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Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
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6.2. SYNTHETIC APPLICATIONS OF SYNPHASE CROWNS
6.2.1. Benzodiazepines
A variety of multistep syntheses that feature SynPhase crowns as the solid support have been published. The first reported example of nonpeptide synthesis on crowns was described by Ellman in 1994. In that work a 192-member benzodiazepine library was prepared and evaluated for binding against the cholecystokinin A receptor.12 Ellman et al.13 have also prepared a library of 1680 benzodiazepines (Scheme 2) using the Wang linker for attachment of a phenol to the crown. The linker was attached to the aminobenzophenone moiety in solution; the assembled unit was then coupled to the crowns in bulk in a round-bottomed flask. The fluoren-9-yl-methoxycarbonyl (FMOC) group was removed and coupling to the poorly nucleophilic aniline nitrogen was achieved using the amino acid fluoride. Deprotection and subsequent treatment with 5% acetic acid in /V-methylpyr-rolidone (NMP) achieved cyclization. The resulting anilide was alkylated with an alkyl halide using lithiated 5-phenylmethyl-2-oxoazolidinone as the base. This unusual base was selected to closely match the pA' . of the anilide group. Cleavage was performed using trifluoroacetic acid with water and dimethyl sulfide as volatile scavengers.
6.2.2. Purines
Schultz and co-workers have described a crown-based synthesis of 406 purines varying at the C-2 and C-6 positions.14 This library was targeted for
6.2. SYNTHETIC APPLICATIONS OF SYNPHASE CROWNS 201
(i) piperidine/DMF
(**) R3 Fx
NHFMOC

NHFMOC
(i) piperidine/DMF >
(ii) 5% AcOH, NMP
(i) *)
OLi N^O
J
Q
,0
link
H
N^O
Scheme 2.
202 SOLID-PHASE ORGANIC SYNTHESIS ON RADIATION-GRAFTED POLYMER SURFACES
cyclin-dependent kinases. Following the incorporation of a common 2-chloropurine derivative onto the Rink amide-forming linker, diversity was introduced into the 6-position via an S^Ar reaction (Scheme 3). The
2-amino function was then acylated with acyl chlorides in the presence of
4-methyl-2,6-di-terr-butylpyridine, and the products cleaved using tri-fluoroacetic acid in dichloromethane with dimethyl sulfide as scavenger. Overall yields of 30-75% were reported.
Scheme 4 outlines an alternative synthesis of a library of disubstituted purines by a strategy similar to that shown in Scheme 315 except that
?' (i) NaH, Mel, DMF 91
N (') (CF3C0)20, CH2CI2 ^ >02 N |[^N\>
HoN^N^N (iii) NaH, DMF, ICH^O^eTu ^N^N^N
2 H (iv) K2C03, H20, MeOH H N |l,e
Cl
(i)TFA, 1,4-(MeO)2C6H4 A/V n^N
(ii) PyBrOP, N'Pr2Et, CH2CI2 02N ^
.OH H Me
02N
rrNH2 H ?'
W NPr2Et, DMF R1COCI, CH2CI2
support bears ^ ^ N
Rink handle
Me
xBu N xBu
Me
Scheme 3.
6.2. SYNTHETIC APPLICATIONS OF SYNPHASE CROWNS 203
(ii) PhCH2OCH2CH2OH / p-TsOH / CH2CI2
(ii) H2 /10% Pd/C / Ac
OEt
Cl
(|I|) ] J PPh3/ DEAD h2n^n^n
() 2M NaOH(aq), dioxane (ii) C6F5OH, DIC, DMF
("') ^^NH2 N'Pr2ET / DMF
h2n n
O^ JQ.
(i) (CF3C0)20 CH2CI2
Bu^ ^N^ *
(ii) R1OH, PPh3, DEAD, THF NH
Cl
O N^4rNxx
A.A.A.?
F3C N N R1
R2NH2/DMSO
heat
NHR
O N^Sr'Nx\
'
O^ jo.
NH
90 % TFA, H20
NHR
HN N
L JLX>
^OH
Scheme 4.
204 SOLID-PHASE ORGANIC SYNTHESIS ON RADIATION-GRAFTED POLYMER SURFACES
Ellmans tetrahydropyranyl linker16 was used to attach the purine through the 9-position.
In another purine library synthesis, Schultz and co-workers attached a 6-aminomethylaniline side chain to the PAL linker17,18 via reductive amination (Scheme 5). Alkylation at the 9-position was achieved using Mitsunobu conditions and an S^Ar reaction was used to functionalize the 2-position with amines. The final cleavage of the aniline was achieved using 90%
ArNH2
NaBH(OAc)3
---------->
1% AcOH in DMF
R1OH PPh3, DEAD ------------>
ch2ci2/thf
r2nh2
BuOH/DMSO
4N~
W //
NH N
n^nhr2
TFA/H20/Me2S ------------->
95:5:5
Scheme 5.
6.2. SYNTHETIC APPLICATIONS OF SYNPHASE CROWNS 205
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