Efficient solution and solid-phase synthesis of a 3,9-diazabicyclo[3.3.1]non-6-en-2-one scaffold

Article abstract of DOI:10.1055/s-2002-33553

The solution and solid-phase syntheses of a 3,9-diazabicyclo[3.3.1]non-6-en-2-one have been realised via sequential Dakin-West/Pictet-Spengler reactions.

Full text of DOI:10.1055/s-2002-33553

LETTER
1443
Efficient Solution and Solid-Phase Synthesis of a 3,9-Diazabicyclo[3.3.1]non-
6-en-2-one Scaffold
Synthesis of
a
3,9-
a
D
iazabicyc
v
lo[3.3.1]non-
i
6-en-2
d
-
one Scaffold Orain,a Riccardo Canova,a Michele Dattilo,a Edgar Klöppner,a Régis Denay,b Guido Koch,*a Rudolf Giger*c
a
Novartis Pharma AG, Core Technology, Combinatorial Chemistry Unit, WSJ-507.7.03, 4002 Basel, Switzerland
Fax +41(61)3244236; E-mail: guido.koch@pharma.novartis.com
b
c
Novartis Pharma AG, Core Technology, NMR Analytic, WSJ-503.12.01, 4002 Basel, Switzerland
Novartis Ophthalmics AG, WKL-127.1.84B, Klybeckstrasse 141, 4057 Basel, Switzerland
Received 22 May 2002
Abstract: The solution and solid-phase syntheses of a 3,9-diazabi-
cyclo[3.3.1]non-6-en-2-one have been realised via sequential
Dakin–West/Pictet–Spengler reactions.
Key words: bicyclic compounds, indoles, solid-phase synthesis,
ring closure, cleavage
With the emergence of automated solution and solid-
phase synthesis, combinatorial chemistry had become an
essential tool in the discovery of new therapeutic agents.
Since the first synthesis of peptide libraries, a large num-
ber of non-peptidic libraries have been produced, particu-
larly heterocyclic libraries.1 In the process of identifying
new active scaffolds, one possible approach is to use the
diversity pool of natural products as a guideline2 to gener-
ate new templates. With this consideration in mind, our at-
tention was attracted by the Saframycin, Safracin,
Renieramycin and Ecteinascidin families (Figure), which
show powerful antiproliferative and antitumoural proper-
ties thus making them very attractive targets.3 In all these
families, a common 3,9-diazabicyclo[3.3.1]non-6-ene
core structure element was present. An indole 3,9-diaza-
bicyclo[3.3.1]non-6-en-2-one structure has been selected
as potential scaffold for combinatorial libraries. Here, we
report the development of a highly efficient solution and
solid-phase synthesis of this core structure. The synthesis
of this type of structure has been already reported in the
literature and the strategy was, in general, to produce first
a -carboline derivative between an aldehyde and tryp-
tophan and then closing the bicycle or generating an acyl
iminium for the cyclisation on an elaborated scaffold.4
Our approach consists in a simple linear construction of
the molecule before its cyclisation to the bicycle via an in-
tramolecular Pictet–Spengler reaction. In addition, with
our route, we are able to introduce a quaternary carbon
with a define stereochemistry which enhances the poten-
tial diversity of our scaffold. A novel sequential Dakin–
West/Pictet–Spengler reaction serves as key step of our
synthetic route, which starts from L-tryptophan. Attach-
ment of the template on solid-phase was achieved by us-
ing the commercially available L-5-hydroxy-tryptophan.
Figure Examples of structure from the Saframycin and Renieramy-
cin families in red is outlined the core 3,9-diazabicyclo[3.3.1]nonene
Solution-Phase Synthesis
Dipeptide 2 was obtained in 63% yield after peptide bond
formation between 1 and phenylalanine methylester and
subsequent hydrolysis. Then, the carboxylic acid moiety
was transformed to a methyl ketone unit through a Dakin–
West5 type reaction. Partial racemisation at the C- stere-
ocenter was observed under the required conditions. After
hydrolysis, the methyl ketone derivative 3 as a mixture of
2 diastereoisomers (57/43) was obtained in 77% yield.
Under acidic conditions (20% TFA in DCM), the Boc
group was cleaved generating a free amino group, which
immediately underwent intramolecular imine formation6
with the methyl ketone. Then, an intramolecular Pictet–
Spengler7 cycli-sation reaction occurred yielding the 3,9-
diazabicyclo[3.3.1]non-6-en-2-one derivative 4 (100%
conversion, 62% isolated yield) (Scheme 1). The quater-
nary stereocenter generated during cyclisation is con-
trolled through the asymmetric center of the L-tryptophan.
Nevertheless, target structure 4 was obtained as a mixture
of diastereoisomers (cis-4/trans-4 57/43) which were sep-
arated by flash chromatography on silica gel.8 The cis or
trans configuration (relative configuration between the
methyl and the benzyl group) of the diastereoisomers was
determined by modified 1H-1H ROESY experiments9 on a
BRUKER DPX 400 MHz. For the cis diastereoisomer,
NOE effects were observed between (CH216)-NH5 and
3
CH3 -NH5 whereas for the trans diastereoisomer, NOE ef-
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1443,1446,ftx,en;G14302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
3
fects were observed between (CH11)-NH5 and CH3 -NH5.

1444
D. Orain et al.
LETTER
Scheme 1 Solution synthesis of 3,9-diazabicyclo[3.3.1]non-6-en-2-one scaffold. Reagents and conditions: i) a) HCl·H2N-Phe-OMe, DCC,
HOBt, Et3N, THF, 16 h, r.t., b) NaOH 2N, THF, 2 h, r.t. (63%). ii) a) AcOH, Ac2O, DMAP, Et3N, THF, 16 h, 45 °C, b) NaOH 2N, THF, 2 h,
r.t. (77%). iii) 20% TFA/CH2Cl2, 16 h, r.t. (62%).
Mohan and co-workers reported a serine based carbamate chloroformate (66% yield after flash chromatography).
linker for the attachment of phenolic compounds stable to Solid-phase experiments were performed on Syn-
TFA and organic bases.10 The cleavage mechanism is phase
.
12 The first part of the linker was introduced via
based on the cleavage of the TIPS protecting group of a peptide formation with BocNH-Ser(OTIPS)-OH. After
serine side chain with a 1 M TBAF/THF solution which Boc deprotection of the immobilised serine, template 6
provides an alkoxy ion able to attack intramolecularly the was loaded on the solid-phase through the creation of an
urethane linkage and so to release the phenol derivative. urethane bond (Scheme 3).
During his study, Mohan has used a BocNH-Trp(OH)-
OMe template (Scheme 2).
Solid-phase synthesis of the 3,9-diazabicyclo[3.3.1]non-
6-en-2-one scaffold was initiated by removal13 of the allyl
Methylester hydrolysis of immobilised BocNH-Trp(OH)- group from functionalised resin 8. Then, phenylalanine al-
OMe resulted in a significant product loss due to linker lyl ester was coupled under standard conditions and the al-
cleavage. No selective hydrolysis reaction conditions lyl group was subsequently removed affording the free
could be found. Therefore, we decided to replace the car- carboxylic acid 9. Completion of the reaction was moni-
boxylate-protecting group by an allyl ester function. We tored by cleavage of cut off lantern’s loops with 1 M
carried out a new efficient synthesis of the Mohan linker TBAF/THF and analysis by LC/MS. The modified
by using a preformed protected template prepared in solu- Dakin–West required significantly prolonged reaction
tion before anchoring to the solid-phase. From 1, esterifi- times compared to its solution phase pendant to go to
cation was performed under conditions described by completion. Cyclisation with 20% TFA/CH2Cl2 at room
Albericio and co-workers11 with a mixture of allyl bro- temperature did not lead to any of the expected scaffold.
mide and acetonitrile. After aqueous work-up, compound Different conditions were examined resulting in complete
5 was directly isolated by precipitation in hexanes in 63% cyclisation after 16 hours with 20% TFA in C2H4Cl2 at
yield and a purity greater than 95%. p-Nitrophenylcarbon- 50 °C (Scheme 4).
ate 6 was generated by treating 5 with paranitrophenyl
Scheme 2 Serine-based linker developed by Mohan
Synlett 2002, No. 9, 1443–1446 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of a 3,9-Diazabicyclo[3.3.1]non-6-en-2-one Scaffold
1445
Scheme 3 Template synthesis and loading. Reactions and conditions: i) CH3CN/allyl bromide (3/2, 10 mL per mmole of 1), i-Pr2EtN, r.t.,
36 h (63%). ii) 4-NO2PhOCOCl, Et3N, Ch2Cl2, r.t., 5 h (64%). iii) a) BocNH-Ser(OTIPS)-OH, HOBt, DIC, NMM, THF, 50 °C, 24 h, b) 20%
TFA/CH2Cl2, 2 x 90 min. iv) 6, TEA, CH2Cl2, 50 °C, 16 h.
Cleavage reactions with 1 M TBAF in THF solution were tained in an overall yield of 35% (after 6 steps) with a pu-
very efficient, however LC/MS analysis of the samples rity of 85% by HPLC after aqueous work-up. The
were sometimes tedious due to the presence of high con- structure was confirmed by NMR and MS.
centrations of tetrabutylammonium salts, which saturated
In addition, the immobilised scaffold was further func-
the mass detector. From our original experiments, we
tionalised. Acylation or alkylation on the bridged nitrogen
knew that cleavage was occurring when inorganic bases
was performed (Scheme 5). After cleavage, samples were
were used. Applying similar conditions, effective cleav-
analysed by LC/MS, which confirmed the mass of the ex-
age of the final scaffold was achieved with a cocktail so-
pected materials with purities around 80% by HPLC for
11 and 12.
lution containing NaOH (aq) 2 N/H2O/THF (2/8/10) for 2
hours at room temperature. Target compound 4 was ob-
Scheme 4 Solid-phase synthesis of the 3,9-diazabicyclo[3.3.1]non-6-en-2-one scaffold. Reagents and conditions: i) Pd(II)acetate, PPh3, mor-
pholine, CH2Cl2, 2 h, r.t. ii) pTsOH·H2N-Phe-OAll, Et3N, DIC, HOBt, THF, 40 °C, 24 h. iii) Ac2O, AcOH, DMAP, Et3N, THF, 30 °C, 4 days.
iv) 20% TFA/C2H4Cl2, 50 °C, 16 h. v) 1M TBAF/THF, r.t., 2 h or NaOH 2N/H2O/THF (2/8/10), r.t., 2 h.
Synlett 2002, No. 9, 1443–1446 ISSN 0936-5214 © Thieme Stuttgart · New York

1446
D. Orain et al.
LETTER
Scheme 5 Functionalisation of the immobilised scaffold. Reagents and conditions: i) AcCl, Pyridine, CH2Cl2, 16 h, r.t. ii) BnBr, i-Pr2NEt,
DMF, 50 °C, 24 h. iii) NaOHaq 2N/H2O/THF (2/8/10), r.t., 2 h.
In conclusion, we have shown an efficient solution and
solid-phase synthesis of a novel diazabicyclo[3.3.1]non-
enone core which might serve as an attractive scaffold for
combinatorial libraries. The key step of this synthesis was
a sequential Dakin–West/Pictet–Spengler reaction. Cur-
rently, optimisation of the linker and the cleavage condi-
tions are under investigation as well as the diversification
of the scaffold.
Scheme 6 i) 20% TFA/CH2Cl2, 16 h, r.t.; ii) NaBH4, MeOH
Acknowledgement
NHCO), 6.60 (dd, 3J (H,H) = 8.60 Hz, 4J (H,H) = 2.15 Hz, 1
We thank the Chemistry Council of Novartis for funding DO, Mr.
F. Houdière for LC/MS and CCU staff for their support.
H, ArH), 6.71 (d, 4J (H,H) = 2.15 Hz, 1 H, ArH), 7.16 (d, 3J
(H,H) = 8.60 Hz, 1 H, ArH), 7.25 (t, 3J (H,H) = 6.98 Hz, 1
H, PhH), 7.28 (d, 3J (H,H) = 6.98 Hz, 2 H, PhH), 7.34 (t, 3J
(H,H) = 6.98 Hz, 2 H, PhH), 8.61 (s, 1 H, OH), 10.67 (s, 1
References
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Synlett 2002, No. 9, 1443–1446 ISSN 0936-5214 © Thieme Stuttgart · New York