Synthesis of proline-based diketopiperazine scaffolds

Article abstract of DOI:10.1021/jo9004876

(Chemical Equation Presented) A number of natural products with interesting biological properties are based on a diketopiperazine scaffold. In this context, we have developed a diversity oriented and efficient synthetic strategy to highly functionalized p

Full text of DOI:10.1021/jo9004876

Synthesis of Proline-Based Diketopiperazine Scaffolds
N. Deppermann, A. H. G. P. Prenzel, A. Beitat, and W. Maison*
Department of Chemistry, UniVersity of Giessen, Heinrich-Buff-Ring 58, 35390 Giessen, Germany
wolfgang.maison@org.chemie.uni-giessen.de
ReceiVed March 6, 2009
A number of natural products with interesting biological properties are based on a diketopiperazine scaffold.
In this context, we have developed a diversity oriented and efficient synthetic strategy to highly
functionalized proline-based diketopiperazines. In this paper we describe the stereoselective synthesis of
various scaffolds resembling abundant natural product core structures. These scaffolds can be conjugated
to a solid phase and are thus platforms for the construction of small compound libraries and the synthesis
of natural products with diketopiperazine cores.
Introduction
As depicted in Figure 1, a common motif of these compounds
is a proline-derived DKP-backbone with an annelated ring
system derived from a prenylated tryptophan. This tricyclic
scaffold forms the core of many natural product families like
the cyclotryprostatines, fumitremorgines and spirotryprostatines
and is thus an extremely interesting synthetic target for the
assembly of natural product-like libraries of high pharmaceutical
potential.
In our attempts to find new cancer-specific small molecules
for the development of diagnostic tools,18 we became interested
in proline-derived diketopiperazines, because some members
have been reported to exert cancer-specific biological effects.11,15,16
A number of excellent syntheses of different members of this
natural product family have been reported and reviewed.19-23
Most strategies follow a biomimetic approach using indole
Small molecules are the key to understanding and modulating
protein function as well as developing new therapies and
diagnostics.1 The prerequirements of biological relevance to be
met by such molecules are fulfilled by natural product-derived
compound collections.2-5
Among small heterocyclic molecules, diketopiperazines (DKPs)
have attracted considerable attention in recent years6 and among
these, proline (or pipecolic acid) and tryptophan-derived struc-
tures with a bicyclo[2.2.x]diazaalkane core constitute a particu-
larly interesting class of natural products.7-9 Various biological
activities, ranging from antihelmintic properties to anti cancer
activity, have been assigned to members of this family.10-17
(1) Imming, P.; Sinning, C.; Meyer, A. Nat. ReV. Drug. DiscoV. 2006, 5,
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Deveau, A. M.; Dieckhaus, C. M.; Johnson, M. A.; Smith, K. S.; Macdonald,
T. L.; Kakeya, H.; Osada, H.; Cook, J. M. Bioorg. Med. Chem. 2008, 16, 4626.
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10.1021/jo9004876 CCC: $40.75
Published on Web 04/24/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4267–4271 4267

Deppermann et al.
FIGURE 1. Examples for fungal metabolites based on proline-derived DKP scaffolds.
SCHEME 1. Diels-Alder Approach to Proline-Based Diketopiperazine Scaffolds
derivatives as precursor for the assembly of the eastern part of
the tricyclic scaffold. However, notable exceptions of this
general strategy are known24 and among these a recently
reported protocol by Bra¨se and co-workers deserves special
credits because it provides an easy and quite general excess to
various diketopiperazine scaffolds.25
Besides their relevance as scaffolds for natural products,
conformationally constrained proline-based diketopiperazines
play an important role in peptide chemistry as a backbone for
artificial peptide receptors26 and as chiral auxiliaries.27-29
In this context, we present a synthetic concept for the tricyclic
core of proline-derived DKPs using a Diels-Alder strategy for
the assembly of the key fragment 1 (Scheme 1). This concept
was pioneered by the Steglich group in a peptide context30 and
was later extended by our group and Arakawas group to the
synthesis of cyclic amino acids31-34 and peptide mimetics.35-37
The route that is outlined in Scheme 1 allows us to vary the
ring size, stereochemistry and substitution pattern of scaffold
1. In addition, conjugation sites X for the attachment of scaffolds
1 to a solid phase can be introduced by using hydroxyproline
as a precursor (R1 ) OH in Scheme 1). Key intermediates are
azabicycloalkenes 3 which can be synthesized easily via
enantioselective or diastereoselective protocols as both endo and
exo isomers.38-41 These strained bicyclic heterocycles are
known to be excellent synthetic intermediates useful for the
introduction of unnatural amino acids into peptides and dike-
topiperazines,30 preparation of peptidomimetics,42 amino acid
derivatives,33 and various other nitrogen heterocycles (for a
review see Maison33).
Results and Discussion
We started our synthesis from azabicycloalkene 4 (Scheme
2), which can be prepared stereoselectively on large scale (50
g and more) in a one-pot procedure from cyclopentadiene and
an imine that is generated in situ from tert-butyl glyoxylate and
(R)-methylbenzylamine.43 After bis-hydroxylation, the chiral
auxiliary is cleaved under hydrogenolytic conditions giving
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45, 4489.
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(24) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945.
(25) Jainta, M.; Nieger, M.; Bra¨se, S. Eur. J. Org. Chem. 2008, 5418.
(26) Wennemers, H.; Conza, M.; Nold, M.; Krattiger, P. Chem.-Eur. J. 2001,
7, 3342.
(27) Guenoun, F.; Zair, T.; Lamaty, F.; Pierrot, M.; Lazaro, R.; Viallefont,
P. Tetrahedron Lett. 1997, 38, 1563.
(28) Hendea, D.; Laschat, S.; Baro, A.; Frey, W. HelV. Chim. Acta 2006,
89, 1894.
(29) Kienle, M.; Argyrakis, W.; Baro, A.; Laschat, S. Tetrahedron Lett. 2008,
49, 1971.
(30) Jaeger, M.; Polborn, K.; Steglich, W. Tetrahedron Lett. 1995, 36, 861.
(31) Maison, W.; Adiwidjaja, G. Tetrahedron Lett. 2002, 43, 5957.
(32) Grohs, D. C.; Maison, W. Tetrahedron Lett. 2005, 46, 4373.
(33) Maison, W. Eur. J. Org. Chem. 2007, 2276.
(36) Prenzel, A. H. G. P.; Deppermann, N.; Maison, W. Org. Lett. 2006, 8,
1681.
(37) Bu¨chert, M.; Meinke, S.; Prenzel, A. H. G. P.; Deppermann, N.; Maison,
W. Org. Lett. 2006, 8, 5553.
(38) Maison, W. In Science of Synthesis; Enders, D., Schaumann, E., Eds.;
Georg Thieme Verlag KG: Stuttgart, 2009; Vol. 40a, p 343.
(39) Abraham, H.; Stella, L. Tetrahedron 1992, 48, 9707.
(40) Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.; Weinreb, S. M. Org.
React. 2005, 65, 141.
(41) Grieco, P. A.; Larsen, S. D.; Fobare, W. F. Tetrahedron Lett. 1986, 27,
1975.
(34) Arakawa, Y.; Murakami, T.; Ozawa, F.; Arakawa, Y.; Yoshifuji, S.
Tetrahedron 2003, 59, 7555.
(35) Maison, W.; Ku¨ntzer, D.; Grohs, D. Synlett 2002, 1795.
(42) Maison, W.; Prenzel, A. H. G. P. Synthesis 2005, 1031.
(43) Maison, W.; Grohs, D. C.; Prenzel, A. H. G. P. Eur. J. Org. Chem.
2004, 1527.
4268 J. Org. Chem. Vol. 74, No. 11, 2009

Proline-Based Diketopiperazine Scaffolds
SCHEME 2. Synthesis of Proline-Derived Diketopiperazine 11
SCHEME 3. Synthesis of Diketopiperazine 16
SCHEME 4. Synthesis of Diketopiperazine 21
aminodiol 5. For large scale applications, the bis-hydroxylation
to 5 can also be performed with KMnO4, if reaction conditions
are controlled carefully.43 It should be noted, that azabicy-
cloalkene 4 and aminodiol 5 are both colorless solids, which
are easy to purify by crystallization from either hexane or a
hexane/ethyl acetate mixture, respectively. Peptide coupling to
aminodiol 5 with Cbz-protected proline was accomplished with
DCC/HOBt to give the dipeptide 6 in good yield. The following
oxidative cleavage of the glycol moiety in 6 was realized via a
two-step sequence of periodate cleavage and subsequent chlorite
oxidation of the intermediate bis-aldehyde 7 or via a one pot
procedure with RuCl3/H5IO6. Both procedures work well with
the former giving a slightly higher yield of dicarboxylic acid 9.
It is interesting to note that the bis-aldehyde 7 is in equilibrium
with the bicyclic hemiacetal 8, which is the major species
observed by NMR in CDCl3. After quantitative esterification
of dicarboxylic acid 9 to ester 10, the Cbz group was cleaved
hydrogenolytically under basic conditions followed by intramo-
lecular lactam formation to give diketopiperazine scaffold 11
in excellent 65% yield over seven steps.
5 or 13. This parallels observations that substituted proline
derivatives are more easily coupled at their N-terminus than
the corresponding pipecolic acid derivatives.31
Stereochemical integrity of the compounds was established
by 2D-NOESY NMR and X-ray analysis for scaffolds 11 and
16, indicating no epimerization of any intermediate in the
sequence.
For the design of small compound libraries for screening,
the attachment of the scaffolds to a solid phase is desirable. In
this context, the careful choice of a suitable anchor group is
important, because the nature of this group is essential for the
Following this general route, we have prepared three enan-
tiomerically pure diketopiperazines 11 (Scheme 2), 16 (Scheme
3) and 21 (Scheme 4) with different ring sizes and stereochem-
istry. The yields of scaffolds 11, 16 and 21 are all acceptable
with pipecolic acid-derived scaffolds like 21 giving slightly
lower yields. This is due to less effective peptide couplings to
azabicyclooctanes like 18 compared to azabicycloheptanes like
J. Org. Chem. Vol. 74, No. 11, 2009 4269

Deppermann et al.
SCHEME 5. Synthesis of Functionalized Diketopiperazines
25 for Attachment to a Solid Phasea
SCHEME 6.
Diketopiperazine 25a
Synthesis of Amino-Substituted
Conclusions
A number of different proline-derived diketopiperazine scaf-
folds have been synthesized in enantiomerically pure form. The
synthetic route to these scaffolds was characterized by high
variability with respect to stereochemistry, ring size and
substitution pattern of the target compounds. It can be performed
on multigram scale as the starting azabicycloalkenes are readily
available by Diels-Alder reaction. Amino-substituted DKPs like
25a are a good platform for the development of small natural
product-like DKP collections using solid phase chemistry as
they can be attached to a solid phase using the amine as an
anchor group.
a Reagents and conditions: (a) DCC/HOBt; (b) HBTU/DIPEA; (c)
HATU/DMAP; (d) PCl5/DIPEA; (e) pentafluorophenyl trifluoroacetate.
Yields for dipeptides 23 are selected examples. For all yields see Supporting
Information
Experimental Section
Dipeptide 23c. A solution of 22c45 (7.5 g, 18.0 mmol) in DMF
(40 mL) was treated with pentafluorophenyltrifluoroacetate47 (5.8
g, 21 mmol) and dry pyridine (1.6 g, 20.0 mmol) for 12 h at rt.
EtOAc (100 mL) was added and the organic phase was washed
with sat. NaHCO3, 1 M HCl and sat. NaCl, dried with Na2SO4,
filtered and the solvent was evaporated in Vacuo. The resulting crude
oil (hydroxyproline-pfp-ester) was used without further purification
in the coupling step.
modularity of small molecules for application in our cancer
targeting concept.18,44 We chose a primary amine as an anchor
group, because it is compatible with the standard conjugation
techniques that are routinely used for the attachment of effector
molecules to generate cancer-specific diagnostic tools.
The amino functionality can be conjugated to our scaffold at
different stages of the synthesis using derivatives of hydroxy-
proline 22a-c as precursors (Scheme 5). All three hydroxy-
proline derivatives can be prepared by literature procedures in
large quantities.45,46 However, the application of azide- or
cyanide-substituted proline-derivatives 22a and 22b turned out
to be low yielding as the substituted dipeptides 23a and 23b
showed only low stability to oxidative conditions and gave both
unacceptable yields for the final hydrogenation to the free amines
25a and 25b. In consequence, we followed an alternative route
in which the tosyl group of hydroxyproline 22c was converted
to the azide/cyanide at a later stage of the synthesis depicted in
Scheme 5. In this case all reactions proceeded smoothly as
expected and DKP 25c was obtained in 30% overall yield for
the four-step sequence.
For the peptide coupling with the tosylated proline 22c, a
variety of generally efficient coupling procedures (a-e) were
tried as depicted in Scheme 5. DCC/HOBt-coupling as well as
HATU and HBTU scored repeatedly 40% yield and less.
Application of a proline acid chloride (method d in Scheme 5)
led to epimerized dipeptides 23. The best yields for dipeptides
23 gave method (e) in Scheme 5 that has been used for similar
coupling reactions by the Wennemers group.26
A solution of azabicycloalkane 543 (4.4 g, 19.2 mmol) in DMF
(40 mL) was stirred overnight with hydroxyproline-pfp-ester (13.5
g, 23.06 mmol). EtOAc (100 mL) was added and the organic phase
was washed with each 50 mL sat. NaHCO3, 1 M HCl and sat. NaCl,
dried with Na2SO4, filtered and the solvent was evaporated in Vacuo.
Flash chromatography gave dipeptide 23c (6.34 g, 10.1 mmol; 52%)
as a colorless foam. 1H NMR (CDCl3, 500 MHz, mixture of
rotamers): δ ) 7.77-7.80 (m, 2H), 7.27-7.39 (m, 7H), 4.87-5.11
(m, 3H), 4.67 (t, J ) 7.7 Hz, 0.65H), 4.55 (t, J ) 7.9 Hz, 0.35H),
4.21 (d, 0.65H, J ) 5.4 Hz), 3.99 (br, 0.65H), 3.94 (d, J ) 5.5 Hz,
0.35H), 3.67 - 3.84 (m, 2.35H), 3.50 (s, 0.35H), 3.16 (br, 0.65H),
2.39-2.58 (m, 5H), 2.15-2.23 (m, 2H), 1.90 (d, J ) 10.8 Hz,
0.65H), 1.80 (d, J ) 11.2 Hz, 0.65H), 1.70-1.77 (m, 0.7H), 1.42
(s, 5.85H), 1.41 (s, 3.15H) ppm. 13C NMR (CDCl3, 100 MHz,
mixture of rotamers): δ ) 169.4, 169.1, 168.4, 168.3, 154.5, 154.0,
145.5, 145.4, 136.0, 136.0, 133.3, 133.2, 132.4, 131.0, 130.3, 130.2,
130.0, 129.1, 128.9, 128.7, 128.6, 128.6, 128.3, 128.2, 128.2, 127.9,
82.0, 81.9, 79.8, 79.1, 72.4, 72.2, 71.9, 71.9, 68.0, 67.5, 60.6, 60.3,
60.2, 56.4, 56.1, 53.1, 52.8, 46.7, 46.5, 37.3, 36.3, 29.8, 29.1, 28.1,
21.8, 21.8 ppm; HRMS (ES): calcd: 653.2139 [C31H38N2O10S +
Na+]; found: 653.2153. [R]D20 ) -49.3 (c 0.7, CHCl3). Elemental
analysis: calcd C 59.03%, H 6.07%, N 4.44%; found C 59.37%, H
6.02%, N 4.65%.
Triester 24c. Diol 23c (6.3 g, 10.1 mmol) was dissolved in a
2:1:1 mixture of H2O/MeCN/CCl4. 4.1 equiv. H5IO6 and a catalytic
amount of RuCl3.3H2O was added. The mixture was stirred at rt
until the TLC showed complete conversion (12 h). CH2Cl2 and H2O
were added and the phases were separated. The aqueous layer was
extracted three times with each 100 mL CH2Cl2 and the combined
organic layers were dried with Na2SO4 and filtered. The solvent
was evaporated in Vacuo and the crude product was used without
further purification in the next step. The crude dicarboxylic acid
was dissolved in MeOH/Toluene 1:4 and TMSCH2N2 in Et2O was
The substitution of tosylate 25c with sodium azide gave 26
in quantitative yield without detectable side reactions (Scheme
6). Reduction of the azide in 26 with H2, Pd/C gave amine 25a,
again in quantitative yield.
(44) Humblet, V.; Misra, P.; Bhushan, K. R.; Nasr, K.; Ko, Y.-S.; Tsukamoto,
T.; Pannier, N.; Frangioni, J. V.; Maison, W. J. Med. Chem. 2009, 52, 544.
(45) Maison, W.; Arce, E.; Renold, P.; Kennedy, R. J.; Kemp, D. S. J. Am.
Chem. Soc. 2001, 123, 10245.
(46) Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; Gold, E. H.; Sommer, J. A.;
Brown, A. D.; Chiu, P. J. S.; Moran, R.; Sybertz, E. J.; Baum, T. J. Med. Chem.
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4270 J. Org. Chem. Vol. 74, No. 11, 2009

Proline-Based Diketopiperazine Scaffolds
added dropwise until TLC showed complete conversion. Excessive
TMSCH2N2 was quenched by careful addition of 10% HOAc in
H2O. Flash chromatography (EtOAc/PE 1:1) gave the title com-
mixture was poured on ice and the aqueous layer was extracted
with EtOAc three times. The solvent was evaporated to give the
title compound (0.7 g, 1.8 mmol, 94%) as a colorless solid. The
1
1
pound as a colorless foam (4.75 g, 7.4 mmol; 73%). H NMR
product was used without further purification in the next step. H
(CDCl3, 400 MHz, mixture of rotamers): δ ) 7.74-7.78 (m, 2H),
7.27-7.34 (m, 7H), 4.92-5.11 (m, 4H), 4.34-4.69 (m, 2H),
3.60-3.75 (m, 8H), 2.96-3.25 (m, 1H), 2.47-2.81 (m, 3H), 2.44
(s, 1.5H), 2.41 (s, 1.5H), 2.26-2.35 (m, 1H), 1.38-1.51 (m, 9H)
ppm. 13C NMR (CDCl3, 100 MHz, mixture of rotamers): δ ) 171.1,
170.9, 170.8, 170.7, 170.6, 170.5, 170.5, 170.4, 170.2, 169.8, 169.7,
168.9, 168.9, 154.3, 154.2, 145.4, 145.3, 136.8, 136.7, 136.6, 136.4,
133.5, 133.4, 130.3, 130.2, 128.7, 128.6, 128.6, 128.5, 128.5, 128.3,
128.3, 128.2, 128.1, 128.1, 84.1, 83.5, 82.6, 82.4, 67.4, 67.3, 67.2,
63.9, 63.2, 63.1, 61.9, 58.8, 58.7, 58.6, 58.3, 57.2, 57.0, 56.8, 56.7,
56.5, 53.0, 52.9, 52.7, 52.6, 52.5, 52.4, 52.3, 52.2, 47.9, 47.8, 45.0,
44.8, 36.7, 36.6, 35.6, 35.4, 32.1, 32.0, 29.6, 29.4, 28.0, 28.0, 21.8,
21.8 ppm. HRMS (ES): calcd: 711.2194 [C33H40N2O12S + Na+];
NMR (CDCl3, 400 MHz): δ ) 4.73 (d, J ) 6.4 Hz, 1H), 4.46 (dd,
J ) 8.0 Hz, 8.0 Hz, 1H), 4.36 (dd, J ) 6.4 Hz, 8.4 Hz, 1H), 4.20
(m, 1H), 3.78 (dd, J ) 12.8 Hz, 3.2 Hz, 1H), 3.73 (s, 3H), 3.51
(dd, J ) 5.6 Hz, 12.4 Hz, 1H), 3.15 (ddd, J ) 6.4 Hz, 8.2 Hz, 8.1
Hz, 1H), 2.62-2.66 (m, 1H), 2.59 (t, J ) 8.1 Hz, 2H), 2.50 (ddd,
J ) 5.7 Hz, 8.8 Hz, 13.9 Hz, 1H), 1.47 (s, 9H) ppm. 13C NMR
(CDCl3, 100 MHz): δ ) 171.4, 169.1, 165.7, 165.1, 83.0, 61.9,
60.2, 58.5, 58.2, 52.8, 50.7, 45.9, 32.7, 31.0, 28.0 ppm. HRMS
(ES): calcd [C17H23N5O6 + Na+]: 416.1541; found: 416.1527. [R]D
20
) -15.1 (c 2.7, CHCl3); Elemental analysis: calcd C 51.90%, H
5.89%, N 17.80%; found C 51.55%, H 5.62%, N 17.98%.
Diketopiperazine 25a. Azide 26 (0.55 g, 1.39 mmol) was
hydrogenolysed using 10 mol % Pd/C in methanol to give the title
compound (0.48 g, 1.30 mmol, 94%) as a colorless solid. 1H NMR
(CDCl3, 400 MHz): δ ) 4.70 (d, J ) 6.5 Hz, 1H), 4.44 (t, J ) 8.0
Hz, 1H), 4.32 (t, J ) 7.8 Hz, 1H), 3.73 (s, 3H), 3.58 (dd, J ) 11.6
Hz, 6.4 Hz, 1H), 3.47 (dd, J ) 11.6 Hz, 5.6 Hz, 1H), 3.14 (m,
1H), 3.10 - 3.16 (m, 1H), 2.52 - 2.63 (m, 2H), 2.47 (ddd, J )
6.1 Hz, 7.8 Hz, 13.4 Hz, 1H), 2.16 (ddd, J ) 6.4 Hz, 7.4 Hz, 13.6
Hz, 1H), 1.75 (br, 2H), 1.47 (s, 9H) ppm. 13C NMR (CDCl3, 100
MHz): δ ) 171.6, 169.2, 165.9, 165.6, 82.9, 61.9, 60.3, 59.4, 57.6,
52.7, 50.8, 45.9, 33.7, 31.2, 28.0 ppm. HRMS (ES): calcd: 390.1636
20
found: 711.2201. [R]D ) -22.7 (c 3.2, MeOH). Elemental
analysis: calcd C 57.55%, H 5.85%, N 4.07%; found C 57.55%, H
5.96%, N 3.79%.
Diketopiperazine 25c. Triester 24c (2.95 g, 4.28 mmol) was
dissolved in abs. MeOH and stirred for 12 h with 1 equiv. DIPEA
and a catalytic amount of 10% Pd/C under a hydrogen atmosphere.
The solution was filtered over diatomite and the solvent removed
in Vacuo to give the title compound (2.21 g, 4.24 mmol; 100%) as
1
a colorless foam. H NMR (CDCl3, 400 MHz): δ ) 7.77-7.79
[C17H25N3O6 + Na+]; found: 390.1661. [R]D ) -69.0 (c 1.0,
20
(m, 2H), 7.36-7.38 (m, 2H), 5.15-5.16 (m, 1H), 4.67 (d, J ) 6.4
Hz, 1H), 4.51 (dd, J ) 6.8 Hz, 11.2 Hz, 1H), 4.68 (dd, J ) 8.4 Hz,
8.4 Hz, 1H), 3.71 (s, 5H), 3.14 (ddd, 1H, J ) 6.4 Hz, 7.6 Hz, 8.5
Hz), 2.44-2.62 (m, 3H), 2.47 (s, 3H), 2.18-2.25 (m, 1H), 1.49
(s, 9H) ppm. 13C NMR (CDCl3, 100 MHz): δ ) 171.7, 169.1, 165.3,
165.0, 145.7, 133.5, 130.4, 127.9, 83.1, 78.3, 61.8, 60.5, 58.5, 52.8,
52.1, 45.7, 35.0, 31.1, 28., 21.9 ppm. HRMS (ES): calcd: 545.1564
CHCl3). Elemental analysis: calcd C 55.58%, H 6.86%, N 11.44%;
found C 55.76%, H 6.80%, N 11.64%.
Acknowledgment. We thank the DFG for financial support
of this work.
[C24H30N2O9S + Na+]; found: 545.1577. [R]D ) -44.8 (c 1.0,
20
Supporting Information Available: Detailed experimental
procedures and copies of NMR-spectra for new compounds as
well as crystallographic data for compounds 11 and 16. This
material is available free of charge via the Internet at
http://pubs.acs.org.
CHCl3). Elemental analysis: calcd C 55.16%, H 5.79%, N 5.36%;
found C 55.14%, H 5.93%, N 5.62%.
Diketopiperazine 26. To a suspension of tosylated diketopip-
erazine 25c (1.0 g, 1.9 mmol) in DMF (40 mL), NaN3 (0.5 g, 7.7
mmol) was added and the reaction was heated to 55 °C until TLC
showed complete consumption of the starting material. Then the
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