom. H). 13C-NMR (75.5 MHz, CDCl3/
(D6)DMSO): 37.1 (q, Me); 42.0 (t, NCH2); 43.6 (t, NHCH2); 51.6 (t, MeNCH2); 56.3 (t, NHCH2COH); 84.1
(s, COH); 122.8 (d, arom. CH); 123.9 (d, arom. CH); 128.3 (d, arom. CH); 129.4 (s, arom. Cq); 130.8 (d, arom.
CH); 138.7 (s, Cq); 164.9 (s, CON); 170.6 (s, CONMe); 171.3 (s, CONH); 172.8 (s, CONH). Anal. calc. for
C16H18N4O5 ¥ 1.5 H2O (346.3): C 55.49, H 5.24, N 16.18; found: C 55.73, H 5.11, N 15.89.
1,2,3,3a,5,6,9,9a-Octahydro-9a-hydroxypyrrolo[2',1':9,10][1,4,7,10]tetraazacyclododecino[2,1-a]iso indole-
4,7,14,17(8H,16H)-tetraone (15). Following the general photolysis procedure, a mixture of 167 mg (0.40 mmol)
of 14 and 28.0 mg (0.20 mmol) of K2CO3 in 20 ml of H2O/acetone 4 :1 was irradiated for 5 h. Extraction of the
aq. phase and subsequent CC (MeOH :CH2Cl2 1:10) afforded 65.5 mg (44%) of 15 as a yellowish oil.
DpHcontrol ˆ ‡0.12; DpHhV ˆ ‡2.90. IR (CsI): 3468, 2934, 1652, 1399, 1312, 1088, 769, 703. 1H-NMR (300 MHz,
CDCl3): 1.76 1.93 (m, 2 CH2); 3.65 (m, CH2); 4.01 4.52 (m, 2 NHCH2, NCH2); 4.74 (m, CH); 7.4 (t
(obscured), NH); 7.7 (t (obscured), NH); 7.38 7.78 (m, 4 arom. H). 13C-NMR (75.5 MHz, CDCl3): 26.0
(t, NCH2CH2); 32.2 (t, NCHCH2); 41.0 (t, NCH2); 42.1 (t, NCH2CH2); 44.3 (t, NHCH2); 54.7 (t, NHCH2COH);
58.2 (d, CH); 86.5 (s, COH); 123.4 (d, arom. CH); 123.7 (d, arom. CH); 130.0 (d, arom. CH); 132.1 (s, arom.
Cq); 132.4 (d, arom. CH); 143.9 (s, arom. Cq); 168.9 (s, CON); 170.8 (s, CONMe); 171.9 (s, CONH); 172.6
(s, CONH). Anal. calc. for C18H20N4O5 (372.4): C 58.06, H 5.41, N 15.05: found: C 57.98, H 5.18, N 14.89.
2,3,6,7,8a,9,10,11,21,22-Decahydro-20b-hydroxy-1H-dipyrrolo[2',1':12,13 :2',1':6,7][ 1,4,7,10,13]pentazacy-
clopentadecino[2,1-a]isoindole-5,8,13,16,23(14H,20bH,23aH)-pentaone (17). Following the general photolysis
procedure, a mixture of 53 mg (0.10 mmol) of 16 and 7.2 mg (0.05 mmol) of K2CO3 in 1 ml of H2O/acetone 1 :1
was irradiated for 5 h. Extraction of the aq. phase and purification by CC (MeOH/CH2Cl2 1:5) afforded 25.6 mg
‡
(53%) of 17 as a colorless oil. ESI-MS: 492.2 (100, [M ‡ Na] ). ESI-HR-MS (peak-matching, reference ion:
‡
PPG505, resolution >7000): 492.186 ([M ‡ Na] , C23H27N5O6Na; calc. 492.1859).
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Received July 16, 2002