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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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Having thus demonstrated the feasibility of two solid-phase routes affording 3,5-disubstituted l,5-benzothiazepin-4-ones 2A-D (Scheme2) or of the molecular type 30 (Scheme 4), we now attempted to further generalize the scope of the synthetic strategy. Interchanging Fmoc-cysteine 10 for Fmoc-penicillamine 31 and Fmoc-homocysteine 32 should potentially provide access to 2,2-dimethyl-l,5-benzothiazepin-4-ones 2b and 1,6-ben-zothiazocin-5-ones (3), respectively. Gratifyingly, both routes could be enabled almost without any additional chemistry optimization work (see Scheme 5).
In the case of 31, slightly harsher conditions were required to drive the nucleophilic aromatic substitution to completion, so the reaction was car-
BENZOFUSED HETEROCYCLES VIA SOLID-PHASE SNAR REACTIONS
12
(i) BrCH2COOCH2CH=CH2 (Bu4N)Br, KOH, THF (submitted twice)
(ii) piperidine, DMF
26 (R = FMOC)
27 (R = H)
(i) R1-COOH,
DIC, DMAP, DMF
(ii) (Ph3P)4Pd, (Bu4N)F TMS-N3, CH2CI2, THF
(i) HNR2R3,
DECP, DIEA, DMF
(ii) TFA, DCM
28 (R = CH2CH=CH2)
29 (R = H)
30
R1
Scheme 4.
3.2. FORMATION OF [6,7]- AND [6,8]-FUSED SYSTEMS 91
HS
COOH
NHFMOC
31
(Scheme 2)
(Scheme 4)
Scheme 5.
ried out at 40-45C instead of 25C. All remaining steps of the synthetic route summarized in Scheme 2 (reductive alkylation route) proceeded smoothly under the conditions previously optimized for Fmoc-cysteine. The same held true when 31 was employed in the alternative synthetic sequence depicted in Scheme 4 (amide alkylation route). Compound 33 is a representative 2,2-dimethyl-1,5-benzothiazepin-4-one synthesized via the reductive alkylation route (Scheme 5).
In the case of the series derived from homocysteine 32, the critical transformation proved to be formation of the eight-membered ring. This was successful only if the aniline nitrogen was present in its nonalkylated form. Thus the synthetic efforts were restricted to the amide alkylation
92 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE SWAR REACTIONS
route, which furnished novel 1,6-benzothiazocin-5-ones such as 34, though in somewhat lower purity than typically observed for the benzothiazepine series.
In summarizing this section, two efficient, high-yielding solid-phase routes to 3,5-disubstituted l,5-benzothiazepin-4(5//)-ones (2a) from resin-bound 4-fluoro-3-nitrobenzoic acid la and Fmoc-cysteine 10 were developed, amenable to both the synthesis of discrete, optically pure compounds and the generation of large encoded libraries. In one scenario, alkylation of N(5) was effected prior to cyclization, using aldehydes under highly optimized reductive alkylation conditions, and involved use of benzotriazole in cases of enolizable aliphatic aldehydes. In the second approach, the N(5) substituents were introduced after formation of the seven-membered ring using phase-transfer amide alkylation conditions. In subsequent experiments, the underlying synthetic strategy was extended to the synthesis of related structures, such as 2,2-dimethyl-l,5-benzothiazepin-4-ones 2b and l,6-benzothiazocin-5-ones 3.
3.2.2. 1,5-Benzodiazepin-2-ones (4)
Given their impressive therapeutic activities, it is not surprising that benzodiazepines were among the first small molecules to be synthesized on solid support.30 The main synthetic interest, however, has so far focused on
1.4-benzodiazepin-2-ones31-33 and l,4-benzodiazepin-2,5-diones,34-38 with
1.5-benzodiazepin-2-ones having received little attention.39 It was therefore opportune to explore the possibility of extending the strategy outlined in Section 3.2.1 to include synthesis of benzodiazepinones 4. We envisaged that this could be done by substituting the (3-mercapto acid nucleophiles (cysteine, penicillamine) with (3-amino acids. Information in the literature suggested that solid-phase S^Ar reactions with nitrogen nucleophiles were possible.40-42 These reactions typically use DMF or NMP as solvents and, occasionally, DIEA as an auxiliary base.42
Preliminary experiments using (3-amino acids as S^Ar nucleophiles showed that they either completely failed to react or afforded product mixtures, due to their poor solubility in nonaqueous solvents. (3-Amino acid esters, on the other hand, are readily soluble in DMF, but only a few are commercially available. In this section, two different approaches are described that have successfully circumvented these problems. The key features are (i) a novel aqueous solvent system allowing the use of free a- and
3.2. FORMATION OF [6,7]- AND [6,8]-FUSED SYSTEMS 93
[3-amino acids for solid-phase S^Ar reactions5,6 and (ii) an efficient solu-tion-phase synthesis to augment the number of (5-amino acid esters available.7
Our approach was based on the observation that it is possible to perform SnAy reactions on solid support with amino acids using a solvent system comprised, in equal parts, of acetone and an aqueous 0.5 M NaHC03 solution at temperatures around 70-75C. Application of this solvent system to the synthesis of quinoxalin-2-ones 6 from la and oc-amino acids is described in Section 3.3.2. With respect to the synthesis of 1,5-ben-zodiazepin-2-ones 4, more than 40 examples of aliphatic and aromatic (3-amino acids 35 were found to furnish the desired 6>-nitro anilines 36, about 80% of which were successfully carried on to eventually afford the ben-zodiazepinone products 4 (Scheme 6). In general, the anthranilic acids required slightly harsher conditions to drive the fluorine displacement to completion (75-80C, 72 h vs. 70-75C, 24 h for aliphatic (3-amino acids).
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